Glycyrrhetinic acid derivatives for use in the treatment of hyperkalemia - Patent Application 20070122997

Abstract

The present invention provides compounds of formula (I) or salts thereof: (Formula (I)), wherein X, L, V, R1, R2, R3, and R4 are as defined herein. The claimed compounds are effective in treating hyperkalemia by inhibiting the enzyme 11-hydroxysteroid dehydrogenase type 2 (11-HSD2), thereby preventing the oxidation of cortisol to cortisone, thus allowing it to occupy the mineralocorticoid receptor and thus stimulating potassium excretion. TIFF2022519714000164.tif6389

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 802,210, filed February 7, 2019. The entire contents of the above-referenced application are incorporated herein by reference.

[0002] The present invention relates to compounds that inhibit 11β-hydroxysteroid dehydrogenase 2 and methods of using these compounds to remove potassium from the gastrointestinal tract, including methods of treating hyperkalemia. [Background technology]

[0003] Potassium is the most abundant cation in intracellular fluid and plays a key role in normal human physiology, particularly with regard to the generation of action potentials in nerve and muscle cells. Total body potassium is approximately 50 mmol / kg body weight, which translates to approximately 3500 mmol of potassium in a 70 kg adult. The majority of total body potassium is intracellular (approximately 98%), with only approximately 70 mmol (approximately 2%) located in the extracellular space. This large difference between intracellular potassium (approximately 120–140 mmol / L) and extracellular potassium (approximately 4 mmol / L) primarily determines the resting membrane potential of cells. As a result, very small absolute changes in extracellular potassium concentration have a significant effect on this ratio and, consequently, on the function of excitable tissues (muscle and nerve). Therefore, extracellular potassium levels are tightly regulated.

[0004] Two separate but cooperative systems are involved in potassium homeostasis: one controls the external potassium balance (the body's parity of potassium intake versus potassium excretion), while the other controls the internal potassium balance (distribution between the intracellular and extracellular fluid compartments). The intracellular / extracellular balance provides short-term control of changes in serum potassium and is primarily responsible for the regulation of Na + ,K +Physiologically, this is caused by the action of the -ATPase "pump," which uses the energy of ATP hydrolysis to convert Na + and K. + Almost all cells pump Na against their concentration gradient. + ,K + The body's potassium levels are managed by excretory mechanisms via the kidneys and gastrointestinal tract; in healthy kidneys, 90-95% of the daily potassium load is excreted through the kidneys, with the balance being excreted in the feces.

[0005] Intracellular / extracellular potassium ratio (K i :K e The fact that the ratio of K to K is the primary determinant of the cell's resting membrane potential e Small changes in serum [K] (i.e., serum [K]) have significant effects on the function of electrically active tissues such as muscles and nerves. Potassium and sodium ions actively move across cell membranes, driving action potentials by shifting the membrane potential, which is the electrical potential difference between the outside and inside of the cell. In addition to active transport, K + K can also move passively between the extracellular and intracellular compartments. Active K movement caused by higher blood potassium levels + Transport overload depolarizes membranes in the absence of stimulation. Excess serum potassium, known as hyperkalemia, can disrupt the membrane potential in cardiac cells that control ventricular conduction and contraction. Clinically, the effects of hyperkalemia on cardiac electrophysiology are of greatest concern because it can cause arrhythmias and death. Because the majority of the body's potassium balance is maintained by renal excretion, the resulting decline in renal function is predicted to impair the body's ability to manage total body potassium levels.

[0006] Hyperkalemia is defined as a serum potassium level above the normal range, typically above 5.0 mmol / L. Moderate hyperkalemia (serum potassium above 6.0 mEq / L) has been reported to have up to a 30-fold higher daily mortality rate than patients with serum potassium below 5.5 mEq / L. Severe hyperkalemia (serum K+ of at least 6.5 mmol / L) is a potentially life-threatening electrolyte disorder that occurs in 1% to 10% of all hospitalized patients and constitutes a medical emergency requiring immediate treatment. Hyperkalemia is caused by insufficient potassium excretion, and because the kidneys are the primary mechanism for potassium removal, hyperkalemia commonly affects patients with kidney disease, such as chronic kidney disease (CKD) or end-stage renal disease (ESRD). However, hyperkalemia can occur in patients with normal kidney function and is still a life-threatening condition. For example, in hospitalized patients, hyperkalemia has been associated with increased mortality in both patients with and without CKD. While CKD is the most common predisposing condition for hyperkalemia, the mechanisms that cause hyperkalemia typically involve a combination of factors, including increased dietary intake of potassium, unregulated distribution of potassium between the intracellular and extracellular compartments, and abnormalities in potassium excretion. These mechanisms can be modulated by various factors with causal relationships other than CKD. These include the presence of other comorbidities, such as type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), or the use of concomitant medications that may disrupt potassium homeostasis as a side effect, such as blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).

[0007] Serum potassium can be reduced by two general mechanisms: first, by shifting potassium intracellularly using medications such as insulin, albuterol, or sodium bicarbonate. Second, by excreting potassium from the body using one of four routes: via the stool using potassium-binding resins such as sodium polystyrene sulfonate (Na PSS), via the urine using diuretics, via the blood using hemodialysis, or via the peritoneal fluid using peritoneal dialysis. Other than Na PSS, medications used to treat hyperkalemia, such as insulin, diuretics, beta-agonists, and sodium bicarbonate, simply cause hypokalemia as a side effect and are not suitable for chronic treatment. Causal therapy requires the removal of potassium from the body. Studies have confirmed that reducing serum potassium levels in patients with hyperkalemia actually reduces mortality risk, further reinforcing the role of excess potassium in mortality risk. While Na PSS is the current standard of care for potassium reduction in the United States, calcium salts of PSS (Ca PSS) are also commonly used in other parts of the world, including Europe (e.g., Resonium) and Japan.

[0008] Kayexalate / Na PSS is poorly tolerated and causes a high incidence of GI side effects, including nausea, vomiting, constipation, and diarrhea. Additionally, Kayexalate is a milled product, consisting of irregularly shaped particles ranging in size from approximately 1 to 150 μm. It has sand-like properties in the human mouth and produces a strong foreign body sensation on the palate upon ingestion, which negatively contributes to patient compliance. Overall, the physical properties and associated side effects of Kayexalate result in poor compliance, making this drug suboptimal for chronic use. These characteristics have created a long-felt need for a drug that is optimal for chronic use.

[0009] The mineralocorticoid receptor (MR, MLR, MCR), also known as the aldosterone receptor or nuclear receptor superfamily 3, group C, member 2 (NR3C2), is a protein encoded by the NR3C2 gene located on chromosome 4q31.1-31.2 in humans. The MR is a receptor with equal affinity for mineralocorticoids and glucocorticoids, including cortisol. It belongs to the nuclear receptor family, in which ligands diffuse into cells, interact with the receptor, and transduce signaling that affects specific gene expression in the nucleus. The MR is expressed in many tissues, including the kidney, colon, heart, central nervous system (hippocampus), brown adipose tissue, and sweat glands. Activation of the mineralocorticoid receptor by ligands aldosterone and cortisol in epithelial tissues promotes potassium excretion. In intact animals, the MR is "protected" from greater concentrations of cortisol (100-1000-fold) by the colocalization of 11β-hydroxysteroid dehydrogenase 2 (herein also referred to as 11β-HSD2 and HSD2), an enzyme that oxidizes cortisol to the inactive metabolite cortisone. HSD2 thus prevents MR activation and, consequently, inhibits potassium excretion.

[0010] Therefore, inhibition of HSD2 to prevent cortisol-activated deactivation of MR is a promising mechanism for promoting potassium excretion, for example, in the treatment of hyperkalemia. Summary of the Invention [Means for solving the problem]

[0011] In one aspect of the invention, there is provided a compound of formula I or a salt thereof: [ka] During the ceremony, X is a bond, -O-, -C(O)-, -N(R x )-, -C(O)N(R x )-, -N(R x )-C(O)-, -S(O)n -N(R x )-, or -N(R x )-S(O) n - and L is a bond, alkylene (wherein one or more non-adjacent methylene groups of said alkylene are replaced with -O-), divalent aryl or divalent heteroaryl, or L is alkylene-Y-alkylene, where Y is O, NR x , S, SO, SO2, or a divalent heterocycle, wherein said alkylene group is optionally substituted with OH, —C(O)O—R1, alkyl, or alkyl substituted with OH or —C(O)O—R1, and the carbons and R of said alkylene group are x optionally, together form a heterocycle, with the proviso that when X is other than a bond, then L is other than a bond; W is O or S; Q is a bond or alkylene; R1 is H, alkyl, carbocycle, or heterocycle (each of the foregoing alkyl, carbocycle, and heterocycle is optionally substituted with halogen, OH, amino, oxo, carboxy, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy, aminocarbonyl), carbocycle optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen, and heterocycle optionally substituted with alkyl, oxo, amino, and halogen; and carbocycle or heterocycle optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen, V is -C(O)O-, -C(O)O-(CHR5)-OC(O)-, -C(O)O-(CHR5)-OC(O)-O-, -C(O)N(R5)-, -C(O)N(R5)O-, -NH-C(O)-N(R5)-, or NH-S(O) n - and R2 is H or R5; R3 is absent or alkyl; R4 is absent, H, OH, =O, -R6, -O-R6, -C(O)O-R6, -OC(O)-R6, -OC(O)-O-R6, -OC(O)-NR5R6, -NR5R6, -NR5-C(O)-R6, -NR5-C(O)-O-R6, -NR5-SO2-R6, =NO-R5; R5 is H or alkyl optionally substituted with a carbocycle or heterocycle, said carbocycle and heterocycle being optionally substituted with halogen, OH, oxo, and alkyl; R6 is H, alkyl, carbocycle, heterocycle (wherein said alkyl, carbocycle, and heterocycle are optionally substituted with halogen, OH, SH, alkylthio, -S(O)-alkyl, -SO2-alkyl, amino, -NHC(O)-alkyl, oxo, alkyl, carboxyl, acyl, acyloxy, alkoxy, alkoxycarbonyl), carbocycle optionally substituted with halogen, OH, amino, or alkyl, or heterocycle optionally substituted with halogen, OH, amino, or alkyl, wherein one or more non-adjacent methylene groups of each of said alkyl groups of R6 are optionally replaced with -O- or -S-; R x is H, —C(O)O—R1, or alkyl optionally substituted with C(O)O—R1; n is 1 or 2.

[0012] In another aspect of the present invention, there is provided a composition comprising a compound of formula I and a carrier, diluent, or excipient.

[0013] In another aspect of the invention, a method of inhibiting the conversion of cortisol to cortisone by HSD2 is provided, the method comprising contacting HSD2 with a compound of formula I.

[0014] In another aspect of the present invention, there is provided a method for promoting activated MR in a mammal, the method comprising administering to said mammal an effective amount of a compound of formula I.

[0015] In another aspect of the present invention, there is provided a method for reducing plasma potassium levels in a mammal, the method comprising administering to said mammal an effective amount of a compound of formula I.

[0016] In another aspect of the present invention, there is provided a method for promoting potassium ion secretion into the colonic lumen of a mammal, the method comprising administering to said mammal an effective amount of a compound of formula I.

[0017] In another aspect of the present invention, there is provided a method for treating hyperkalemia in a mammal, the method comprising administering to said mammal an effective amount of a compound of formula I.

[0018] In another aspect of the invention, there is provided a method for treating or preventing hyperkalemia in a mammal, the method comprising co-administering a compound of formula I with an inhibitor of the renin-angiotensin-aldosterone system (RAAS). [Brief explanation of the drawings]

[0019] [Figure 1] 1 shows the synergistic effect on fecal potassium excretion following administration of an HSD2 inhibitor in combination with an NHE3 inhibitor. [Figure 2] This is an illustration of HSD2 inhibition in epithelial cells, allowing cortisol to activate the mineralocorticoid receptor (MR), facilitating potassium excretion into the lumen. [Figure 3] 1 shows the structure of glycyrrhetinic acid with carbon atom numbering. DETAILED DESCRIPTION OF THE INVENTION

[0020] Glycyrrhizin (also glycyrrhizic acid or glycyrrhizinic acid) is an extract of the plant Glycyrrhiza, derived from the Ancient Greek terms "glykos," meaning "sweet," and "rhiza," meaning root. Many prophets and pharaohs enjoyed glycyrrhizin. Licorice extract was used for cleansing and in the desert, and soldiers and travelers drank it to suppress dry mouth on long journeys. Glycyrrhetinic acid, the active metabolite in licorice, inhibits HSD2, resulting in cortisol-induced mineralocorticoid effects and a tendency to reduce potassium levels. Glycyrrhetinic acid reduces potassium levels, which is associated with abnormal heartbeat, hypertension, edema, lethargy, congestive heart failure, hypokalemia, and rhabdomyolysis. It would therefore be desirable to provide compounds that promote potassium excretion in patients suffering from hyperkalemia, such as glycyrrhetinic acid, without causing undesirable side effects.

[0021] The present invention provides a compound of formula I or a salt thereof: [ka] During the ceremony, X is a bond, -O-, -C(O)-, -N(R x )-, -C(O)N(R x )-, -N(R x )-C(O)-, -S(O) n -N(R x )-, or -N(R x )-S(O) n - and L is a bond, alkylene (wherein one or more non-adjacent methylene groups of said alkylene are replaced with -O-), divalent aryl or divalent heteroaryl, or L is alkylene-Y-alkylene, where Y is O, NR x, S, SO, SO2, or a divalent heterocycle, wherein said alkylene group is optionally substituted with OH, —C(O)O—R1, alkyl, or alkyl substituted with OH or —C(O)O—R1, and the carbons and R of said alkylene group are x optionally, together form a heterocycle, with the proviso that when X is other than a bond, then L is other than a bond; W is O or S; Q is a bond or alkylene; R1 is H, alkyl, carbocycle, or heterocycle (each of the foregoing alkyl, carbocycle, and heterocycle is optionally substituted with halogen, OH, amino, oxo, carboxy, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy, aminocarbonyl), carbocycle optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen, and heterocycle optionally substituted with alkyl, oxo, amino, and halogen; and carbocycle or heterocycle optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen, V is -C(O)O-, -C(O)O-(CHR5)-OC(O)-, -C(O)O-(CHR5)-OC(O)-O-, -C(O)N(R5)-, -C(O)N(R5)O-, -NH-C(O)-N(R5)-, or NH-S(O) n - and R2 is H or R1; R3 is absent or alkyl; R4 is absent, H, OH, =O, -R6, -O-R6, -C(O)O-R6, -OC(O)-R6, -OC(O)-O-R6, -OC(O)-NR5R6, -NR5R6, -NR5-C(O)-R6, -NR5-C(O)-O-R6, -NR5-SO2-R6, =NO-R5; R5 is H or alkyl; R6 is H, alkyl, carbocycle, heterocycle (wherein said alkyl, carbocycle, and heterocycle are optionally substituted with halogen, OH, SH, alkylthio, -S(O)-alkyl, -SO2-alkyl, amino, -NHC(O)-alkyl, oxo, alkyl, carboxyl, acyl, acyloxy, alkoxy, alkoxycarbonyl), carbocycle optionally substituted with halogen, OH, amino, or alkyl, or heterocycle optionally substituted with halogen, OH, amino, or alkyl, wherein one or more non-adjacent methylene groups of each of said alkyl groups of R6 are optionally replaced with -O- or -S-; R x is H, —C(O)O—R1, or alkyl optionally substituted with C(O)O—R1; n is 1 or 2.

[0022] The dashed line between the 2- and 3-positions of the fused ring system indicates a single or double bond. The dashed lines centered within the fused ring system indicate that R4 (if present) and the group containing -XLC(O)-Q- (and the dioxalone ring) can be attached to the 3-position (e.g., as in Formula Ie) or the 4-position (e.g., as in Formula Ic) of the fused ring system. The numbering rules for the fused rings are shown in Figure 3. In certain embodiments, the compounds of the present invention have a group containing a dioxolone ring pendant from the 4-position of the fused ring system. In one embodiment, after administration of the compound of the present invention to a subject, the ester moiety is metabolized to a less active acid form in the plasma or liver. In another embodiment, the compounds of the present invention have HSD2 inhibitory activity equal to or greater than that of glycyrrhetinic acid. In another embodiment, the compounds of the present invention have HSD2 inhibitory activity greater than that of glycyrrhetinic acid.

[0023] "Acyl" means a group of the formula means a carbonyl containing a substituent represented by -C(O)-R, where R is H, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, where alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. Acyl groups include alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl), and heteroaroyl.

[0024] Unless otherwise specified, "alkyl" refers to a branched or unbranched, saturated or unsaturated (i.e., alkenyl, alkynyl) aliphatic hydrocarbon group having up to 12 carbon atoms. When used as part of another term, such as "alkylamino," "cycloalkyl," or "alkylene," the alkyl moiety can be a saturated hydrocarbon chain, but also includes unsaturated hydrocarbon chains such as "alkenylamino" and "alkynylamino." Examples of specific alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, n-heptyl, 3-heptyl, and 2-methylhexyl. The terms "lower alkyl," "C1-C4 alkyl," and "alkyl of 1 to 4 carbon atoms" are synonymous and are used interchangeably to mean methyl, ethyl, 1-propyl, isopropyl, cyclopropyl, 1-butyl, sec-butyl, or t-butyl. Unless specified, a substituted alkyl group can contain, for example, one, two, three, or four substituents, which may be the same or different. Examples of substituents, unless otherwise defined, are halogen, amino, hydroxyl, protected hydroxyl, mercapto, carboxy, alkoxy, nitro, cyano, amidino, guanidino, urea, sulfonyl, sulfinyl, aminosulfonyl, alkylsulfonylamino, arylsulfonylamino, aminocarbonyl, acylamino, alkoxy, acyl, acyloxy, carbocycle, and heterocycle. Examples of such substituted alkyl groups include, but are not limited to, cyanomethyl, nitromethyl, hydroxymethyl, trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, carboxyethyl, carboxypropyl, alkyloxycarbonylmethyl, allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-amino(isopropyl), 2-carbamoyloxyethyl, and the like.Alkyl groups can also be substituted with carbocyclic groups. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl groups, as well as the corresponding ethyl, propyl, butyl, pentyl, and hexyl groups. Substituted alkyls include substituted methyls, e.g., "substituted C. n -C m and methyl groups substituted by the same substituents as "alkyl" groups. Examples of substituted methyl groups include groups such as hydroxymethyl, protected hydroxymethyl (e.g., tetrahydropyranyloxymethyl), acetoxymethyl, carbamoyloxymethyl, trifluoromethyl, chloromethyl, carboxymethyl, bromomethyl, and iodomethyl. In one embodiment, the alkyl is saturated. In one embodiment, the alkyl is unsaturated. In one embodiment, the alkyl is partially unsaturated.

[0025] "Amidine" refers to the group -C(NH)-NHR, where R is H, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, where alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. A particular amidine is the group -NH-C(NH)-NH.

[0026] "Amino" refers to primary (i.e., -NH), secondary (i.e., -NRH), and tertiary (i.e., -NRR) amines, where R is H, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, where alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. Particular secondary and tertiary amines are alkylamines, dialkylamines, arylamines, diarylamines, aralkylamines, and diaralkylamines, where alkyl is as defined herein and is optionally substituted. Particular secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, phenylamine, benzylamine, dimethylamine, diethylamine, dipropylamine, and diisopropylamine.

[0027] As used herein, "amino-protecting group" refers to derivatives of groups commonly used to block or protect amino groups while reactions are carried out on other functional groups on a compound. Examples of such protecting groups include carbamates, amides, alkyl and aryl groups, imines, and many N-heteroatom derivatives that can be removed to regenerate the desired amine group. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butyloxycarbonyl ("Boc"), benzyloxycarbonyl ("CBz"), and 9-fluorenylmethyleneoxycarbonyl ("Fmoc"). Further examples of these groups can be found in Wuts. Greene's Protective Groups in Organic Synthesis. 5th ed. New York: John Wiley & Sons, Inc., 2014. The term "protected amino" refers to an amino group substituted with one of the above amino-protecting groups.

[0028] "Aryl," when used alone or as part of another term, refers to a carbocyclic aromatic group (fused or not) having the specified number of carbon atoms, or, if no number is specified, up to 14 carbon atoms. Particular aryl groups are phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like (see, for example, Dean, JA, ed. Lange's Handbook of Chemistry. 13th ed. New York: McGraw-Hill, 1985, Table 7-2). Particular aryl is phenyl. Substituted phenyl or substituted aryl refers to a phenyl or aryl group substituted with one, two, three, four, or five substituents, for example, one to two, one to three, or one to four substituents selected from halogen (F, Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (e.g., C-C alkyl), alkoxy (e.g., C-C alkoxy), benzyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylamino, arylsulonylaminoalkyl, heterocyclylsulfonylamino, heterocyclylsulfonylaminoalkyl, heterocyclyl, aryl, or other specified groups, unless otherwise specified. In turn, one or more methine (CH) and / or methylene (CH) groups in these substituents can be substituted with the analogous groups shown above. The term "substituted phenyl" is exemplified by mono- or di(halo)phenyl groups, such as 2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl, and the like; mono- or di(hydroxy)phenyl groups, such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, protected hydroxy derivatives thereof, and the like;Nitrophenyl groups, for example, 3- or 4-nitrophenyl; cyanophenyl groups, for example, 4-cyanophenyl; mono- or di(lower alkyl)phenyl groups, for example, 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4-(isopropyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl, etc.; mono- or di(alkoxy)phenyl groups, for example, 3,4-dimethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl, etc.; 3- or 4-trifluoromethylphenyl; mono- or dicarboxyphenyl or (protected carboxy)phenyl groups, for example, 4-carboxyphenyl; mono- or di(hydroxymethyl)phenyl mono- or di(aminomethyl)phenyl or (protected hydroxymethyl)phenyl, for example, 3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl, for example, 2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; mono- or di(N-(methylsulfonylamino))phenyl, for example, 3-(N-methylsulfonylamino))phenyl; disubstituted phenyl groups, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl; trisubstituted phenyl groups, for example, 3-methoxy-4-benzyloxy-6-methylsulfonylamino, 3-methoxy-4-benzyloxy-6-phenylsulfonylamino;and tetrasubstituted phenyl groups, such as, but not limited to, 3-methoxy-4-benzyloxy-5-methyl-6-phenylsulfonylamino. Specific substituted phenyl groups include 2-chlorophenyl, 2-aminophenyl, 2-bromophenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 4-benzyloxyphenyl, 4-methoxyphenyl, 3-ethoxy-4-benzyloxyphenyl, 3,4-diethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl, and 3-methoxy-4-(1-chloromethyl)benzyloxy-6-methylsulfonylaminophenyl. Fused aryl rings can also be substituted with any of the substituents specified herein, for example, one, two, or three, in the same manner as substituted alkyl groups.

[0029] The terms "carbocyclyl," "carbocyclic," "carbocycle," and "carbocyclo," used alone and as part of complex groups such as carbocycloalkyl groups, refer to monocyclic, bicyclic, or tricyclic aliphatic rings having 3 to 14 carbon atoms, e.g., 3 to 7 carbon atoms or 3 to 6 carbon atoms, which may be saturated or unsaturated, aromatic or non-aromatic. Particular saturated carbocyclic groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A particular saturated carbocycle is cyclopropyl. Another particular saturated carbocycle is cyclohexyl. A particular unsaturated carbocycle is aromatic, e.g., an aryl group as previously defined, e.g., phenyl. The terms "substituted carbocyclyl," "carbocycle," and "carbocyclo" refer to these groups substituted by the same substituents as the "substituted alkyl" group.

[0030] As used herein, a "carboxy protecting group" refers to one of the ester derivatives of a carboxylic acid group that are commonly used to block or protect the carboxylic acid group while reactions are carried out on other functional groups on a compound. Examples of such carboxylic acid protecting groups include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, alkyl, such as t-butyl or t-amyl, trimethylbenzyl, 4,4'-dimethoxybenzyl, 4,4'-dimethoxybenzyl, 2,2',4,4'-tetramethoxybenzyl, 4,4'-di ... methyl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, beta-(trimethylsilyl)ethyl, beta-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)propanol Examples of suitable carboxy-protecting groups include prop-1-en-3-yl, prop-1-en-3-yl, and similar moieties. The type of carboxy-protecting group used is not critical, so long as the derivatized carboxylic acid is stable to the conditions of subsequent reaction(s) elsewhere in the molecule and can be removed at the appropriate point without destroying the remainder of the molecule. Specifically, it is important not to subject the carboxy-protected molecule to reducing conditions using strong nucleophilic bases such as lithium hydroxide or NaOH, or highly activated metal hydrides such as LiAlH4. Such harsh removal conditions should also be avoided when removing amino- and hydroxy-protecting groups, as discussed below. Specific carboxylic acid-protecting groups are alkyl (e.g., methyl, ethyl, t-butyl), allyl, benzyl, and p-nitrobenzyl groups. Similar carboxy-protecting groups used in the cephalosporin, penicillin, and peptide arts can also be used to protect carboxy group substituents.Further examples of these groups can be found in Greene, T.W., and P.G.M. Buts. Protective Groups in Organic Synthesis. 2nd ed. New York: John Wiley & Sons, Inc. 1991, Chapter 5; Haslam, E. Protective Groups in Organic Chemistry. New York: Plenum Press 1973, Chapter 5; and Greene, T.W. Protective Groups in Organic Synthesis. New York: John Wiley & Sons, Inc. 1981, Chapter 5. The term "protected carboxy" refers to a carboxy group substituted with one of the above carboxy-protecting groups.

[0031] "Alkoxycarbonyl" refers to the group -C(=O)OR where R is alkyl. A particular group is C1-C6 alkoxycarbonyl where the R group is C1-C6 alkyl.

[0032] "Guanidine" refers to the group -NH-C(NH)-NHR, where R is hydrogen, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, where alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. A particular guanidine is the group -NH-C(NH)-NH.

[0033] As used herein, a "hydroxy protecting group" refers to a derivative of a hydroxy group commonly used to block or protect the hydroxy group while reactions are carried out on other functional groups on a compound. Examples of such protecting groups include tetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, and silyl ether (e.g., TBS, TBDPS) groups. Further examples of these groups can be found in Greene, T.W., and P.G.M. Buts. Protective Groups in Organic Synthesis. 2nd ed. New York: John Wiley & Sons, Inc. 1991, Chapters 2-3; Haslam, E. Protective Groups in Organic Chemistry. New York: Plenum Press 1973, Chapter 5; and Greene, T.W. Protective Groups in Organic Synthesis. New York: John Wiley & Sons, Inc., 1981. The term "protected hydroxy" refers to a hydroxy group substituted with one of the above hydroxy protecting groups.

[0034] The terms "heterocyclic group," "heterocyclic," "heterocycle," "heterocyclyl," or "heterocyclo" are used interchangeably, both alone and when used as part of a complex group such as a heterocycloalkyl group, and refer to any monocyclic, bicyclic, or tricyclic, saturated or unsaturated, aromatic (heteroaryl) or non-aromatic ring having the specified number of ring atoms, generally 5 to 14, where the ring atoms are carbon and at least one heteroatom (nitrogen, sulfur, or oxygen), e.g., 1 to 4 heteroatoms. Heterocyclic groups include 4- to 7-membered ring groups containing 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Typically, 5-membered rings have 0 to 2 double bonds, and 6- or 7-membered rings have 0 to 3 double bonds. The nitrogen and sulfur heteroatoms may be optionally oxidized (e.g., SO, SO), and any nitrogen heteroatom may be optionally quaternized. Particular non-aromatic heterocycles are morpholinyl (morpholino), pyrrolidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2H-pyranyl, tetrahydropyranyl, thiiranyl, thietanyl, tetrahydrothietanyl, aziridinyl, azetidinyl, 1-methyl-2-pyrrolyl, piperazinyl, and piperidinyl. A "heterocycloalkyl" group is a heterocyclic group as defined above covalently bonded to an alkyl group as defined above. Particular 5-membered heterocycles containing a sulfur or oxygen atom and one to three nitrogen atoms include thiazolyl, specifically thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, specifically 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, e.g., oxazol-2-yl, and oxadiazolyl, e.g., 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl. Particular 5-membered heterocycles containing two to four nitrogen atoms include imidazolyl, e.g., imidazol-2-yl; triazolyl, e.g., 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl; and tetrazolyl, e.g., 1H-tetrazol-5-yl.Particular benzo-fused 5-membered heterocycles are benzoxazol-2-yl, benzothiazol-2-yl, and benzimidazol-2-yl. Particular 6-membered heterocycles contain one to three nitrogen atoms, and optionally sulfur or oxygen atoms, such as pyridyl, e.g., pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, e.g., pyrimid-2-yl and pyrimid-4-yl; triazinyl, e.g., 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, specifically, pyridazin-3-yl and pyrazinyl. Pyridine N-oxide and pyridazine N-oxide, as well as pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl, and 1,3,4-triazin-2-yl groups, are particular groups. Substituents for the "optionally substituted heterocycles" discussed above, as well as further examples of 5- and 6-membered ring systems, can be found in W. Druckheimer et al., U.S. Patent No. 4,278,793. In certain embodiments, such optionally substituted heterocycle groups are substituted with hydroxyl, alkyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, halo-substituted alkyl, amino, cyano, nitro, amidino, and guanidino.

[0035] "Heteroaryl," both alone and as part of a complex group such as a heteroaralkyl group, refers to any monocyclic, bicyclic, or tricyclic aromatic ring system having the specified number of atoms, wherein at least one ring is a 5-, 6-, or 7-membered ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; in certain embodiments, at least one heteroatom is nitrogen (Lange's Handbook of Chemistry, supra). In one example, a heteroaryl is a 5- or 6-membered aromatic ring containing one, two, or three heteroatoms selected from nitrogen, oxygen, and sulfur. Included in the definition are any bicyclic groups in which any of the above heteroaryl rings are fused to a benzene ring. Certain heteroaryls incorporate nitrogen or oxygen heteroatoms. The following ring systems are examples of heteroaryl (whether substituted or unsubstituted) groups denoted by the term "heteroaryl": thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, tetrazolo[1,5-b]pyridazinyl, and purinyl, and benzo-fused derivatives such as benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, and indolyl. Particular "heteroaryl" may be selected from: 1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl, 1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 2-hydroxy-1,3,4-Triazol-5-yl, 2-carboxy-4-methyl-1,3,4-triazol-5-yl, 2-carboxy-4-methyl-1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl, 2-(hydroxymethyl)-1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 2-thiol-1,3,4-thiadiazol-5-yl, 2-(methylthio) -1,3,4-thiadiazol-5-yl, 2-amino-1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 2-methyl-1H-tetrazol-5 -yl, 1,2,3-triazol-5-yl, 1-methyl-1,2,3-triazol-5-yl, 2-methyl-1,2,3-triazol-5-yl, 4-methyl-1,2,3-triazol-5-yl, pyrid-2-yl N-oxide, 6-methoxy-2-(N-oxide)-pyridaz-3-yl, 6-hydroxypyridaz-3-yl, 1-methylpyrid-2-yl, 1-methylpyrid-4-yl, 2-hydroxypyrimid-4-yl, 1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl, 1,4, 5,6-tetrahydro-4-(formylmethyl)-5,6-dioxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-methoxy-2-methyl-as-triazin-3-yl, 2,5-Dihydro-5-oxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-2,6-dimethyl-as-triazin-3-yl, tetrazolo[1,5-b]pyridazin-6-yl, and 8-aminotetrazolo[1,5-b]pyridazin-6-yl. Alternative groups for "heteroaryl" include: 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 1-(1-(dimethylamino)eth-2-yl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(methylsulfonate)-1H-tetrazole Heteroaryl groups include 1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl, 1,4,5,6-tetrahydro-4-(2-formylmethyl)-5,6-dioxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, tetrazolo[1,5-b]pyridazin-6-yl, and 8-aminotetrazolo[1,5-b]pyridazin-6-yl. Heteroaryl groups are optionally substituted as described for heterocycles.

[0036] By "inhibitor" is meant a compound that reduces or prevents the enzymatic conversion of cortisol to cortisone by HSD2.

[0037] Unless otherwise specified, "optionally substituted" means that a group can be unsubstituted or, if valences allow, substituted with one or more (e.g., 0, 1, 2, 3, and / or 4) of the substituents listed for that group, which may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents.

[0038] "Pharmaceutically acceptable salts" include both acid and base addition salts. "Pharmaceutically acceptable acid addition salts" refers to salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable; the organic acids may be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0039] "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Particularly, base addition salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins. Particular organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.

[0040] "Sulfanyl" refers to the group -SR, where R is alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, where alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. Particular sulfanyl groups are alkylsulfanyl (i.e., -SO2-alkyl), such as methylsulfanyl; arylsulfanyl, such as phenylsulfanyl; and aralkylsulfanyl, such as benzylsulfanyl.

[0041] "Sulfinyl" refers to the group -SO-R, where R is hydrogen, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, where alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. Particular sulfonyl groups are alkylsulfinyl (i.e., -SO-alkyl), such as methylsulfinyl; arylsulfinyl, such as phenylsulfinyl; and aralkylsulfinyl, such as benzylsulfinyl.

[0042] "Sulfonyl" refers to the group -SO2-R, where R is hydrogen, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, where alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. Particular sulfonyl groups are alkylsulfonyl (i.e., -SO2-alkyl), such as methylsulfonyl; arylsulfonyl, such as phenylsulfonyl; and aralkylsulfonyl, such as benzylsulfonyl.

[0043] The phrase "salts and solvates thereof" as used herein means that the compounds of the present invention can exist in one or a mixture of salt and solvate forms. For example, the compounds of the present invention can be substantially pure in one particular salt or solvate form, or can be a mixture of two or more salt or solvate forms.

[0044] In certain embodiments of the invention, compounds of formula I have a structure defined by formulas Ia-Ip: [ka] [ka] [ka] wherein X, L, Q, V, R1, R2, R3, and R4 are as defined herein. In certain embodiments, the compound has a structure according to Formula Ia. In certain embodiments, the compound has a structure according to Formula Ib. In certain embodiments, the compound has a structure according to Formula Ic. In certain embodiments, the compound has a structure according to Formula Id. In certain embodiments, the compound has a structure according to Formula Ie. In certain embodiments, the compound has a structure according to Formula If. In certain embodiments, the compound has a structure according to Formula Ig. In certain embodiments, the compound has a structure according to Formula Ih. In certain embodiments, the compound has a structure according to Formula Ii. In certain embodiments, the compound has a structure according to Formula Ij. In certain embodiments, the compound has a structure according to Formula Ik. In certain embodiments, the compound has a structure according to Formula Il. In certain embodiments, the compound has a structure according to Formula Im. In certain embodiments, the compound has a structure according to Formula In. In certain embodiments, the compound has a structure according to Formula Io. In certain embodiments, the compound has a structure according to Formula Ip.

[0045] In certain embodiments of the invention, compounds of Formula I have a structure defined by Formulas Ia'-If': [ka] wherein X, L, V, R1, R2, R3, R4, and R5 are as defined herein. In certain embodiments, the compound has a structure according to Formula Ib'. In certain embodiments, the compound has a structure according to Formula Ic'. In certain embodiments, the compound has a structure according to Formula Id'. In certain embodiments, the compound has a structure according to Formula If'.

[0046] In one embodiment, the compounds of the invention have the formula of any one of Formula I:

[0047] In one embodiment, X is a bond, —O—, —N(R x )-, -C(O)N(R x )-, -N(R x)-C(O)-, -S(O) n -N(R x )-, or -N(R x )-S(O) n -, wherein R x is H, —C(O)O—R, or alkyl optionally substituted with —C(O)O—R. In one embodiment, X is a bond. In one embodiment, X is —O—. In one embodiment, X is —N(R x )-. In one embodiment, X is -NH-. In one embodiment, X is -C(O)N(R x )-. In one embodiment, X is -C(O)NH-. In one embodiment, X is -N(R x )—C(O)—. In one embodiment, X is —NH—C(O)—. In one embodiment, X is —S(O) n -N(R x )-. In one embodiment, X is -S(O)-NH-. In one embodiment, X is -S(O)-NH-. In one embodiment, X is -N(R x )-S(O) n In one embodiment, X is -NH-S(O)-. In one embodiment, X is -NH-S(O)-. In one embodiment, X is -NH-S(O)-.

[0048] W is O or S. In one embodiment, W is O. In another embodiment, W is S.

[0049] Q is a bond or alkylene. In one embodiment, Q is a bond. In one embodiment, Q is methylene. In one embodiment, Q is ethylene.

[0050] V is -C(O)O-, -C(O)O-(CHR5)-OC(O)-, -C(O)O-(CHR5)-OC(O)-O-, -C(O)N(R5)-, -C(O)N(R5)O-, -NH-C(O)-N(R5)-, or NH-S(O) n -It is. In one embodiment, V is -C(O)O-. In one embodiment, V is -C(O)O- and R2 is H. In one embodiment, V is -C(O)O- and R2 is a prodrug group. In one embodiment, V is -C(O)O- and R2 is alkyl. In one embodiment, V is -C(O)O- and R2 is methyl. In another embodiment, V is -C(O)O- and R2 is oxo, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkyl optionally substituted with alkoxycarbonyloxy, carbocycle optionally substituted with alkyl and oxo, and heterocycle optionally substituted with alkyl and oxo.

[0051] In one embodiment, V is -C(O)N(R)-. In one embodiment, V is -C(O)N(R)-, and R2 and R5 are both H. In one embodiment, V is -C(O)N(R)-, and R2 and R5 are independently H, and alkyl optionally substituted with OH. In one embodiment, V is -C(O)N(R)-, R5 is H, and R2 is hydroxyethyl.

[0052] In one embodiment, V is -C(O)N(R5)O-. In one embodiment, V is -C(O)N(R5)O-, where R2 and R5 are independently H or alkyl. In one embodiment, V is -C(O)N(R5)O-, where R2 is methyl and R5 is H.

[0053] In one embodiment, V is -NH-C(O)-N(R)-, where R and R are independently H or alkyl. In one embodiment, V is -NH-C(O)-N(R)-, where R is methyl, and R is H. In one embodiment, V is -NH-C(O)-N(R)-, where R and R are both H.

[0054] In one embodiment, V is NH—S(O) nIn one embodiment, V is NH—S(O)—. In one embodiment, V is NH—S(O)— and R is alkyl. In one embodiment, V is NH—S(O)— and R is methyl.

[0055] L is a bond, alkylene (wherein one or more non-adjacent methylene groups of said alkylene are replaced with -O-), divalent aryl or divalent heteroaryl, or L is alkylene-Y-alkylene, where Y is O, NR x , S, SO, SO2, or a divalent heterocycle, wherein said alkylene group is optionally substituted with OH, —C(O)O—R1, alkyl, or alkyl substituted with OH or —C(O)O—R1, and the carbons and R of said alkylene group are x optionally, together form a heterocycle, with the proviso that when X is other than a bond, then L is other than a bond.

[0056] In one embodiment, L is a bond or alkylene, wherein one or more non-adjacent methylene groups of said alkylene are replaced with -O-. In one embodiment, L is a bond. In one embodiment, L is alkylene. In one embodiment, L is alkylene. In one embodiment, L is alkylene, wherein one or more non-adjacent methylene groups of said alkylene are replaced with -O-. In one embodiment, L is -[(CH2)2-O] 1-5 In one embodiment, L is -(CH2)2-O-. In one embodiment, L is -[(CH2)2-O]2-. In one embodiment, L is -[(CH2)2-O]3-. In one embodiment, L is -[(CH2)2-O]4-. In one embodiment, L is -[(CH2)2-O]5-.

[0057] In one embodiment, L is alkylene-Y-alkylene, where Y is O, NR x, S, SO, SO2, or a divalent heterocycle, wherein said alkylene group is optionally substituted with OH, —C(O)O—R1, alkyl, or alkyl substituted with OH or —C(O)O—R1, and the carbons and R of said alkylene group are x optionally, together form a heterocycle, with the proviso that when X is other than a bond, then L is other than a bond. In one embodiment, L is alkylene-Y-alkylene, where Y is O. In one embodiment, L is alkylene-Y-alkylene, where Y is NR x In one embodiment, L is alkylene-Y-alkylene, where Y is NR x and the carbon of the alkylene group and R x together form a heterocycle. In one embodiment, L is alkylene-Y-alkylene, where Y is S. In one embodiment, L is alkylene-Y-alkylene, where Y is SO. In one embodiment, L is alkylene-Y-alkylene, where Y is SO. In one embodiment, L is alkylene-Y-alkylene, where Y is a divalent heterocycle. In one embodiment, L is aryl. In one embodiment, L is phenyl. In one embodiment, L is 1,4-phenylene. In one embodiment, L is heteroaryl. In one embodiment, L is triazole. In one embodiment, L is isoxazole.

[0058] R1 is H, alkyl, carbocycle, or heterocycle (each of the foregoing alkyl, carbocycle, and heterocycle is optionally substituted with halogen, OH, amino, oxo, carboxy, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy, or aminocarbonyl), carbocycle optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen, and heterocycle optionally substituted with alkyl, oxo, amino, and halogen; and carbocycle or heterocycle optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen. In one embodiment, R1 is H. In one embodiment, R1 is alkyl. In one embodiment, R1 is methyl. In one embodiment, R1 is ethyl. In one embodiment, R1 is n-propyl. In one embodiment, R1 is i-propyl. In one embodiment, R1 is cyclohexyl. In one embodiment, R1 is alkyl substituted with OH. In one embodiment, R1 is alkyl substituted with oxo. In one embodiment, R1 is alkyl substituted with carboxy. In one embodiment, R1 is alkyl substituted with acyloxy. In one embodiment, R1 is alkyl substituted with alkoxycarbonyl. In one embodiment, R1 is alkyl substituted with alkoxyacyloxy. In one embodiment, R1 is alkyl substituted with alkoxycarbonyloxy. In one embodiment, R1 is alkyl substituted with aminocarbonyl. In one embodiment, R1 is methyl. In one embodiment, R1 is propyl. In one embodiment, R1 is hydroxyethyl.

[0059] In one embodiment, R2 is H or R5. In one embodiment, R2 is H. In one embodiment, R2 is R5. In one embodiment, R2 is methyl. In one embodiment, R2 is t-butyl. In one embodiment, R2 is benzhydryl. In one embodiment, R2 is benzyl.

[0060] R3 is absent or alkyl. In one embodiment, R3 is methyl. In one embodiment, R3 is absent.

[0061] R4 is absent, H, OH, =0, -R6, -O-R6, -C(O)O-R6, -OC(O)-R6, -OC(O)-O-R6, -OC(O)-NR5R6, -NR5R6, -NR5-C(O)-R6, -NR5-C(O)-O-R6, -NR5-SO2-R6, =NO-R5. In one embodiment, R4 is H. In one embodiment, R4 is OH. In one embodiment, R4 is =0. In one embodiment, R4 is -O-R6. In one embodiment, R4 is -C(O)O-R6. In one embodiment, R4 is -OC(O)-R6. In one embodiment, R4 is -OC(O)-O-R6. In one embodiment, R4 is -OC(O)-NR5R6. In one embodiment, R4 is -NR5R6. In one embodiment, R4 is -NR5-SO2-R6. In one embodiment, R4 is =NO-R5. In one embodiment, R4 is as defined and the carbon to which it is pendant is part of a double bond. In one embodiment, R4 is H and the carbon to which it is pendant is not part of a double bond. In one embodiment, R4 is -R6.

[0062] R5 is H or alkyl optionally substituted with a carbocycle or heterocycle, wherein the carbocycle and heterocycle are optionally substituted with halogen, OH, oxo, and alkyl. In one embodiment, R5 is H. In one embodiment, R5 is alkyl. In one embodiment, R5 is methyl.

[0063] R6 is H, alkyl, carbocycle, heterocycle (wherein the foregoing alkyl, carbocycle, and heterocycle are optionally substituted with halogen, OH, SH, alkylthio, -S(O)-alkyl, -SO2-alkyl, amino, -NHC(O)-alkyl, oxo, alkyl, carboxyl, acyl, acyloxy, alkoxy, alkoxycarbonyl), carbocycle optionally substituted with halogen, OH, amino, or alkyl, or heterocycle optionally substituted with halogen, OH, amino, or alkyl, wherein one or more non-adjacent methylene groups in each of the foregoing alkyl groups of R6 are optionally replaced with -O- or -S-. In one embodiment, R6 is H. In one embodiment, R6 is alkyl. In one embodiment, R6 is methyl. In one embodiment, R6 is ethyl. In one embodiment, R6 is cyclopropyl. In one embodiment, R6 is allyl. In one embodiment, R6 is vinyl. In one embodiment, R6 is OH. In one embodiment, R6 is alkoxycarbonyl. In one embodiment, R6 is methyloxycarbonyl. In one embodiment, R6 is ethyloxycarbonyl. In one embodiment, R6 is amino. In one embodiment, R6 is NH2. In one embodiment, R6 is alkoxy. In one embodiment, R6 is polyalkoxyalkyl. In one embodiment, R6 is oxo. In one embodiment, R6 is alkylthio. In one embodiment, R6 is -S-Me. In one embodiment, R6 is -S-Et.

[0064] In one embodiment, R x is H. In one embodiment, R x is —C(O)O—R. In one embodiment, R x is alkyl. In one embodiment, R x is alkyl optionally substituted with -C(O)O-R1.

[0065] In one embodiment, "n" is 1. In another embodiment, "n" is 2.

[0066] In a further aspect of the invention, there is provided a compound of formula II: [ka] wherein R1, R2, R3, R4, L, X, Q, V, and W are as defined for compounds of formula I. Additionally, certain embodiments of formula II are similar to the embodiments specified herein for formula I. For example, certain embodiments of formula II include compounds according to formulas Ia-Ip, Ia'-If', except that the dioxolone ring is saturated.

[0067] In one embodiment, the compound of the present invention is selected from the group consisting of: (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylic acid (122-3), (2S,4aS,6aS,6bR, 8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (176-2), (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(((5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (178-1), (2S,4aS,6a S,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(2-(methylthio)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (194-10), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(2-(methylsulfonyl)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (195-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((L-valyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (196-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(benzoyloxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (197-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopropanecarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (198-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((R)-2-methoxypropanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (203-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((S)-2-methoxypropanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (204-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(methoxymethoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (205-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((ethylcarbamoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (206-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((butylcarbamoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (207-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-((pyrrolidine-1-carbonyl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (208-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (209-3), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-(propionyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (211-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopentanecarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (212-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-((3-(piperidin-1-yl)propanoyl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (215-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((isopropoxycarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (216-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,2-difluoroacetoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (223-1), (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-9-((2-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)-2-oxoethoxy)methyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (240-8), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (243-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2-hydroxyacetoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (244-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2-methoxyacetoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (245-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxadodecanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate carboxylic acid (246-3), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (249-5), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (252-2), (2S,4aS,6aS,6bR,8aR,9R,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (253-4), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (254-3), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-((((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (255-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,2-difluoroacetoxy)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (256-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(methoxymethoxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (258-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxatetradecane-14-oyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (264-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxatetradecane-14-oyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (265-2) (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(2-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)-2-oxoethoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (279-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-amino-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (280-7), (2S,4a S,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((methoxycarbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (281-3), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-(pentanoyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (282-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(2-(4-methylpiperazin-1-yl)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (283-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-((3-morpholinopropanoyl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (284-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(methylsulfonamido)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (285-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(((2-morpholinoethyl)carbamoyl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (286-4), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(2-(methylsulfinyl)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (289-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((dimethylglycyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (290-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((acetylglycyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (291-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetamido-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid, (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(allyloxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (297-5), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(3-methoxy-3-oxopropanamido)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (298-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4-methoxy-4-oxobutanamido)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (299-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((butoxycarbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (300-1), ( 2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-((methoxycarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (301-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (302-3), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylic acid (307-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(2-methoxyacetoxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (308-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,2-difluoroacetamido)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (309-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopropanecarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (314-4), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopropanecarbonyl)oxy)-9-((((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (315-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-(((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (316-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-13-oxo-10-(propionyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (317-6), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-((((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-10-(propionyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (318-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-13-oxo-10-(propionyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (319-1), (3S,4S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-4-((((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-4,6a,6b,8a,11,14b-hexamethyl-11-(methylcarbamoyl)-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-ylpropionate (320-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopropanecarbonyl)oxy)-9-((((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (321-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-13-oxo-10-propoxy-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (322-6), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-((((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-10-propoxy-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (323-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (324-3), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-((((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (325-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-((((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (326-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4,4-difluoropiperidin-1-yl)-9-((((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (327-8), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-((((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (326-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4,4-difluoropiperidin-1-yl)-9-((((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (327-8), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-(1H-pyrrol-1-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (328-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-(1H-pyrazol-1-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid, (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-10-(1H-pyrazol-1-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (330-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-(5-methyl-1H-pyrazol-1-yl)-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (331-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-(3-methyl-1H-pyrazol-1-yl)-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (332-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-((((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-10-(propionyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (333-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (334-8), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (335-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(5-(ethoxycarbonyl)-3-methyl-1H-pyrazol-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (336-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (337-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-(4-methyl-1H-pyrazol-1-yl)-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (338-4), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-10-(4-methyl-1H-pyrazol-1-yl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (339-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (341-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2-amino-2-oxoethyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (342-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (343-3), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(allyl(2-methoxy-2-oxoethyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (344-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((S)-1-methoxy-1-oxopropan-2-yl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (345-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(1-methylcyclopropane-1-carboxamido)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (346-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-(2-oxopyrrolidin-1-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (347-4), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-((S)-2-(methoxycarbonyl)pyrrolidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (348-11), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((S)-2-(methoxycarbonyl)pyrrolidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (349-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-((S)-2-(methoxycarbonyl)pyrrolidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (350-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-((R)-2-(methoxycarbonyl)pyrrolidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (351-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((S)-2-(ethoxycarbonyl)pyrrolidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (352-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((R)-2-(ethoxycarbonyl)pyrrolidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (353-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-(piperidin-1-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (356-2), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4,4-difluoropiperidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (357-7), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((R)-3-(ethoxycarbonyl)pyrrolidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (358-7), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((R)-3-(ethoxycarbonyl)piperidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (359-1) (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((S)-3-(ethoxycarbonyl)piperidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (360-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4-(ethoxycarbonyl)piperidin-1-yl)-9-(((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (361-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4-(ethoxycarbonyl)piperidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (362-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-acetamido-2,4a,6a,6b,9,12a-hexamethyl-10-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (363-5), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-acetamido-2,4a,6a,6b,9,12a-hexamethyl-10-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (363-5), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-((R)-5-methyl-2-oxooxazolidin-3-yl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (364-5), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,5-dioxoimidazolidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (365-8), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-((R)-4-methyl-2,5-dioxoimidazolidin-1-yl)-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (366-1), 2-(3-((1-PEG 5K-1H-1,2,3-triazol-4-yl)methoxy)-4-nitrobenzyl)9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxatetradecane-14-oyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (605-2), (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-{[(2-oxo-1,3-dioxolan-4-yl)methoxy]carbonyl}-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (compound 700-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-{[2-(methylsulfanyl)acetyl]oxy}-13-oxo-9-({[2-oxo-5-(propan-2-yl)-2H-1,3-dioxol-4-yl]methoxy}carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (compound 701-1), (2S,4aS,6aS,6bR,8aR,9S,10R,12aS,12bR,14bR)-10-(acetyloxy)-2,4a,6a,6b,9,10,12a-heptamethyl-13-oxo-9-({[2-oxo-5-(propan-2-yl)-2H-1,3-dioxol-4-yl]methoxy}carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (compound 702-1), (2S,4aS,6aS,6bR,8aR,9S,10R,12aS,12bR,14bR)-10-(acetyloxy)-9-{[(5-ethyl-2-oxo-2H-1,3-dioxol-4-yl)methoxy]carbonyl}-2,4a,6a,6b,9,10,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (compound 703-1), (2S,4aS,6aS,6bR,8aR,9S,10R,12aS,12bR,14bR)-10-(acetyloxy)-2,4a,6a,6b,9,10,12a-heptamethyl-9-{[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methoxy]carbonyl}-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (compound 704-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(acetyloxy)-9-{[(5-tert-butyl-2-oxo-2H-1,3-dioxol-4-yl)methoxy]carbonyl}-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (compound 705-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(acetyloxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-9-{[(2-oxo-5-propyl-2H-1,3-dioxol-4-yl)methoxy]carbonyl}-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (compound 706-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(acetyloxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-9-{[(2-oxo-5-phenyl-2H-1,3-dioxol-4-yl)methoxy]carbonyl}-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (compound 707-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-[(2-methoxyacetyl)oxy]-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-9-({[2-oxo-5-(propan-2-yl)-2H-1,3-dioxol-4-yl]methoxy}carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (compound 708-1), (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-[(2-methoxyacetyl)oxy]-2,4a,6a,6b,9,12a-hexamethyl-9-{[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methoxy]carbonyl}-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (compound 709-1), (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(2-oxo-2-{[2-oxo-5-(2,5,8-trioxa-11-thiadodecan-12-yl)-2H-1,3-dioxol-4-yl]methoxy}ethoxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (compound 710-1), (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-{[5-(hydroxymethyl)-2-oxo-2H-1,3-dioxol-4-yl]methoxy}-2-oxoethoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (compound 711-1), (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-{2-[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methoxy]-2-oxoethoxy}-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (compound 712-1), and (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-[4-(ethoxycarbonyl)-5-methoxy-1H-pyrazol-1-yl]-2,4a,6a,6b,9,12a-hexamethyl-9-{[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methoxy]carbonyl}-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (compound 713-1).

[0068] The compounds of the present invention are "soft drugs" in parent form, which are active inhibitors of 11b-HSD2 in the gastrointestinal tract of patients, but are enzymatically converted into inactive or less active metabolites when taken into plasma.This effect provides the desired selective inhibition of HSD2 in GI tract compared with HSD2 in kidney.The compounds of the present invention disclosed herein are tested in the assay described in Example 112, and are found to inhibit HSD2 by measuring the amount of cortisol before and after contacting human cell lysate or colonic monolayer organoids derived from human colon tissue.In addition, each of the tested compounds is found to be a more potent HSD2 inhibitor than their corresponding metabolites.

[0069] The compounds of the present invention may contain one or more asymmetric or chiral centers. Thus, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds may use racemates, diastereomers, or enantiomers as starting materials or intermediates. Diastereomeric compounds may be separated by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated using the same techniques, or other techniques known in the art. Unless specified, each asymmetric center may be in the R or S configuration, and both of these configurations are within the scope of the present invention. All stereoisomeric forms of the compounds described herein, including, but not limited to, diastereomers, enantiomers, and atropisomers, and mixtures thereof, such as racemic mixtures, are intended to form part of the parent compound.

[0070] It will also be understood that certain compounds of Formula I may be used as intermediates for additional compounds of Formula I. Additionally, it is understood that the compounds described herein can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the compounds encompass both solvated and unsolvated forms.

[0071] The compounds of the present invention are prepared from commercially available starting materials and reagents using standard organic synthesis techniques. It will be understood that the synthetic procedures used in preparing the compounds of the present invention depend on the specific substituents present in the compound, and that various protection and deprotection steps that are standard in organic synthesis may be required but may not be illustrated in the following general scheme. Starting materials are generally available from commercial sources or are easily prepared using methods well known to those skilled in the art. For example, the compounds of the present invention can be prepared from glycyrrhetinic acid as shown in Figure 3. For illustrative purposes, the schemes herein show general methods for preparing the compounds of the present invention, as well as key intermediates. Those skilled in the art will understand that other synthetic routes can be used to synthesize the compounds. Although specific starting materials and reagents are illustrated in the schemes and discussed below, other starting materials and reagents can be substituted to provide various derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of the present disclosure using conventional chemistry well known to those skilled in the art. As illustrated in Scheme I, compounds of the present invention (where -QWC(O)-LX- forms an ester linkage -CH2-OC(O)- to a dioxalone) can be prepared starting with a carboxylic acid derivative of glycyrrhetinic acid (at either the 3- or 4-position) and reacting it with, for example, a halogenated dioxalone. [ka]

[0072] Compounds of the invention (where -QWC(O)-LX- forms the linkage -CH2-OC(O)-O- to the dioxalone) can be prepared according to general scheme 2. [ka]

[0073] Compounds of the invention (where -QWC(O)-LX- forms an amide linkage to the dioxalone, -CH-OC(O)-NH-) can be prepared beginning by reacting an isocyanate at the 3- or 4-position of the fused ring system with a hydroxylated dioxalone, as illustrated in Scheme 3. [ka]

[0074] In preparing the compounds of the present invention, protection of remote functional groups (e.g., primary or secondary amines, etc.) of intermediates may be necessary. The need for such protection depends on the nature of the remote functional group and the conditions of the preparation method. The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see Greene, TW, and PG M Buts. Greene's Protective Groups in Organic Synthesis. 4th ed. New York: Wiley-Interscience, 2006.

[0075] It may be advantageous to separate reaction products from each other and / or from starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter, "separated") to the desired degree of homogeneity by techniques common in the art. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods, including, for example, reverse-phase and normal-phase; size exclusion; ion exchange; high-pressure, medium-pressure, and low-pressure liquid chromatography methods and devices; small-scale analytical; simulated moving bed ("SMB") and preparative thin- or thick-layer chromatography, and small-scale thin-layer and flash chromatography techniques. Those skilled in the art will apply the technique most likely to achieve the desired separation.

[0076] Diastereomeric and enantiomeric mixtures can be separated into their individual stereoisomers based on their physical chemical differences by methods well known to those skilled in the art, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol, or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using a chiral HPLC column.

[0077] The present invention also includes pharmaceutical compositions or medicaments containing a compound of the present invention and a pharmaceutically inert carrier, diluent, or excipient, as well as methods for preparing such compositions and medicaments using a compound of the present invention. Typically, the compound of Formula I used in the methods of the present invention is formulated by mixing with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to recipients at the dosage and concentration employed, at ambient temperature, an appropriate pH, and the desired purity. The pH of the formulation will depend primarily on the specific use and concentration of the compound, but can range from about 3 to about 8. A formulation in acetate buffer at pH 5 is a preferred embodiment. In one embodiment, formulations containing the compounds of the present invention are sterile. The compounds are typically stored as solid compositions, although lyophilized formulations or aqueous solutions are acceptable.

[0078] The composition comprising the compound of the present invention is formulated, dosed and administered in a manner consistent with proper medical practice.Factors to be considered in this context include the specific disease to be treated, the specific mammal to be treated, the clinical condition of individual patient, the cause of disease, administration site, administration method, administration schedule and other factors known to physicians.The "effective amount" of the compound to be administered is controlled by such considerations, and is the minimum amount required to inhibit the conversion of cortisol to cortisone by HSD2.Such amount can be less than the amount that is toxic to normal cells or to mammals as a whole.

[0079] The compounds of the present invention can be administered by any suitable means. In certain embodiments, the compounds are administered orally. In certain embodiments, the compounds are administered rectally.

[0080] Generally, the initial pharmaceutically effective amount of a compound of the present invention administered parenterally per dose ranges from about 0.01 to 1,000 mg / kg / day, e.g., about 0.1 to 100 mg / kg of patient body weight per day; a typical initial range for the compound used is 0.5 to 50 mg / kg / day. Oral unit dosage forms, such as tablets and capsules, may contain from about 25 to about 1,000 mg of a compound of the present invention. In certain embodiments, an effective amount is an amount of a compound of the present invention sufficient to enhance colonic potassium secretion by about 15 mmol / day. In certain embodiments, an effective amount is an amount of a compound of the present invention sufficient to enhance colonic potassium secretion by about 1 mmol / day. In certain embodiments, an effective amount is an amount of a compound of the present invention sufficient to enhance colonic potassium secretion by about 5 mmol / day. In certain embodiments, an effective amount is an amount of a compound of the present invention sufficient to enhance colonic potassium secretion by about 10 mmol / day. In certain embodiments, an effective amount is an amount of a compound of the present invention sufficient to enhance colonic potassium secretion by about 15 mmol / day. In a particular embodiment, the effective amount is an amount of a compound of the invention sufficient to enhance colonic potassium secretion by about 20 mmol / day.

[0081] The compound can be administered in any convenient dosage form, such as tablets, capsules, solutions, dispersions, suspensions, sachets, suppositories, gels, emulsions, etc. One example of a suitable oral dosage form is a tablet containing about 25 mg, 50 mg, 100 mg, 250 mg, or 500 mg of a compound of the invention, compounded with about 90-30 mg of anhydrous lactose, about 5-40 mg of croscarmellose sodium, about 5-30 mg of polyvinylpyrrolidone ("PVP") K30, and about 1-10 mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablets using conventional equipment.

[0082] Other preparations can be prepared by mixing the compound described herein with carrier or excipient.Suitable carrier and excipient are well known to those skilled in the art, and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams & Wilkins, 2004, Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy.Philadelphia: Lippincott, Williams & Wilkins, 2000 and Rowe, Raymond C.Handbook of Pharmaceutical Excipients.Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide elegant presentation of the drug (i.e., a compound described herein or a pharmaceutical composition thereof) or to aid in the manufacture of the pharmaceutical product (i.e., a medicament).

[0083] In one embodiment, the formulation releases the compound in response to contact with colonic enzymes, such as enzymes produced by intestinal bacteria. Certain starch-based capsule coatings may be used that are resistant to digestion in the stomach and small intestine, but are degraded by microbial (normal intestinal flora) enzymes once the dosage form reaches the colon.

[0084] In one embodiment, the compound of the present invention is orally administered.In another embodiment, the compound is formulated for colonic delivery.Colonic delivery can be induced by pH, time, microorganisms, and pressure.In one embodiment, the formulation releases the compound in response to colonic pH.The release of the compound is triggered by the pH increase as the formulation moves through the GI tract.The formulation is based on a polymer that is insoluble at the lower pH in the stomach and upper small intestine, but soluble at the higher pH found in the distal small intestine, for example, a polymer that is a derivative of acrylic acid and cellulose, which can withstand an environment as low as about pH 1.2. Suitable enteric polymers include polyvinyl acetate phthalate (PVAP), such as Coateric®, cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), such as HP-50, HP-55, HP-55S, hydroxypropyl methylcellulose acetate succinate (HPMCAS), such as the LF grade, MF grade, or HF grade, methacrylic acid copolymers, such as Eudragit® L100-55, L30D-55, L-1000, L12.5, S-100, S12.5, FS30D, cellulose acetate phthalate (CAP), such as Aquateric®, and shellac, such as MarCoat® 125 or 125N.

[0085] In one aspect of the present invention, there is provided a method for inhibiting the conversion of cortisol to cortisone by HSD2, the method comprising contacting HSD2 with a compound of formula I. In another aspect of the present invention, there is provided a method for promoting activated MR in a mammal, the method comprising administering to said mammal an effective amount of a compound of formula I. In another aspect of the present invention, there is provided a method for reducing potassium levels in the plasma of a mammal, the method comprising administering to said mammal an effective amount of a compound of formula I. In another aspect of the present invention, there is provided a method for promoting potassium ion secretion into the colonic lumen of a mammal, the method comprising administering to said mammal an effective amount of a compound of formula I.

[0086] In one aspect of the present invention, a method for treating and / or preventing hyperkalemia in a mammal is provided, comprising administering to the mammal an effective amount of a compound of Formula I. Hyperkalemia occurs particularly frequently in patients with chronic kidney disease (CKD), hypertension, heart failure, and diabetes. Accordingly, in an embodiment of the present invention, the method for treating and / or preventing hyperkalemia is in patients with CKD, hypertension, heart failure, and diabetes. Patients suffering from these conditions are often treated with certain classes of medications, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or other inhibitors of the renin-angiotensin-aldosterone system (RAAS), to control blood pressure. However, such medications promote potassium retention. Accordingly, a method for treating and / or preventing hyperkalemia in a mammal is provided, comprising administering a compound of Formula I in combination with an inhibitor of the RAAS system. In one embodiment, the RAAS inhibitor is an ACE inhibitor.

[0087] The compounds described herein, as well as their stereoisomers, diastereomers, enantiomers, tautomers, and pharmaceutically acceptable salts, may be used alone or in combination with other antihyperkalemia agents that operate by different mechanisms of action. The compounds of the present invention may be administered together with other antihyperkalemia agents in a single pharmaceutical composition or separately, and when administered separately, this may be simultaneous or sequential in any order. Such sequential administration may be close in time or remote in time.

[0088] In one embodiment, the other antihyperkalemia compound is a potassium ion binder, such as a cross-linked polystyrene sulfonate (PSS) polymer resin. In one embodiment, the PSS resin is cross-linked with a divinylbenzene (DVB) copolymer. DVB-cross-linked PSS is the most common agent used in the management of hyperkalemia in hospitalized patients. PSS is typically provided as a sodium or calcium salt, and in the intestinal lumen, it exchanges the sodium or calcium salt for secreted potassium ions. Most of this occurs in the colon, and the site of most potassium secretion is in the intestine. In one embodiment, an antihyperkalemia PSS resin is described in WO2016111855 (incorporated herein by reference). In one embodiment, the PSS resin is a calcium salt of a PSS polymer resin cross-linked with a DVB copolymer. In one embodiment, the PSS resin is cross-linked with 1.0 to 1.9 percent DVB. In one embodiment, the PSS resin is cross-linked with 1.6 to 1.9 percent DVB. In one embodiment, the PSS resin is crosslinked with about 1.8 percent of DVB.

[0089] In one embodiment, the other antihyperkalemia agent is Kayexalate®, Argamate®, Kionex®, Resonium®, or RDX7675. In another embodiment, the other antihyperkalemia agent is a fluoroacrylate polymer incorporating potassium-binding carboxylate groups, e.g., patiromer (Veltassa®). In one embodiment, the other antihyperkalemia agent is an insoluble, nonabsorbable zirconium-sodium silicate that traps potassium ions within its crystalline lattice structure, e.g., ZS-9 (Lokelma®). In one embodiment, the other antihyperkalemia agent is a cross-linked polyacrylic acid, e.g., CLP-1001.

[0090] In another aspect of the present invention, it has been unexpectedly discovered that HSD2 inhibition in combination with inhibition of the sodium-hydrogen exchanger (NHE) synergistically increases fecal potassium excretion. NHE is found in the proximal tubules of nephrons in the kidney and in the apical membrane of enterocytes in the intestine. The isoform known as NHE3 is primarily involved in maintaining sodium balance and is also indirectly involved in buffering blood pH. The NHE3 antiporter transports one sodium ion into the cytosol of cells, releasing one hydrogen ion from the cell into the intestinal lumen and the lumen of the proximal tubule. As shown in Figure 1, inhibition of HSD2 and NHE has been demonstrated to have a synergistic effect on fecal potassium excretion. Thus, a method for removing potassium from mammalian plasma and / or tissues is provided, comprising administering to the mammal an effective amount of an HSD2 inhibitor or an MR agonist in combination with a compound that increases fluid volume in the colon. Also provided is a method for removing potassium from the plasma and / or tissues of a mammal, the method comprising administering to the mammal an effective amount of an HSD2 inhibitor or an MR agonist in combination with a compound that removes sodium from the plasma and / or tissues. Also provided is a method for removing potassium from the plasma and / or tissues of a mammal, the method comprising administering to the mammal an effective amount of an HSD2 inhibitor or an MR agonist in combination with a compound that promotes sodium excretion into the gastrointestinal tract. In one embodiment, the compound is a laxative that increases fluid in the colon. In one embodiment, the laxative is bisacodyl. In one embodiment, the laxative is picosulfate. In one embodiment, the laxative is MgOH. In one embodiment, the laxative is MiraLAX® (PEG 3350). In one embodiment, the laxative is lactulose. In one embodiment, the compound is an activator of intestinal guanylate cyclase. In one embodiment, the guanylate cyclase agonist is linaclotide. In one embodiment, the guanylate cyclase agonist is plecanatide. In one embodiment, the compound is an activator of the intestinal ClC-2 chloride channel. In one embodiment, the ClC-2 chloride channel activator is lubiprostone.

[0091] Also provided is a method for removing potassium from plasma and / or tissues of a mammal, the method comprising administering to the mammal an effective amount of an HSD2 inhibitor or MR agonist in combination with an NHE inhibitor. In one embodiment, the HSD2 inhibitor or MR agonist and the NHE inhibitor compound are administered simultaneously. In one embodiment, the HSD2 or MR agonist and the NHE inhibitor compound are administered sequentially. In one embodiment, the HSD2 inhibitor or MR agonist is administered before the NHE inhibitor or MR agonist. In one embodiment, the NHE inhibitor or MR agonist compound is administered before the HSD2 inhibitor or MR agonist. In one embodiment, the NHE inhibitor is an NHE3 inhibitor.

[0092] In another aspect of the present invention, there is provided a pharmaceutical composition comprising an HSD2 inhibitor and an NHE inhibitor. In another aspect, there is provided a pharmaceutical composition comprising an MR agonist and an NHE inhibitor.

[0093] In another aspect, a method for treating hyperkalemia in a mammal is provided, the method comprising administering to the mammal an effective amount of an HSD2 inhibitor or an MR agonist in combination with an NHE inhibitor. In one embodiment, the NHE inhibitor is an NHE3 inhibitor.

[0094] In one embodiment, the MR agonist is fludrocortisone.

[0095] In another aspect, a method for treating hyperkalemia in a mammal is provided, the method comprising administering to the mammal an effective amount of an HSD2 inhibitor in combination with an NHE inhibitor. In one embodiment, the NHE inhibitor is an NHE3 inhibitor. In another aspect, a composition comprising an HSD2 inhibitor and an NHE inhibitor is provided. In one embodiment, the composition is a pharmaceutical composition. In one embodiment, there are effective amounts of an HSD2 inhibitor compound and an NHE inhibitor compound. In one embodiment, the composition further comprises a pharmaceutically acceptable carrier, excipient, and / or diluent. In one embodiment, the HSD2 inhibitor is glycyrrhetinic acid or an analog thereof. In one embodiment, the HSD2 inhibitor is glycyrrhetinic acid. In one embodiment, the HSD2 inhibitor is glycyrrhizin. In one embodiment, the HSD2 inhibitor is a compound according to Formula I herein. In one embodiment, the NHE inhibitor is an NHE3 inhibitor.In one embodiment, the NHE3 inhibitor is any of the compounds described in U.S. Patent Nos. 5,866,610, 6,399,824, 6,911,453, 6,703,405, 6,005,010, 6,736,705, 6,887,870, 6,737,423, 7,326,705, 5,824,691 (WO94 / 026709), 6,399,824 (WO02 / 024637), U.S. Patent Publication Nos. 2004 / 0039001 (WO02 / 020496), 2005 / 00 20612 (WO03 / 055490), 2004 / 0113396 (WO03 / 051866), 2005 / 0020612, 2005 / 0054705, 2008 / 0194621, 2007 / 0225323, 2004 / 0039001, 2004 / 0224965, 2005 / 0113396, 2007 / 0135383, 2007 / 0135385, 2005 / 0244367, 2007 / 0270414, International Publication No. WO and European Patent No. EP0744397 (CA2177007), each of which is incorporated herein by reference in its entirety.

[0096] In one embodiment, the NHE inhibitor is a minimally permeable compound, i.e., it inhibits NHE in the intestine and is substantially bioavailable. In one embodiment, the NHE inhibitor is a compound of formula (I) or (IX): [ka] During the ceremony, NHE is an NHE-binding small molecule comprising (i) a heteroatom-containing moiety and (ii) a cyclic or heterocyclic backbone or support moiety bonded directly or indirectly thereto, wherein the heteroatom-containing moiety is selected from a substituted guanidinyl moiety and a substituted heterocyclic moiety, which can optionally be fused with the backbone or support moiety to form a fused bicyclic structure; Z is a moiety having at least one site thereon for attachment to an NHE-binding small molecule, and the resulting NHE-Z molecule has overall physicochemical properties that render it substantially impermeable or substantially systemically non-bioavailable; E is an integer having a value of 1 or greater.

[0097] In certain embodiments, the total number of freely rotatable bonds in the NHE-Z molecule is at least about 10. In certain embodiments, the total number of hydrogen bond donors in the NHE-Z molecule is at least about 5. In some embodiments, the total number of hydrogen bond acceptors in the NHE-Z molecule is at least about 10. In certain embodiments, the total number of hydrogen bond donors and hydrogen bond acceptors in the NHE-Z molecule is at least about 10. In some embodiments, the Log P of the NHE-Z binding compound is at least about 5. In certain embodiments, the log P of the NHE-Z binding compound is less than about 1 or less than about 0. In certain embodiments, the backbone is a 5- or 6-membered cyclic or heterocyclic moiety. In certain embodiments, the backbone is aromatic.

[0098] In some embodiments, the backbone of the NHE-binding small molecule is linked to a moiety Z, and the compound has the structure of formula (II): [ka] During the ceremony, Z is a core having one or more sites thereon for attachment to one or more NHE-binding small molecules, and the resulting NHE-Z molecule has overall physicochemical properties that render it substantially impermeable or substantially systemically non-bioavailable; B is a heteroatom-containing portion of an NHE-binding small molecule selected from a substituted guanidinyl moiety and a substituted heterocyclic moiety, which can optionally be fused with the backbone moiety to form a fused bicyclic structure; the backbone is a cyclic or heterocyclic backbone or support moiety of an NHE-linked small molecule, which is directly or indirectly attached to a heteroatom-containing moiety and is optionally substituted with one or more additional hydrocarbyl or heterohydrocarbyl moieties; X is a bond or a substituted or unsubstituted hydrocarbyl or heterohydrocarbyl moiety, and specifically a substituted or unsubstituted C 1-7 a spacer moiety selected from the group consisting of hydrocarbyl or heterohydrocarbyl, and substituted or unsubstituted, saturated or unsaturated, cyclic or heterocyclic moieties, which connects B to the backbone; D and E are integers, each independently having a value of 1 or greater.

[0099] In some embodiments, the compound is an oligomer, dendrimer, or polymer, and further, Z is a core moiety having two or more moieties thereon for attachment to multiple NHE-binding small molecules, either directly or indirectly through linking moieties L, and the compound has the structure of formula (X): [ka] where L is a bond or linker connecting the core to the NHE-binding small molecule, n is an integer greater than or equal to 2, and further, each NHE-binding small molecule can be the same or different from the others.

[0100] In some embodiments, the NHE-binding small molecule has the structure of formula (IV): [ka] or a stereoisomer, prodrug, or pharmaceutically acceptable salt thereof, wherein: each R, R, R, R, and R is independently selected from H, halogen, —NR(CO)R, —(CO)NR, —SO—NR, —NRSO, —NR, —OR, —SR, —O(CO)NR, —NR(CO)OR, and —NRSONR, wherein R and R are independently H or a bond connecting an NHE-binding small molecule to L, provided that at least one is a bond connecting an NHE-binding small molecule to L; R4 is selected from H, C1-C7 alkyl, or a bond connecting an NHE-linked small molecule to L; R6 is absent or selected from H and C1-C7 alkyl; Ar1 and Ar2 independently represent an aromatic ring or a heteroaromatic ring.

[0101] In certain embodiments, the NHE-binding small molecule has the following structure: [ka] or a stereoisomer, prodrug, or pharmaceutically acceptable salt thereof, wherein: Each R1, R2, and R3 is independently selected from H, halogen, —NR7(CO)R8, —(CO)NR7R8, —SO2-NR7R8, —NR7S02R8, —NR7R8, —OR7, —SR7, —O(CO)NR7R8, —NR7(CO)OR8, and —NR7S02NR8, where R7 and R8 are independently H or a bond connecting an NHE-binding small molecule to L, provided that at least one is a bond connecting an NHE-binding small molecule to L.

[0102] In some embodiments, the NHE-binding small molecule has one of the following structures: [ka] or a stereoisomer, prodrug, or pharmaceutically acceptable salt thereof. In certain embodiments, L is a polyalkylene glycol linker. In certain embodiments, L is a polyethylene glycol linker. In some embodiments, n is 2.

[0103] In certain embodiments, the core has the following structure: [ka] During the ceremony, X is a bond, -O-, -NH-, -S-, or C 1-6 selected from the group consisting of alkylene, —NHC(═O)—, —C(═O)NH—, —NHC(═O)NH—, —SO2NH—, and —NHSO2—; Y is a bond, an optionally substituted C 1-8 alkylene, optionally substituted aryl, optionally substituted heteroaryl, polyethylene glycol linker, -(CH2) 1-6 O(CH2) 1-6 - and -(CH2) 1-6 NY1(CH2) 1-6 - selected from the group consisting of Y1 is hydrogen, optionally substituted C 1-8 It is selected from the group consisting of alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0104] In some embodiments, the core is selected from the group consisting of: [ka] where L is a bond or linking moiety, NHE is an NHE-binding small molecule, and n is a non-zero integer.

[0105] In one embodiment, the NHE inhibitor is: N,N',N"-(2,2',2"-nitrilotris(ethane-2,1-diyl))tris(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N,N'-(2,2'-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N,N'-(1,4-phenylenebis(methylene))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N,N'-(1,4-phenylenebis(methylene))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N,N'-(butane-1,4-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N,N'-(dodecan-1,12-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N,N',N”,N'''-(3,3',3”,3'''-(butane-1,4-diylbis(azanetriyl))tetrakis(propane-3,1-diyl))tetrakis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N,N'-(butane-1,4-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N,N'-(dodecan-1,12-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N,N',N"-(2,2',2"-nitrilotris(ethane-2,1-diyl))tris(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N,N',N”,N'''-(3,3',3”,3'''-(butane-1,4-diylbis(azanetriyl))tetrakis(propane-3,1-diyl))tetrakis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N,N'-(1,4-phenylenebis(methylene))bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N,N'-(2,2'-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N1,N8-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)octanediamide, 2-(N-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfamoylamino)ethylphosphonic acid, 2-(N-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfamoylamino)ethylphosphonic acid, N,N'-(butane-1,4-diyl)bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide], N,N'-(1,4-phenylenebis(methylene))bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide], N,N'-(2,2'-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide], N,N'-(2,2'-(2,2'-oxybis(ethane-2,1-diyl)bis(oxy))bis(ethane-2,1-diyl))bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide] (E)-3-(4-(4-(N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-3,5-difluorophenyl)-N-(diaminomethylene)-2-methylacrylamide, N,N'-(13-oxo-3,6,9,17,20,23-hexaoxa-12,14-diazapentacosane-1,25-diyl)bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide], N,N'-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,21-diazadotricontane-1,32-diyl)bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide], N,N'-(2,2'-(2,2'-(2,2'-(2,2'-(4,4'-oxybis(methylene)bis(1H-1,2,3-triazole-4,1-diyl))bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide], N,N'-(2,2'-(2,2'-(2,2'-(2,2'-(4,4'-oxybis(methylene)bis(1H-1,2,3-triazole-4,1-diyl))bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide) 1-(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazole-4,5-dicarboxylic acid, N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, N1,N4-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, N1,N31-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-4,7,10,13,16,19,22,25,28-nonaoxahentriacontane-1,31-diamide, N1,N31-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-4,7,10,13,16,19,22,25,28-nonaoxahentriacontane-1,31-diamide, N,N'-(13-oxo-3,6,9,17,20,23-hexaoxa-12,14-diazapentacosane-1,25-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N1,N31-bis(2-(2-(2-(2-(4-(4-((E)-3-(diaminomethyleneamino)-2-methyl-3-oxoprop-1-enyl)-2,6-difluorophenoxy)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-4,7,10,13,16,19,22,25,28-nonaoxahentriacontane-1,31-diamide, N,N'-(13-oxo-3,6,9,17,20,23-hexaoxa-12,14-diazapentacosane-1,25-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N1,N4-bis(20-(4-(4-((E)-3-(diaminomethyleneamino)-2-methyl-3-oxoprop-1-enyl)-2,6-difluorophenoxy)phenylsulfonamido)-3,6,9,12,15,18-hexaoxaicosyl)-2,3-dihydroxysuccinamide, N1,N4-bis(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroiso-quinolin-4-yl)phenylsulfonamido)ethyl)-2,3-dihydroxysuccinamide, N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, 3,3'-(2,2'-(2,2'-(2,2'-oxybis(ethane-2,1-diyl)bis(oxy))bis(ethane-2,1-diyl))bis(6,8-dichloro-1,2,3,4-tetrahydroisoquinoline-4,2-diyl))dianiline, N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamino)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, N1,N4-bis(1-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamino)-1-oxo-5,8,11-trioxa-2-azatridecan-13-yl)-2,3-dihydroxysuccinamide, N1,N2-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)oxalamide, N1,N4-bis(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethyl)-2,3-dihydroxysuccinamide, N1,N4-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)succinamide, 2,2'-oxybis(N-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)acetamide), (2R,3R)-N1,N4-bis(2-(2-(2-(3-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamino)-3-oxopropoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, N1,N2-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)oxalamide, N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)succinamide, N1,N3-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,2-dimethylmalonamide, N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-2,2-dimethylmalonamide, N,N'-(2,2'-(2,2'-(2,2'-(2,2'-(pyridine-2,6-diylbis(oxy))bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), 2,2'-(methylazanediyl)bis(N-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)acetamide)tris(2,2,2-trifluoroacetate), 5-amino-N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)isophthalamide tris(2,2,2-trifluoroacetate), 2,2'-oxybis(N-(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)acetamide), 5-bromo-N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)isophthalamide bis(2,2,2-trifluoroacetate), N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-2-hydroxymalonamide bis(2,2,2-trifluoroacetate), N1,N2-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)oxalamide, N1,N4-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)succinamide, 3,5-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethylcarbamoyl)benzenesulfonic acid, N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-5-hydroxyisophthalamide, (2R,3R)-N1,N4-bis(3-((3-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)propyl)(methyl)amino)propyl)-2,3-dihydroxysuccinamide, 2,2'-oxybis(N-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)acetamide), N1,N3-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-2,2-dimethylmalonamide, N1,N2-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)oxalamide, 2,2'-oxybis(N-(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)acetamide), N1,N4-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)succinamide, N1,N4-bis(2-(2-(2-(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)succinamide, 2,2'-oxybis(N-(2-(2-(2-(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)acetamide), (S or R)-N,N'-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis(3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), (S or R)-N,N'-(2,2'-(2,2'-(2,2'-(1,4-phenylenebis(azanediyl))bis(oxamethylene)bis(azanediyl)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(3-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N,N'-(butane-1,4-diyl)bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)acetamido)acetamido)acetamido), N1,N4-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, N,N'-(2,2'-(2,2'-(2,2'-(1,4-phenylenebis(methylene))bis(azanediyl)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), (2R,3R)-N1,N4-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, N,N'-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,14,19,21-tetraazadotriacontan-1,32-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N,N'-(1,1'-(1,4-phenylenebis(azanediyl))bis(1-oxo-5,8,11-trioxa-2-azatridecane-13,1-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), (2R,3R)-N1,N4-bis(20-(4-(4-((E)-3-(diaminomethyleneamino)-2-methyl-3-oxoprop-1-enyl)-2,6-difluorophenoxy)phenylsulfonamido)-3,6,9,12,15,18-hexaoxaicosyl)-2,3-dihydroxysuccinamide, (E)-3-(4-(4-(N-(20-amino-3,6,9,12,15,18-hexaoxaicosyl)sulfamoyl)phenoxy)-3,5-difluorophenyl)-N-(diaminomethylene)-2-methylacrylamide, (2R,3R)-N1,N4-bis(2-(2-(2-(2-(4-(4-((E)-3-(diaminomethyleneamino)-2-methyl-3-oxoprop-1-enyl)-2,6-difluorophenoxy)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, 2,2',2"-nitrilotris(N-(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)acetamide), N-(32-amino-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide, N1,N3,N5-tris(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)benzene-1,3,5-tricarboxamide, N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)terephthalamide, N1,N31-bis(32-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamide)-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)-4,7,10,13,16,19,22,25,28-nonaoxahentriacontane-1,31-diamide, 2R,3R)-N1,N4-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, N1,N3-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)benzene-1,3-disulfonamide, N4,N4'-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)biphenyl-4,4'-disulfonamide, (14R,15R)-1-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)-14,15-dihydroxy-13-oxo-3,6,9-trioxa-12-azahexadecano-16-oic acid, (2S,3S)-N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, N1,N4-bis(2-(2-(2-(2-(3-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, N1,N4-bis(2-(2-(2-(2-(3-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, N1,N4-bis(2-(2-(2-(2-(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, N1,N4-bis(2-(2-(2-(2-(4-((R or S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, N1,N4-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, N1,N3-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)isophthalamide, (2R,3S)-N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, N1,N2-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)phthalamide, N1,N4-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)terephthalamide, N,N'-(10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecane-1,19-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N1,N4-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)terephthalamide, N1,N4-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)terephthalamide, N,N'-(10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecan-1,19-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N,N'-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N,N'-(2,2'-(2,2'-(2,2'-(1,4-phenylenebis(azanediyl))bis(oxamethylene)bis(azanediyl)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N,N'-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), phenylenebis(azanediyl))bis(oxamethylene)bis(azanediyl)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide, (2S,3S)-N1,N4-bis(2-(2-(2-(2-(3-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, (2R,3R)-N1,N4-bis(2-(2-(2-(2-(3-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, (2S,3S)-N1,N4-bis(2-(2-(2-(2-(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, (2R,3R)-N1,N4-bis(2-(2-(2-(2-(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide, (S or R)-N,N'-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,14,19,21-tetraazadotriacontan-1,32-diyl)bis(3-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), (S or R)-N,N'-(1,1'-(1,4-phenylenebis(azanediyl))bis(1-oxo-5,8,11-trioxa-2-azatridecane-13,1-diyl))bis(3-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N1,N4-bis(2-(2-(2-(2-(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-terephthalamide, N1-(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)succinamide, N,N'-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,14,19,21-tetraazadotriacontan-1,32-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), N,N'-(1,1'-(1,4-phenylenebis(azanediyl))bis(1-oxo-5,8,11-trioxa-2-azatridecane-13,1-diyl))bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), (S or R)-N,N'-(13-oxo-3,6,9,17,20,23-hexaoxa-12,14-diazapentacosane-1,25-diyl)bis(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), (S or R)-N,N'-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,14,19,21-tetraazadotriacontan-1,32-diyl)bis(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide), or (S or R)-N,N'-(1,1'-(1,4-phenylenebis(azanediyl))bis(1-oxo-5,8,11-trioxa-2-azatridecan-13,1-diyl))bis(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide).

[0106] In one embodiment, the NHE inhibitor is: [ka]

[0107] In some embodiments, the compound has the structure of formula (IH): [ka] or a stereoisomer, prodrug, or pharmaceutically acceptable salt thereof; During the ceremony, (a) n is an integer of 2 or greater; (b) the core is a core moiety having two or more sites thereon for attachment to two or more NHE-binding small molecule moieties; (c) L is a bond or linker connecting the core moiety to two or more NHE-binding small molecule moieties; (d) NHE is an NHE-linked small molecule moiety having the structure of formula (XI-H): [ka] During the ceremony, B is selected from the group consisting of aryl and heterocyclyl; Each R5 is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 1-4 thioalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxyl, oxo, cyano, nitro, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, -NR7C(=O)NR8R9, -NR7SO2R8, -NR7S(O)2NR8R9, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -S(O) 1-2 R7, R8, and R9 are independently selected from the group consisting of hydrogen, C 1-4 alkyl, or a bond connecting the NHE-binding small molecule moiety to L, provided that at least one is a bond connecting the NHE-binding small molecule moiety to L; R3 and R4 are independently hydrogen, optionally substituted C 1-4 selected from the group consisting of alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; or R3 and R4 together with the nitrogen to which they are attached form an optionally substituted 4- to 8-membered heterocyclyl; Each R1 is independently hydrogen, halogen, or an optionally substituted C 1-6 Alkyl, and optionally substituted C 1-6In some embodiments, n is 2. In certain embodiments, L is a polyalkylene glycol linker. In certain embodiments, L is a polyethylene glycol linker.

[0108] In certain embodiments, the core has the following structure: [ka] During the ceremony, X is a bond, -O-, -NH-, -S-, C 1-6 Alkylene, -NHC(=O)-, -C(=O)NH-, -NHC(=O)NH-, -SO2NH-, and -NHSO2-, Y is a bond, an optionally substituted C 1-8 alkylene, optionally substituted aryl, optionally substituted heteroaryl, polyethylene glycol linker, -(CH2) 1-6 O(CH2) 1-6 - and -(CH2) 1-6 NY1(CH2) 1-6 - selected from the group consisting of Y1 is hydrogen, optionally substituted C 1-8 It is selected from the group consisting of alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0109] In some embodiments, the core is selected from the group consisting of: [ka]

[0110] In certain embodiments, the NHE-binding small molecule moiety has the structure of formula (XII-H): [ka] During the ceremony, Each R and R independently represents hydrogen and optionally substituted C 1-4 alkyl, or R3 and R4 together with the nitrogen to which they are attached form an optionally substituted 4- to 8-membered heterocyclyl; Each R1 is independently hydrogen, halogen, or C 1-6 Alkyl, and C 1-6 haloalkyl; R5 is selected from the group consisting of -SO2-NR7- and -NHC(=O)NH-, wherein R7 is hydrogen or C 1-4 It is alkyl.

[0111] In some embodiments, R3 and R4, together with the nitrogen to which they are attached, form an optionally substituted 5- or 6-membered heterocyclyl. In certain embodiments, the optionally substituted 5- or 6-membered heterocyclyl is pyrrolidinyl or piperidinyl. In certain embodiments, the optionally substituted 5- or 6-membered heterocyclyl is pyrrolidinyl or piperidinyl, each substituted with at least one amino or hydroxyl. In some embodiments, R3 and R4 are independently C 1-4 In certain embodiments, R and R are alkyl. In certain embodiments, R and R are methyl. In some embodiments, each R is independently selected from the group consisting of hydrogen or halogen. In certain embodiments, each R is independently selected from the group consisting of hydrogen, F, and Cl.

[0112] In certain embodiments, the compound has the structure of formula (II): [ka] or a stereoisomer, prodrug, or pharmaceutically acceptable salt thereof, wherein: (a) NHE is an NHE-binding small molecule moiety having the structure of formula (AI): [ka] During the ceremony, each R, R, R, R, and R is independently selected from H, halogen, —NR(CO)R, —(CO)NR, —SO—NR, —NRSO, —NR, —OR, —SR, —O(CO)NR, —NR(CO)OR, and —NRSO; 1-6 Alkyl, -C 1-6 alkyl-OH, or a bond connecting an NHE-binding small molecule to L, provided that at least one is a bond connecting an NHE-binding small molecule to L; R4 is selected from H, C1-C7 alkyl, or a bond connecting an NHE-linked small molecule to L; R6 is absent or selected from H and C1-C7 alkyl; Ar1 and Ar2 independently represent an aromatic ring or a heteroaromatic ring; (b) the core is a core moiety having the structure of formula (BI): [ka] During the ceremony, X is a function of C(X1), N, and N(C 1-6 alkyl), X1 is hydrogen, optionally substituted alkyl, -NX a X b , -NO2, -NX c -C(=O)-NX c -X a , -C(=O)NX c -X a , -NX c -C(=O)-X a , -NX c -SO2-X a , -C(=O)-X a , and -OX a is selected from each X a and X bare independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; Y is C 1-6 is alkylene, Z is -NZ if X is CX1 a -C(=O)-NZ a -, -C(=O)NZ a -, -NZ a -C(=O)-, and heteroaryl; Z is a criterion for X being N or N(C 1-6 alkyl), -NZ a -C(=O)-NZ a -, -NZ a -C(=O)-, and heteroaryl; each X c and Z a are independently hydrogen and C 1-6 alkyl, (c) L is a bond or linker connecting the core moiety to the NHE-binding small molecule moiety.

[0113] In some embodiments, the NHE-binding small molecule moiety has the structure: [ka] During the ceremony, each R, R, and R is independently selected from H, halogen, —NR(CO)R, —(CO)NR, —SO—NR, —NRSO, —NR, —OR, —SR, —O(CO)NR, —NR(CO)OR, and —NRSO; 1-6 Alkyl, -C 1-6alkyl-OH, or a bond connecting an NHE-binding small molecule to L, provided that at least one is a bond connecting an NHE-binding small molecule to L.

[0114] In some embodiments, the NHE-binding small molecule moiety has one of the following structures: [ka]

[0115] In some embodiments, L is a polyalkylene glycol linker. In certain embodiments, L is a polyethylene glycol linker. In some embodiments, X is C(X). In some embodiments, each X c is hydrogen. In certain embodiments, X is N. In certain embodiments, each Z a is hydrogen.

[0116] In some embodiments, the compound has the structure of Formula (II): [ka] or a stereoisomer, prodrug, or pharmaceutically acceptable salt thereof; During the ceremony, (a) NHE is an NHE-binding small molecule moiety having the structure of formula (AI): [ka] During the ceremony, each R, R, R, R, and R is independently selected from H, halogen, —NR(CO)R, —(CO)NR, —SO—NR, —NRSO, —NR, —OR, —SR, —O(CO)NR, —NR(CO)OR, and —NRSO; 1-6 Alkyl, -C 1-6alkyl-OH, or a bond connecting an NHE-binding small molecule to L, provided that at least one is a bond connecting an NHE-binding small molecule to L; R4 is selected from H, C1-C7 alkyl, or a bond connecting an NHE-linked small molecule to L; R6 is absent or selected from H and C1-C7 alkyl; Ar1 and Ar2 independently represent an aromatic ring or a heteroaromatic ring; (b) the core is a core moiety having the structure of formula (CI): [ka] During the ceremony, W is selected from alkylene, polyalkylene glycol, -C(=O)-NH-(alkylene)-NH-C(=O)-, -C(=O)-NH-(polyalkylene glycol)-NH-C(=O)-, -C(=O)-(alkylene)-C(=O)-, -C(=O)-(polyalkylene glycol)-C(=O)-, and cycloalkyl; X is N, Y is C 1-6 is alkylene, Z is -NZ a -C(=O)-NZ a -, -C(=O)NZ a -, -NZ a -C(=O)-, and heteroaryl; each Z a are independently hydrogen and C 1-6 alkyl, (c) L is a bond or linker connecting the core moiety to the NHE-binding small molecule.

[0117] In certain embodiments, the NHE-binding small molecule moiety has the structure: [ka] During the ceremony, each R, R, and R is independently selected from H, halogen, —NR(CO)R, —(CO)NR, —SO—NR, —NRSO, —NR, —OR, —SR, —O(CO)NR, —NR(CO)OR, and —NRSO; 1-6 Alkyl, -C 1-6 alkyl-OH, or a bond connecting an NHE-binding small molecule to L, provided that at least one is a bond connecting an NHE-binding small molecule to L.

[0118] In certain embodiments, the NHE-binding small molecule moiety has one of the following structures: [ka]

[0119] In another embodiment, the NHE inhibitor is [ka] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers thereof; During the ceremony, The linker is -(CHR 13 ) p -[Y-(CH2) r ] s -ZR 13 -(CH2) t -Z-, W is independently, at each occurrence, S(O)2, C(O), or -(CH2) m - and Z is independently, at each occurrence, a bond, C(O), or —C(O)NH—; Y is independently at each occurrence O, S, NH, N(C1-C3 alkyl), or —C(O)NH—; Q is a bond, NH, -C(O)NH-, -NHC(O)NH-, -NHC(O)N(CH3)-, or -NHC(O)NH-(CHR 13) wherein m is an integer of 1 to 2, and n is an integer of 1 to 4; r and p are independently, at each occurrence, an integer from 0 to 8; s is an integer from 0 to 4, t is an integer from 0 to 4, u is an integer from 0 to 2, R 1 and R 2 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl (containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O), where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may optionally be selected from one or more of halogen, OH, CN, —NO2, oxo, —SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O)2N(R 9 )2-, -S(O)2R 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 9 R 10 , -NR 9 S(O)2R 10 , -S(O)R 9 , -S(O)NR 9 R 10 , -NR 8 S(O)R 9 , C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl, or R 1 and R 2can be taken together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl (containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O), where the heterocyclyl or heteroaryl group can contain one or more halogen, OH, CN, —NO, oxo, —SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O)2N(R 9 )2-, -S(O)2R 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 9 R 10 , -NR 9 S(O)2R 10 , -S(O)R 9 , -S(O)NR 9 R 10 , -NR 9 S(O)R 10 , optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl; R 3 and R 4 are independently halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -C(O)NR 9 R 10 and R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl (containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O), -SR 9 , -OR 9 , -NHR 9 , -NR 9 R10 , -S(O)2N(R 9 )2-, -S(O)2R 9 , -C(O)R 9 , -C(O)OR 9 , -NR 9 S(O)2R 10 , -S(O)R 9 , -S(O)NR 9 R 10 , -NR 8 S(O)R 9 and R 9 and R 10 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl (containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O); X is a bond, H, N, O, or CR 11 R 12 , C.R. 11 , C, —NHC(O)NH—, or C-C cycloalkyl; R 11 and R 12 are independently H, C1-C6 alkyl, OH, NH2, CN, or NO2; R 13 is independently, at each occurrence, a bond, H, C-C alkyl, C-C cycloalkenyl, C-C cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R 19 optionally replaced by R 14 is independently, at each occurrence, H, C1-C6 alkyl, or C1-C6 haloalkyl; R 6 and R 14 can, together with the atoms to which they are attached, independently form, at each occurrence, a 5- to 6-membered heterocyclyl, where each C-C cycloalkyl or heterocyclyl can be selected from one or more R 19optionally replaced by, or R 13 and R 14 can be combined together with the atoms to which they are attached independently at each occurrence to form a C-C cycloalkyl, heterocyclyl, aryl, or heteroaryl (containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O), where each heterocyclyl or heteroaryl is selected from one or more R 19 optionally replaced by R 15 , R 16 , R 17 , and R 18 is independently, at each occurrence, H, OH, NH, or C-C alkyl, where alkyl is selected from one or more R 19 optionally replaced by R 19 is independently, at each occurrence, H, OH, NH, oxo, C-C alkyl, C-C H haloalkyl, C-C alkoxy.

[0120] In one embodiment, the NHE3 inhibitor is a compound according to the formula above, provided that: (1) When X is H, n is 1; (2) X is a bond, O, or CR 11 R 12 when n is 2, (3) When n is 3, X is CR 11 or N, (4) When n is 4, X is C; (5) only one of Q or X is -NHC(O)NH- at that time; (6)R 1 and R 2 but cannot form pyrrolidinyl with the nitrogen to which they are attached, (7)R 1 and R 2 is methyl, R 3 and R 4 is a halogen, and R 5 and R 8is H and the linker is [ka] Instead, (8)R 1 and R 2 together with the nitrogen to which they are attached to form piperidinyl, R 3 and R 4 is a halogen, and R 5 and R 8 is H and the linker is [ka] Not or (9)R 1 and R 2 together with the nitrogen to which they are attached to form 3-aminopiperidin-1-yl, R 3 and R 4 is a halogen, and R 5 , R 6 , R 7 , and R 8 is H and the linker is [ka] provided that it is not.

[0121] In one embodiment, the NHE3 compound has a structure according to the following formula: [ka] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers thereof, wherein: The linker is -(CHR 8 ) p -[Y-(CH2) r ] s -ZR 8 -(CH2) t -Z-, Q is a bond or -NHC(O)NH-; Z is independently, at each occurrence, a bond, C(O), or —C(O)NH—; Y is independently at each occurrence O, S, NH, N(C1-C3 alkyl), or —C(O)NH—; X is a bond, N, O, or CR 11 R 12 , C.R. 11 , C, or -NHC(O)NH-; n is an integer from 2 to 4, r and p are independently, at each occurrence, an integer from 0 to 8; s is an integer from 0 to 4, t is an integer from 0 to 4, u is an integer from 0 to 2, R 1 and R 2 are independently halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -C(O)NR 9 R 10 and R 3 , R 4 , R 5 , and R 6 are independently H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl (containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O), -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O)2N(R 9 )2-, -S(O)2R 9 , -C(O)R 9 , -C(O)OR 9 , -NR 9 S(O)2R 10 , -S(O)R 9 , -S(O)NR 9 R 10 , -NR 8 S(O)R 9 and R 7 is independently, at each occurrence, H, C-C alkyl, or C-C haloalkyl; R 8 is independently, at each occurrence, a bond, H, C-C alkyl, C-C cycloalkenyl, C-C cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more R 17 optionally replaced by, or R 7 and R 8 can be combined together with the atoms to which they are attached to independently form, at each occurrence, a heterocyclyl or heteroaryl (containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O), where each heterocyclyl or heteroaryl is selected from one or more R 17 optionally replaced by R 9 and R 10 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl (containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O); R 11 and R 12 are independently H, C1-C6 alkyl, OH, NH2, CN, or NO2; R 13 , R 14 , R 15 , and R 16 is independently, at each occurrence, H, OH, NH, or C-C alkyl, where alkyl is selected from one or more R 17 optionally replaced by R 17 is independently, at each occurrence, H, OH, NH, oxo, C-C alkyl, C-C haloalkyl, or C-C alkoxy.

[0122] In one embodiment, the NHE3 inhibitor compound has a structure according to the formula above, except that: (1) X is a bond, O, or CR 11 R 12 when n is 2, (2) When n is 3, X is CR 11 or N, (3) When n is 4, X is C; (4) only one of Q or X is -NHC(O)NH- at that time; (5)R 1 and R 2 is chloro, Q is -NHC(O)NH-, and R 3 , R 4 , R 5 , and R 6 is H and the linker is [ka] Not or (6)R 1 and R 2 is chloro, Q is -NHC(O)NH-, and R 3 , R 4 , R 5 , and R 6 is H and the linker is [ka] provided that it is not.

[0123] In one embodiment, the NHE3 inhibitor compound has a structure according to the following formula: N,N'-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide], N,N'-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide], N,N'-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylbenzenesulfonamide], N,N'-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylbenzenesulfonamide], N,N'-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylbenzenesulfonamide], N,N'-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-2-methylbenzenesulfonamide], N,N'-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[5-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-2-methylbenzenesulfonamide], N,N'-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis(5-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-2-methylbenzenesulfonamide), N,N'-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide], N,N'-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide, N,N'-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide], N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide], N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide], N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide], N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylbenzenesulfonamide], N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylbenzenesulfonamide], N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylbenzenesulfonamide], N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-2-methylbenzenesulfonamide], N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[5-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-2-methylbenzenesulfonamide], N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[5-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-2-methylbenzenesulfonamide], N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide], N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide], N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide], N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide], N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide], N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide], N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylbenzenesulfonamide], N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylbenzenesulfonamide], N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-methylbenzenesulfonamide], N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-2-methylbenzenesulfonamide], N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[5-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-2-methylbenzenesulfonamide], N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[5-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-2-methylbenzenesulfonamide], N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide], N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide], N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide], N,N'-[(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(piperidine-1,4-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide], N,N'-[(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(piperidine-1,4-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide], 1,1'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[N-([3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]sulfonyl)formamide], 1,1'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[N-([3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]sulfonyl)formamide], 1,1'-(5,12-dioxo-4,6,11,13-tetraazahexadecane-1,16-diyl)bis[N-([3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]sulfonyl)piperidine-4-carboxamide], 1,1'-(5,12-dioxo-4,6,11,13-tetraazahexadecane-1,16-diyl)bis[N-([3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]sulfonyl)piperidine-3-carboxamide], N 1 ,N 18 -bis([3-(6,8-dichloro-2-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]sulfonyl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide, N,N'-[(3S,3'S)-(6,13-dioxo-5,7,12,14-tetraazaoctadecandioyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide], N,N'-[(3S,3'S)-(6,13-dioxo-5,7,12,14-tetraazaoctadecandioyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide], 1-[2-(2-[(1-[(3-[(S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl)sulfonyl]piperidin-4-yl)oxy]ethoxy)ethyl]-3-[4-(3-[2-(2-[(1-[(3-[(S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl)sulfonyl]piperidin-4-yl)oxy]ethoxy)ethyl]ureido)butyl]urea, 1-(2-(2-(((R)-1-((3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfonyl)pyrrolidin-3-yl)oxy)ethoxy)ethyl)-3-(4-(3-(2-(2-(((R)-1-((3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfonyl)pyrrolidin-3-yl)oxy)ethoxy)ethyl)ureido)butyl)urea, 1-(2-[2-([(S)-1-[(3-[(S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl)sulfonyl]pyrrolidin-3-yl]oxy)ethoxy]ethyl)-3-(4-[3-(2-[2-([(S)-1-[(3-[(S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl)sulfonyl]pyrrolidin-3-yl]oxy)ethoxy]ethyl)ureido]butyl)urea, 3-[(S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]-N-[(3R,28R)-28-[(3-[(S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl)sulfonamido]-2,29-dimethyl-12,19-dioxo-5,8,23,26-tetraoxa-11,13,18,20-tetraazatriacontan-3-yl]benzenesulfonamide, N,N'-(10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecane-1,19-diyl)bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide], N,N'-[(3S,3'S)-(7-oxo-3,11-dioxa-6,8-diazatridecane-1,13-diyl]bis[pyrrolidine-1,3-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide], N 1 ,N 18 -bis(1-[(3-[(S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl)sulfonyl]piperidin-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide, N 1 ,N 18 bis(1-[(3-[(S)-6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl)sulfonyl]piperidin-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide, or N 1 ,N 18 -bis(1-[(3-[(S)-6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl)sulfonyl]piperidin-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide.

[0124] In one embodiment of the present invention, the NHE3 inhibitor is a compound according to the following formula: [ka]

[0125] In one embodiment of the present invention, the NHE3 inhibitor is a compound according to the following formula: [ka]

[0126] In one embodiment, the NHE3 inhibitor is one of the following compounds: 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro,-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 1-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-carbamoyl]amino)butyl]urea, 1-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea dihydrochloride, 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea, 3-[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea, 3-[(4-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea, 3-[(4-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea, 3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea, 3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea, 3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea, 3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea, 1-([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-3-(4-[[([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)carbamoyl]amino]butyl)urea, (2R,3S,4R,5S)-N1,N6-bis([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-2,3,4,5-tetrahydroxyhexanediamide, 3-[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)methyl]-1-[4-([[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)methyl]carbamoyl]amino)butyl]urea, 3-[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]hexyl]-1H-1,2,3-triazol-4-yl)methyl]-1-[4-([[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]hexyl]-1H-1,2,3-triazol-4-yl)methyl]carbamoyl]amino)butyl]urea, (4R,4aS,8S,8aR)-N4,N8-bis([1-(4-[4-((1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenylsulfonamido]butyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-tetrahydro-[1,3]dioxino[5,4-d][1,3]dioxine-4,8-dicarboxamide, (4R,4aS,8S,8aR)-N4,N8-bis([1-(6-[4-((1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenylsulfonamido]hexyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-tetrahydro-[1,3]dioxino[5,4-d][1,3]dioxine-4,8-dicarboxamide, 3-[8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea, 3-[8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea, 3-[8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea, 3-[8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2S)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2S)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.1]heptan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.1]heptan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 1-[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.2]octan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.2]octan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.2.1]octan-8-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.2.1]octan-8-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 1-[2-(2-[2-[(4-[[(1S,2S)-2-[9-azabicyclo[3.3.1]nonan-9-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[9-azabicyclo[3.3.1]nonan-9-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 4-[(1S,2S)-4,6-dichloro-1-[4-[(2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[4-(dimethylcarbamoyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)ethoxy]ethoxy]ethyl)sulfamoyl]phenoxy]-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperazine-1-carboxamide, 4-[(1S,2S)-4,6-dichloro-1-[4-[(2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[4-(dimethylcarbamoyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)ethoxy]ethoxy]ethyl)sulfamoyl]-2-methylphenoxy]-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperazine-1-carboxamide, 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; hydrochloride, 1-[2-(2-[2-[(3-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,4-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-carbamoyl]amino)butyl]urea; hydrochloride, 1-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-difluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-difluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3,5-difluorophenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]-3,5-difluorobenzenesulfonamide, 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea, 1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea, 3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]piperidin-4-yl]oxy)ethoxy]ethyl]-1-[4-[([2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]piperidin-4-yl]oxy)ethoxy]ethyl]carbamoyl)amino]butyl]urea, 1-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-3-(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea; hydrochloride, 3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea, 3-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea dihydrochloride, 3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea, 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-2-methylpropoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-2-methylpropoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; hydrochloride, 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, 4-([(1S,2S)-2-[(R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-2-[(R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy)-2-chlorophenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]-2-chlorobenzenesulfonamide, 4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide; tetra(trifluoroacetate), 4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide; tetra(trifluoroacetate), 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; tetra(trifluoroacetate), 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; tetra(trifluoroacetate), 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide; tetra(trifluoroacetate), 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide; tetra(trifluoroacetate), 4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)-3-fluorobenzenesulfonamide; tetra(trifluoroacetate), 4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)-3-fluorobenzenesulfonamide; tetra(trifluoroacetate), 4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamide; tetra(trifluoroacetate), 4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamide; tetra(trifluoroacetate), 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl)pyrrolidin-3-yl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-[(2S,13S)-14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2,13-dimethyl-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl]pyrrolidin-3-yl]benzenesulfonamide, N1,N14-bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide, N1,N14-bis(2-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide, N1,N18-bis(1-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)piperidin-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide, 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide, -([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido]piperidin-1-yl)-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl]piperidin-4-yl)benzenesulfonamide, N1,N18-bis([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide, N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-1-[16-(4-[([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)carbamoyl]piperidin-1-yl)-5,12-dioxo-4,6,11,13-tetraazahexadecyl]piperidine-4-carboxamide, 4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide, 4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazabicosyl)pyrrolidin-3-yl]benzenesulfonamide, 4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazabicosyl)pyrrolidin-3-yl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-2-oxopiperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)-2-oxopiperidin-3-yl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[2-(2-[2-(3-[(1r,4r)-4-(3-[2-(2-[2-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)ethoxy]ethoxy)ethyl]ureido)cyclohexyl]ureido)ethoxy]ethoxy)ethyl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(18-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide, N-(2-[2-(2-aminoethoxy)ethoxy]ethyl)-4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide, N-[1-(4-aminobutanoyl)piperidin-4-yl]-4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-(3-oxo-7,10-dioxa-2,4-diazadodecan-12-yl)benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-(1-[4-(3-methylureido)butanoyl]piperidin-4-yl)benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-yl]benzenesulfonamide, 4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-yl]piperidine-1-carboxamide, 4-(3-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-4-oxobutyl]ureido)-N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)butanamide, 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(4-[3-(4-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-4-oxobutyl)ureido]butanoyl)piperidin-4-yl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[19-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecyl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-amido-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-amido-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide, 4-([(1S,2S)-4-cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-4-cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide, 1,1'-(butane-1,4-diyl)bis[3-(4-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinolin-2(1H)-yl]-4-oxobutyl)urea], 1,1'-(butane-1,4-diyl)bis[3-(4-[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinolin-2(1H)-yl]-4-oxobutyl)urea], N,N'-(6,14-dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide], N,N'-(6,14-dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide], 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(18-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(18-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide, 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide, N1,N14-bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide, 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)piperidin-4-yl]benzenesulfonamide, 4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide, N1,N14-bis(2-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide, 1,1'-(butane-1,4-diyl)bis(3-[2-(2-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindolin-2-yl]ethoxy)ethyl]urea), and 1,1'-(butane-1,4-diyl)bis(3-[2-(2-[5-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindolin-2-yl]ethoxy)ethyl]urea). [Example]

[0127] The present invention will be more fully understood with reference to the following examples. However, the examples should not be construed as limiting the scope of the present invention. For example, the synthesis of compounds not exemplified can be successfully carried out by modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and / or by routinely modifying reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds described herein.

[0128] Example 1 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(methoxycarbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (1-9) [ka] Synthesis of (4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-octadecahydropicene-3-carboxylic acid (1-2) A 1 L pressure tank reactor (10 atm) purged and maintained with an inert atmosphere of CO was charged with benzyl(2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,1 2a,12b,13,14b-Octadecahydropicene-2-carboxylate 1-1 (prepared according to the method described in U.S. Patent Application Publication No. 20160151387) (11 g, 15.92 mmol, 1.00 equiv.), tetrakis(triphenylphosphine)palladium(0) (4 g, 3.46 mmol, 0.20 equiv.), THF (250 mL), and water (150 mL) were added. The resulting solution was stirred at 50° C. for 2 days. The resulting solution was extracted with CHCl (3×150 mL), and the organic layers were combined. The resulting mixture was washed with brine (3×150 mL). The mixture was dried over anhydrous NaSO and concentrated under vacuum. The residue was applied to a silica gel column with petroleum ether (1:10) (20 mL). The crude product was purified by flash preparative HPLC (CombiFlash®-1) with the following conditions: Column: C 18 Silica gel, mobile phase: MeCN:water=100:0, detector: UV 254 nm. 1 L of product was obtained, which gave 6.5 g (69.6%) of 1-2 as a pale yellow solid.

[0129] Synthesis of 2-benzyl 10-((2-(trimethylsilyl)ethoxy)methyl)(2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropicene-2,10-dicarboxylate (1-3) TEA (3 mL, 5.80 equiv.) was added dropwise to 1-2 (3 g, 5.11 mmol, 1 equiv.) and DMAP (102.4 mg, 0.84 mmol, 0.10 equiv.) in DMF (30 mL) with stirring at 0 °C. This was followed by the dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (4.2 mL, 4.8 equiv.) with stirring at 0 °C. The reaction was stirred at room temperature for 1.5 h and then quenched by the addition of aqueous K2CO3 (50 mL). The mixture was diluted with CHCl2 (250 mL), washed with brine (3 × 150 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:10). This afforded 3.5 g (95.5%) of 1-3 as a pale yellow solid.

[0130] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(((2-(trimethylsilyl)ethoxy)methoxy)carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (1-4) A 300 mL pressure tank reactor (40 atm) purged and maintained with an inert atmosphere of hydrogen was charged with 1-3 (6.6 g, 9.20 mmol, 1.00 equiv), Pd / C (1.32 g, 0.20 equiv), and acetone (150 mL). The reaction was stirred at 50 °C overnight and then concentrated in vacuo. This afforded 4.2 g (73%) of 1-4 as a white solid.

[0131] Synthesis of 2-benzyl 10-((2-(trimethylsilyl)ethoxy)methyl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate (1-5) A mixture of 1-4 (5.25 g, 8.35 mmol, 1 equiv.), cesium carbonate (4.1 g, 12.58 mmol, 1.5 equiv.), and benzyl bromide (2.86 g, 16.72 mmol, 2 equiv.) in DMF (70 mL) was stirred at 60 °C for 2 h. The reaction was diluted with water (250 mL) and extracted with CHCl (2 × 100 mL). The organic layers were combined, dried (NaSO), and concentrated. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:10). This afforded 6 g (99%) of 1-5 as an off-white solid.

[0132] Synthesis of (3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicene-3-carboxylic acid (1-6) Hydrogen chloride (4 M in dioxane, 30 mL) was added to 1-5 (5.6 g, 7.79 mmol, 1 equiv.) in THF (40 mL), and the reaction was stirred at 60° C. for 2 h. The solution was adjusted to pH=3 with aqueous sodium bicarbonate (saturated). The mixture was extracted with CHCl (3×100 mL). The organic layers were combined, washed with brine (2×150 mL), dried (NaSO), and concentrated. The residue was purified by flash preparative HPLC (CombiFlash®-1) with the following conditions—Column: C 18 Silica gel, mobile phase: MeCN:water = 100:0, detector: UV 254 nm. This gave 3.1 g (68%, purity 97%) of 1-6 as a white solid. MS (ES, m / z): [M+H] + =589.4; 1 H-NMR (400 MHz, chloroform-d): δ 0.76(s,4H),0.91(s,5H),1.01-1.21(m,12H),1.24-1.49(m,9H),1.56-1.75(m,4H),1.83(td,J=13.6,4.6 Hz,1H),1.91-2.10(m,5H),2.23(d,J=8.2 Hz,1H),2.37(s,1H),2.86(d,J=13.2 Hz,1H),5.11(d,J=12.0 Hz,1H),5.23(d,J=12.4 Hz,1H),5.57(s,1H),7.30-7.45(m,5H).

[0133] Synthesis of benzyl (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(chlorocarbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (1-7) Oxalyl chloride (0.144 mL, 1.70 mmol) was added to 1-6 (0.50 g, 0.85 mmol) and DMF (1 drop) in CHCl (50 mL) at room temperature. The mixture was stirred at room temperature for 1 hour and then evaporated to dryness. The material was used in the next step without purification.

[0134] Synthesis of 2-benzyl 10-methyl (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate (1-8) 1-7 (200 mg, 0.33 mmol, 1 equiv.) and TEA (0.274 mL, 6 equiv.) in MeOH (20 mL) were stirred overnight at room temperature. The reaction was concentrated in vacuo to afford 198 mg (100%) of 1-8 as a crude pale yellow solid.

[0135] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(methoxycarbonyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (1-9) 1-8 (198 mg, 0.33 mmol, 1.00 equiv) and Pd / C (20 mg) in MeOH (40 mL) were placed under a hydrogen atmosphere and stirred at room temperature for 1 h. The reaction was filtered and concentrated in vacuo. The crude product (200 mg) was purified by preparative HPLC with the following conditions: Column: XBridge Prep C18 OBD, 190*150 mm, 5 μm; Mobile phase: water (10 mM NH4HCO3 + 0.1% NH4OH) and CH3CN (50.0% CH3CN to 62.0% in 7 min); Detector: UV 254 / 220 nm. This afforded 111.8 mg (66%) of 1-9 as a pale yellow solid. MS (ES, m / z): [M+H]+ = 513.60; 1H NMR(400 MHz,chloroform-d)δ 0.76(d,J=11.2 Hz,1H),0.84(s,3H),0.88-0.96(m,4H),0.99-1.08(m,4H),1.18(s,3H),1.19-1.28(m,7H),1.31-1.39(m,4H),1.40-1.48(m,4H), 1.50-1.59(m,1H),1.60-1.72(m,3H),1.79-1.89(m,1H),1.91-2.09(m,4H),2.15-2.25(m,2H),2.37(s,1H),2.82(dt,J=10.4,3.2 Hz,1H),3.65(s,3H),5.70(s,1H),9.89(s,1H).

[0136] Example 2 (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(carboxymethoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (78-2) [ka] Synthesis of benzhydryl (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(prop-2-yn-1-yloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (76-2) 76-1 (prepared as described in Bioorg. Med. Chem. 2010, 18, 433-454) (1.674 g, 2.63 mmol, 1 equiv.), NaHMDS (2.63 mL, 2 equiv.), 3-bromoprop-1-yne (0.45 mL, 2 equiv.), and tetrabutylammonium iodide (486 mg, 1.32 mmol, 0.5 equiv.) in THF (2 mL) was stirred overnight at room temperature. The reaction was diluted with water (30 mL) and extracted with DCM (2 × 50 mL). The extract was dried (NaSO) and concentrated in vacuo. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:10). This afforded 1.395 g (79%) of 76-2 as a pale yellow solid.

[0137] Synthesis of 2-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzhydryloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl)oxy)acetic acid (78-1) Ruthenium(III) chloride hydrate (20 mg, 0.10 mmol, 6.8 equiv.), 76-2 (100 mg, 0.15 mmol, 1 equiv.), and sodium periodate (150 mg, 0.70 mmol, 5 equiv.) in THF (4 mL) and water (1 mL) were stirred at room temperature for 2 h. The reaction was diluted with water (20 mL) and extracted with DCM (2 × 50 mL). The extracts were dried (NaSO) and concentrated in vacuo. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:5). This afforded 80 mg (78%) of 78-1 as a white solid.

[0138] Synthesis of (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(carboxymethoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (78-2) 78-1 (148 mg, 0.21 mmol, 1 equiv.) and Pd / C (100 mg) in EtOAc (15 mL) were placed under a hydrogen atmosphere (1 atm) and stirred overnight at room temperature. The reaction was filtered and concentrated in vacuo. The residue was purified by preparative HPLC with the following conditions: column: XBridge Shield RP18 OBD, 5 μm, 19*150 mm; mobile phase: water (0.05% NHOH) and CHCN (10.0% CHCN to 40.0% in 8 min); detector: UV 254 nm. This afforded 31.1 mg (28%) of 78-2 as a white solid. MS (ES, m / z): [M+H] += 529.40; 1 H NMR(300 MHz,MeOH-d4,ppm)δ 0.78-0.88(m,7H),0.94-1.08(m,5H),1.16-1.18(m,9H),1.27(d,J=13.5 Hz,1H),1.39-1.51(m,8H),1.56-2.12(m,8H),2.13-2.26(m,2H),2.47(s,1H),2.76(dt,J=13.5,3.5 Hz,1H),2.94(dd,J=11.7,4.2 Hz,1H),3.93(d,J=15.6 Hz,1H),4.05(d,J=15.6 Hz,1H),5.61(s,1H).

[0139] Example 3 (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (121-2) [ka] Synthesis of benzyl (2S,4aS,6aS,6bR,8aR,9S,12aS,12bR,14bR,E)-10-(acetoxyimino)-9-(acetoxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (120-2) Prepared from (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid in acetic acid (100 mL) A mixture of 120-1 (prepared as described in Bioorg. Med. Chem. 2010, 18, 433-454) (1.0 g, 1.7 mmol, 1 equiv.), sodium tetrachloropalladate(II) (0.76 g, 2.04 mmol, 1.2 equiv.), and sodium acetate (0.21 g, 1.36 mmol, 0.8 equiv.) was stirred at room temperature for 72 h. The reaction was poured onto ice, and the resulting precipitate was collected by filtration and dried under vacuum. DCM (120 mL), acetic anhydride (0.435 g, 3.24 mmol, 1.8 equiv.), TEA (0.364 g, 2.72 mmol, 1.6 equiv.), and DMAP (6 mg, 0.02 equiv.) were added, and the mixture was stirred at room temperature for 1 h. The reaction was washed with water (1 × 300 mL), dried (NaSO), and concentrated under vacuum. Pyridine (0.6 mL) and THF (100 mL) were added, and the mixture was stirred at room temperature for 15 minutes. The reaction was cooled to -78 °C in a dry ice / acetone bath, and lead tetraacetate (4.9 g, 8.5 mmol, 5 equiv.) in acetic acid (100 mL) was slowly added. The mixture was warmed to room temperature and stirred at room temperature for 16 hours. A solution of sodium borohydride (60 mg) in 1 N aqueous NaOH (50 mL) was added, and stirring was continued for 10 minutes. The reaction was filtered through Celite and extracted with DCM (300 mL). The extract was washed with aqueous saturated NaHCO3 (3 × 300 mL) and brine (2 × 300 mL), dried (Na2SO4), and concentrated in vacuo. This afforded 1.03 g (88%, crude) of 120-2 as a pale yellow solid.

[0140] Synthesis of benzyl (2S,4aS,6aS,6bR,8aR,9S,12aS,12bR,14bR,E)-10-(hydroxyimino)-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (120-3) 120-2 (1.03 g, 1.53 mmol, 1 equiv.) and sodium carbonate (820 mg, 7.74 mmol, 5 equiv.) in MeOH (120 mL) were stirred at room temperature for 16 h. The reaction was concentrated in vacuo, and the residue was dissolved in DCM (200 mL). The mixture was washed with aqueous saturated sodium bicarbonate (2 × 200 mL) and brine (1 × 200 mL) and concentrated in vacuo. This gave 1.1 g (crude) of 120-3 as a yellow solid.

[0141] Synthesis of benzyl (2S,4aS,6aS,6bR,8aR,9R,12aS,12bR,14bR)-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (120-4) 120-3 (1.1 g, 1.87 mmol, 1 equiv.) in THF (70 mL) was added dropwise to ammonium acetate (3.88 g, 27 equiv.) and titanium(III) chloride (4 mL) in water (80 mL). The reaction was stirred at room temperature overnight and then partially concentrated in vacuo. The remaining solution was extracted with DCM (200 mL), washed with aqueous saturated sodium bicarbonate (1 × 200 mL) and brine (1 × 200 mL), dried (NaSO), and concentrated in vacuo. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:1). This afforded 190 mg (18%) of 120-4 as a white solid.

[0142] Synthesis of (2S,4aS,6aS,6bR,8aR,9R,12aS,12bR,14bR)-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (120-5) 120-4 (100 mg, 0.17 mmol) and Pd / C (20 mg) in EtOAc (15 mL) were placed under a hydrogen atmosphere (1 atm) and stirred at room temperature for 1 h. The reaction was filtered and concentrated in vacuo. The residue was purified by preparative HPLC with the following conditions: column: XBridge Shield RP18 OBD, 5 mm, 19*150 mm, mobile phase: water (0.05% TFA) and MeCN (20.0% MeCN to 30.0% in 10 min), detector: UV 254 nm. This gave 5.3 mg (6%) of 120-5 as a white solid. MS (ES, m / z): [M+H] + =485.30; 1 H NMR(400 MHz,MeOH-d4,ppm):δ 0.86(s,3H),0.96(s,3H),1.01-1.09(m,1H),1.13(s,3H),1.19-1.42(m,9H),1.46-1.73(m,8H),1.80-2.08(m,5H),2.12-2.29(m,1H),2.19 -2.48(m,2H),2.48-2.64(m,1H),2.66(s,1H),2.77-2.98(m,1H),3.35-3.42(m,2H),3.65(d,J=10.8 Hz,1H),5.75(s,1H).

[0143] Synthesis of benzyl (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (121-1) 120-4 (150 mg, 0.26 mmol, 1 equiv) and sodium borohydride (40 mg, 1.06 mmol, 4 equiv) in MeOH (20 mL) were stirred at room temperature for 1 h. The reaction was quenched by the addition of water (5 mL), and the mixture was concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried (NaSO), and concentrated. This gave 140 mg (93%) of 121-1 as a white solid.

[0144] Synthesis of (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (121-2) 121-1 (180 mg, 0.31 mmol) and Pd / C (36 mg) in EtOAc (15 mL) were placed under a hydrogen atmosphere (1 atm) and stirred at room temperature for 1 h. The reaction was filtered and concentrated in vacuo. The residue was purified by preparative HPLC with the following conditions: column: XBridge Shield RP18 OBD, 5 μm, 19*150 mm, mobile phase: water (0.05% TFA) and MeCN (42.0% MeCN to 57.0% in 8 min), detector: UV 254 nm. This gave 37.9 mg (25%) of 121-2 as a white solid. MS (ES, m / z): [M+H] + =487.25; 1 H NMR (400 MHz, MeOH-d 4, ppm):δ 0.72(s,3H),0.86(s,3H),0.97-1.12(m,2H),1.14-1.33(m,11H),1.37-1.65(m,10H),1. 67-1.79(m,2H),1.80-2.03(m,4H),2.10-2.27(m,2H),2.51(s,1H),2.73(dt,J=13.5,3.6 Hz,1H),3.29-3.32(m,1H),3.56(d,J=11.0 Hz,1H),3.64(dd,J=11.8,4.7 Hz,1H),5.60(s,1H).

[0145] Example 4 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylic acid (122-3) [ka] Synthesis of benzyl (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-formyl-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (122-1) A mixture of 121-1 (300 mg, 0.52 mmol, 1 equiv.) in DCM (25 mL), pH 8.6 phosphate buffer (5 mL), TEMPO (240 mg, 1.54 mmol, 3 equiv.), tetrabutylammonium chloride (0.36 g, 2.5 equiv.), and N-chlorosuccinimide (280 mg, 2.10 mmol, 4 equiv.) was stirred at 40 °C overnight. The reaction was extracted with DCM (200 mL). The extract was washed with water (1 × 200 mL) and brine (1 × 200 mL), dried (NaSO), and concentrated. This afforded 0.4 g (134%, crude) of 122-1 as a yellow semisolid.

[0146] Synthesis of (3S,4S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-3-hydroxy-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicene-4-carboxylic acid (122-2) A mixture of 122-1 (400 mg, 0.70 mmol, 1 equiv.), 2-methylbut-2-ene (2 mL), monobasic sodium phosphate (0.5 g, 6.00 equiv.), and sodium chlorite (0.38 g, 6.00 equiv.) in water (6 mL) and t-butanol (12 mL) was stirred at −2° C. for 30 min. The reaction was partially concentrated in vacuo, and the residue was extracted with DCM (200 mL). The extract was washed with brine (1×200 mL), dried (NaSO), and concentrated in vacuo. This afforded 0.758 g (184%, crude) of 122-2 as a yellow semisolid.

[0147] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylic acid (122-3) 122-2 (225 mg, 0.38 mmol) and Pd / C (45 mg) in EtOAc (16 mL) were placed under a hydrogen atmosphere (1 atm) and stirred overnight at room temperature. The reaction was filtered and concentrated in vacuo. The residue was purified by preparative HPLC with the following conditions: column: XBridge Shield RP18 OBD, 5 μm, 19*150 mm, mobile phase: water (0.05% TFA) and MeCN (38.0% MeCN to 55.0% in 8 min), detector: UV 254 nm. This afforded 18.5 mg (10%) of 122-3 as a white solid. MS (ES, m / z): [M+H] + =501.20; 1 H NMR(400 MHz,MeOH-d4,ppm):δ 0.85(s,3H),1.01-1.31(m,16H),1.44(d,J=13.4 Hz,7H),1.54(d,J=10.8 Hz,1H),1.59-1.81(m,5H),1.81-2.01(m,3H),2.10-2.28(m,2H),2.54(s,1H),2.79(dt,J=13.7,3.6 Hz,1H),3.99(dd,J=11.8,4.7 Hz,1H),5.62(s,1H).

[0148] Example 5 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (176-2) [ka] Synthesis of 2-benzyl 10-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,10-dicarboxylate (176-1) A mixture of 1-6 (400 mg, 0.68 mmol, 1 equiv.), potassium iodide (56 mg, 0.5 equiv.), 4-(chloromethyl)-5-methyl-2H-1,3-dioxol-2-one (182 mg, 1.23 mmol, 1.8 equiv.), and potassium carbonate (282 mg, 2.04 mmol, 3 equiv.) in DMF (2.5 mL) was stirred at 60 °C for 2 h. The reaction was diluted with EtOAc, washed with water and brine, dried (Na SO ), and concentrated in vacuo. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:3). This afforded 460 mg (97%) of 176-1 as a pale yellow solid.

[0149] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (176-2) 176-1 (70 mg) and Pd(OH)2 / C (5.6 mg) in THF (5 mL) were placed under a hydrogen atmosphere (1 atm) and stirred at room temperature for 13 hours. The reaction was filtered and concentrated. The residue was purified by preparative HPLC with the following conditions: column: XBridge Shield RP18 OBD, 5 μm, 19*150 mm, mobile phase: water (0.05% TFA) and MeCN (68% B phase to 77% in 10 min), detector: UV. This gave 13.2 mg (21.64%) of 176-2 as a white solid. MS (ES, m / z): [M+H] += 611.45; 1 H NMR(400 MHz,MeOH-d4)δ 0.88(d,J=13.9 Hz,6H),0.90-0.93(m,1H),0.95-1.09(m,5H),1.10-1.24(m,9H),1.25-1.30(m,1H),1.31- 1.55(m,9H),1.63-1.80(m,3H),1.81-2.06(m,4H),2.09-2.22(m,5H),2.29(dd,J=13.2,3.2 Hz,1H),2.50(s,1H),2.76(d,J=13.6 Hz,1H),4.89-4.99(m,2H),5.57(s,1H).

[0150] Example 6 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(((5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (178-1) [ka] 176-1 (110 mg) and Pd(OH)2 / C (11 mg) in THF (10 mL) and EtOH (10 mL) were stirred at room temperature for 1 hour. The reaction was filtered and concentrated. The residue was purified by preparative HPLC with the following conditions: column: XBridge Shield RP18 OBD, 5 μm, 19*150 mm, mobile phase: water (0.05% TFA) and MeCN (5% B phase ~ 84% in 1 min, up to 93% in 7 min), detector: UV. This gave 26.4 mg of 178-1 as a white solid. MS (ES, m / z): [M+H] += 613.40; 1 H NMR(400 MHz,MeOH-d4)δ 0.83(s,3H),0.85-0.91(m,4H),0.97-1.09(m,5H),1.13-1.16(m,3H),1.18-1.19(m,5H),1.21 -1.31(m,2H),1.38-1.58(m,12H),1.63-1.78(m,3H),1.79-2.08(m,4H),2.16(qd,J=12.8,4.4 Hz,2H),2.28(dt,J=13.2,4.4 Hz,1H),2.51(s,1H),2.77(d,J=13.2 Hz,1H),4.19-4.32(m,1H),4.36-4.50(m,1H),4.91-4.99(m,1H),5.00-5.09(m,1H),5.57(s,1H).

[0151] Example 7 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxatetradecane-14-oyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylic acid (190-3) [ka] Synthesis of (3S,4S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-4-formyl-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl 2,5,8,11-tetraoxatetradecane-14-oate (190-1) EDCI (250 mg, 1.30 mmol, 2.5 equiv) was added to 122-1 (300 mg, 0.52 mmol, 1 equiv), 2,5,8,11-tetraoxatetradecanoic-14-oic acid (370 mg, 1.57 mmol, 3 equiv), and DMAP (130 mg, 1.06 mmol, 2 equiv) in DCM (20 mL). The reaction was stirred at room temperature for 3 h and then concentrated in vacuo. The residue was purified by silica gel column eluting with EtOAc / hexane (2:1). This afforded 0.2 g (48%) of 190-1 as a yellow semi-solid.

[0152] Synthesis of (3S,4S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-3-((2,5,8,11-tetraoxatetradecane-14-oyl)oxy)-11-((benzyloxy)carbonyl)-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicene-4-carboxylic acid (190-2) A mixture of 190-1 (200 mg, 0.25 mmol, 1 equiv.), 2-methylprop-1-ene (2 mL), sodium dihydrogen phosphate (0.18 g, 6.00 equiv.), and sodium chlorite (0.14 g, 6.00 equiv.) in t-butanol (9 mL) and water (3 mL) was stirred at room temperature for 2 h. The reaction was concentrated in vacuo, diluted with DCM, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. This afforded 0.2 g (98%) of 190-2 as a yellow solid.

[0153] Example 8 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(2-(methylthio)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (194-10) [ka] Synthesis of benzhydryl (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (194-1) In a 2 L round-bottom flask, 76-1 (prepared as described in Bioorg. Med. Chem. 2010, 18, 433-454) (105 g, 165 mmol, 1 equiv.), CHCl 2( 800 mL), and Dess-Martin periodinane (139.8 g, 330 mmol, 2 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of 300 mL of sodium bicarbonate. The reaction mixture was washed with 3×1 L of HO. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was recrystallized from petroleum ether and CHCl to give 194-1 (100 g, 96%) as a white solid.

[0154] Synthesis of benzhydryl (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR,E)-10-(hydroxyimino)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (194-2) A 2 L round-bottom flask was charged with 194-1 (59.5 g, 93.7 mmol, 1 equiv.), pyridine (1 L), and NHOH·HCl (23.2 g, 335 mmol, 3.6 equiv.). The reaction slurry was stirred at 70 °C for 1 h. The reaction mixture was concentrated in vacuo, diluted with 2 L of CHCl, and washed with 4 × 1 L of 3 N HCl and 1 L of brine. The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was recrystallized from CHCl / petroleum ether to give 194-2 (55.1 g, 90%) as a white solid. MS (ES, m / z): [M+1] + =650.15; 1 H NMR(300 MHz,chloroform-d)δ 7.58-7.21(m,10H),6.96(s,1H),5.55(s,1H),5.32(s,1H),3.09(ddd,J=15.5,5.1,3.6 Hz,1H),2.90(ddd,J=13.3,5.7,3.6 Hz,1H),2.41-2.21(m,2H),2.12-1.96(m,4H),1.92-1.76(m,1H),1.65(q,J=18.6,16.7 Hz,3H),1.56-1.25(m,11H),1.24-0.92(m,16H),0.70(s,3H).

[0155] Synthesis of benzhydryl (2S,4aS,6aS,6bR,8aR,9S,12aS,12bR,14bR,E)-10-(acetoxyimino)-9-(acetoxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (194-3) A 2 L round-bottom flask was charged with 194-2 (53.4 g, 82.2 mmol, 1 equiv), AcOH (400 mL), AcO (400 mL), Pd(OAc) (3.3 g, 14.8 mmol, 0.18 equiv), and PhI(OAc) (31.8 g, 98.6 mmol, 1.2 equiv). The reaction slurry was stirred at 60 °C overnight. The reaction mixture was concentrated, diluted in CHCl, and washed with saturated NaHCO. 3(水性)The residue was purified by silica gel column chromatography eluting with 0-40% EtOAc in petroleum ether to give 194-3 (31.3 g, 51%) as a pale yellow solid (a mixture of isomers, ca. 6:1 C-23:C-24 acetate).

[0156] Synthesis of benzhydryl (2S,4aS,6aS,6bR,8aR,9R,12aS,12bR,14bR)-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (194-4) A 1000 mL round-bottom flask was charged with diphenylmethyl 194-3 (15 g, 20 mmol), THF (90 mL), MeOH (90 mL), acetone (90 mL), and 2 N HCl (90 mL). The reaction slurry was stirred at 50 °C overnight. The reaction mixture was concentrated, diluted with CHCl, and washed with 2 × 300 mL of saturated NaHCO and 2 × 300 mL of brine. The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The solid was dried in an oven under reduced pressure. The residue was applied to a silica gel column with CHCl / ethyl acetate (4:1) to give 9 g (69%) of 194-4 as a yellow solid (single C-23 OH isomer).

[0157] Synthesis of benzhydryl (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (194-5) To a stirred slurry of 194-4 (10 g, 15.4 mmol) in methanol (200 mL) was added NaBH (0.6 g, 17 mmol, 1.1 equiv) in portions at −10° C. The reaction slurry was stirred at room temperature for 1 h. Upon completion, the reaction was quenched with ice-water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was applied to a silica gel column with ethyl acetate in petroleum ether (0% to 60% in 30 min) to give 8.4 g (84%) of 194-5 as a white foam (single C-3-beta isomer).

[0158] Synthesis of benzhydryl (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-formyl-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (194-6) A 250 mL round-bottom flask was charged with 194-5 (4 g, 6.13 mmol), CHCl (40 mL), pH 8.6 buffer (20 mL), TEMPO (2.87 g, 18.4 mmol, 3 equiv.), TBACl (4.26 g), and NCS (3.2 g, 24 mmol, 3.9 equiv.). The resulting solution was stirred at 40 °C for 1.5 h. The reaction mixture was cooled and extracted with 3 × 50 mL of CHCl. ​​The combined organic layers were washed with 2 × 100 mL of brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was applied to a silica gel column with ethyl acetate (0–60%) in petroleum ether to give 3.8 g (95%) of 194-6 as a white solid.

[0159] Synthesis of (3S,4S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzhydryloxy)carbonyl)-3-hydroxy-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicene-4-carboxylic acid (194-7) To a stirred solution of 194-6 (4 g, 6.2 mmol) and 2-methylbut-2-ene (6.6 mL) in water (8.9 mL) and t-BuOH (26.6 mL), NaHPO (4.4 g, 36.87 mmol, 6 equiv) was added at 0 °C. To the above mixture, NaClO (3.3 g, 37 mmol, 6 equiv) was added in portions at 0 °C. The reaction slurry was stirred at room temperature for 2 h. The reaction mixture was extracted with CHCl, and the combined organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated to give 4 g of crude product 194-7 as a pale yellow solid, which was used directly in the next step without further purification.

[0160] Synthesis of (3S,4S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzhydryloxy)carbonyl)-3-hydroxy-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicene-4-carboxylic acid (194-8) A solution of 194-7 (6.0 g, 9 mmol), K2CO3 (3.7 g, 27 mmol, 3 equiv.), and KI (0.75 g, 4.5 mmol, 0.5 equiv.) in DMF was stirred at 60 °C for 2 h. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 2:1 petroleum ether / EtOAc to give 194-8 (6.0 g, 86%) as a pale yellow solid. MS (ES, m / z): [M+1] + =779.00; 1H NMR(400 MHz,chloroform-d)δ 7.50-7.29(m,10H),6.95(s,1H),5.54(s,1H),5.04(d,J=13.8 Hz,1H),4.80(d,J=13.9 Hz,1H),4.44(s,2H),4.03(dd,J=9.9,6.5 Hz,1H),2.98(s,1H),2.88(d,J=19.4 Hz,2H),2.79(s,4H),2.40(s,1H),2.22(d,J=6.6 Hz,6H),2.14-1.93(m,4H),1.70(dddd,J=37.5,31.0,16.9,7.4 Hz,8H),1.48(d,J=10.1 Hz,1H),1.41-1.32(m,6H),1.27(dd,J=14.6,3.4 Hz,1H),1.24-1.10(m,11H),1.08(s,3H),1.04-0.94(m,1H),0.88(d,J=8.8 Hz,1H),0.67(s,3H).

[0161] Synthesis of 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-(2-(methylthio)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (194-9) EDCI (250 mg, 1.30 mmol, 5 equiv) was added to 194-8 (200 mg, 0.26 mmol, 1 equiv), 2-(methylsulfanyl)acetic acid (270 mg, 2.54 mmol, 10 equiv), and DMAP (120 mg, 0.98 mmol, 4 equiv) in CHCl (4 mL). The reaction was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography with 1:1 EtOAc:petroleum ether to give 240 mg (quantitative) of 194-9 as a pale yellow solid.

[0162] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(2-(methylthio)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (194-10) 194-9 (130 mg, 0.15 mmol, 1 equiv.) and TFA (0.2 mL) in CHCl (2 mL) were stirred at room temperature for 1 h. The reaction was concentrated in vacuo, and the residue was purified by preparative HPLC with the following conditions: column: XBridge Shield RP18 OBD, 30*150 mm, 5 μm; mobile phase: water (0.05% TFA) and MeCN (65% B phase to 75% in 8 min); detector: UV. This afforded 24.8 mg (24%) of 194-10 as an off-white solid. MS (ES, m / z): [M+H] += 701.10; 1 H-NMR(300 MHz,MeOH-d4)δ 5.62(s,1H),5.22(dd,J=11.3,5.3 Hz,1H),5.04(d,J=13.9 Hz,1H),4.91(s,1H),3.15(s,2H),2.85(d,J=13.7 Hz,1H),2.59(s,1H),2.19(d,J=8.2 Hz,8H),2.04-1.62(m,9H),1.45(d,J=13.6 Hz,7H),1.35-1.12(m,14H),1.02(dd,J=29.5,10.7 Hz,2H),0.85(s,3H).

[0163] Example 9 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(2-(methylsulfonyl)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (195-2) [ka] Synthesis of 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-(2-(methylsulfonyl)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (195-1) EDCI (175 mg, 0.91 mmol, 5 equiv.) in CHCl 2( To a solution of 194-8 (140 mg, 0.18 mmol, 1 equiv.), 2-methanesulfonylacetic acid (248 mg, 1.80 mmol, 10 equiv.), and DMAP (84 mg, 0.69 mmol, 4 equiv.) in 2.5 mL of HCl was added, and the reaction was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography with EtOAc / petroleum ether (1 / 1). This afforded 160 mg (99%) of 195-1 as a pale yellow solid.

[0164] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(2-(methylsulfonyl)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (195-2) A mixture of 195-1 (100 mg, 0.11 mmol, 1 equiv.) and TFA (0.1 mL, 0.01 equiv.) in DCM was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC with the following conditions: column: XBridge Shield RP18 OBD, 5 μm, 19*150 mm, mobile phase: water (0.05% TFA) and MeCN (50% B phase to 63% in 13 min), detector: UV. This gave 195-2 (35.1 mg, 43.06%) as a pale yellow solid. MS (ES, m / z): [M+H] += 732.95; 1 H NMR(300 MHz,MeOH-d4)δ 5.63(s,1H),5.39-5.26(m,1H),5.05(d,J=13.9 Hz,1H),4.21(s,2H),3.14(d,J=1.0 Hz,3H),2.87(d,J=14.0 Hz,1H),2.60(s,1H),2.21(s,5H),1.85(s,6H),1.77(d,J=13.2 Hz,1H),1.70(d,J=16.6 Hz,2H),1.46(d,J=13.0 Hz,7H),1.30(s,4H),1.25-1.13(m,10H),1.00(s,1H),0.86(s,3H).

[0165] Example 10 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((L-valyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (196-2) [ka] Synthesis of 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((tert-butoxycarbonyl)-L-valyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (196-1) EDCI (172.3 mg, 0.90 mmol, 5 equiv) was added to 194-8 (140 mg, 0.18 mmol, 1 equiv), (2S)-2-[[(tert-butoxy)carbonyl]amino]-3-methylbutanoic acid (195.2 mg, 0.90 mmol, 5 equiv), and DMAP (87.8 mg, 0.72 mmol, 4 equiv) in DCM. The reaction was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / EtOAc 1:1) to give 196-1 (170 mg, 96.70%) as a pale yellow solid.

[0166] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((L-valyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (196-2) 196-1 (170 mg, 0.17 mmol, 1 equiv.) and TFA (0.15 mL, 2.02 mmol, 12 equiv.) in DCM were stirred at room temperature for 1 h and then concentrated in vacuo. The crude product was purified by preparative HPLC with the following conditions: column: Xselect CSH OBD, 30*150 mm, 5 μm; mobile phase A: water (0.05% TFA); mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 37% B to 65% B in 8 min; detector UV 254 nm) to give 196-2 (51.5 mg, 41.63%) as an off-white solid. MS (ES, m / z): [M+H] += 712.45; 1 H NMR(400 MHz,MeOH-d4)δ 5.63(s,1H),5.43-5.34(m,1H),5.11(d,J=14.0 Hz,1H),4.84(d,J=14.0 Hz,1H),3.92(d,J=4.2 Hz,1H),2.87(d,J=13.6 Hz,1H),2.59(s,1H),2.27-2.12(m,2H),2.21(s,4H),1.98(d,J=10.0 Hz,1H),1.87(d,J=9.7 Hz,4H),1.80-1.60(m,4H),1.44(d,J=16.3 Hz,6H),1.25(d,J=31.4 Hz,7H),1.20(s,3H),1.16(s,3H),1.09(s,1H),1.03(dd,J=7.0,2.9 Hz,5H),0.99-0.92(m,1H),0.85(s,3H).

[0167] Example 12 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(benzoyloxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (197-2) [ka] Synthesis of 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(benzoyloxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (197-1) EDCI (175 mg, 0.91 mmol, 5 equiv) was added to 194-8 (140 mg, 0.18 mmol, 1 equiv), benzoic acid (110 mg, 0.90 mmol, 5 equiv), and DMAP (84 mg, 0.69 mmol, 4 equiv) in DCM (2.5 mL). The reaction was stirred overnight at room temperature and then concentrated in vacuo. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:1). This afforded 160 mg (101%) of 197-1 as a pale yellow solid.

[0168] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(benzoyloxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (197-2) 197-1 (160 mg, 0.18 mmol, 1 equiv.) and TFA (0.2 mL, 2.69 mmol, 15 equiv.) in DCM were stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo, and the residue was purified by preparative TLC with the following conditions: column: Xselect CSH OBD, 30*150 mm, 5 μm; mobile phase A: water (0.05% TFA); mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 37% B to 65% B in 8 min; detector: UV 254 nm) to give 197-2 (27.8 mg, 21.40%) as an off-white solid. MS (ES, m / z): [M+H] += 717.00; 1 H NMR(300 MHz,MeOH-d4)δ 8.02-7.88(m,2H),7.63(t,J=7.4 Hz,1H),7.49(t,J=7.6 Hz,2H),5.65(s,1H),5.41(dd,J=11.5,5.1 Hz,1H),4.95(s,2H),2.91(d,J=13.9 Hz,1H),2.65(s,1H),2.25(d,J=14.8 Hz,2H),1.97(s,8H),1.85-1.68(m,4H),1.51(s,3H),1.43(d,J=7.6 Hz,7H),1.34(d,J=12.3 Hz,2H),1.27(s,3H),1.20(d,J=6.8 Hz,6H),1.06(t,J=13.9 Hz,2H),0.87(s,3H).

[0169] Example 13 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopropanecarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (198-2) [ka] Synthesis of 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopropanecarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (198-1) EDCI (250 mg, 1.30 mmol, 5 equiv.) was added to 194-8 (200 mg, 0.26 mmol, 1 equiv.), cyclopropanecarboxylic acid (220 mg, 2.56 mmol, 10 equiv.), and DMAP (120 mg, 0.98 mmol, 4 equiv.) in DCM (4 mL), and the reaction was stirred at room temperature overnight. The mixture was concentrated in vacuo, and the residue was purified by silica gel column eluting with EtOAc / petroleum ether (1 / 1). This afforded 230 mg (106%) of 198-1 as a pale yellow solid.

[0170] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopropanecarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (198-2) 198-1 (115 mg, 0.14 mmol, 1 equiv.) and TFA (0.15 mL) in DCM (1.5 mL) were stirred at room temperature for 1 h. The reaction was concentrated in vacuo, and the residue (115 mg) was purified by preparative HPLC with the following conditions: Column: Xselect CSH OBD, 30*150 mm, 5 μm, Mobile Phase A: Water (0.05% TFA), Mobile Phase B: MeCN, Flow Rate: 60 mL / min, Gradient: 30% B to 60% B in 8 min, Detector: 254 nm. This afforded 26.9 mg (29%) of 198-2 as an off-white solid. MS (ES, m / z): [M+H] += 681.20; 1 H NMR(300 MHz,MeOH-d4)δ 5.62(s,1H),5.14(dd,J=11.5,5.1 Hz,1H),5.02(d,J=13.9 Hz,1H),4.93(s,1H),2.83(d,J=13.6 Hz,1H),2.58(s,1H),2.20(s,5H),2.01-1.58(m,8H),1.57-1.33(m,10H),1.33-1.13(m,10H),1.07(d,J=12.8 Hz,3H),0.95(s,2H),0.87(d,J=13.2 Hz,6H).

[0171] Example 14 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((R)-2-methoxypropanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (203-2) [ka] Synthesis of 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((R)-2-methoxypropanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (203-1) EDCI (240 mg, 1 mmol, 5 equiv.) was added to 194-8 (200 mg, 0.2 mmol, 1 equiv.), (2R)-2-methoxypropanoic acid (132 mg, 1 mmol, 5 equiv.), and DMAP (132 mg, 0.8 mmol, 4 equiv.) in DCM (2 mL), and the reaction was stirred at room temperature for 2 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography with EtOAc / petroleum ether (1 / 1). This afforded 150 mg of 203-1 as a pale yellow solid.

[0172] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((R)-2-methoxypropanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (203-2) 203-1 (150 mg, 0.17 mmol, 1 equiv) and TFA (0.2 mL) in DCM (2 mL) were stirred at room temperature for 2 h. The resulting mixture was concentrated, and the residue was purified by flash preparative HPLC to give 47.5 mg (39.20%) of 203-1 as a white solid. MS (ES, m / z): [M+H] += 699; 1H NMR(300 MHz,chloroform-d)δ 5.72(s,1H),5.25(dd,J=11.6,5.0 Hz,1H),4.99(d,J=13.7 Hz,1H),4.69(d,J=13.8 Hz,1H),3.79(q,J=6.8 Hz,1H),3.34(s,3H),2.89(d,J=13.7 Hz,1H),2.44(s,1H),2.19(s,4H),1.99(s,7H),1.79(s,10H),1.42-1.30(m,14H),1.27-1.15(m,1H),0.82(s,4H).

[0173] Example 15 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((S)-2-methoxypropanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (204-2) [ka] Synthesis of 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((S)-2-methoxypropanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (204-1) EDCI (240 mg, 1.2 mmol, 5 equiv.) was added to 194-8 (200 mg, 0.2 mmol, 1 equiv.), (2S)-2-methoxypropanoic acid (132 mg, 1.2 mmol, 5 equiv.), and DMAP (120 mg, 0.8 mmol, 4 equiv.) in DCM (2 mL), and the reaction was stirred at 25 °C for 3 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography with EtOAc / petroleum ether (1 / 1). This afforded 150 mg of 204-1 as a pale yellow solid.

[0174] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((S)-2-methoxypropanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (204-2) 204-1 (150 mg, 0.17 mmol, 1 equiv.) and TFA (0.2 mL, 0.01 equiv.) in DCM (2 mL) were stirred at 25° C. for 2 h. The reaction was concentrated, and the crude product was purified by preparative HPLC with the following conditions: column: Xselect CSH OBD, 30*150 mm, 5 μm; mobile phase: water (0.05% TFA) and MeCN (57% B phase to 85% in 8 min); detector: UV. This gave 204-2 as a white solid. MS (ES, m / z): [M+H] += 699; 1H NMR(300 MHz,chloroform-d)δ 5.72(s,1H),5.26(dd,J=11.6,4.9 Hz,1H),4.98(d,J=13.7 Hz,1H),4.68(d,J=13.8 Hz,1H),3.79(t,J=6.9 Hz,1H),3.36(s,3H),2.89(d,J=13.8 Hz,1H),2.45(s,1H),2.19(s,4H),2.00(s,3H),1.87-1.71(m,7H),1.39(s,6H),1.33(d,J=6.9 Hz,4H),1.27-1.15(m,12H),1.11(s,3H),1.04(d,J=12.6 Hz,1H),0.82(s,4H).

[0175] Example 16 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(methoxymethoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (205-2) [ka] Synthesis of 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(methoxymethoxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (205-1) Bromo(methoxy)methane (0.063 mL, 4.0 equiv.) was added dropwise to 194-8 (150 mg, 1 equiv.) and DIEA (0.318 mL, 10.0 equiv.) in DCM (10 mL) at 0° C., then heated at 60° C. for 1 h. The reaction was concentrated, and the residue was purified by silica gel column chromatography with EtOAc / petroleum ether (1:1). This afforded 178.1 mg (112.38%) of 205-1 as a crude white solid.

[0176] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(methoxymethoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (205-2) 205-1 (178.1 mg) and 10% TFA / DCM (10 mL) were stirred at room temperature for 5 hours. The reaction mixture was washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC with the following conditions: column: Xselect CSH OBD, 30*150 mm, 5 μm, mobile phase: water (0.05% TFA) and CH3CN (58% B phase to 76% in 8 min), detector: UV. This gave 40.0 mg (28%) of 205-2 as a white solid. MS (ES, m / z): [M+H] += 657.25; 1H NMR(400 MHz,chloroform-d)δ 0.85(s,4H),1.01-1.15(m,5H),1.20(d,J=12.0 Hz,6H),1.26(s,4H),1.33-1.58(m,8H),1.59-1.61(m,1H),1.65-1.70(m,2H),1.72-1.9 1(m,2H),1.92-2.17(m,4H),2.18-2.20(m,1H),2.22(s,3H),2.43(s,1H),2.87(d,J=14.0 Hz,1H),3.29(s,3H),3.97(dd,J=11.6,4.4 Hz,1H),4.52(d,J=6.8 Hz,1H),4.66(d,J=7.2 Hz,1H),4.75(d,J=13.6 Hz,1H),5.06(d,J=13.6 Hz,1H),5.74(s,1H).

[0177] Example 17 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((ethylcarbamoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (206-2) [ka] Synthesis of 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((ethylcarbamoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (206-1) Isocyanatoethane (0.061 mL, 3 equiv.), chlorotrimethylsilane (0.111 mL, 5 equiv.), and 194-8 (200 mg, 0.26 mmol) in CHCl (10 mL) were stirred overnight at room temperature. The reaction was concentrated in vacuo, and the residue was purified by silica gel column chromatography with EtOAc / petroleum ether (1:1). This afforded 239.9 mg (quantitative) of 206-1 as a crude white solid.

[0178] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((ethylcarbamoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (206-2) 206-1 (239.9 mg) and 10% TFA / CHCl (10 mL) were stirred at room temperature for 1 hour. The reaction was concentrated, and the residue was purified by preparative HPLC with the following conditions: column: Xselect CSH OBD, 30*150 mm, 5 μm; mobile phase: water (0.05% TFA) and MeCN (57% B phase to 77% in 8 min); detector: UV. This gave 65.7 mg (34%) of 206-2 as a white solid. MS (ES, m / z): [M+H] += 684.05; 1 H NMR(400 MHz,MeOH-d4)δ 0.82(s,3H),0.89-0.99(m,1H),1.01-1.04(m,1H),1.09(t,J=7.2 Hz,3H),1.13(s,3H),1.17-1.28(m,11H),1.33-1.48(m,7H),1.61-1.79(m,6H),1.81-1.90(m,2H),1.95(d,J=10.0 Hz,1H),2.11-2.28(m,5H),2.55(s,1H),2.79(d,J=14.0 Hz,1H),2.98-3.17(m,2H),4.89(d,J=14.0 Hz,1H),4.95-5.05(m,2H),5.59(s,1H).

[0179] Example 18 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((butylcarbamoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (207-2) [ka] Synthesis of 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((butylcarbamoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (207-1) 1-Isocyanatobutane (0.0868 mL, 3 equiv.), TMSCl (0.111 mL, 5 equiv.), and 194-8 (200 mg, 0.26 mmol, 1 equiv.) in CHCl (10 mL) were stirred at room temperature overnight. The reaction was concentrated in vacuo, and the residue was purified by silica gel column chromatography with EtOAc / petroleum ether (1:1). This afforded 256.9 mg (114%) of 207-1 as a crude white solid.

[0180] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((butylcarbamoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (207-2) 207-1 (256.9 mg) and 10% TFA / CHCl (10 mL) were stirred at room temperature for 1 hour. The reaction was concentrated under vacuum, and the crude product was purified by preparative HPLC with the following conditions: column: XBridge Shield RP18 OBD, 5 μm, 19*150 mm; mobile phase: water (0.05% TFA) and MeCN (71% B phase to 72% in 8 min); detector: UV. This gave 28.8 mg (14%) of 207-2 as an off-white solid. MS (ES, m / z): [M+H] += 712.05; 1 H NMR(400 MHz,MeOH-d4)δ 0.85(s,3H),0.94(t,J=7.4 Hz,4H),1.07(d,J=13.6 Hz,1H),1.12-1.30(m,14H),1.31-1.59(m,11H),1.63-1.82(m,6H),1.83-1. 93(m,2H),1.96-2.08(m,1H),2.09-2.32(m,5H),2.57(s,1H),2.81(d,J=14.0 Hz,1H),2.97-3.14(m,2H),4.90(d,J=13.6 Hz,1H),4.97-5.11(m,2H),5.62(s,1H).

[0181] Example 19 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-((pyrrolidine-1-carbonyl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (208-2) [ka] Synthesis of 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-10-((pyrrolidine-1-carbonyl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (208-1) 194-8 (400 mg), pyrrolidine-1-carbonyl chloride (0.17 mL, 3 equiv.), and DMAP (62.7 mg, 1 equiv.) in pyridine (10 mL) were stirred at 90° C. for 9 days. The reaction mixture was concentrated, and the residue was dissolved in EtOAc. The solution was washed with 1 M HCl (3×50 mL) and brine (1×50 mL), dried over anhydrous NaSO, and concentrated to give 170 mg (38%) of 208-1 as a white solid.

[0182] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-((pyrrolidine-1-carbonyl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (208-2) 208-1 (170 mg, 1 equiv.) and 10% TFA / CHCl (10 mL) were stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was purified by preparative HPLC with the following conditions: column: Xselect CSH OBD, 30*150 mm, 5 μm; mobile phase: water (0.05% TFA) and CHCN (68% B phase to 80% in 8 min); detector: UV. This gave 9.5 mg (6.5%) of 208-2 as a white solid. MS (ES, m / z): [M+H] += 710.20; 1 H NMR(400 MHz,MeOH-d4)δ 0.83(s,3H),0.94-0.99(m,1H),1.04(d,J=13.6 Hz,1H),1.15(s,3H),1.18(s,6H),1.21-1.27(m,6H),1.29-1.36(m,2H),1.38-1.41(m ,3H),1.44(s,3H),1.57-1.61(m,1H),1.63-1.79(m,6H),1.87(s,6H),1.95(d,J=10.0 Hz,1H),2.10-2.15(m,5H),2.56(s,1H),2.80(d,J=14.0 Hz,1H),3.13-3.24(m,1H),3.29(s,3H),4.90-5.04(m,3H),5.60(s,1H).

[0183] Example 20 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (209-3) [ka] Synthesis of 2-benzhydryl 9-((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (209-1) 4-(Bromomethyl)-5-isopropyl-1,3-dioxol-2-one was prepared according to a literature procedure (Sun et al., Tetrahedron Letters, 2002, 43, 1161-1164). A mixture of 4-(bromomethyl)-5-isopropyl-1,3-dioxol-2-one (2.7 g, 1.5 equiv.), K2CO3 (3.4 g, 3 equiv.), KI (0.68 g, 0.5 equiv.), and 194-7 (5.5 g, 1 equiv.) in DMF (80 mL) was stirred at 60 °C for 1 h. The reaction mixture was cooled to room temperature and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 3:1 petroleum ether:EtOAc to give 209-1 (5.5 g, 83%) as a pale yellow solid. MS(ES, m / z):[M+1] + =806.95; 1 H NMR(400 MHz,chloroform-d)δ 7.48-7.28(m,10H),6.95(s,1H),5.54(s,1H),5.07(d,J=13.8 Hz,1H),4.83(d,J=13.8 Hz,1H),4.10-3.93(m,1H),3.11-2.94(m,2H),2.94-2.82(m,2H),2.40(s,1H),2.17-1.93(m,5H),1.91-1.53(m,7H),1.48(d,J=10.6 Hz,2H),1.43-1.31(m,6H),1.31-1.22(m,8H),1.22-1.11(m,12H),1.08(s,3H),1.00(d,J=13.7 Hz,1H),0.90(t,J=10.1 Hz,1H),0.67(s,3H).

[0184] Synthesis of 2-benzhydryl 9-((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (209-2). In an 8 mL round-bottom flask, add 209-1 (100 mg, 0.12 mmol), CHCl 2( 2 mL), DMAP (29 mg, 0.24 mmol, 1.9 equiv), AcOH (21.2 mg, 0.35 mmol, 2.85 equiv), and then EDCI (57 mg, 0.3 mmol, 2.4 equiv) were added. The reaction slurry was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:1) to give 60 mg (57%) of 209-2 as a white solid.

[0185] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (209-3) A 25 mL round-bottom flask was charged with 209-2 (60 mg, 0.07 mmol), CHCl (5 mL), and TFA (0.5 mL, 6.7 mmol, 95 equiv). The reaction slurry was stirred at room temperature for 1 hour. The resulting mixture was concentrated, and the crude product was purified by preparative HPLC with the following conditions: column, XSelect CSH Prep C18 OBD, 5 μm, 19*150 mm; mobile phase, water (0.05% TFA) and CHCN (70% B phase to 90% in 8 min); detector, UV. This afforded 29.6 mg (61%) of 209-3 as a white solid. The product was tested in the assay described in Example 112 and had a pIC of 5.9. 50 demonstrated a pIC50 of 7.2 compared to the corresponding acid metabolite (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(acetyloxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylic acid. MS (ES, m / z): [M+1] + =683; 1 H NMR (300 MHz, methanol-d4)δ 0.85(s,3H),0.95(s,1H),1.07(d,J=13.8 Hz,1H),1.18(d,J=13.4 Hz,8H),1.22-1.34(m,9H),1.45(d,J=12.8 Hz,6H),1.65-1.83(m,5H),1.88(dd,J=12.1,4.9 Hz,1H),1.96(s,3H),2.09-2.29(m,2H),2.58(s,1H),2.83(d,J=13.7 Hz,1H),3.07(h,J=6.9 Hz,1H),4.89(d,J=13.9 Hz,1H),5.07(d,J=13.9 Hz,1H),5.16(dd,J=11.4,5.2 Hz,1H),5.62(s,1H).

[0186] Example 21 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-(propionyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (211-1) [ka] The title compound was prepared according to the method for compound 194-10, starting from 194-8 and propanoic acid. The crude product was purified by preparative HPLC with the following conditions: column, XSelect CSH OBD, 30*150 mm, 5 μm; mobile phase, water (0.05% TFA) and CH3CN (60% B phase to 85% in 8 min); detector, UV. 69.7 mg of 211-1 was obtained as a white solid. MS (ES, m / z): [M+1] + =669; 1 H NMR(300 MHz,chloroform-d)δ 5.72(s,1H),5.22-5.11(m,1H),4.96(d,J=13.8 Hz,1H),4.72(d,J=13.8 Hz,1H),2.86(d,J=13.9 Hz,1H),2.45(s,1H),2.32-2.16(m,6H),1.99(s,3H),1.79(s,5H),1.70(d,J=9.9 Hz,2H),1.39(s,4H),1.24(s,3H),1.19(d,J=9.0 Hz,12H),1.14-1.03(m,6H),0.83(s,4H).

[0187] Example 22 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopentanecarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (212-1) [ka] The title compound was prepared according to the method for compound 194-10, starting from 194-8 and cyclopentanoic acid. The crude product was purified by preparative HPLC with the following conditions: column, Kinetex EVO C18, 21.2*150, 5 μm; mobile phase, water (0.05% TFA) and CH3CN (70% B phase to 88% in 8 min); detector, UV. This gave 66.3 mg of 212-1 as a white solid. MS (ES, m / z): [M+1] + =709; 1 H NMR(300 MHz,chloroform-d)δ 5.72(s,1H),5.14(dd,J=10.5,6.3 Hz,1H),4.94(d,J=13.8 Hz,1H),4.71(d,J=13.8 Hz,1H),2.86(d,J=14.0 Hz,1H),2.64(q,J=8.0,7.5 Hz,1H),2.44(s,1H),2.18(s,4H),1.99(s,3H),1.82(d,J=8.5 Hz,14H),1.39(s,7H),1.27-1.14(m,13H),1.11(s,1H),1.03(d,J=12.7 Hz,1H),0.83(s,4H).

[0188] Example 23 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-((3-(piperidin-1-yl)propanoyl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (215-1) [ka] The title compound was prepared according to the method for compound 194-10, starting from 194-8 and 3-(piperidin-1-yl)propanoic acid. The crude product was purified by preparative HPLC with the following conditions: column, Xselect CSH OBD Column 30*150mm 5μm, n, mobile phase, water (0.05% TFA) and ACN (40% B phase to 53% in 8 min), detector, UV 254nm. This gave 35.2mg (33%) of 215-1 as a white solid. MS (ES, m / z): [M+1] + =752.43; 1 H NMR(300 MHz,chloroform-d)δ 11.9(s,1H),5.71(s,1H),5.16(s,1H),4.86(d,J=4.5 Hz,2H),3.56(s,3H),3.27(s,6H),2.88(d,J=17.7 Hz,3H),2.66(s,2H),2.20(s,5H),1.98(s,4H),1.88(d,J=14.0 Hz,5H),1.61(d,J=12.0 Hz,7H),1.39(d,J=6.4 Hz,9H),1.26-1.14(m,16H),1.12(s,2H),0.82(s,3H).

[0189] Example 24 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((isopropoxycarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (216-2) [ka] Synthesis of 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((isopropoxycarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (216-1) To an 8 mL sealed tube, 194-8 (200 mg, 0.26 mmol), pyridine (3 mL), DMAP (94.1 mg, 0.77 mmol, 3 equiv), and isopropyl chloroformate (315 mg, 2.6 mmol, 10 equiv) were added at room temperature. The reaction slurry was stirred at 60° C. for 6 hours under a nitrogen atmosphere. To the above mixture, an additional portion of isopropyl chloroformate (315 mg, 2.6 mmol, 10 equiv) was added at 60° C. The reaction slurry was stirred at 60° C. for an additional 6 hours. To the reaction mixture, a third portion of isopropyl chloroformate (315 mg, 2.6 mmol, 10 equiv) was added at 60° C. The reaction slurry was stirred at 60° C. for an additional 6 hours. The reaction mixture was concentrated under vacuum. The residue was purified by preparative TLC (PE / EtOAc 1:1) to give 216-1 (130 mg, 59%) as a pale yellow foam.

[0190] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((isopropoxycarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (216-2) A 25 mL round-bottom flask was charged with 216-1 (130 mg, 0.15 mmol, 1 equiv.), CHCl (2 mL), and TFA (0.2 mL). The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated. The crude product was purified by preparative HPLC with the following conditions: column, Xselect CSHOBD 30*150 mm, 5 μm; mobile phase, water (0.05% TFA) and CHCN (64% B phase to 87% in 8 minutes); detector, UV. This afforded 40.9 mg (39%) of 216-2 as a white solid. MS (ES, m / z): [M+1] + =698.37; 1 H NMR(400 MHz,chloroform-d)δ 7.38(dd,J=17.4,5.5 Hz,1H),5.75(s,1H),5.14-4.93(m,2H),4.87-4.75(m,2H),2.90(d,J=13.8 Hz,1H),2.45(s,1H),2.21(s,4H),2.11-1.90(m,4H),1.87-1.76(m,3H),1.65(dd,J=12.4,6.5 Hz,5H),1.57-1.32(m,9H),1.28(dd,J=6.3,3.4 Hz,7H),1.25(d,J=6.9 Hz,7H),1.19(d,J=5.5 Hz,5H),1.13(s,4H),1.10-1.00(m,2H),0.85(s,5H),0.09(s,3H).

[0191] Example 25 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,2-difluoroacetoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (223-1) [ka] The title compound was prepared according to the method for compound 194-10, starting from 194-8 and 2,2-difluoroacetic acid. The crude product was purified by preparative HPLC with the following conditions: column: Xselect CSH OBD 30*150 mm, 5 μm, mobile phase: water (0.05% TFA) and CHCN (68% B phase to 80% in 8 min), detector: UV. This gave 82.1 mg (46%) of 223-1 as a white solid. MS (ES, m / z): [M+H] += 691.15; 1 H NMR(400 MHz,MeOH-d4)δ 0.83(s,3H),0.97(d,J=7.6 Hz,1H),1.05(d,J=13.6 Hz,1H),1.14(s,3H),1.18(d,J=8.4 Hz,6H),1.22-1.31(m,5H),1.40(s,4H),1.45(s,3H),1.64-1.80(m,5H),1.82- 1.90(m,3H),1.92-2.00(m,1H),2.09-2.29(m,5H),2.57(s,1H),2.88(d,J=10.4 Hz,1H),4.88(d,J=14.0 Hz,1H),5.02(d,J=14.0 Hz,1H),5.33(dd,J=14.0,5.2 Hz,1H),5.61(s,1H),6.05(t,J=53.2 Hz,1H).

[0192] Example 26 (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-9-((2-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)-2-oxoethoxy)methyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (240-8) [ka] Synthesis of benzyl (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-9-((2-(tert-butoxy)-2-oxoethoxy)methyl)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (240-1) Sodium bis(trimethylsilyl)amide (0.5 mL, 2 equiv.) was added to 121-1 (355 mg, 0.62 mmol, 1 equiv.) and tert-butyl 2-bromoacetate (240.6 mg, 1.24 mmol, 2 equiv.) in DMF (5 mL). The reaction slurry was stirred overnight at room temperature, diluted with CHCl (100 mL), washed with brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:1) to give 300 mg (71%) of 240-1 as a white solid.

[0193] Synthesis of 2-(((3S,4R,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-3-hydroxy-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-4-yl)methoxy)acetic acid (240-2) 240-1 (300 mg, 0.43 mmol, 1 equiv) and TFA (1 mL) were mixed in CHCl (10 mL) at room temperature for 1 h. The reaction mixture was diluted with CHCl (100 mL), washed with brine (3 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated. This gave 270 mg (98%) of 240-2 as a yellow solid.

[0194] Synthesis of benzyl (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-9-((2-methoxy-2-oxoethoxy)methyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (240-3) (Trimethylsilyl)diazomethane (1 mL) was added dropwise to 240-2 (270 mg, 0.43 mmol, 1 equiv) in MeOH (5 mL) and CHCl (10 mL). The reaction slurry was stirred at room temperature for 2 h. The reaction mixture was concentrated to give 260 mg (94%) of 240-3 as a white solid.

[0195] Synthesis of (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-9-((2-methoxy-2-oxoethoxy)methyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (240-4) 240-3 (270 mg, 0.42 mmol) and Pd / C (20 mg, 10 wt%) in EtOAc (30 mL) were stirred under H (1 atm) for 2 h. The reaction mixture was filtered and concentrated to give 216 mg (93%) of 240-4 as a white solid.

[0196] Synthesis of benzhydryl (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-9-((2-methoxy-2-oxoethoxy)methyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (240-5) (Diazomethylene)dibenzene (180 mg) in MeOH (20 mL) was added to 240-4 (216 mg, 1 equiv.) in ether (10 mL). The reaction slurry was stirred at room temperature for 3 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:10) to give 220 mg (79%) of 240-5 as a white solid.

[0197] Synthesis of 2-(((3S,4R,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzhydryloxy)carbonyl)-3-hydroxy-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-4-yl)methoxy)acetic acid (240-6) 240-5 (220 mg, 0.30 mmol, 1 equiv) and lithium hydroxide (73 mg, 3 mmol, 10 equiv) were combined in THF (10 mL), HO (1 mL), and MeOH (1 mL) with stirring at room temperature for 2 h. The reaction mixture was adjusted to pH = 4 with 1 M HCl and extracted with CHCl (2 × 100 mL). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated to give 200 mg (93%) of 240-6 as a white solid.

[0198] Synthesis of benzhydryl (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-9-((2-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)-2-oxoethoxy)methyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (240-7) 240-6 (200 mg, 0.28 mmol, 1 equiv), 4-(chloromethyl)-5-methyl-2H-1,3-dioxol-2-one (84 mg, 0.57 mmol, 2 equiv), KCO (194 mg, 1.40 mmol, 5 equiv), and potassium iodide (70 mg, 0.42 mmol, 1.5 equiv) were combined in DMF (10 mL) and stirred at 50 °C for 1 h. The reaction mixture was diluted with CHCl (100 mL), washed with brine (3 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated to give 200 mg (86%) of 240-7 as a white solid.

[0199] Synthesis of (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-9-((2-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)-2-oxoethoxy)methyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (240-8) 240-7 (200 mg, 0.24 mmol, 1 equiv.) and TFA (1 mL) were combined in CHCl (10 mL) and stirred for 1 h. The solid was collected by filtration. The resulting mixture was concentrated, and the residue was purified by preparative HPLC with the following conditions: mobile phase: water (0.05% TFA) and CHCN (hold 5% B phase at 0 min, up to 63% at 1 min, up to 68% at 8 min), detector: UV. This gave 14.5 mg (9%) of 240-8 as a white solid. MS (ES, m / z): [M+H] += 657.25; 1 H NMR(400 MHz,chloroform-d)δ 0.72(s,3H),0.86(s,3H),1.03(t,J=15.2 Hz,2H),1.13-1.22(m,9H),1.22-1.37(m,2H),1.43(d,J=5.6 Hz,8H),1.66 -1.97(m,8H),2.21(s,5H),2.51(s,1H),2.73(d,J=13.6 Hz,1H),3.39(s,2H),3.72(dd,J=11.8,4.8 Hz,1H),4.09(d,J=16.8 Hz,1H),4.26(d,J=16.8 Hz,1H),4.92(s,1H),5.03(s,2H),5.60(s,1H).

[0200] Example 27 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (243-1) [ka] The title compound was prepared according to the method for compound 194-10, starting from 194-8 and acetic acid. The crude product was purified by preparative HPLC with the following conditions: column: XSelect CSH Prep C18 OBD, 5 μm, 19*150 mm; mobile phase: water (0.05% TFA) and CH3CN (hold 5% B phase at 0 min, up to 65% at 1 min, up to 85% at 8 min); detector: UV. This gave 24.7 mg (20%) of 243-1 as a white solid. MS (ES, m / z): [M+H] += 655.15;1H NMR (400 MHz, methanol-d4)δ 0.85(s,3H),0.96(d,J=5.6 Hz,1H),1.06(d,J=14.1 Hz,1H),1.16-1.29(m,14H),1.36-1.49(m,7H),1.63-1.80(m,6H),1.80-1.92(m,2H), 1.92-2.01(m,4H),2.08-2.08(m,5H),2.55(s,1H),2.78-2.86(m,1H),4.89(d,J=13.9 Hz,1H),5.03(d,J=14.0 Hz,1H),5.15(dd,J=11.7,4.9 Hz,1H),5.62(s,1H).

[0201] Example 28 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2-hydroxyacetoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (244-1) [ka] The title compound was prepared according to the method for compound 194-10, starting from 194-8 and 2-[(4-methoxyphenyl)methoxy]acetic acid. The crude product was purified by preparative HPLC with the following conditions: column: XBridge Prep C18 OBD, 19*150 mm, 5 μm, mobile phase: water (0.05% TFA) and CH3CN (35% B phase to 90% in 7 min), detector: UV. This gave 25.8 mg (28%) of 244-1 as a white solid. MS (ES, m / z): [M+H] += 671.35; 1 H NMR(400 MHz, methanol-d4)δ 0.85(s,3H),0.95(s,1H),1.06(d,J=14.0 Hz,1H),1.15(s,3H),1.17-1.27(m,10H),1.27(d,J=8.0 Hz,1H),1.33-1.524(m,7H),1.61-2.00(m,9H),2.20(s,5H),2.58(s,1H),2.80-2.88(m,1H),3.96-4.11(m,2H),4.87(d,J=13.9 Hz,1H),5.06(d,J=14.0 Hz,1H),5.26(dd,J=11.7,5.0 Hz,1H),5.62(s,1H).

[0202] Example 29 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2-methoxyacetoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (245-1) [ka] The title compound was prepared according to the method for compound 194-10, starting from 194-8 and 2-methoxyacetic acid. The crude product was purified by preparative HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD, 5 μm, 19*150 mm; Mobile phase: Water (0.05% TFA) and CH3CN (hold 5% B phase at 0 min, up to 62% at 1 min, up to 82% at 8 min); Detector: UV. This gave 25.9 mg (19%) of 245-1 as a white solid. MS (ES, m / z): [M+H] += 685.15; 1 H NMR(400 MHz, methanol-d4)δ 0.85(s,3H),1.06(d,J=14.1 Hz,1H),1.00-1.10(m,1H),1.10-1.30(m,14H),1.35-1.51(m,7H),1.61-2.08(m,9 H),2.09-2.28(m,5H),2.59(s,1H),2.80-2.88(m,1H),3.39(s,3H),3.97(d,J=1.3 Hz,2H),4.88(d,J=14.0 Hz,1H),5.05(d,J=13.9 Hz,1H),5.27(dd,J=11.8,5.0 Hz,1H),5.62(s,1H).

[0203] Example 30 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxadodecanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (246-3) [ka] Synthesis of 2-(2-(2-methoxyethoxy)ethoxy)ethyl(4-nitrophenyl)carbonate (246-1) 2-[2-(2-methoxyethoxy)ethoxy]ethan-1-ol (3.0 g, 18.3 mmol, 1 equiv.), p-nitrophenyl chloroformate (4.4 g, 20.4 mmol, 1.1 equiv.), and EtN (5 mL, 36 mmol, 2 equiv.) in CHCl (20 mL) were stirred at room temperature for 1 h. The reaction was concentrated, and the residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:1) to give 4.2 g (67%) of 246-1 as a clear liquid.

[0204] Synthesis of 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxadodecanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (246-2) 194-8 (150 mg, 0.19 mmol, 1 equiv), 246-1 (640 mg, 1.9 mmol, 10 equiv), and DMAP (94 mg, 0.77 mmol, 4 equiv) in THF (8 mL) were stirred at 50 °C for 24 h. The reaction mixture was diluted with CHCl (300 mL), washed with brine (3 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:1) to give 156 mg (84%) of 246-2 as a yellow oil.

[0205] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxadodecanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (246-3) 246-2 (156 mg, 0.16 mmol, 1 equiv.) and TFA (1 mL) in CHCl (10 mL) were stirred at room temperature for 1 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC with the following conditions: column, XBridge Prep C18 OBD, 19*150 mm, 5 μm, mobile phase: water (0.05% TFA) and CHCN (35% B phase to 90% in 7 min), detector: UV. This gave 21.5 mg (16%) of 246-3 as a white solid. MS (ES, m / z): [M+H] += 803.20; 1 H NMR(400 MHz, methanol-d4)δ 0.85(s,3H),0.98(d,J=9.2 Hz,1H),1.06(d,J=14.1 Hz,1H),1.13-1.25(m,14H),1.44(d,J=18.2 Hz,7H),1.61-1.93(m,8H),1.97(d,J=9.6 Hz,1H),2.11-2.37(m,5H),2.58(s,1H),2.81-2.89(m,1H),3.38(s,3H),3.52-3. 61(m,2H),3.61-3.73(m,8H),4.12-4.30(m,2H),4.91-5.07(m,3H),5.62(s,1H).

[0206] Example 31 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (249-5) [ka] Synthesis of 2-benzhydryl 9-methyl (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (249-1) (Trimethylsilyl)diazomethane (1 mL) was added to 194-7 (200 mg, 0.30 mmol, 1 equiv.) in CHCl (5 mL) and MeOH (2.5 mL). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was concentrated to give 200 mg (98%) of 249-1 as a white solid.

[0207] Synthesis of 2-benzhydryl 9-methyl (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (249-2) Sodium hydride (100 mg, 4.17 mmol, 14 equiv) was added portionwise to 249-1 (200 mg, 0.29 mmol, 1 equiv) and iodomethane (0.5 mL, 8.03 mmol) in THF (10 mL) at room temperature. The reaction slurry was stirred at 50 °C overnight and then quenched by the addition of water. The reaction mixture was extracted with EtOAc (3 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:1) to give 180 mg (88%) of 249-2 as a white solid.

[0208] (3S,4S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzhydryloxy)carbonyl)-3-methoxy-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicene-4-carvone Synthesis of acid (249-3) A slurry of 249-2 (180 mg, 0.26 mmol, 1 equiv) and lithium iodide (100 mg, 0.75 mmol, 2.9 equiv) in pyridine (5 mL) was stirred at 125 °C for 2 days. The reaction mixture was diluted with CHCl, washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:1) to give 110 mg (62%) of 249-3 as a yellow solid.

[0209] Synthesis of 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (249-4) A mixture of 249-3 (110 mg, 0.16 mmol, 1 equiv), 4-(chloromethyl)-5-methyl-2H-1,3-dioxol-2-one (150 mg, 1.0 mmol, 6.3 equiv), KCO (150 mg, 1.1 mmol, 6.7 equiv), and potassium iodide (50 mg, 0.30 mmol, 1.9 equiv) in DMF (10 mL) was stirred at 50 °C for 1 h. The reaction mixture was diluted with CHCl (100 mL), washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:1) to give 100 mg (78%) of 249-4 as a white solid.

[0210] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (249-5) 249-4 (150 mg, 0.19 mmol, 1 equiv.) and TFA (1 mL) in CHCl (10 mL) were stirred at room temperature for 1 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC with the following conditions: mobile phase: water (0.05% TFA) and CHCN (66% B phase to 74% in 8 min), detector: UV. This afforded 38.3 mg (32%) of 249-5 as a white solid. MS (ES, m / z): [M+H] += 627.55; 1H NMR(400 MHz, methanol-d4)δ 0.85(s,3H),0.90(d,J=9.8 Hz,1H),0.96-1.29(m,15H),1.44(d,J=8.1 Hz,5H),1.54(t,J=13.0 Hz,2H),1.60-1.99(m,6H),2.22(s,5H),2.54(s,1H),2.83(d,J=13.8 Hz,1H),3.26(s,3H),3.64(dd,J=11.8,4.2 Hz,1H),4.92(s,1H),5.13(d,J=14.0 Hz,1H),5.61(s,1H).

[0211] Example 32 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (252-2) [ka] Synthesis of 2-benzhydryl 9-((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (252-1) A mixture of 249-3 (300 mg, 0.44 mmol, 1 equiv.), 4-(bromomethyl)-5-(propan-2-yl)-2H-1,3-dioxol-2-one (100 mg, 0.45 mmol, 1.03 equiv.), KCO (200 mg, 1.45 mmol, 3.3 equiv.), and potassium iodide (50 mg, 0.30 mmol, 0.68 equiv.) in DMF (30 mg, 0.41 mmol, 0.93 equiv.) was stirred at 50 °C for 1 h. The reaction mixture was diluted with CHCl (100 mL), washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:1) to give 190 mg (52%) of 252-1 as a white solid.

[0212] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (252-2) 252-1 (190 mg, 0.23 mmol, 1 equiv) and TFA (1 mL) in CHCl (10 mL) were stirred at room temperature for 1 h. The reaction was concentrated and purified by preparative TLC (PE / EtOAc, 1:1). This afforded 68.6 mg (45%) of 252-2 as a white solid. MS (ES, m / z): [M+H] += 657.25; 1H NMR(400 MHz,chloroform-d)δ 0.85(s,4H),1.00(d,J=12.8 Hz,1H),1.07(s,1H),1.10-1.41(m,20H),1.36-1.57(m,8H),1.65-1.92(m,6H),2.01(s,3H),2.21(d,J=10.9 Hz,1H),2.43(s,1H),2.90(d,J=13.8 Hz,1H),3.03(p,J=7.2 Hz,1H),3.27(s,3H),3.60(dd,J=11.8,4.4 Hz,1H),4.88(d,J=13.8 Hz,1H),5.02(d,J=13.8 Hz,1H),5.74(s,1H).

[0213] Example 33 (2S,4aS,6aS,6bR,8aR,9R,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (253-4) [ka] Synthesis of 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-10-((phenoxycarbonothioyl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (253-1) 194-8 (120 mg, 0.15 mmol, 1 equiv), phenylchloromethanethioate (133.0 mg, 0.77 mmol, 5 equiv), and DMAP (37.6 mg, 0.31 mmol, 2 equiv) in CHCl (5 mL) were stirred at 40° C. for 2 days. The reaction mixture was concentrated, and the residue was purified by preparative TLC (petroleum ether / EtOAc, 5:1) to give 253-1 (100 mg, 71%) as a pale yellow solid.

[0214] Synthesis of (4R,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzhydryloxy)carbonyl)-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicene-4-carboxylic acid (253-2) A mixture of 253-1 (100 mg, 0.11 mmol, 1 equiv.), azobisisobutyronitrile (43.1 mg, 0.26 mmol, 2.4 equiv.), and tributyltin hydride (139.4 mg, 0.48 mmol, 4.4 equiv.) in toluene (3 mL) was stirred at 110° C. overnight. The reaction mixture was concentrated, diluted with EtOAc, washed with brine, dried over anhydrous NaSO, and concentrated. The crude product 253-2 was used directly in the next step without further purification.

[0215] Synthesis of 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9R,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2,9-dicarboxylate (253-3) 253-2 (100 mg, 0.15 mmol, 1 equiv.), 4-(chloromethyl)-5-methyl-2H-1,3-dioxol-2-one (45.6 mg, 0.31 mmol, 2 equiv.), KCO in DMF (3 mL). 3(A mixture of 253-3 (23.7 mg, 0.46 mmol, 3 equiv.), potassium iodide (12.8 mg, 0.08 mmol, 0.5 equiv.), and 253-3 (23.7 mg, 0.46 mmol, 3 equiv.) was stirred at 60° C. for 2 h. The reaction was diluted with EtOAc, washed with brine, dried over anhydrous NaSO, and concentrated. The crude product 253-3 was used directly in the next step without further purification.

[0216] Synthesis of (2S,4aS,6aS,6bR,8aR,9R,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (253-4) 253-3 (100 mg, 0.13 mmol, 1 equiv.) and TFA (0.1 mL, 1.35 mmol, 10 equiv.) in CHCl (5 mL) were stirred at room temperature for 1 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC with the following conditions: column: Xselect CSH OBD, 30*150 mm, 5 μm; mobile phase: water (0.05% TFA) and CHCN (68% B phase to 80% in 8 min); detector: UV. This gave 253-4 (8.1 mg, 10%) as a colorless oil. MS (ES, m / z): [M+H] += 597.15; 1 H NMR(400 MHz,chloroform-d)δ 6.89(d,J=102.7 Hz,2H),5.74(s,1H),5.00(d,J=13.8 Hz,1H),4.75(d,J=13.8 Hz,1H),2.78(d,J=13.1 Hz,1H),2.52(s,1H),2.22(s,4H),2.11-1.89(m,3H),1.88-1.47(m,9H),1.47-1.31(m,8H),1.26(s,4H),1.20(d,J=7.8 Hz,6H),1.14(s,3H),1.10-0.88(m,4H),0.85(s,3H).

[0217] Example 34 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (254-3) [ka] Synthesis of benzhydryl (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-isocyanato-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (254-1) Triethylamine (0.135 mL, 0.97 mmol, 1.5 equiv) was added to 210-1 (450 mg, 0.63 mmol, 1 equiv) and DPPA (0.225 mL, 1.04 mmol, 1.6 equiv) in anisole (5 mL) at room temperature. The reaction was stirred at 90 °C for 1.5 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative TLC (CHCl / MeOH, 5:1) to give 254-1 (400 mg, 89%) as a pale yellow solid.

[0218] Synthesis of benzhydryl (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (254-2) 4-(hydroxymethyl)-5-methyl-2H-1,3-dioxol-2-one (66.3 mg, 0.51 mmol, 3 equiv) in CHCl was added dropwise to 254-1 (120 mg, 0.17 mmol, 1 equiv) and chlorotrimethylsilane (92.3 mg, 0.85 mmol, 5 equiv) in CHCl (5 mL) at room temperature. The reaction slurry was stirred overnight at room temperature and then concentrated. The residue was purified by preparative TLC (petroleum ether / EtOAc 2:1) to give 254-2 (120 mg, 84%) as a pale yellow solid.

[0219] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (254-3) 254-2 (120 mg, 0.14 mmol, 1 equiv) and TFA (0.1 mL, 1.35 mmol, 9.4 equiv) in CHCl were stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative TLC to give 254-3 (21.2 mg, 22%) as an off-white solid. MS (ES, m / z): [M+H] += 670.25; 1 H NMR(400 MHz,chloroform-d)δ 6.94(d,J=67.6 Hz,2H),5.75(s,1H),5.47(t,J=5.7 Hz,1H),4.77(s,2H),4.44(s,1H),2.81(d,J=13.5 Hz,1H),2.50(s,1H),2.21(s,2H),2.05(s,3H),1.91-1.53(m,8H),1.42(d,J=19.1 Hz,8H),1.26(s,5H),1.19-0.97(m,11H),0.86(s,3H).

[0220] Example 35 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-((((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (255-2) [ka] Synthesis of benzhydryl (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-((((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (255-1) 4-(hydroxymethyl)-5-(propan-2-yl)-2H-1,3-dioxol-2-one (67.2 mg, 0.42 mmol, 3 equiv.) in CHCl was added dropwise to 254-1 (100 mg, 0.14 mmol, 1 equiv.) and chlorotrimethylsilane (76.9 mg, 0.71 mmol, 5 equiv.) in CHCl at room temperature. The r...

Claims

1. A compound of formula I or a salt thereof, 【Chemistry 154】 During the ceremony, X is a bond, —O—, —C(O)—, —N(R ｘ )-, -C(O)N(R ｘ ) -, -N(R ｘ )-C(O)-,-S(O) ｎ -N(R ｘ ) - or -N(R ｘ )-S(O) ｎ - and L is a bond, alkylene wherein one or more non-adjacent methylene groups of said alkylene are replaced with —O—, a divalent aryl or a divalent heteroaryl, or L is alkylene-Y-alkylene, where Y is O, NR ｘ , S, SO, SO ２ or a divalent heterocycle, and the alkylene group is OH, —C(O)O—R １ , alkyl, or OH or —C(O)O—R １ and the carbon of said alkylene group and R ｘ optionally, together form a heterocycle, with the proviso that when X is other than a bond, then L is other than a bond; W is O or S; Q is a bond or alkylene; R １ is H, alkyl, carbocycle, or heterocycle (said alkyl, carbocycle, and heterocycle are each optionally substituted with halogen, OH, amino, oxo, carboxy, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy, aminocarbonyl), carbocycle optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen, and heterocycle optionally substituted with alkyl, oxo, amino, and halogen; and carbocycle or heterocycle optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen; V is -C(O)O-, -C(O)O-(CHR ５ )-O-C(O)-, -C(O)O-(CHR ５ )-O-C(O)-O-, -C(O)O-(CH ２ ) ｎ -Y-, -C(O)N(R ５ )-, -C(O)N(R ５ )-O-, -NH-C(O)-N(R ５ )-, or NH-S(O) ｎ -, where Y is a divalent heterocycle optionally substituted with alkyl, halogen, OH, amino, carboxyl, and oxo; R ２ is H or R ５ and R ３ is absent or is alkyl; R ４ does not exist, H, OH, =O, -R ６ , -O-R ６ , -C(O)O-R ６ , -O-C(O)-R ６ , -O-C(O)-OR ６ , -O-C(O)-NR ５ R ６ , -NR ５ R ６ , -NR ５ -C(O)-R ６ , -NR ５ -C(O)-O-R ６ , -NR ５ -SO ２ -R ６ , =N-O-R ５ and The dashed line between the 2-position and the 3-position of the fused ring system indicates that the bond between the 2-position and the 3-position of the fused ring system is optionally a single bond or a double bond, and the dashed lines converging on the inside of the fused ring system indicate that R ４ indicates that (when present) and the group containing -XL-C(O)-W-Q- may be alternatively attached to the 3- or 4-position of the fused ring system; R ５ is H or alkyl optionally substituted with carbocycle or heterocycle, said carbocycle and heterocycle being optionally substituted with halogen, OH, oxo, and alkyl; R ６ is H, alkyl, carbocycle, heterocycle (wherein the alkyl, carbocycle, and heterocycle are not halogen, OH, SH, alkylthio, —S(O)-alkyl, —SO ２ -alkyl, amino, -NHC(O)-alkyl, oxo, alkyl, carboxyl, acyl, acyloxy, alkoxy, alkoxycarbonyl), carbocycle optionally substituted with halogen, OH, amino, or alkyl, or heterocycle optionally substituted with halogen, OH, amino, or alkyl; ６ wherein one or more non-adjacent methylene groups of each of said alkyl groups are optionally replaced with —O— or —S—; R ｘ H, -C(O)O-R １ , or C(O)O-R １ is alkyl optionally substituted with n is 1 or 2; provided that said compound of formula I (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4,4-difluoropiperidin-1-yl)-9-((((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid A compound of formula I or a salt thereof, which is not

2. Ia to Io: 【Chemistry 155】 【Chemistry 156】 【Chemistry 157】 2. The compound of claim 1, or a salt thereof, having the structure of any one of formulas Ia' to If': 【158】

3. V is —C(O)—O—, and R ２ The compound or salt thereof according to claim 1 or claim 2, wherein is H.

4. R １ 3. The compound or salt thereof according to claim 1 or 2, wherein is methyl, ethyl, or isopropyl.

5. 2. The compound or salt thereof of claim 1, wherein X and L are both bonds.

6. The compound or salt thereof according to any one of claims 1 to 5, wherein Q is O.

7. R ３ The compound or salt thereof according to any one of claims 1 to 6, wherein is methyl.

8. R ４ But -O-C(O)-R ６ and R ６ is alkyl, carbocycle, or heterocycle, wherein the alkyl is optionally substituted with hydroxyl, halogencarboxy, alkoxy, alkylthio, amino, NHC(O)-alkyl, heterocycle optionally substituted with alkyl, the carbocycle and heterocycle are optionally substituted with halogen, hydroxyl, and alkyl, the alkyl is optionally substituted with hydroxyl, halogencarboxy, and one or more non-adjacent methylene groups are replaced with -O-.

9. R ４ But NH ２ 8. The compound according to any one of claims 1 to 7, wherein the alkoxy group is alkoxy, OH, =N-O-alkyl, or =N-OH, or a salt thereof.

10. R ４ But, R ６ and R ６ The compound according to any one of claims 1 to 7, or a salt thereof, wherein is phenyl optionally substituted with alkoxy.

11. R ４ But, R ６ and R ６ The compound or salt thereof according to any one of claims 1 to 7, wherein is a heterocycle optionally substituted with halogen, alkyl, oxo, and alkoxycarbonyl.

12. R ４ But -NHC(O)-R ６ The compound according to any one of claims 1 to 7, or a salt thereof, wherein

13. R ４ is -NHC(O)-OR ６ The compound according to any one of claims 1 to 7, or a salt thereof, wherein

14. R ４ is -OC(O)-OR ６ The compound according to any one of claims 1 to 7, or a salt thereof, wherein

15. R ４ But O-R ６ The compound according to any one of claims 1 to 7, or a salt thereof, wherein

16. R ４ But, -NR ５ R ６ The compound according to any one of claims 1 to 7, or a salt thereof, wherein

17. R ４ But -O-C(O)-R ６ and R ６ The compound or salt thereof according to any one of claims 1 to 7, wherein is methyl, ethyl, or cyclopropyl.

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