Selective chemical modulation of human cytochrome p450 3a4

Abstract

The present disclosure relates to relates to compounds that inhibit CYP3A4 selectively, pharmaceutical compositions, and methods of using the compounds and composition for treating a disease or disorder with a drug that is a P450 enzyme substrate. In addition, the disclosed compounds and compositions can be used for preventing P450 enzyme metabolism of a drug. 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.19116.0058P1 SELECTIVE CHEMICAL MODULATION OF HUMAN CYTOCHROME P4503A4 CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Application No.63 / 664,080, filed on June 25, 2024, the contents of which are incorporated herein by reference in their entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under grant number GM118041 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND

[0003] Human cytochrome P450 enzymes (CYPs) are heme-containing monooxygenases that catalyze the oxidation or hydroxylation of substrates using molecular oxygen and the cofactor NADPH (Guengerich, F. P., (2018) ACS Catal 8 (12), 10964-10976). Due to their large and flexible ligand binding pockets, CYPs have a broad substrate profile and are responsible for the removal of many toxins and xenobiotics (Wright, W. C.; et al., (2019) Liver Res 3 (3-4), 132-142; Gay, S. C.; et al., (2010) Future medicinal chemistry 2 (9), 1451- 1468). It is estimated that more than 90% of common chemicals, 66% of carcinogens (Rendic, S.; Guengerich, F. P., (2012) Chem Res Toxicol 25 (7), 1316-83; Rendic, S.; Guengerich, F. P., (2015) Chem Res Toxicol 28 (1), 38-42), and over half of marketed drugs were metabolized by CYPs (Zhao, M.; et al., (2021) Int J Mol Sci 22 (23)). As a result, these enzymes play a major role in the phase I human drug metabolism system, and CYP-mediated drug clearance has a large impact on drug development and clinical practice (Esteves, F.; et al., (2021) J Xenobiot 11 (3), 94-114). Drugs that induce CYP activity can lead to reduced or even loss of their efficacy, while CYP inhibition can increase drug toxicity and cause unintended drug-drug interactions (Tornio, A.; et al., (2019) Clin Pharmacol Ther 105 (6), 1345-1361). Some drugs with narrow therapeutic windows, such as tacrolimus, may even require personalized dosage adjustment based on the patient’s genotype due to CYP-mediated metabolism (Yang, H.; et al., (2021) Clin Pharmacokinet 60 (7), 877-885). The U.S. Food and Drug Administration also issued guidelines to help developers to better evaluate the 1Attorney Docket No.19116.0058P1 interactions between drug candidates and CYPs (In Vitro Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions; Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions).

[0004] Currently, there are a total of the 57 known human CYPs which are classified into 18 families and 43 subfamilies (Danielson, P. B., (2002) Curr Drug Metab 3 (6), 561-97). Of these enzymes, CYP3A4 and CYP3A5 are the most important CYPs as these two enzymes alone are also responsible for 30-50% of CYP-mediated drug clearance (Williams, J. A.; et al., (2004) Drug Metab Dispos 32 (11), 1201-8; Zanger, U. M.; Schwab, M., (2013). Pharmacol Ther 138 (1), 103-41). The other two members of the CYP3A subfamily, CYP3A7 and CYP3A43, have limited contribution to adult drug metabolism due to their low expression levels (Williams, J. A.; et al., (2004) Drug Metab Dispos 32 (11). Because of the critical role of CYP3A4 and CYP3A5 in drug metabolism, some CYP3A-metabolized drugs,such as darunavir and lopinavir, are often co-administered with a low dose of the CYP3A inhibitor ritonavir to increase their plasma concentrations (McKeage, K.; et al., (2009) Drugs 69 (4), 477-503; Cvetkovic, R. S.; Goa, K. L., (2003) Drugs 63 (8), 769-802). A recent example is the anti-COVID drug Paxlovid, which uses ritonavir to decrease the metabolism of its active ingredient nirmatrelvir by CYP3A4 (Owen, D. R.; et al., (2021) Science 374 (6575), 1586-1593). Several other studies have also explored the possibility of co- administrating other CYP3A inhibitors with the drug of interest to reduce their CYP3A- mediated metabolism (Liddy, A. M.; et al., (2017) Br J Clin Pharmacol 83 (10), 2235-2241; O'Brien, S. G.; et al., (2003) Br J Cancer 89 (10), 1855-9; Yu, C. Y.; et al., (2014) Clin Drug Investig 34 (7), 475-82).

[0005] Although CYP3A4 and CYP3A5 are highly homologous proteins with 83% sequence identity and high structural similarity (Wright, W. C.; et al., (2019) Liver Res 3 (3- 4), 132-142), the two enzymes are not functionally identical or redundant, as they have their own metabolic preferences for drug clearance (Tseng, E.; et al., (2014) Drug Metab Dispos 42 (7), 1163-73). Limited clinical studies have already demonstrated that certain drugs such as everolimus (Moes, D. J.; et al., (2014) CPT Pharmacometrics Syst Pharmacol 3 (2), e100), quetiapine (Bakken, G. V.; et al., (2009) Drug Metab Dispos 37 (2), 254-8), and testosterone (Patki, K. C.; et al., (2003) Drug Metab Dispos 31 (7), 938-44), are primarily metabolized by CYP3A4, while CYP3A5 plays a more important role in the clearance of other drugs such as tacrolimus (Birdwell, K. A.; et al., (2015) Clin Pharmacol Ther 98 (1), 19-24), vincristine (Egbelakin, A.; et al., (2011) Pediatr Blood Cancer 56 (3), 361-7), and atazanavir (Anderson, 2Attorney Docket No.19116.0058P1 P. L.; et al., (2009) J Antimicrob Chemother 2009, 64 (5), 1071-9). There are probably more clinically important drugs that are preferentially metabolized by one of the two enzymes. In addition, the expression levels of CYP3A4 and CYP3A5 vary widely among tissues. CYP3A4 is abundantly expressed in the liver and small intestine, while CYP3A5 is the major CYP3A isoform in kidney and lungs (Lolodi, O.; et al., (2017) Curr Drug Metab 2017, 18 (12), 1095-1105). The differences between CYP3A4 and CYP3A5 in substrate specificity and expression site indicate that the two enzymes should not be inhibited non-selectively.

[0006] However, the commonly used CYP3A4 / 5 inhibitor, ritonavir, does not distinguish the two enzymes and inhibits them similarly (Wright, W. C.; et al., (2020) J Med Chem 2020, 63 (3), 1415-1433). Unnecessary inhibition of the other CYP may result in elevated plasma drug levels and unintended drug-drug interactions. For example, ritonavir is co- administered in Paxlovid to slow down the metabolism of the active ingredient nirmatrelvir by CYP3A4, but it also increases the risk of the immunosuppressive drug tacrolimus in kidney transplant patients, as tacrolimus metabolism in the kidney is largely influenced by CYP3A5 (Tang, Y.; Li, Y.; Song, T., (2023) Front Immunol 14, 1150341; Eng, H.; et al., (2022) Drug Metab Dispos 2022, 50 (5), 576-590). As a result, co-administration of a CYP3A4 selective inhibitor will be more beneficial than the pan-CYP3A inhibitor ritonavir in maintaining a safe tacrolimus concentration. Similarly, other CYP3A5-metablized drugs will also benefit from CYP3A4 selective inhibitors when CYP3A4 inhibition is desired.

[0007] While several CYP3A4 selective inhibitors have been reported in the literature, the structural basis of CYP3A4 selective inhibition remains unclear. This is because these compounds are not crystallized with CYP3A4 (e.g. SR-9186 (Li, X.; et al., (2012) Drug Metab Dispos 2012, 40 (9), 1803-9), mifepristone (Khan, K. K.; et al., (2002) Drug Metab Dispos 30 (9), 985-90), raloxifene (Pearson, J. T.; et al., (2007) Chem Res Toxicol 20 (12), 1778-86), CYP3cide (Walsky, R. L.; et al., (2012) Drug Metab Dispos 40 (9), 1686-97)) and / or behave as mechanism-2004) Drug Metab Dispos 32 (1), 105-12)) that inactivate CYPs upon metabolism. In the latter case, the mechanism of CYP3A4 selective inhibition is complicated by the enzymatic reaction, and the resulting mechanism may not be applicable as a general guideline for designing better CYP3A4 selective inhibitors.

[0008] Despite increased awareness regarding co-administered CYP inhibitors with active therapeutic agents to increase their plasma concentrations, the currently utilized inhibitors do not provide selectivity and may cause unnecessary inhibition of the other CYP resulting in elevated plasma drug levels and unintended drug-drug interactions. Thus, there remains a 3Attorney Docket No.19116.0058P1 need for compounds that are selectively CYP inhibitors and compositions for treating a disease or disorder with a drug that is a P450 enzyme substrate, and methods of making and using same. SUMMARY

[0009] In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to compounds that inhibit CYP3A4 selectively, pharmaceutical compositions, and methods of using the compounds and composition for treating a disease or disorder with a drug that is a P450 enzyme substrate. In addition, the disclosed compounds and compositions can be used for preventing P450 enzyme metabolism of a drug.

[0010] Thus, disclosed are compounds having a structure represented by a formula: wherein R1is selected from hydrogen; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R2is selected from –NR10Ar2, –CH2Cy1, and Cy2; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; 4Attorney Docket No.19116.0058P1 wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; and wherein Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, provided that when R2is –NR10Ar2, then at least one of R1and R10is not hydrogen, and provided that the compound is not: .

[0011] Also disclosed are phap ns comprising an effective amount of a compound having a structure represented by a formula: , wherein R1is selected from hydrogenand –CH2Ar ; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R2is selected from –NR10Ar2, –CH2Cy1, and Cy2; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – 5Attorney Docket No.19116.0058P1 NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0012] Also disclosed are methods of inhibiting CYP3A4 in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula: , wherein R1is selected from hydrogenand –CH2Ar ; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R2is selected from –NR10Ar2, –CH2Cy1, and Cy2; wherein R10is 6Attorney Docket No.19116.0058P1 selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof.

[0013] Also disclosed are methods of inhibiting CYP3A4 in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein R1is selected from hydrogen and –CH2Ar1; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, 7Attorney Docket No.19116.0058P1 C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R2is selected from –NR10Ar2, –CH2Cy1, and Cy2; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof.

[0014] Also disclosed are methods of preventing P450 enzyme metabolism of a drug in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula: , erein R1wh is selected from hydrogen and –CH2Ar1; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected 8Attorney Docket No.19116.0058P1 from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R2is selected from –NR10Ar2, –CH2Cy1, and Cy2; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof.

[0015] Also disclosed are methods of preventing P450 enzyme metabolism of a drug in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: ,9Attorney Docket No.19116.0058P1 wherein R1is selected from hydrogen and –CH2Ar1; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R2is selected from –NR10Ar2, –CH2Cy1, and Cy2; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof.

[0016] Also disclosed are methods of treating a disease or disorder 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: 10Attorney Docket No.19116.0058P1 , wherein R1is selected from hydroge ; w1herein Ar is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R2is selected from C1-C8 alkyl, C1-C8 haloalkyl, –NR10Ar2, – CH2Cy1, and Cy3; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy3is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a 11Attorney Docket No.19116.0058P1 pharmaceutically acceptable salt thereof, wherein the subject has been diagnosed as needing treatment with a drug that is a P450 enzyme substrate.

[0017] Also disclosed are kits comprising a compound having a structure represented by a formula: , wherein R1is selected from hydrogen1; wherein Ar is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R2is selected from C1-C8 alkyl, C1-C8 haloalkyl, –NR10Ar2, – CH2Cy1, and Cy3; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6- C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy3is selected from C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, 12Attorney Docket No.19116.0058P1 C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) a drug that is a P450 enzyme substrate; (b) instructions for administering the compound in combination with a drug that is a P450 enzyme substrate; (c) instructions for administering the compound to maintain efficacy of a drug that is a CYP3A4 substrate; and (d) instructions for administering the compound so as not to alter the metabolism of a drug that is a P450 enzyme substrate.

[0018] 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 DRAWINGS

[0019] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description serve to explain the principles of the invention.

[0020] FIG.1A and FIG.1B show representative data for primary screen against CYP3A4.

[0021] FIG.2A and FIG.2B shows representative assessment of assay robustness and screened compound drug-like properties.

[0022] FIG.3A-I show inhibition data, representative structures and structural comparisons indicating that the C-terminal loop plays an important role in CYP3A4 selective inhibition.

[0023] FIG.4 shows representative inhibition data indicating that SCM-01, SCM-02, and SCM-03 are selective CYP3A4 inhibitors in the cellular context. 13Attorney Docket No.19116.0058P1

[0024] FIG.5A-D show representative inhibition data indicating selective inhibitors bind preferentially to CYP3A4.

[0025] FIG.6 shows representative inhibition data indicating that SCM-01 is a non- suicide CYP3A4 / 5 inhibitor.

[0026] FIG.7A-F show representative views of SCM-01, SCM-02, SCM-03 co- crystallized with CYP3A4.

[0027] FIG.8A-D shows representative analysis of CYP3A4 crystal structures bound to SCM-01, SCM-02 and SCM-03, and their comparison to CYP3A5 crystal structures.

[0028] FIG.9A-C shows representative structure-activity relationship analysis of SCM-01 analogs, and overlay of CYP3A4-SCM01 and CYP3A4-SCM-08 crystal structures.

[0029] FIG.10 shows additional representative structure-activity relationship analysis of SCM-01 analogs.

[0030] FIG.11A-E show representative crystal structures of CYP3A4 bound to various SCM-1 analogs.

[0031] FIG.12 shows representative data indicating that most of SCM-01 analogs are non-suicide CYP3A4 / 5 inhibitors.

[0032] FIG.13A-D shows the identification of two distinct ligand binding surfaces of CYP3A4 / 5 by docking studies.

[0033] FIG.14A-E show representative overlays for two surfaces in the ligand binding site with distinct chemical environment.

[0034] FIG.15A-I show representative data and overlays indicating that SCM-18 is a highly selective and non-suicide CYP3A4 inhibitor

[0035] FIG.16 shows hypothetical docking model to regarding the loss of CYP3A5 inhibition by SCM-18.

[0036] FIG.17A and FIG.17B show structure-activity relationship analysis of representative meta- and para-substituted benzene derivatives of SCM-18, and structural analysis showing that these derivatives would be unfavorable for CYP3A4 binding.

[0037] FIG.18A-C show representative data indicating a trade-off between potency and selectivity of SCM-18 analogs.

[0038] FIG.19A and FIG.19B show representative data indicating that increases in CYP3A4 inhibitory potency resulted in loss of CYP3A4 selectivity.

[0039] FIG.20A-G show representative docking poses showing unfavorable interactions.

[0040] FIG.21 shows representative inhibition data indicating that SCM-08 is a highly selective CYP3A4 inhibitor that does not target other CYPs. 14Attorney Docket No.19116.0058P1

[0041] FIG.22 shows representative inhibition data showing structure-activity relationship analysis of SCM-01 analogs.

[0042] FIG.23A-C show the structure of SCM-08 and representative cellular inhibition data.

[0043] FIG.24A and FIG.24B show representative schematic for the molecular basis for the selective CYP3A4 inhibition by SCM-01 analogs.

[0044] FIG.25 shows representative sequence alignment indicating that the C-terminal loop region is not conserved among major human CYPs.

[0045] 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

[0046] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

[0047] 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.

[0048] 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 15Attorney Docket No.19116.0058P1 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.

[0049] 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

[0050] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

[0051] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of” and “consisting essentially of.”

[0052] 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.

[0053] 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 16Attorney Docket No.19116.0058P1 is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0054] 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.

[0055] 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.

[0056] 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, IC50refers to the half-maximal (50%) inhibitory concentration (IC) of a substance.

[0057] 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, EC50refers to the concentration of agonist that provokes a response halfway between the baseline and maximum response. 17Attorney Docket No.19116.0058P1

[0058] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0059] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease, disorder, or condition. The term “patient” includes human and veterinary subjects.

[0060] 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.).

[0061] 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. 18Attorney Docket No.19116.0058P1

[0062] 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.

[0063] As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0064] As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the condition being treated and the severity of the condition; 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 19Attorney Docket No.19116.0058P1 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.

[0065] 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, polyoxyethylene 9-10 nonyl phenol, sodium desoxycholate), solution and / or cryo / lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2- phenoxyethanol, EDTA), polymeric stabilizers and viscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethylene glycol, ethanol). A dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.

[0066] 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.

[0067] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information 20Attorney Docket No.19116.0058P1 (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0068] 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 major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; anti-cancer and anti-neoplastic agents such as kinase inhibitors, poly ADP ribose polymerase (PARP) inhibitors and other DNA damage response modifiers, epigenetic agents such as bromodomain and extra-terminal (BET) inhibitors, histone deacetylase (HDAc) inhibitors, iron chelators 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-1) / 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 21Attorney Docket No.19116.0058P1 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, anti- epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term “therapeutic agent” also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0069] 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.

[0070] 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 22Attorney Docket No.19116.0058P1 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.

[0071] 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.

[0072] 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 23Attorney Docket No.19116.0058P1 heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0073] 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.

[0074] 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.

[0075] 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, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl. 24Attorney Docket No.19116.0058P1

[0076] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like.

[0077] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

[0078] 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, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one 25Attorney Docket No.19116.0058P1 or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0079] 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.

[0080] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —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 alkyl and / or cycloalkyl groups.

[0081] 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 alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0082] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, 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. 26Attorney Docket No.19116.0058P1

[0083] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0084] 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.

[0085] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized π electrons above and below the plane of the molecule, where the π clouds contain (4n+2) π electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups.

[0086] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, ─NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon- carbon bond. For example, biaryl can be two aryl groups that are bound together via a fused 27Attorney Docket No.19116.0058P1 ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] The term “carboxylic acid” as used herein is represented by the formula — C(O)OH.

[0092] The term “ester” as used herein is represented by the formula —OC(O)A1or — C(O)OA1, 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.

[0093] The term “ether” as used herein is represented by the formula A1OA2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, 28Attorney Docket No.19116.0058P1 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, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0094] The terms “halo,” “halogen,” or “halide” as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0095] 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.

[0096] The term “heteroalkyl” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0097] 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, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl. 29Attorney Docket No.19116.0058P1

[0098] The terms “heterocycle” or “heterocyclyl” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl”, “heteroaryl”, “bicyclic heterocycle” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3- oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2- C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group, which 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.

[0099] 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-1,4-benzodioxinyl, 3,4-dihydro-2H- chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H- pyrazolo[3,2-b]pyridin-3-yl. 30Attorney Docket No.19116.0058P1

[0100] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0101] The term “hydroxyl” or “hydroxyl” as used herein is represented by the formula — OH.

[0102] 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.

[0103] The term “azide” or “azido” as used herein is represented by the formula —N3.

[0104] The term “nitro” as used herein is represented by the formula —NO2.

[0105] The term “nitrile” or “cyano” as used herein is represented by the formula —CN.

[0106] The term “silyl” as used herein is represented by the formula —SiA1A2A3, where A1, A2, and A3can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0107] The term “sulfo-oxo” as used herein is represented by the formulas —S(O)A1, — S(O)2A1, —OS(O)2A1, or —OS(O)2OA1, where 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)2A1, 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 A1S(O)2A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A1S(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0108] The term “thiol” as used herein is represented by the formula —SH. 31Attorney Docket No.19116.0058P1

[0109] “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 be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0110] 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).

[0111] 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.

[0112] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0-4Ro, – O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; – (CH2)0–4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; –N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°; –C(S)R°; –(CH2)0–4C(O)OR°; –(CH2)0–4C(O)SR°; -(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; –OC(O)(CH2)0–32Attorney Docket No.19116.0058P1 4SR–, SC(S)SR°; –(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; -(CH2)0–4OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; –C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; –S(O)2NR°2; -(CH2)0–4S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°)R°; –C(NH)NR°2; –P(O)2R°; -P(O)R°2; -OP(O)R°2; –OP(O)(OR°)2; SiR°3; –(C1–4 straight or branched alkylene)O–N(R°)2; or –(C1–4straight or branched alkylene)C(O)O–N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, - CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0113] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, –(CH2)0–2R^, –(haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2; -O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR^, –(CH2)0–2NR^2, –NO2, –SiR^3, –OSiR^3, -C(O)SR^, –(C1–4 straight or branched alkylene)C(O)OR^, or –SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0114] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =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, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6 aliphatic which may be 33Attorney Docket No.19116.0058P1 substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0115] 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, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0116] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, – S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; 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 R†, 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.

[0117] 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 C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0118] 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.

[0119] 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). 34Attorney Docket No.19116.0058P1

[0120] 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.

[0121] A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4- thiazolidinedione radical in a particular compound has the structure: , regardless of whether thiazolidinedioneprepare the compound. In some embodiments the radical (for example an alkyl) can be further modified (i.e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

[0122] “Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example, of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2- naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an 35Attorney Docket No.19116.0058P1 alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di- substituted 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.

[0123] 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.

[0124] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

[0125] 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 l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non- superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different 36Attorney Docket No.19116.0058P1 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.

[0126] 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.

[0127] Designation of a specific absolute configuration at a chiral carbon in a disclosed compound is understood to mean that the designated enantiomeric form of the compounds can be provided in enantiomeric excess (e.e.). Enantiomeric excess, as used herein, is the presence of a particular enantiomer at greater than 50%, for example, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%. In one aspect, the designated enantiomer is substantially free from the other enantiomer. For example, the “R” forms of the compounds can be substantially free from the “S” forms of the compounds and are, thus, 37Attorney Docket No.19116.0058P1 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.

[0128] 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.

[0129] The compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, etc., groups as the prodrug forming moieties. For instance, the hydroxymethyl position may form mono-, di-, or triphosphates and again these phosphates can form prodrugs. Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem.1988, 31, 318; Aligas-Martin et al., PCT WO 2000 / 041531, p.30). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the disclosure.

[0130] “Derivatives” of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, solvates and combinations thereof. The “combinations” mentioned in this context refer to derivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, and solvates. Examples of radio- actively labeled forms include compounds labeled with tritium, phosphorous-32, iodine-129, carbon-11, fluorine-18, and the like.

[0131] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically- labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of 38Attorney Docket No.19116.0058P1 hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,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, i.e.,3H, and carbon-14, i.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.

[0132] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

[0133] The term “co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p- toluenesulfonic acid and benzenesulfonic acid.

[0134] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an α-hydrogen can exist in an equilibrium of the keto form and the enol form. 39Attorney Docket No.19116.0058P1

[0135] 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, N1-unsubstituted, 3-A3and N1-unsubstituted, 5-A3as shown below. Unless stated to the contrible tautomers.

[0136] It is known that chemical substances form solids, which are present in different states of order which 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.

[0137] In some aspects, a structure of a compound can be represented by a formula: , which is understood to be equivalent toa ormu a: , wherein n is typically an integer. That is, Rnis understood to represent five independent substituents, Rn(a), Rn(b), Rn(c), Rn(d), Rn(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance Rn(a)is halogen, then Rn(b)is not necessarily halogen in that instance.

[0138] 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 40Attorney Docket No.19116.0058P1 disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Strem Chemicals (Newburyport, MA), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0139] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0140] Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, 41Attorney Docket No.19116.0058P1 for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[0141] 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

[0142] In one aspect, the invention relates to compounds that inhibit CYP3A4 selectively, pharmaceutical compositions, and methods of using the compounds and composition for treating a disease or disorder with a drug that is a P450 enzyme substrate. In addition the disclosed compounds and compositions can be used for preventing P450 enzyme metabolism of a drug.

[0143] 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

[0144] In one aspect, disclosed are compounds having a structure represented by a formula:42Attorney Docket No.19116.0058P1 wherein R1is selected from hydrogen and –CH2Ar1; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R2is selected from –NR10Ar2, –CH2Cy1, and Cy2; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; and wherein Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, provided that when R2is –NR10Ar2, then at least one of R1and R10is not hydrogen, and provided that the compound is not: 43Attorney Docket No.19116.0058P1 .

[0145] In one aspect, disclosed are compounds having a structure represented by a formula: , wherein R1is selected from hydroge; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R2is selected from C1-C8 alkyl, C1-C8 haloalkyl, –NR10Ar2, – CH2Cy1, and Cy3; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 44Attorney Docket No.19116.0058P1 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy3is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof.

[0146] In one aspect, disclosed are compounds having a structure represented by a formula: , wherein R1is selected from hydrogen; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R2is selected from C1-C8 alkyl, C1-C8 haloalkyl, –NR10Ar2, – CH2Cy1, and Cy3; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups 45Attorney Docket No.19116.0058P1 independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy3is selected from C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof.

[0147] In various aspects, the compound has a structure represented by a formula: CF3O r2, or a pharmaceutically acceptable sa

[0148] In various aspects, the compound has a structure represented by a formula: CF3O r2r3, or a pharmaceutically acceptable sat t ereo .

[0149] In various aspects, the compound has a structure represented by a formula: ,or a pharmaceutically acceptable salt thereof.

[0150] In various aspects, the compound has a structure represented by a formula: 46Attorney Docket No.19116.0058P1 , or a pharmaceutically acceptable salt

[0151] In various aspects, the compound is selected from: , , or a pharmaceutically acceptable salt thereof.

[0152] In various aspects, the compound is selected from: 47Attorney Docket No.19116.0058P1 , , , , , ,48Attorney Docket No.19116.0058P1 CF3O , , or a phara. R1GROUPS

[0153] In one aspect, R1is selected from hydrogen and –CH2Ar1. In a further aspect, R1 is hydrogen. In a still further aspect, R1 is –CH2Ar1. b. R2GROUPS

[0154] In one aspect, R2is selected from –NR10Ar2, –CH2Cy1, and Cy2. In a further aspect, R2is selected from –NR10Ar2and –CH2Cy1. In a still further aspect, R2is selected from –NR10Ar2and Cy2. In yet a further aspect, R2is selected from –CH2Cy1and Cy2. In an 49Attorney Docket No.19116.0058P1 even further aspect, R2is –NR10Ar2. In a still even further aspect, R2is –CH2Cy1. In yet an even further aspect, R2is Cy2.

[0155] In one aspect, R2is selected from C1-C8 alkyl, C1-C8 haloalkyl, –NR10Ar2, – CH2Cy1, and Cy3. In a further aspect, R2is selected from C1-C4 alkyl, C1-C4 haloalkyl, – NR10Ar2, –CH2Cy1, and Cy3. In a still further aspect, R2is selected from methyl, ethyl, propyl, isopropyl, –CH2F, –CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, –CH2CH2CH2F, –CH2CH2CHF2, –CH2CH2CF3, –CH(CH3)CH2F, –CH(CH3)CHF2, –CH(CH3)CF3, – CH(CH2F)2, –CH(CHF2)2, –CH(CF3)2, –CH2Cl, –CHCl2, –CCl3, –CH2CH2Cl, –CH2CHCl2, – CH2CCl3, –CH2CH2CH2Cl, –CH2CH2CHCl2, –CH2CH2CCl3, –CH(CH3)CH2Cl, – CH(CH3)CHCl2, –CH(CH3)CCl3, –CH(CH2Cl)2, –CH(CHCl2)2, –CH(CCl3)2, –NR10Ar2, – CH2Cy1, and Cy3. In yet a further aspect, R2is selected from methyl, ethyl, –CH2F, –CHF2, – CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, –CH2Cl, –CHCl2, –CCl3, –CH2CH2Cl, –CH2CHCl2, –CH2CCl3, –NR10Ar2, –CH2Cy1, and Cy3. In an even further aspect, R2is selected from methyl, –CH2F, –CHF2, –CF3, –CH2Cl, –CHCl2, –CCl3, –NR10Ar2, –CH2Cy1, and Cy3.

[0156] In various aspects, R2is selected from C1-C8 alkyl and C1-C8 haloalkyl. In a further aspect, R2is selected from C1-C4 alkyl and C1-C4 haloalkyl. In a still further aspect, R2is selected from methyl, ethyl, propyl, isopropyl, –CH2F, –CHF2, –CF3, –CH2CH2F, – CH2CHF2, –CH2CF3, –CH2CH2CH2F, –CH2CH2CHF2, –CH2CH2CF3, –CH(CH3)CH2F, – CH(CH3)CHF2, –CH(CH3)CF3, –CH(CH2F)2, –CH(CHF2)2, –CH(CF3)2, –CH2Cl, –CHCl2, – CCl3, –CH2CH2Cl, –CH2CHCl2, –CH2CCl3, –CH2CH2CH2Cl, –CH2CH2CHCl2, – CH2CH2CCl3, –CH(CH3)CH2Cl, –CH(CH3)CHCl2, –CH(CH3)CCl3, –CH(CH2Cl)2, – CH(CHCl2)2, –CH(CCl3)2. In yet a further aspect, R2is selected from methyl, ethyl, –CH2F, – CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, –CH2Cl, –CHCl2, –CCl3, –CH2CH2Cl, – CH2CHCl2, –CH2CCl3. In an even further aspect, R2is selected from methyl, –CH2F, –CHF2, –CF3, –CH2Cl, –CHCl2, –CCl3.

[0157] In various aspects, R2is C1-C8 alkyl. In a further aspect, R2is C1-C4 alkyl. In a still further aspect, R2is selected from methyl, ethyl, propyl and isopropyl. In yet a further aspect, R2is selected from methyl and ethyl. In an even further aspect, R2is methyl.

[0158] In various aspects, R2is C1-C8 haloalkyl. In a further aspect, R2is C1-C4 haloalkyl. In a still further aspect, R2is selected from –CH2F, –CHF2, –CF3, –CH2CH2F, – CH2CHF2, –CH2CF3, –CH2CH2CH2F, –CH2CH2CHF2, –CH2CH2CF3, –CH(CH3)CH2F, – CH(CH3)CHF2, –CH(CH3)CF3, –CH(CH2F)2, –CH(CHF2)2, –CH(CF3)2, –CH2Cl, –CHCl2, – CCl3, –CH2CH2Cl, –CH2CHCl2, –CH2CCl3, –CH2CH2CH2Cl, –CH2CH2CHCl2, – CH2CH2CCl3, –CH(CH3)CH2Cl, –CH(CH3)CHCl2, –CH(CH3)CCl3, –CH(CH2Cl)2, – 50Attorney Docket No.19116.0058P1 CH(CHCl2)2, –CH(CCl3)2. In yet a further aspect, R2is selected from –CH2F, –CHF2, –CF3, – CH2CH2F, –CH2CHF2, –CH2CF3, –CH2Cl, –CHCl2, –CCl3, –CH2CH2Cl, –CH2CHCl2, – CH2CCl3. In an even further aspect, R2is selected –CH2F, –CHF2, –CF3, –CH2Cl, –CHCl2, – CCl3.

[0159] In various aspects, R2is selected from –NR10Ar2, –CH2Cy1, and Cy3. In a further aspect, R2is selected from –NR10Ar2and –CH2Cy1. In a still further aspect, R2is selected from –NR10Ar2and Cy3. In yet a further aspect, R2is selected from –CH2Cy1and Cy3. In an even further aspect, R2is –NR10Ar2. In a still even further aspect, R2is –CH2Cy1. In yet an even further aspect, R2is Cy3. c. R10GROUPS

[0160] In one aspect, R10is selected from hydrogen and –CH2Ar3. In a further aspect, R10is hydrogen. In a further aspect, R10is –CH2Ar3. d. AR1GROUPS

[0161] In one aspect, Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an 51Attorney Docket No.19116.0058P1 even further aspect, Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is unsubstituted.

[0162] In various aspects, Ar1is selected from C6 aryl and C2-C5, 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Ar1is selected from rom C6 aryl and C2-C5, 6-membered heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar1is selected from C6 aryl and C2-C5, 6-membered heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar1is selected from C6 aryl and C2-C5, 6-membered heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar1is selected from C6 aryl and C2-C5, 6-membered heteroaryl, and is unsubstituted.

[0163] In various aspects, Ar1is a C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of C6-C10 aryl include, but are not limited to, phenyl and naphthyl. In a further aspect, Ar1is a C6-C10 aryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar1is a C6-C10 aryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, 52Attorney Docket No.19116.0058P1 –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar1is a C6-C10 aryl monosubstituted with a group selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar1is an unsubstituted C6-C10 aryl.

[0164] In various aspects, Ar1is a C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Ar1is a C6 aryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar1is a C6 aryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar1is a C6 aryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1- C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar1is an unsubstituted C6 aryl.

[0165] In various aspects, Ar1is a C6 aryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

[0166] In various aspects, Ar1is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 53Attorney Docket No.19116.0058P1 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of C2-C9 heteroaryl include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl. In a further aspect, Ar1is a C2-C9 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, – CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar1is a C2-C9 heteroaryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar1is a C2-C9 heteroaryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar1is an unsubstituted C2-C9 heteroaryl.

[0167] In various aspects, Ar1is a C2-C5, 6-membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of C2-C5, 6- membered heteroaryl include, but are not limited to, pyridine, pyrimidine, pyridazine, and pyrazine. In a further aspect, Ar1is a C2-C5, 6-membered heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar1is a C2-C5, 6-membered heteroaryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 54Attorney Docket No.19116.0058P1 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar1is a C2-C5, 6-membered heteroaryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar1is C2-C5, 6-membered heteroaryl, and is unsubstituted. e. AR2GROUPS

[0168] In one aspect, Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is unsubstituted.

[0169] In various aspects, Ar2is selected from C6 aryl and C2-C4, 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, 55Attorney Docket No.19116.0058P1 C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Ar2is selected from rom C6 aryl and C2-C4, 6-membered heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar2is selected from C6 aryl and C2-C4, 6-membered heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar2is selected from C6 aryl and C2-C4, 6-membered heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar2is selected from C6 aryl and C2-C4, 6-membered heteroaryl, and is unsubstituted.

[0170] In various aspects, Ar2is a C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of C6-C10 aryl include, but are not limited to, phenyl and naphthyl. In a further aspect, Ar2is a C6-C10 aryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar2is a C6-C10 aryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar2is a C6-C10 aryl monosubstituted with a group selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, 56Attorney Docket No.19116.0058P1 C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar2is an unsubstituted C6-C10 aryl.

[0171] In various aspects, Ar2is a C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Ar2is a C6 aryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar2is a C6 aryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar2is a C6 aryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1- C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar2is an unsubstituted C6 aryl.

[0172] In various aspects, Ar2is a C6 aryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

[0173] In various aspects, Ar2is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of C2-C9 heteroaryl include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl. In a further aspect, Ar2is a C2-C9 57Attorney Docket No.19116.0058P1 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, – CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar2is a C2-C9 heteroaryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar2is a C2-C9 heteroaryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar2is an unsubstituted C2-C9 heteroaryl.

[0174] In various aspects, Ar2is a C2-C4, 6-membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of C2-C4, 6- membered heteroaryl include, but are not limited to, pyrimidinyl, pyridazinyl, and pyrazinyl. In a further aspect, Ar2is a C2-C4, 6-membered heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar2is a C2-C4, 6- membered heteroaryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar2is a C2-C4, 6-membered heteroaryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and 58Attorney Docket No.19116.0058P1 (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar2is C2-C4, 6-membered heteroaryl, and is unsubstituted. f. AR3GROUPS

[0175] In one aspect, Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is unsubstituted.

[0176] In various aspects, Ar3is selected from C6 aryl and C2-C4, 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Ar3is selected from rom C6 aryl and C2-C4, 6-membered heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 59Attorney Docket No.19116.0058P1 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar3is selected from C6 aryl and C2-C4, 6-membered heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar3is selected from C6 aryl and C2-C4, 6-membered heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar3is selected from C6 aryl and C2-C4, 6-membered heteroaryl, and is unsubstituted.

[0177] In various aspects, Ar3is a C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of C6-C10 aryl include, but are not limited to, phenyl and naphthyl. In a further aspect, Ar3is a C6-C10 aryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar3is a C6-C10 aryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar3is a C6-C10 aryl monosubstituted with a group selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar3is an unsubstituted C6-C10 aryl.

[0178] In various aspects, Ar3is a C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 60Attorney Docket No.19116.0058P1 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Ar3is a C6 aryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar3is a C6 aryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar3is a C6 aryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1- C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar3is an unsubstituted C6 aryl.

[0179] In various aspects, Ar3is a C6 aryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

[0180] In various aspects, Ar3is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of C2-C9 heteroaryl include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl. In a further aspect, Ar3is a C2-C9 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, – CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar3is a C2-C9 heteroaryl substituted with 0 or 1 group selected from 61Attorney Docket No.19116.0058P1 halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar3is a C2-C9 heteroaryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar3is an unsubstituted C2-C9 heteroaryl.

[0181] In various aspects, Ar3is a C2-C4, 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 C2-C4, 6-membered heteroaryl include, but are not limited to, pyrimidinyl, pyridazinyl, and pyrazinyl. In a further aspect, Ar3is a C2-C4, 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-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, Ar3is a C2-C4, 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, Ar3is a C2-C4, 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, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Ar3is C2-C4, 6-membered heteroaryl, and is unsubstituted. g. CY1GROUPS

[0182] In one aspect, Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 62Attorney Docket No.19116.0058P1 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy1is selected from C3- C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, – CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is monosubstituted with a group selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is unsubstituted.

[0183] In one aspect, Cy1is selected from C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy1is selected from C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is selected from C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, 63Attorney Docket No.19116.0058P1 Cy1is selected from C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is selected from C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is unsubstituted.

[0184] In various aspects, Cy1is selected from C3-C6 cycloalkyl and C2-C4 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy1is selected from C3-C6 cycloalkyl and C2-C4 heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is selected from C3-C6 cycloalkyl and C2-C4 heterocycloalkyl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is selected from C3-C6 cycloalkyl and C2-C4 heterocycloalkyl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is selected from C3-C6 cycloalkyl and C2-C4 heterocycloalkyl, and is unsubstituted.

[0185] In various aspects, Cy1is a C3-C6 cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of C3-C6 cycloalkyl include but 64Attorney Docket No.19116.0058P1 are not limited to, cyclopropane, cyclobutane, cyclopentane, and cyclohexane. In a further aspect, Cy1is a C3-C6 cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino. In a still further aspect, Cy1is a C3-C6 cycloalkyl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is a C3-C6 cycloalkyl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, – NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1- C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is an unsubstituted C3-C6 cycloalkyl.

[0186] In various aspects, Cy1is a C2-C4 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of C2-C4 heterocycloalkyl include but are not limited to, azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, and thiomorpholinyl. In a further aspect, Cy1is a C2-C4 heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is a C2-C4 heterocycloalkyl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is a C2-C4 heterocycloalkyl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 65Attorney Docket No.19116.0058P1 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is an unsubstituted C2-C4 heterocycloalkyl.

[0187] In various aspects, Cy1is selected from C6 aryl and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy1is selected from C6 aryl and 5- and 6-membered heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is selected from C6 aryl and 5- and 6-membered heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is selected from C6 aryl and 5- and 6-membered heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino. In an even further aspect, Cy1is selected from C6 aryl and 5- and 6- membered heteroaryl, and is unsubstituted.

[0188] In various aspects, Cy1is a C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy1is a C6 aryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is a C6 aryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 66Attorney Docket No.19116.0058P1 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is a C6 aryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1- C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is an unsubstituted C6 aryl.

[0189] In various aspects, Cy1is a 5- and 6-membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of 5- and 6- membered heteroaryl groups include, but are not limited to, furanyl, thiophenyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, lH-l,2,3-triazolyl, 2H- l,2,3-triazolyl, l,2,4-triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, l,3,5-triazinyl, 1 ,2,4-triazinyl, l,2,3-triazinyl, l,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, l,2,5-oxadiazolyl, 1 ,2,4- thiadiazolyl, l,3,4-thiadiazolyl, l,2,5-thiadiazolyl and tetrazolyl. In a further aspect, Cy1is a 5- and 6-membered heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is a 5- and 6-membered heteroaryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is a 5- and 6- membered heteroaryl monosubstituted with a group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is an unsubstituted 5- and 6-membered heteroaryl.

[0190] In various aspects, Cy1is selected from C3-C10 cycloalkyl and C2-C9 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 67Attorney Docket No.19116.0058P1 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy1is selected from C3-C10 cycloalkyl and C2-C9 heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is selected from C3-C10 cycloalkyl and C2-C9 heterocycloalkyl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is selected from C3-C10 cycloalkyl and C2-C9 heterocycloalkyl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is selected from C3-C10 cycloalkyl and C2-C9 heterocycloalkyl, and is unsubstituted.

[0191] In various aspects, Cy1is a C3-C10 cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy1is a C3-C10 cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, – CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is a C3-C10 cycloalkyl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is a C3-C10 cycloalkyl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, 68Attorney Docket No.19116.0058P1 C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is an unsubstituted C3-C10 cycloalkyl.

[0192] In various aspects, Cy1is a C2-C9 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy1is a C2-C9 heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is a C2-C9 heterocycloalkyl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is a C2-C9 heterocycloalkyl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is an unsubstituted C2-C9 heterocycloalkyl.

[0193] In various aspects, Cy1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0 or 1 group 69Attorney Docket No.19116.0058P1 selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is unsubstituted.

[0194] In various aspects, Cy1is a C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of C6-C10 aryl include, but are not limited to, phenyl and naphthyl. In a further aspect, Cy1is a C6-C10 aryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is a C6-C10 aryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is a C6-C10 aryl monosubstituted with a group selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is an unsubstituted C6-C10 aryl.

[0195] In various aspects, Cy1is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy1is a C2-C9 heteroaryl 70Attorney Docket No.19116.0058P1 substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is a C2-C9 heteroaryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1- C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is a C2-C9 heteroaryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is an unsubstituted C2-C9 heteroaryl. h. CY2GROUPS

[0196] In one aspect, Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino. In a further aspect, Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5-membered heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5-membered heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5-membered heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 71Attorney Docket No.19116.0058P1 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5-membered heteroaryl, and is unsubstituted.

[0197] In various aspects, Cy2is selected from C3-C6 cycloalkyl and C2-C4 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy2is selected from C3-C6 cycloalkyl and C2-C4 heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy2is selected from C3-C6 cycloalkyl and C2-C4 heterocycloalkyl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy2is selected from C3-C6 cycloalkyl and C2-C4 heterocycloalkyl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy2is selected from C3-C6 cycloalkyl and C2-C4 heterocycloalkyl, and is unsubstituted.

[0198] In various aspects, Cy2is a C3-C6 cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of C3-C6 cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, and cyclohexane. In a further aspect, Cy2is a C3-C6 cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 72Attorney Docket No.19116.0058P1 C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino. In a still further aspect, Cy2is a C3-C6 cycloalkyl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy2is a C3-C6 cycloalkyl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, – NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1- C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy2is an unsubstituted C3-C6 cycloalkyl.

[0199] In various aspects, Cy2is a 5-membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of 5-membered heteroaryl include, but are not limited to, furanyl, thiophenyl (also referred to as thienyl), pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, lH-l,2,3-triazolyl, 2H- l,2,3-triazolyl, and l,2,4-triazolyl. In a further aspect, Cy2is a 5-membered heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy2is a 5-membered heteroaryl substituted with 0 or 1 group selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy2is a 5-membered heteroaryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino. In an even further aspect, Cy2is an unsubstituted 5-membered heteroaryl. 73Attorney Docket No.19116.0058P1 i. CY3GROUPS

[0200] In one aspect, Cy3is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy3is selected from C3- C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy3is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, – CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy3is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is monosubstituted with a group selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy3is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is unsubstituted.

[0201] In one aspect, Cy3is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy3is selected from C3- C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, 74Attorney Docket No.19116.0058P1 C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy3is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, – CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy3is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is monosubstituted with a group selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy3is selected from Cy3is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is unsubstituted.

[0202] In one aspect, Cy3is selected from C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy3is selected from C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy3is selected from C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy3is selected from C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, 75Attorney Docket No.19116.0058P1 C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy3is selected from C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is unsubstituted.

[0203] In various aspects, Cy3is selected from C3-C6 cycloalkyl and C2-C4 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy3is selected from C3-C6 cycloalkyl and C2-C4 heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy3is selected from C3-C6 cycloalkyl and C2-C4 heterocycloalkyl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy3is selected from C3-C6 cycloalkyl and C2-C4 heterocycloalkyl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy3is selected from C3-C6 cycloalkyl and C2-C4 heterocycloalkyl, and is unsubstituted.

[0204] In various aspects, Cy3is a C3-C6 cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of C3-C6 cycloalkyl include but are not limited to, cyclopropane, cyclobutane, cyclopentane, and cyclohexane. In a further aspect, Cy3is a C3-C6 cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, 76Attorney Docket No.19116.0058P1 C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino. In a still further aspect, Cy3is a C3-C6 cycloalkyl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy3is a C3-C6 cycloalkyl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, – NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1- C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy3is an unsubstituted C3-C6 cycloalkyl.

[0205] In various aspects, Cy3is a C2-C4 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of C2-C4 heterocycloalkyl include but are not limited to, azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, morpholinyl, and thiomorpholinyl. In a further aspect, Cy3is a C2-C4 heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy3is a C2-C4 heterocycloalkyl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy3is a C2-C4 heterocycloalkyl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy3is an unsubstituted C2-C4 heterocycloalkyl.

[0206] In various aspects, Cy3is selected from C6 aryl and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, 77Attorney Docket No.19116.0058P1 –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy3is selected from C6 aryl and 5- and 6-membered heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy3is selected from C6 aryl and 5- and 6-membered heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy3is selected from C6 aryl and 5- and 6-membered heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino. In an even further aspect, Cy3is selected from C6 aryl and 5- and 6- membered heteroaryl, and is unsubstituted.

[0207] In various aspects, Cy3is a C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy3is a C6 aryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy3is a C6 aryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy3is a C6 aryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1- 78Attorney Docket No.19116.0058P1 C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1- C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy3is an unsubstituted C6 aryl.

[0208] In various aspects, Cy3is a 5- and 6-membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of 5- and 6- membered heteroaryl groups include, but are not limited to, furanyl, thiophenyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, lH-l,2,3-triazolyl, 2H- l,2,3-triazolyl, l,2,4-triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, l,3,5-triazinyl, 1 ,2,4-triazinyl, l,2,3-triazinyl, l,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, l,2,5-oxadiazolyl, 1 ,2,4- thiadiazolyl, l,3,4-thiadiazolyl, l,2,5-thiadiazolyl and tetrazolyl. In a further aspect, Cy3is a 5- and 6-membered heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy3is a 5- and 6-membered heteroaryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy3is a 5- and 6- membered heteroaryl monosubstituted with a group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy3is an unsubstituted 5- and 6-membered heteroaryl.

[0209] In various aspects, Cy3is selected from C3-C10 cycloalkyl and C2-C9 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy3is selected from C3-C10 cycloalkyl and C2-C9 heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from 79Attorney Docket No.19116.0058P1 halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy3is selected from C3-C10 cycloalkyl and C2-C9 heterocycloalkyl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy3is selected from C3-C10 cycloalkyl and C2-C9 heterocycloalkyl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy3is selected from C3-C10 cycloalkyl and C2-C9 heterocycloalkyl, and is unsubstituted.

[0210] In various aspects, Cy3is a C3-C10 cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy3is a C3-C10 cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, – CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy3is a C3-C10 cycloalkyl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy3is a C3-C10 cycloalkyl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy3is an unsubstituted C3-C10 cycloalkyl. 80Attorney Docket No.19116.0058P1

[0211] In various aspects, Cy3is a C2-C9 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy3is a C2-C9 heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy3is a C2-C9 heterocycloalkyl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy3is a C2-C9 heterocycloalkyl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy3is an unsubstituted C2-C9 heterocycloalkyl.

[0212] In various aspects, Cy3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy3is selected from C6-C10 aryl and 81Attorney Docket No.19116.0058P1 C2-C9 heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is unsubstituted.

[0213] In various aspects, Cy3is a C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of C6-C10 aryl include, but are not limited to, phenyl and naphthyl. In a further aspect, Cy3is a C6-C10 aryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy3is a C6-C10 aryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy3is a C6-C10 aryl monosubstituted with a group selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy3is an unsubstituted C6-C10 aryl.

[0214] In various aspects, Cy3is a C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy3is a C2-C9 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further 82Attorney Docket No.19116.0058P1 aspect, Cy3is a C2-C9 heteroaryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1- C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy3is a C2-C9 heteroaryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy3is an unsubstituted C2-C9 heteroaryl. 2. EXAMPLE COMPOUNDS

[0215] In one aspect, a compound can be present as: , , ,83Attorney Docket No.19116.0058P1 , or a pharmac

[0216] In one aspect, a compound can be present as: , , , ,84Attorney Docket No.19116.0058P1 CF3CF3O O Cl , , ,85Attorney Docket No.19116.0058P1 or a pharmaceutically acceptable salt thereof.

[0217] It is contemplated that one or more compounds can optionally be omitted from the disclosed invention.

[0218] It is understood that the disclosed compounds can be used in connection with the disclosed methods, compositions, kits, and uses.

[0219] 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 COMPOUNDS

[0220] The compounds of this invention can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.

[0221] 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-IV, as described and exemplified below. The following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting. 1. ROUTE I

[0222] In one aspect, carboxamide compounds can be prepared as shown below. SCHEME 1A.86Attorney Docket No.19116.0058P1

[0223] Compounds are represented in generic form, wherein substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 1B.

[0224] In one aspect, compounds of type 1.6, and similar compounds, can be prepared according to reaction Scheme 1B above. Thus compounds of type 1.6 can be prepared by a coupling reaction of a suitable aniline, e.g., 1.4 with an appropriate carboxylic acid, e.g., 1.5 as shown above. Appropriate anilines and appropriate carboxylic acids are commercially available or prepared by methods known to a person of ordinary skill in the art. The reduction can be carried out in the presence of an appropriate coupling reagent, e.g., hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU), in the presence of an appropriate base, e.g., diisopropylethylamine, in an appropriate solvent, e.g., dimethylformamide, at an appropriate temperature, e.g., room temperature, for an appropriate amount of time, e.g., 16 h. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.1 and 1.2), can be substituted in the reaction to provide analogs similar to Formula 1.3. 2. ROUTE II

[0225] In one aspect, urea compounds can be prepared as shown below. 87Attorney Docket No.19116.0058P1 SCHEME 2A.

[0226] Compounds are represented in generic form, wherein substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 2B.88Attorney Docket No.19116.0058P1

[0227] In one aspect, compounds of type 2.8, and similar compounds, can be prepared according to reaction Scheme 2B above. Thus, compounds of type 2.6 can be prepared by phosgenation of an appropriate aniline, e.g., 2.5 as shown above. Appropriate anilines are commercially available or prepared by methods known to a person of ordinary skill in the art. The phosgenation is carried out in the presence of an appropriate phosgene reagent, e.g., triphosgene, in the presence of an appropriate base, e.g., triethylamine, in an appropriate solvent. e.g., dichloromethane, at an appropriate temperature, e.g., 0 °C, for an appropriate amount of time, e.g., 0.5h. Compounds of type 2.8 can be prepared by reaction of an appropriate isocyanate, e.g., 2.6, as shown above with an appropriate aniline, e.g., 2.7, as shown above. The reaction is carried out in an appropriate solvent. e.g., dichloromethane, at an appropriate temperature, e.g., room temperature, for an appropriate amount of time, e.g., 16h. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 2.1, 2.2, and 2.3), can be substituted in the reaction to provide analogs similar to Formula 2.4. 3. ROUTE III

[0228] In one aspect, substituted urea compounds can be prepared as shown below. SCHEME 3A. CF3CF3Ar289Attorney Docket No.19116.0058P1

[0229] Compounds are represented in generic form, wherein X is a halogen and with other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 3B.

[0230] In one aspect, compounds of type 3.10, and similar compounds, can be prepared according to reaction Scheme 2B above. Thus compounds of type 3.8 can be prepared by alkylation of an appropriate aniline, e.g., 3.6 as shown above with an appropriate alkyl halide, e.g., 3.7 as shown above. Appropriate anilines and appropriate alkyl halides are commercially available or prepared by methods known to a person of ordinary skill in the art. The alkylation is carried out in the presence of an appropriate base, e.g., diisopropylethylamine, in an appropriate solvent. e.g., dimethylformamide, at an appropriate temperature, e.g., 50 °C, for an appropriate amount of time, e.g., 16h. Compounds of type 3.10 can be prepared by reaction of an appropriate aniline, e.g., 3.8, as shown above, with an appropriate isocyanate, e.g., 3.9, as shown above. The reaction is carried out in the presence of an appropriate base, e.g., triethylamine, in an appropriate solvent. e.g., acetonitrile, at an appropriate temperature, e.g., 0 °C, for an appropriate amount of time, e.g., 16h. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds 90Attorney Docket No.19116.0058P1 similar to compounds of type 3.1, 3.2, 3.3, and 3.4), can be substituted in the reaction to provide analogs similar to Formula 3.5. 4. ROUTE IV

[0231] In one aspect, urea compounds can be prepared as shown below. SCHEME 4A.

[0232] Compounds are represented in generic form, wherein substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 4B.

[0233] In one aspect, compounds of type 4.3, and similar compounds, can be prepared according to reaction Scheme 4B above. Thus compounds of type 4.6 can be prepared by reaction of an appropriate aniline, e.g., 4.4 as shown above, with an appropriate isocyanate, e.g., 4.5, as shown above. Appropriate anilines and appropriate isocyanates are commercially available or prepared by methods known to a person of ordinary skill in the art. The reaction is carried out in the presence of an appropriate base, e.g., triethylamine, in an appropriate solvent. e.g., acetonitrile, at an appropriate temperature, e.g., 0 °C, for an appropriate amount 91Attorney Docket No.19116.0058P1 of time, e.g., 16h. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 4.1 and 4.2), can be substituted in the reaction to provide analogs similar to Formula 4.3. D. PHARMACEUTICAL COMPOSITIONS

[0234] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a disclosed CYP3A4-selective inhibitor compound and a pharmaceutically acceptable carrier.

[0235] Thus, in one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula: , wherein R1is selected from hydrogen; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R2is selected from –NR10Ar2, –CH2Cy1, and Cy2; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, 92Attorney Docket No.19116.0058P1 and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0236] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically acceptable sa.

[0237] In various aspects, the compound is selected from: , ,93Attorney Docket No.19116.0058P1 CF3O , , or a pharma

[0238] In various aspects, the pharmaceutical composition further comprises a drug that is a substrate of a P450 enzyme. In a further aspect, the drug is nirmatrelvir, darunavir, lopinavir, everolimus, quetiapine, testosterone, vincristine, atazanavir, indinavir, docetaxel, or tacrolimus. In a still further aspect, the P450 enzyme is selected from CYP3A4, CYP3A5, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A7. In yet a further aspect, the P450 enzyme is CYP3A4. In an even further aspect, the P450 enzyme is selected from CYP3A5, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A7.

[0239] 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.

[0240] 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 94Attorney Docket No.19116.0058P1 compositions featured in the invention can contain carriers or excipients, many of which are known to skilled artisans. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol. The nucleic acids, polypeptides, small molecules, and other modulatory compounds featured in the invention can be administered by any standard route of administration. For example, administration can be parenteral, intravenous, subcutaneous, or oral. A modulatory compound can be formulated in various ways, according to the corresponding route of administration. For example, liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application. Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.

[0241] In various aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0242] 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.

[0243] 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.

[0244] In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, 95Attorney Docket No.19116.0058P1 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.

[0245] 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.

[0246] The pharmaceutical compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0247] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0248] 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 96Attorney Docket No.19116.0058P1 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.

[0249] 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.

[0250] Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

[0251] 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.

[0252] 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. INHIBITING CYP3A4 IN A CELL

[0253] In one aspect, disclosed are methods of inhibiting CYP3A4 in a cell, the method comprising contacting the cell with an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof. 97Attorney Docket No.19116.0058P1

[0254] Thus, in one aspect, disclosed are methods of inhibiting CYP3A4 in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula: , wherein R1is selected from hydrogewherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R2is selected from –NR10Ar2, –CH2Cy1, and Cy2; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, 98Attorney Docket No.19116.0058P1 C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof.

[0255] In various aspects, the cell is mammalian.

[0256] In various aspects, the cell is a human.

[0257] In various aspects, the cell has been isolated from a mammal prior to the contacting step.

[0258] In various aspects, the contacting is ex vivo.

[0259] In various aspects, the contacting is in vitro.

[0260] In various aspects, contacting is via administration to a mammal. In a further aspect, the mammal has been diagnosed with a need for inhibiting CYP3A4 prior to the administering step. In a still further aspect, the mammal has been diagnosed with a need for inhibition of CYP3A4 prior to the administering step. F. INHIBITING CYP3A4 IN A SUBJECT

[0261] In one aspect, disclosed are methods of inhibiting CYP3A4 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.

[0262] Thus, in one aspect, disclosed are methods of inhibiting CYP3A4 in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein R1is selected from hydrogenand –CH2Ar ; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R2is selected from –NR10Ar2, –CH2Cy1, and Cy2; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – 99Attorney Docket No.19116.0058P1 NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof.

[0263] In various aspects, the subject is a mammal.

[0264] In various aspects, the subject is a human.

[0265] In various aspects, the subject has been diagnosed with a need for inhibiting CYP3A4 prior to the administering step.

[0266] In various aspects, the method further comprising identifying a subject in need of inhibition of CYP3A4. G. PREVENTING P450 ENZYME METABOLISM OF A DRUG IN A CELL

[0267] In one aspect, disclosed are methods of preventing P450 enzyme metabolism of a drug in a cell, the method comprising contacting the cell with an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0268] Thus, in one aspect, disclosed are methods of preventing P450 enzyme metabolism of a drug in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula: 100Attorney Docket No.19116.0058P1 , wherein R1is selected from hydroge ; w1herein Ar is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R2is selected from –NR10Ar2, –CH2Cy1, and Cy2; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof. 101Attorney Docket No.19116.0058P1

[0269] In various aspects, the P450 enzyme is selected from CYP3A4, CYP3A5, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A7.

[0270] In various aspect, the P450 enzyme is CYP3A4.

[0271] In various aspect, the P450 enzyme is selected from CYP3A5, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A7.

[0272] In various aspects, the cell is mammalian.

[0273] In various aspects, the cell is a human.

[0274] In various aspects, the cell has been isolated from a mammal prior to the contacting step.

[0275] In various aspects, the contacting is ex vivo.

[0276] In various aspects, the contacting is in vitro.

[0277] In various aspects, contacting is via administration to a mammal. In a further aspect, the mammal has been diagnosed with a need for prevention of P450 enzyme metabolism of a drug prior to the administering step. In a still further aspect, the mammal has been diagnosed with a need for prevention of P450 enzyme metabolism of a drug prior to the administering step. H. PREVENTING P450 ENZYME METABOLISM OF A DRUG IN A SUBJECT

[0278] In one aspect, disclosed are methods of preventing P450 enzyme metabolism of a drug 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.

[0279] Thus, in one aspect, disclosed are methods of preventing P450 enzyme metabolism of a drug in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , herein R1w is selected from hydrogen and –CH2Ar1; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, 102Attorney Docket No.19116.0058P1 C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R2is selected from –NR10Ar2, –CH2Cy1, and Cy2; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof.

[0280] In various aspects, the P450 enzyme is selected from CYP3A4, CYP3A5, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A7.

[0281] In various aspect, the P450 enzyme is CYP3A4.

[0282] In various aspect, the P450 enzyme is selected from CYP3A5, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A7.

[0283] In various aspects, the subject is a mammal.

[0284] In various aspects, the cell is a human.

[0285] In a further aspect, the subject has been diagnosed with a need for preventing P450 enzyme metabolism of a drug prior to the administering step. In a still further aspect, the mammal has been diagnosed with a need for prevention of P450 enzyme metabolism of a drug. 103Attorney Docket No.19116.0058P1 I. TREATING A DISEASE OR DISORDER IN A SUBJECT NEEDING TREATMENT WITH A DRUG THAT IS A P450 ENZYME SUBSTRATE

[0286] In one aspect, disclosed are methods of treating a disease or disorder 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 R1is selected from hydrogen; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R2is selected from C1-C8 alkyl, C1-C8 haloalkyl, –NR10Ar2, – CH2Cy1, and Cy3; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy3is selected from C3-C6 104Attorney Docket No.19116.0058P1 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, wherein the subject has been diagnosed as needing treatment with a drug that is a P450 enzyme substrate.

[0287] In various aspects, R2is selected from C1-C8 alkyl and C1-C8 haloalkyl. In a further aspect, R2is selected from C1-C4 alkyl and C1-C4 haloalkyl. In a still further aspect, R2is selected from methyl, ethyl, propyl, isopropyl, –CH2F, –CHF2, –CF3, –CH2CH2F, – CH2CHF2, –CH2CF3, –CH2CH2CH2F, –CH2CH2CHF2, –CH2CH2CF3, –CH(CH3)CH2F, – CH(CH3)CHF2, –CH(CH3)CF3, –CH(CH2F)2, –CH(CHF2)2, –CH(CF3)2, –CH2Cl, –CHCl2, – CCl3, –CH2CH2Cl, –CH2CHCl2, –CH2CCl3, –CH2CH2CH2Cl, –CH2CH2CHCl2, – CH2CH2CCl3, –CH(CH3)CH2Cl, –CH(CH3)CHCl2, –CH(CH3)CCl3, –CH(CH2Cl)2, – CH(CHCl2)2, –CH(CCl3)2. In yet a further aspect, R2is selected from methyl, ethyl, –CH2F, – CHF2, –CF3, –CH2CH2F, –CH2CHF2, –CH2CF3, –CH2Cl, –CHCl2, –CCl3, –CH2CH2Cl, – CH2CHCl2, –CH2CCl3. In an even further aspect, R2is selected from methyl, –CH2F, –CHF2, –CF3, –CH2Cl, –CHCl2, –CCl3.

[0288] In various aspects, R2is C1-C8 alkyl. In a further aspect, R2is C1-C4 alkyl. In a still further aspect, R2is selected from methyl, ethyl, propyl and isopropyl. In yet a further aspect, R2is selected from methyl and ethyl. In an even further aspect, R2is methyl.

[0289] In various aspects, R2is C1-C8 haloalkyl. In a further aspect, R2is C1-C4 haloalkyl. In a still further aspect, R2is selected from –CH2F, –CHF2, –CF3, –CH2CH2F, – CH2CHF2, –CH2CF3, –CH2CH2CH2F, –CH2CH2CHF2, –CH2CH2CF3, –CH(CH3)CH2F, – CH(CH3)CHF2, –CH(CH3)CF3, –CH(CH2F)2, –CH(CHF2)2, –CH(CF3)2, –CH2Cl, –CHCl2, – CCl3, –CH2CH2Cl, –CH2CHCl2, –CH2CCl3, –CH2CH2CH2Cl, –CH2CH2CHCl2, – CH2CH2CCl3, –CH(CH3)CH2Cl, –CH(CH3)CHCl2, –CH(CH3)CCl3, –CH(CH2Cl)2, – CH(CHCl2)2, –CH(CCl3)2. In yet a further aspect, R2is selected from –CH2F, –CHF2, –CF3, – CH2CH2F, –CH2CHF2, –CH2CF3, –CH2Cl, –CHCl2, –CCl3, –CH2CH2Cl, –CH2CHCl2, – CH2CCl3. In an even further aspect, R2is selected –CH2F, –CHF2, –CF3, –CH2Cl, –CHCl2, – CCl3.

[0290] In various aspects, R2is Cy3.

[0291] In various aspects, Cy3is selected from C6 aryl and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, 105Attorney Docket No.19116.0058P1 –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy3is selected from C6 aryl and 5- and 6-membered heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy3is selected from C6 aryl and 5- and 6-membered heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy3is selected from C6 aryl and 5- and 6-membered heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino. In an even further aspect, Cy3is selected from C6 aryl and 5- and 6- membered heteroaryl, and is unsubstituted.

[0292] In various aspects, Cy3is a C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy3is a C6 aryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy3is a C6 aryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy3is a C6 aryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1- 106Attorney Docket No.19116.0058P1 C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1- C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy3is an unsubstituted C6 aryl.

[0293] In various aspects, Cy3is a 5- and 6-membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of 5- and 6- membered heteroaryl groups include, but are not limited to, furanyl, thiophenyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, lH-l,2,3-triazolyl, 2H- l,2,3-triazolyl, l,2,4-triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, l,3,5-triazinyl, 1 ,2,4-triazinyl, l,2,3-triazinyl, l,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, l,2,5-oxadiazolyl, 1 ,2,4- thiadiazolyl, l,3,4-thiadiazolyl, l,2,5-thiadiazolyl and tetrazolyl. In a further aspect, Cy3is a 5- and 6-membered heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy3is a 5- and 6-membered heteroaryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy3is a 5- and 6- membered heteroaryl monosubstituted with a group selected from halogen, –NO2, –CN, – OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy3is an unsubstituted 5- and 6-membered heteroaryl.

[0294] In various aspects, the compound is selected from: ,107Attorney Docket No.19116.0058P1 , , , , , ,108Attorney Docket No.19116.0058P1 CF3O , , or a phar

[0295] In various aspects, the P450 enzyme is selected from CYP3A4, CYP3A5, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A7.

[0296] In various aspect, the P450 enzyme is CYP3A4.

[0297] In various aspect, the P450 enzyme is selected from CYP3A5, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A7.

[0298] In various aspects, the drug is nirmatrelvir, darunavir, lopinavir, everolimus, quetiapine, testosterone, vincristine, atazanavir, indinavir, docetaxel, or tacrolimus.

[0299] In various aspects, the subject is a mammal.

[0300] In various aspects, the subject is a human.

[0301] In various aspects, the subject has been diagnosed with a need for treatment of the disease or disorder prior to the administering step.

[0302] In various aspects, the method further comprises the step of identifying a subject in need of treatment of the disease or disorder.

[0303] In various aspects, the effective amount is a therapeutically effective amount.

[0304] In various aspects, the effective amount is a prophylactically effective amount. 109Attorney Docket No.19116.0058P1

[0305] In various aspects, the method further comprises administering to the subject a drug that is a P450 enzyme substrate. In a further aspect, the drug that is a P450 enzyme substrate is administered simultaneously with the compound. In a still further aspect, the drug that is a P450 enzyme substrate is administered sequentially with the compound. In yet a further aspect, the drug that is a P450 enzyme substrate is administered prior to administration of the compound. In an even further aspect, the drug that is a P450 enzyme substrate is administered subsequent to administration of the compound. In a still even further aspect, the drug that is a P450 enzyme substrate is administered within one week or less of administration of the compound. In yet an even further aspect, the drug that is a P450 enzyme substrate is administered within twenty-four hours or less of administration of the compound. In a further aspect, the drug that is a P450 enzyme substrate is administered within twelve hours or less of administration of the compound. In a still further aspect, the drug that is a P450 enzyme substrate is administered within six hours or less of administration of the compound. In yet a further aspect, the drug that is a P450 enzyme substrate is administered within one hour or less of administration of the compound. In an even further aspect, the drug that is a P450 enzyme substrate is co-formulated with the compound.

[0306] In various aspects, a drug that is a P450 enzyme substrate has been administered to the subject before administration of the compound. In a further aspect, the drug that is a P450 enzyme substrate has been administered to the subject one week or less before administration of the compound. In a still further aspect, the drug that is a P450 enzyme substrate has been administered to the subject twenty-four hours or less before administration of the compound. In yet a further aspect, the drug that is a P450 enzyme substrate has been administered to the subject twelve hours or less before administration of the compound. In an even further aspect, the drug that is a P450 enzyme substrate has been administered to the subject six hours or less before administration of the compound. In an even still further aspect, the drug that is a P450 enzyme substrate has been administered to the subject one hour or less before administration of the compound. J. METHODS OF USING THE COMPOSITIONS

[0307] The compounds and pharmaceutical compositions of the invention are useful as CYP3A4-selective inhibitors for use with a drug that is a P450 enzyme substrate used to treat a disease or condition. 110Attorney Docket No.19116.0058P1

[0308] To prevent CYP3A4 metabolism of a drug, 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 with a drug that is a P450 enzyme substrate used to treat a disease or condition.

[0309] The compounds or compositions can be administered to the subject according to any method. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. A preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.

[0310] 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 111Attorney Docket No.19116.0058P1

[0311] 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 compounds that inhibit CYP3A4 selectively, pharmaceutical compositions, and methods of using the compounds and composition for treating a disease or disorder with a drug that is a P450 enzyme substrate. In addition the disclosed compounds and compositions can be used for preventing P450 enzyme metabolism of a drug.

[0312] 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.

[0313] 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.

[0314] 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.

[0315] In various aspects, the use relates to a treatment of a condition associated with cardiomyopathy 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 condition associated right ventricular failure.

[0316] In a further aspect, the use relates to the manufacture of a medicament for the treatment of a disease or disorder with a drug that is a P450 enzyme substrate. In a further aspect, the use relates to the manufacture of a medicament for preventing P450 enzyme metabolism of a drug in a subject.

[0317] It is understood that the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits. In a further aspect, the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of a disease or disorder with a drug that is a P450 enzyme substrate. In a further aspect, the use relates to 112Attorney Docket No.19116.0058P1 the manufacture of a medicament for preventing P450 enzyme metabolism of a drug in a mammal. 2. MANUFACTURE OF A MEDICAMENT

[0318] In one aspect, the invention relates to a method for the manufacture of a medicament for treatment of a disease or disorder with a drug that is a P450 enzyme substrate, 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.

[0319] 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 a condition associated with cardiomyopathy. 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 timeframe. 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.

[0320] 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 for humans, and more preferably between 200 mg / kg and about 400 mg / kg of body weight for humans per daily dose. This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.

[0321] 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.

[0322] 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. 113Attorney Docket No.19116.0058P1 3. KITS

[0323] In one aspect, disclosed are kits comprising a disclosed compound, and one or more selected from: (a) a drug that is a P450 enzyme substrate; (b) instructions for administering the compound in combination with a drug that is a P450 enzyme substrate; (c) instructions for administering the compound to maintain efficacy of a drug that is a CYP3A4 substrate; and (d) instructions for administering the compound so as not to alter the metabolism of a drug that is a P450 enzyme substrate.

[0324] In one aspect, are kits comprising a compound having a structure represented by a formula: , wherein R1is selected from hydrogen; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino; wherein R2is selected from C1-C8 alkyl, C1-C8 haloalkyl, –NR10Ar2, – CH2Cy1, and Cy3; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6- C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently 114Attorney Docket No.19116.0058P1 selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy3is selected from C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) a drug that is a P450 enzyme substrate; (b) instructions for administering the compound in combination with a drug that is a P450 enzyme substrate; (c) instructions for administering the compound to maintain efficacy of a drug that is a CYP3A4 substrate; and (d) instructions for administering the compound so as not to alter the metabolism of a drug that is a P450 enzyme substrate.

[0325] In various aspects, the drug that is a P450 enzyme substrate is nirmatrelvir, darunavir, lopinavir, everolimus, quetiapine, testosterone, vincristine, atazanavir, indinavir, docetaxel, or tacrolimus.

[0326] In various aspects, the drug that is a P450 enzyme substrate is darunavir, lopinavir, vincristine, atazanavir, or tacrolimus.

[0327] In various aspects, the drug that is a CYP3A4 substrate is nirmatrelvir, everolimus, quetiapine, or testosterone.

[0328] In various aspects, the compound and the agent are co-packaged.

[0329] In various aspects, the compound and the agent are co-formulated.

[0330] 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. 115Attorney Docket No.19116.0058P1

[0331] 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

[0332] 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.

[0333] The Examples are provided herein to illustrate the invention, and should not be construed as limiting the invention in any way. 1. CHEMISTRY EXAMPLES a. GENERAL METHODS

[0334] All reagents and solvents were purchased from Sigma-Aldrich (St. Louis, MO), or Enamine, Ltd. (Monmouth Jct., NJ) unless otherwise noted and were used without further purification. All NMR spectra were recorded on a Bruker 400 MHz or 500 MHz spectrometer in the solvents indicated, and spectra were processed using MestReNova (14.1.1). Flash column chromatography was performed using Biotage Isolera Flash Systems with Biotage Sfär Silica or Biotage Sfär C18 columns. All compounds used for biological assays have >95% purity as determined by using a Waters Acquity UPLC MS system with a C18 column in a 2 min gradient (H2O + 0.1% formic acid (FA) → acetonitrile (ACN) + 0.1% formic acid) and detectors of PDA (215−400 nm), ELSD, and Acquity SQD ESI-positive mass spectrometer (Waters Corporation, Milford, MA). High-resolution mass spectra were determined by using a Waters Acquity UPLC system with a C18 column (H2O + 0.1% FA → ACN + 0.1% FA gradient over 2.5 min) and a Xevo G2Q-TOF ESI-positive mass spectrometer in resolution mode. Compounds were internally normalized to leucine−enkephalin lock solution, with a calculated error of <3 ppm. 116Attorney Docket No.19116.0058P1 b. SYNTHESIS OF COMPOUNDS

[0335] SCHEME 1. SYNTHESIS OF SCM-06 TO SCM-12, SCM-16, AND SCM-17. (TRIFLUOROMETHYL)PHENYL)-2-CHLOROBENZAMIDE (SCM-11).

[0336] Compound SCM-11 (25.0 mg, 52%) was synthesized according to General Procedure A: To a solution of 2-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (1, 1.0 equiv) in anhydrous DMF was added an acid chloride (3.0 equiv) by dropwise addition at 0 °C under a N2atmosphere, and then this reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated under reduced pressure. The reaction mixture was concentrated under reduced pressure. The residue was purified by the reversed-phase flash chromatography (running a gradient of 0%-100% acetonitrile in water over 16 min) to yield the product.1H NMR (500 MHz, MeOD) δ 8.10 (s, 1H), 7.97 (s, 1H), 7.78 (d, J = 8.40 Hz, 1H), 7.69 (d,J = 8.25 117Attorney Docket No.19116.0058P1 Hz, 1H), 7.50 – 7.37 (m, 5H), 7.19 (s, 1H);13C NMR (126 MHz, MeOD) δ 167.38, 135.62, 135.17, 132.64, 131.37, 131.05, 130.78, 130.62, 129.77, 128.69, 127.77, 126.81, 124.48, 124.45, 124.23, 124.20; ESI-TOF HRMS: m / z 366.0633 (C17H12ClF3N3O + H+requires 366.0621). ii. N-(2-(1H-IMIDAZOL-1-YL)-5- (TRIFLUOROMETHYL)PHENYL)CYCLOPROPANECARBOXAM IDE (SCM-07).

[0337] Compound SCM-07 (56.0 mg, 43%) was synthesized according to general procedure A, ;1H NMR (500 MHz, CDCl3) δ 8.65 (s, 1H), 7.48 (s, 1H), 7.44 – 7.42 (m, 1H), 7.31 (d, J = 8.20 Hz, 1H), 7.15 (s, 1H), 7.11 (s, 1H), 1.71 – 1.66 (m, 1H), 1.10 – 1.07 (m, 2H), 0.87 – 0.83 (m, 2H);13C NMR (126 MHz, CDCl3) δ 173.28, 134.62, 132.50, 132.23, 131.97, 131.71, 130.73, 127.46, 124.56, 122.39, 121.28, 120.11, 15.31, 8.72; ESI-TOF HRMS: m / z 296.1024 (C14H13F3N3O + H+requires 296.1010). iii. N-(2-(1H-IMIDAZOL-1-YL)-5- (TRIFLUOROMETHYL)PHENYL)CYCLOBUTANECARBOXAMI DE (SCM-08).

[0338] Compound SCM-08 (58.0 mg, 40%) was synthesized according to general procedure A:1H NMR (500 MHz, CDCl3) δ 7.67 (s, 1H), 7.48 – 7.46 (m, 1H), 7.37 (d, J = 8.20 Hz, 1H), 7.32 (s, 1H), 7.17 (s, 1H), 7.12 (s, 1H), 3.10 – 3.03 (m, 1H), 2.31 – 2.23 (m, 2H), 2.18 – 2.12 (m, 2H), 2.01 – 1.84 (m, 2H);13C NMR (126 MHz, CDCl3) δ 173.79, 134.35, 132.81, 132.55, 132.28, 132.02, 131.03, 129.68, 124.54, 122.37, 121.43, 120.08, 40.73, 25.26, 18.14; ESI-TOF HRMS: m / z 310.1173 (C15H15F3N3O + H+requires 310.1167). iv. N-(2-(1H-IMIDAZOL-1-YL)-5- (TRIFLUOROMETHYL)PHENYL)CYCLOHEXANECARBOXAMI DE (SCM-10).

[0339] Compound SCM-10 (60.0 mg, 35%) was synthesized according to general procedure A:1H NMR (500 MHz, CDCl3) δ 7.65 (s, 1H), 7.47 – 7.45 (m, 1H), 7.38 – 7.30 (m, 3H), 7.14 (s, 1H), 2.19 – 2.13 (m, 1H), 1.85 – 1.76 (m, 4H), 1.68 – 1.65 (m, 1H), 1.44 – 1.36 (m, 2H), 1.29 – 1.17 (m, 3H);13C NMR (126 MHz, CDCl3) δ 174.81, 134.42, 132.76, 132.49, 132.23, 131.97, 131.34, 129.79, 127.41, 124.54, 122.37, 121.39, 120.16, 46.19, 29.47, 25.62, 25.56; ESI-TOF HRMS: m / z 338.1487 (C17H19F3N3O + H+requires 338.1480). 118Attorney Docket No.19116.0058P1 v. N-(2-(1H-IMIDAZOL-1-YL)-5- (TRIFLUOROMETHYL)PHENYL)THIAZOLE-2- CARBOXAMIDE (SCM-09).

[0340] Compound SCM-09 (70.0 mg, 47%) was synthesized according to general procedure A:1H NMR (500 MHz, CDCl3) δ 7.71 (s, 1H), 7.60 (s, 1H), 7.57 (d, J = 4.95 Hz, 1H), 7.51 (d, J = 8.15 Hz, 1H), 7.46 (d, J = 8.25 Hz, 1H), 7.40 (s, 1H), 7.28 (d, J = 3.50 Hz, 1H), 7.20 (s, 1H), 7.08 (t, J = 4.05 Hz, 1H);13C NMR (126 MHz, CDCl3) δ 159.88, 137.95, 134.19, 132.72, 132.39, 131.70, 129.16, 128.36, 127.41, 126.82, 124.52, 122.35, 121.59, 120.03, 119.44; ESI-TOF HRMS: m / z 338.0590 (C15H11F3N3OS + H+requires 338.0575). vi. N-(2-(1H-IMIDAZOL-1-YL)-5- (TRIFLUOROMETHYL)PHENYL)THIAZOLE-2- CARBOXAMIDE (SCM-16).

[0341] Compound SCM-16 (77.0 mg, 48%) was synthesized according to general procedure A:1H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 2.10 Hz, 1H), 7.68 (s, 1H), 7.57 (d, J = 2.05 Hz, 1H), 7.45 (d, J = 8.10 Hz, 1H), 7.39 – 7.34 (m, 3H), 7.18 – 7.16 (m, 1H);13C NMR (126 MHz, CDCl3) δ 162.18, 157.68, 144.19, 133.37, 132.73, 132.47, 132.20, 131.94, 130.00, 127.62, 126.19, 124.52, 121.91, 119.07; ESI-TOF HRMS: m / z 339.0540 (C14H10F3N4OS + H+requires 339.0527). vii. N-(2-(1H-IMIDAZOL-1-YL)-5- (TRIFLUOROMETHYL)PHENYL)NICOTINAMIDE (SCM-17).

[0342] Compound SCM-17 (56.0 mg, 32%) was synthesized according to general procedure A:1H NMR (500 MHz, CDCl3) δ 8.75 (s, 1H), 8.71 (s, 1H), 8.56 (s, 1H), 8.07 (d, J = 8.00 Hz, 1H), 7.81 (s, 1H), 7.60 (dd, J = 2.00 and 8.30 Hz, 1H), 7.48 (d, J = 8.20 Hz, 1H), 7.43 – 7.40 (m, 1H), 7.30 (s, 1H), 7.21 (s, 1H);13C NMR (126 MHz, CDCl3) δ 164.12, 152.97, 148.08, 135.49, 133.61, 132.90, 132.64, 132.37, 132.11, 130.98, 129.30, 127.38, 124.29, 123.86, 122.73, 121.56; ESI-TOF HRMS: m / z 333.0974 (C16H12F3N4O + H+requires 333.0963). 119Attorney Docket No.19116.0058P1 viii. N-(2-(1H-IMIDAZOL-1-YL)-5- (TRIFLUOROMETHYL)PHENYL)-3,3- DIMETHYLBUTANAMIDE (SCM-12).

[0343] Compound SCM-12 (87.0 mg, 53%) was synthesized according to general procedure A:1H NMR (500 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.89 (s, 1H), 7.69 (dd, J = 2.30 and 8.25 Hz, 1H), 7.61 (d, J = 8.25 Hz, 1H), 7.40 (s, 1H), 7.11 (s, 1H), 2.15 (s, 2H), 0.95 (s, 9H);13C NMR (126 MHz, DMSO) δ 170.79, 137.96, 134.55, 133.02, 129.21, 128.63, 128.37, 127.74, 124.73, 123.69, 122.85, 122.56, 120.23, 48.52, 30.78, 29.56; ESI-TOF HRMS: m / z 326.1491 (C16H19F3N3O + H+requires 326.1480). ix. N-(2-(1H-IMIDAZOL-1-YL)-5- (TRIFLUOROMETHYL)PHENYL)-2-ETHYLBUTANAMIDE (SCM-06).

[0344] Compound SCM-06 (91.0 mg, 49%) was synthesized according to general procedure A:1H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.90 (s, 1H), 7.71 (d, J = 8.40 Hz, 1H), 7.63 (d, J = 8.40 Hz, 1H), 7.40 (s, 1H), 7.12 (s, 1H), 2.21 – 2.16 (m, 1H), 1.54 – 1.45 (m, 2H), 1.43 – 1.34 (m, 2H), 0.79 (t, J = 7.45 Hz, 6H);13C NMR (126 MHz, DMSO) δ 175.28, 135.40, 133.40, 129.56, 129.15, 128.90, 128.64, 128.23, 125.16, 124.47, 123.58, 123.00, 120.72, 49.45, 25.36, 12.22; ESI-TOF HRMS: m / z 326.1488 (C16H19F3N3O + H+requires 326.1480). SCHEME 2. SYNTHESIS OF SCM-25120Attorney Docket No.19116.0058P1 x. N-(2-(1H-IMIDAZOL-1-YL)-5- (TRIFLUOROMETHYL)PHENYL)-2-(2- CHLOROPHENYL)ACETAMIDE (SCM-25).

[0345] To a solution of 2-chlorophenylacetic acid (30.0 mg, 0.176 mmol) in DMF (2.0 mL) were added 2-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (1, 60.0 mg, 0.264 mmol), hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) (100.0 mg, 0.264 mmol), and N,N-diisopropylethylamine (46.0 μL, 0.264 mmol), and then this reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned with ethyl acetate (10 mL) and water (10 mL), and the aqueous layer was extracted with ethyl acetate (5 mL × 2). The combined organic layer was washed with brine (3 mL), dried with Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by the flash chromatography (running a gradient of 0%-100% ethyl acetate in hexane over 16 min) to yield compound SJYHJ-075 (52.0 mg, 78%) as a white solid;1H NMR (500 MHz, MeOD) δ 8.08 (s, 1H), 7.86 (s, 1H), 7.69 (d, J = 8.10 Hz, 1H), 7.61 (d, J = 8.30 Hz, 1H), 7.41 – 7.39 (m, 1H), 7.32 – 7.27 (m, 4H), 7.13 (s, 1H), 3.82 (s, 2H);13C NMR (126 MHz, DMSO) δ 169.48, 137.82, 134.10, 133.90, 133.08, 132.73, 129.85, 129.47, 129.18, 129.02, 128.76, 127.99, 127.54, 125.17, 123.01, 120.56, 38.72; ESI-TOF HRMS: m / z 380.0783 (C18H14ClF3N3O + H+requires 380.0777). SCHEME 3. SYNTHESIS OF SCM-24xi. 1-(2-(1H-IMIDAZOL-1-YL)-5- (TRIFLUOROMETHYL)PHENYL)-3-(2-(2- CHLOROETHYL)PHENYL)UREA (SCM-24).

[0346] To a solution of triphosgene (38.0 mg, 0.129 mmol) in dichloromethane (3.0 ml) was added 2 (20.0 mg, 0.129 mmol) in dichloromethane(3.0 mL) by dropwise addition at 0 °C under a N2 atmosphere, and then triethylamine (53.7 μL, 0.386 mmol) in dichloromethane 121Attorney Docket No.19116.0058P1 (3.0 mL) was added to the reaction mixture by dropwise addition. After the mixture was stirred at room temperature for 0.5 h, the solvent was removed on a rotary evaporator. The residue was dissolved in dichloromethane (5.0 mL), and 2-(1H-imidazol-1-yl)-5- (trifluoromethyl)aniline (1, 23.4 mg, 0.129 mmol) in tetrahydrofuran (3.0 mL) was added. The reaction mixture was stirred for 16 h at room temperature under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by the reversed-phase flash chromatography (running a gradient of 0%-100% acetonitrile in water over 16 min) to yield compound SCM-24 (23.0 mg, 43%) as a white solid;1H NMR (400 MHz, MeOD) δ 8.42 (s, 1H), 7.98 (broad s, 1H), 7.55 (s, 2H), 7.45 (dd, J = 1.40 and 7.96 Hz, 2H), 7.32 – 7.24 (m, 3H), 7.21 – 7.17 (m, 1H), 3.73 (t, J = 7.40 Hz, 2H), 3.05 (t, J = 7.40 Hz, 2H);13C NMR (126 MHz, MeOD) δ 155.49, 137.25, 136.54, 136.20, 133.41, 132.82, 132.56, 131.21, 128.99, 128.53, 126.95, 126.90, 126.87, 126.51, 125.79, 123.63, 121.76, 44.50, 35.50; ESI-TOF HRMS: m / z 409.1058 (C19H17ClF3N4O + H+requires 409.1043). SCHEME 4. SYNTHESIS OF SCM-26xii. 3-(((2-CHLOROPHENYL)AMINO)METHYL)PHENOL (5).

[0347] To a solution of 2-chloroaniline (4, 243.0 mg, 1.902 mmol) in DMF (5.0 mL) were added 3-(bromomethyl)phenol (356.0 mg, 1.902 mmol), and N,N-diisopropylethylamine 122Attorney Docket No.19116.0058P1 (497.0 μL, 2.850 mmol) under a N2 atmosphere, and then this reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by the reversed-phase flash chromatography (running a gradient of 0%-100% acetonitrile in water over 16 min) to yield compound 5 (210.0 mg, 47%) as a white solid;1H NMR (500 MHz, DMSO-d6) δ 7.23 (dd, J = 1.50 and 7.85 Hz, 1H), 7.09 (t, J = 7.75 Hz, 1H), 7.03 – 6.99 (m, 1H), 6.75 – 6.72 (m, 2H), 6.59 (dd, J = 1.60 and 8.20 Hz, 1H), 6.54 – 6.49 (m, 2H), 4.31 (d, 2H);13C NMR (126 MHz, DMSO) δ 157.95, 144.41, 141.76, 129.79, 129.37, 128.28, 118.19, 117.80, 116.83, 114.10, 113.84, 112.09, 46.40; LCMS: m / z = 232.16 [M–H]−. xiii. 3-(2-(1H-IMIDAZOL-1-YL)-5- (TRIFLUOROMETHYL)PHENYL)-1-(2-CHLOROPHENYL)-1- (3-HYDROXYBENZYL)UREA (SCM-26).

[0348] To a solution of triphosgene (54.4 mg, 0.183 mmol) in ACN (3.0 ml) was added 1 (50.0 mg, 0.220 mmol) in CH3CN (1.0 mL) by dropwise addition at 0 °C under a N2 atmosphere, and then triethylamine (102.0 μL, 0.734 mmol) in ACN (1.0 mL) was added to the reaction mixture by dropwise addition. After the mixture was stirred at room temperature for 0.5 h, 5 (42.9 mg, 0.183 mmol) in CH3CN (1.0 mL) was added to the reaction mixture. The reaction mixture was stirred for 16 h at room temperature under a N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by the reversed-phase flash chromatography (running a gradient of 0%-65% acetonitrile in water over 16 min) to yield compound SJYHJ-110 (20.0 mg, 22%);1H NMR (500 MHz, CDCl3) δ 8.24 (s, 1H), 7.74 (broad s, 1H), 7.50 – 7.45 (m, 2H), 7.36 (d, J = 8.15 Hz, 1H), 7.30 (t, J = 7.70 Hz, 1H), 7.13 – 7.06 (m, 3H), 6.98 – 6.88 (m, 1H), 6.81 – 6.77 (m, 2H), 6.73 (s, 1H), 6.54 (d, J = 7.45 Hz, 1H), 5.37 (d, J = 15.1 Hz, 1H), 3.98 (d, J = 15.1 Hz, 1H);13C NMR (126 MHz, CDCl3) δ 157.22, 153.63, 138.62, 137.03, 135.23, 133.55, 132.64, 132.38, 131.48, 131.23, 130.71, 129.73, 129.49, 128.70, 127.72, 124.46, 122.29, 121.97, 121.38, 120.74, 120.07, 115.43, 115.16, 51.94; ESI-TOF HRMS: m / z 487.1159 (C24H19ClF3N4O2 + H+requires 487.1148). 123Attorney Docket No.19116.0058P1 SCHEME 5. SYNTHESIS OF SCM-27xiv. 3-(((2-(1H-IMIDAZOL-1-YL)-5- (TRIFLUOROMETHYL)PHENYL)AMINO)METHYL)PHENOL (6).

[0349] Compound 6 (50.0 mg, 26%) was afforded through the same procedure as compound 5;1H NMR (500 MHz, MeOD) δ 7.86 (s, 1H), 7.35 (s, 1H), 7.27 (d, J = 7.95 Hz, 1H), 7.23 (s, 1H), 7.13 (t, J = 7.75 Hz, 1H), 6.96 (d, J = 8.10 Hz, 1H), 6.89 (s, 1H), 6.78 (d, J = 7.65 Hz, 1H), 6.75 (s, 1H), 6.65 (dd, J = 2.50 and 8.10 Hz, 1H), 4.31 (d, 2H);13C NMR (126 MHz, MeOD) δ 157.51, 144.09, 140.15, 137.69, 136.54, 131.55, 129.34, 128.78, 127.68, 126.19, 120.53, 117.63, 113.71, 113.08, 112.36, 108.13, 45.28; LCMS: m / z = 334.08 [M+H]+. xv. 1-(2-(1H-IMIDAZOL-1-YL)-5- (TRIFLUOROMETHYL)PHENYL)-3-(2-CHLOROPHENYL)-1- (3-HYDROXYBENZYL)UREA (SCM-27).

[0350] To a solution of 1-chloro-2-isocyanatobenzene (1.3 mg, 9.0 mmol) in ACN (1.0 ml) was added triethylamine (3.1 μL, 22.50 mmol) in ACN (1.0 mL) by dropwise addition at 0 °C under a N2atmosphere, and then compound 6 (2.5 mg, 7.5 mmol) in ACN (1.0 mL) was 124Attorney Docket No.19116.0058P1 added to the reaction mixture by dropwise addition. The reaction mixture was stirred for 16 h at room temperature under a N2atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by the reversed-phase flash chromatography (running a gradient of 0%-65% acetonitrile in water over 16 min) to yield compound SJYHJ- 111 (2.0 mg, 54%);1H NMR (500 MHz, CDCl3) δ 8.11 – 8.09 (m, 2H), 7.41 – 7.39 (m, 2H), 7.33 – 7.30 (m, 2H), 7.24 – 7.21 (m, 1H), 7.14 (d, J = 8.10 Hz, 1H), 7.10 – 7.07 (m, 3H), 7.00 – 6.96 (m, 2H), 6.89 (s, 1H), 4.32 – 4.31 (m, 2H);13C NMR (126 MHz, CDCl3) δ 151.23, 151.02, 143.52, 139.37, 134.27, 132.88, 132.62, 130.22, 129.34, 128.09, 127.77, 124.89, 124.62, 124.51, 122.73, 121.18, 120.43, 114.20, 114.17, 108.80, 108.77, 47.39; ESI-TOF HRMS: m / z 487.1162 (C24H19ClF3N4O2+ H+requires 487.1148). 2. MATERIALS AND METHODS a. COMPOUNDS

[0351] The identities of compounds purchased from vendors are shown in Table 1 and were verified using mass spectrometry, and their purities were determined to be >95% by high-performance liquid chromatography, using a system equipped with UV-vis and evaporative light-scattering detectors. The names of commercially available compounds, are shown in the form of “vendor name + catalog number”. TABLE 1. No. Alternative name Library number 1 Ch mBrid SJ000132055125Attorney Docket No.19116.0058P1 No. Alternative name Library number 4 ChemBridge SJ000137498126Attorney Docket No.19116.0058P1 No. Alternative name Library number 11 ChemBridge SJ000064999127Attorney Docket No.19116.0058P1 No. Alternative name Library number 18 ChemBridge SJ000176651128Attorney Docket No.19116.0058P1 No. Alternative name Library number 26 ChemBridge SJ000475206129Attorney Docket No.19116.0058P1 No. Alternative name Library number 33 Enamine SJ000388260130Attorney Docket No.19116.0058P1 No. Alternative name Library number 39 Molport SJ000484828

[00352] C emca structures o compounds stud ed, i.e., SCM-01 to SCM-27, are s own in Table 2. The details of the chemical synthesis of SCM-01 analogs are described herein. TABLE 2. Compound Structure Alternative name131Attorney Docket No.19116.0058P1 CompoundStructureAlternative nameS 1132Attorney Docket No.19116.0058P1 CompoundStructureAlternative nameCF3133Attorney Docket No.19116.0058P1 CompoundStructureAlternative name134Attorney Docket No.19116.0058P1 CompoundStructureAlternative name135Attorney Docket No.19116.0058P1 CompoundStructureAlternative name136Attorney Docket No.19116.0058P1 CompoundStructureAlternative nameb. HIGH THROUGHPUT SCREENING CAMPAIGN

[0353] The chemical library was composed of compounds acquired from several commercial sources with molecular descriptors conforming to drug-like physicochemical characteristics, while minimizing pan assay interference compounds (PAINS) (Nishiguchi, G.; et al., (2021) Drug Discov Today 26 (4), 1060-1069). The P450-Glo luminescence assays were conducted in 384-well white plates (PerkinElmer, Waltham, MA, catalog number 6007290) as described below at single compound concentration of 10 µM.956 compounds with ≥80% inhibition were selected for dose-response confirmatory screen against both CYP3A4 and CYP3A5 using the same assay. HTS data was analyzed using in-house software written in Pipeline Pilot (BIOVIA, San Diego, CA), including fitting data points from dose response experiments to sigmoidal models to obtain IC50 values, and in the determination of Z’ factor for assay quality assessment (Guiguemde, W. A.; et al., (2010) Nature 465 (7296), 311-5).

[0354] Tanimoto coefficient-based hierarchical clustering analysis of compounds was performed using ChemMine Tools (Backman, T. W.; et al., (2011) Nucleic Acids Res 39 (Web Server issue), W486-91), and the results were displayed as a circular cladogram using Interactive Tree of Life (Letunic, I. and Bork, P., (2021) Nucleic Acids Res 49 (W1), W293- W296). c. P450-GLO BIOCHEMICAL INHIBITION ASSAY

[0355] The inhibitory effects of compounds on CYP3A4, 3A5, or 3A7 were measured using the P450-Glo luminescence assay (Promega, Madison, WI, catalog no. V9002 and V8912) as previously described (Wright, W. C.; et al., (2020) J Med Chem 63 (3), 1415- 1433; Wang, J.; et al., (2021) J Am Chem Soc 143 (44), 18467-18480). The inhibitory profiles of CYP3A4 and CYP3A5 were determined using the substrate luciferin-IPA, and the 137Attorney Docket No.19116.0058P1 inhibition of CYP3A7 was quantified using the substrate luciferin-PPXE. The CYP3A4, 3A5, and 3A7 SupersomeTMhuman recombinant enzymes (catalog no.456202, 456256, 456237) were purchased from Discovery Life Sciences (Huntsville, AL). These enzymes contain 1000 pmol / mL of the full-length CYP protein mixed with NADPH–cytochrome P450 reductase, cytochrome b5, and membrane components.

[0356] The P450-Glo assays were carried out in 384-well white assay plates (PerkinElmer, Waltham, MA, catalog no.6007290) with a 25 µL reaction volume. Each well was first added with 25 nL (in primary high-throughput screening) or 37.5 nL (all other assays) of the test compound in DMSO using an Echo 650 Acoustic Liquid Handler (Beckman Coulter, Brea, CA), followed by 12.5 µL of 2× enzyme-substrate mixture. The reaction was initiated by adding another 12.5 µL of 2× NADPH regeneration system (Promega, catalog no. V9510), and the plate was incubated for 25 min at room temperature. The final concentrations of reaction components were: 100 mM potassium phosphate at pH 7.4, 4 nM (luciferin-IPA as the substrate) or 10 nM (luciferin-PPXE as the substrate) CYP3A4 / 5 / 7, 3 µM luciferin-IPA or 25µM luciferin-PPXE substrate, 0.00017—60 µM of the test compound. The reaction was quenched by adding 25 µL of luciferin detection reagent supplied in the P450-Glo kit, and the mixture was incubated at room temperature for additional 20 min. Luminescence signals were determined with an EnVision Multimode Plate Reader (PerkinElmer, Waltham, MA). The experiment at each compound concentration was repeated three times, except for the primary high-throughput screening which was carried out once at 10 µM final compound concentration.

[0357] The luminescence signals were normalized to DMSO (set as 0% inhibition) and 30 µM ketoconazole or 15 μM ritonavir (set as 100% inhibition) within each plate. The resulting percentage inhibition values were analyzed by plot percentage inhibition against the log10[compound] and fitted to equation 1 in GraphPad Prism (GraphPad, San Diego, CA): (1) where top and bottom are minimaa a u pe ce age o va ues, respectively, and the hill slope is the factor for possible non-single-site binding events. d. P450-GLO CELL-BASED INHIBITION ASSAY

[0358] The P450-Glo cell-based inhibition assay was performed as previously reported (Wang, J.; et al., (2021) J Am Chem Soc 143 (44), 18467-18480). The 293T / 17 cell line 138Attorney Docket No.19116.0058P1 (catalog no. CRL-11268) used for this assay was obtained from the American Type Culture Collection (Manassas, VA), and the cell line was authenticated by short tandem repeat DNA profiling. The cells were maintained in growth medium (Dulbecco Modified Eagle Medium with 10% fetal bovine serum) in a humidified atmosphere at 37 °C with 5% CO2and verified to be mycoplasma free with the MycoProbe Mycoplasma Detection Kit (R&D Systems, Minneapolis, MN). Cell counts were obtained with a Countess II Automated Cell Counter (Thermo Fisher Scientific) and trypan blue exclusion staining.

[0359] The transfection mixture was prepared by mixing 90 µL of FuGENE 6 transfection reagent (Promega, catalog no. E2692) and 30 µg of pcDNA3 plasmids encoding ZsGreen1- IRES-CYP3A4 or ZsGreen1-IRES-CYP3A5 in 2 mL Opti-MEM I Reduced Serum Medium (Thermo Fisher Scientific) for 15 min at room temperature (Wang, J.; et al., (2021) J Am Chem Soc 143 (44), 18467-18480). The 2 mL mixture was subsequently added to a 10 cm tissue culture-treated dish plated with 10×106293T / 17 cells in 8 mL growth medium. The medium was replaced with 10 mL fresh growth medium 24 hours post transfection, and the cells were trypsinized and diluted in fresh growth medium to prepare for the P450-Glo cell- based inhibition assay 48 hours post transfection.

[0360] The inhibition assa...

Claims

Attorney Docket No.19116.0058P1 CLAIMS What is claimed is:

1. A compound having a structure represented by a formula: , wherein R1is selected from hydroge a – 2Ar1; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R2is selected from –NR10Ar2, –CH2Cy1, and Cy2; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) 178Attorney Docket No.19116.0058P1 dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5- membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, provided that when R2is –NR10Ar2, then at least one of R1and R10is not hydrogen, and provided that the compound is not: .

2. The compound of claim 1, wherein R1is hydrogen.

3. The compound of claim 1, wherein R1is –CH2Ar1.

4. The compound of claim 3, wherein Ar1is selected from C6 aryl and C2-C5, 6- membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 179Attorney Docket No.19116.0058P1 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

5. The compound of claim 3, wherein Ar1is C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

6. The compound of claim 3, wherein Ar1is C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

7. The compound of claim 3, wherein Ar1is C6 aryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

8. The compound of any one of claims 1 to 7, wherein R2is–NR10Ar2.

9. The compound of claim 8, wherein R10is hydrogen.

10. The compound of claim 8, wherein R10is –CH2Ar3.

11. The compound of claim 10, wherein Ar3is selected from C6 aryl and C2-C4, 6- membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

12. The compound of claim 10, wherein Ar3is C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, 180Attorney Docket No.19116.0058P1 C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

13. The compound of claim 10, wherein Ar3is C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

14. The compound of claim 10, wherein Ar3is C6 aryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

15. The compound of claim 8, wherein Ar2is selected from C6 aryl and C2-C4, 6- membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

16. The compound of claim 8, wherein Ar2is C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

17. The compound of claim 8, wherein Ar2is C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

18. The compound of claim 8, wherein Ar2is C6 aryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 181Attorney Docket No.19116.0058P1 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

19. The compound of any one of claims 1 to 7, wherein R2is –CH2Cy1.

20. The compound of claim 19, wherein Cy1is selected from C3-C6 cycloalkyl and C2- C4 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

21. The compound of claim 19, wherein Cy1is selected from C6 aryl and 5- and 6- membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

22. The compound of any one of claims 1 to 7, wherein R2is Cy2.

23. The compound of claim 22, wherein Cy2is selected from C3-C6 cycloalkyl and C2- C4 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

24. The compound of claim 22, wherein Cy2is a C3-C6 cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

25. The compound of claim 22, wherein Cy2is an unsubstituted C3-C6 cycloalkyl. 182Attorney Docket No.19116.0058P1 26. The compound of claim 22, wherein Cy2is a 5-membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1- C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

27. The compound of claim 22, wherein Cy2is an unsubstituted 5-membered heteroaryl.

28. 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: ,183Attorney Docket No.19116.0058P1 or a pharmaceutically acceptable salt thereof.

31. The compound of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptablesa e eo .

32. The compound of claim 1, wherein the compound is selected from: , , ,184Attorney Docket No.19116.0058P1 CF3O , or a pharaceu ca y accep a e sa e eo .

33. A pharmaceutical composition comprising an effective amount of a compound having a structure represented by a formula: , wherein R1is selected from hydrogen and –CH2Ar1; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R2is selected from –NR10Ar2, –CH2Cy1, and Cy2; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; 185Attorney Docket No.19116.0058P1 wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5- membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

34. The pharmaceutical composition of claim 33, wherein the compound has a structure represented by a formula: ,or a pharmaceutically acceptable salt thereof.

35. The pharmaceutical composition of claim 33, wherein the compound is selected from: 186Attorney Docket No.19116.0058P1 , , , ,or a pharmaceutically acceptable salt thereof.

36. The pharmaceutical composition of any one of claims 33 to 35, wherein the pharmaceutical composition further comprises a drug that is a substrate of a P450 enzyme. 187Attorney Docket No.19116.0058P1 37. The pharmaceutical composition of claim 36, wherein the drug is nirmatrelvir, darunavir, lopinavir, everolimus, quetiapine, testosterone, vincristine, atazanavir, indinavir, docetaxel, or tacrolimus.

38. The pharmaceutical composition of claim 36, wherein the P450 enzyme is selected from CYP3A4, CYP3A5, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A7.

39. The pharmaceutical composition of claim 36, wherein the P450 enzyme is CYP3A4.

40. The pharmaceutical composition of claim 36, wherein the P450 enzyme is selected from CYP3A5, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A7.

41. A method of inhibiting CYP3A4 in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula: , herein R1w is selected from hydrogen and –CH2Ar1; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R2is selected from –NR10Ar2, –CH2Cy1, and Cy2; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 188Attorney Docket No.19116.0058P1 C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5- membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof.

42. The method of claim 41, wherein the cell is mammalian.

43. The method of claim 41, wherein the cell is human.

44. The method of claim 41, wherein the cell has been isolated from a mammal prior to the contacting step.

45. The method of claim 41, wherein the contacting is ex vivo.

46. The method of claim 41, wherein the contacting is in vitro. 189Attorney Docket No.19116.0058P1 47. The method of claim 41, wherein contacting is via administration to a mammal.

48. The method of claim 47, wherein the mammal has been diagnosed with a need for inhibiting CYP3A4 prior to the administering step.

49. The method of claim 47, wherein the mammal has been diagnosed with a need for inhibition of CYP3A4 prior to the administering step.

50. A method of inhibiting CYP3A4 in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein R1is selected from hydrogen and –CH2Ar1; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R2is selected from –NR10Ar2, –CH2Cy1, and Cy2; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted 190Attorney Docket No.19116.0058P1 with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5- membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof.

51. The method of claim 50, wherein the subject is a mammal.

52. The method of claim 50, wherein the subject is a human.

53. The method of claim 50, wherein the subject has been diagnosed with a need for inhibiting CYP3A4 prior to the administering step.

54. The method of claim 50, further comprising identifying a subject in need of inhibition of CYP3A4.

55. A method of preventing P450 enzyme metabolism of a drug in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula: 191Attorney Docket No.19116.0058P1 , wherein R1is selected from hydroAr1; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R2is selected from –NR10Ar2, –CH2Cy1, and Cy2; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 192Attorney Docket No.19116.0058P1 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5- membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof.

56. The method of claim 55, wherein the P450 enzyme is selected from CYP3A4, CYP3A5, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A7.

57. The method of claim 55, wherein the P450 enzyme is CYP3A4.

58. The method of claim 55, wherein the P450 enzyme is selected from CYP3A5, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A7.

59. The method of claim 55, wherein the cell is mammalian.

60. The method of claim 55, wherein the cell is human.

61. The method of claim 55, wherein the cell has been isolated from a mammal prior to the contacting step.

62. The method of claim 55, wherein the contacting is ex vivo.

63. The method of claim 55, wherein the contacting is in vitro.

64. The method of claim 55, wherein contacting is via administration to a mammal.

65. The method of claim 64, wherein the mammal has been diagnosed with a need for prevention of P450 enzyme metabolism of a drug prior to the administering step.

66. The method of claim 64, wherein the mammal has been diagnosed with a need for prevention of P450 enzyme metabolism of a drug prior to the administering step. 193Attorney Docket No.19116.0058P1 67. A method of preventing P450 enzyme metabolism of a drug in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein R1is selected from hydrog Ar1; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R2is selected from –NR10Ar2, –CH2Cy1, and Cy2; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; 194Attorney Docket No.19116.0058P1 wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy2is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, and 5- membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof.

68. The method of claim 67, wherein the P450 enzyme is selected from CYP3A4, CYP3A5, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A7.

69. The method of claim 67, wherein the P450 enzyme is CYP3A4.

70. The method of claim 67, wherein the P450 enzyme is selected from CYP3A5, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A7.

71. The method of claim 67, wherein the subject is a mammal.

72. The method of claim 67, wherein the subject is a human.

73. The method of claim 67, wherein the subject has been diagnosed with a need for preventing P450 enzyme metabolism of a drug prior to the administering step.

74. The method of claim 67, further comprising identifying a subject in need of prevention of P450 enzyme metabolism of a drug.

75. A method of treating a disease or disorder 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: 195Attorney Docket No.19116.0058P1 , wherein R1is selected from hydroAr1; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R2is selected from C1-C8 alkyl, C1-C8 haloalkyl, –NR10Ar2, –CH2Cy1, and Cy3; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 196Attorney Docket No.19116.0058P1 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy3is selected from C3-C6 cycloalkyl, C2-C4 heterocycloalkyl, C6 aryl, and 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, wherein the subject has been diagnosed as needing treatment with a drug that is a P450 enzyme substrate.

76. The method of claim 75, wherein R2is selected from C1-C8 alkyl and C1-C8 haloalkyl.

77. The method of claim 75, wherein R2is selected from C1-C4 alkyl and C1-C4 haloalkyl.

78. The method of claim 75, wherein R2is Cy3.

79. The method of claim 78, wherein Cy3is selected from C6 aryl and 5- and 6- membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

80. The method of claim 78, wherein Cy3is C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. 197Attorney Docket No.19116.0058P1 81. The method of claim 78, wherein Cy3is selected from a 5- and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

82. The method of claim 75, wherein the compound is selected from: , , , ,198Attorney Docket No.19116.0058P1 CF3O Cl199Attorney Docket No.19116.0058P1 , or a parmaceut ca y accepta e sa t t ereo .

83. The method of any one of claims 75 to 82, wherein the P450 enzyme is selected from CYP3A4, CYP3A5, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A7.

84. The method of any one of claims 75 to 82, wherein the P450 enzyme is CYP3A4.

85. The method of any one of claims 75 to 82, wherein the P450 enzyme is selected from CYP3A5, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A7.

86. The method of any one of claims 75 to 85, wherein the drug is nirmatrelvir, darunavir, lopinavir, everolimus, quetiapine, testosterone, vincristine, atazanavir, indinavir, docetaxel, or tacrolimus.

87. The method of any one of claims 75 to 86, wherein the subject is a mammal.

88. The method of any one of claims 75 to 86, wherein the subject is a human.

89. The method of any one of claims 75 to 88, wherein the subject has been diagnosed with a need for treatment of the disease or disorder prior to the administering step.

90. The method of any one of claims 75 to 89, further comprising the step of identifying a subject in need of treatment of the disease or disorder.

91. The method of any one of claims 75 to 90, wherein the effective amount is a therapeutically effective amount.

92. The method of any one of claims 75 to 90, wherein the effective amount is a prophylactically effective amount. 200Attorney Docket No.19116.0058P1 93. The method of any one of claims 75 to 90, further comprising administering to the subject a drug that is a P450 enzyme substrate.

94. The method of claim 93, wherein the drug that is a P450 enzyme substrate is administered simultaneously with the compound.

95. The method of claim 93, wherein the drug that is a P450 enzyme substrate is administered sequentially with the compound.

96. The method of claim 95, wherein the drug that is a P450 enzyme substrate is administered prior to administration of the compound.

97. The method of claim 95, wherein the drug that is a P450 enzyme substrate is administered subsequent to administration of the compound.

98. The method of claim 95, wherein the drug that is a P450 enzyme substrate is administered within one week or less of administration of the compound.

99. The method of claim 95, wherein the drug that is a P450 enzyme substrate is administered within twenty-four hours or less of administration of the compound.

100. The method of claim 95, wherein the drug that is a P450 enzyme substrate is administered within twelve hours or less of administration of the compound.

101. The method of claim 95, wherein the drug that is a P450 enzyme substrate is administered within six hours or less of administration of the compound.

102. The method of claim 95, wherein the drug that is a P450 enzyme substrate is administered within one hour or less of administration of the compound.

103. The method of claim 93, wherein the drug that is a P450 enzyme substrate is co- formulated with the compound.

104. The method of claim 93, wherein a drug that is a P450 enzyme substrate has been administered to the subject before administration of the compound.

105. The method of claim 104, wherein the drug that is a P450 enzyme substrate has been administered to the subject one week or less before administration of the compound. 201Attorney Docket No.19116.0058P1 106. The method of claim 104, wherein the drug that is a P450 enzyme substrate has been administered to the subject twenty-four hours or less before administration of the compound.

107. The method of claim 104, wherein the drug that is a P450 enzyme substrate has been administered to the subject twelve hours or less before administration of the compound.

108. The method of claim 104, wherein the drug that is a P450 enzyme substrate has been administered to the subject six hours or less before administration of the compound.

109. The method of claim 104, wherein the drug that is a P450 enzyme substrate has been administered to the subject one hour or less before administration of the compound.

110. A kit comprising a compound having a structure represented by a formula: , wherein R1is selected from hydrogen and –CH2Ar1; wherein Ar1is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R2is selected from C1-C8 alkyl, C1-C8 haloalkyl, –NR10Ar2, –CH2Cy1, and Cy3; wherein R10is selected from hydrogen and –CH2Ar3; wherein Ar3is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 202Attorney Docket No.19116.0058P1 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Ar2is selected from C6-C10 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein Cy1is selected from C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6- C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Cy3is selected from C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6- C10 aryl, and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) a drug that is a P450 enzyme substrate; (b) instructions for administering the compound in combination with a drug that is a P450 enzyme substrate; (c) instructions for administering the compound to maintain efficacy of a drug that is a CYP3A4 substrate; and (d) instructions for administering the compound so as not to alter the metabolism of a drug that is a P450 enzyme substrate. 203Attorney Docket No.19116.0058P1 111. The kit of claim 110, wherein the drug that is a P450 enzyme substrate is nirmatrelvir, darunavir, lopinavir, everolimus, quetiapine, testosterone, vincristine, atazanavir, indinavir, docetaxel, or tacrolimus.

112. The kit of claim 110, wherein the drug that is a P450 enzyme substrate is darunavir, lopinavir, vincristine, atazanavir, or tacrolimus.

113. The kit of claim 110, wherein the drug that is a CYP3A4 substrate is nirmatrelvir, everolimus, quetiapine, or testosterone. 204

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