Synthesis of cantharidin

Abstract

To provide methods of preparing a compound useful as an intermediate in synthesis of cantharidin and analogs thereof.SOLUTION: A method of preparing a compound represented by formula (I) comprises reacting a compound represented by formula (II) in the presence of Pd, CO and a reagent of the formula R2OH. In the formulas, X1 is halogen, sulfonate, or phosphonate; and R1 and R2 are alkyl, aryl, heteroaryl, or the like.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 568,004, filed October 4, 2017, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Background of the Invention Cantharidin (1,2-dimethyl-3,6-epoxyperhydrophthalic anhydride) is a lipophilic compound traditionally obtained primarily from blister beetles of the Meloidae family. Cantharidin is an inhibitor of protein phosphatase 2A and has vesicant activity when applied to the skin. Due to its biological activity, cantharidin is used to treat various skin conditions, including common warts and molluscum. Chemical names for cantharidin include (3aR,4S,7R,7aS)-3a,7a-dimethylhexahydro-4,7-epoxyisobenzofuran-1,3-dione and 1,2-dimethyl-3,6-epoxyperhydrophthalic anhydride. Common names include cantharidin, cantharone, cantharidine, and cantaridin. The structure of cantharidin is as follows: [ka] As shown in.

[0003] The chemical synthesis of cantharidin has proven difficult. Early reported syntheses were time-consuming, low-yielding processes involving potentially hazardous operating conditions, making them commercially impractical. Some cantharidin syntheses have fewer steps and improved yields, but may require extreme reaction conditions or the use of dangerous reagents. Von Bruchhausen attempted the synthesis of cantharidin in 1928. See, for example, Von Bruchhausen, F.; Bersch, IW Arch. Pharm. Ber. Disch. Phurm. Ges. 1928, 266, 697-702 (incorporated herein by reference). His synthetic approach was based on the following retrosynthetic analysis: [ka]

[0004] Unfortunately, the Diels-Alder reaction between two reactants leads to an unfavorable equilibrium with respect to the desired product. As demonstrated in the following experiment, when natural cantharidin is dehydrogenated, it spontaneously undergoes a retro-Diels-Alder reaction. Studies have shown that the instability of the Diels-Alder product is due to repulsion between the methyl groups at C1 and C2, and between these methyl groups and the internal hydrogens at C3 and C6. [ka]

[0005] In 1951, Stork published a synthesis of cantharidin, but it was not economically viable. See, for example, Stork, G.; et al. J. Am. Chem. Soc. 1951, 73, 4501; and Stork, G.; van Tamelen, EE; Friedman, LI; Burgstahler, AWJ Am. Chem. Soc. 1953, 75, 384 (both of which are incorporated herein by reference). This is a time-consuming, linear, multi-step, and low-yield process. On a large scale, this process is expensive and requires the use of hazardous reagents that can cause worker injuries and unacceptable environmental disposal problems.

[0006] In 1953, Schenck published a Diels-Alder-based approach to cantharidin. See, e.g., Schenck, G.; Wirtz, R. Naturwissenshaften 1953, 40, 531 (incorporated herein by reference). However, it still suffers from many of the problems mentioned above, including a lengthy, low-yielding, linear, multi-step synthesis. Its use on a manufacturing scale may require the large-scale use of toxic bromine and the disposal of environmentally harmful wastewater streams of brominated by-products.

[0007] In 1976, Dauben began investigating extremely high-pressure conditions for synthesizing cantharidin. See, for example, Dauben, WG; Kessel, CR; Takemura, KHJ Am. Chem. Soc. 1980, 102, 6893-6894; and Dauben, WG; Krabbenhoft, II. OJ Am. Chem. Soc. 1976, 98, 1992-1993 (both of which are incorporated herein by reference). While this synthesis requires fewer steps to prepare cantharidin in good yield, the extreme pressures of 4–15 kilobars (kbar) required for the Diels-Alder step can be dangerous for commercial-scale production. When performed in multiple small batches, the process may not be economically attractive. This step also requires significant capital investment in exotic hydraulic high-pressure manufacturing equipment and protective containment vessels to ensure the safety of workers and the community. The Dauben process is shown in the following scheme: [ka]

[0008] In 1990, Grieco demonstrated that the addition of 5 molar (M) lithium perchlorate in diethyl ether could promote the Diels-Alder reaction reported by Dauben at ambient temperature and pressure, rather than the extreme pressures described above. See, for example, Grieco, PA et al. J. Am. Chem. Soc. 1990, 112, 4595–4596 (incorporated herein by reference). Unfortunately, lithium perchlorate is a highly energetic oxidizing agent and can form explosion-sensitive or highly explosive mixtures when combined with organic materials or metals. This includes standard reagents (sodium) and standard plant materials (stainless steel). Therefore, the use of this procedure significantly impacts the equipment required to carry out this process, e.g., a completely glass-lined reactor system, including all piping and valves. Additionally, diethyl ether is a highly volatile and flammable solvent. This reaction mixture of an energetic oxidizing agent and an easily ignitable solvent can be dangerous even under controlled, small-scale conditions. Additionally, perchlorate ions may be considered a serious environmental pollutant, especially if released into groundwater. Perchlorate may exhibit adverse effects on human health, specifically targeting iodine metabolism in the thyroid gland. This combination of serious safety and environmental impact issues for this synthesis makes its use untenable as a process for the commercial production of cantharidin. However, the basic outline of this process is attractive for a commercial process using this short synthetic strategy. The Grieco process is outlined in the following scheme: [ka]

[0009] Subsequent work by Handy in 1995 demonstrated that lithium trifluoromethanesulfonimide in diethyl ether or acetone also afforded good yields of the Diels-Alder adduct. See, for example, Handy, ST; Grieco, PA; Mineur, C.; Ghosez, L.; Synlett 1995, 565-567 (incorporated herein by reference). Unfortunately, this variant exhibits a significant erosion in the exo-endo Diels-Alder product ratio. The exo-endo product can be difficult to separate, resulting in significant loss of the desired product required for subsequent conversion to cantharidin. Such losses, occurring very slowly in the synthesis, can adversely affect the cost and ultimate profitability of drug production. Additionally, controlling the increased amount of endo by-products in the production stream can add to regulatory and production quality control burdens and waste disposal costs.

[0010] Some recent developments useful for the synthesis of cantharidin and its analogs are described, for example, in International Publication No. WO2016 / 100732, published June 23, 2016, the entire contents of which are incorporated herein by reference.

[0011] Despite these advances in cantharidin synthesis, there remains a need for useful new methods for the synthesis of cantharidin and its analogs. Preferably, these methods include mild conditions that can be used to produce cantharidin on a commercial scale, with continued improvements in yield and selectivity, and cantharidin analogs and derivatives that may be biologically active. Summary of the Invention

[0012] SUMMARY OF THE INVENTION This invention relates, in part, to improved methods for preparing cantharidin and its analogs. For example, it has been discovered that the Diels-Alder reaction of compound (2) with furan can be carried out in the absence of increased pressure and / or in the absence of added acid (e.g., Lewis acid) to produce compound (1) (see Scheme 1). [ka]

[0013] This advance eliminates many of the disadvantages associated with previous cantharidin syntheses, including the high pressures and / or Lewis acids typically required for the key Diels-Alder step. For example, in certain embodiments, compound (1) is formed by reacting compound (2) with furan at atmospheric pressure in the absence of a Lewis acid. In certain embodiments, compound (1) is formed by reacting compound (2) with furan in a polar solvent (e.g., a polar aprotic solvent, e.g., NMP) at atmospheric pressure in the absence of a Lewis acid. In certain embodiments, compound (1) is formed by reacting compound (2) with furan at temperatures above room temperature (e.g., 40-50°C) in a polar solvent (e.g., NMP) at atmospheric pressure in the absence of a Lewis acid. As discussed herein, the product of the Diels-Alder reaction, compound (1), is useful as a key intermediate in the synthesis of cantharidin and its analogs.

[0014] As discussed herein, provided herein is compound (1): [ka] A method for preparing compound (2): [ka] in the presence of furan; wherein the reaction is carried out in the absence of an acid (i.e., in the absence of a Lewis acid or a Bronsted acid) and in the absence of increased pressure (e.g., at about atmospheric pressure). In certain embodiments, the reaction is carried out in the absence of a Lewis acid. In certain embodiments, the reaction is carried out in the absence of a Bronsted acid.

[0015] In some embodiments, the Diels-Alder reaction is carried out in a solvent. In some embodiments, the solvent is a polar solvent. In some embodiments, the Diels-Alder reaction is carried out in an aprotic polar solvent (e.g., acetone, ethyl acetate, furan, acetonitrile, N-methyl-2-pyrrolidone (NMP), dimethylformamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, sulfolane, dimethyl sulfone). In some embodiments, the reaction is carried out at room temperature or above (e.g., room temperature to 100°C, e.g., 40 to 50°C). In some embodiments, the reaction is carried out in the absence of increased pressure (e.g., at about atmospheric pressure). In some embodiments, the reaction is carried out in an aprotic polar solvent (e.g., NMP) with slight heating (e.g., at a temperature of room temperature to 100°C, e.g., at approximately 45°C) and at atmospheric pressure (i.e., at about 1 atm).

[0016] Also provided herein is a method for preparing compounds of formula (I), which are useful as intermediates in the synthesis of cantharidin and its analogs. The method for preparing compounds of formula (I) involves a novel palladium-mediated carbonylation of compounds of formula (II), as shown in Scheme 2. [ka]

[0017] As shown in Scheme 2, provided herein are compounds of formula (I): [ka] A method for preparing a compound represented by formula (II): [ka] is reacted with palladium, carbon monoxide, and a compound represented by formula R 2 reacting in the presence of an alcohol of OH, During the ceremony: X 1 is a halogen, an optionally substituted sulfonate, or an optionally substituted phosphate; R 1 and R 2 are independently optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or an oxygen protecting group; The method includes:

[0018] The methods provided herein can be applied to the synthesis of cantharidin, for example, as shown in Scheme 3. After the Diels-Alder reaction, compound (1) can be hydrogenated and reduced to form cantharidin (Scheme 3). In some embodiments, the hydrogenation and reduction are carried out in the same step. [ka]

[0019] The present invention further provides methods useful in the preparation of cantharidin and its analogs. For example, alternative routes to cantharidin provided herein are outlined in Scheme 5. These routes also include novel Diels-Alder reactions; specifically, the Diels-Alder reaction between a compound of formula (III) and furan to produce a cycloadduct of formula (IV). In some embodiments, the Diels-Alder reaction is carried out in the absence of added acid (e.g., a Lewis acid) and without the aid of elevated pressure (i.e., at about atmospheric pressure). The compound of formula (IV) can then be hydrogenated, desulfurized, and hydrolyzed / dehydrated, in any order, to produce cantharidin. [ka]

[0020] The present invention also provides compounds useful in the synthesis of cantharidin and its analogs (e.g., compounds represented by formulas (I), (II), (III), (IV), (V), and (VI)).

[0021] The synthetic intermediates provided herein may also have promising biological activity. Accordingly, provided herein is a pharmaceutical composition comprising a compound represented by Formula (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Also provided herein is a method for treating a disease or condition (e.g., an infectious disease or a skin condition) in a subject, comprising administering to the subject a compound represented by Formula (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein is the use of a compound represented by Formula (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating a disease or condition (e.g., an infectious disease or a skin condition). In yet another aspect, the present invention provides a kit comprising a compound or pharmaceutical composition described herein.

[0022] Details of certain aspects of the invention are set forth in the Detailed Description of Certain Aspects below. Other features, objects, and advantages of the invention will be apparent from the definition, examples, and claims. DETAILED DESCRIPTION OF THE INVENTION

[0023] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS The present invention provides methods for the synthesis of cantharidin and its analogs and intermediates useful in the synthesis. In one aspect, the present invention provides a method for the synthesis of compound (1) using the Diels-Alder reaction between compound (2) and furan. For this reaction, the present invention provides improved conditions that provide a safer, scalable, and / or more economical synthesis of compound (1). In another aspect, the present invention provides a method for the preparation of a compound represented by formula (I) based on palladium-mediated carbonylation of a compound represented by formula (II). The compound represented by formula (I) is useful as an intermediate in the preparation of cantharidin and its analogs. In yet another aspect, the present invention provides compounds / intermediates useful in the synthesis of cantharidin and its analogs.

[0024] The synthetic intermediates provided herein may also have promising biological activity, for example, as anti-infective agents or agents for treating various skin conditions. Accordingly, provided herein are pharmaceutical compositions, methods, uses, and kits for treating diseases or conditions.

[0025] Method for preparing compound (1) Provided herein is compound (1): [ka] A method for preparing compound (2): [ka] reacting with furan; wherein the reaction is carried out in the absence of an acid; and wherein the reaction is carried out in the absence of increased pressure (e.g., at approximately 1 atm); The method comprises:

[0026] The Diels-Alder reaction described above is carried out in the absence of an acid. In some embodiments, the reaction is carried out in the absence of added acid (i.e., no acid is added to the reaction mixture). In some embodiments, the reaction is carried out in the absence of a Lewis acid. In some embodiments, the reaction is carried out in the absence of added Lewis acid or added Bronsted acid. In some embodiments, the reaction mixture consists essentially of compound (2), furan, and a solvent.

[0027] In some embodiments, the reaction is carried out in the absence of perchlorate. In some embodiments, the reaction is carried out in the absence of magnesium perchlorate (MgClO4). In some embodiments, the reaction is carried out in the absence of lithium perchlorate (LiClO4). In some embodiments, the reaction is carried out in the absence of lithium trifluoromethanesulfonimide. In some embodiments, the reaction is carried out in the absence of one or more Lewis acids described in International Publication No. WO2016 / 100732, published June 23, 2016, the entire contents of which are incorporated herein by reference.

[0028] The Diels-Alder reaction provided above is carried out in the absence of increased pressure (i.e., at approximately atmospheric pressure (1 atm)).

[0029] In some embodiments, the reaction is carried out in a solvent. In some embodiments, the solvent is a polar solvent. In some embodiments, the Diels-Alder reaction is carried out in an aprotic polar solvent (e.g., acetone, ethyl acetate, tetrahydrofuran, acetonitrile, N-methyl-2-pyrrolidone (NMP), dimethylformamide, dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, sulfolane, dimethyl sulfone). In some embodiments, the solvent is an amide, lactam, or urea, such as N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone (DMI), or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU). In other embodiments, the solvent is a sulfone (e.g., sulfolane, dimethyl sulfone). In some embodiments, the solvent is NMP. In some embodiments, the solvent is a co-solvent containing NMP. Other examples of polar solvents include, but are not limited to, ketones and nitriles, such as acetone and acetonitrile. In some embodiments, the polar solvent is selected from the group consisting of DMF, NMP, DMI, DMPU, acetone, and acetonitrile. In some embodiments, the polar solvent is selected from the group consisting of NMP, DMPU, acetone, and acetonitrile.

[0030] In some embodiments, the reaction is carried out in the absence of a solvent. In some embodiments, the reaction is carried out in an ionic liquid. In some embodiments, the reaction is carried out in a ball mill reactor.

[0031] The reaction can be carried out at any concentration of reactants in the solvent or reaction mixture. In some embodiments, the concentration of compound (2) in the solvent or reaction mixture is approximately 0.01 molar (mol / L, M), 0.02M, 0.03M, 0.04M, 0.05M, 0.06M, 0.07M, 0.08M, 0.09M, 0.1M, 0.2M, 0.3M, 0.4M, 0.5M, 0.6M, 0.7M, 0.8M, 0.9M, 1M, 2M, 3M, 4M, 5M, 6M, 7M, 8M, 9M, or 10M. In some embodiments, the reaction is carried out at a concentration of 1 to 20M in solution with respect to compound (2). In some embodiments, the concentration is 5 to 15M. In some embodiments, the concentration is 10 to 15M.

[0032] The reaction may be carried out at any temperature. The reaction temperature may be approximately 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, or 150°C. In some embodiments, the reaction temperature is greater than 100°C. In some embodiments, the reaction is carried out at a temperature less than 100°C. In some embodiments, the reaction is carried out at a temperature greater than room temperature (21°C or 70°F). In some embodiments, the temperature is between room temperature and 100°C. In some embodiments, the reaction is carried out at a temperature between 30 and 60°C. In some embodiments, the reaction is carried out at a temperature between 40 and 50°C. In some embodiments, the reaction is carried out at approximately 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, or 50°C. In some embodiments, the reaction is carried out at approximately 45°C.

[0033] The reaction may be carried out for any length of time. The reaction time may be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, more than 5 hours, 10 hours, more than 10 hours, 15 hours, or 20 hours or more. In some embodiments, the reaction time is more than 20 hours. In some embodiments, the reaction time is one day or more. In some embodiments, the reaction time is more than one day.

[0034] The reaction mixture may contain any ratio of reactants, specifically, compound (2) and furan. In some embodiments, furan is present in the reaction mixture in an amount greater than 1 equivalent (i.e., in excess) relative to the amount of compound (2). In some embodiments, the ratio of compound (2) to furan in the reaction mixture is 1:1 to 1:20. In some embodiments, the ratio of compound (2) to furan in the reaction mixture is 1:1 to 1:10. In some embodiments, the ratio of compound (2) to furan in the reaction mixture is approximately 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or 1:20. In some embodiments, the ratio of compound (2) to furan in the reaction mixture is 1:4 to 1:5. In certain embodiments, the ratio of compound (2) to furan in the reaction mixture is about 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, or 1:4.9.

[0035] As described herein, the reaction may be carried out in the absence of added acid (e.g., Lewis acid and / or Bronsted acid) at approximately 1 atm. In some cases, the reaction solvent and temperature may be varied as follows: In some embodiments, the reaction is carried out in a polar solvent at room temperature or above. In some embodiments, the reaction is carried out in a polar solvent at room temperature to 100°C. In some embodiments, the reaction is carried out in a polar solvent at elevated temperatures (i.e., above room temperature). In some embodiments, the reaction is carried out in a polar solvent at a temperature of room temperature to 100°C. In some embodiments, the reaction is carried out in a polar solvent at a temperature of 30°C to 100°C. In some embodiments, the reaction is carried out in a polar solvent at a temperature of 30°C to 60°C. In some embodiments, the reaction is carried out in a polar solvent at a temperature of 40°C to 50°C. In some embodiments, the reaction is carried out in a polar solvent at a temperature of approximately 50°C. In some embodiments, the reaction is carried out in a polar solvent at a temperature of approximately 45°C. In some embodiments, the reaction is carried out in a polar solvent at a temperature of approximately 40°C. In some embodiments, the reaction is carried out in NMP at room temperature or above. In some embodiments, the reaction is carried out in NMP at room temperature to 100°C. In some embodiments, the reaction is carried out in NMP at elevated temperatures (i.e., above room temperature). In some embodiments, the reaction is carried out in NMP at a temperature of room temperature to 100°C. In some embodiments, the reaction is carried out in NMP at a temperature of 30°C to 100°C. In some embodiments, the reaction is carried out in NMP at a temperature of 30°C to 60°C. In some embodiments, the reaction is carried out in NMP at a temperature of 40°C to 50°C. In some embodiments, the reaction is carried out in NMP at a temperature of approximately 50°C. In some embodiments, the reaction is carried out in NMP at a temperature of approximately 45°C. In some embodiments, the reaction is carried out in NMP at a temperature of approximately 40°C.

[0036] In the methods provided herein, compound (1) can be formed as an exo or endo cycloadduct, or as a mixture of exo and endo cycloadducts. The "exo" and "endo" adducts are shown below. [ka]

[0037] For cantharidin, a high exo-to-endo ratio is desirable. In some embodiments, the Diels-Alder method provided herein provides a preferred exo-to-endo ratio. For example, the exo-to-endo product ratio produced by the methods disclosed herein can be at least about 80:20, 81:19, 82:18, 83:17, 84:16, 85:15, 86:14, 87:13, 88:12, 89:11, 90:10, 91:9, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. The percentage of exo product per total amount of product can be at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, 99.999%, or 100%. In some embodiments, the exo / endo ratio is about 70:30 to 99:1. In some embodiments, the exo / endo ratio is about 70:30 to 90:10. In some embodiments, the exo / endo ratio is about 70:30 to 80:20. In some embodiments, the exo / endo ratio is about 70:30, 71:29, 72:28, 73:27, 74:26, 75:25, 76:24, 77:23, 78:22, 79:21, or 80:20. In some embodiments, the exo / endo ratio is about 75:25. In some embodiments, the exo / endo ratio is about 80:20 to about 90:10. In some embodiments, the exo / endo ratio is about 80:20. In some embodiments, the exo / endo ratio is about 81:19. In some embodiments, the exo / endo ratio is about 82:18. In some embodiments, the exo / endo ratio is about 83:17. In some embodiments, the exo / endo ratio is about 84:16. In some embodiments, the exo / endo ratio is about 85:15. In some embodiments, the exo / endo ratio is about 86:14. In some embodiments, the exo / endo ratio is about 87:13. In some embodiments, the exo / endo ratio is about 88:12. In some embodiments, the exo / endo ratio is about 89:11. In some embodiments, the exo / endo ratio is about 90:10.In some embodiments, the exo / endo ratio is about 95:5. In some embodiments, the exo / endo ratio is about 98:2. In some embodiments, the exo / endo ratio is about 99:1. In some embodiments, the exo / endo ratio is about 99.10:0.10.

[0038] Any of these exo / endo ratios can be achieved, in some embodiments, by reacting compound (2) with furan in an aprotic polar solvent (e.g., NMP) at about atmospheric pressure in the absence of added acid while heating above room temperature (e.g., room temperature to 100°C, e.g., 40 to 50°C). In some embodiments, an exo / endo ratio of about 70:30 to about 90:10 can be achieved by reacting compound (2) with furan in an aprotic polar solvent (e.g., NMP) at about atmospheric pressure in the absence of added acid while heating above room temperature (e.g., room temperature to 100°C, e.g., 40 to 50°C). In one embodiment, an exo / endo ratio of about 80:20 to about 90:10 is achieved by reacting compound (2) with furan in an aprotic polar solvent (e.g., NMP) at about atmospheric pressure in the absence of added acid while heating above room temperature (e.g., room temperature to 100°C, e.g., 40 to 50°C). In one embodiment, an exo / endo ratio of about 75:25 is achieved by reacting compound (2) with furan in an aprotic polar solvent (e.g., NMP) at about atmospheric pressure in the absence of added acid while heating above room temperature (e.g., room temperature to 100°C, e.g., 40 to 50°C). In one embodiment, an exo / endo ratio of approximately 84:16 is achieved by reacting compound (2) with furan in an aprotic polar solvent (e.g., NMP) at about atmospheric pressure in the absence of added acid while heating above room temperature (e.g., room temperature to 100°C, e.g., 40 to 50°C).

[0039] Compound (1) can be formed in any chemical yield. In some embodiments, the compound is produced in a yield of 1-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%. In some embodiments, the compound is produced in a yield of approximately 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%. In some embodiments, compound (1) is isolated in a yield of greater than 50%. In some embodiments, compound (1) is isolated in a yield of about 50-60%. The compounds may be isolated as mixtures or endo and exo products as described above and herein.

[0040] In some embodiments, compound (1) can be prepared and isolated with high chemical purity by the methods described herein. In some embodiments, compound (1) is isolated with greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% purity. In some embodiments, compound (1) is isolated with greater than 90% purity. In some embodiments, compound (1) is isolated with greater than 95% purity. In some embodiments, compound (1) is isolated with greater than 98% purity. In some embodiments, compound (1) is isolated with greater than 99% purity.

[0041] In some embodiments, any chemical yield can be achieved by reacting compound (2) with furan in an aprotic polar solvent (e.g., NMP) at about atmospheric pressure in the absence of added acid while heating above room temperature (e.g., room temperature to 100°C, e.g., 40 to 50°C). For example, in some embodiments, a chemical yield of at least 50% of compound (1) can be achieved by reacting compound (2) with furan in an aprotic polar solvent (e.g., NMP) at about atmospheric pressure in the absence of added acid while heating above room temperature (e.g., room temperature to 100°C, e.g., 40 to 50°C). In some embodiments, a chemical yield of 50 to 60% of compound (1) can be achieved by reacting compound (2) with furan in an aprotic polar solvent (e.g., NMP) at about atmospheric pressure in the absence of added acid while heating above room temperature (e.g., room temperature to 100°C, e.g., 40 to 50°C).

[0042] After formation, compound (1) may be purified via one or more purification steps. For example, in certain embodiments, compound (1) is purified by chromatography, extraction, filtration, precipitation, crystallization, trituration, or any other method known in the art. In certain embodiments, the compound is carried forward to subsequent synthetic steps without purification (i.e., crude). In certain embodiments, the purification step improves the exo / endo ratio of the product mixture.

[0043] In certain embodiments, the reaction for preparing compound (1) described herein is followed by a step of recrystallizing compound (1). Compound (1) may be recrystallized from any solvent or mixture of solvents. In certain embodiments, compound (1) is dissolved in a solvent, and then a second solvent is added to the solution to promote precipitation of the recrystallized compound (1). As an example, in certain embodiments, compound (1) is recrystallized from ethyl acetate (EtOAc) and hexane. For example, compound (1) may be dissolved in EtOAc, and crystalline compound (1) may be precipitated by adding hexane to the solution. The recrystallizing step may include heating and / or cooling the solution.

[0044] In certain embodiments, the recrystallization step improves the exo / endo ratio of the compound mixture. In certain embodiments, compound (1) is isolated with an exo / endo ratio of greater than 90:10 after recrystallization. For example, in certain embodiments, compound (1) is isolated with an exo / endo ratio of 95:5, 96:4, 97:3, 98:2, or 99:1 after recrystallization. In certain embodiments, compound (1) is isolated with a yield of greater than 30% after recrystallization. For example, in certain embodiments, compound (1) is isolated with a yield of 30-40% after recrystallization.

[0045] As described herein, compound (1) can be formed via the Diels-Alder reaction of compound (2) with furan without the aid of acid or increased pressure. This invention is significant for several reasons. Based on Dauben's work in the 1980s (see, e.g., JACS, 102, 6893 (1980) and JOC, 50, 2576-2578 (1985)), this Diels-Alder cycloaddition was predicted to be highly demanding, exotic, and require extreme pressure. At this time, previous work demonstrated that the retro-Diels-Alder reaction of dehydrocantharidin and related systems was facile. Recognizing this, Dauben pursued the cycloaddition of compound (2) to compound (1) using extremely high pressures (>7 kbar). Later, Grieco (see, e.g., JACS, 112, 4595-459 (1990)) used a highly concentrated ethereal solution of lithium perchlorate (Lewis acid) to promote the reaction. A second Grieco method using lithium trifluoromethanesulfonimide (Lewis acid) also produced the desired adduct (1), but with erosion of the desired exo-endo ratio. As noted herein, neither Dauben's nor Grieco's conditions supported large-scale commercial production. It was later discovered that alternative Lewis acids could replace the lithium Lewis acid in Grieco's procedure (International Publication No. WO2016 / 100732, published June 23, 2016, the entire contents of which are incorporated herein by reference).

[0046] The discovery that compound (1) can be formed using the reaction conditions described herein is a surprising advance. It is particularly unexpected that compound (1) can be formed from compound (2) in the absence of an acid promoter and without the assistance of pressure. For example, in certain embodiments, mixing solutions of the two reactants in an aprotic polar solvent (e.g., acetonitrile, NMP, DMPU, and acetone) with moderate warming produces compound (1) with a favorable ratio of exo-endo isomers (e.g., greater than 80:20). Furthermore, in certain embodiments, isolation of the desired product, compound (1), can be easily achieved in favorable yield and high purity. The fact that such simple reaction conditions are all that is required for the successful formation of adduct (1) from compound (2) and furan is surprising and unexpected, based on 37 years of precedent. The success of these specific Diels-Alder conditions is unexpected for these two substrates. Notably, these new reaction conditions are highly suitable for industrial-scale production of cantharidin. A reaction mixture consisting essentially of compound (2), furan, and solvent is ideal for commercial production because industrial hazards and toxic waste disposal are minimized.

[0047] As described herein, compound (1) can be used to prepare cantharidin, for example, as shown in Scheme 6. Compound (1) can be hydrogenated and reduced to form cantharidin. In some embodiments, the hydrogenation and reduction steps are performed in the same reaction. In other embodiments, the hydrogenation and reduction steps are performed in separate, subsequent reactions. [ka]

[0048] Thus, in some embodiments, the methods provided herein comprise administering to a subject a compound (1): [ka] is hydrogenated to give compound (3): [ka] The method further includes providing:

[0049] The hydrogenation reaction may be carried out in the presence of palladium or platinum. The hydrogenation reaction may be carried out using, for example, Pd / C, Pd, PdCl, PtO, or Pt / C. In some embodiments, the reaction may be carried out in the presence of H. The reaction may be carried out under transfer hydrogenation conditions (e.g., in the presence of 1,4-cyclohexadiene). The hydrogenation reaction may be carried out as described in International Publication No. WO2016 / 100732, published June 23, 2016, the entire contents of which are incorporated herein by reference.

[0050] The hydrogenation reaction may be carried out in a solvent. Examples of solvents are provided herein. In some embodiments, the solvent is ethyl acetate. The reaction may be carried out at any concentration of reactants in the solvent or reaction mixture. In some embodiments, the concentration of compound (1) in the solvent or reaction mixture is approximately 0.01 molar (mol / L, M), 0.02M, 0.03M, 0.04M, 0.05M, 0.06M, 0.07M, 0.08M, 0.09M, 0.1M, 0.2M, 0.3M, 0.4M, 0.5M, 0.6M, 0.7M, 0.8M, 0.9M, 1M, 2M, 3M, 4M, 5M, 6M, 7M, 8M, 9M, or 10M.

[0051] The reaction may be carried out at any temperature. The reaction temperature may be approximately -100°C, -90°C, -0°C, -78°C, -70°C, -60°C, -50°C, -40°C, -30°C, -20°C, -10, 0°C, -10°C, 20°C, room temperature, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, or 150°C. In some embodiments, the reaction temperature is greater than 150°C. In some embodiments, the reaction temperature is about room temperature (21°C or 70°F). In some embodiments, the reaction is carried out at a temperature greater than room temperature. In some embodiments, the temperature is between room temperature and 100°C.

[0052] The reaction may be carried out for any length of time. The reaction time may be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, more than 5 hours, 10 hours, more than 10 hours, 15 hours, or 20 hours or more. In some embodiments, the reaction time is more than 20 hours. In some embodiments, the reaction time is one day or more. In some embodiments, the reaction time is more than one day.

[0053] Compound (3) can be formed in any chemical yield. In some embodiments, the compound is produced in a yield of 1-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%. In some embodiments, the compound is produced in a yield of approximately 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%.

[0054] In some embodiments, compound (3) can be isolated with high chemical purity by the methods described herein. In some embodiments, compound (3) is isolated with greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% purity. In some embodiments, compound (3) is isolated with greater than 90% purity. In some embodiments, compound (3) is isolated with greater than 95% purity. In some embodiments, compound (3) is isolated with greater than 98% purity. In some embodiments, compound (3) is isolated with greater than 99% purity.

[0055] After formation, compound (3) may be purified via one or more purification steps. For example, in some embodiments, compound (3) is purified by chromatography, extraction, filtration, precipitation, crystallization, or any other method known in the art. In some embodiments, the compound is carried forward to subsequent synthetic steps without purification (i.e., crude).

[0056] In one embodiment, as shown in Scheme 6, the method comprises the step of preparing compound (3): [ka] Reduces to cantharidin: [ka] The method further includes the step of producing the

[0057] In some embodiments, reduction (also referred to as "desulfurization") is carried out in the presence of a reducing agent. In some embodiments, the reducing agent is Raney nickel, Ni(II) / NaBH, Co(II) / NaBH, Li / EtNH, LAH / TiCl, LAH / CuCl, Ni(II) / Zn, Ni(II) / Al, or LAH / CpNi. In some embodiments, the reducing agent is Raney Ni.

[0058] The reaction may be carried out in a solvent. Examples of solvents are provided herein. The reaction may be carried out in a solvent or reaction mixture at any concentration of reactants. In some embodiments, the concentration of compound (3) in the solvent or reaction mixture is approximately 0.01 molar (mol / L, M), 0.02M, 0.03M, 0.04M, 0.05M, 0.06M, 0.07M, 0.08M, 0.09M, 0.1M, 0.2M, 0.3M, 0.4M, 0.5M, 0.6M, 0.7M, 0.8M, 0.9M, 1M, 2M, 3M, 4M, 5M, 6M, 7M, 8M, 9M, or 10M.

[0059] The reaction may be carried out at any temperature. The reaction temperature may be approximately -100°C, -90°C, -0°C, -78°C, -70°C, -60°C, -50°C, -40°C, -30°C, -20°C, -10, 0°C, -10°C, 20°C, room temperature, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, or 150°C. In some embodiments, the reaction temperature is greater than 150°C. In some embodiments, the reaction temperature is approximately room temperature (21°C or 70°F). In some embodiments, the reaction is carried out at a temperature greater than room temperature. In some embodiments, the temperature is between room temperature and 100°C. The reaction temperature may be between -20°C and 100°C in other embodiments. In some cases, these reactions may be facilitated with the aid of sonication or microwave heating.

[0060] The reaction may be carried out for any length of time. The reaction time may be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, more than 5 hours, 10 hours, more than 10 hours, 15 hours, or 20 hours or more. In some embodiments, the reaction time is more than 20 hours. In some embodiments, the reaction time is one day or more. In some embodiments, the reaction time is more than one day.

[0061] Cantharidin can be formed in any chemical yield. In some embodiments, the compound is produced in a yield of 1-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%. In some embodiments, the compound is produced in a yield of approximately 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%.

[0062] After formation, cantharidin can be purified through one or more purification steps.For example, in some embodiments, cantharidin can be purified by chromatography, extraction, filtration, precipitation, crystallization or any other method known in the art.In some embodiments, compound can be carried forward to the next synthesis step without purification (i.e., crude).

[0063] In some embodiments, the hydrogenation step and the reduction step are carried out in separate reactions. In some embodiments, the hydrogenation step and the reduction step are carried out in the same reaction. The hydrogenation step and the reduction step can be carried out in any order. Other examples of reagents and conditions useful for these hydrogenation and desulfurization reactions can be found, for example, in International Publication No. WO2016 / 100732, published June 23, 2016, the entire contents of which are incorporated herein by reference.

[0064] In some embodiments, cantharidin can be prepared and isolated with high chemical purity by the method described herein.In some embodiments, cantharidin is isolated with a purity of more than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%.In some embodiments, cantharidin is isolated with a purity of more than 90%.In some embodiments, cantharidin is isolated with a purity of more than 95%.In some embodiments, cantharidin is isolated with a purity of more than 98%.In some embodiments, cantharidin is isolated with a purity of more than 99%.In some embodiments, cantharidin is isolated with a purity of more than 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%.

[0065] Also provided herein is a high-purity cantharidin composition produced by any of the methods described herein. A high-purity cantharidin composition as described herein is highly pure with respect to the cantharidin component of the composition (i.e., without taking into account other active agents, excipients, carriers, solvents, etc. present in the composition). For example, a high-purity cantharidin component of the composition contains a high concentration of cantharidin with respect to synthetic intermediates, reaction by-products, or degradation products of cantharidin. In some embodiments, the purity is greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% with respect to the cantharidin component. In some embodiments, the purity is greater than 90% with respect to the cantharidin component. In some embodiments, the purity is greater than 95% with respect to the cantharidin component. In some embodiments, the purity is greater than 98% with respect to the cantharidin component. In some embodiments, the purity is greater than 99% with respect to the cantharidin component. In some embodiments, the purity is greater than 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% pure.

[0066] Other methods useful for the synthesis of cantharidin Scheme 5 outlines other methods provided herein that are useful for preparing cantharidin and its analogs. Specifically, an intermediate represented by formula (IV) can be formed via a novel Diels-Alder reaction between a compound represented by formula (III) and furan. The Diels-Alder reaction can proceed with or without the assistance of an acid (e.g., a Lewis acid) and with or without the assistance of increased pressure. In some embodiments, the Diels-Alder reaction proceeds without the assistance of added acid and without increased pressure (i.e., at about atmospheric pressure). The compound represented by formula (IV) can then be hydrogenated to provide a compound represented by formula (V). The compound represented by formula (V) can then be converted to cantharidin via two alternative pathways as shown in Scheme 5. [ka]

[0067] Provided herein are compounds of formula (IV): [ka] A method for preparing a compound represented by formula (III): [ka] in the presence of furan, wherein: n is 0, 1, 2, 3, 4, or 5; R 3 each occurrence is independently selected from hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR O , -N(R N )2, or -SR S and; R O each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; R Neach occurrence of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally, two R on the same nitrogen N are joined together with the intervening atoms to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; and R S each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; The method includes:

[0068] In certain embodiments, the reaction is carried out in the presence of a Lewis acid, and at least one Lewis acid may contain a Lewis metal selected from the group consisting of Li(I), Mg(II), B(III), Al(III), Ti(IV), Zr(IV), Zn(II), Cu(I), Cu(II), Sn(II), Sn(IV), Si(IV), La(III), Sc(III), Yb(III), Eu(III), Ga(III), Sb(V), Nb(V), Fe(III), and Co(III). The at least one Lewis acid may be selected from lithium perchlorate, magnesium perchlorate, aluminum chloride, lithium trifluoromethanesulfonate, lithium trifluoromethanesulfonamide, tin(II) trifluoromethanesulfonate, bis(cyclopentadienyl)zirconium(IV) bis(trifluoromethanesulfonate)tetrahydrofuran complex, bis(cyclopentadienyl)titanium(IV) bis(trifluoromethanesulfonate), boron trifluoride diethyl etherate, and gallium(III) chloride. The at least one Lewis acid may be selected from copper(II) tetrafluoroborate hydrate, aluminum bromide, niobium(V) chloride, ytterbium(III) trifluoromethanesulfonate, scandium(III) trifluoromethanesulfonate, magnesium trifluoromethanesulfonate, trimethylsilyl trifluoromethanesulfonate, and copper(II) trifluoromethanesulfonate. The concentration of the Lewis acid may be 0.01 molar (moles per liter, M), 0.02M, 0.03M, 0.04M, 0.05M, 0.06M, 0.07M, 0.08M, 0.09M, 0.1M, 0.2M, 0.3M, 0.4M, 0.5M, 0.6M, 0.7M, 0.8M, 0.9M, 1M, 2M, 3M, 4M, 5M, 6M, 7M, 8M, 9M, or 10M or more.

[0069] The reaction can be carried out at any pressure. In some embodiments, the reaction is carried out at a pressure of about 1000 atmospheres (atm), 980 atm, 975 atm, 950 atm, 925 atm, 900 atm, 875 atm, 850 atm, 825 atm, 800 atm, 775 atm, 750 atm, 725 atm, 700 atm, 675 atm, 650 atm, 625 atm, 600 atm, 575 atm, 550 atm, 525 atm, 500 atm, 475 atm, 450 atm, 425 atm, 400 atm, 3 The reaction is carried out at a pressure of 75 atm, 350 atm, 325 atm, 300 atm, 275 atm, 250 atm, 225 atm, 200 atm, 175 atm, 150 atm, 125 atm, 100 atm, 75 atm, 50 atm, 45 atm, 40 atm, 35 atm, 30 atm, 25 atm, 20 atm, 15 atm, 10 atm, 9 atm, 8 atm, 7 atm, 6 atm, 5 atm, 4 atm, 3 atm, 2 atm, or 1 atm or less. In some embodiments, the reaction is carried out at a pressure greater than 1000 atmospheres (atm).

[0070] The described Diels-Alder reaction is carried out in the absence of an acid. In some embodiments, the reaction is carried out in the absence of added acid (i.e., no acid is added to the reaction mixture). In some embodiments, the reaction is carried out in the absence of added Lewis acid or added Bronsted acid. In some embodiments, the reaction mixture consists essentially of a compound represented by Formula (III), furan, and a solvent.

[0071] In some embodiments, the reaction is carried out in the absence of perchlorate. In some embodiments, the reaction is carried out in the absence of magnesium perchlorate (MgClO4). In some embodiments, the reaction is carried out in the absence of lithium perchlorate (LiClO4). In some embodiments, the reaction is carried out in the absence of bis(trifluoromethanesulfonyl)imide. In some embodiments, the reaction is carried out in the absence of one or more Lewis acids described in International Publication No. WO2016 / 100732, published June 23, 2016, the entire contents of which are incorporated herein by reference.

[0072] The Diels-Alder reaction provided above may be carried out in the absence of increased pressure (i.e., at approximately atmospheric pressure (1 atm)).

[0073] In some embodiments, the reaction is carried out in a solvent. In some embodiments, the solvent is a non-polar solvent or a polar solvent. In some embodiments, the solvent is a polar solvent. For example, in some embodiments, the reaction may be carried out in a solvent such as acetone, toluene, benzene, xylene, chlorobenzene, methylene chloride, ethylene dichloride, dioxane, tetrahydrofuran (THF), tert-butyl methyl ether, diisopropyl ether, 1,2-dimethoxyethane (glyme), acetonitrile, ethyl acetate, isopropyl acetate, water, or a mixture thereof.

[0074] In some embodiments, the solvent is an amide, lactam, or urea, such as N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone (DMI), or 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU). In some embodiments, the solvent is a sulfone solvent, such as dimethyl sulfone, dimethyl sulfoxide (DMSO), or sulfolane. In some embodiments, the solvent is NMP. In some embodiments, the solvent is a co-solvent that includes NMP. Other examples of polar solvents include, but are not limited to, ketones and nitriles, such as acetone and acetonitrile. In some embodiments, the aprotic polar solvent is selected from the group consisting of DMF, NMP, DMI, DMPU, acetone, and acetonitrile. In some embodiments, the aprotic polar solvent is selected from the group consisting of NMP, DMPU, acetone, and acetonitrile.

[0075] In some embodiments, the reaction is carried out in the absence of a solvent. In some embodiments, the reaction is carried out in an ionic liquid. In some embodiments, the reaction is carried out in a ball mill reactor.

[0076] The reaction can be carried out at any concentration of reactants in a solvent or reaction mixture. In some embodiments, the concentration of the compound represented by Formula (III) in the solvent or reaction mixture is approximately 0.01 molar (mol / L, M), 0.02M, 0.03M, 0.04M, 0.05M, 0.06M, 0.07M, 0.08M, 0.09M, 0.1M, 0.2M, 0.3M, 0.4M, 0.5M, 0.6M, 0.7M, 0.8M, 0.9M, 1M, 2M, 3M, 4M, 5M, 6M, 7M, 8M, 9M, or 10M. In some embodiments, the reaction is carried out at a concentration of 1 to 20M in solution with respect to the compound represented by Formula (III). In some embodiments, the concentration is 5 to 15M. In some embodiments, the concentration is 10 to 15M.

[0077] The reaction may be carried out at any temperature. The reaction temperature may be approximately -100°C, -90°C, -0°C, -78°C, -70°C, -60°C, -50°C, -40°C, -30°C, -20°C, -10, 0°C, -10°C, 20°C, room temperature, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, or 150°C. In some embodiments, the reaction temperature is greater than 100°C. In some embodiments, the reaction is carried out at a temperature less than 100°C. In some embodiments, the reaction is carried out at a temperature of about room temperature (21°C or 70°F). In some embodiments, the temperature is between room temperature and 100°C. In some embodiments, the reaction is carried out at a temperature between 30 and 60°C. In some embodiments, the reaction is carried out at a temperature between 40 and 50°C. In some embodiments, the reaction is carried out at approximately 40° C., 41° C., 42° C., 43° C., 44° C., 45° C., 46° C., 47° C., 48° C., 49° C., or 50° C. In some embodiments, the reaction is carried out at approximately 45° C.

[0078] The reaction may be carried out for any length of time. The reaction time may be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, more than 5 hours, 10 hours, more than 10 hours, 15 hours, or 20 hours or more. In some embodiments, the reaction time is more than 20 hours. In some embodiments, the reaction time is one day or more. In some embodiments, the reaction time is more than one day.

[0079] The reaction mixture may contain any ratio of reactants, specifically, the compound represented by Formula (III) and furan. In some embodiments, the furan is present in the reaction mixture in an amount greater than 1 equivalent (i.e., in excess) relative to the amount of the compound represented by Formula (III). In some embodiments, the ratio of the compound represented by Formula (III) to furan in the reaction mixture is 1:1 to 1:20. In some embodiments, the ratio of the compound represented by Formula (III) to furan in the reaction mixture is 1:1 to 1:10. In some embodiments, the ratio of the compound represented by Formula (III) to furan in the reaction mixture is approximately 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or 1:20. In some embodiments, the ratio of the compound represented by Formula (III) to furan in the reaction mixture is 1:4 to 1:5. In some embodiments, the ratio of the compound represented by Formula (III) to furan in the reaction mixture is about 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, or 1:4.9.

[0080] As described herein, the reaction may be carried out in the absence of added acid at approximately 1 atm. In some cases, the reaction solvent and temperature may be varied as follows: In some embodiments, the reaction is carried out in a polar solvent at room temperature or above. In some embodiments, the reaction is carried out in a polar solvent at room temperature to 100°C. In some embodiments, the reaction is carried out in a polar solvent at elevated temperatures (i.e., above room temperature). In some embodiments, the reaction is carried out in a polar solvent at a temperature of room temperature to 100°C. In some embodiments, the reaction is carried out in a polar solvent at a temperature of 30°C to 100°C. In some embodiments, the reaction is carried out in a polar solvent at a temperature of 30°C to 60°C. In some embodiments, the reaction is carried out in a polar solvent at a temperature of 40°C to 50°C. In some embodiments, the reaction is carried out in a polar solvent at a temperature of approximately 50°C. In some embodiments, the reaction is carried out in an aprotic polar solvent at a temperature of approximately 45°C. In some embodiments, the reaction is carried out in a polar solvent at a temperature of approximately 40°C. In some embodiments, the reaction is carried out in NMP at room temperature or above. In some embodiments, the reaction is carried out in NMP at room temperature to 100°C. In some embodiments, the reaction is carried out in NMP at elevated temperatures (i.e., above room temperature). In some embodiments, the reaction is carried out in NMP at a temperature of room temperature to 100°C. In some embodiments, the reaction is carried out in NMP at a temperature of 30°C to 100°C. In some embodiments, the reaction is carried out in NMP at a temperature of 30°C to 60°C. In some embodiments, the reaction is carried out in NMP at a temperature of 40°C to 50°C. In some embodiments, the reaction is carried out in NMP at a temperature of approximately 50°C. In some embodiments, the reaction is carried out in NMP at a temperature of approximately 45°C. In some embodiments, the reaction is carried out in NMP at a temperature of approximately 40°C.

[0081] In the methods provided herein, the compound represented by formula (IV) can be formed as an exo or endo cycloadduct, or as a mixture of exo and endo cycloadducts. The "exo" and "endo" adducts are shown below. [ka]

[0082] For cantharidin, a high exo-to-endo ratio is desirable. In some embodiments, the Diels-Alder method provided herein produces a preferred exo-to-endo ratio. By way of example, the exo-to-endo product ratio produced by the methods disclosed herein can be at least about 80:20, 81:19, 82:18, 83:17, 84:16, 85:15, 86:14, 87:13, 88:12, 89:11, 90:10, 91:9, 92:8, 93:7, 94:6, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. The percentage of exo product per total amount of product can be at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, 99.999%, or 100%. In some embodiments, the exo / endo ratio is about 70:30 to 99:1. In some embodiments, the exo / endo ratio is about 70:30 to 90:10. In some embodiments, the exo / endo ratio is about 70:30 to 80:20. In some embodiments, the exo / endo ratio is about 70:30, 71:29, 72:28, 73:27, 74:26, 75:25, 76:24, 77:23, 78:22, 79:21, or 80:20. In some embodiments, the exo / endo ratio is about 75:25. In some embodiments, the exo / endo ratio is about 80:20 to about 90:10. In some embodiments, the exo / endo ratio is about 80:20. In some embodiments, the exo / endo ratio is about 81:19. In some embodiments, the exo / endo ratio is about 82:18. In some embodiments, the exo / endo ratio is about 83:17. In some embodiments, the exo / endo ratio is about 84:16. In some embodiments, the exo / endo ratio is about 85:15. In some embodiments, the exo / endo ratio is about 86:14. In some embodiments, the exo / endo ratio is about 87:13. In some embodiments, the exo / endo ratio is about 88:12. In some embodiments, the exo / endo ratio is about 89:11. In some embodiments, the exo / endo ratio is about 90:10.In some embodiments, the exo / endo ratio is about 95:5. In some embodiments, the exo / endo ratio is about 98:2. In some embodiments, the exo / endo ratio is about 99:1. In some embodiments, the exo / endo ratio is about 99.10:0.10.

[0083] The compound represented by Formula (IV) can be formed in any chemical yield. In some embodiments, the compound is produced in a yield of 1-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%. In some embodiments, the compound is produced in a yield of approximately 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%. In some embodiments, the compound represented by Formula (IV) is isolated in a yield of greater than 50%.

[0084] In some embodiments, the compound represented by formula (IV) can be prepared and isolated with high chemical purity by the methods described herein. In some embodiments, the compound represented by formula (IV) is isolated with a purity of greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%. In some embodiments, the compound represented by formula (IV) is isolated with a purity of greater than 90%. In some embodiments, the compound represented by formula (IV) is isolated with a purity of greater than 95%. In some embodiments, the compound represented by formula (IV) is isolated with a purity of greater than 98%. In some embodiments, the compound represented by formula (IV) is isolated with a purity of greater than 99%.

[0085] After formation, the compound of formula (IV) may be purified through one or more purification steps. For example, in some embodiments, the compound of formula (IV) is purified by chromatography, extraction, filtration, precipitation, crystallization, trituration, or any other method known in the art. In some embodiments, the compound is carried forward to subsequent synthetic steps without purification (i.e., crude). In some embodiments, the purification step improves the exo / endo ratio of the product mixture.

[0086] In some embodiments, the reaction for preparing a compound of Formula (IV) described herein is followed by a step of recrystallizing the compound of Formula (IV). The compound of Formula (IV) may be recrystallized from any solvent or mixture of solvents. In some embodiments, the compound of Formula (1V) is dissolved in a solvent, and then a second solvent is added to the solution to promote precipitation of the recrystallized compound of Formula (IV).

[0087] In some embodiments, the recrystallization step improves the exo / endo ratio of the compound mixture. In some embodiments, the compound of formula (IV) is isolated after recrystallization with an exo / endo ratio of greater than 90:10. For example, in some embodiments, the compound of formula (IV) is isolated after recrystallization with an exo / endo ratio of 95:5, 96:4, 97:3, 98:2, or 99:1.

[0088] Also provided herein are compounds of formula (V): [ka] A method for preparing a compound represented by formula (IV): [ka] hydrogenating a compound represented by the formula: n is 0, 1, 2, 3, 4, or 5; R 3each occurrence is independently selected from hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR O , -N(R N )2, or -SR S and; R O each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; R N each occurrence of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally, two R on the same nitrogen N are joined together with the intervening atoms to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R S each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; The method includes:

[0089] The hydrogenation may be carried out in the presence of palladium or platinum. The hydrogenation reaction may be carried out using, for example, Pd / C, Pd, PdCl, PtO, or Pt / C. In some embodiments, the reaction may be carried out in the presence of H. The reaction may be carried out under transfer hydrogenation conditions (e.g., in the presence of 1,4-cyclohexadiene). Other reagents / conditions useful for the hydrogenation reaction are described, for example, in International Publication No. WO2016 / 100732, published June 23, 2016, the entire contents of which are incorporated herein by reference.

[0090] The hydrogenation reaction may be carried out in a solvent. Examples of solvents are provided herein. In some embodiments, the solvent is ethyl acetate. The reaction may be carried out at any concentration of reactants in the solvent or reaction mixture. In some embodiments, the concentration of the compound represented by Formula (IV) in the solvent or reaction mixture is approximately 0.01 molar (mol / L, M), 0.02M, 0.03M, 0.04M, 0.05M, 0.06M, 0.07M, 0.08M, 0.09M, 0.1M, 0.2M, 0.3M, 0.4M, 0.5M, 0.6M, 0.7M, 0.8M, 0.9M, 1M, 2M, 3M, 4M, 5M, 6M, 7M, 8M, 9M, or 10M.

[0091] The reaction may be carried out at any temperature. The reaction temperature may be approximately -100°C, -90°C, -0°C, -78°C, -70°C, -60°C, -50°C, -40°C, -30°C, -20°C, -10, 0°C, -10°C, 20°C, room temperature, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, or 150°C. In some embodiments, the reaction temperature is greater than 150°C. In some embodiments, the reaction temperature is about room temperature (21°C or 70°F). In some embodiments, the reaction is carried out at a temperature greater than room temperature. In some embodiments, the temperature is between room temperature and 100°C.

[0092] The reaction may be carried out for any length of time. The reaction time may be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, more than 5 hours, 10 hours, more than 10 hours, 15 hours, or 20 hours or more. In some embodiments, the reaction time is more than 20 hours. In some embodiments, the reaction time is one day or more. In some embodiments, the reaction time is more than one day.

[0093] The compound represented by Formula (V) can be formed in any chemical yield. In some embodiments, the compound is produced in a yield of 1-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%. In some embodiments, the compound is produced in a yield of approximately 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%.

[0094] In some embodiments, the compound represented by formula (V) can be prepared and isolated with high chemical purity by the methods described herein. In some embodiments, the compound is isolated with a purity of greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%. In some embodiments, the compound represented by formula (V) is isolated with a purity of greater than 90%. In some embodiments, the compound represented by formula (V) is isolated with a purity of greater than 95%. In some embodiments, the compound represented by formula (V) is isolated with a purity of greater than 98%. In some embodiments, the compound represented by formula (V) is isolated with a purity of greater than 99%.

[0095] After formation, the compound of formula (V) may be purified through one or more purification steps. For example, in some embodiments, the compound of formula (V) is purified by chromatography, extraction, filtration, precipitation, crystallization, or any other method known in the art. In some embodiments, the compound is carried forward to subsequent synthetic steps without purification (i.e., crude).

[0096] Also provided herein are compounds of formula (VI): [ka] A method for preparing a compound represented by formula (V): [ka] reducing a compound represented by the formula: n is 0, 1, 2, 3, 4, or 5; R 3 each occurrence is independently selected from hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR O , -N(R N )2, or -SR S and; R O each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; R Neach occurrence of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally, two R on the same nitrogen N are joined together with the intervening atoms to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; and R S each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; The method includes:

[0097] In some embodiments, the reduction (also referred to as "desulfurization") is carried out in the presence of a reducing agent. In some embodiments, the reducing agent is Raney nickel, Ni(II) / NaBH, Co(II) / NaBH, Li / EtNH, LAH / TiCl, LAH / CuCl, Ni(II) / Zn, Ni(II) / Al, or LAH / CpNi. In some embodiments, the reducing agent is Raney Ni. Other reagents / conditions useful for the reduction reaction are described in International Publication No. WO2016 / 100732, published June 23, 2016, the entire contents of which are incorporated herein by reference.

[0098] The reduction may be carried out in a solvent. Examples of solvents are provided herein. Typical solvents for the desulfurization reaction can be alcohols, ethers, ester-based solvents, and water, or various mixtures of these solvents. The reaction can be carried out at any concentration of reactants in the solvent or reaction mixture. In some embodiments, the concentration of the compound represented by Formula (V) in the solvent or reaction mixture is approximately 0.01 molar (mol / L, M), 0.02M, 0.03M, 0.04M, 0.05M, 0.06M, 0.07M, 0.08M, 0.09M, 0.1M, 0.2M, 0.3M, 0.4M, 0.5M, 0.6M, 0.7M, 0.8M, 0.9M, 1M, 2M, 3M, 4M, 5M, 6M, 7M, 8M, 9M, or 10M.

[0099] The reaction may be carried out at any temperature. The reaction temperature may be approximately -100°C, -90°C, -0°C, -78°C, -70°C, -60°C, -50°C, -40°C, -30°C, -20°C, -10, 0°C, -10°C, 20°C, room temperature, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, or 150°C. In some embodiments, the reaction temperature is greater than 150°C. In some embodiments, the reaction temperature is approximately room temperature (21°C or 70°F). In some embodiments, the reaction is carried out at a temperature greater than room temperature. In some embodiments, the temperature is between room temperature and 100°C. The reaction temperature may be between -20°C and 100°C in other embodiments. In some cases, these reactions may be facilitated with the aid of sonication or microwave heating.

[0100] The reaction may be carried out for any length of time. The reaction time may be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, more than 5 hours, 10 hours, more than 10 hours, 15 hours, or 20 hours or more. In some embodiments, the reaction time is more than 20 hours. In some embodiments, the reaction time is one day or more. In some embodiments, the reaction time is more than one day.

[0101] The compound represented by Formula (VI) can be formed in any chemical yield. In some embodiments, the compound is produced in a yield of 1-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%. In some embodiments, the compound is produced in a yield of approximately 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%.

[0102] In some embodiments, the compound represented by formula (VI) can be prepared and isolated with high chemical purity by the methods described herein. In some embodiments, the compound represented by formula (VI) is isolated with a purity of greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%. In some embodiments, the compound represented by formula (VI) is isolated with a purity of greater than 90%. In some embodiments, the compound represented by formula (VI) is isolated with a purity of greater than 95%. In some embodiments, the compound represented by formula (VI) is isolated with a purity of greater than 98%. In some embodiments, the compound represented by formula (VI) is isolated with a purity of greater than 99%.

[0103] After formation, the compound of formula (VI) may be purified through one or more purification steps. For example, in some embodiments, the compound of formula (VI) is purified by chromatography, extraction, filtration, precipitation, crystallization, or any other method known in the art. In some embodiments, the compound is carried forward to subsequent synthetic steps without purification (i.e., crude).

[0104] Also provided herein is cantharidin: [ka] 1. A method for preparing (a) Formula (VI): [ka] by hydrolysis of a compound represented by the formula: [ka] or a salt thereof; and (b) dehydrating the compound formed in step (a) under suitable conditions to form cantharidin; n is 0, 1, 2, 3, 4, or 5; R 3 each occurrence is independently selected from hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR O , -N(R N )2, or -SR S and; R O each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; R N each occurrence of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally, two R on the same nitrogen Nare joined together with the intervening atoms to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; and R S each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; The method includes:

[0105] In some embodiments, the hydrolyzing step (i.e., step (a)) is carried out in the presence of a base. In some embodiments, the base is a hydroxide (e.g., NaOH, KOH, LiOH). In some embodiments, the hydrolysis is carried out in the presence of water.

[0106] The reduction may be carried out in a solvent. The reaction may be carried out at any concentration of reactants in the solvent or reaction mixture. In some embodiments, the concentration of the compound represented by Formula (VI) in the solvent or reaction mixture is approximately 0.01 molar (mol / L, M), 0.02M, 0.03M, 0.04M, 0.05M, 0.06M, 0.07M, 0.08M, 0.09M, 0.1M, 0.2M, 0.3M, 0.4M, 0.5M, 0.6M, 0.7M, 0.8M, 0.9M, 1M, 2M, 3M, 4M, 5M, 6M, 7M, 8M, 9M, or 10M.

[0107] The reaction may be carried out at any temperature. The reaction temperature may be approximately -100°C, -90°C, -0°C, -78°C, -70°C, -60°C, -50°C, -40°C, -30°C, -20°C, -10, 0°C, -10°C, 20°C, room temperature, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, or 150°C. In some embodiments, the reaction temperature is greater than 150°C. In some embodiments, the reaction temperature is approximately room temperature (21°C or 70°F). In some embodiments, the reaction is carried out at a temperature greater than room temperature. In some embodiments, the temperature is between room temperature and 100°C. The reaction temperature may be between -20°C and 100°C in other embodiments. In some cases, these reactions may be facilitated with the aid of sonication or microwave heating.

[0108] The reaction may be carried out for any length of time. The reaction time may be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, more than 5 hours, 10 hours, more than 10 hours, 15 hours, or 20 hours or more. In some embodiments, the reaction time is more than 20 hours. In some embodiments, the reaction time is one day or more. In some embodiments, the reaction time is more than one day.

[0109] formula: [ka] The compound represented by formula (I) can be formed in any chemical yield. In some embodiments, the compound is produced in a yield of 1-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%. In some embodiments, the compound is produced in a yield of approximately 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%.

[0110] In some embodiments, compounds can be prepared and isolated with high chemical purity by the methods described herein. In some embodiments, compounds are isolated with greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% purity. In some embodiments, compounds are isolated with greater than 90% purity. In some embodiments, compounds are isolated with greater than 95% purity. In some embodiments, compounds are isolated with greater than 98% purity. In some embodiments, compounds are isolated with greater than 99% purity.

[0111] After formation, the formula: [ka] The compound represented by may be purified through one or more purification steps. For example, in some embodiments, the compound is purified by chromatography, extraction, filtration, precipitation, crystallization, or any other method known in the art. In some embodiments, the compound is carried forward to subsequent synthetic steps without purification (i.e., crude).

[0112] In some embodiments, the dehydrating step (i.e., step (b)) is carried out in the presence of a reagent capable of effecting dehydration. For example, in some embodiments, acid chlorides, acid anhydrides, and mixed anhydrides (e.g., mixed anhydrides of sulfonic acid and phosphonic acid) can be used. In some embodiments, propylphosphonic anhydride can be used. In some embodiments, acetic anhydride, thionyl chloride, or POCl3 can be used.

[0113] The reduction may be carried out in a solvent. The reaction may be carried out at any concentration of reactants in the solvent or reaction mixture. In some embodiments, the concentration of the starting material in the solvent or reaction mixture is approximately 0.01 molar (mol / L, M), 0.02M, 0.03M, 0.04M, 0.05M, 0.06M, 0.07M, 0.08M, 0.09M, 0.1M, 0.2M, 0.3M, 0.4M, 0.5M, 0.6M, 0.7M, 0.8M, 0.9M, 1M, 2M, 3M, 4M, 5M, 6M, 7M, 8M, 9M, or 10M.

[0114] The reaction may be carried out at any temperature. The reaction temperature may be approximately -100°C, -90°C, -0°C, -78°C, -70°C, -60°C, -50°C, -40°C, -30°C, -20°C, -10, 0°C, -10°C, 20°C, room temperature, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, or 150°C. In some embodiments, the reaction temperature is greater than 150°C. In some embodiments, the reaction temperature is approximately room temperature (21°C or 70°F). In some embodiments, the reaction is carried out at a temperature greater than room temperature. In some embodiments, the temperature is between room temperature and 100°C. The reaction temperature may be between -20°C and 100°C in other embodiments. In some cases, these reactions may be facilitated with the aid of sonication or microwave heating.

[0115] The reaction may be carried out for any length of time. The reaction time may be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, more than 5 hours, 10 hours, more than 10 hours, 15 hours, or 20 hours or more. In some embodiments, the reaction time is more than 20 hours. In some embodiments, the reaction time is one day or more. In some embodiments, the reaction time is more than one day.

[0116] Cantharidin can be formed in any chemical yield. In some embodiments, the compound is produced in a yield of 1-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%. In some embodiments, the compound is produced in a yield of approximately 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%.

[0117] After formation, cantharidin can be purified through one or more purification steps.For example, in some embodiments, cantharidin can be purified by chromatography, extraction, filtration, precipitation, crystallization or any other method known in the art.In some embodiments, compound can be carried forward to the next synthesis step without purification (i.e., crude).

[0118] In some embodiments, cantharidin can be prepared and isolated with high chemical purity by the method described herein.In some embodiments, cantharidin is isolated with a purity of more than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%.In some embodiments, cantharidin is isolated with a purity of more than 90%.In some embodiments, cantharidin is isolated with a purity of more than 95%.In some embodiments, cantharidin is isolated with a purity of more than 98%.In some embodiments, cantharidin is isolated with a purity of more than 99%.In some embodiments, cantharidin is isolated with a purity of more than 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. Also provided herein is a highly pure cantharidin composition produced by any of the methods described herein.

[0119] Also provided herein is compound (3): [ka] 1. A method for preparing (a) Formula (V): [ka] by hydrolysis of a compound represented by the formula: [ka] or a salt thereof; and (b) dehydrating the compound formed in step (a) under suitable conditions to form compound (3); n is 0, 1, 2, 3, 4, or 5; R 3 each occurrence is independently selected from hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR O , -N(R N )2, or -SR S and; R O each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; R Neach occurrence of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally, two R on the same nitrogen N are joined together with the intervening atoms to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; and R S each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; The method includes:

[0120] In some embodiments, the hydrolyzing step (i.e., step (a)) is carried out in the presence of a base. In some embodiments, the base is a hydroxide (e.g., NaOH, KOH, LiOH). In some embodiments, the hydrolysis is carried out in the presence of water.

[0121] The reduction may be carried out in a solvent. The reaction may be carried out at any concentration of reactants in the solvent or reaction mixture. In some embodiments, the concentration of the compound represented by Formula (V) in the solvent or reaction mixture is approximately 0.01 molar (mol / L, M), 0.02M, 0.03M, 0.04M, 0.05M, 0.06M, 0.07M, 0.08M, 0.09M, 0.1M, 0.2M, 0.3M, 0.4M, 0.5M, 0.6M, 0.7M, 0.8M, 0.9M, 1M, 2M, 3M, 4M, 5M, 6M, 7M, 8M, 9M, or 10M.

[0122] The reaction may be carried out at any temperature. The reaction temperature may be approximately -100°C, -90°C, -0°C, -78°C, -70°C, -60°C, -50°C, -40°C, -30°C, -20°C, -10, 0°C, -10°C, 20°C, room temperature, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, or 150°C. In some embodiments, the reaction temperature is greater than 150°C. In some embodiments, the reaction temperature is approximately room temperature (21°C or 70°F). In some embodiments, the reaction is carried out at a temperature greater than room temperature. In some embodiments, the temperature is between room temperature and 100°C. The reaction temperature may be between -20°C and 100°C in other embodiments. In some cases, these reactions may be facilitated with the aid of sonication or microwave heating.

[0123] The reaction may be carried out for any length of time. The reaction time may be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, more than 5 hours, 10 hours, more than 10 hours, 15 hours, or 20 hours or more. In some embodiments, the reaction time is more than 20 hours. In some embodiments, the reaction time is one day or more. In some embodiments, the reaction time is more than one day.

[0124] formula: [ka] The compound represented by formula (I) can be formed in any chemical yield. In some embodiments, the compound is produced in a yield of 1-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%. In some embodiments, the compound is produced in a yield of approximately 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%.

[0125] In some embodiments, compounds can be prepared and isolated with high chemical purity by the methods described herein. In some embodiments, compounds are isolated with greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% purity. In some embodiments, compounds are isolated with greater than 90% purity. In some embodiments, compounds are isolated with greater than 95% purity. In some embodiments, compounds are isolated with greater than 98% purity. In some embodiments, compounds are isolated with greater than 99% purity.

[0126] After formation, the formula: [ka] The compound represented by may be purified through one or more purification steps. For example, in some embodiments, the compound is purified by chromatography, extraction, filtration, precipitation, crystallization, or any other method known in the art. In some embodiments, the compound is carried forward to subsequent synthetic steps without purification (i.e., crude).

[0127] In some embodiments, the dehydrating step (i.e., step (b)) is carried out in the presence of a reagent capable of effecting dehydration. For example, in some embodiments, acid chlorides, acid anhydrides, and mixed anhydrides (e.g., mixed anhydrides of sulfonic acid and phosphonic acid) can be used. In some embodiments, propylphosphonic anhydride can be used. In some embodiments, acetic anhydride, thionyl chloride, or POCl3 can be used.

[0128] The reduction may be carried out in a solvent. The reaction may be carried out at any concentration of reactants in the solvent or reaction mixture. In some embodiments, the concentration of the starting material in the solvent or reaction mixture is approximately 0.01 molar (mol / L, M), 0.02M, 0.03M, 0.04M, 0.05M, 0.06M, 0.07M, 0.08M, 0.09M, 0.1M, 0.2M, 0.3M, 0.4M, 0.5M, 0.6M, 0.7M, 0.8M, 0.9M, 1M, 2M, 3M, 4M, 5M, 6M, 7M, 8M, 9M, or 10M.

[0129] The reaction may be carried out at any temperature. The reaction temperature may be approximately -100°C, -90°C, -0°C, -78°C, -70°C, -60°C, -50°C, -40°C, -30°C, -20°C, -10, 0°C, -10°C, 20°C, room temperature, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, or 150°C. In some embodiments, the reaction temperature is greater than 150°C. In some embodiments, the reaction temperature is approximately room temperature (21°C or 70°F). In some embodiments, the reaction is carried out at a temperature greater than room temperature. In some embodiments, the temperature is between room temperature and 100°C. The reaction temperature may be between -20°C and 100°C in other embodiments. In some cases, these reactions may be facilitated with the aid of sonication or microwave heating.

[0130] The reaction may be carried out for any length of time. The reaction time may be 30 seconds, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, more than 5 hours, 10 hours, more than 10 hours, 15 hours, or 20 hours or more. In some embodiments, the reaction time is more than 20 hours. In some embodiments, the reaction time is one day or more. In some embodiments, the reaction time is more than one day.

[0131] Compound (3) can be formed in any chemical yield. In some embodiments, the compound is produced in a yield of 1-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%. In some embodiments, the compound is produced in a yield of approximately 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%.

[0132] In some embodiments, compound (3) can be prepared and isolated with high chemical purity by the methods described herein. In some embodiments, compound (3) is isolated with greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% purity. In some embodiments, compound (3) is isolated with greater than 90% purity. In some embodiments, compound (3) is isolated with greater than 95% purity. In some embodiments, compound (3) is isolated with greater than 98% purity. In some embodiments, compound (3) is isolated with greater than 99% purity.

[0133] After formation, compound (3) may be purified through one or more purification steps. For example, in some embodiments, cantharidin is purified by chromatography, extraction, filtration, precipitation, crystallization, or any other method known in the art. In some embodiments, the compound is carried forward to subsequent synthetic steps without purification (i.e., crude).

[0134] In some embodiments, the method further comprises reducing (i.e., desulfurizing) compound (3) to produce cantharidin, which may be carried out as described above and as described herein.

[0135] As defined herein, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0136] As defined herein, R 3 each occurrence is independently selected from hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR O , -N(R N )2, or -SR S In some embodiments, R 3 At least one occurrence of R is hydrogen. 3 At least one occurrence of R is halogen. 3 At least one occurrence of R is -CN. 3 At least one occurrence of R is -NO. 3 At least one occurrence of R is -N3. 3 At least one occurrence of R is optionally substituted alkyl. 3 At least one occurrence of R is optionally substituted alkenyl. 3 At least one occurrence of R is optionally substituted alkynyl. 3 At least one occurrence of R is an optionally substituted carbocyclyl. 3At least one occurrence of R is optionally substituted heterocyclyl. 3 At least one occurrence of R is optionally substituted aryl. 3 At least one occurrence of R is optionally substituted heteroaryl. 3 At least one occurrence of R is optionally substituted acyl. 3 At least one occurrence of R is an optionally substituted sulfonyl. 3 At least one occurrence of R is an optionally substituted sulfinyl. 3 At least one occurrence of -OR O In some embodiments, R 3 At least one occurrence of -N(R N )2. In some embodiments, R 3 At least one occurrence of -SR S is.

[0137] Methods for preparing other cantharidin intermediates Also provided herein is a method for preparing a compound of formula (I), which is useful as an intermediate in the synthesis of cantharidin and its analogs. The method for preparing a compound of formula (I) comprises palladium-mediated carbonylation of a compound of formula (II), as shown in Scheme 2 below. [ka]

[0138] Provided herein are compounds of formula (I): [ka] A method for preparing a compound represented by formula (II): [ka] The compound represented by formula R 2 reacting in the presence of a reagent of formula: X 1 is a halogen, an optionally substituted sulfonate, or an optionally substituted phosphate; R 1 and R 2 are independently optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or an oxygen protecting group; The method includes:

[0139] The carbonylation reaction is carried out in the presence of palladium. In some embodiments, the palladium is a palladium salt. In some embodiments, the palladium is a palladium(II) salt. Examples of palladium(II) salts include, but are not limited to, palladium chloride (PdCl), palladium acetate (Pd(OAc)), and palladium trifluoroacetate (Pd(TFA)). In some embodiments, Pd(OAc) is used. In some embodiments, Pd(PPh) is used. In some embodiments, Pd(dba) is used. In some embodiments, one or more ligands are used in addition to the palladium source. For example, in some embodiments, Pd(dba) / dppf is used in the reaction. In other embodiments, Pd(OAc) / PPh is used in the reaction.

[0140] The palladium source may be present in the reaction in a catalytic amount relative to the compound represented by Formula (II). For example, in some embodiments, palladium is present in approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 98, or 99 mol% relative to the compound represented by Formula (II). In some embodiments, palladium is present in 1-10 mol%. In some embodiments, palladium is present in approximately 4 mol%. In some embodiments, palladium is present in approximately 5 mol%. In some embodiments, palladium is present in approximately 6 mol%.

[0141] The carbonylation reaction may be carried out in the presence of one or more palladium ligands. In some embodiments, the reaction is carried out in the presence of a phosphine ligand. In some embodiments, the reaction is carried out in the presence of a triarylphosphine ((aryl)3P). In some embodiments, the reaction is carried out in the presence of triphenylphosphine (Ph3P). In some embodiments, the reaction is carried out in the presence of 1,1'-bis(diphenylphosphino)ferrocene (dppf).

[0142] In some embodiments, the phosphine is present in a catalytic amount. For example, in some embodiments, the phosphine is present at approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 98, or 99 mol % relative to the compound represented by Formula (II). In some embodiments, the phosphine is present at approximately 1-10 mol %. In some embodiments, the phosphine is present at approximately 1-20 mol %. In some embodiments, the phosphine is present at approximately 10-20 mol %. In some embodiments, the phosphine is present at approximately 3 mol %. In some embodiments, the phosphine is present at approximately 14 mol %.

[0143] The carbonylation reaction is represented by the formula R2 In some embodiments, the reaction is carried out in the presence of an alcohol represented by formula (II) (i.e., more than 1 equivalent relative to the compound represented by formula (II)). 2 The alcohol, represented by OH, is present as a solvent or co-solvent. In some embodiments, the alcohol is selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, and tert-butanol. In some embodiments, the alcohol is methanol. In some embodiments, the alcohol is ethanol. In some embodiments, the alcohol is n-propanol. In some embodiments, the alcohol is iso-propanol. In some embodiments, the alcohol is n-butanol. In some embodiments, the alcohol is iso-butanol. In some embodiments, the alcohol is sec-butanol. In some embodiments, the alcohol is tert-butanol.

[0144] The carbonylation reaction may be carried out in a solvent or a mixture of solvents (i.e., a co-solvent). The solvent may be polar or non-polar, protic or aprotic. Any solvent may be used in the reactions described herein, including but not limited to, a particular solvent or combination of solvents. Examples of solvents are provided herein. In some embodiments, the reaction is carried out in a polar solvent, such as DMF. In some embodiments, the reaction is carried out in a solvent containing DMF and an alcohol (i.e., R 2 In some embodiments, the reaction is carried out in the presence of DMF and methanol.

[0145] The carbonylation reaction may be carried out at any temperature. In some embodiments, the reaction is carried out at about room temperature (rt) (21° C. or 70° F.). In some embodiments, the reaction is carried out below room temperature (e.g., between −100° C. and 21° C.). In some embodiments, the reaction is carried out above room temperature. In some embodiments, the reaction is carried out at 30, 40, 50, 60, 70, 80, 110, 120, 130, 140, or 150° C. In some embodiments, the reaction is carried out above 150° C.

[0146] In some embodiments, the carbonylation is carried out using palladium, CO, R 2 In some embodiments, the carbonylation is carried out in the presence of palladium, CO, R in a polar solvent at about room temperature. 2 In some embodiments, the reaction is carried out in the presence of Pd(OAc) 2 , CO 2 , MeOH, and Ph 3 P. In some embodiments, the reaction is carried out in the presence of Pd(OAc) 2 , CO 2 , MeOH, and Ph 3 P in a polar solvent at about room temperature. In some embodiments, the reaction is carried out in the presence of Pd(OAc) 2 , CO 2 , MeOH, and Ph 3 P in DMF at about room temperature. In some embodiments, the reaction is carried out in the presence of catalytic Pd(OAc) 2 (e.g., approximately 5 mol%), excess CO 2 , excess MeOH, and catalytic Ph 3 P (e.g., approximately 14 mol%). In some embodiments, the reaction is carried out in the presence of catalytic Pd(OAc) 2 (e.g., approximately 5 mol%), excess CO 2 , excess MeOH, and catalytic Ph 3 P (e.g., approximately 14 mol%) in DMF at about room temperature.

[0147] In some embodiments, the reaction is carried out in the presence of Pd(dba)3, CO, MeOH, and dppf. In some embodiments, the reaction is carried out in the presence of Pd(dba)3, CO, MeOH, and dppf in a polar solvent at about room temperature. In some embodiments, the reaction is carried out in the presence of Pd(dba)3, CO, MeOH, and dppf in a polar solvent at above room temperature. In some embodiments, the reaction is carried out in the presence of Pd(dba)3, CO, MeOH, and dppf in DMF at about room temperature. In some embodiments, the reaction is carried out in the presence of Pd(dba)3, CO, MeOH, and dppf in DMF at above room temperature. In some embodiments, the reaction is carried out in the presence of catalytic Pd(dba)3 (e.g., approximately 1.5 mol%), excess CO, excess MeOH, and catalytic dppf (e.g., approximately 3 mol%). In some embodiments, the reaction is carried out in the presence of catalytic Pd(dba) (e.g., approximately 1.5 mol%), excess CO, excess MeOH, and catalytic dppf (e.g., approximately 3 mol%) in DMF at about room temperature. In some embodiments, the reaction is carried out in the presence of catalytic Pd(dba) (e.g., approximately 1.5 mol%), excess CO, excess MeOH, and catalytic dppf (e.g., approximately 3 mol%) in DMF at above room temperature.

[0148] The compound represented by Formula (II) can be formed in any chemical yield. In some embodiments, the compound is produced in a yield of 1-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%. In some embodiments, the chemical yield is greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In some embodiments, the chemical yield is greater than 50%. In some embodiments, the chemical yield is greater than 60%. In some embodiments, the chemical yield is greater than 70%. In some embodiments, the chemical yield is greater than 80%. In some embodiments, the chemical yield is greater than 90%. In some embodiments, the chemical yield is greater than 95%. In some embodiments, the chemical yield is greater than 98%. In some embodiments, the chemical yield is greater than 99%.

[0149] In some embodiments, the compound represented by formula (II) can be prepared and isolated with high chemical purity by the methods described herein. In some embodiments, the compound represented by formula (II) is isolated with a purity of greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%. In some embodiments, the compound represented by formula (II) is isolated with a purity of greater than 90%. In some embodiments, the compound represented by formula (II) is isolated with a purity of greater than 95%. In some embodiments, the compound represented by formula (II) is isolated with a purity of greater than 98%. In some embodiments, the compound represented by formula (II) is isolated with a purity of greater than 99%.

[0150] The methods described herein may further include one or more purification steps. For example, in some embodiments, the compounds produced by the methods described herein may be purified by chromatography, extraction, filtration, precipitation, crystallization, or any other method known in the art. In some embodiments, the compounds or mixtures are carried forward to subsequent synthetic steps without purification (i.e., crude).

[0151] As defined herein, X 1is halogen, optionally substituted sulfonate, or optionally substituted phosphate. 1 is halogen (e.g., —Br, —I, —Cl, —F). In some embodiments, X 1 is an optionally substituted phosphate. In some embodiments, X 1 is an optionally substituted sulfonate. 1 is -OSO2-alkyl. In some embodiments, X 1 is a mesylate (—OSO2CH3; “OMs”). In some embodiments, X 1 is -OSO2-aryl. In some embodiments, X 1 In some embodiments, X is -OSO2Ph. 1 is a tosylate (—OSO2C6H4p—CH3; “OTs”). In some embodiments, X 1 is triflate (—OSOCF; “OTf”). In some embodiments, X 1 is a brosylate (—OSO2C6H4p-Br; “OBs”), in some embodiments, X 1 is nonaflate (—OSO2(CF2)3CF3; “ONf”). In some embodiments, X 1 is a nosylate (-SO2C6H4p-NO2 or -SO2C6H4o-NO2; "ONs"). In some embodiments, X 1 are dansilates ("ODs").

[0152] In one embodiment, X 1 is a leaving group. "Leaving group" is defined herein.

[0153] As defined herein, R 1 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or an oxygen protecting group. 1is optionally substituted alkyl. In some embodiments, R 1 is optionally substituted aryl. In some embodiments, R 1 is optionally substituted heteroaryl. In some embodiments, R 1 is an optionally substituted carbocyclyl. In some embodiments, R 1 is optionally substituted heterocyclyl. In some embodiments, R 1 is an oxygen protecting group. In some embodiments, R 1 is an optionally substituted C 1~6 In some embodiments, R 1 is the unsubstituted C 1~6 In some embodiments, R 1 is an optionally substituted C 1~4 In some embodiments, R 1 is the unsubstituted C 1~4 In some embodiments, R 1 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. 1 is methyl.

[0154] As defined herein, R 2 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or an oxygen protecting group. 2 is optionally substituted alkyl. In some embodiments, R 2 is optionally substituted aryl. In some embodiments, R 2 is optionally substituted heteroaryl. In some embodiments, R 2 is an optionally substituted carbocyclyl. In some embodiments, R 2is optionally substituted heterocyclyl. In some embodiments, R 2 is an oxygen protecting group. In some embodiments, R 2 is an optionally substituted C 1~6 In some embodiments, R 2 is the unsubstituted C 1~6 In some embodiments, R 2 is an optionally substituted C 1~4 In some embodiments, R 2 is the unsubstituted C 1~4 In some embodiments, R 2 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. 2 is methyl.

[0155] In some embodiments, R 1 and R 2 are the same. In some embodiments, R 1 and R 2 are different. In some embodiments, R 1 and R 2 Both are methyl.

[0156] In some embodiments, the compound of formula (I) has the formula: [ka] is.

[0157] In some embodiments, the compound of formula (II) has the formula: [ka] is.

[0158] In some embodiments, the compound of formula (II) has the formula: [ka] is.

[0159] In one embodiment, X 1 is a sulfonate and R 1 is an optionally substituted alkyl, and the carbonylation is carried out using palladium, CO, R 2 OH(R 2 is optionally substituted alkyl), and a phosphine. 1 is a sulfonate and R 1 is an optionally substituted alkyl, and the carbonylation is carried out by reacting palladium, CO, R in a polar solvent at about room temperature. 2 OH(R 2 is optionally substituted alkyl), and a phosphine. 1 is a triflate and R 1 is an optionally substituted alkyl, and the carbonylation is carried out using palladium, CO, R 2 OH(R 2 is optionally substituted alkyl), and a phosphine. 1 is a triflate and R 1 is an optionally substituted alkyl, and the carbonylation is carried out by reacting palladium, CO, R in a solvent at about room temperature. 2 OH(R 2 is optionally substituted alkyl), and a phosphine. 1 is a triflate and R 1 is methyl, and the carbonylation is carried out in the presence of palladium, CO, MeOH, and a phosphine. 1 is a triflate and R 1 is methyl, and the carbonylation is carried out in the presence of palladium, CO, MeOH, and phosphine in a polar solvent at about room temperature.1 is a triflate and R 1 is methyl, and the reaction is carried out in the presence of Pd(OAc), CO, MeOH, and PhP. In some embodiments, X 1 is a triflate and R 1 is methyl, and the reaction is carried out in the presence of Pd(OAc), CO, MeOH, and PhP in a polar solvent at about room temperature. 1 is a triflate and R 1 is methyl, and the reaction is carried out in the presence of Pd(OAc), CO, and PhP in DMF / MeOH at about room temperature. 1 is a triflate and R 1 is methyl, and the reaction is carried out in the presence of catalytic Pd(OAc) (e.g., approximately 5 mol%), excess CO, excess MeOH, and catalytic PhP (e.g., approximately 14 mol%). 1 is a triflate and R 1 is methyl, and the reaction is carried out in the presence of catalytic Pd(OAc) (e.g., approximately 5 mol%), excess CO, and catalytic PhP (e.g., approximately 14 mol%) in DMF / MeOH at about room temperature.

[0160] compound Also provided herein are compounds (i.e., intermediates) useful for the synthesis of cantharidin and its analogs.In some embodiments, the compounds provided herein are useful as pharmaceuticals (e.g., for the treatment of infectious diseases).For example, compounds represented by formula (IV), (V), and (VI), and their pharmaceutically acceptable salts, are useful for treating diseases or conditions in subjects in need thereof.

[0161] In one aspect, the present invention provides a compound of formula (II): [ka] During the ceremony: X 1 is a halogen, an optionally substituted sulfonate, or an optionally substituted phosphate; R 1 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or an oxygen protecting group; The present invention provides a compound represented by the formula:

[0162] As defined herein, X 1 is halogen, optionally substituted sulfonate, or optionally substituted phosphonate. 1 is halogen (e.g., —Br, —I, —Cl). 1 is an optionally substituted phosphate. In some embodiments, X 1 is an optionally substituted sulfonate. 1 is -OSO2-alkyl. In some embodiments, X 1 is a mesylate (—OSO2CH3; “OMs”). In some embodiments, X 1 is -OSO2-aryl. In some embodiments, X 1 In some embodiments, X is -OSO2Ph. 1 is a tosylate (—OSO2C6H4p—CH3; “OTs”). In some embodiments, X 1 is triflate (—OSOCF; “OTf”). In some embodiments, X 1 is a brosylate (—OSO2C6H4p-Br; “OBs”). In some embodiments, R 1 is nonaflate (—OSO(CF)CF; “ONf”). In some embodiments, X 1 is a nosylate (-SO2C6H4p-NO2 or -SO2C6H4o-NO2; "ONs"). In some embodiments, X 1are dansilates ("ODs").

[0163] In one embodiment, X 1 is a leaving group. "Leaving group" is defined herein.

[0164] As defined herein, R 1 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or an oxygen protecting group. 1 is optionally substituted alkyl. In some embodiments, R 1 is optionally substituted aryl. In some embodiments, R 1 is optionally substituted heteroaryl. In some embodiments, R 1 is an optionally substituted carbocyclyl. In some embodiments, R 1 is optionally substituted heterocyclyl. In some embodiments, R 1 is an oxygen protecting group. In some embodiments, R 1 is an optionally substituted C 1~6 In some embodiments, R 1 is the unsubstituted C 1~6 In some embodiments, R 1 is an optionally substituted C 1~4 In some embodiments, R 1 is the unsubstituted C 1~4 In some embodiments, R 1 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. 1 is methyl.

[0165] As defined herein, R 2is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or an oxygen protecting group. 2 is optionally substituted alkyl. In some embodiments, R 2 is optionally substituted aryl. In some embodiments, R 2 is optionally substituted heteroaryl. In some embodiments, R 2 is an optionally substituted carbocyclyl. In some embodiments, R 2 is optionally substituted heterocyclyl. In some embodiments, R 2 is an oxygen protecting group. In some embodiments, R 2は、 optionally substituted C 1~6 In some embodiments, R 2 is a non-substituted C 1~6 In some embodiments, R 2 is an optionally substituted C 1~4 In some embodiments, R 2 is the unsubstituted C 1~4 In some embodiments, R 2 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. 2 is methyl.

[0166] In some embodiments, R 1 and R 2 are the same. In some embodiments, R 1 and R 2 are different. In some embodiments, R 1 and R 2 Both of these are methyl.

[0167] In some embodiments, the compound of formula (II) has the formula: [ka] is.

[0168] In some embodiments, the compound of formula (II) has the formula: [ka] is.

[0169] Also provided herein are compounds of formula (IV): [ka] During the ceremony: n is 0, 1, 2, 3, 4, or 5; R 3 each occurrence is independently selected from hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR O , -N(R N )2, or -SR S and; R O each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; R Neach occurrence of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally, two R on the same nitrogen N are joined together with the intervening atoms to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R S each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; and pharmaceutically acceptable salts thereof.

[0170] Also provided herein are compounds of formula (V): [ka] During the ceremony: n is 0, 1, 2, 3, 4, or 5; R 3 each occurrence is independently selected from hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR O , -N(R N )2, or -SRS and; R O each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; R N each occurrence of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally, two R on the same nitrogen N are joined together with the intervening atoms to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R S each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; and pharmaceutically acceptable salts thereof.

[0171] Also provided herein are compounds of formula (III): [ka] During the ceremony: n is 0, 1, 2, 3, 4, or 5; R 3each occurrence is independently selected from hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR O , -N(R N )2, or -SR S and; R O each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; R N each occurrence of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally, two R on the same nitrogen N are joined together with the intervening atoms to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R S each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; It is a compound represented by the formula:

[0172] Also provided herein are compounds of formula (VI): [ka] During the ceremony: n is 0, 1, 2, 3, 4, or 5; R 3 each occurrence is independently selected from hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR O , -N(R N )2, or -SR S and; R O each occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; R N each occurrence of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally, two R on the same nitrogen N are joined together with the intervening atoms to form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; and R Seach occurrence is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; It is a compound represented by the formula:

[0173] As defined herein, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0174] As defined herein, R 3 each occurrence is independently selected from hydrogen, halogen, —CN, —NO2, —N3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR O , -N(R N )2, or -SR S In some embodiments, R 3 At least one occurrence of R is hydrogen. 3 At least one occurrence of R is halogen. 3 At least one occurrence of R is -CN. 3 At least one occurrence of R is -NO. 3 At least one occurrence of R is -N3. 3At least one occurrence of R is optionally substituted alkyl. 3 At least one occurrence of R is optionally substituted alkenyl. 3 At least one occurrence of R is optionally substituted alkynyl. 3 At least one occurrence of R is an optionally substituted carbocyclyl. 3 At least one occurrence of R is optionally substituted heterocyclyl. 3 At least one occurrence of R is optionally substituted aryl. 3 At least one occurrence of R is optionally substituted heteroaryl. 3 At least one occurrence of R is optionally substituted acyl. 3 At least one occurrence of R is an optionally substituted sulfonyl. 3 At least one occurrence of R is an optionally substituted sulfinyl. 3 At least one occurrence of -OR O In some embodiments, R 3 At least one occurrence of -N(R N )2. In some embodiments, R 3 At least one occurrence of -SR S is.

[0175] Pharmaceutical Compositions, Kits, and Administration The present disclosure provides a pharmaceutical composition comprising a compound represented by Formula (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the compound described herein is provided in an effective amount in the pharmaceutical composition. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount. In some embodiments, the effective amount is an amount effective to treat an infectious disease or a skin condition in a subject in need thereof.

[0176] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. Generally, such preparation methods involve bringing a compound described herein (i.e., the "active ingredient" or "active compound") into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary, shaping into the desired form and / or packaging the product into the desired single or multiple dosage units. In some embodiments, the "active ingredient" or "active compound" is a compound represented by Formula (IV), (V), or (VI) or a pharmaceutically acceptable salt thereof.

[0177] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk as a single unit dose and / or a plurality of single unit doses. A "unit dose" is a discrete amount of pharmaceutical composition that contains a predetermined amount of active ingredient. The amount of active ingredient is generally equal to the dosage of the active ingredient administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0178] The relative amounts of the active ingredient, pharmaceutically acceptable excipient, and / or any additional ingredients in the pharmaceutical compositions described herein will vary depending on the identity, size, and / or condition of the subject being treated, and further depending on the route by which the composition is administered. In some embodiments, the composition may contain 0.1% to 100% (w / w) of the active ingredient.

[0179] In some cases, the composition may contain at least about 50% (w / v) active compound, at least about 10% (w / v) active compound, at least about 5% (w / v) active compound, at least about 1% (w / v) active compound, at least about 0.75% (w / v) active compound, at least about 0.5% (w / v) active compound, at least about 0.1% (w / v) active compound, at least about 0.01% (w / v) active compound, or at least about 0.001% (w / v) active compound. The active compound may be present in an amount of about 0.001% to 50% by weight, or about 1% to about 10% by weight, or about 0.001% to 1% by weight.

[0180] The pharmaceutical composition is about 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1.0 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2.0 mg / mL, 2.1 mg / mL, 2.2 mg / mL, 2.3 mg / mL, 2.4 mg / mL, 2.5 mg / mL, 2.6 mg / mL, 2.7 mg / mL, 2.8 mg / mL, 2.9 mg / mL, 3.0 mg / mL, 3.1 mg / mL, 3.2 mg / mL, 3.3 mg / mL, 3.4 mg / mL, 3.5 mg / mL, 3.6 mg / mL, 3.7 mg / mL, 3.8 mg / mL, 3.9 mg / mL, 4.0 mg / mL, 4.1 mg / mL, 4.2 mg / mL, 4.3 mg / mL, 4.4 mg / mL, 4.5 mg / mL, 4.6 mg / mL, 4.7 mg / mL, 4.8 mg / mL, 4.9 mg / mL, 5.0 mg / mL, 5.1 mg / mL, 5.2 mg / mL, 5.3 mg / mL, 5.4 mg / mL, 5.5 mg / mL, 5.6 mg / mL, 5.7 mg / mL, 5.8 mg / mL, 5.9 mg / mL, 6.0 mg / mL, 6.1 mg / mL, 6.2 mg / mL, 6.3 mg / mL, 6.4 mg / mL, 6.5 mg / mL, 6.6 mg / mL, 6.7 mg / mL, 6.8 mg / mL, 6.9 mg / mL, 7.0 mg / mL, 7.1 mg / mL, 7.2 mg / mL, 7.3 mg / mL, 7.4 mg / mL, 7.5 mg / mL, 7.6 mg / mL, 7.7 mg / mL, 7.8 mg / mL, 7.9 mg / mL, 8.0 mg / mL, 8.1 mg / mL, 8.2 mg / mL, 8.3 mg / mL, 8.4 mg / mL, 8.5 mg / mL, 8.6 mg / mL, 8.7 mg / mL, 8.8 mg / mL, 8.9 mg / mL, 9.0 mg / mL, 9.1 mg / mL, 9.2 mg / mL, 9.3 mg / mL, 9.4 mg / mL, 9.5 mg / mL, 9.6 mg / mL, 9.7 mg / mL, 9.8 mg / mL, 9.9 mg / mL, 10.0 mg / mL, 10.1 mg / mL, 10.2 mg / mL, 10.3 mg / mL, 10.4 mg / mL, 10.5 mg / mL, 10.6 mg / mL, 10.7 mg / mL, 10.8 mg / mL, 10.9mg / mL, 11.0mg / mL, 11.1mg / mL, 11.2mg / mL, 11.3mg / mL, 11.4mg / mL, 11.5mg / mL, 11.6mg / mL, 11.7mg / mL, 11.8mg / mL, 11.9mg / mL, 12.0mg / mL, 12.1mg / mL, 12.2mg / mL, 12. 3mg / mL, 12.4mg / mL, 12.5mg / mL, 12.6mg / mL, 12.7mg / mL, 12.8mg / mL, 12.9mg / mL, 13.0mg / mL, 13.1mg / mL, 13.2mg / mL, 13.3mg / mL, 13.4mg / mL, 13.5mg / mL, 13.6mg / mL, 13. The active compound may have an active compound concentration (milligrams (mg) active ingredient / milliliter (mL) formulation) of 7 mg / mL, 13.8 mg / mL, 13.9 mg / mL, 14.0 mg / mL, 14.1 mg / mL, 14.2 mg / mL, 14.3 mg / mL, 14.4 mg / mL, 14.5 mg / mL, 14.6 mg / mL, 14.7 mg / mL, 14.8 mg / mL, 14.9 mg / mL, 15.0 mg / mL, 15.5 mg / mL, 16.0 mg / mL, 16.5 mg / mL, 17.0 mg / mL, 17.5 mg / mL, 18.0 mg / mL, 18.5 mg / mL, 19.0 mg / mL, 19.5 mg / mL, or 20.0 mg / mL. In some examples, the active ingredient concentration is from 0.5 milligrams (mg) to 20 mg per milliliter (ml), or from 1 mg to 10 mg per ml.

[0181] Alternatively, the pharmaceutical composition is at least about 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1.0 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2.0 mg / mL, 2.1 mg / mL, 2.2 mg / mL, 2.3 mg / mL, 2.4 mg / mL, 2.5 mg / mL, 2.6 mg / mL, 2.7 mg / mL, 2.8 mg / mL, 2.9 mg / mL, 3.0 mg / mL, 3.1 mg / mL, 3.2 mg / mL, 3.3 mg / mL, 3.4 mg / mL, 3.5 mg / mL, 3.6 mg / mL, 3.7 mg / mL, 3.8 mg / mL, 3.9 mg / mL, 4.0 mg / mL, 4.1 mg / mL, 4.2 mg / mL, 4.3 mg / mL, 4.4 mg / mL, 4.5 mg / mL, 4.6 mg / mL, 4.7 mg / mL, 4.8 mg / mL, 4.9 mg / mL, 5.0 mg / mL, 5.1 mg / mL, 5.2 mg / mL, 5.3 mg / mL, 5.4 mg / mL, 5.5 mg / mL, 5.6 mg / mL, 5.7 mg / mL, 5.8 mg / mL, 5.9 mg / mL, 6.0 mg / mL, 6.1 mg / mL, 6.2 mg / mL, 6.3 mg / mL, 6.4 mg / mL, 6.5 mg / mL, 6.6 mg / mL, 6.7 mg / mL, 6.8 mg / mL, 6.9 mg / mL, 7.0 mg / mL, 7.1 mg / mL, 7.2 mg / mL, 7.3 mg / mL, 7.4 mg / mL, 7.5 mg / mL, 7.6 mg / mL, 7.7 mg / mL, 7.8 mg / mL, 7.9 mg / mL, 8.0 mg / mL, 8.1 mg / mL, 8.2 mg / mL, 8.3 mg / mL, 8.4 mg / mL, 8.5 mg / mL, 8.6 mg / mL, 8.7 mg / mL, 8.8 mg / mL, 8.9 mg / mL, 9.0 mg / mL, 9.1 mg / mL, 9.2 mg / mL, 9.3 mg / mL, 9.4 mg / mL, 9.5 mg / mL, 9.6 mg / mL, 9.7 mg / mL, 9.8 mg / mL, 9.9 mg / mL, 10.0 mg / mL, 10.1 mg / mL, 10.2 mg / mL, 10.3 mg / mL, 10.4 mg / mL, 10.5 mg / mL, 10.6 mg / mL, 10.7 mg / mL, 10.8mg / mL, 10.9mg / mL, 11.0mg / mL, 11.1mg / mL, 11.2mg / mL, 11.3mg / mL, 11.4mg / mL, 11.5mg / mL, 11.6mg / mL, 11.7mg / mL, 11.8mg / mL, 11.9mg / mL, 12.0mg / mL, 12.1mg / mL, 1 2.2mg / mL, 12.3mg / mL, 12.4mg / mL, 12.5mg / mL, 12.6mg / mL, 12.7mg / mL, 12.8mg / mL, 12.9mg / mL, 13.0mg / mL, 13.1mg / mL, 13.2mg / mL, 13.3mg / mL, 13.4mg / mL, 13.5mg / mL, The active ingredient may have an active ingredient concentration (mg active ingredient / mL formulation) of 13.6 mg / mL, 13.7 mg / mL, 13.8 mg / mL, 13.9 mg / mL, 14.0 mg / mL, 14.1 mg / mL, 14.2 mg / mL, 14.3 mg / mL, 14.4 mg / mL, 14.5 mg / mL, 14.6 mg / mL, 14.7 mg / mL, 14.8 mg / mL, 14.9 mg / mL, 15.0 mg / mL, 15.5 mg / mL, 16.0 mg / mL, 16.5 mg / mL, 17.0 mg / mL, 17.5 mg / mL, 18.0 mg / mL, 18.5 mg / mL, 19.0 mg / mL, 19.5 mg / mL, or 20.0 mg / mL. In some situations, the formulation may have an active ingredient concentration that is less than or equal to about 40 mg / mL, 30 mg / mL, 20 mg / mL, 10 mg / mL, 5 mg / mL, or 1 mg / mL.

[0182] Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweeteners, flavoring agents, and perfuming agents may also be present in the composition.

[0183] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0184] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-soluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0185] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitol, ... Sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), ... monooleate (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), polyoxyethylene sorbitan monopalmitate (Span® 40), polyoxyethylene sorbitan monolaurate (Tween® 60), polyoxyethylene sorbitan monooleate (Span® 80), polyoxyethylene sorbitan monooleate (Span® 60), polyoxyethylene sorbitan monooleate (Span® 60), polyoxyethylene sorbitan monooleate (Span® 60), polyoxyethylene sorbitan monooleate (Span® 60), polyoxyethylene sorbitan monooleate (Span® 60), polyoxyethylene sorbitan monooleate (Span® 60), polyoxyethylene sorbitan monooleate (Span® 60), polyoxyethylene sorbitan Diethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate,Triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, Polyoxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0186] Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husk, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabinogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0187] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In some embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0188] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0189] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., edetate sodium, edetate disodium, edetate trisodium, edetate calcium, edetate disodium, edetate dipotassium, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzathonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxyl enol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0190] Exemplary antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0191] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0192] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0193] Other preservatives include tocopherol, tocopheryl acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium sulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.

[0194] Exemplary buffering agents include citrate buffer solution, acetate buffer solution, phosphate buffer solution, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0195] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0196] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, blackcurrant seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grapeseed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, and aloe.

[0013] Examples of synthetic oils include linseed oil, macadamia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savory, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, camellia, vetiver, walnut, and wheat germ oil. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0197] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (such as by powder, ointment, cream, and / or drops), mucosal, nasal, buccal, sublingual; intratracheal instillation, bronchial instillation, and / or by inhalation; and / or as oral spray, nasal spray, and / or aerosol. Specifically, the intended route is topical in nature.

[0198] The dosage form for topical and / or transdermal administration of the compounds described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches.Generally, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any necessary preservatives and / or buffers as may be required.Such dosage forms can be prepared, for example, by dissolving and / or dispersing the active ingredient in a suitable medium.Alternatively or additionally, the rate can be controlled by providing a rate-controlling membrane and / or dispersing the active ingredient in a polymer matrix and / or gel.

[0199] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations, such as liniments, lotions, etc., oil-in-water and / or water-in-oil emulsions, such as creams, ointments, etc., and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may contain, for example, about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further include one or more additional ingredients described herein.

[0200] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to animals of all kinds. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well understood, and a skilled veterinary pharmacologist can design and / or perform such modifications with routine experimentation.

[0201] The compound provided herein is usually formulated into dosage unit form for ease of administration and uniformity of dosage.However, it is understood that the total daily use amount of the compositions described herein is determined by a doctor within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific subject or organism depends on various factors, including the severity of the disease and disorder being treated; the activity of the specific active ingredient being used; the specific composition being used; the age, weight, general health, sex and diet of the subject; the time of administration, route of administration and the excretion rate of the specific active ingredient being used; the duration of treatment; the drug that is used in combination with or at the same time as the specific active ingredient being used; and factors that are well known in the medical field.

[0202] The exact amount of compound required to achieve an effective dose will vary from subject to subject, depending, for example, on the species, age, and general condition of the subject, the severity of any side effects or disorders, the identity of the particular compound, the mode of administration, etc. An effective amount may be contained in a single dose or in multiple doses.

[0203] The composition may be delivered to the subject (e.g., to an area of ​​the subject's skin that has or is suspected of having a wart or skin lesion) from once per day to once per month or more. Alternatively, or in addition, the composition may be delivered to the subject from once per day to once per week. Alternatively, or in addition, the composition may be delivered to the subject at least once per day, once every two days, once per three days, once per four days, once per five days, once per six days, once per week, once per ten days, once per two weeks, once per three weeks, once per month, once per two months, once per three months, once per four months, once per five months, once per six months, once per year, or more. Alternatively, or in addition, the composition may be delivered to the subject at least once per day, or twice per day, or three times per day, or four times per day, or five times per day, or six times per day, or seven times per day, or eight times per day, or nine times per day, or ten times per day, or eleven times per day, or 12 times per day, or 13 times per day, or 14 times per day, or 15 times per day, or 16 times per day, or 17 times per day, or 18 times per day, or 19 times per day, or 20 times per day, or 21 times per day, or 22 times per day, or 23 times per day, or 24 times per day. Alternatively, or in addition, the composition may be delivered to the subject as soon as the skin begins to epithelialize after a previous treatment. Alternatively, or in addition, the composition may be delivered to the subject as soon as the skin begins to epithelialize after a previous treatment. Alternatively, or in addition, the composition may be delivered to the subject as soon as the skin is partially epithelialized after a previous treatment. Alternatively, or in addition, the composition may be delivered to the subject as soon as the skin is fully epithelialized after a previous treatment.

[0204] The dosage ranges described herein provide guidance for administering the provided pharmaceutical compositions to adults. For example, the amount administered to a child or adolescent can be determined by a practitioner or person skilled in the art and can be less than or the same as the amount administered to an adult.

[0205] The compounds or compositions described herein may be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutic and / or prophylactic active agents). The compounds or compositions may be administered in combination with additional pharmaceutical agents to improve their activity (e.g., activity (e.g., efficacy and / or effectiveness) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, or in reducing the risk of developing a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or alter metabolism, inhibit excretion, and / or alter distribution in a subject or cell. It is also understood that the treatments employed may achieve desired effects for the same disorder and / or may achieve different effects. In some embodiments, the pharmaceutical compositions described herein comprising the compounds described herein and the additional pharmaceutical agents exhibit a synergistic effect that is not present in pharmaceutical compositions comprising one of the compounds and the additional pharmaceutical agents but not both.

[0206] The compound or composition may be administered simultaneously with, prior to, or subsequent to one or more additional pharmaceutical agents that may be useful in combination therapy, for example. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (for example, compounds approved for human or veterinary use by the U.S. Food and Drug Administration, as defined in the Code of Federal Regulations (CFR)).

[0207] The pharmaceutical compositions of the present disclosure may contain other topical agents, including, but not limited to, local anesthetics, topical analgesics, antibacterial agents, disinfectants, antiseptics, antibiotics, bacteriocidal agents, bacteriostatic agents, cleansing agents, anti-inflammatory agents, anti-infective agents (e.g., gentian violet), emollients, astringents, anti-acne agents, antiviral agents, antifungal agents, fungicides, antipsoriatic agents, anthelmintics, and steroid hormones such as corticosteroids.Examples of topical agents include, but are not limited to, Altavax (retapamulin), Amebiv (alefacept), Avita gel, Bactroban cream, benzamycin, erythromycin, Botox, cefazolin, dextrose, Chloraprep (chlorhexidine gluconate), clindamycin phosphate, Condylox (pocofilox), Desonate (desonide), Differin (adapalene), Dynabac, Elidel, Erivage (vismodegib), Estrostep, norethindrone acetate, ethinyl estradiol, Extina (ketoconazole), Fiacea (azelaic acid), Finnevin, Firasil (icatibant), Glarize (gabapentin), Horizant (gapapentin enacarbil), hydrochloric acid, hydrogen peroxide, Iamine, Invanz, Iontocaine, IvyBlock, Kuralon (sulfacetamide sodium), Lamisil (terbinafine hydrochloride), Raviv (Azficel-T), Lustra, Luxic (betamethasone valerate), Mentax (butenafine HCl), Metrolox ion, minoxidil, noritate, nitric acid, omnicef, orthotricycle, norgestimate, Picato (ingenol mebutate), Propecia, Protopic (tacrolimus), Condylox (podofotoxin), Regranex (becaplermin), Renova, trachnoid, Salagen, sandalwood oil, salicylic acid, Sucrice (ivermectin), Stelara (ustekinumab), sulfamiron, Silatron (peginterferon alginate) These include: rufa-2b), Tazorac, Teflaro (ceftaroline fosamil), Talomid, trichloroacetic acid, Tigacyl (tigecycline), Vertin (clindamycin phosphate), tretinoin, Vergen (green tea syncatechin), Verdeso (desonide), Bibativ (telavancin), Bibativ (telavancin), Xyzal (levocetirizine dihydrochloride), Yervoy (ipilimumab), Zelboraf (vemurafenib), and Zyclara (imiquimod).

[0208] Also encompassed by the present disclosure are kits (e.g., pharmaceutical packs). The provided kits may include a pharmaceutical composition or compound described herein and a container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a disposable package, or other suitable container). In some embodiments, the provided kits may optionally further include a second container containing a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form a single unit dosage form.

[0209] Thus, in one aspect, provided is a kit comprising a first container containing a compound or pharmaceutical composition described herein. In some embodiments, the kit is useful for treating a disease (e.g., an infectious disease or a skin condition) in a subject in need thereof. In some embodiments, the kit is useful for preventing a disease (e.g., an infectious disease or a skin condition) in a subject in need thereof. In some embodiments, the kit is useful for reducing the risk of developing or contracting a disease (e.g., an infectious disease or a skin condition) in a subject in need thereof. In some embodiments, the kit described herein includes instructions for using the kit. The kit described herein also includes information required by regulatory authorities, such as the U.S. Food and Drug Administration (FDA). In some embodiments, the information included in the kit is prescribing information.

[0210] In some embodiments, the active ingredient in the pharmaceutical composition is present at a high purity with respect to the active ingredient (i.e., without taking into account other active ingredients, excipients, carriers, solvents, etc.). In some embodiments, the purity is greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% with respect to the active ingredient. In some embodiments, the purity is greater than 90% with respect to the active ingredient. In some embodiments, the purity is greater than 95% with respect to the active ingredient. In some embodiments, the purity is greater than 98% with respect to the active ingredient. In some embodiments, the purity is greater than 99% with respect to the active ingredient. In some embodiments, the purity is greater than 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% pure.

[0211] Methods of Treatment and Use The compounds provided herein may have biological activity and therefore may be useful in treating a disease or condition (eg, infectious disease, skin conditions).

[0212] Provided herein is a method for treating a disease or condition in a subject, the method comprising administering to the subject an effective amount of a compound represented by Formula (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The present invention also provides compounds represented by Formula (IV), (V), and (VI), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in treating diseases and conditions in a subject. The present invention also provides use of compounds represented by Formula (IV), (V), and (VI), or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of a medicament for treating diseases and conditions in a subject. In some embodiments, the disease is an infectious disease. In some embodiments, the condition is a skin condition.

[0213] In some embodiments, the disease is an infectious disease. "Infectious disease" refers to any disease caused by a pathogen (i.e., a pathogenic microorganism). An infectious disease may be caused by a bacterium, a virus, a parasite, or a fungus. An infectious disease may be a microbial infection. "Microbial infection" refers to an infection caused by a microorganism such as a fungus, a bacterium, or a virus. In some embodiments, the microbial infection is an infection caused by a fungus, i.e., a fungal infection. In some embodiments, the microbial infection is an infection caused by a virus, i.e., a viral infection. In some embodiments, the microbial infection is an infection caused by a bacterium, i.e., a bacterial infection. Various microbial infections include, but are not limited to, skin infections, GI infections, urinary tract infections, genitourinary infections, sepsis, blood infections, and systemic infections. In some embodiments, the infectious disease is a bacterial infection. In some embodiments, the infectious disease is a viral infection. In some embodiments, the infectious disease is a microbial infection.

[0214] In certain embodiments, the compounds described herein are useful in the treatment of infectious diseases or skin conditions. Examples of infectious diseases or skin conditions include, but are not limited to, acral fibrokeratoma, acrodermatitis enterica, acral keratoelastoid, actinic keratosis (solar keratosis), sebaceous adenoma, angiokeratoma, atopic dermatitis, basal cell carcinoma, benign fibrous histiocytoma, bladder cancer, Bowen's disease, breast cancer, Buschke-Ollendorff syndrome, cervical cancer, cervical dysplasia, senile hemangioma, chronic nodular chondrodermatitis helicalis, common warts, cutaneous endometriosis, leukemia cutis, cutaneous lymphoma, cutaneous meningioma, cutaneous myxoma, Darier's disease, dermal dendritic cell hamartoma, dermatofibroma, dermatofibrosarcoma protuberans, eccrine angiomatoid hamartoma, ectodermal dysplasia, epidermal inclusion cyst, epidermal nevus, epithelioid cell histiocytoma, familial myxovascular fibromas, fungal skin diseases, granular cell tumor, glucagonoma syndrome, genital warts, ichthyosis, idiopathic guttate hypomelanosis, infantile acropustulosis, infantile fibromatosis, Kaposi's sarcoma, keloid, keratoacanthoma, keratocyst, knuckle pads, lentigo, melanoma, microvenular hemangioma, molluscum contagiosum, Morton's neuroma, multifocal lymphangioendotheliomatosis, multinucleate cell angiohistiocytoma angiohistocytoma), multiple cutaneous leiomyomas, mycosis fungoides, cutaneous neuromas, nerve capsules, flaming nevi, superficial lipomatous nevi, pachydermodactyly, palisade encapsulation Neuromas, parasitic skin diseases, pityriasis pilaris, Piloleiomyomas, plantar warts, plexiform fibrous histiocytic tumors, pokeratotic eccrine and dermal canal nevi. eccrine ostial and dermal duct nevus), Progressive nodular histiocytoma psoriasis (progressive nodular histiocytoma) Psoriasis, porokeratosis, seborrheic dermatitis, seborrheic keratosis, rhinophyma, solitary cutaneous leiomyoma, spider angioma, target-like hemosiderinoma, squamous cell carcinoma, tufted vessels, vein lakes, pigmented urticaria, xanthelasmoid mastocytosismastocytosis, zosteriform metastasis, benign epidermal cyst, birthmark, callus, corn, eczema, small spot, mole, pigmentation disorder, drug-induced hyperpigmentation, hereditary symmetrical dyschromatosis, hereditary generalized dyschromatosis, familial progressive hyperpigmentation, garigari disease, hemosiderin hyperpigmentation, idiopathic guttate hypomelanosis, iron metallic discoloration, vitiligo, melasma, Mukamel syndrome, necklace of Venus, anemic nevus, depigmented nevus, Pallister-Killian syndrome, phylloid hypomelanosis, mottling, reticular facial pigmentation, pilonidal cyst Cysts, pityriasis alba, poikiloderma of Civat, poikiloderma vasculare atrophicans, post-inflammatory hyperpigmentation, progressive macular hypomelanosis, pruritus, reticular pigmented anomaly of the flexures, acropigmentary reticular hyperpigmentation, Lille melanosis, Schar-Waardenburg syndrome, shiitake dermatitis, tar melanosis, titanium metal discoloration, transient neonatal pustular melanosis, Vagabond's leukomelanoderma, vasospastic macules, Wende-Bauckus syndrome, X-linked reticular pigmentation, Yemeni deaf-blind hypopigmentation syndrome, scars, soft fibroma, tattoo removal, and vitiligo.

[0215] definition Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. (inside cover), and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry and specific functional moieties and reactivities are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001;Larock, Comprehensive Organic Transformations, 2 nd Edition, Wiley-VCH Publishers, Inc., New York, 1999; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0216] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched with one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725(1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present invention additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, or alternatively, as mixtures of various isomers.

[0217] Unless so stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium; 19 F 18 Replace with F, or 12 C 13 C or 14Compounds having this structure, except for the replacement with C, are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0218] "Sulfonyl" is -SO2N(R bb )2, -SO2R aa , and -SO2OR aa where R aa and R bb is as defined herein.

[0219] "Sulfinyl" is the group -S(=O)R aa where R aa is as defined herein.

[0220] The term "phosphoryl" refers to -P(=O)(OR cc )2, -P(=O)(R aa )2, and -P(=O)(N(R bb )2)2, where R aa , R bb , and R cc is as defined herein.

[0221] "Sulfonate" is -OSON(R bb )2, -OSO2R aa , and -OSO2OR aa where R aa and R bb is as defined herein. Examples of sulfonate groups include, but are not limited to, -OSOPh, tosylate (-OSOCH-CH; "OTs"), triflate (-OSOCF; "OTf"), brosylate (-OSOCH-Br; "OBs"), nonaflate (-OSO(CF)CF; "ONf"), nosylate (-SOCH-NO or -SOCH-NO; "ONs"), and dansylate ("ODs").

[0222] "Phosphate" is -O(P=O)(R aa )2, -O(P=O)(OR cc )R aa , -O(P=O)(OR cc )2, -O(P=O)(NR bb )2, where R aa , R bb , and R cc is as defined herein.

[0223] The term "acyl" refers to a group having the general formula -C(=O)R X1 , -C(=O)OR X1 , -C(=O)-OC(=O)R X1 , -C(=O)SR X1 , -C(=O)N(R X1 )2, -C(=S)R X1 , -C(=S)N(R X1 )2, -C(=S)O(R X1 ), -C(=S)S(R X1 ), -C(=NR X1 )R X1 , -C(=NR X1 ) OR X1 , -C(=NR X1 )SR X1 , and -C(=NR X1 )N(R X1 )2, where R X1 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -R aa , -OR cc , or -OR bb or two R X1 The groups are linked together to form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-COH), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.

[0224] The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0225] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 is intended to cover alkyls of the formula:

[0226] The term "alkyl" refers to the radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms ("C 1~10 In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1~3In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless so specified, each occurrence of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted with one or more substituents (e.g., halogens such as F) (a "substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 Alkyl (unsubstituted C 1~6 Alkyl, for example, -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, for example, unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, for example, unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In some embodiments, the alkyl group is substituted C 1~12 Alkyl (substituted C 1~6 alkyl, for example, -CF3, Bn).

[0227] The term "haloalkyl" refers to a substituted alkyl group in which one or more of the hydrogen atoms are independently replaced by a halogen, such as fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("C 1~8In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("C 1~6 In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("C 1~4 In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C 1~2 Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CCl3, -CFCl2, -CF2Cl, and the like.

[0228] The term "heteroalkyl" refers to an alkyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (interposed between adjacent carbon atoms of the parent chain) and / or at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and one or more heteroatoms within the parent chain ("heteroC"). 1~10 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 9 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~9 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 8 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~8 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 7 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~7 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 6 carbon atoms and one or more heteroatoms in the parent chain ("heteroC 1~6In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1~5 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms in the parent chain ("heteroC 1~4 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 3 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1~3 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 2 carbon atoms and 1 heteroatom in the parent chain ("heteroC 1~2 In some embodiments, heteroalkyl refers to saturated groups having one carbon atom and one heteroatom ("heteroC1 alkyl"). In some embodiments, heteroalkyl refers to saturated groups having two to six carbon atoms and one or two heteroatoms in the parent chain ("heteroC 2~6 Unless so specified, each occurrence of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~10 In some embodiments, the heteroalkyl group is a substituted heteroC 1~10 It is alkyl.

[0229] The term "alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2~7In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the aforementioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless so specified, each occurrence of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents (a "substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In some embodiments, the alkenyl group is a substituted C 2~10 Alkenyl. In alkenyl groups, the stereochemistry of the C=C double bond is not specified (e.g., -CH=CHCH3, or [ka] may be an (E)- or (Z)-double bond.

[0230] The term "heteroalkenyl" refers to an alkenyl group that further contains at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (interposed between adjacent carbon atoms of the parent chain) and / or at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and one or more heteroatoms within the parent chain ("heteroalkenyl"). 2~10 In some embodiments, a heteroalkenyl group refers to a group having 2 to 9 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~9 In some embodiments, a heteroalkenyl group refers to a group having 2 to 8 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~8 In some embodiments, a heteroalkenyl group refers to a group having 2 to 7 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~7 In some embodiments, a heteroalkenyl group refers to a group having 2 to 6 carbon atoms, at least one double bond, and one or more heteroatoms in the parent chain ("heteroC 2~6 In some embodiments, a heteroalkenyl group refers to a group having 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~5 In some embodiments, a heteroalkenyl group refers to a group having 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~4 In some embodiments, a heteroalkenyl group refers to a group having 2 to 3 carbon atoms, at least one double bond, and one heteroatom in the parent chain ("heteroC 2~3 alkenyl). In some embodiments, a heteroalkenyl group refers to a group having 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~6 Unless so specified, each occurrence of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2~10 In some embodiments, the heteroalkenyl group is a substituted heteroC 2~10 It is alkenyl.

[0231] The term "alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C 2~10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C 2~4Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkenyl groups include the aforementioned C 2~4 Alkynyl groups include pentynyl (C), hexynyl (C), and the like. Additional examples of alkynyl include heptynyl (C), octynyl (C), and the like. Unless so specified, each occurrence of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents (a "substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In some embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0232] The term "heteroalkynyl" refers to an alkynyl group that further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur, located within the parent chain (interposed between adjacent carbon atoms of the parent chain) and / or at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and one or more heteroatoms within the parent chain ("heteroalkynyl"). 2~10 In some embodiments, heteroalkynyl groups have 2 to 9 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~9 In some embodiments, heteroalkynyl groups have 2 to 8 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~9 In some embodiments, heteroalkynyl groups have 2 to 7 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC 2~7 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and one or more heteroatoms in the parent chain ("heteroC2~6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~4 In some embodiments, heteroalkynyl groups have 2 to 3 carbon atoms, at least one triple bond, and one heteroatom in the parent chain ("heteroC 2~3 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms in the parent chain ("heteroC 2~6 Unless so specified, each occurrence of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2~10 In some embodiments, the heteroalkynyl group is a substituted heteroC 2~10 It is alkynyl.

[0233] The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms and zero heteroatoms in its non-aromatic ring system ("C 3~14 In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3~7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6In some embodiments, the carbocyclyl group has 4 to 6 ring carbon atoms ("C 4~6 In some embodiments, the carbocyclyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 Carbocyclyl). 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. Exemplary C 3~8 The carbocyclyl group may be any of the aforementioned C 3~6 Carbocyclyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3~10 The carbocyclyl group may be any of the aforementioned C 3~8 Carbocyclyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10), and the like. As the above examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (containing, for example, fused, bridged, or spiro ring systems such as a bicyclic system ("bicyclic carbocyclyl") or a tricyclic system ("tricyclic carbocyclyl")), and can be saturated or contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring is fused to one or more aryl or heteroaryl groups, as defined above (where the point of attachment is on the carbocyclyl ring; in such instances, the number of carbons designates the number of carbons in the carbocyclic ring system throughout). Unless so specified, each occurrence of a carbocyclyl group is independently unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C 3~14 In some embodiments, the carbocyclyl group is a substituted C 3~14 It is a carbocyclyl.

[0234] In some embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C 3~14 In some embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10Cycloalkyl). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups are the aforementioned C 5~6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups are the aforementioned C 3~6 Cycloalkyl groups include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless so specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3~14 In some embodiments, the cycloalkyl group is a substituted C 3~14 It is cycloalkyl.

[0235] The term "heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 14-membered nonaromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3- to 14-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., fused, bridged, or spiro ring systems, such as a bicyclic system ("bicyclic heterocyclyl") or a tricyclic system ("tricyclic heterocyclyl"). Heterocyclyl groups can be saturated or contain one or more carbon-carbon double or triple bonds. Polycyclic ring systems of heterocyclyls can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring is fused with one or more carbocyclyl groups, as defined above (where the point of attachment is on either the carbocyclyl ring or the heterocyclyl ring), or ring systems in which the heterocyclyl ring is fused with one or more aryl or heteroaryl groups, as defined above (where the point of attachment is on the heterocyclyl ring); in such instances, the number of ring members designates the number of ring members in the heterocyclyl ring system throughout. Unless so specified, each occurrence of heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 14-membered heterocyclyl. In some embodiments, the heterocyclyl is a substituted 3- to 14-membered heterocyclyl.

[0236] In some embodiments, heterocyclyl groups are 5-10 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-8 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, heterocyclyl groups are 5-6 membered non-aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, 5-6 membered heterocyclyls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0237] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxathiolanyl, and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diphenylmethyl ... azepinyl, 1,4,5,7-tetrahydropyran o[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

[0238] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6 to 14 ring carbon atoms and zero heteroatoms ("C") provided in the aromatic ring system. 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl"; for example, anthracyl). "Aryl" also encompasses ring systems in which an aryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above, where the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms designates the number of carbon atoms in the aryl ring system throughout. Unless so specified, each occurrence of an aryl group is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6~14 In some embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0239] The term "heteroaryl" refers to a radical of a 5- to 14-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array) having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. Polycyclic heteroaryl ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring is fused with one or more carbocyclyl or heterocyclyl groups, as defined above, where the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members is designated throughout the heteroaryl ring system. "Heteroaryl" also encompasses ring systems in which a heteroaryl ring is fused with one or more aryl groups, as defined above, where the point of attachment is on the aryl ring or the heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. In polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, e.g., the ring bearing the heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0240] In some embodiments, heteroaryl groups are 5- to 10-membered aromatic ring systems having provided ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 8-membered aromatic ring systems having provided ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 6-membered aromatic ring systems having provided ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, 5- to 6-membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless so specified, each occurrence of a heteroaryl group is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In some embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In some embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0241] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0242] Groups may be optionally substituted (are optionally substituted) unless expressly provided as such. The term "optionally substituted" refers to substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups may be optionally substituted (are optionally substituted). "Optionally substituted" refers to a group that may be substituted or unsubstituted (e.g., a "substituted" or "unsubstituted" alkyl group, a "substituted" or "unsubstituted" alkenyl group, a "substituted" or "unsubstituted" alkynyl group, a "substituted" or "unsubstituted" heteroalkyl group, a "substituted" or "unsubstituted" heteroalkenyl group, a "substituted" or "unsubstituted" heteroalkynyl group, a "substituted" or "unsubstituted" carbocyclyl group, a "substituted" or "unsubstituted" heterocyclyl group, a "substituted" or "unsubstituted" aryl group, or a "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen present on a group is replaced with a permissible substituent (e.g., a substituent that, when substituted, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction). Unless so indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to encompass substitution with all permissible substituents of organic compounds and includes any of the substituents described herein that result in the formation of stable compounds. The present invention contemplates any and all such combinations in order to arrive at stable compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety. It is not intended that the present invention be limited in any way by the exemplary substituents described herein.

[0243] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(R bb )2, -NR bb C(=O)R aa , -NR bb CO2R aa , -NR bb C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -OC(=NR bb )R aa , -OC(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -OC(=NR bb )N(R bb )2, -NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(=O)R aa , -OS(=O)Raa 、-Si(R aa )3、-OSi(R aa )3、-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)(R aa )2、-P(=O)(OR cc )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)(N(R bb )2)2、-OP(=O)(N(R bb )2)2、-NR bb P(=O)(R aa )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(N(R bb )2)2、-P(R cc )2、-P(OR cc )2、-P(R cc )3 + X - 、-P(OR cc )3 + X - 、-P(R cc )4、-P(OR cc )4、-OP(R cc )2、-OP(R cc )3 + X - 、-OP(OR cc )2、-OP(OR cc )3 + X - 、-OP(R cc )4、-OP(OR cc )4、-B(R aa )2、-B(OR cc )2、-BR aa (OR cc )、C 1~10 アルキル、C 1~10 ペルハロアルキル、C2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; where X - is the counterion; Alternatively, two geminal hydrogens on a carbon atom can be bonded to the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc has been replaced by; R aa Each occurrence of C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl; or two R aaThe groups are joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb Each occurrence of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)(N(R cc )2)2, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl; or two R bbThe groups are joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; where X - is the counterion; R cc Each occurrence of is independently hydrogen, C 1~10 Alkyl, C 1~10 Perhaloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, Hetero C 1~10 Alkyl, Hetero C 2~10 Alkenyl, Hetero C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3-14 membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl; or two R cc The groups are joined to form a 3- to 14-membered heterocyclyl ring or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd Each occurrence of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2Ree , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)(OR ee )2, -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg group or two geminal R dd The substituents may be joined to form =O or =S; where X - is the counterion; R ee Each occurrence of C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl and 5- to 10-membered heteroaryl, or two R ffThe groups are joined to form a 3- to 10-membered heterocyclyl ring or a 5- to 10-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group; and R gg Each occurrence of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(=NH)NH(C 1~6 alkyl), -OC(=NH)NH2, -NHC(=NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2(C 1~6 alkyl), -SO2O(C 1~6 alkyl), -OSO2(C 1~6 alkyl), -SO(C 1~6 alkyl), -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3, -C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)(OC 1~6 alkyl)2, -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6アル Kinir, C. 3~10 Carbocyclyl, C 6~10aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg The substituents may be joined to form =O or =S; where X - is the counter ion.

[0244] In certain embodiments, carbon atom substituents include: halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(=NH)NH(C 1~6 alkyl), -OC(=NH)NH2, -NHC(=NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2(C 1~6 alkyl), -SO2O(C 1~6 alkyl), -OSO2(C 1~6 alkyl), -SO(C 1~6 alkyl), -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3, -C(=S)N(C 1~6 alkyl)2, C(=S)NH(C 1~6 alkyl), C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)(OC 1~6 alkyl)2, -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Perhaloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Hetero C 1~6 Alkyl, Hetero C 2~6 Alkenyl, Hetero C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R ggThe substituents may be joined to form =O or =S; where X - is the counter ion.

[0245] A "counterion" or "anionic counterion" is a negatively charged group attached to a positively charged group to maintain electronic neutrality (we are much more likely to form cationic salts of our mono- and dicarboxylic acids, such as Na, K, NR4 salts). Anionic counterions may be monovalent (i.e., contain one formal negative charge). Anionic counterions may also be multivalent (i.e., contain more than one formal negative charge), such as divalent or trivalent. Exemplary counterions are halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HCO3 - , HSO4 - , sulfonate ions (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1-sulfonic acid-5-sulfonic acid, ethane-1-sulfonic acid-2-sulfonic acid, etc.), carboxylate ions (e.g., acetic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, gluconic acid, etc.), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4] - , B(C6F5)4 - , BPh4 - , Al(OC(CF3)3)4 - , and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me5Br6) -Exemplary counterions, which may be multivalent, include CO3 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- , carboxylate anions (e.g., tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, malonic acid, gluconic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, salicylic acid, phthalic acid, aspartic acid, glutamic acid, etc.), and carboranes.

[0246] As used herein, use of the phrase "at least one instance" refers to one, two, three, four, or more instances, but also, by way of example, covers ranges such as one to four, one to three, one to two, two to four, two to three, or three to four instances (inclusive).

[0247] Any compound provided herein or used in the methods provided herein may be provided and / or used as its salt. As used herein, the term "salt" refers to any and all salts, including pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals, without undue toxicity, irritation, allergic reaction, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmacologically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art (such as ion exchange).Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-methyl-N ... + (C 1~4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additionally, pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0248] The term "leaving group" is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or group displaceable by a nucleophile. See, e.g., Smith, March, Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformates. In some cases, the leaving group is a sulfonate ester such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), p-bromobenzenesulfonyloxy (brosylate, -OBs), -OS(=O)2(CF2)3CF3 (nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate such as 2-nitrobenzenesulfonyloxy. The leaving group may also be a phosphine oxide (e.g., formed during the Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other non-limiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties. Further exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., —OC(═O)SR aa , -OC(=O)R aa , -OCO2R aa , -OC(=O)N(R bb )2, -OC(=NR bb )R aa , -OC(=NR bb ) ORaa , -OC(=NR bb )N(R bb )2, -OS(=O)R aa , -OSO2R aa , -OP(R cc )2, -OP(R cc )3, -OP(=O)2R aa , -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -OP(=O)2N(R bb )2, and -OP(=O)(NR bb )2, where R aa , R bb , and R cc is as defined herein).

[0249] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to herein as a "hydroxyl protecting group"). Oxygen protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3 + X - , -P(OR cc )2, -P(OR cc )3 + X - , -P(=O)(R aa )2, -P(=O)(OR cc )2, and -P(=O)(N(R bb )2)2, where X - , Raa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 5 th edition, John Wiley & Sons, 2014, which is incorporated herein by reference.

[0250] The term "solvent" refers to a substance that dissolves one or more solutes, resulting in a solution. A solvent may serve as a medium for any of the reactions or transformations described herein. A solvent may dissolve one or more reactants or reagents in a reaction mixture. A solvent may facilitate mixing of one or more reagents or reactants in a reaction mixture. A solvent may also serve to increase or decrease the rate of a reaction compared to a reaction in a different solvent. A solvent may be polar or non-polar, protic or aprotic. In certain embodiments, the reactions described herein are carried out in an ionic liquid.Common organic solvents useful in the methods described herein include, but are not limited to, acetone, acetonitrile, benzene, benzonitrile, 1-butanol, 2-butanone, butyl acetate, tert-butyl methyl ether, carbon disulfide, carbon tetrachloride, chlorobenzene, 1-chlorobutane, chloroform, cyclohexane, cyclopentane, 1,2-dichlorobenzene, 1,2-dichloroethane, dichloromethane (DCM), N,N-dimethylacetamide, N,N-dimethylformamide (DMF), 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU), 1,4-dioxane, 1,3-dioxane, diethyl ether, 2-ethoxyethyl ether, ethyl acetate, ethyl alcohol, ethylene glycol, dimethyl ether, heptane, n-hexane, hexane, hexame Examples of suitable methyl methyl ethers include methyl methyl ether (HMPA), 2-methoxyethanol, 2-methoxyethyl acetate, methyl alcohol, 2-methylbutane, 4-methyl-2-pentanone, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-methyl-2-pyrrolidinone, dimethyl sulfoxide (DMSO), dimethyl sulfone, sulfolane, nitromethane, 1-octanol, pentane, 3-pentanone, 1-propanol, 2-propanol, pyridine, tetrachloroethylene, tetrahydrofuran (THF), 2-methyltetrahydrofuran, toluene, trichlorobenzene, 1,1,2-trichlorotrifluoroethane, 2,2,4-trimethylpentane, trimethylamine, triethylamine, N,N-diisopropylethylamine, diisopropylamine, water, o-xylene, and p-xylene.

[0251] The terms "catalysis," "catalyze," or "catalytic" refer to an increase in the rate of a chemical reaction due to the addition of a substance called a "catalyst." In some embodiments, the amount and nature of the catalyst remain essentially unchanged during the reaction. In some embodiments, the catalyst is regenerated, or the properties of the catalyst are essentially restored after the reaction. A catalyst may participate in multiple chemical transformations. The effectiveness of a catalyst may vary due to the presence of other substances known as inhibitors or poisons (which reduce catalytic activity) or promoters (which increase its activity). A catalyzed reaction has a lower activation energy (rate-limiting free energy of activation) than the corresponding uncatalyzed reaction, resulting in a higher reaction rate at the same temperature. A catalyst may favorably influence the reaction environment, bind to a reagent to polarize bonds, form specific intermediates not typically produced by uncatalyzed reactions, or cause dissociation of a reagent to its reactive form.

[0252] A "subject" to which administration is contemplated refers to a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, or an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or the elderly)) or a non-human animal. In some embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus monkey or a rhesus monkey), a commercially relevant mammal (e.g., a cow, a pig, a horse, a sheep, a goat, a cat, or a dog), or a bird (e.g., a commercially relevant bird such as a chicken, a duck, a goose, or a turkey). In some embodiments, the non-human animal is a fish, a reptile, or an amphibian. The non-human animal may be male or female, at any stage of progression. The non-human animal may be a transgenic or genetically engineered animal. The term "patient" refers to a human subject in need of treatment for a disease.

[0253] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing into a subject a compound described herein, or a composition thereof.

[0254] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of, a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of disease have occurred or are observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of medical history and / or exposure to a pathogen). Treatment may also be continued after resolution of symptoms, e.g., to delay or prevent recurrence.

[0255] The terms "condition," "disease," and "disorder" are used interchangeably.

[0256] An "effective amount" of a compound described herein refers to an amount sufficient to elicit a desired biological response. The effective amount of a compound described herein may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactic treatment. In some embodiments, the effective amount is the amount of a compound described herein in a single dose. In some embodiments, the effective amount is the combined amount of a compound described herein in multiple doses.

[0257] A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in treating a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in treating a condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids symptoms, signs, or causes of a condition, and / or enhances the therapeutic effectiveness of another therapeutic agent. [Example]

[0258] example In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

[0259] The methods provided herein may be applied to the synthesis of cantharidin, for example, as shown in Scheme 4. [ka]

[0260] As described herein, research into the industrial-scale preparation of cantharidin led to the discovery of surprising and unprecedented Diels-Alder reaction conditions for the reaction of furan with compound (2) to produce compound (1), a key synthetic tetracyclic intermediate. [ka]

[0261] Starting from the work reported by Dauben in the 1980s (see, for example, JACS, 102, 6893 (1980) and JOC, 50, 2576-2578 (1985)), it was speculated that this Diels-Alder cycloaddition would require exotic and highly harsh reaction conditions. This assumption arose from the expected steric hindrance that would be generated in the formation of compound (1). Although not the same molecule, Bruchhausen's work in 1928 demonstrated that dehydrocantharidin spontaneously undergoes a retro-Diels-Alder reaction to relieve this hindrance. In addition, Diels and Alder reported that the forward reaction of furan with dimethyl maleate to form dehydrocantharidin was not possible (see, for example, BER, 62, 554-562 (1929)). Recognizing this facile retro-Diels-Alder tendency, Dauben used very high pressures (>7 kbar) to drive the electrocycloaddition of 2 to 1 in a volume-shrinkage-driven process. Grieco (see, e.g., JACS, 112, 4595-459 (1990)) subsequently used a highly concentrated ethereal solution of the Lewis acid lithium perchlorate (5 M) to catalyze the reaction, creating a high-salt-driven effect ("high" internal solvent pressure) to drive the formation of the adduct 1.

[0262] Unfortunately, neither Dauben's nor Grieco's conditions are viable large-scale production methods for commercial products. Both the extreme pressure used in Dauben's protocol and the use of ethereal perchlorate solutions in Grieco's method pose significant explosion risks that manufacturers cannot tolerate. Grieco's second method, using lithium trifluoromethanesulfonimide in either diethyl ether or acetone, also produces the desired adduct (1), but at the expense of higher reagent costs. More importantly, there is a severe erosion of the favorable exo-endo ratio, which leads to a significant decrease in the yield of compound (1).

[0263] It was discovered that other Lewis acids could replace the lithium Lewis acid in the Grieco procedure (International Publication No. WO2016 / 100732, published June 23, 2016, the entire contents of which are incorporated herein by reference). These studies demonstrated that the exo / endo ratio was significantly improved and the product yield was viable.

[0264] However, mixing the two reactant solutions in polar solvents such as acetonitrile, NMP, DMPU, and acetone with moderate heating was recently found to give 64% conversion to compound (1) with a highly favorable 84:16 ratio of exo-endo isomers (using NMP). Isolation of the desired product, compound (1), was easily achieved by a simple basic workup to remove the starting material for reuse and a simple recrystallization procedure to remove the small amount of the undesired endo isomer. The isolated yield for this reaction was 58% at 99% purity. The fact that such simple reaction conditions are all that is required for the successful formation of adduct (1) from compound (2) and furan is completely unexpected based on 37 years of precedent. The success of these specific Diels-Alder conditions was unexpected for these two substrates and is highly suitable for industrial-scale production of cantharidin. [ka]

[0265] Compound (5) is a key intermediate in the synthesis of cantharidin. Although soot-free reports of its synthesis have been published in the literature, industrial production of compound (5) is impractical (use of cyanide or nitromethane) and / or expensive. In a previously unreported process, intermediate (4) (a compound of formula (II), where X 1(Is a sulfonate) can be carboxylated by palladium-catalyzed addition of carbon monoxide to give the key synthetic intermediate (5). This single-step process affords compound (5) in 85% yield despite the presence of sulfur, a typical palladium catalyst poison, in both the starting material and the product. The presence of sulfur as a catalyst poison is most likely the reason why this transformation has not been reported to date.

[0266] Experimental procedure Preparation of [3-(methoxycarbonyl)-4-oxotetrahydro-3-thienyl]lithium [ka] Methyl acrylate (9.16 mL, 102 mmol) is added to a mixture of methyl mercaptoacetate (8.42 mL, 94.2 mmol) and piperidine (0.186 mL, 1.88 mmol) over 30 minutes at room temperature. Once the addition is complete, the mixture is stirred at room temperature for 30 minutes. In a separate flask, lithium (0.654 g, 94.2 mmol) is dissolved in 40 mL of MeOH under N2. The methyl acrylate mixture is added to the lithium methoxide solution at room temperature over 1 hour under N2. Once the addition is complete, the mixture is warmed to reflux for 6 hours. The MeOH is evaporated and the resulting thick oil is taken up in 30 mL of ice-cold water. The resulting mixture is stirred with ice bath cooling for 1 hour. The solid that forms is collected by filtration and dried under N2 pressure for 2 hours. The solid is suspended in MTBE (20 mL, 2 vol) and stirred for 2 hours at room temperature. The solid is collected by filtration and dried for 2 hours at room temperature under N2 pressure to give [3-(methoxycarbonyl)-4-oxotetrahydro-3-thienyl]lithium (11.0 g; yield=70.3%) as a pale yellow solid.

[0267] Preparation of methyl 4-oxotetrahydrothiophene-3-carboxylate [ka] [3-(Methoxycarbonyl)-4-oxotetrahydro-3-thienyl]lithium (17.7 g, 106 mmol) was suspended in 100 mL of water, and the suspension was acidified to approximately pH 5 by the addition of 1.0 N HCl. The resulting mixture was extracted with 3 x 50 mL of CHCl. ​​The combined CHCl layers were dried over NaSO and evaporated to give methyl 4-oxotetrahydrothiophene-3-carboxylate (14 g; yield = 82%) as a pale yellow oil.

[0268] Preparation of methyl 4-{[(trifluoromethyl)sulfonyl]oxy}-2,5-dihydrothiophene-3-carboxylate [ka] A solution of methyl 4-oxotetrahydrothiophene-3-carboxylate (62.0 g, 387 mmol), methylene chloride (310 mL, 4800 mmol) (5 volumes), and N,N-diisopropylethylamine (74.2 mL, 426 mmol) was cooled to −30° C. under N. Trifluoromethanesulfonic anhydride (68.4 mL, 406 mmol) was added to the solution at a rate to maintain the reaction mixture at or below −20° C. Upon completion of the addition, the mixture was stirred for ½ hour at −30° C., at which point TLC in CHCl indicated no starting material remained. The reaction was quenched by the addition of 300 mL of water, and the layers were separated. The CHCl layer was extracted with 200 mL of water and dried over NaSO. Evaporation of the solvent gave 172 g of a dark oil. The oil was taken up in 200 mL of 1:1 CHCl / hexane and absorbed onto a silica gel pad (258 g, 1.5 wt). The pad was eluted with 3 L of 1:1 CHCl / hexane. Evaporation of the filtrate and drying overnight under high vacuum at room temperature gave 101 g of methyl 4-{[(trifluoromethyl)sulfonyl]oxy}-2,5-dihydrothiophene-3-carboxylate (101 g; yield=89%) as a pale yellow oil.

[0269] Preparation of dimethyl 2,5-dihydrothiophene-3,4-dicarboxylate [ka] An oil bath was preheated to 50 °C. A mixture of methyl 4-{[(trifluoromethyl)sulfonyl]oxy}-2,5-dihydrothiophene-3-carboxylate (15.58 g, 53.31 mmol), tris(dibenzylideneacetone)dipalladium(0) (742 mg, 0.810 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (888 mg, 1.60 mmol) was suspended in methanol (10.2 mL, 252 mmol) and DMF (5.1 mL, 66 mmol) in a 100 mL pressure tube equipped with a pressure gauge. The tube was pressurized with 40 psi of CO and the CO was released. The purging process was repeated once more, and then the reaction was repressurized with 40 psi of CO. The tube was placed in the preheated oil bath and stirred for 24 h. After 24 h, HPLC analysis showed complete conversion of the starting material. The reaction mixture was transferred to a round-bottom flask and concentrated under vacuum to remove methanol. The thick residual mixture was filtered through a pad of magnesol (60 g) and the filter cake was washed with TBME (400 mL). The filtrate was concentrated under vacuum to give the product (13.05 g; yield = 84.73%; purity = 70%; as an orange oil). If the reaction is slow, additional Pd2(dba)3 and dppf can be added. HCl was added in CDCl3 w / p-xylene as an internal standard. 1 H NMR was obtained. On a 3.0 g scale, this procedure gave an 85% yield at 72% purity. On a 19.4 g scale, the concentrated reaction mixture was filtered through a glass frit with a layer of magnesol (top layer, 40 g) and silica gel (bottom layer, 30 g), and the filter cake was washed with 20% EtOAc / hexane (500 mL). The filtrate was concentrated under vacuum to give 9.3 g of product as a pale yellow oil (69% yield, 103% purity by quantitative NMR as described above).

[0270] Preparation of 2,5-dihydrothiophene-3,4-dicarboxylic acid [ka] To a solution of dimethyl 2,5-dihydrothiophene-3,4-dicarboxylate (13.05 g, 45.17 mmol; purity = 70%) in THF (60 mL) was added 6 M sodium hydroxide in water (40 mL, 250.0 mmol). After an induction period (approximately 10 min), there was a clear exotherm (not measured). After 2.5 h, HPLC analysis showed complete conversion to the diacid. The reaction mixture was concentrated in vacuo to remove the THF. The mixture was diluted with TBME (100 mL), the layers were separated in a separatory funnel, and the organic layer was set aside. The aqueous layer was returned to the reaction flask and acidified to pH 1 with 2 M HCl (45 mL). The precipitate that formed was filtered (0.9 g). 1 H NMR analysis was consistent with the diacid. The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined extracts were dried over NaSO, filtered, and concentrated in vacuo to give the product (7.36 g; yield = 76.7%; purity = 82%) as a pale orange solid. DMSO-d6 w / p-xylene was used as an internal standard. 1 H NMR was obtained. When the reaction was carried out on a small scale (2.31 g; 72% purity), 1.2 g of the title compound was obtained as a tan solid in 92% purity (76% yield). If the reaction was run by adding the diester to the NaOH solution, the exotherm was more easily controlled, but this led to a lower isolated yield (approximately 50%) and the isolated product was less pure (60-75%).

[0271] Preparation of 4,6-dihydro-1H,3H-thieno[3,4-c]furan-1,3-dione [ka] A suspension of 2,5-dihydrothiophene-3,4-dicarboxylic acid (1.22 g, 7.00 mmol) and acetyl chloride (1.20 mL, 16.8 mmol) in toluene (4.9 mL, 46 mmol) was heated to reflux for 4 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was suspended in acetone (10 mL) and filtered through a pad of magnesol (5 wts). The filter cake was washed with acetone (200 mL), and the filtrate was concentrated in vacuo to give the product (0.801 g; yield=70.3%; purity=96%) as a tan solid.

[0272] Equivalents and Scope In the claims, articles such as "a," "an," and "the" may mean one or more, unless specified to the contrary or otherwise clear from the context. A claim or description containing "or" between one or more members of a group is considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise involved in a given product or process, unless specified to the contrary or otherwise clear from the context. The invention includes embodiments in which exactly one member of a group is present in, employed in, or otherwise involved in a given product or process. The invention includes embodiments in which more than one or all of the group members are present in, employed in, or otherwise involved in a given product or process.

[0273] Furthermore, the present invention covers all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms contained in one or more of the recited claims are introduced into another claim. For example, any claim that depends on another claim can be amended to include one or more limitations found in any other claim that depends on the same base claim. When elements are listed, for example, in Markush group format, each subgroup of elements is also disclosed, and any element may be removed from the group. Generally, where the invention, or aspects of the invention, are referred to as including specific elements and / or features, it should be understood that the invention, or aspects of the invention, consists of, or consists essentially of, such elements and / or features. For simplicity, those aspects have not been specifically presented herein.

[0274] Furthermore, the terms "comprise," "include," and "contain," as well as other tenses thereof, are intended to be open-ended, permitting the inclusion of additional elements or steps. Where ranges are expressed, endpoints are included. Furthermore, unless otherwise specified or otherwise apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can, in different embodiments of the invention, encompass any specific value or subrange within the stated range, down to one-tenth of the unit of the lower limit of that range, unless the context dictates otherwise.

[0275] This application references various issued patents, published patent applications, academic literature, and other publications, all of which are incorporated herein by reference in their entireties. In the event of a conflict between any of the incorporated references and this specification, this specification controls. In addition, any specific aspects of the present invention that are prior art may be expressly excluded from any one or more of the claims because such aspects are deemed known to those skilled in the art and may be excluded even if the exclusion is not presented herein. Any specific aspects of the present invention may be excluded from any claim for any reason, regardless of whether or not it relates to the existence of prior art.

[0276] Those skilled in the art will recognize or be able to identify, using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments of the invention described herein is not intended to be limited to the above detailed description, but instead is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this description can be made without departing from the spirit or scope of the invention, as defined in the following claims.

Claims

1. Formula (I): 【Chemistry 1】 A method for preparing a compound represented by formula (II): 【Chemistry 2】 is reacted with palladium, carbon monoxide, and a compound represented by formula R ２ reacting in the presence of an OH reagent; During the ceremony: X １ is halogen, optionally substituted sulfonate, or optionally substituted phosphonate; R １ and R ２ are independently optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or an oxygen protecting group; The method comprising:

2. The method of claim 1 wherein the palladium is a palladium salt.

3. 3. The method of claim 1, wherein the palladium is palladium(II) or palladium(0).

4. Palladium is preferably palladium chloride (PdCl ２ ), palladium acetate (Pd(OAc) ２ ), palladium trifluoroacetate (Pd(TFA) ２ ), or tris(dibenzylideneacetone)dipalladium (Pd ２ (dba) ３ The method according to any one of claims 1 to 3, wherein

5. 5. The process according to any one of claims 1 to 4, wherein palladium is present in a catalytic amount relative to the compound of formula (II).

6. The method of any one of claims 1 to 5, wherein the reacting step is carried out in the presence of a phosphine.

7. The phosphine is triphenylphosphine (Ph ３ 7. The method of claim 6, wherein the compound is 1,1'-bis(diphenylphosphino)ferrocene (dppf).

8. 8. The process according to claim 6 or 7, wherein the phosphine is present in a catalytic amount relative to the compound of formula (II).

9. The method of any one of claims 1 to 8, wherein the reacting step is carried out in a solvent.

10. The method of claim 9 , wherein the solvent is a polar solvent.

11. The reaction is Pd ２ (dba) ３ 11. The process of any one of claims 1 to 10, wherein the process is carried out in the presence of CO, MeOH, and dppf.

12. The reaction is carried out in a polar solvent with Pd ２ (dba) ３ 11. The process of any one of claims 1 to 10, wherein the process is carried out in the presence of CO, MeOH, and dppf.

13. The method of any one of claims 1 to 10 and 12, wherein the polar solvent is DMF.

14. The process according to any one of claims 1 to 13, wherein the reaction is carried out at a temperature of 50°C.

15. X １ The method of any one of claims 1 to 14, wherein is an optionally substituted sulfonate.

16. X １ However, mesylate (-OSO ２ CH ３ ), tosylate (-OSO ２ C ６ H ４ p-CH ３ ), or triflate (-OSO ２ CF ３ 16. The method according to claim 1, wherein

17. R １ and R ２ The method according to any one of claims 1 to 16, wherein are the same.

18. R １ and R ２ are independently optionally substituted C １～６ The method of any one of claims 1 to 10 and 13 to 17, wherein the alkyl is alkyl.

19. R １ and R ２ is independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl.

20. R １ and R ２ The method of any one of claims 1 to 19, wherein each is methyl.

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