Green synthesis of unsymmetrical phosphorous disulfides

Abstract

The present disclosure is concerned with unsymnietrical phosphorus disulfide compounds and methods of making the same. 'The disclosed compounds can be useful as therapeutics, for example, anti-viral agents, anti-cancer reagents, and anti-alcoholism drugs. In addition, the disclosed methods are useful in that methods have the advantages of short reaction time, green solvent, high atom economy, and avoidance of using harsh reagents such as oxidants, chlorinating reagents, and transition metal catalysts. 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.37474.0111P1 GREEN SYNTHESIS OF UNSYMMETRICAL PHOSPHOROUS DISULFIDES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Application No.63 / 657,529, filed on June 07, 2024, the contents of which are incorporated herein by reference in their entirety. BACKGROUND

[0002] Organophosphorus and organosulfur chemistry have seen a renaissance of research interest due to its widespread applications (X. Liu, et al., Advanced Synthesis & Catalysis, 2023, 365, 2280-2298; S.-W. Rhee, et al., Journal of Labelled Compounds and Radiopharmaceuticals, 2012, 55, 197-200; R. Xie, et al., Bioorganic & Medicinal Chemistry, 2013, 21, 278-282; H. Yan, et al., Bioorganic & Medicinal Chemistry Letters, 2008, 18, 5631-5634; T. S. Kumar, et al., Journal of Medicinal Chemistry, 2013, 56, 902-914; Y. Zhang, et al., Advanced Synthesis & Catalysis, 2022, 364, 2221-2226; S. Demkowicz, et al., RSC Advances, 2016, 6, 7101-7112; U. Pradere, et al., Chemical Reviews, 2014, 114, 9154- 9218; B. K. Singh and A. Walker, FEMS Microbiology Reviews, 2006, 30, 428-471; T. Baumgartner and R. Réau, Chemical Reviews, 2006, 106, 4681-4727; C.-S. Jiang, et al., Chemical Reviews, 2012, 112, 2179-2207; l) Z. Wu and D. A. Pratt, Nature Reviews Chemistry, 2023, 7, 573-589). Especially, disulfides have received significant attention in a plethora of fields (C.-S. Jiang, et al., Chemical Reviews, 2012, 112, 2179-2207; X. Xiao, et al., Angew. Chem. Int. Ed., 2016, 55, 14121-14125; X. Xiao, et al., Nat. Commun., 2018, 9, 2191; J. Xue and X. Jiang, Nat. Commun., 2020, 11, 4170). They are prevalent in the body as oxidized cysteine residues and stabilize the secondary and tertiary protein structures (S. F. Betz, Protein Sci., 1993, 2, 1551-1558). Small molecule disulfides have been used as therapeutics; anti-viral agents, anti-cancer reagents, and anti-alcoholism drugs (C. Wright and R. D. Moore, Am. J. Med., 1990, 88, 647-655; A. Vogt, et al., J. Pharmacol. Exp. Ther., 2000, 294, 1070; J.-G. Wang, et al., Bioorg. Med. Chem., 2007, 15, 374-380; L. Wang, et al., Eur. J. Med. Chem., 2017, 137, 450-461). Naturally occurring disulfides in garlic have demonstrated antithromic, antimicrobial, and anticancer properties (E. Block, et al., J. Am. Chem. Soc., 1986, 108, 7045-7055). Furthermore, disulfides have been employed as a silaneAttorney Docket No.37474.0111P1 coupling agent to link silica filler and rubber polymer in passenger car tires to provide better fuel economy, wear and tear, and wet traction.

[0003] Therefore, much effort has been dedicated to synthesizing symmetrical and unsymmetrical disulfides (B. Mandal and B. Basu, RSC Advances, 2014, 4, 13854-13881; F. Wang, et al., Nature Communications, 2022, 13, 2588; M. Narayan, et al., Accounts of Chemical Research, 2000, 33, 805-812; D. Witt, Synthesis, 2008, 2008, 2491-2509). The synthesis of symmetrical disulfides is straightforward compared to the unsymmetrical disulfides due to the low potential side reactions. Symmetrical disulfides have been synthesized using molecular oxygen as the oxidizing agent with metal catalysts such as iron and cobalt (N. Iranpoor and B. Zeynizadeh, Synthesis, 1999, 1999, 49-50; S. M. S. Chauhan, et al., Chem. Comm.2003, 2348-2349; H. Huang, et al., Organic & Biomolecular Chemistry, 2018, 16, 4236-4242). Other oxidizing agents include iodine and hydrogen peroxide (R. Priefer, et al., J. Am. Chem. Soc., 2002, 124, 5626-5627; S. Harusawa, et al., Tetrahedron, 2004, 60, 11911-11922; A. Hatano, et al., Bioorg. Med. Chem. Lett., 2004, 14, 2459-2462). Disulfur chloride has been also utilized as a bis-electrophile to react with two equivalents of thiol which produces symmetrical disulfides through dual nucleophilic substitution (T. J. Korn and P. Knochel, Synlett, 2005, 2005, 1185-1187). Other chlorinating agents such as TMSCl and cyanuric chloride with DMSO as the oxidant have also been used to synthesize symmetric disulfides (B. Karimi, et al., Synthesis, 2002, 2002, 2513-2516).

[0004] The synthesis of unsymmetrical disulfides, however, poses more challenges due to the undesired homodimers, especially challenging in disulfide-linked glycopeptide synthesis (O. Schäfer and M. Barz, Chemistry – A European Journal, 2018, 24, 12131-12142; G. Ribeiro Morais and R. A. Falconer, Organic & Biomolecular Chemistry, 2021, 19, 82-100; G. M. Watt and G.-J. Boons, Carbohydrate Research, 2004, 339, 181-193; N. Stellenboom, et al., Tetrahedron Letters, 2010, 51, 5309-5312). A rational design of oxidative dehydrogenative coupling reaction enables unsymmetrical disulfides. This reaction employs two sterically distinct thiols to utilize the reactivity differences rendered by sterics and kinetics of oxidation (X. Qiu, et al., Organic Chemistry Frontiers, 2019, 6, 2220-2225; F. Yang, et al., Tetrahedron Lett., 2017, 58, 218-222; B. Dong, et al., Org. Biomol. Chem., 2023, 21, 930-934). Catalytic approaches to unsymmetrical disulfides have been also achieved using rhodium, palladium, and NFSI catalysts (M. Arisawa and M. Yamaguchi, J. Am. Chem. Soc., 2003, 125, 6624-6625; J. Guo, et al., Org. Lett., 2021, 23, 3167-3172; M. Song, et al., Chin Chem Lett, 2022, 33, 4269-4272). In addition, the umpolung strategy hasAttorney Docket No.37474.0111P1 been used to reduce the homodimer by-products. For example, thiol nucleophiles react with preactivated sulfur electrophiles such as sulfenamides, thiosulfonate, mercaptobenzotriazole, mercaptobenzothiazole, phosphorous disulfide, 2-pyridyl disulfide, and Bunte salts (D. N. Harpp and T. G. Back, Tetrahedron Lett., 1972, 13, 1481-1484; D. H. R. Barton, et al., Tetrahedron, 1991, 47, 6127-6138; E. Brzezinska and A. L. Ternay, Jr., J. Org. Chem., 1994, 59, 8239-8244; P. Hiver, et al., Tetrahedron Lett., 1994, 35, 9569-9572; M. Uragami, et al., Langmuir, 2000, 16, 8010-8015; R. Hunter, et al., J. Org. Chem., 2006, 71, 8268-8271; S. Antoniow and D. Witt, Synthesis, 2007, 2007, 363-366; L. Delarue Bizzini, et al., Eur. J. Org. Chem., 2019, 2019, 6956-6960; M. Bao and M. Shimizu, Tetrahedron, 2003, 59, 9655- 9659). Recently, the Jiang group has revealed a disulfurating agent in a copper-catalyzed Suzuki and Hiyama-type cross-coupling reaction to furnish disulfides (X. Xiao, et al., Angew. Chem. Int. Ed., 2016, 55, 14121-14125; Z. Dai, et al., Tetrahedron, 2017, 73, 3702-3706). Additionally, they have reported S-O bond-containing disulfurating reagents which demonstrated late-stage functionalization of biomolecules under borane catalysis (b) X. Xiao, et al., Nat. Commun., 2018, 9, 2191; J. Xue and X. Jiang, Nat. Commun., 2020, 11, 4170). Disulfurating agents have also been employed in a Sandmeyer and photocatalytic C-H functionalization reaction (S. Chen, et al., Org. Lett., 2021, 23, 7428-7433; S. Wu, et al., J. Org. Chem., 2022, 87, 16297-16306). Furthermore, the Lei group reported a direct electrochemical synthesis of disulfide without metals or oxidants. However, this strategy relies on a bulky thiol to minimize homodimer by-products (P. Huang, et al., Angew. Chem. Int. Ed., 2018, 57, 8115-8119).

[0005] Although many symmetrical and unsymmetrical disulfide syntheses have been developed, there is only one precedent example to access the unsymmetrical P(O)-S-S bond motif. The thiophosphate analogues containing the P(O)S-S unit are promising antioxidants and produgs (B. Levi Hevroni, et al., Inorganic Chemistry, 2014, 53, 1594-1605; V. Janout, et al., Bioconjugate Chemistry, 2002, 13, 351-356). The Cao group has recently reported a mechanochemical disulfur transfer between dithioperoxate and secondary phosphine oxides using ball milling to form P(O)-S-S bonds (Z. Zhang, et al., Org. Lett., 2022, 24, 7222-7226). The substrate scope to access the P(O)-S-S bond motif, however, is limited to alkyl dithioperoxate; when aryl dithioperoxates were used, an alternative thiophosphate product was generated via different reaction pathway.

[0006] As both thiophosphates and disulfides possess useful properties, small molecules containing P(O)-S-S bonds would be of interest to chemists in academia and industry.Attorney Docket No.37474.0111P1 Previous work revealed the bifunctionality P(O)(OEt)2SH, serving as both Bronsted acid and thiolate nucleophile (J. Ash and J. Y. Kang, Org. Biomol. Chem., 2023, 21, 2370-2374). Despite a rapidly growing interest in the application of aryl phosphorous disulfides (P(O)-S-S unit) a synthetic method to access aryl phosphorous disulfides (P(O)-S-S unit) remained undeveloped. Accordingly, there remains a need for rapid and green synthetic methods to access phosphorous disulfides. SUMMARY

[0007] In accordance with the purpose(s) of the invention, as embodied and broadlydescribed herein, the invention, in one aspect, relates to phosphorous disulfide compounds and methods for making the same. The disclosed compounds can be useful as therapeutics, for example, anti-viral agents, anti-cancer reagents, and anti-alcoholism drugs. In addition, the disclosed methods are useful in that methods have the advantages of short reaction time, green solvent, high atom economy, and avoidance of using harsh reagents such as oxidants, chlorinating reagents, and transition metal catalysts.

[0008] Thus, disclosed are methods for making a compound having a structure representedby a formula:, wherein A is selected from O, S, and Se; wherein R1is selected from C1-C8 alkyl, – C(O)(C1-C8 alkyl), Cy1, and –CH2Cy1; wherein Cy1is selected from C3-C6 cycloalkyl, C2- C5 heterocycloalkyl, C6-C14 aryl, and C2-C10 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 each of R2and R3is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, ‒O(C2-C4 alkenyl), ‒O(C2-C4 alkynyl), and ‒OC6H5, or wherein R2and R3are covalently bonded and, together with the intermediate atoms, comprise a 5-membered ring having a structure represented by a formula selected from:Attorney Docket No.37474.0111P1wherein Q is selected from O, S, and NR20; wherein R20, when present, is selected from hydrogen, C1-C4 alkyl, and Ar1; wherein Ar1, when present, is 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-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and unsubstituted phenyl; wherein each of R10a, R10b, and R11is independently selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1; or wherein R10ais selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R10band R11are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, 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 R12is selected from hydrogen, C1-C4 alkyl, and Ar1; or wherein each of R10aand R10bis independently selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R11and R12are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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, or a salt thereof, the method comprising reacting a N-thiosuccinimide having a structure represented by a formula:Attorney Docket No.37474.0111P1, and a thioacid nucleophile having a structure represented by a formula:.

[0009] Also disclosed are compounds having a structure represented by a formula:, wherein A is selected from O, S, and Se; wherein R1is selected from C1-C8 alkyl, – C(O)(C1-C8 alkyl), Cy1, and –CH2Cy1; wherein Cy1is selected from C3-C6 cycloalkyl, C2- C5 heterocycloalkyl, C6-C14 aryl, and C2-C10 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 each of R2and R3is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, ‒O(C2-C4 alkenyl), ‒O(C2-C4 alkynyl), and ‒OC6H5, or wherein R2and R3are covalently bonded and, together with the intermediate atoms, comprise a 5-membered ring having a structure represented by a formula selected from:Attorney Docket No.37474.0111P1wherein Q is selected from O, S, and NR20; wherein R20, when present, is selected from hydrogen, C1-C4 alkyl, and Ar1; wherein Ar1, when present, is 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, (C1-C4)(C1-C4) dialkylamino, and unsubstituted phenyl; wherein each of R10a, R10b, and R11is independently selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1; or wherein R10ais selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R10band R11are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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; and wherein R12is selected from hydrogen, C1-C4 alkyl, and Ar1; or wherein each of R10aand R10bis independently selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R11and R12are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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, or a salt thereof.

[0010] Also disclosed are kits comprising: (a) a N-thiosuccinimide having a structure represented by a formula:,Attorney Docket No.37474.0111P1 wherein R1is selected from C1-C8 alkyl, –C(O)(C1-C8 alkyl), Cy1, and –CH2Cy1; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C14 aryl, and C2-C10 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; a thioacid nucleophile having a structure represented by a formula:, wherein A is selected from O and S; wherein each of R2and R3is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, ‒O(C2-C4 alkenyl), ‒O(C2-C4 alkynyl), and ‒OC6H5, or wherein R2and R3are covalently bonded and, together with the intermediate atoms, comprise a 5-membered ring having a structure represented by a formula selected from:wherein Q is selected from O, S, and NR20; wherein R20, when present, is selected from hydrogen, C1-C4 alkyl, and Ar1; wherein Ar1, when present, is 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-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and unsubstituted phenyl; wherein each of R10a, R10b, and R11is independently selected from hydrogen, C1-C4 alkyl,Attorney Docket No.37474.0111P1 Ar1, and ‒CH2Ar1; or wherein R10ais selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R10band R11are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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; and wherein R12is selected from hydrogen, C1-C4 alkyl, and Ar1; or wherein each of R10aand R10bis independently selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R11and R12are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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; and (b) a protic solvent.

[0011] 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

[0012] 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.

[0013] FIG.1 shows a pictorial description of reaction tubes for the reaction.

[0014] FIG.2 shows representative structures of the scope of N-thiosuccinimide electrophiles.Attorney Docket No.37474.0111P1

[0015] FIG.3 shows representative structures of the scope of thioacid nucleophiles.

[0016] 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

[0017] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

[0018] 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.

[0019] 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.

[0020] 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 referencesAttorney Docket No.37474.0111P1 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

[0021] 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.

[0022] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of” and “consisting essentially of.”

[0023] 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.

[0024] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factorsAttorney Docket No.37474.0111P1 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0029] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissibleAttorney Docket No.37474.0111P1 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).

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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.Attorney Docket No.37474.0111P1 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.

[0034] 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.

[0035] 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 or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.Attorney Docket No.37474.0111P1

[0036] The term “polyalkylene group” as used herein is a group having two or more CH2groups 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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 alkynylAttorney Docket No.37474.0111P1 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.

[0041] 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.

[0042] 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.

[0043] 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 fusedAttorney Docket No.37474.0111P1 ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] The term “dialkylamino” as used herein is represented by the formula —N(-alkyl)2where 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.

[0048] The term “carboxylic acid” as used herein is represented by the formula —C(O)OH.

[0049] 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.

[0050] The term “ether” as used herein is represented by the formula A1OA2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,Attorney Docket No.37474.0111P1 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.

[0051] The terms “halo,” “halogen,” or “halide” as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0052] 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.

[0053] 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.

[0054] 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.Attorney Docket No.37474.0111P1

[0055] 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.

[0056] 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.Attorney Docket No.37474.0111P1

[0057] 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.

[0058] The term “hydroxyl” or “hydroxyl” as used herein is represented by the formula — OH.

[0059] 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.

[0060] The term “azide” or “azido” as used herein is represented by the formula —N3.

[0061] The term “nitro” as used herein is represented by the formula —NO2.

[0062] The term “nitrile” or “cyano” as used herein is represented by the formula —CN.

[0063] 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.

[0064] 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.

[0065] The term “thiol” as used herein is represented by the formula —SH.Attorney Docket No.37474.0111P1

[0066] “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.

[0067] 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).

[0068] 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.

[0069] Suitable monovalent substituents on a substitutable carbon atom of an “optionallysubstituted” group are independently halogen; –(CH2)0–4R ; –(CH2)0–4OR ; -O(CH2)0-4Ro, –which may besubstituted 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 substitutedwith 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–Attorney Docket No.37474.0111P14OC(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 –(C1–4 straight or branched alkylene)C(O)O–N(R )2, wherein each R may be substitutedas 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 withtheir 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.

[0070] Suitable monovalent substituents on R (or the ring formed by taking twoindependent occurrences of R together with their intervening atoms), are independentlyhalogen, –-O(haloR2SR , –(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 isunsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from 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. Suitable divalent substituents on a saturated carbon atom ofR include =O and =S.

[0071] 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, C1–6aliphatic which may beAttorney Docket No.37474.0111P1 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.

[0072] 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 ormore 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.

[0073] 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, C1–6aliphatic 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.

[0074] 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 withone 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.

[0075] 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.

[0076] 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,Attorney Docket No.37474.0111P1 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).

[0077] The term “organic residue” defines a carbon-containing residue, i.e., a residuecomprising 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.

[0078] A very close synonym of the term “residue” is the term “radical,” which as used inthe specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4- thiazolidinedione radical in a particular compound has the structure:, regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyl) can be further modified (i.e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

[0079] “Organic radicals,” as the term is defined and used herein, contain one or morecarbon 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-Attorney Docket No.37474.0111P1 naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, 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.

[0080] 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.

[0081] 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.

[0082] 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-Attorney Docket No.37474.0111P1 superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0083] 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.

[0084] 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 theAttorney Docket No.37474.0111P1 presence of a particular enantiomer at greater than 50%, for example, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%. In one aspect, the designated enantiomer is substantially free from the other enantiomer. For example, the “R” forms of the compounds can be substantially free from the “S” forms of the compounds and are, thus, in enantiomeric excess of the “S” forms. Conversely, “S” forms of the compounds can be substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the “R” forms.

[0085] 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.

[0086] 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.

[0087] “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.Attorney Docket No.37474.0111P1

[0088] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically- labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such 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.

[0089] 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.

[0090] 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., TheAttorney Docket No.37474.0111P1 Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p- toluenesulfonic acid and benzenesulfonic acid.

[0091] It is also appreciated that certain compounds described herein can be present as anequilibrium of tautomers. For example, ketones with an α-hydrogen can exist in an equilibrium of the keto form and the enol form.

[0092] Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide formand 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 contrary, the invention includes all such possible tautomers.

[0093] It is known that chemical substances form solids, which are present in differentstates 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.

[0094] In some aspects, a structure of a compound can be represented by a formula:, which is understood to be equivalent to a formula:Attorney Docket No.37474.0111P1, 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.

[0095] Certain materials, compounds, compositions, and components disclosed herein canbe obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Strem Chemicals (Newburyport, MA), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0096] Unless otherwise expressly stated, it is in no way intended that any method set forthherein 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.

[0097] Disclosed are the components to be used to prepare the compositions of theinvention 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 whenAttorney Docket No.37474.0111P1 combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[0098] 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

[0099] In one aspect, the invention relates to unsymmetrical phosphorous disulfides compounds. The disclosed phosphorous disulfides can be used as therapeutics (e.g., anti- viral agents, anti-cancer reagents, and anti-alcoholism drugs).

[0100] 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.Attorney Docket No.37474.0111P1 1. STRUCTURE

[0101] In one aspect, disclosed are compounds having a structure represented by a formula:, wherein A is selected from O, S, and Se; wherein R1is selected from C1-C8 alkyl, – C(O)(C1-C8 alkyl), Cy1, and –CH2Cy1; wherein Cy1is selected from C3-C6 cycloalkyl, C2- C5 heterocycloalkyl, C6-C14 aryl, and C2-C10 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 each of R2and R3is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, ‒O(C2-C4 alkenyl), ‒O(C2-C4 alkynyl), and ‒OC6H5, or wherein R2and R3are covalently bonded and, together with the intermediate atoms, comprise a 5-membered ring having a structure represented by a formula selected from:wherein Q is selected from O, S, and NR20; wherein R20, when present, is selected from hydrogen, C1-C4 alkyl, and Ar1; wherein Ar1, when present, is 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-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and unsubstituted phenyl;Attorney Docket No.37474.0111P1 wherein each of R10a, R10b, and R11is independently selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1; or wherein R10ais selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R10band R11are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, 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 R12is selected from hydrogen, C1-C4 alkyl, and Ar1; or wherein each of R10aand R10bis independently selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R11and R12are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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, or a salt thereof.

[0102] In various aspects, the compound has a structure represented by a formula:, or a salt thereof.

[0103] In various aspects, the compound has a structure represented by a formula:, or a salt thereof.

[0104] In various aspects, the compound has a structure represented by a formula:Attorney Docket No.37474.0111P1, wherein n is selected from 0 and 1; and wherein each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, provided that at least two of R13a, R13b, R13c, R13d, and R13eare hydrogen, or a salt thereof.or a salt thereof.

[0105] In various aspects, the compound has a structure represented by a formula:, or a salt thereof.

[0106] In various aspects, the compound has a structure represented by a formula:, or a salt thereof.

[0107] In various aspects, the compound has a structure represented by a formula:, or a salt thereof.

[0108] In various aspects, the compound has a structure represented by a formula:Attorney Docket No.37474.0111P1, or a salt thereof.

[0109] In various aspects, the compound has a structure represented by a formula:,or a salt thereof.

[0110] In various aspects, compound is selected from:,,Attorney Docket No.37474.0111P1or a salt thereof.Attorney Docket No.37474.0111P1 a. A GROUPS

[0111] In one aspect, A is selected from O, S, and Se. In a further aspect, A is selected from O and S. In a still further aspect, A is selected from S and Se. In a yet further aspect, A is selected from O and Se. In an even further aspect, A is O. In an even still further aspect, A is S. In yet an even further aspect, A is Se. b. Q GROUPS

[0112] In one aspect, Q is selected from O, S, and NR20. In a further aspect, Q is selected from O and S. In a still further aspect, Q is selected from O and NR20. In yet a further aspect, Q is selected from S and NR20. In an even further aspect, Q is O. In a still further aspect, Q is S. In yet a further aspect, Q is NR20. c. R1GROUPS

[0113] In one aspect, R1is selected from C1-C8 alkyl, –C(O)(C1-C8 alkyl), Cy1, and – CH2Cy1. In a further aspect, R1is selected from C1-C4 alkyl, –C(O)(C1-C4 alkyl), Cy1, and –CH2Cy1. In a still further aspect, R1is selected from methyl, ethyl, n-propyl, isopropyl, – C(O)(methyl), –C(O)(ethyl), –C(O)(n-propyl), –C(O)(isopropyl), Cy1, and –CH2Cy1. In yet a further aspect, R1is selected from methyl, ethyl, –C(O)(methyl), –C(O)(ethyl), Cy1, and – CH2Cy1. In an even further aspect, R1is selected from methyl, –C(O)(methyl), Cy1, and – CH2Cy1.

[0114] In various aspects, R1is selected from C1-C8 alkyl and –C(O)(C1-C8 alkyl). In a further aspect, R1is selected from C1-C4 alkyl and –C(O)(C1-C4 alkyl. In a still further aspect, R1is selected from methyl, ethyl, n-propyl, isopropyl, –C(O)(methyl), –C(O)(ethyl), – C(O)(n-propyl), and –C(O)(isopropyl). In yet a further aspect, R1is selected from methyl, ethyl, –C(O)(methyl), and –C(O)(ethyl). In an even further aspect, R1is selected from methyl, and –C(O)(methyl).

[0115] In various aspects, R1is C1-C8 alkyl. In a further aspect, R1is C1-C4 alkyl. In a still further aspect, R1is selected from methyl, ethyl, n-propyl, and isopropyl. In yet a further aspect, R1is selected from methyl and ethyl. In an even further aspect, R1is from methyl.

[0116] In various aspects, R1is –C(O)(C1-C8 alkyl). In a further aspect, R1is –C(O)(C1- C4 alkyl. In a still further aspect, R1is selected from –C(O)(methyl), –C(O)(ethyl), –C(O)(n- propyl), and –C(O)(isopropyl). In yet a further aspect, R1is selected from –C(O)(methyl), and –C(O)(ethyl). In an even further aspect, R1is –C(O)(methyl).Attorney Docket No.37474.0111P1

[0117] In various aspects, R1 is selected from Cy1 and –CH2Cy1. In a futher aspect, R1 isCy1. In a still further aspect, R1is s–CH2Cy1. d. R2 AND R3 GROUPS

[0118] In one aspect, each of R2 and R3 is independently selected from C1-C4 alkyl, C2-C4alkenyl, C1-C4 alkoxy, ‒O(C2-C4 alkenyl), ‒O(C2-C4 alkynyl), and ‒OC6H5, or R2and R3are covalently bonded and, together with the intermediate atoms, comprise a 5-membered ring having a structure represented by a formula selected from:

[0119] In variouos aspects, each of R2 and R3 is independently selected from C1-C4 alkyl,C2-C4 alkenyl, C1-C4 alkoxy, ‒O(C2-C4 alkenyl), ‒O(C2-C4 alkynyl), and ‒OC6H5. In a further aspect, each of R2and R3is independently selected from methyl, ethyl, n-propyl, i- propyl, ethenyl, propenyl, isopropenyl, –OCH3, –OCH2CH3, –OCH2CH2CH3, – OCH(CH3)CH3, –OCH=CH2, –OCH=CHCH3, –OCH2CH=CH2, ‒OC≡CH, ‒OC≡CCH3, ‒OCH2C≡CH, and ‒OC6H5. In a still further aspect, each of R2and R3is independently selected from methyl, ethyl, ethenyl, –OCH3, –OCH2CH3–OCH=CH2, ‒OC≡CH, and ‒OC6H5. In yet a further aspect, each of R2and R3is independently selected from methyl, – OCH3, and ‒OC6H5.

[0120] In various aspects, each of R2 and R3 is independently selected from C1-C4 alkyland C2-C4 alkenyl. In a further aspect, each of R2and R3is independently selected from methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, and isopropenyl. In a still further aspect, each of R2and R3is independently selected from methyl, ethyl, and ethenyl. In yet a further aspect, each of R2and R3is methyl.Attorney Docket No.37474.0111P1

[0121] In variouos aspects, each of R2 and R3 is independently selected from C1-C4alkoxy, ‒O(C2-C4 alkenyl), ‒O(C2-C4 alkynyl), and ‒OC6H5. In a further aspect, each of R2and R3is independently selected from –OCH3, –OCH2CH3, –OCH2CH2CH3, – OCH(CH3)CH3, –OCH=CH2, –OCH=CHCH3, –OCH2CH=CH2, ‒OC≡CH, ‒OC≡CCH3, ‒OCH2C≡CH, and ‒OC6H5. In a still further aspect, each of R2and R3is independently selected from –OCH3, –OCH2CH3–OCH=CH2, ‒OC≡CH, and ‒OC6H5. In yet a further aspect, each of R2and R3is independently selected from –OCH3, and ‒OC6H5.

[0122] In variouos aspects, each of R2 and R3 is independently selected from C1-C4alkoxy, ‒O(C2-C4 alkenyl), ‒O(C2-C4 alkynyl), and ‒OC6H5. In a further aspect, each of R2and R3is independently selected from –OCH3, –OCH2CH3, –OCH2CH2CH3, – OCH(CH3)CH3, –OCH=CH2, –OCH=CHCH3, –OCH2CH=CH2, ‒OC≡CH, ‒OC≡CCH3, ‒OCH2C≡CH, and ‒OC6H5. In a still further aspect, each of R2and R3is independently selected from –OCH3, –OCH2CH3–OCH=CH2, ‒OC≡CH, and ‒OC6H5. In yet a further aspect, each of R2and R3is independently selected from –OCH3and ‒OC6H5.

[0123] In various aspects, each of R2 and R3 is ethoxy.

[0124] In various aspects, each of R2 and R3 is the same.

[0125] In various aspects, R2 and R3 are covalently bonded and, together with theintermediate atoms, comprise a 5-membered ring having a structure represented by a formula selected from:e. R10A, R10B, AND R11 GROUPS

[0126] In one aspect, each of R10a, R10b, and R11 is independently selected from hydrogen,C1-C4 alkyl, Ar1, and ‒CH2Ar1; or R10ais selected from hydrogen, C1-C4 alkyl, Ar1, andAttorney Docket No.37474.0111P1 ‒CH2Ar1, and R10band R11are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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 or each of R10aand R10bis independently selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R11and R12are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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.

[0127] In various aspects, each of R10a, R10b, and R11is independently selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1. In a further aspect, each of R10a, R10b, and R11is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, Ar1, and ‒CH2Ar1. In a still further aspect, each of R10a, R10b, and R11is independently selected from hydrogen, methyl, ethyl, Ar1, and ‒CH2Ar1. In yet a further aspect, each of R10a, R10b, and R11is independently selected from hydrogen, methyl, Ar1, and ‒CH2Ar1.

[0128] In various aspects, each of R10a, R10b, and R11is independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each of R10a, R10b, and R11is independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, each of R10a, R10b, and R11is independently selected from hydrogen, methyl, ethyl. In yet a further aspect, each of R10a, R10b, and R11is independently selected from hydrogen and methyl.

[0129] In various aspects, each of R10a, R10b, and R11is independently selected from hydrogen Ar1, and ‒CH2Ar1.

[0130] In various aspects, R10ais selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R10band R11are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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.Attorney Docket No.37474.0111P1

[0131] In various aspects, R10ais selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1. In a further aspect, R10ais selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, Ar1, and ‒CH2Ar1. In a still further aspect, R10ais selected from hydrogen, methyl, ethyl, Ar1, and ‒CH2Ar1. In yet a further aspect, R10ais selected from hydrogen, methyl, Ar1, and ‒CH2Ar1.

[0132] In various aspects, R10band R11are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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, R10band R11are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, – CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R10band R11are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered cycloalkyl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, R10band R11are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered cycloalkyl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, R10band R11are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered cycloalkyl, and is unsubstituted. f. R12GROUPS

[0133] In one aspect, R12is selected from hydrogen, C1-C4 alkyl, and Ar1. In a further aspect, R12is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and Ar1. In a still further aspect, R12is selected from hydrogen, methyl, ethyl, and Ar1. In yet a further aspect, R12is selected from hydrogen, methyl, and Ar1.Attorney Docket No.37474.0111P1

[0134] In various aspects, R12is selected from hydrogen and C1-C4 alkyl. In a further aspect, R12is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R12is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R12is selected from hydrogen and methyl. In a further aspect, R12is methyl.

[0135] In various aspects, R12is selected from hydrogen and Ar1. In a further aspect, R12is hydrogen. In a still further aspect, R12is Ar1.

[0136] In various aspects, R11and R12are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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, R11and R12are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, – CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R11and R12are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered cycloalkyl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, R11and R12are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered cycloalkyl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, R11and R12are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered cycloalkyl, and is unsubstituted.R13A, R13B, R13C, R13D, AND R13EGROUPS

[0137] In one aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-Attorney Docket No.37474.0111P1 C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and unsubstituted phenyl, provided that at least two of R13a, R13b, R13c, R13d, and R13eis hydrogen. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, –NO2, –CN, –OH, – SH, –NH2, methyl, ethyl, n-propyl, isopropyl, ethenyl, propenyl, isopropenyl, −CH2F, −CH2CH2F, −CH2CH2CH2F, −CH(CH3)CH2F, −CH2Cl, −CH2CH2Cl, −CH2CH2CH2Cl, −CH(CH3)CH2Cl, −CH2CN, −CH2CH2CN, −CH2CH2CH2CN, −CH(CH3)CH2CN, −CH2OH, −CH2CH2OH, −CH2CH2CH2OH, −CH(CH3)CH2OH, −OCF3, −OCHF3, −OCH2F, −OCH2CH2F, −OCH2CH2CH2F, −OCH(CH3)CH2F, −OCH3, −OCH2CH3, −OCH2CH2CH3, −OCH(CH3)2, −NHCH3, −NHCH2CH3, −NHCH2CH2CH3, −NHCH(CH3)2, −N(CH3)2, −N(CH3)CH2CH3, −N(CH3)CH2CH2CH3, −N(CH3)CH(CH3)2, −CH2NH2, −CH2CH2NH2, −CH2CH2CH2NH2, −CH(CH3)CH2NH2, and unsubstituted phenyl. In a still further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, –NO2, –CN, –OH, –SH, –NH2, methyl, ethyl, ethenyl, −CH2F, −CH2CH2F, −CH2Cl, −CH2CH2Cl, −CH2CN, −CH2CH2CN, −CH2OH, −CH2CH2OH, −OCF3, −OCHF3, −OCH2F, −OCH2CH2F, −OCH3, −OCH2CH3, −NHCH3, −NHCH2CH3, −N(CH3)2, −N(CH3)CH2CH3, −CH2NH2, −CH2CH2NH2, and unsubstituted phenyl. In yet a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, –NO2, –CN, –OH, –SH, –NH2, methyl, −CH2F, −CH2Cl, −CH2CN, −CH2OH, −OCF3, −OCHF3, −OCH2F, −OCH3, −NHCH3, −N(CH3)2, −CH2NH2, and unsubstituted phenyl.

[0138] In various aspects, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and unsubstituted phenyl. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, –NO2, –CN, –OH, –SH, –NH2, methyl, ethyl, n-propyl, isopropyl, ethenyl, propenyl, isopropenyl, −CH2OH, −CH2CH2OH, −CH2CH2CH2OH, −CH(CH3)CH2OH, −OCH3, −OCH2CH3, −OCH2CH2CH3, −OCH(CH3)2, −NHCH3, −NHCH2CH3, −NHCH2CH2CH3, −NHCH(CH3)2, −N(CH3)2, −N(CH3)CH2CH3, −N(CH3)CH2CH2CH3, −N(CH3)CH(CH3)2, −CH2NH2, −CH2CH2NH2, −CH2CH2CH2NH2, −CH(CH3)CH2NH2, and unsubstituted phenyl. In a still further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, –NO2, –CN, –OH, –SH, –NH2, methyl, ethyl,Attorney Docket No.37474.0111P1 ethenyl, −CH2OH, −CH2CH2OH, −OCH3, −OCH2CH3, −NHCH3, −NHCH2CH3, −N(CH3)2, −N(CH3)CH2CH3, −CH2NH2, −CH2CH2NH2, and unsubstituted phenyl. In yet a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, –NO2, –CN, –OH, –SH, –NH2, methyl, −CH2OH, −OCH3, −NHCH3, −N(CH3)2, −CH2NH2, and unsubstituted phenyl.

[0139] In various aspects, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, –NO2, –CN, – OH, –SH, –NH2, methyl, ethyl, n-propyl, isopropyl, ethenyl, propenyl, isopropenyl, −CH2F, −CH2CH2F, −CH2CH2CH2F, −CH(CH3)CH2F, −CH2Cl, −CH2CH2Cl, −CH2CH2CH2Cl, −CH(CH3)CH2Cl, −CH2CN, −CH2CH2CN, −CH2CH2CH2CN, −CH(CH3)CH2CN, −NHCH3, −NHCH2CH3, −NHCH2CH2CH3, −NHCH(CH3)2, −N(CH3)2, −N(CH3)CH2CH3, −N(CH3)CH2CH2CH3, −N(CH3)CH(CH3)2, −CH2NH2, −CH2CH2NH2, −CH2CH2CH2NH2, and −CH(CH3)CH2NH2. In a still further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, –NO2, –CN, –OH, – SH, –NH2, methyl, ethyl, ethenyl, −CH2F, −CH2CH2F, −CH2Cl, −CH2CH2Cl, −CH2CN, −CH2CH2CN, −NHCH3, −NHCH2CH3, −N(CH3)2, −N(CH3)CH2CH3, −CH2NH2, and −CH2CH2NH2. In yet a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, –NO2, –CN, –OH, – SH, –NH2, methyl, −CH2F, −CH2Cl, −CH2CN, −NHCH3, −N(CH3)2, and −CH2NH2.

[0140] In various aspects, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, –NO2, –CN, –OH, – SH, –NH2, methyl, ethyl, n-propyl, isopropyl, ethenyl, propenyl, isopropenyl, −CH2F, −CH2CH2F, −CH2CH2CH2F, −CH(CH3)CH2F, −CH2Cl, −CH2CH2Cl, −CH2CH2CH2Cl, −CH(CH3)CH2Cl, −CH2CN, −CH2CH2CN, −CH2CH2CH2CN, −CH(CH3)CH2CN, −CH2OH, −CH2CH2OH, −CH2CH2CH2OH, −CH(CH3)CH2OH, −OCF3, −OCHF3, −OCH2F, −OCH2CH2F, −OCH2CH2CH2F, −OCH(CH3)CH2F, −OCH3, −OCH2CH3, −OCH2CH2CH3, and −OCH(CH3)2. In a still further aspect, each of R13a, R13b, R13c, R13d, and R13eisAttorney Docket No.37474.0111P1 independently selected from the group consisting of hydrogen, halogen, –NO2, –CN, –OH, – SH, –NH2, methyl, ethyl, ethenyl, −CH2F, −CH2CH2F, −CH2Cl, −CH2CH2Cl, −CH2CN, −CH2CH2CN, −CH2OH, −CH2CH2OH, −OCF3, −OCHF3, −OCH2F, −OCH2CH2F, −OCH3, and −OCH2CH3. In yet a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, –NO2, –CN, –OH, – SH, –NH2, methyl, −CH2F, −CH2Cl, −CH2CN, −CH2OH, −OCF3, −OCHF3, −OCH2F, and −OCH3.

[0141] In various aspects, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, ethenyl, propenyl, isopropenyl, −CH2OH, −CH2CH2OH, −CH2CH2CH2OH, −CH(CH3)CH2OH, −OCH3, −OCH2CH3, −OCH2CH2CH3, −OCH(CH3)2, −NHCH3, −NHCH2CH3, −NHCH2CH2CH3, −NHCH(CH3)2, −N(CH3)2, −N(CH3)CH2CH3, −N(CH3)CH2CH2CH3, −N(CH3)CH(CH3)2, −CH2NH2, −CH2CH2NH2, −CH2CH2CH2NH2, and −CH(CH3)CH2NH2. In a still further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, ethenyl, −CH2OH, −CH2CH2OH, −OCH3, −OCH2CH3, −NHCH3, −NHCH2CH3, −N(CH3)2, −N(CH3)CH2CH3, −CH2NH2, and −CH2CH2NH2. In yet a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, methyl, −CH2OH, −OCH3, −NHCH3, −N(CH3)2, and −CH2NH2.

[0142] In various aspects, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, ethenyl, propenyl, isopropenyl, −CH2F, −CH2CH2F, −CH2CH2CH2F, −CH(CH3)CH2F, −CH2Cl, −CH2CH2Cl, −CH2CH2CH2Cl, −CH(CH3)CH2Cl, −CH2CN, −CH2CH2CN, −CH2CH2CH2CN, −CH(CH3)CH2CN, −NHCH3, −NHCH2CH3, −NHCH2CH2CH3, −NHCH(CH3)2, −N(CH3)2, −N(CH3)CH2CH3, −N(CH3)CH2CH2CH3, −N(CH3)CH(CH3)2, −CH2NH2, −CH2CH2NH2, −CH2CH2CH2NH2, and −CH(CH3)CH2NH2. In a still further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the groupAttorney Docket No.37474.0111P1 consisting of hydrogen, halogen, methyl, ethyl, ethenyl, −CH2F, −CH2CH2F, −CH2Cl, −CH2CH2Cl, −CH2CN, −CH2CH2CN, −NHCH3, −NHCH2CH3, −N(CH3)2, −N(CH3)CH2CH3, −CH2NH2, and −CH2CH2NH2. In yet a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, methyl, −CH2F, −CH2Cl, −CH2CN, −NHCH3, −N(CH3)2, and −CH2NH2.

[0143] In various aspects, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, ethenyl, propenyl, isopropenyl, −CH2F, −CH2CH2F, −CH2CH2CH2F, −CH(CH3)CH2F, −CH2Cl, −CH2CH2Cl, −CH2CH2CH2Cl, −CH(CH3)CH2Cl, −CH2CN, −CH2CH2CN, −CH2CH2CH2CN, −CH(CH3)CH2CN, −CH2OH, −CH2CH2OH, −CH2CH2CH2OH, −CH(CH3)CH2OH, −OCF3, −OCHF3, −OCH2F, −OCH2CH2F, −OCH2CH2CH2F, −OCH(CH3)CH2F, −OCH3, −OCH2CH3, −OCH2CH2CH3, and −OCH(CH3)2. In a still further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, ethenyl, −CH2F, −CH2CH2F, −CH2Cl, −CH2CH2Cl, −CH2CN, −CH2CH2CN, −CH2OH, −CH2CH2OH, −OCF3, −OCHF3, −OCH2F, −OCH2CH2F, −OCH3, and −OCH2CH3. In yet a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from the group consisting of hydrogen, halogen, methyl, −CH2F, −CH2Cl, −CH2CN, −CH2OH, −OCF3, −OCHF3, −OCH2F, and −OCH3.

[0144] In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis selected from the group consisting of hydrogen and halogen. In a still further aspect, each of R13a, R13b, R13c, R13d, and R13eis selected from the group consisting of hydrogen, ‒F, ‒Cl, and ‒Br. In yet a further aspect, each of R13a, R13b, R13c, R13d, and R13eis selected from the group consisting of hydrogen, ‒F, and ‒Cl. In an even further aspect, each of R13a, R13b, R13c, R13d, and R13eis selected from the group consisting of hydrogen and ‒Cl. In a still further aspect, each of R13a, R13b, R13c, R13d, and R13eis selected from the group consisting of hydrogen and ‒F.

[0145] In various aspects, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, halogen, and C1-C4 haloalkyl. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, ‒F, ‒Cl, −CH2F, −CH2CH2F, −CH2CH2CH2F, −CH(CH3)CH2F, −CH2Cl, −CH2CH2Cl, −CH2CH2CH2Cl, and −CH(CH3)CH2Cl. In a still further aspect, each of R13a, R13b, R13c, R13d, and R13eisAttorney Docket No.37474.0111P1 independently selected from hydrogen, ‒F, ‒Cl, −CH2F, −CH2CH2F, −CH2Cl, and −CH2CH2Cl. In yet a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, ‒F, ‒Cl, −CH2F, and −CH2Cl.

[0146] In various aspects, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen and unsubstituted phenyl.

[0147] In various aspects, at least two of R13a, R13b, R13c, R13d, and R13eis hydrogen. In a still further aspect, at least three of R13a, R13b, R13c, R13d, and R13eis hydrogen. In yet a further aspect, at least four of R13a, R13b, R13c, R13d, and R13eis hydrogen. In an even further aspect, each of R13a, R13b, R13c, R13d, and R13eis hydrogen. a. R20GROUPS

[0148] In one aspect, R20is selected from hydrogen, C1-C4 alkyl, and Ar1. In a further aspect, R20is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and Ar1. In a still further aspect, R20is selected from hydrogen, methyl, ethyl, and Ar1. In yet a further aspect, R20is selected from hydrogen, methyl, and Ar1.

[0149] In various aspects, R20is selected from hydrogen and C1-C4 alkyl. In a further aspect, R20is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R20is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R20is selected from hydrogen and methyl. In a further aspect, R20is methyl.

[0150] In various aspects, R20is selected from hydrogen and Ar1. In a further aspect, R20is hydrogen. In a still further aspect, R20is Ar1. b. AR1GROUPS

[0151] In one aspect, Ar1, when present, is 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, (C1-C4)(C1-C4) dialkylamino, and unsubstituted phenyl. In a further aspect, Ar1, when present, is 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, (C1-C4)(C1-C4) dialkylamino, and unsubstituted phenyl. In a still further aspect, Ar1, when present, is C6 aryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4Attorney Docket No.37474.0111P1 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and unsubstituted phenyl. In yet a further aspect, Ar1, when present, is 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, (C1-C4)(C1-C4) dialkylamino, and unsubstituted phenyl. In an even further aspect, Ar1, when present, is unsubstituted C6 aryl. c. CY1GROUPS

[0152] In one aspect, Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6- C14 aryl, and C2-C10 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-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C14 aryl, and C2-C10 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, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is unsubstituted.Attorney Docket No.37474.0111P1

[0153] In various aspects, Cy1is selected from C3-C6 cycloalkyl and C2-C5 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-C5 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, C1-C4 haloalkyl, C1- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, 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-C5 heterocycloalkyl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, 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-C5 heterocycloalkyl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, 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-C5 heterocycloalkyl, and is unsubstituted.

[0154] 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 cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and spiro[2.2]pentane. 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, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, 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, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, andAttorney Docket No.37474.0111P1 (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, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is an unsubstituted C3-C6 cycloalkyl.

[0155] In various aspects, Cy1is a C2-C5 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-C5 heterocycloalkyls include, but are not limited to, thiirane, oxirane, aziridine, thietane, azetidine, oxetane, pyrrolidine, imidazolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, piperazine, thiane, and morpholine. In a further aspect, Cy1is a C2-C5 heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is a C2-C5 heterocycloalkyl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is a C2-C5 heterocycloalkyl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is an unsubstituted C2-C5 heterocycloalkyl.

[0156] In various aspects, Cy1is selected from C6-C14 aryl and C2-C10 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-C14 aryl and C2-C10 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, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-Attorney Docket No.37474.0111P1 C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is selected C6-C14 aryl and C2-C10 heteroaryl, and is substituted with 0 or 1 group selected from halogen, ‒–NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is selected from C6-C14 aryl and C2-C10 heteroaryl, and is unsubstituted.

[0157] In various aspects, Cy1is a C6-C14 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-C14 aryls include, but are not limited to, phenyl, naphthyl, anthracenyl, and phenanthrenyl. In a further aspect, Cy1is a C6-C14 aryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, – CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is a C6-C14 aryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is a C6-C14 aryl monosubstituted with a group selected from halogen, – NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is an unsubstituted C6-C14 aryl.

[0158] In various aspects, Cy1is a C2-C10 heteroarylsubstituted 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-C4Attorney Docket No.37474.0111P1 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of C2-C10 heteroaryls include, but are not limited to, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, imidazolyl, purinyl, indolyl, and quinolinyl. In a further aspect, Cy1is a C2-C10 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is a C2-C10 heteroaryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is a C2-C10 heteroaryl monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is an unsubstituted C2-C10 heteroaryl.

[0159] In various aspects, Cy1is selected from C3-C6 cycloalkyl and C6-C14 aryl, 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 C6-C14 aryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is selected from C3-C6 cycloalkyl and C6-C14 aryl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, – NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino. In yet a further aspect, Cy1is selected from C3-C6 cycloalkyl and C6-C14 aryl, and is monosubstituted with a group selected from halogen–NO2, –CN, –OH, –SH, – NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, andAttorney Docket No.37474.0111P1 (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is selected from C3-C6 cycloalkyl and C6-C14 aryl, and is unsubstituted.

[0160] In various aspects, Cy1is selected from C2-C5 heterocycloalkyl and C2-C10 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 C2-C5 heterocycloalkyl and C2-C10 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, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is selected from C2-C5 heterocycloalkyl and C2-C10 heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is selected from C2-C5 heterocycloalkyl and C2-C10 heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is selected from C2-C5 heterocycloalkyl and C2-C10 heteroaryl, and is unsubstituted.

[0161] In various aspects, Cy1is selected from C6 cycloalkyl, C2-C56-membered heterocycloalkyl, C6 aryl, and C2-C56-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, C6 cycloalkyl, C2-C56-membered heterocycloalkyl, C6 aryl, and C2-C56-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, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is selectedAttorney Docket No.37474.0111P1 from C6 cycloalkyl, C2-C56-membered heterocycloalkyl, C6 aryl, and C2-C56-membered heteroaryl, and is substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, – SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is selected from C6 cycloalkyl, C2-C56-membered heterocycloalkyl, C6 aryl, and C2-C56-membered heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is selected from C6 cycloalkyl, C2-C56- membered heterocycloalkyl, C6 aryl, and C2-C56-membered heteroaryl, and is unsubstituted.

[0162] In various aspects, Cy1 is 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 C6 aryl substituted with 0, 1, or 2 groups independently selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy1is C6 aryl substituted with 0 or 1 group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy1is C6 aryl monosubstituted with a group selected from halogen–NO2, –CN, –OH, –SH, – NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy1is unsubstituted C6 aryl. 2. EXEMPLARY COMPOUNDS

[0163] In one aspect, a compound can be present as:Attorney Docket No.37474.0111P1, , ,,,,Attorney Docket No.37474.0111P1 ,or a salt thereof.C. METHODS OF MAKING UNSYMMETRICAL PHOSPHOROUS DISULFIDES

[0164] In one aspect, disclosed are methods of making unsymmetrical phosphorousdisulfides compounds.

[0165] In one aspect, disclosed are methods for making a compound having a structurerepresented by a formula:, wherein A is selected from O, S, and Se; wherein R1is selected from C1-C8 alkyl, – C(O)(C1-C8 alkyl), Cy1, and –CH2Cy1; wherein Cy1is selected from C3-C6 cycloalkyl, C2- C5 heterocycloalkyl, C6-C14 aryl, and C2-C10 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 each of R2and R3is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, ‒O(C2-C4 alkenyl),Attorney Docket No.37474.0111P1 ‒O(C2-C4 alkynyl), and ‒OC6H5, or wherein R2and R3are covalently bonded and, together with the intermediate atoms, comprise a 5-membered ring having a structure represented by a formula selected from:wherein Q is selected from O, S, and NR20; wherein R20, when present, is selected from hydrogen, C1-C4 alkyl, and Ar1; wherein Ar1, when present, is 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-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and unsubstituted phenyl; wherein each of R10a, R10b, and R11is independently selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1; or wherein R10ais selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R10band R11are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, 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 R12is selected from hydrogen, C1-C4 alkyl, and Ar1; or wherein each of R10aand R10bis independently selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R11and R12are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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-C4Attorney Docket No.37474.0111P1 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a salt thereof, the method comprising reacting a N-thiosuccinimide having a structure represented by a formula:, and a thioacid nucleophile having a structure represented by a formula:.

[0166] In various aspects, the N-thiosuccinimide has a structure represented by a formula:, wherein n is selected from 0 and 1; and wherein each of R13a, R13b, R13c, R13d, and R13eis 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, provided that at least two of R13a, R13b, R13c, R13d, and R13eare hydrogen, or a salt thereof.

[0167] In various aspects, the N-thiosuccinimide has a structure represented by a formula:.

[0168] In various aspects, the N-thiosuccinimide has a structure represented by a formula:Attorney Docket No.37474.0111P1.

[0169] In various aspects, the N-thiosuccinimide has a structure represented by a formula:.

[0170] In various aspects, the N-thiosuccinimide is selected from:Attorney Docket No.37474.0111P1 ,

[0171] In various aspects, the thioacid nucleophile is selected from.

[0172] In various aspects, reacting is in the presence of a protic solvent. In a further aspect,the protic solvent is selected from water, methanol, ethanol, isopropyl alcohol, and butanol. In a still further aspect, the protic solvent is ethanol.Attorney Docket No.37474.0111P1

[0173] In various aspects, reacting is at a temperature of from about 0 °C to about 100 °C. In a further aspect, a temperature of from about 10 °C to about 90 °C. In a still further aspect, a temperature of from about 20 °C to about 80 °C. In yet a further aspect, a temperature of from about 30 °C to about 70 °C. In an even further aspect, a temperature of from about 40 °C to about 60 °C.

[0174] In various aspects, reacting is at a temperature of from about 0 °C to about 10 °C. In a further aspect, a temperature of from about 10 °C to about 20 °C. In a still further aspect, a temperature of from about 20 °C to about 30 °C. In yet a further aspect, a temperature of from about 30 °C to about 40 °C. In an even further aspect, a temperature of from about 40 °C to about 50 °C. In an even still further aspect, a temperature of from about 50 °C to about 60 °C. In yet an even further aspect, a temperature of from about 60 °C to about 70 °C. In a further aspect, a temperature of from about 70 °C to about 80 °C. In a still further aspect, a temperature of from about 80 °C to about 90 °C. In yet a further aspect, a temperature of from about 90 °C to about 100 °C.

[0175] In various aspects, reacting is at a temperature of from about 20 °C to about 25 °C.

[0176] In various aspects, reacting is for a time period of less than about 1 hour. In a further aspect, reacting is for a time period of less than about thirty minutes. In a still further aspect, reacting is for a time period of less than about fifteen minutes. In a yet an even further aspect, reacting is for a time period of about 10 minutes.

[0177] 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.

[0178] 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-III, 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

[0179] In one aspect, thiosuccinimide compounds can be prepared as shown below.Attorney Docket No.37474.0111P1 SCHEME 1A.

[0180] Compounds are represented in generic form with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 1B.

[0181] In one aspect, compounds of type 1.4, and similar compounds, can be prepared according to reaction Scheme 1B above. Thus, compounds of type 1.4 can be prepared by reaction of an appropriate thiol, e.g., 1.3 as shown above, and N-chlorosuccinimide. Appropiate thiols are commercially available or prepared by methods known to person of ordinary skill in the art. The reaction can be carried out in an appropriate solvent, e.g., toulene, at an appropriate temperature, e.g., room temperature, for an appropriate period of time, e.g., 45 minutes. 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), can be substituted in the reaction to provide substituted tetrahydrobenzothiophene and tetrahydropyridothiophene analogs similar to Formula 2.2. 2. ROUTE II

[0182] In one aspect, thiophosphoric acid compounds can be prepared as shown below.Attorney Docket No.37474.0111P1 SCHEME 2A.

[0183] Compounds are represented in generic form with substituents as noted in compounddescriptions elsewhere herein. A more specific example is set forth below. SCHEME 2B.

[0184] In one aspect, compounds of type 2.4, and similar compounds, can be preparedaccording to reaction Scheme 2B above. Thus, compounds of type 2.4 can be prepared by reaction of an appropriate H-phosphonate, e.g., 2.3 as shown above, and elemental sulfur. Appropiate H-phosphonates are commercially available or prepared by methods known to person of ordinary skill in the art. The reaction can be carried out in the presence of and appropriate base, e.g., triethylamine, in an appropriate solvent, e.g., ether, at an appropriate temperature, e.g., room temperature, for an appropriate period of time, e.g., 12 hours. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 2.1), can be substituted in the reaction to providesubstituted tetrahydrobenzothiophene and tetrahydropyridothiophene analogs similar toFormula 2.2. 3. ROUTE III

[0185] In one aspect, phosphorous disulfide compounds can be prepared as shown below.Attorney Docket No.37474.0111P1 SCHEME 3A.

[0186] Compounds are represented in generic form with substituents as noted in compounddescriptions elsewhere herein. A more specific example is set forth below. SCHEME 3B.

[0187] In one aspect, compounds of type 3.6, and similar compounds, can be preparedaccording to reaction Scheme 3B above. Thus, compounds of type 3.6 can be prepared by reaction of an appropriate N-thiosuccinimide, e.g., 3.4 as shown above, and an appropriate thiophosphinic acid, e.g., 3.5 as shown above. Appropiate N-thiosuccinimides and thiophosphinic acid are commercially available or prepared by methods known to person of ordinary skill in the art. The reaction can be carried out in an appropriate solvent, e.g., ethanol, at an appropriate temperature, e.g., room temperature, for an appropriate period of time, e.g., 10 minutes. 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 3.1 and 3.2), can be substituted in the reaction to provide substituted tetrahydrobenzothiophene andtetrahydropyridothiophene analogs similar to Formula 3.3.D. KITS

[0188] In one aspect, disclosed are kits for making unsymmetrical phosphorous disulfidescompounds.

[0189] In one aspect, disclosed are kits comprising: a N-thiosuccinimide having a structurerepresented by a formula:Attorney Docket No.37474.0111P1, wherein R1is selected from C1-C8 alkyl, –C(O)(C1-C8 alkyl), Cy1, and –CH2Cy1; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C14 aryl, and C2-C10 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; a thioacid nucleophile having a structure represented by a formula: , wherein A is selected from O and S; wherein each of R2and R3is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, ‒O(C2-C4 alkenyl), ‒O(C2-C4 alkynyl), and ‒OC6H5, or wherein R2and R3are covalently bonded and, together with the intermediate atoms, comprise a 5-membered ring having a structure represented by a formula selected from:wherein Q is selected from O, S, and NR20; wherein R20, when present, is selected from hydrogen, C1-C4 alkyl, and Ar1; wherein Ar1, when present, is 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-C4Attorney Docket No.37474.0111P1 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and unsubstituted phenyl; wherein each of R10a, R10b, and R11is independently selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1; or wherein R10ais selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R10band R11are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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; and wherein R12is selected from hydrogen, C1-C4 alkyl, and Ar1; or wherein each of R10aand R10bis independently selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R11and R12are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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; and a protic solvent.

[0190] In various aspects, the protic solvent is selected from methanol, ethanol, and isopropyl alcohol. In a further aspect, the protic solvent is ethanol.

[0191] 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.

[0192] 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 byAttorney Docket No.37474.0111P1 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. E. EXAMPLES

[0193] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

[0194] The Examples are provided herein to illustrate the invention, and should not be construed as limiting the invention in any way. Examples are provided herein to illustrate the invention and should not be construed as limiting the invention in any way. 1. EXPERIMENTAL a. GENERAL INFORMATION

[0195] All reactions were carried out under air atmosphere in oven-dried glassware with magnetic stirring bar. Dry solvents (THF, toluene, ACN, diethyl ether, and DCM) were obtained by solvent purification system under argon. All commercially available reagents were used as received without further purification. The tubes used for the reaction are shown in FIG.1. Purification of reaction products was carried out by flash column chromatography using silica gel 60 (230-400 mesh). Analytical thin layer chromatography was performed on 0.25 mm aluminum-backed silica gel 60-F plates. Visualization was accompanied with UV light and KMnO4 solution. Concentration under reduced pressure refers to the removal of volatiles using a rotary evaporator attached to a dry diaphragm pump (10-15 mm Hg) followed by pumping to a constant weight with an oil pump (<300 mTorr). Infrared (IR) spectra were recorded on an IR spectrometer with KBr wafers or a film on KBr plate. High- resolution mass spectra (HRMS) were recorded on LCMS-IT-TOF mass spectrometer using ESI (electrospray ionization) or APCI (Atmospheric Pressure Chemical Ionization).1H NMR spectra were recorded in CDCl3on 400 MHz NMR spectrometer. The1H chemical shifts are referenced to residual solvent signals at δ 7.26 (CHCl3) or δ 0.00 (TMS).1H NMR couplingAttorney Docket No.37474.0111P1 constants (J) are reported in Hertz (Hz) and multiplicities are indicated as follows: s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), tt (triplet of triplets).13C NMR spectra were proton decoupled and recorded in CDCl3on 100.5 MHz NMR spectrometer. The13C chemical shifts are referenced to solvent signals at δ 77.16 (CDCl3).31P NMR spectra were proton decoupled and recorded in CDCl3on 162 MHz NMR spectrometer.31P chemical shifts are reported relative to 85% H3PO4(0.00 ppm) as an external standard. b. SYNTHESIS

[0196] To a solution of thiol (1.0 mmol), in toluene (3.0 mL) was added n-Chlorosuccinimide (1.0 mmol) portionwise and was stirred for 45 minutes at room temperature. Triethyl amine (1.0 mmol) was added dropwise, and the reaction mixture was stirred for 12 hours. The residue was concentrated under reduced pressure and subjected to column chromatography on silica gel to give the corresponding thiosuccinimides 1. ii. GENERAL PROCEDURE FOR THE SYNTHESIS OFTHIOPHOSPHORIC ACID (2)

[0197] To a solution of H-phosphonate (1.0 mmol) in ether (5.0 mL), triethylamine (1.1mmol) was added, followed by elemental sulfur (1.05 mmol). The reaction was stirred for 12 hours and then washed with 1M HCl (3×), followed by washing with brine. The organic extract was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2.Attorney Docket No.37474.0111P1 iii. GENERAL PROCEDURE FOR THE SYNTHESIS OFPHOSPHOROUS DISULFIDE 3 AND 4

[0198] To a solution of thiophosphoric acid 2 (0.10 mmol) in ethanol (0.5 mL) was addedthiosuccinimide 1a (0.10 mmol) at room temperature. The reaction mixture was stirred for 10 minutes. After stirring for 10 minutes at room temperature, the reaction mixture was concentrated under reduced pressure and subjected to column chromatography on silica gel to give the corresponding phosphorous disulfide products 3 (Table 1) and FIG.2 and FIG.4 (Table 2) and FIG.3. Table 1.Attorney Docket No.37474.0111P1Attorney Docket No.37474.0111P1Attorney Docket No.37474.0111P1Attorney Docket No.37474.0111P1Attorney Docket No.37474.0111P1TABLE 2.Attorney Docket No.37474.0111P1Attorney Docket No.37474.0111P1 iv. PROCEDURES FOR SYNTHETIC UTILITY OF PHOSPHOROUSDISULFIDES a. 1-(PHENYLTHIO)NAPHTHALEN-2-OL (6A)

[0199] To a solution of 3a (0.1 mmol) in CH2Cl2 (0.5 mL) was added beta naphthol 5a (0.1mmol), followed by an iodine catalyst (0.01 mmol). The reaction was stirred at room temperature for 12 h, concentrated under reduced pressure, and directly purified by columnchromatography (8:2 Hexane:EtOAc) to give 6a (10.8mg, 43%) as a white solid. IR (thinfilm, cm-1) 3400, 3019, 2921, 1620, 1476, 1255, 936, 864, 818, 738, 689;1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.51-7.47 (m, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 9.2 Hz, 1H), 7.18-7.14 (m, 3H),7.11-7.08 (m, 1H), 7.03-7.01 (m, 2H); 13C NMR (100.5 MHz, CDCl3) δ 156.9, 135.4, 135.3,132.8, 129.4, 129.2, 128.5, 127.9, 126.3, 125.8, 124.6, 123.8, 116.8, 108.0. (FIG.23A and FIG.23B)

[0200] To a solution of 3a (0.1 mmol) in EtOH (0.5 mL) was added imidazopyridine 5b(0.2 mmol), followed by an ammonium iodide catalyst (0.01 mmol). The reaction was refluxed for 12 h, concentrated under reduced pressure, and directly purified by columnchromatography (7:3 Hexane:EtOAc) to give 6b (27.4 mg, 91%) as a yellow solid. IR (thinfilm, cm-1) 3068, 2930, 1631, 1496, 1361, 1232, 1100, 1034, 968, 775, 692;1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 6.8 Hz, 1H), 8.22-8.20 (m, 2H), 7.73 (d, J = 9.2 Hz, 1H), 7.43 (t, J = 7.2 Hz, 2H), 7.38-7.30 (m, 2H), 7.22-7.17 (m, 2H), 7.13 (t, J = 7.2 Hz, 1H), 7.0 (d, J =8.0 Hz, 2H), 6.86-6.83 (m, 1H); 13C NMR (100.5 MHz, CDCl3) δ 151.4, 147.1, 135.2, 133.3,Attorney Docket No.37474.0111P1 129.4, 128.6, 128.4, 128.3, 126.6, 126.0, 125.5, 124.5, 117.6, 113.0, 106.2. (FIG.24A and FIG.24B) c. TRIPHENYL PHOSPHINE SULFIDE (6C)

[0201] To a solution of 3p (0.1 mmol) in DCM (0.5 mL) was added triphenylphosphine(0.1 mmol). The reaction was stirred at room temperature for 12 h, concentrated under reduced pressure, and directly purified by column chromatography (95:5 Hexane:EtOAc) togive 6c (16.7 mg, 95%) as a solid. IR (thin film, cm-1) 3056, 2361, 1585, 1419, 1433, 1307,1103, 996, 752, 692;1H NMR (400 MHz, CDCl3) δ 7.75-7.69 (m, 6H), 7.52-7.48 (m, 3H),7.46-7.41 (m, 6H); 13C NMR (100.5 MHz, CDCl3): δ 132.9 (d, J = 84.9 Hz), 132.3 (d, J =11.2 Hz), 131.5 (d, J = 2.9 Hz), 128.5 (d, J = 12.7 Hz);31P NMR (162 MHz, CDCl3): δ 43.8. (FIG.25A-C) d. SS-(4-CHLOROPHENYL) O,O-DIETHYLPHOSPHORO(DITHIOPEROXO)THIOATE (7A)

[0202] To a solution of dithiophosphoric acid 2d (0.2 mmol) in EtOH (1.0 mL),thiosuccinimide 1d (0.2 mmol) was added. The reaction was stirred for 10 minutes, concentrated under reduced pressure, and directly purified by column chromatography (8:2Hexane:DCM) to give 7a (49.3 mg, 75%) as an oil. IR (thin film, cm-1) 3076, 2935, 1571,1442, 1387, 1263, 1160, 818, 744;NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), 4.21-4.14 (m, 2H), 3.93-3.86 (m, 2H), 1.26-1.22 (m, 6H);13C NMR (100.5 MHz, CDCl3) δ 134.6, 134.3 (d, J = 2.3 Hz), 131.9 (d, J = 1.5 Hz), 129.2, 64.5 (d, J = 5.2 Hz), 15.6 (d, J = 8.9 Hz);31P NMR (162 MHz, CDCl3): δ 86.2; HRMS(ESI): m / z calcd. For C10H14ClO2PS3([M+H]+): 328.9660; found 328.9660. (FIG.26A-C)Attorney Docket No.37474.0111P1 e. (O-ETHYL CARBONOTHIOIC) (DIETHYL PHOSPHORIC)DITHIOPEROXYANHYDRIDE (7B)

[0203] To a solution of thiophosphoric acid 2a (0.1 mmol) in EtOH (0.5 mL),thiosuccinimide 1q (0.1 mmol) was added. The reaction was refluxed for 2 hours, concentrated under reduced pressure, and directly purified by column chromatography (7:3Hexane:EtOAc) to give 7a (22.6 mg, 78%) as an oil. IR (thin film, cm-1) 2984, 2935, 1735,1442, 1393, 1261, 1025, 789;1H NMR (400 MHz, CDCl3) δ 4.76-4.69 (m, 2H), 4.32-4.18(m, 4H), 1.52-1.48 (m, 3H), 1.42-1.36 (m, 6H); 13C NMR (100.5 MHz, CDCl3) δ 207.9 (d, J= 1.5 Hz), 71.7 (d, J = 9.7 Hz), 64.8 (d, J = 6.0 Hz), 16.1 (d, J = 6.7 Hz), 13.6;31P NMR (162 MHz, CDCl3): δ 20.5; HRMS(ESI): m / z calcd. For C7H15O4PS3([M+Na]+): 312.9768; found 312.9767. (FIG.27A-C) c. DISCUSSIONi. OPTIMIZATION OF REACTION CONDITIONS

[0204] N-thiosuccinimide 1a and P(O)(OEt)2SH 2a were used as model substrates in thepresence of various solvents following the general procedure for the the synthesis of phosphorous disulfide 3 described above and the results shown in Table 3. TABLE 3.Attorney Docket No.37474.0111P1a Reaction conditions: 1a (0.1 mmol) and 2a (0.1 mmol) in solvent (0.5 mL) for 10 min.bIsolated yield

[0205] The reaction with ethanol as solvent afforded 3a in 95% yield (Table 1, entry 1).Other solvents also provided the product in high yields (Table 1, entries 2-7). Ultimately, ethanol was chosen since it is environmentally friendly and readily available through biomass fermentation (Y. Lin and S. Tanaka, Appl. Microbiol. Biotechnol., 2006, 69, 627-642). The reaction addresses many of the 12 principles of green chemistry as defined by the American Chemical Society (P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Practice, Oxford University Press, 2000). The reaction is highly atom economical as there are no additives used or excess of reagents. Additionally, the reaction is energy neutral as no heating is required. The use of safer solvents and renewable feedstocks is met by using ethanol. Lastly, the procedure runs without transition metal catalysts and harsh chlorinating reagents, which are typically used for disulfide synthesis. ii. SUBSTRATE SCOPE OF THIOPHOSPHORYLATIONREACTION a. N-THIOSUCCINIMIDE ELECTROPHILES

[0206] With the optimized reaction conditions in hand, the scope of N-thiosuccinimideelectrophiles was evaluated to study the steric and electronic effects on the reaction outcome (Scheme 4) following the general procedure for the the synthesis of phosphorous disulfide 3 describe above and the results shown in Table 1 and FIG.2. SCHEME 4.Attorney Docket No.37474.0111P1

[0207] Overall, the reaction provided the products (3a-3p) in high yields (74-96%) and thesteric and electronic factors of the N-thiosuccinimides were well tolerated (Scheme 4). For example, halogenated aryl N-thiosuccinimides 1b-1e generated the products (3b-3e) in high yields (93-96%). Aryl N-thiosuccinimides bearing electron-donating groups 1e, 1f (4-Me, 4- MeO) gave the corresponding products 3e and 3f in 94% and 90%, respectively. Next, aryl N-thiosuccinimides 1g and 1h containing sterically demanding groups (2,5-dimethyl, 4- tertbutyl) afforded the desired products (3g and 3h) in a high yield of 90%. Alkyl N- thiosuccinimides 1i and 1j (cyclohexyl, n-hexyl) were also well tolerated providing the target products 3i and 3j with high yields of 90 and 79%, respectively. Additionally, benzylic N- thiosuccinimide 1k furnished product 3k in an 89% yield; no competing substitution reactions at the benzylic carbon occurred. Benzylic N-thiosuccinimides containing halogens and electron donating groups 1l-1o (4-fluoro, 4-chloro, 2-chloro, and 4-tertbutyl) also generated the target products 3l-3o in high yields (83-95%). Furthermore, acyl N- thiosuccinimide 1p was tolerated and gave product 3p in a high yield of 90%. The substrate scope of N-succinimide revealed that the steric and electronic effects were well tolerated. b. N-THIOSUCCINIMIDE ELECTROPHILES

[0208] Next, the scope of the thioacid nucleophile was evaluated (Scheme 5) following thegeneral procedure for the the synthesis of phosphorous disulfide 4 describe above and the results shown in Table 2 and FIG.3. SCHEME 5.

[0209] Thioacids with different alkoxy substituents 2b, 2c, and 2d (butyl, isopropyl, andpropargyl) were well tolerated, giving the target products 4a, 4b, and 4c in 79%, 71%, and 84% yields, respectively. However, when diphenylthiophosphinic acid was tested, no desired product was formed even at elevated temperatures, presumably due to a weaker acidity than 2a (pKa = –5.14) (D. Churchill, et al., Canadian Journal of Chemistry, 2007, 85, 421-431).Attorney Docket No.37474.0111P1 iii. SYNTHETIC UTILITY

[0210] Having an array of substrate scopes studied, the synthetic utility of thistransformation was conducted (Scheme 6). SCHEME 6.

[0211] Beta naphthol 5a was thiolated to give thionaphthol 6a using the parent compound3a (H. Huang, et al., Angewandte Chemie International Edition, 2018, 57, 6624-6628; b) H. Huang, et al., Organic Letters, 2018, 20, 4938-4941; J. Ash, H. et al., Organic & Biomolecular Chemistry, 2019, 17, 3812-3818). Imidazopyridine 5b was also successfully thiolated to give 6b under the catalytic conditions. The imidazopyridine structural motif has been shown to possess antibacterial properties (B. K. R. Sanapalli, et al., Antibiotics, 2022, 11, 1680). In addition, the compound 3p can be used for sulphurization of triphenylphosphine 5c to triphenylphosphine sulfide 6c. These results demonstrate that phosphorous disulfides can serve as electrophilic sulfur sources to functionalize heteroarenes.

[0212] Next, this methodology was applied to synthesize known pesticides 7a and 7b(Scheme 7) (U.S. Patent No.3,109,770).Attorney Docket No.37474.0111P1 SCHEME 7.

[0213] Pesticide 7a was synthesized by treating 1d and 2d under the standard reactionconditions. Pesticide 7b was also readily prepared from 1q and 2a under heating conditions. These results demonstrate a direct application of this methodology toward various pesticide synthesis. iv. CONTROL EXPERIMENTS

[0214] To gain insight into the reaction mechanism, control experiments were performed(Scheme 8). SCHEME 8.

[0215] The reaction between 1a and diphenyl phosphoric acid 2g (pKa = –3.95)(D. R.Edwards, et al., J. Am. Chem. Soc., 2009, 131, 368-377) did not yield the target product 4f(eq 1). This outcome reveals that a stronger acid and more nucleophilic thiolate are needed for a successful reaction. Furthermore, the role of the proton was investigated by using theAttorney Docket No.37474.0111P1 potassium salt of 2h, which generated the desired product in a much lower yield (29%) compared to 2a (eq 2). This result indicates that a proton donor (Bronsted acid) is necessary to increase the electrophilicity of 1a. v. PROPOSED MECHANISM

[0216] A plausible mechanism is proposed in Scheme 9.SCHEME 9.

[0217] Mechanistically the nitrogen atom on 1a is protonated by P(O)(OEt)2SH 2a to forma pyrrolidinium intermediate I. The electrophilic sulfur intermediate I undergoes a substitution reaction with phosphorus thiolate intermediate II to generate the disulfide product 3a by liberating the succinimide leaving group. d. CONCLUSIONS

[0218] A rapid and green synthetic method to access phosphorous disulfides has beendeveloped. This method addressed the persistent homodimerization issues in unsymmetrical disulfide synthesis. The advantages of this method are the short reaction time, green solvent, high atom economy, and avoidance of using harsh reagents such as oxidants, chlorinating reagents, and transition metal catalysts. The substrate scope of both the sulfur electrophile 1 and phosphorus thioacid 2 were successfully demonstrated. The synthetic utility study revealed the functionalization of heteroarenes and sulfurization of phosphine. Known pesticides were synthesized to demonstrate the applicability of the developed methodology. A series of control experiments support a plausible mechanism that disclosed a bifunctionality (Bronsted acid and sulfur nucleophile) of the phosphorothioic acid.Attorney Docket No.37474.0111P1 F. REFERENCES

[0219] 1. a) X. Liu, L. Zhou, R. Yang, X.-R. Song and Q. Xiao, Advanced Synthesis & Catalysis, 2023, 365, 2280-2298; b) S.-W. Rhee, R. P. Iyer, J. E. Coughlin, S. Padmanabhan, J. P. Malerich and M. J. Tanga, Journal of Labelled Compounds and Radiopharmaceuticals, 2012, 55, 197-200; c) R. Xie, Q. Zhao, T. Zhang, J. Fang, X. Mei, J. Ning and Y. Tang, Bioorganic & Medicinal Chemistry, 2013, 21, 278-282; d) H. Yan, X. Wang, R. KuoLee and W. Chen, Bioorganic & Medicinal Chemistry Letters, 2008, 18, 5631-5634; e) T. S. Kumar, T. Yang, S. Mishra, C. Cronin, S. Chakraborty, J.-B. Shen, B. T. Liang and K. A. Jacobson, Journal of Medicinal Chemistry, 2013, 56, 902-914; f) Y. Zhang, Y. Cao, Y. Chi, S. Chen, X. Zeng, Y. Liu, G. Tang and Y. Zhao, Advanced Synthesis & Catalysis, 2022, 364, 2221-2226; g) S. Demkowicz, J. Rachon, M. Daśko and W. Kozak, RSC Advances, 2016, 6, 7101-7112; h) U. Pradere, E. C. Garnier-Amblard, S. J. Coats, F. Amblard and R. F. Schinazi, Chemical Reviews, 2014, 114, 9154-9218; i) B. K. Singh and A. Walker, FEMS Microbiology Reviews, 2006, 30, 428-471; j) T. Baumgartner and R. Réau, Chemical Reviews, 2006, 106, 4681- 4727; k) C.-S. Jiang, W. E. G. Müller, H. C. Schröder and Y.-W. Guo, Chemical Reviews, 2012, 112, 2179-2207; l) Z. Wu and D. A. Pratt, Nature Reviews Chemistry, 2023, 7, 573- 589.

[0220] 2. X. Xiao, M. Feng and X. Jiang, Angew. Chem. Int. Ed., 2016, 55, 14121-14125; b) X. Xiao, J. Xue and X. Jiang, Nat. Commun., 2018, 9, 2191; c) J. Xue and X. Jiang, Nat. Commun., 2020, 11, 4170.

[0221] 3. S. F. Betz, Protein Sci., 1993, 2, 1551-1558.

[0222] 4. a) C. Wright and R. D. Moore, Am. J. Med., 1990, 88, 647-655; b) A. Vogt, K. Tamura, S. Watson and J. S. Lazo, J. Pharmacol. Exp. Ther., 2000, 294, 1070; c) J.-G. Wang, Y.-J. Xiao, Y.-H. Li, Y. Ma and Z.-M. Li, Bioorg. Med. Chem., 2007, 15, 374-380; d) L. Wang, B.-B. Bao, G.-Q. Song, C. Chen, X.-M. Zhang, W. Lu, Z. Wang, Y. Cai, S. Li, S. Fu, F.-H. Song, H. Yang and J.-G. Wang, Eur. J. Med. Chem., 2017, 137, 450-461.

[0223] 5. E. Block, S. Ahmad, J. L. Catalfamo, M. K. Jain and R. Apitz-Castro, J. Am. Chem. Soc., 1986, 108, 7045-7055.

[0224] 6. W. Kaewsakul, K. Sahakaro, W. K. Dierkes and J. W. M. Noordermeer, Polym Eng Sci, 2015, 55, 836-842.

[0225] 7. a) B. Mandal and B. Basu, RSC Advances, 2014, 4, 13854-13881; b) F. Wang, Y. Chen, W. Rao, L. Ackermann and S.-Y. Wang, Nature Communications, 2022, 13, 2588; c)Attorney Docket No.37474.0111P1 M. Narayan, E. Welker, W. J. Wedemeyer and H. A. Scheraga, Accounts of Chemical Research, 2000, 33, 805-812; d) D. Witt, Synthesis, 2008, 2008, 2491-2509.

[0226] 8. a) N. Iranpoor and B. Zeynizadeh, Synthesis, 1999, 1999, 49-50; b) S. M. S. Chauhan, A. Kumar and K. A. Srinivas, Chem. Comm., 2003, DOI: 10.1039 / B305888C, 2348-2349; c) H. Huang, J. Ash and J. Y. Kang, Organic & Biomolecular Chemistry, 2018, 16, 4236-4242.

[0227] 9. a) R. Priefer, Y. J. Lee, F. Barrios, J. H. Wosnick, A.-M. Lebuis, P. G. Farrell, D. N. Harpp, A. Sun, S. Wu and J. P. Snyder, J. Am. Chem. Soc., 2002, 124, 5626-5627; b) S. Harusawa, K. Yoshida, C. Kojima, L. Araki and T. Kurihara, Tetrahedron, 2004, 60, 11911- 11922; c) A. Hatano, S. Makita and M. Kirihara, Bioorg. Med. Chem. Lett., 2004, 14, 2459- 2462.

[0228] 10. T. J. Korn and P. Knochel, Synlett, 2005, 2005, 1185-1187.

[0229] 11. B. Karimi, H. Hazarkhani and D. Zareyee, Synthesis, 2002, 2002, 2513-2516.

[0230] 12. a) O. Schäfer and M. Barz, Chemistry – A European Journal, 2018, 24, 12131- 12142; b) G. Ribeiro Morais and R. A. Falconer, Organic & Biomolecular Chemistry, 2021, 19, 82-100; c) G. M. Watt and G.-J. Boons, Carbohydrate Research, 2004, 339, 181-193; d) N.Stellenboom, R. Hunter, M. R. Caira and L. Szilágyi, Tetrahedron Letters, 2010, 51, 5309- 5312.

[0231] 13. a) X. Qiu, X. Yang, Y. Zhang, S. Song and N. Jiao, Organic Chemistry Frontiers, 2019, 6, 2220-2225; b) F. Yang, W. Wang, K. Li, W. Zhao and X. Dong, Tetrahedron Lett., 2017, 58, 218-222; c) B. Dong, Y. Chen, S. Xie, J. Zhang, J. Shen and L.- G. Xie, Org. Biomol. Chem., 2023, 21, 930-934.

[0232] 14. a) M. Arisawa and M. Yamaguchi, J. Am. Chem. Soc., 2003, 125, 6624-6625; b) J. Guo, J. Zha, T. Zhang, C.-H. Ding, Q. Tan and B. Xu, Org. Lett., 2021, 23, 3167-3172; c) M. Song, Q. Hu, Z.-Y. Li, X. Sun and K. Yang, Chin Chem Lett, 2022, 33, 4269-4272.

[0233] 15. a) D. N. Harpp and T. G. Back, Tetrahedron Lett., 1972, 13, 1481-1484; b) D. H. R. Barton, C. Chen and G. Michael Wall, Tetrahedron, 1991, 47, 6127-6138; c) E. Brzezinska and A. L. Ternay, Jr., J. Org. Chem., 1994, 59, 8239-8244; d) P. Hiver, A. Dicko and D. Paquer, Tetrahedron Lett., 1994, 35, 9569-9572; e) M. Uragami, Y. Miyake, N. Tokutake, L.-h. Zhang and S. L. Regen, Langmuir, 2000, 16, 8010-8015; f) R. Hunter, M. Caira and N. Stellenboom, J. Org. Chem., 2006, 71, 8268-8271; g) S. Antoniow and D. Witt, Synthesis, 2007, 2007, 363-366; h) L. Delarue Bizzini, P. Zwick and M. Mayor, Eur. J. Org.Attorney Docket No.37474.0111P1 Chem., 2019, 2019, 6956-6960; i) M. Bao and M. Shimizu, Tetrahedron, 2003, 59, 9655- 9659.

[0234] 16. Z. Dai, X. Xiao and X. Jiang, Tetrahedron, 2017, 73, 3702-3706.

[0235] 17. a) S. Chen, S. Cao, C. Liu, B. Wang, X. Ren, H. Huang, Z. Peng and X. Wang, Org. Lett., 2021, 23, 7428-7433; b) S. Wu, D. Hu, X. Wan, J. Zhao, Q. He, Z. Su and H. Cao, J. Org. Chem., 2022, 87, 16297-16306.

[0236] 18. P. Huang, P. Wang, S. Tang, Z. Fu and A. Lei, Angew. Chem. Int. Ed., 2018, 57, 8115-8119.

[0237] 19. a) B. Levi Hevroni, A. H. Sayer, E. Blum and B. Fischer, Inorganic Chemistry, 2014, 53, 1594-1605; b) V. Janout, B. Jing and S. L. Regen, Bioconjugate Chemistry, 2002, 13, 351-356.

[0238] 20. Z. Zhang, T. Lao, L. Deng, C. Zhang, J. Liu, M. Fu, Z. Su, Y. Yu and H. Cao, Org. Lett., 2022, 24, 7222-7226.

[0239] 21. J. Ash and J. Y. Kang, Org. Biomol. Chem., 2023, 21, 2370-2374.

[0240] 22. Y. Lin and S. Tanaka, Appl. Microbiol. Biotechnol., 2006, 69, 627-642.

[0241] 23. P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Practice, Oxford University Press, 2000.

[0242] 24. D. Churchill, J. M. Dust and E. Buncel, Canadian Journal of Chemistry, 2007, 85, 421-431.

[0243] 25. a) H. Huang, J. Denne, C.-H. Yang, H. Wang and J. Y. Kang, Angewandte Chemie International Edition, 2018, 57, 6624-6628; b) H. Huang, J. Ash and J. Y. Kang, Organic Letters, 2018, 20, 4938-4941; c) J. Ash, H. Huang and J. Y. Kang, Organic & Biomolecular Chemistry, 2019, 17, 3812-3818.

[0244] 26. B. K. R. Sanapalli, A. Ashames, D. K. Sigalapalli, A. B. Shaik, R. R. Bhandare and V. Yele, Antibiotics, 2022, 11, 1680.

[0245] 27. US Patent 3,109,770, 1963.

[0246] 28. D. R. Edwards, A. A. Neverov and R. S. Brown, Journal of the American Chemical Society, 2009, 131, 368-377.

[0247] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It isAttorney Docket No.37474.0111P1 intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

Attorney Docket No.37474.0111P1 CLAIMS What is claimed is:

1. A method for making a compound having a structure represented by a formula:, wherein A is selected from O, S, and Se; wherein R1is selected from C1-C8 alkyl, –C(O)(C1-C8 alkyl), Cy1, and –CH2Cy1; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C14 aryl, and C2-C10 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 each of R2and R3is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, ‒O(C2-C4 alkenyl), ‒O(C2-C4 alkynyl), and ‒OC6H5, or wherein R2and R3are covalently bonded and, together with the intermediate atoms, comprise a 5-membered ring having a structure represented by a formula selected from:wherein Q is selected from O, S, and NR20;Attorney Docket No.37474.0111P1 wherein R20, when present, is selected from hydrogen, C1-C4 alkyl, and Ar1; wherein Ar1, when present, is 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, (C1-C4)(C1-C4) dialkylamino, and unsubstituted phenyl; wherein each of R10a, R10b, and R11is independently selected from hydrogen, C1- C4 alkyl, Ar1, and ‒CH2Ar1; or wherein R10ais selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R10band R11are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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; and wherein R12is selected from hydrogen, C1-C4 alkyl, and Ar1; or wherein each of R10aand R10bis independently selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R11and R12are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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, or a salt thereof, the method comprising reacting a N-thiosuccinimide having a structure represented by a formula:Attorney Docket No.37474.0111P1, and a thioacid nucleophile having a structure represented by a formula:. The method of claim 1, wherein the N-thiosuccinimide has a structure represented bya formula:, wherein n is selected from 0 and 1; and wherein each of R13a, R13b, R13c, R13d, and R13eis 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, provided that at least two of R13a, R13b, R13c, R13d, and R13eare hydrogen, or a salt thereof.

3. The method of claim 2, wherein the compound has a structure represented by aformula:.Attorney Docket No.37474.0111P1 The method of claim 2, wherein the compound has a structure represented by aformula:.

5. The method of claim 2, wherein the compound has a structure represented by aformula:.

6. The method of claim 1, wherein the compound is selected from:Attorney Docket No.37474.0111P17. The method of any one of claims 1 to 6, wherein the thioacid nucleophile is selectedfrom:.

8. The method of any one of claims 1 to 7, wherein reacting is in the presence of a proticsolvent.

9. The method of claim 8, wherein the protic solvent is selected from water, methanol,ethanol, isopropyl alcohol, and butanol.Attorney Docket No.37474.0111P110. The method of claim 8, wherein the protic solvent is ethanol.

11. The method of any one of claims 1 to 10, wherein reacting is at a temperature of fromabout 20 °C to about 25 °C.

12. The method of any one of claims 1 to 11, wherein reacting is for a time period of lessthan about 1 hour.

13. The method of any one of claims 1 to 11, wherein reacting is for a time period of lessthan about thirty minutes.

14. The method of any one of claims 1 to 11, wherein reacting is for a time period of lessthan about fifteen minutes.

15. The method of any one of claims 1 to 11, wherein reacting is for a time period ofabout 10 minutes.

16. A compound having a structure represented by a formula:, wherein A is selected from O, S, and Se; wherein R1is selected from C1-C8 alkyl, –C(O)(C1-C8 alkyl), Cy1, and –CH2Cy1; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C14 aryl, and C2-C10 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 each of R2and R3is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, ‒O(C2-C4 alkenyl), ‒O(C2-C4 alkynyl), and ‒OC6H5, or wherein R2and R3are covalently bonded and, together with the intermediate atoms, comprise a 5-membered ring having a structure represented by a formula selected from:Attorney Docket No.37474.0111P1wherein Q is selected from O, S, and NR20; wherein R20, when present, is selected from hydrogen, C1-C4 alkyl, and Ar1; wherein Ar1, when present, is 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-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and unsubstituted phenyl; wherein each of R10a, R10b, and R11is independently selected from hydrogen, C1- C4 alkyl, Ar1, and ‒CH2Ar1; or wherein R10ais selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R10band R11are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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-C4hydroxyalkyl, 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 R12is selected from hydrogen, C1-C4 alkyl, and Ar1; or wherein each of R10aand R10bis independently selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R11and R12are covalently bonded and, together with theAttorney Docket No.37474.0111P1 intermediate atoms, comprise a 5- to 6-membered 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, or a salt thereof.

17. The compound of claim 16, wherein A is O.

18. The compound of claim 16 or claim 17, wherein R1is selected from C1-C8 alkyl and –C(O)(C1-C8 alkyl).

19. The compound of claim 16 or claim 17, wherein R1is selected from Cy1and – CH2Cy1.

20. The compound of claim 19, wherein Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C14 aryl, and C2-C10 heteroaryl, and is monosubstituted with a group selected from halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2- C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, 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 cycloalkyl, C2-C56- membered heterocycloalkyl, C6 aryl, and C2-C56-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 claim 19, wherein Cy1is selected from C6 cycloalkyl, C2-C56- membered heterocycloalkyl, C6 aryl, and C2-C56-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.Attorney Docket No.37474.0111P1 23. The compound of claim 19, wherein Cy1is selected from C3-C6 cycloalkyl and C6- C14 aryl, 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 19, wherein Cy1is selected from C3-C6 cycloalkyl and C6- C14 aryl, 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.

25. The compound of claim 19, wherein Cy1is 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.

26. The compound of claim 19, wherein Cy1is 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.

27. The compound of any one of claims 16 to 26, wherein each of R2and R3is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, ‒O(C2-C4 alkenyl), ‒O(C2-C4 alkynyl), and ‒OC6H5.

28. The compound of any one of claims 16 to 26, wherein each of R2and R3is independently selected from C1-C4 alkoxy, ‒O(C2-C4 alkenyl), ‒O(C2-C4 alkynyl), and ‒OC6H5.

29. The compound of any one of claims 16 to 26, wherein each of R2and R3is ethoxy.

30. The compound of any one of claims 16 to 26, wherein each of R2and R3is the same.Attorney Docket No.37474.0111P131. The compound of claim 16, wherein the compound has a structure represented by aformula:, or a salt thereof.

32. The compound of claim 16, wherein the compound has a structure represented by aformula:, or a salt thereof.

33. The compound of claim 16, wherein the compound has a structure represented by aformula:, wherein n is selected from 0 and 1; and wherein each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, halogen, –NO2, –CN, –OH, –SH, –NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, provided that at least two of R13a, R13b, R13c, R13d, and R13eare hydrogen, or a salt thereof.Attorney Docket No.37474.0111P134. The compound of claim 33, wherein the compound has a structure represented by aformula:, or a salt thereof.

35. The compound of claim 33, wherein the compound has a structure represented by aformula:, or a salt thereof.

36. The compound of claim 33, wherein the compound has a structure represented by aformula:, or a salt thereof.

37. The compound of claim 33, wherein the compound has a structure represented by aformula:, or a salt thereof.Attorney Docket No.37474.0111P138. The compound of claim 33, wherein the compound has a structure represented by aformula:,or a salt thereof.

39. The compound of claim 16, wherein the compound is selected from:,Attorney Docket No.37474.0111P1 ,or a salt thereof.

40. A kit comprising:(a) a N-thiosuccinimide having a structure represented by a formula:, wherein R1is selected from C1-C8 alkyl, –C(O)(C1-C8 alkyl), Cy1, and –CH2Cy1; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C14Attorney Docket No.37474.0111P1 aryl, and C2-C10 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; (b) a thioacid nucleophile having a structure represented by a formula:, wherein A is selected from O and S; wherein each of R2and R3is independently selected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, ‒O(C2-C4 alkenyl), ‒O(C2-C4 alkynyl), and ‒OC6H5, or wherein R2and R3are covalently bonded and, together with the intermediate atoms, comprise a 5-membered ring having a structure represented by a formula selected from:wherein Q is selected from O, S, and NR20; wherein R20, when present, is selected from hydrogen, C1-C4 alkyl, and Ar1; wherein Ar1, when present, is 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,Attorney Docket No.37474.0111P1 C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and unsubstituted phenyl; wherein each of R10a, R10b, and R11is independently selected from hydrogen, C1- C4 alkyl, Ar1, and ‒CH2Ar1; or wherein R10ais selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R10band R11are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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; and wherein R12is selected from hydrogen, C1-C4 alkyl, and Ar1; or wherein each of R10aand R10bis independently selected from hydrogen, C1-C4 alkyl, Ar1, and ‒CH2Ar1, and R11and R12are covalently bonded and, together with the intermediate atoms, comprise a 5- to 6-membered 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; and (c) a protic solvent.

41. The kit of claim 40, wherein the protic solvent is selected from methanol, ethanol, and isopropyl alcohol.

42. The kit of claim 40, wherein the protic solvent is ethanol.

Images