Glycyrrhetinic acid derivatives for treating hyperkalemia

Abstract

To provide a method for treating disease.SOLUTION: The present invention provides a compound of formula (I) or a salt thereof [where X, L, V, R1, R2, R3 and R4 are as defined herein]. These compounds are inhibitors of 11-hydroxysteroid dehydrogenase type 2 (11-HSD-2) and are used to treat hyperkalemia.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 541,095, filed August 4, 2017, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present invention relates to compounds that inhibit 11β-HSD2 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 fluids and plays a key role in normal human physiology, particularly with regard to the firing of action potentials in nerve and muscle cells. Total body potassium content 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%) 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 large effect on this ratio and, therefore, on the function of excitable tissues (muscle and nerve). Extracellular potassium levels are therefore tightly regulated.

[0004] Two separate but coordinated systems are involved in potassium homeostasis: one regulates the external potassium balance (body parity of potassium intake versus potassium excretion), and the other regulates 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 + and K. +Na uses the energy of ATP hydrolysis to pump Na up their concentration gradient + ,K + -ATPase "pump" drives physiological production of Na + ,K + -ATPase. Body balance is controlled by excretory mechanisms via the kidneys and the gastrointestinal tract: in healthy kidneys, 90-95% of the daily potassium load is excreted via the kidneys, with the remainder 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 Even small changes in serum [K] have profound effects on the function of electrically active tissues such as muscles and nerves. Potassium and sodium ions drive action potentials in nerve and muscle cells by actively moving across cell membranes and shifting the membrane potential, which is the difference in electrical potential between the inside and outside of the cell. In addition to active transport, K + can also passively move between the extracellular and intracellular compartments. + Transport overload results from high levels of blood potassium, which depolarizes membranes in the absence of stimulation. Excess serum potassium, known as hyperkalemia, can disrupt the membrane potential of cardiac cells, which regulates ventricular conduction and contraction. Clinically, the effects of hyperkalemia on cardiac electrophysiology are of great concern because they can lead to arrhythmias and death. Therefore, because much of the body's balance is maintained by renal excretion, as renal function declines, one might expect the ability to manage total body potassium to become impaired.

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

[0007] Serum potassium can be reduced by two general mechanisms: first, by intracellular potassium shift using agents such as insulin, albuterol, or sodium bicarbonate. Second, by excreting potassium from the body using one of four routes: via feces using potassium-binding resins such as sodium polystyrene sulfonate (NaPSS), via urine using diuretics, via blood using hemodialysis, or via peritoneal fluid using peritoneal dialysis. Other than NaPSS, medications used to treat hyperkalemia, such as insulin, diuretics, beta-agonists, and sodium bicarbonate, can easily produce hypokalemia as a side effect and are unsuitable for long-term treatment. Causal therapy requires the removal of potassium from the body. Studies have confirmed that lowering 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. Kayexalate / Na PSS is poorly tolerated and results in a high incidence of GI side effects, including nausea, vomiting, constipation, and diarrhea. In addition, Kayexalate is a milled product, consisting of irregularly shaped particles ranging in size from approximately 1 to 150 μm, which have sand-like properties in the human oral cavity: upon ingestion, a strong foreign body sensation occurs in the palate, a sensation that negatively contributes to patient compliance. Overall, the physical properties and associated side effects of Kayexalate lead to poor compliance, making the drug suboptimal for long-term use. These properties have led to a long-felt need for a drug that is optimal for long-term use.

[0008] The mineralocorticoid receptor (MR, MLR, MCR), also known as the aldosterone receptor or nuclear receptor subfamily 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, where ligands diffuse into cells, interact with the receptor, and transduce signals in the nucleus that affect specific gene expression. 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 its ligands aldosterone and cortisol in epithelial tissues promotes potassium excretion. In intact animals, the MR converts cortisol to its inactive metabolite, cortisol. Cortisol is "protected" (100-1000-fold) from high concentrations of cortisol by co-localization with the enzyme 11β-hydroxysteroid dehydrogenase 2 (HSD2), which oxidizes it to luteinizing agent 11β-hydroxysteroid dehydrogenase 2 (HSD2). HSD2 thus prevents MR activation and, therefore, inhibits potassium extrusion.

[0009] Therefore, inhibition of HSD2 to prevent cortisol-activated inactivation of MR is a promising mechanism for promoting potassium excretion, for example, in the treatment of hyperkalemia. Summary of the Invention

[0010] In one aspect of the present invention, there is provided a compound of formula I or a salt thereof: [ka] I [In the formula, 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(Rx )-S(O) n - and; V is -C(O)O-, -C(O)N(R5)-, -C(O)N(R5)O-, -NH-C(O)-N(R5)- or NH-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, wherein 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 wherein the carbons and R of said alkylene group are x optionally taken together form a heterocycle; with the proviso that when X is other than a bond, then L is other than a bond; R1 is alkyl optionally substituted with halogen, OH, amino, oxo, carboxy, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy, aminocarbonyl, alkyl, haloalkyl, oxo, amino, and halogen, carbocycle optionally substituted with halogen, and heterocycle optionally substituted with halogen, oxo, amino, and halogen; and carbocycle or heterocycle optionally substituted with halogen, haloalkyl, oxo, amino, and halogen; wherein one or more non-adjacent methylene groups in any of said alkyl groups are replaced with O; R2 is H or R1; R3 is absent or Me; provided that if -XLC(O)O-R1 is pendant from the carbon to which R3 is pendant, then R3 is absent; or R3 is -ZLC(O)O-R1, where Z 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 - and; and R4 is absent, H, or OH; provided that when -XLC(O)O-R1 is pendant from the carbon to which R4 is pendant, then R4 is H or absent; R5 is H or alkyl; R x is H, —C(O)O—R1, or alkyl optionally substituted with —C(O)O—R1; and n is 1 or 2].

[0011] Another aspect of the invention provides compositions comprising a compound of formula I and a carrier, diluent, or excipient.

[0012] In another aspect of the invention, there is provided a method of inhibiting the conversion of cortisol to cortisone by HSD2, comprising contacting HSD2 with a compound of formula I.

[0013] In another aspect of the invention, there is provided a method for promoting activation of MR in a mammal, comprising administering to said mammal an effective amount of a compound of formula I.

[0014] In another aspect of the invention, there is provided a method for lowering plasma potassium levels in a mammal, comprising administering to said mammal an effective amount of a compound of formula I.

[0015] Another aspect of the present invention provides a method for promoting potassium ion secretion into the colonic lumen of a mammal, 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 treating hyperkalemia in a mammal, comprising administering to said mammal an effective amount of a compound of formula I.

[0017] In another aspect of the invention, there is provided a method for treating or preventing hyperkalemia in a mammal, comprising co-administering a compound of formula I with an inhibitor of the renin-angiotensin-aldosterone system (RAAS). [Brief explanation of the drawings]

[0018] [Figure 1] Illustrates the synergistic effect on fecal potassium excretion when an HSD2 inhibitor is administered in combination with an NHE3 inhibitor. [Figure 2] Illustrates 11-β-hydroxysteroid dehydrogenase 2 (HSD2) inhibition in epithelial cells, allowing cortisol to activate the mineralocorticoid receptor (MR) and promoting potassium excretion into the lumen. [Figure 3] The structure of glycyrrhetinic acid is shown, with the carbon atoms numbered. DETAILED DESCRIPTION OF THE INVENTION

[0019] Glycyrrhizin (or glycyrrhizic acid or glycyrrhizinic acid) is an extract of the plant called Glycyrrhiza, derived from the ancient Greek words "glykos" meaning sweet and "rhiza" meaning root. Licorice was enjoyed by many prophets and pharaohs. Licorice extracts have been used on the battlefield and in the desert, where soldiers and travelers drank it to suppress the sensation of thirst on long marches. Glycyrrhetinic acid, the active metabolite of licorice, inhibits HSD2, leading to a tendency to cortisol-induced mineralocorticoid action and to lower potassium levels. While glycyrrhetinic acid lowers potassium levels, it also reduces abnormal cardiac rhythms. Hyperkalemia is associated with rhabdomyolysis, hypertension, edema, lethargy, congestive heart failure, hypokalemia, and rhabdomyolysis. Therefore, it would be desirable to provide a compound similar to glycyrrhetinic acid that promotes potassium excretion in patients suffering from hyperkalemia but without the undesirable side effects.

[0020] The present invention provides a compound of formula I, or a salt thereof: [ka] I [In the formula, 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; V is -C(O)O-, -C(O)N(R5)-, -C(O)N(R5)O-, -NH-C(O)-N(R5)- or NH-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, wherein 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 wherein the carbons and R of said alkylene group are x optionally taken together form a heterocycle; with the proviso that when X is other than a bond, then L is other than a bond; R1 is alkyl optionally substituted with halogen, OH, amino, oxo, carboxy, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy, aminocarbonyl, alkyl, haloalkyl, oxo, amino, and halogen, carbocycle optionally substituted with halogen, and heterocycle optionally substituted with halogen, oxo, amino, and halogen; and carbocycle or heterocycle optionally substituted with halogen, haloalkyl, oxo, amino, and halogen; wherein one or more non-adjacent methylene groups in any of said alkyl groups are replaced with O; R2 is H or R1; R3 is absent or Me; provided that if -XLC(O)O-R1 is pendant from the carbon to which R3 is pendant, then R3 is absent; or R3 is -ZLC(O)O-R1, where Z 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 - and; and R4 is absent, H, or OH; provided that when -XLC(O)O-R1 is pendant from the carbon to which R4 is pendant, then R4 is H or absent; R5 is H or alkyl; R x is optionally substituted with H, -C(O)O-R1, or -C(O)O-R1 is an alkyl having n is 1 or 2].

[0021] In one particular embodiment, the compounds of the present invention contain an ester moiety pendant from the 3-, 23-, and / or 24-position of the fused ring system. In one embodiment, after administration of the compounds of the present invention to a subject, the ester moiety is metabolized in the plasma or liver to a less active acidic form. 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.

[0022] "Acyl" means a carbonyl containing a substituent represented by the formula: -C(O)-R, where R is H, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, where said alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. Acyl groups include alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl), and heteroaroyl.

[0023] "Alkyl," unless otherwise specified, 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 may be a saturated hydrocarbon chain; however, unsaturated hydrocarbon carbon chains, such as those in "alkenylamino" and "alkynylamino," are also included. 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, 1, 2, 3, or 4 substituents, which can 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 the above 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 may be substituted with carbocyclic groups. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl groups, as well as the corresponding -ethyl, -propyl, -butyl, -pentyl, -hexyl groups, and the like. 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, an alkyl is saturated. In one embodiment, an alkyl is unsaturated. In one embodiment, an alkyl is The alkyl is partially unsaturated.

[0024] "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.

[0025] "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 said alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. Particular secondary and tertiary amines are alkylamines, dialkylamines, arylamines, diarylamines, aralkylamines, and diaralkylamines, where said 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.

[0026] As used herein, "amino-protecting group" refers to derivatives of groups commonly used to block or protect amino groups while reactions are performed on other functional groups on a compound. Examples of such protecting groups include carbamates, amides, alkyl and aryl groups, imines, as well as many N-heteroatom derivatives, which 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.

[0027] "Aryl," when used alone or as part of another term, refers to a carbocyclic aromatic group, whether fused or unfused, having a specified number of carbon atoms, or up to 14 carbon atoms if no number is specified. 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 means, unless otherwise specified, a phenyl or aryl group substituted with 1, 2, 3, 4, or 5 substituents, for example, 1 to 2, 1 to 3, or 1 to 4 substituents selected from halogen (F, Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), benzyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylamino, arylsulfonylaminoalkyl, heterocyclylsulfonylamino, heterocyclylsulfonylaminoalkyl, heterocyclyl, aryl, or other defined groups. One or more methine (CH) and / or methylene (CH) groups in these substituents may then be replaced with similar groups, such as those set forth above. Examples of the term "substituted phenyl" include, but are not limited to, 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; mono- or di(hydroxy)phenyl groups such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, and protected hydroxy derivatives thereof. nitrophenyl groups such as 3- or 4-nitrophenyl; cyanophenyl groups, for example, 4-cyanophenyl; mono- or di(lower alkyl)phenyl groups, such as 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4-(isopropyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl; mono- or di(alkoxy)phenyl groups, for example, 3,4-dimethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4-(1-chloromethyl)benzyloxyphenyl; mono- or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; mono- or di(N-(methylsulfonylamino))phenyl such as 3-(N-methylsulfonylamino)phenyl; disubstituted phenyl groups such as 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 include 3-methoxy-4-benzyloxy-6-methylsulfonylamino and 3-methoxy-4-benzyloxy-6-phenylsulfonylamino; and tetrasubstituted phenyl groups include 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. The fused aryl ring may be substituted with any of the substituents defined herein, for example, one, two, or three, in the same manner as substituted alkyl groups.

[0028] 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 groups. A particular saturated carbocycle is cyclopropyl. Another particular saturated carbocycle is cyclohexyl. A particular unsaturated carbocycle is aromatic, e.g., an aryl group as defined above, e.g., phenyl. The terms "substituted carbocyclyl," "carbocycle," and "carbocyclo" refer to these groups substituted by the same substituents as the "substituted alkyl" group.

[0029] As used herein, a "carboxy-protecting group" refers to one of the ester derivatives of a carboxylic acid group that is commonly used to block or protect the carboxylic acid group while reactions are carried out with other functional groups on the compound. Examples of such carboxylic acid protecting groups include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, and the like. alkyl, such as t-butyl or t-amyl, trityl, 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)prop-1-en-3-yl, and similar moieties. The type of carboxy-protecting group used is not critical, so long as it is stable to the conditions of the subsequent reaction(s) at the site and can be removed at the appropriate time without destroying the remainder of the molecule. In particular, 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 strong 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 fields can also be used to protect carboxy group substituents. Further examples of these groups can be found in Greene, TW, and PGMWuts.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,TWProtective 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.

[0030] "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.

[0031] "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.

[0032] As used herein, a "hydroxy-protecting group" refers to a derivative of a hydroxy group that is commonly used to block or protect the hydroxy group while reactions are carried out on other functional groups on the 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.Wuts. Protective Groups in Organic Synthesis. 2nd ed. New York: John Wiley & Sons, 1999. & Sons, Inc. 1991, Chapters 2-3; Haslam, E. Protective Groups in Organic Chemistry. New York: Plenum Press 1973, Chapter 5; and Greene, TWProtective Groups in Organic Syn thesis. 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.

[0033] The terms "heterocyclic group," "heterocyclic," "heterocycle," "heterocyclyl," or "heterocyclo," used alone and as part of a complex group such as a heterocycloalkyl group, are used interchangeably 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 about 14, in which 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 or sulfur heteroatom 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 linked to an alkyl group as defined above. Particular 5-membered heterocycles containing one sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, especially thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, especially 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, and oxadiazolyl, for example 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, for example imidazol-2-yl; triazolyl, for example 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, for example 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 1 to 3 nitrogen atoms and optionally 1 sulfur or oxygen atom, 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, especially pyridazin-3-yl and pyrazinyl. Particular groups are pyridine N-oxide and pyridazine N-oxide, and pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and 1,3,4-triazin-2-yl groups. Substituents for "optionally substituted heterocycles" and further examples of the 5- and 6-membered ring systems discussed above can be found in W. Druckheimer et al., U.S. Patent No. 4,278,793. In one particular embodiment, 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.

[0034] "Heteroaryl," both by itself 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 from 1 to 4 heteroatoms selected from the group of nitrogen, oxygen, and sulfur, and in one particular embodiment, at least one heteroatom is nitrogen (see Lange's Handbook of In one example, heteroaryl is selected from nitrogen, oxygen, and sulfur. A 5- or 6-membered aromatic ring containing one, two, or three heteroatoms is defined as a heteroaryl ring. This definition includes any bicyclic group in which any of the above heteroaryl rings is fused to a benzene ring. Certain heteroaryls incorporate a nitrogen or oxygen heteroatom. 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, as well as benzo-fused derivatives such as benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl and indolyl. Particular "heteroaryl" includes 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-triazole. -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-tetrazole- 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)-pyridazin-3-yl, 6-hydroxypyridazin-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. Alternatives to "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-(methylsulfonic acid)-1H-tetrazol-5-yl, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1,2,3-triazol-5-yl, 1,4,5,6-tetrahydro-5, Heteroaryl groups include 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.

[0035] "Inhibitor" means a compound that reduces or blocks the enzymatic conversion of cortisol to cortisone by HSD2.

[0036] "Optionally substituted" means, unless otherwise specified, that a group may be unsubstituted or, if valence permits, substituted with one or more (e.g., 0, 1, 2, 3, or 4) of the substituents listed for that group, where the substituents 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.

[0037] "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 base and are not biologically or otherwise undesirable, and the organic acids may be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acid groups 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.

[0038] "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 preferred 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, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperidine, N-ethylpiperidine, polyamine resins, and the like. Particular organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.

[0039] "Sulfanyl" refers to the radical -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.

[0040] "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.

[0041] "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.

[0042] As used herein, the phrase "and salts and solvates thereof" 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 may be substantially pure in one particular salt or solvate form, or alternatively, may be a mixture of two or more salt or solvate forms.

[0043] In certain embodiments of the present invention, compounds of Formula I have a structure defined by Formulas Ia-Ir: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] wherein X, L, R1, R2, R3, and R4 are as defined herein. In one particular embodiment, the compound has a structure according to Formula Ia. In one particular embodiment, the compound has a structure according to Formula Ib. In one particular embodiment, the compound has a structure according to Formula Ic. In one particular embodiment, the compound has a structure according to Formula Id. In one particular embodiment, the compound has a structure according to Formula Ie. In one particular embodiment, the compound has a structure according to Formula If. In one particular embodiment, the compound has a structure according to Formula Ig. In one particular embodiment, the compound has a structure according to Formula Ih. In one particular embodiment, the compound has a structure according to Formula Ii. In one particular embodiment, the compound has a structure according to Formula Ii. In one particular embodiment, the compound has a structure according to Formula Ij. In one particular embodiment, the compound has a structure according to Formula Ik. In one particular embodiment, the compound has a structure according to Formula Il. In one particular embodiment, the compound has a structure according to Formula Im. In one particular embodiment, the compound has a structure according to Formula In. In one particular embodiment, the compound has a structure according to Formula Io. In one particular embodiment, the compound has a structure according to Formula Ip. In one particular embodiment, the compound has a structure according to Formula Iq. In one particular embodiment, the compound has a structure according to Formula Ir.

[0044] In certain embodiments of the invention, compounds of formula I have structures defined by formulas Ib', Ic', Id', If', Ih', Ij', Ik', Il', Im', In', Io', Ip', and Iq': [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] wherein X, L, R1, R2, R3, R4, and R5 are as defined herein. In one particular embodiment, the compound has a structure according to Formula Ib'. In one particular embodiment, the compound has a structure according to Formula Ic'. In one particular embodiment, the compound has a structure according to Formula Id'. In one particular embodiment, the compound has a structure according to Formula If'. In one particular embodiment, the compound has a structure according to Formula Ih'. In one particular embodiment, the compound has a structure according to Formula Ij'. In one particular embodiment, the compound has a structure according to Formula Ik'. In one particular embodiment, the compound has a structure according to Formula Il'. In one particular embodiment, the compound has a structure according to Formula Im'. In one particular embodiment, the compound has a structure according to Formula Io'. In one particular embodiment, the compound has a structure according to Formula Ip'. In one particular embodiment, the compound has a structure according to Formula Iq'. do.

[0045] In one embodiment, the compounds of the invention have the formula of any one of Formula I.

[0046] 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 - where 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)-.

[0047] V is -C(O)O-, -C(O)N(R5)-, -C(O)N(R5)O-, -NH-C(O)-N(R5)- or NH-S(O) n 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 alkyl optionally substituted with oxo, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy; carbocycle optionally substituted with alkyl and oxo; and heterocycle optionally substituted with alkyl and oxo.

[0048] 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 alkyl optionally substituted with H and OH. In one embodiment, V is -C(O)N(R)-, and R5 is H, and R2 is hydroxyethyl.

[0049] In one embodiment, V is —C(O)N(R)O—. In one embodiment, V is —C(O)N(R)O—, and R and R are independently H or alkyl. In one embodiment, V is —C(O)N(R)O—, and R is methyl, and R is H.

[0050] In one embodiment, V is -NH-C(O)-N(R)-, and R and R are independently H or alkyl. In one embodiment, V is -NH-C(O)-N(R)-, and R is methyl, and R is H. In one embodiment, V is -NH-C(O)-N(R)-, and R and R are both H.

[0051] In one embodiment, V is NH—S(O) n In 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.

[0052] L is a bond, alkylene (wherein one or more non-adjacent methylene groups of said alkylene) group is replaced with -O-); a divalent aryl or a 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 wherein 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.

[0053] 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-.

[0054] 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 wherein the carbons and R of said alkylene group are x are optionally taken together to 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 wherein the carbons of the alkylene group and R xtogether 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.

[0055] R1 is an alkyl optionally substituted with halogen, OH, amino, oxo, carboxy, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy, aminocarbonyl, alkyl, haloalkyl, oxo, amino, and halogen; and a carbocycle or heterocycle optionally substituted with alkyl, oxo, amino, and halogen; wherein one or more non-adjacent methylene groups in any of the aforementioned alkyl groups are replaced with O. In one embodiment, R1 is an alkyl. In one embodiment, R1 is an alkyl substituted with OH. In one embodiment, R1 is an alkyl substituted with oxo. In one embodiment, R1 is an alkyl substituted with carboxy. In one embodiment, R1 is an alkyl substituted with acyloxy. In one embodiment, R1 is an alkyl substituted with alkoxycarbonyl. In one embodiment, one or more non-adjacent methylene groups in any of the alkyl groups in R1 are replaced with O. In one embodiment, R1 is substituted with alkoxyacyloxy. In one embodiment, R1 is alkyl. 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. In one embodiment, R1 is 2,2,2-trifluoroethyl. In one embodiment, R1 is 1,1-trifluoromethylethyl. In one embodiment, R1 is 2-morpholinoethyl. In one embodiment, R1 is 2-(1H-imidazol-1-yl)ethyl. In one embodiment, R1 is 2-(pyridin-2-yl)ethyl. In one embodiment, R1 is -CH2-C(O)OH.

[0056] In one embodiment, R1 is —CH2—C(O)O-Me. In one embodiment, R1 is —CH2—C(O)NH2. In one embodiment, R1 is —CH2—C(O)NMe2. In one embodiment, R1 is —CH2—C(O)Ot-butyl. In one embodiment, R1 is (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl. In one embodiment, R1 is (pivaloyloxy)methyl. In one embodiment, R1 is ((isopropoxycarbonyl)oxy)methyl. In one embodiment, R1 is (S)-1-((isopropoxycarbonyl)oxy)ethyl. In one embodiment, R1 is (R)-1-((isopropoxycarbonyl)oxy)ethyl. In one embodiment, R1 is 2-morpholino-2-oxoethyl. In one embodiment, R1 is 2-(4-methylpiperazin-1-yl)-2-oxoethyl. In one embodiment, R1 is (R)-quinuclidin-3-yl.

[0057] In one embodiment, R1 is -[(CH2)2-O] p-Me, where p is 1 to 20. In one embodiment, p is 1 to 19. In one embodiment, p is 1 to 18. In one embodiment, p is 1 to 17. In one embodiment, p is 1 to 16. In one embodiment, p is 1 to 15. In one embodiment, p is 1 to 14. In one embodiment, p is 1 to 13. In one embodiment, p is 1 to 12. In one embodiment, p is 1 to 11. In one embodiment, p is 1 to 10. In one embodiment, p is 1 to 9. In one embodiment, p is 1 to 8. In one embodiment, p is 1 to 7. In one embodiment, p is 1 to 6. In one embodiment, p is 1 to 5. In one embodiment, p is 1 to 4. In one embodiment, p is 1 to 3. In one embodiment, p is 1 to 2. In one embodiment, p is 1 to 1.

[0058] In one embodiment, R2 is H or R1. In one embodiment, R2 is H. In one embodiment, R2 is R1. 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.

[0059] R3 is absent or Me; provided that if X is pendant from the carbon to which R3 is pendant, then R3 is absent; or R3 is -ZLC(O)O-R1, where Z 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 In one embodiment, R3 is methyl. In one embodiment, R3 is absent and X is pendant from the carbon to which R3 is pendant. In one embodiment, R3 is -ZLC(O)O-R1, where Z is a bond, -O-, -N(R x )-, -C(O)N(R x )-, -N(Rx )-C(O)-, -S(O) n -N(R x )- or -N(R x )-S(O) n In one embodiment, Z is -O-. In one embodiment, Z is -N(R x )-. In one embodiment, Z is -NH-. In one embodiment, R3 is -C(O)N(R x )-. In one embodiment, R3 is -C(O)NH-. In one embodiment, R3 is -N(R x )-C(O)-. In one embodiment, R3 is -NH-C(O)-. In one embodiment, R3 is -S(O) n -N(R x )-. In one embodiment, R3 is -S(O)-NH-. In one embodiment, R3 is -S(O)2-NH-. In one embodiment, R3 is -N(R x )-S(O) n In one embodiment, R3 is -NH-S(O)1-. In one embodiment, R3 is -NH-S(O)2-.

[0060] R4 is absent, H, or OH; provided that when -XLC(O)O-R1 is pendant from the carbon to which R4 is pendant, then R4 is H or absent; In one embodiment, R4 is H. In one embodiment, R4 is H and the carbon to which R4 is pendant is part of a double bond. In one embodiment, R4 is H and the carbon to which R4 is pendant is not part of a double bond. In one embodiment, R4 is OH. In one embodiment, R4 is absent and X is pendant to -XLC(O)O-R1, pendant from the carbon to which R4 is pendant, and said carbon is part of a double bond.

[0061] R5 is H or alkyl optionally substituted with carbocycle or heterocycle, wherein said carbocycle and heterocycle are optionally substituted with oxo and alkyl. In one embodiment, R5 is H. In one embodiment, R5 is alkyl. In one embodiment, R5 is methyl. In one embodiment, R5 is

[0062] 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.

[0063] In one embodiment, "n" is 1. In another embodiment, "n" is 2.

[0064] In one embodiment, the compound of the invention is one of the following compounds: (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; 2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(isopropoxycarbonyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl)oxy)carbonyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-hydroxyethoxy)carbonyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-((2,2,2-trifluoroethoxy)carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-isopropyl Dropicene-2-carboxylic acid; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(1H-imidazol-1-yl)ethoxy)carbonyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-morpholinoethoxy)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,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-((((R)-quinuclidin-3-yl)oxy)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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-((2-(pyridin-2-yl)ethoxy)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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-amino-2-oxoethoxy)carbonyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((carboxymethoxy)carbonyl)-,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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethoxy)carbonyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(tert-butoxy)-2-oxoethoxy)carbonyl)-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; (2S,4aS,6aS,6bR,8aR,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,9,12,12a,12b,13,14b-octadecahydropicene-2-carboxylic acid; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)carbamoyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((carboxymethyl)carbamoyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)(methyl)-carbamoyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((R)-2-(methoxycarbonyl)pyrrolidine-1-carbonyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1,5-dimethoxy-1,5-dioxopentan-2-yl)carbamoyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((R)-1,4-dimethoxy-1,4-dioxobutan-2-yl)carbamoyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-methoxy-1-oxopropan-2-yl)carbamoyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl)carbamoyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-(1H-imidazol-1-yl)ethoxy)-2-oxoethyl)carbamoyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-hydroxyethoxy)-2-oxoethyl)carbamoyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-(2-morpholinoethoxy)-2-oxoethyl)carbamoyl)-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,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(((pivaloyloxy)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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((((isopropoxycarbonyl)oxy)methoxy)carbonyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-((isopropoxycarbonyl)oxy)-ethoxy)carbonyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((R)-1-((isopropoxycarbonyl)oxy)ethoxy)carbonyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(diethylamino)-2-oxoethoxy)carbonyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-morpholino-2-oxoethoxy)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,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)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,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)amino)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(bis(2-methoxy-2-oxoethyl)amino)-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; Dibenzyl 2,2'-(((3S,4aR,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-icosahydropicen-3-yl)azanediyl)diacetate; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-methoxy-2,2-dimethyl-3-oxopropanamido)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-methoxy-2-oxoacetamido)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-methoxy-3-oxopropanamido)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-methoxy-4-oxobutanamido)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((E)-4-methoxy-4-oxobut-2-enamido)-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; Benzyl (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-methoxy-3,3-dimethyl-4-oxobutanamido)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-methoxy-3,3-dimethyl-4-oxobutanamido)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)sulfonamido)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((3-methoxy-3-oxopropyl)sulfonamido)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2-methoxy-2-oxoethoxy)acetamido)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((1-(2-methoxy-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methoxy)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((1,3-dimethoxy-1,3-dioxopropan-2-yl)oxy)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-(4-(ethoxycarbonyl)piperidin-1-yl)-2-hydroxypropoxy)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-((3-oxo-2,6,9,12-tetraoxatetradecan-14-yl)carbamoyl)-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,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-((12-oxo-2,5,8,11-tetraoxatetradecane)sulfonamide)-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,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(4-oxo-2,8,11,14-tetraoxa-5-azapentadecanoyl)-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-hydroxy-9-(methoxycarbonyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-((2-oxo-2-(((R)-quinuclidin-3-yl)oxy)ethyl)carbamoyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid.

[0065] In another embodiment, the compound of the invention is one of the following compounds: (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-((12-oxo-2,5,8,11-tetraoxatridecan-13-yl)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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((10-methyl-12-oxo-2,5,8,11-tetraoxatridecan-13-yl)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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2,5,9,12-tetraoxatridecan-7-yloxy)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2-ethoxy-2-oxoethoxy)ethoxy)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2-(2-methoxyethoxy)-2-oxoethoxy)ethoxy)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-(2-((1-methoxypropan-2-yl)oxy)-2-oxoethoxy)ethoxy)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(bis(2-(2-(2-methoxyethoxy)ethoxy)-2-oxoethyl)amino)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)(2-(2-(2-methoxyethoxy)ethoxy)ethyl)amino)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-4-oxobutanamide)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(2,5,8,11-tetraoxadodecane-1-oyl)-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; (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(4-oxo-2,5,8,11,14-pentaoxapentadecan-1-oyl)-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,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(5-methyl-4-oxo-2,8,11,14-tetraoxa-5-azapentadecan-1-oyl)-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,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(3-methyl-4-oxo-2,8,11,14-tetraoxa-5-azapentadecan-1-oyl)-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,8aS,10S,12aS,12bR,14bR)-10-(3,5-dimethyl-4-oxo-2,8,11,14-tetraoxa-5-azapentadecan-1-oyl)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-(4-(2,5,8,11,14-pentaoxapentadecan-1-oyl)piperidin-1-yl)-2-hydroxypropoxy)-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; (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-hydroxy-9-(methoxycarbonyl)-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; (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,5,8,11-tetraoxatetradecane-14-oyloxy)-9-(methoxycarbonyl)-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-{3-[4,4-bis(methoxycarbonyl)piperidin-1-yl]-2-hydroxypropoxy}-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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-{[(2-methoxy-2-oxoethyl)carbamoyl]oxy}-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; (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(acetyloxy)-9-[(ethylsulfanyl)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; (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-[3-(tert-butoxy)-3-oxopropoxy]-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; (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-[(3R)-3-(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-2,9-dicarboxylic acid; and (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-[4-(methoxycarbonyl)piperidin-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-2,9-dicarboxylic acid.

[0066] Many of the compounds listed above (more than 50%) were tested in the assay described in Example 59 by measuring the amount of cortisol before and after contact with cell lysates (human and rat) or colonic monolayer organoids derived from human colon tissue to determine their activity in inhibiting HSD2. 50 The HSD2 inhibition of the compounds of the present invention, as expressed as pIC50, ranged from 8.9 to 7.7 (human lysate), 8.9 to 7.5 (rat lysate), and >8 to 5.9 (human organoids). For reference, glycyrrhetinic acid was tested in the same HSD2 assay: 8.5 (human lysate), 6.4 (human organoids). The pIC50 between the compounds of the present invention and their corresponding acid compounds was 1.3 in human organoids, except for one test compound that had a negative pIC50 difference (less than HSD2 inhibitory activity) in both lysates.50 The differences ranged from 2.2 to 0.4 (human lysates) and 1.3 to 0.8 (human organoids). Positive differences demonstrate greater HSD2 inhibitory activity of the compounds of the present invention compared to the corresponding acid compounds.

[0067] 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 utilize racemates, diastereomers, or enantiomers as starting materials or intermediates. Diastereomeric compounds can be separated by chromatographic or crystallization methods. Similarly, enantiomeric mixtures can 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, as well as mixtures thereof, such as racemic mixtures, are intended to form part of the present compounds.

[0068] It will also be recognized that certain compounds of Formula I can be used as intermediates for additional compounds of Formula I. It will further be recognized that the compounds described herein can exist in unsolvated 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.

[0069] 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 the preparation of the compounds of the present invention will depend on the particular 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 schemes. The starting materials are generally available from commercial sources or are readily prepared using methods well known to those skilled in the art. For illustrative purposes, the schemes herein are not intended to be limiting unless otherwise specified. General methods for preparing the compounds of the invention, as well as key intermediates, are presented below. Those skilled in the art will recognize that other synthetic routes may be used to synthesize the compounds. While specific starting materials and reagents are shown in the schemes and discussed below, other starting materials and reagents can be readily substituted to obtain 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 this disclosure and using conventional chemistry well known to those skilled in the art. In general, the compounds of the invention can be prepared according to Scheme 1 by starting with a carboxylic acid derivative of glycyrrhetinic acid (i), which is converted to the corresponding acid halide, e.g., acid chloride intermediate (ii), using, for example, oxalyl chloride, catalyzed by dimethylformamide. Intermediate (ii) is then reacted with alcohol intermediate (iii) to obtain the final ester compound of Formula I. Scheme 1 [ka] In preparing compounds of Formula I, protection of remote functional groups (e.g., primary or secondary amines, etc.) of intermediates may be necessary. The need for such protection will vary depending 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 review of protecting groups and their use, see Greene, TW, and See PGM Wuts. Greene's Protective Groups in Organic Synthesis. 4th ed. New York: Wiley-Interscience, 2006.

[0070] It may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps are separated and / or purified (separated herein below) 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 apparatus; small-scale analytical; simulated moving bed ("SMB") and preparative thin- or thick-layer chromatography, as well as small-scale thin-layer and flash chromatography techniques. Those skilled in the art will apply the techniques most likely to achieve the desired separation.

[0071] Diastereomeric and enantiomeric mixtures can be separated into their individual stereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can also 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 diastereomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using a chiral HPLC column.

[0072] The present invention also encompasses pharmaceutical compositions or medicaments containing the compounds of the present invention and therapeutically inert carriers, diluents, or excipients, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments. Typically, the compounds of Formula I used in the methods of the present invention are prepared by subjecting the compounds of Formula I to physiologically acceptable solubility in water at ambient temperature, at an appropriate pH, and to the desired degree of purity. The formulations are prepared by mixing with a carrier, i.e., a carrier that is nontoxic to the recipient at the dosage and concentration used. The pH of the formulation will depend primarily on the specific use and concentration of the compound, but can range anywhere from about 3 to about 8. Formulation in acetate buffer at pH 5 is one suitable embodiment. In one embodiment, formulations containing the compounds of the invention are sterile. The compounds are typically stored as solid compositions, although lyophilized formulations or aqueous solutions are also acceptable.

[0073] The composition comprising the compound of the present invention is formulated, dosed, and administered in accordance with good medical practice.The factors to be considered in this context include the specific disorder to be treated, the specific mammal to be treated, the clinical condition of each patient, the cause of the disorder, the administration site, the administration method, the administration schedule, and other factors known to physicians.The "effective amount" of the compound to be administered will be adjusted according to such considerations and is the minimum amount necessary to inhibit the conversion of cortisol to cortisone by HSD2.Such an amount may be less than the amount that is toxic to normal cells or to the mammal as a whole.

[0074] The compounds of the present invention can be administered by any suitable means. In one particular embodiment, the compounds are administered orally. In one particular embodiment, the compounds are administered rectally.

[0075] Generally, the initial pharmaceutically effective amount of a compound of the 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 invention. In a specific embodiment, an effective amount is an amount of a compound of the invention sufficient to enhance colonic potassium secretion by about 15 mmol / day. In a specific embodiment, an effective amount is an amount of a compound of the invention sufficient to enhance colonic potassium secretion by about 1 mmol / day. In a specific embodiment, an effective amount is an amount of a compound of the invention sufficient to enhance colonic potassium secretion by about 5 mmol / day. In a specific embodiment, an effective amount is an amount of a compound of the invention sufficient to enhance colonic potassium secretion by about 10 mmol / day. In one particular embodiment, an effective amount is an amount of a compound of the invention sufficient to increase colonic potassium secretion by about 15 mmol / day, hi one particular embodiment, an effective amount is an amount of a compound of the invention sufficient to increase colonic potassium secretion by about 20 mmol / day.

[0076] The compounds can be administered in any convenient dosage form, such as tablets, capsules, solutions, dispersions, suspensions, syrups, suppositories, gels, emulsions, etc. An 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 tablet form using conventional equipment.

[0077] Other formulations can be prepared by mixing the compounds described herein with carriers or excipients. Suitable carriers and excipients are well known to those skilled in the art and are described, for example, in 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 formulations may contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to obtain superior presentation of the drug (i.e., a compound described herein or a pharmaceutical composition thereof) or to facilitate the manufacture of a pharmaceutical product (i.e., a drug product).

[0078] In one embodiment, the formulation releases the compound in response to contact with colonic enzymes, e.g., 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 broken down by microbial (normal intestinal flora) enzymes once the dosage form reaches the colon.

[0079] In one embodiment, the compounds of the present invention are administered orally. In another embodiment, the compounds are formulated for colonic delivery. Colonic delivery can be performed in response to pH, time, microorganisms, and pressure. In one embodiment, the formulation releases the compound in response to colonic pH. As the formulation moves through the GI tract, the release of the compound is triggered by an increase in pH. The formulation is based on a polymer that is insoluble at the lower pH in the stomach and upper small intestine and 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 a low pH environment of about 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.

[0080] In one aspect of the present invention, there is provided a method for inhibiting the conversion of cortisol to cortisone by HSD2, comprising contacting HSD2 with a compound of formula I. In another aspect of the present invention, there is provided a method for promoting MR activation in a mammal, comprising administering to the mammal an effective amount of a compound of formula I. In another aspect of the present invention, there is provided a method for lowering plasma potassium levels in a mammal, comprising administering to the 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, comprising administering to the mammal an effective amount of a compound of formula I.

[0081] In one aspect of the present invention, there is provided a method for treating and / or preventing hyperkalemia in a mammal, 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 one 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 drugs, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or other inhibitors of the renin-angiotensin-aldosterone system (RAAS), to regulate blood pressure. However, such drugs promote potassium retention. Accordingly, there is provided a method for treating and / or preventing hyperkalemia in a mammal, 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.

[0082] The compounds described herein, as well as their stereoisomers, diastereomers, enantiomers, tautomers, and pharmaceutically acceptable salts, can be used alone or in combination with other antihyperkalemia agents that act by a different mechanism of action. The compounds of the present invention can be administered together with other antihyperkalemia agents in a unit pharmaceutical composition or separately, and when administered separately, this can be done simultaneously or sequentially in any order. Such sequential administration can be close in time or remote in time.

[0083] In one embodiment, the other antihyperkalemic compound is a potassium ion-binding drug, such as 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 to exchange sodium or calcium ions in the intestinal lumen for secreted potassium ions, the majority of which occurs in the colon, the site of greatest potassium secretion in the intestine. In one embodiment, an antihyperkalemic 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 cross-linked with approximately 1.8 percent DVB.

[0084] 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.

[0085] 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 responsible for maintaining sodium balance and is also indirectly involved in buffering blood pH. The NHE3 antiporter exports one sodium ion into the cytosol of the cell while exporting one hydrogen ion from the cell into the intestinal lumen and the lumen of the proximal tubule. As shown in Figure 1, it has been demonstrated that there is a synergistic effect on fecal potassium excretion when HSD2 and NHE are inhibited. Accordingly, provided is a method for removing potassium from mammalian plasma and / or tissues, comprising administering to the mammal an effective amount of an HSD2 inhibitor or 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, comprising administering to the mammal an effective amount of an HSD2 inhibitor or 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, comprising administering to the mammal an effective amount of an HSD2 inhibitor or 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® (PEG3350). 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 intestinal ClC-2 chloride channels. In one embodiment, the ClC-2 chloride channel activator is lubiprostone.

[0086] Also provided is a method for removing potassium from plasma and / or tissues of a mammal, 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.

[0087] In another aspect, the present invention provides a pharmaceutical composition comprising an HSD2 inhibitor and an NHE inhibitor. In another aspect, the present invention provides a pharmaceutical composition comprising an MR agonist and an NHE inhibitor.

[0088] In another aspect, there is provided a method for treating hyperkalemia in a mammal, 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.

[0089] In one embodiment, the MR agonist is fludrocortisone.

[0090] In another aspect, there is provided a method for treating hyperkalemia in a mammal, 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, there is provided a composition comprising an HSD2 inhibitor and an NHE inhibitor. In one embodiment, the composition is a pharmaceutical composition. In one embodiment, effective amounts of an HSD2 inhibitor compound and an NHE inhibitor compound are present. 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 one 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 / 00206 No. 12 (WO03 / 055490); No. 2004 / 0113396 (WO03 / 051866); No. 2005 / 0020612; No. 2005 / 0054705; No. 2008 / 0194621; No. 2007 / 0225323; No. 2004 / 0039001; No. 2004 / 0224965; No. 2005 / 0113396; No. 2007 / 0135383; No. 2007 / 0135385; No. 2005 / 0244367; No. 2007 / 0270414; International Publication No. WO01 / 0727 42; WO01 / 021582 (CA2387529); WO97 / 024113 (CA02241531) WO2010078449; WO2014029983; WO2014029984; and compounds described in European Patent No. EP0744397 (CA2177007); each of which is incorporated by reference herein in its entirety.

[0091] In one embodiment, the NHE inhibitor is a compound that is minimally systemic, 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] (I) [ka] (IX) [In formula: NHE is an NHE-binding small molecule comprising (i) a heteroatom-containing moiety, and (ii) a cyclic or heterocyclic backbone or supporting moiety bonded directly or indirectly thereto, said heteroatom-containing moiety being selected from a substituted guanidinyl moiety and a substituted heterocyclic moiety optionally fused with the backbone or supporting moiety to form a fused bicyclic structure; and Z is a moiety having at least one site thereon for binding to an NHE-binding small molecule, wherein the resulting NHE-Z molecule has overall physicochemical properties that render the molecule substantially impermeable or substantially systemically non-bioavailable; and E is an integer having a value greater than or equal to 1.

[0092] 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.

[0093] 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] (II) [In formula: Z is a core having one or more sites thereon for binding to one or more NHE-binding small molecules, and the resulting NHE-Z molecule has overall physicochemical properties that render the molecule substantially impermeable or substantially systemically non-bioavailable; B is a heteroatom-containing moiety of an NHE-binding small molecule and is selected from a substituted guanidinyl moiety and a substituted heterocyclic moiety that may optionally be fused with the backbone moiety to form a fused bicyclic structure; The backbone is a cyclic or heterocyclic backbone or supporting moiety of an NHE-linked small molecule that is directly or indirectly bonded to the heteroatom-containing moiety B and is additionally optionally substituted with one or more hydrocarbyl or heterohydrocarbyl moieties; X is a bond or a substituted or unsubstituted hydrocarbyl or heterohydrocarbyl moiety connecting B and the backbone, and in particular a substituted or unsubstituted C 1~7a linking or spacer moiety selected from the group consisting of hydrocarbyl or heterohydrocarbyl, and substituted or unsubstituted, saturated or unsaturated, cyclic or heterocyclic moieties; and D and E are each independently an integer having a value of 1 or greater.

[0094] In some embodiments, the compound is an oligomer, dendrimer, or polymer, further wherein Z is a core moiety having two or more sites thereon for binding to multiple NHE-binding small molecules, either directly or indirectly via linking moieties L, and the compound has the structure of formula (X): [ka] (X) [wherein L is a bond or linker connecting the core and the NHE-binding small molecule, n is an integer greater than or equal to 2, and further, each NHE-binding small molecule may be the same or different from each other].

[0095] In some embodiments, the NHE-binding small molecule has the structure of formula (IV): [ka] (IV) or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof [In the formula, 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, where R and R are independently selected from 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; and Ar1 and Ar2 independently represent an aromatic ring or a heteroaromatic ring.

[0096] In certain embodiments, the NHE-binding small molecule has the following structure: [ka] or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof [In the formula, 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 selected from 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.

[0097] In some embodiments, the NHE-binding small molecule has one of the following structures: [ka] or [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.

[0098] In certain embodiments, the core has the following structure: [ka] [In the formula, X is a bond, -O-, -NH-, -S-, or C1~6 selected from the group consisting of alkylene, —NHC(═O)—, —C(═O)NH—, —NHC(═O)NH—, —SO2NH—, and —NHSO2—; Y is a bond, optionally substituted with C 1~8 alkylene, optionally substituted aryl, optionally substituted heteroaryl, polyethylene glycol linker, -(CH) 1~6 O(CH2) 1~6 - and -(CH2) 1~6 NY1(CH2) 1~6 - selected from the group consisting of; and Y1 is hydrogen, optionally substituted C 1~8 alkyl, optionally substituted aryl or optionally substituted heteroaryl.

[0099] In some embodiments, the core is selected from the group consisting of: [ka] ; [ka] ; [ka] ; [ka] ; [ka] ; [ka] ; [ka] ; [ka] and [ka] [In the formula, L is a bond or linking moiety; NHE is an NHE-binding small molecule; and n is an integer that is not 0.

[0100] 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] phenyl)-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)phenylsulfonamide)-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 (iii)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)acetamido)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(oxomethylene)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)acetamide; 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-azatridecan-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-azahexadecan-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)phenylsulfonamide )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-diazanonadecane-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(oxomethylene)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(oxomethylene)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-azatridecan-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).

[0101] In one embodiment, the NHE inhibitor is: [ka]

[0102] In some embodiments, the compound has the structure of formula (IH): [ka] (IH) or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof [In the formula, (a) n is an integer greater than or equal to 2; (b) the core is a core moiety having two or more sites thereon for binding to two or more NHE-binding small molecule moieties; (c) L is a linker that connects the bond or core moiety to two or more NHE-binding small molecule moieties; and (d) The NHE is an NHE-binding small molecule moiety having the structure of formula (XI-H): [ka] (XI-H) (In the formula: B is selected from the group consisting of aryl and heterocyclyl; Each R5 is hydrogen, halogen, or 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 linking the NHE-binding small molecule moiety to L, provided that at least one is a bond linking the NHE-binding small molecule moiety to L; R3 and R4 are hydrogen, optionally substituted C 1~4 independently 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; and Each R1 is hydrogen, halogen, or optionally substituted C 1~6 Alkyl and optionally substituted C 1~6 In some embodiments, n is 2. In certain embodiments, L is a polyalkylene glycol linker. In certain embodiments, L is a polyethylene glycol linker.

[0103] In certain embodiments, the core has the following structure: [ka] [In the formula, 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, optionally substituted with C 1~8 alkylene, optionally substituted aryl, optionally substituted heteroaryl, polyethylene glycol linker, -(CH) 1~6 O(CH2) 1~6 - and -(CH2) 1~6 NY1(CH2) 1~6 - selected from the group consisting of; and Y1 is hydrogen, optionally substituted C 1~8 alkyl, optionally substituted aryl or optionally substituted heteroaryl.

[0104] In some embodiments, the core is selected from the group consisting of: [ka]

[0105] In certain embodiments, the NHE-binding small molecule moiety has the structure of formula (XII-H): [ka] (XII-H) [In the formula, Each R3 and R4 is hydrogen and optionally substituted C 1~4 A group consisting of alkyl or R3 and R4 together with the nitrogen to which they are attached form an optionally substituted 4-8 membered heterocyclyl; Each R1 is hydrogen, halogen, or C 1~6 Alkyl, and C 1~6 independently selected from the group consisting of haloalkyl; and R5 is selected from the group consisting of -SO2-NR7- and -NHC(=O)NH-, where R7 is hydrogen or C 1~4 alkyl].

[0106] 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 selected from 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.

[0107] In certain embodiments, the compound has the structure of formula (II): [ka] (II) or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof [In the formula, (a) NHE is an NHE-binding small molecule moiety having the structure of formula (AI): [ka] (AI) (In the formula, 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 independently selected from alkyl-OH or bonds linking an NHE-binding small molecule to L, provided that at least one is a bond linking 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; and 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] (BI) (In the formula: X is 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 b are 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; If X is CX1, then Z is -NZ a -C(=O)-NZ a -, -C(=O)NZ a -, -NZ a selected from —C(═O)— and heteroaryl; X is N or N(C 1~6 alkyl), then Z is -NZ a -C(=O)-NZ a -, -NZ a -C(=O)- and heteroaryl; and each X c and Z a is hydrogen and C 1~6 alkyl); and (c) L is a linker connecting the bond or core moiety to the NHE-binding small molecule moiety].

[0108] In some embodiments, the NHE-binding small molecule moiety has the structure: [ka] [In formula: 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].

[0109] In some embodiments, the NHE-binding small molecule moiety has one of the following structures: [ka] or [ka]

[0110] 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.

[0111] In some embodiments, the compound has the structure of Formula (II): [ka] (II-I) or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof [In formula: (a) NHE is an NHE-binding small molecule moiety having the structure of formula (AI): [ka] (A) (In the formula: 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 independently selected from 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; and 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] (CI) (In the formula: 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 selected from —C(═O)— and heteroaryl; each Z a is hydrogen and C 1~6 alkyl); and (c) L is a linker connecting the bond or core moiety to the NHE-binding small molecule).

[0112] In certain embodiments, the NHE-binding small molecule moiety has the following structure: [ka] [In formula: 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].

[0113] In certain embodiments, the NHE-binding small molecule moiety has one of the following structures: [ka] or [ka]

[0114] In another embodiment, the NHE inhibitor is: [ka] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers thereof. [In formula: The linker is -(CHR 13 ) p -[Y-(CH2) r ] s -ZR 13 -(CH2) t -Z-; W, independently at each occurrence, is 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 ) m is an integer of 1 to 2; n is an integer of 1 to 4; r and p, independently at each occurrence, are integers 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, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from the group consisting of one or more 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)R9 , optionally substituted with 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 2 may, together with the nitrogen to which they are attached, form a heterocyclyl or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, wherein the heterocyclyl or heteroaryl group may contain one or more of 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 8are 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 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 one or more R 19 is optionally replaced by; R14 is independently at each occurrence H, C1-C6 alkyl, or C1-C6 haloalkyl; or R 6 and R 14 may, independently at each occurrence, combine together with the atom to which they are attached to form a 5-6 membered heterocyclyl, wherein each C-C cycloalkyl, or heterocyclyl may be selected from one or more R 19 optionally replaced by; or R 13 and R 14 are combined with the atoms to which they are attached, and each independently form a C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each heterocyclyl or heteroaryl is selected from one or more R 19 is optionally replaced by; R 15 , R 16 , R 17 , and R 18 is independently at each occurrence H, OH, NH, or C-C alkyl, wherein said alkyl is selected from one or more R 19 is optionally replaced by; and R 19 is independently at each occurrence H, OH, NH2, oxo, C1-C6 alkyl, C1-C6H haloalkyl, C1-C6 alkoxy].

[0115] In one embodiment, the NHE3 inhibitor is a compound according to the formula above, however: (1) If X is H, then n is 1; (2) X is a bond, O, or CR 11 R 12 , then n is 2; (3) If n is 3, X is CR 11 or N; (4) When n is 4, X is C; (5) wherein only one of Q or X is —NHC(O)NH—; (6)R 1 and R 2 together with the nitrogen to which they are attached must not form a pyrrolidinyl; (7)R 1 and R 2 is methyl and R 3 and R 4 is a halogen and R 5 and R 8 is H, the linker is [ka] isn't it; (8)R 1 and R 2 together with the nitrogen to which they are attached to form piperidinyl, and R 3 and R 4 is a halogen and R 5 and R 8 is H, the linker is [ka] is not; or (9)R 1 and R 2 together with the nitrogen to which they are attached form 3-aminopiperidin-1-yl, and R 3 and R 4 is a halogen and R 5 , R 6 , R 7 , and R 8 is H, the linker is [ka] isn't it This is subject to the condition that:

[0116] In one embodiment, the NHE3 compound has a structure according to the 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, independently at each occurrence, are integers 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, C1-C6 alkyl, or C1-C6 haloalkyl; R 8 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 one or more R 17 optionally replaced by; or R 7 and R 8 may combine together with the atom to which they are attached to form, independently at each occurrence, a heterocyclyl or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each heterocyclyl or heteroaryl is selected from one or more R 17 is 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 R16 is independently at each occurrence H, OH, NH, or C-C alkyl, wherein said alkyl is selected from one or more R 17 is optionally replaced by; and R 17 is independently at each occurrence H, OH, NH2, oxo, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkoxy.

[0117] 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 then n is 2; (2) If n is 3, X is CR 11 or N; (3) When n is 4, X is C; (4) In this case, only one of Q or X is -NHC(O)NH-; (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] is 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] isn't it This is subject to the condition that:

[0118] In one embodiment, the NHE3 inhibitor compound has a structure according to the 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-tetraazaicosane-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-tetraazaicosane-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-tetraazaicosane-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-tetraazaicosane-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-tetraazaicosane-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-tetraazaicosane-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-tetraazaicosane-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-tetraazaicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl) yl)]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-tetraazaicosane-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-tetraacetate] Zaoctadecandioyl)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)sulfonamide]-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.

[0119] In one embodiment of the present invention, the NHE3 inhibitor is a compound according to the following formula: [ka] (Ia)

[0120] In one embodiment of the present invention, the NHE3 inhibitor is a compound according to the following formula: [ka] (Ib)

[0121] 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-aminopiperidine Lysin-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) 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]e 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 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-([ ... Benzene-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-aminopiperidine Lysin-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]sulfonamide)-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-fluorobenzene 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-methylbenzenesulfonamido Mido;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]sulfonamide)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]sulfonamido)-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]sulfonamide)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]sulfonamide)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-indene -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-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-[(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]sulfonamide)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-di 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-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)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]sulfonamide)-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]sulfonamide)-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]sulfonamide)-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]sulfonamide)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]sulfonamide)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]

[0122] The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the invention. For example, compounds not exemplified may be successfully synthesized by modifications apparent to one skilled in the art, such as by appropriate protection of interfering groups, by utilizing other suitable reagents known in the art other than those described, and / or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds described herein.

[0123] 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). In a 1 L pressure tank reactor (10 atm) purged and maintained with an inert atmosphere of CO, 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,6 b,7,8,8a,9,12,12a,12b,13,14b-Octadecahydropicene-2-carboxylate (prepared by the method described in U.S. Patent 20160151387) (11 g, 15.92 mmol, 1.00 equiv.), Pd(PPh3)4 (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 3 × 150 mL of DCM, and the organic layers were combined. The resulting mixture was washed with 3 × 150 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:10). The crude product (20 mL) was purified by flash preparative HPLC under the following conditions (CombiFlash- 1) Purified by column, C 18Silica gel; mobile phase, ACN: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.

[0124] 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). In a 250 mL round-bottom flask, add 1-2 (3 g, 5.11 mmol, 1.00 equiv), DMF (30 mL), and DMAP (102.4 mg, 0.84 mmol, 0.10 equiv). Subsequently, TEA (3 mL, 5.80 equiv.) was added dropwise with stirring at 0° C. To this, SEMCl (4.2 mL, 4.80 equiv.) was added dropwise with stirring at 0° C. The resulting solution was stirred at room temperature for 1.5 hours. The reaction was then quenched by the addition of 50 mL of aqueous KCO solution. The resulting solution was diluted with 250 mL of DCM. The resulting mixture was washed with 3×150 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:10). This gave 3.5 g (95.5%) of 1-3 as a pale yellow oil.

[0125] 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 H was charged with 1-3 (6.6 g, 9.20 mmol, 1.00 equiv.), palladium on dry activated carbon (1.32 g, 0.20 equiv.), and acetone (150 mL). The resulting solution was stirred overnight at 50 °C. The solid was collected by filtration. The resulting mixture was concentrated under vacuum. This afforded 4.2 g (73%) of 1-4 as a white solid.

[0126] 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 250 mL round-bottom flask was charged with 1-4 (5.25 g, 8.35 mmol, 1.00 equiv), DMF (70 mL), CsCO (4.1 g, 12.58 mmol, 1.50 equiv), and BnBr (2.86 g, 16.72 mmol, 2.00 equiv). The resulting solution was stirred at 60 °C for 2 h. The resulting solution was diluted with 250 mL of DCM. The resulting solution was extracted with 2 × 100 mL of DCM, and the organic layers were combined and dried in an oven under reduced pressure. The resulting residue was applied to a silica gel column with EtOAc / petroleum ether (1:10). This afforded 6 g (99%) of 1-5 as an off-white solid.

[0127] 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). A 250 mL round-bottom flask was charged with 1-5 (5.6 g, 7.79 mmol, 1.00 equiv.) and THF (40 mL). This was followed by the addition of hydrogen chloride (4 M, 30 mL). The resulting solution was stirred at 60 °C for 2 h. Solution The pH value of the solution was adjusted to 3 with sodium bicarbonate (saturated). The resulting solution was extracted with 3×100 mL of DCM and the organic layers were combined. The resulting mixture was washed with 2×150 mL of brine. The mixture was dried over anhydrous sodium sulfate. The crude product (20 mL) was purified by flash preparative HPLC under the following conditions (CombiFlash-1): column, C 18 Silica gel; mobile phase, ACN:water = 100:0; detector, UV 254 nm. 1 L of product was obtained, which 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).

[0128] 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 dropwise to 1-6 (0.50 g, 0.85 mmol) and DMF (1 drop) in DCM (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.

[0129] 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). A 250 mL round-bottom flask was charged with 1-7 (200 mg, 0.33 mmol, 1.00 equiv.), MeOH (20 mL), and TEA (0.274 mL, 6.00 equiv.). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo. This yielded 198 mg (100%) of 1-8 as a crude pale yellow solid.

[0130] 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). A 250 mL round-bottom flask purged and maintained with an inert atmosphere of H was charged with 1-8 (198 mg, 0.33 mmol, 1.00 equiv), MeOH (40 mL), and Pd / C (20 mg). The resulting solution was stirred at room temperature for 1 h. The solid was filtered off. The resulting mixture was concentrated in vacuo. The crude product (200 mg) was purified by preparative HPLC using the following conditions: column, XBridge Prep C18 OBD column, 190 × 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O) and ACN (ACN 50.0% to 62.0% in 7 min); detector, UV 254 / 220 nm. 111.8 mg of product was obtained. This gave 111.8 mg (66%) of 1-9 as a pale yellow solid. MS (ES, m / z): [M+H] + = 513.60; 1 H 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).

[0131] Example 2 (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-dicarboxylic acid (2-1) [ka] A 50 mL round-bottom flask was charged with 1-6 (300 mg, 0.51 mmol, 1.00 equiv.), MeOH (30 mL), and Pd / C (30 mg, 0.10 equiv.). Hydrogen (1 atm) was introduced to the above. The resulting solution was stirred at room temperature for 2 hours. The solid was filtered off. The crude product was purified by preparative HPLC using the following conditions: mobile phase, water (0.05% TFA) and ACN (ACN 60.0% to 77.0% in 8 minutes); detector, UV 254 nm. This gave 110 mg (43%) of 2-1 as a white solid. MS (ES, m / z): [M+H] + =499.25; 1 H-NMR (400 MHz, MeOH-d4): δ 0.81 (s, 4H), 0.91 (s, 3H), 0.93-1.01 (m, 2H), 1.11 (s, 3H), 1.13-1.20 (m, 9H), 1.21-1.31 (m, 1H), 1.32-1.54 (m, 9H), 1.63-1.81 (m, 3H), 1.81-2.00 (m, 4H), 2.09-2.26 (m, 3H), 2.50 (s, 1H), 2.75 (d, J = 13.2 Hz, 1H), 3.34 (s, 2H), 5.59 (s, 1H).

[0132] Example 3 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(isopropoxycarbonyl)-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 (3-2) [ka] Synthesis of 2-benzyl 10-isopropyl (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 (3-1). A 25 mL round-bottom flask was charged with 1-7 (154 mg, 0.25 mmol, 1.00 equiv), DCM (10 mL), propan-2-ol (46 mg, 0.77 mmol, 3.00 equiv), DMAP (3 mg, 0.02 mmol, 0.10 equiv), and TEA (0.05 mL, 1.50 equiv). The resulting solution was stirred at room temperature for 2 days. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:5). This afforded 114 mg (71%) of 3-1 as a white solid.

[0133] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(isopropoxycarbonyl)-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 (3-2). A 50 mL round-bottom flask purged and maintained with an inert atmosphere of H was charged with 3-1 (114 mg, 0.18 mmol, 1.00 equiv), THF (10 mL), and Pd / C (12 mg). The resulting solution was stirred overnight at room temperature. The solid was filtered off. The resulting mixture was concentrated in vacuo. The crude product (100 mg) was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% NH3H2O) and ACN (ACN 41.0% to 57.0% in 8 min); detector, UV 254 nm. 34.9 mg of product was obtained. This resulted in 34.9 mg (36%) of 3-2 as a white solid. MS (ES, m / z): [M+H] + = 541.40; 1 H NMR (400 MHz, chloroform-d) δ 0.74 (d, J = 11.2 Hz, 1H), 0.83-0.94 (m, 7H), 1.01-1.05 (m, 4H), 1.13-1.17 (m, 3H), 1.18-1.27 (m, 13H), 1.32-1.52 (m, 9H), 1.60-1.70 (m, 3H), 1.78-1.88 (m, 1H), 1.91-2.07 (m, 4H), 2.11-2.21 (m, 2H), 2.37 (s, 1H), 2.83 (d, J = 13.2 Hz, 1H), 4.97-5.04 (m, 1H), 5.70 (s, 1H), 9.9 (s, 1H).

[0134] Example 4 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl)oxy)carbonyl)-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 (4-2) [ka] 2-benzyl 10-(1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl) (2S,4aS,6aS,6bR, 8aS,10S,12aS,12bR, Synthesis of (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 (4-1). In a 50 mL round-bottom flask, add 1-7 (154 mg, 0.25 mmol, 1.00 equiv), DCM (10 mL), 1,1,1,3,3,3-hexafluoro-2-methylpropan-2-ol (93 mg, 0.51 mmol, 2.00 equiv), DMAP (3 mg, 0.02 mmol, 0.10 equiv), and TEA (0.053 mL, 1.50 equiv). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:5). This gave 226 mg (118%) of 4-1 as a crude white solid.

[0135] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl)oxy)carbonyl)-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 (4-2). A 100 mL round-bottom flask purged and maintained with an inert atmosphere of H was charged with 4-1 (226 mg, 0.30 mmol, 1.00 equiv.), MeOH (10 mL), THF (10 mL), and Pd / C (23 mg). The resulting solution was stirred overnight at room temperature. The solids were filtered off. The resulting mixture was concentrated in vacuo. The crude product (190 mg) was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O) and ACN (ACN 5.0% to 55.0% in 1 min, to 68.0% in 7 min); detector, UV 254 nm. 80.9 mg of product was obtained. This yielded 80.9 mg (41%) of 4-2 as a white solid. MS (ES, m / z): [M+H] + = 663.30; 1 H NMR (400 MHz, MeOH-d4) δ 0.82-0.98 (m, 7H), 1.00-1.13 (m, 5H), 1.17-1.30 (m, 10H), 1.39-1.61 (m, 9H), 1.65-1.83 (m, 3H), 1.84-2.09 (m, 7H), 2.12-2.28 (m, 2H), 2.35 (dd, J = 12.8, 3.2 Hz, 1H), 2.53 (s, 1H), 2.81 (dt, J = 10.4, 3.6 Hz, 1H), 5.62 (s, 1H).

[0136] Example 5 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-hydroxyethoxy)carbonyl)-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 (5-2) [ka] 2-Benzyl 10-(2-(benzyloxy)ethyl)(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-icosahydropiperidin Synthesis of sen-2,10-dicarboxylate (5-1). A 25 mL round-bottom flask was charged with 1-7 (154 mg, 0.25 mmol, 1.00 equiv), DCM (10 mL), 2-(benzyloxy)ethan-1-ol (58 mg, 0.38 mmol, 1.50 equiv), DMAP (3 mg, 0.02 mmol, 0.10 equiv), and TEA (0.05 mL, 1.50 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:5). This yielded 107 mg (58%) of 5-1 as a white solid.

[0137] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-hydroxyethoxy)carbonyl)-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 (5-2). A 100 mL round-bottom flask purged and maintained under an inert atmosphere of H was charged with 5-1 (107 mg, 0.15 mmol, 1.00 equiv), MeOH (10 mL), THF (10 mL), and Pd / C (20 mg). The resulting solution was stirred at room temperature for 7 days. The solid was filtered off. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O) and ACN (ACN 40.0% to 70.0% in 8 min); detector, UV 254 nm. 23.2 mg of product was obtained. This resulted in 23.2 mg (29%) of 5-2 as a white solid. MS (ES, m / z): [M+H] + = 543.35; 1 H NMR (400 MHz, MeOH-d4): δ 0.74 (s, 3H), 0.77-0.83 (m, 4H), 0.89 -0.95 (m, 5H), 1.05-1.09 (m, 9H), 1.13-1.17 (m, 1H), 1.26-1.44 (m, 9H), 1.55-1.71 (m, 3H), 1.72-1.81 (m, 2H), 1.82-1.94 (m, 2H), 1.96-2.10 (m, 1H), 2.11-2.24 (m, 2H), 2.40 (s, 1H), 2.67 (d, J = 13.2 Hz, 1H), 3.63 (t, J = 5.0 Hz, 2H), 4.03 (t, J = 5.0 Hz, 2H), 5.51 (s, 1H).

[0138] Example 6 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-((2,2,2-trifluoroethoxy)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 (6-2) [ka] Synthesis of 2-benzyl 10-(2,2,2-trifluoroethyl)(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 (6-1). In a 25 mL round-bottom flask, add 1 A mixture of 6-7 (154 mg, 0.25 mmol, 1.00 equiv.), DCM (10 g, 117.74 mmol, 464.30 equiv.), 2,2,2-trifluoroethan-1-ol (51 mg, 0.51 mmol, 2.00 equiv.), DMAP (3 mg, 0.02 mmol, 0.10 equiv.), and TEA (0.053 mL, 1.50 equiv.) was added. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:5). This gave 256 mg (150%) of 6-1 as a crude white solid.

[0139] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-((2,2,2-trifluoroethoxy)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 (6-2). A 100 mL round-bottom flask purged and maintained under an inert atmosphere of H was charged with 6-1 (256 mg, 0.38 mmol, 1.00 equiv), MeOH (10 mL), THF (10 mL), and Pd / C (26 mg). The resulting solution was stirred overnight at room temperature. The solid was filtered off. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by preparative HPLC using the following conditions: column, XBridge Prep OBD C18 column, 19 x 250 mm, 5 um; mobile phase, water (0.05% TFA) and ACN (ACN 82.0% to 89.0% in 8 min); detector, UV 254 nm. 96.9 mg of product was obtained. This resulted in 96.9 mg (44%) of 6-2 as a white solid. MS (ES, m / z): [M+H] + = 581.30; 1 H NMR (400 MHz, MeOH-d4): δ 0.82-1.00 (m, 7H), 1.01-1.11 (m, 5H), 1.17-1.37 (m, 10H), 1.38-1.60 (m, 9H), 1.67-1.81 (m, 3H), 1.82-1.92 (m, 2H), 1.93-2.09 (m, 2H), 2.11-2.27 (m, 2H), 2.38 (dd, J = 12.8, 3.6 Hz, 1H), 2.54 (s, 1H), 2.81 (dt, J = 13.5, 3.4 Hz, 1H), 4.50-4.76 (m, 2H), 5.61 (s, 1H).

[0140] Example 7 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(1H-imidazol-1-yl)ethoxy)carbonyl)-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 (7-2) [ka] Synthesis of 10-(2-(1H-imidazol-1-yl)ethyl) 2-benzyl (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 (7-1). In a 25 mL round-bottom flask, add 1-7 (137 mg, 0.23 mmol, 1.00 equiv), DCM (10 mL), 2-(1H-imidazol-1-yl)ethan-1-ol (51 mg, 0.45 m mol, 2.00 equiv), DMAP (3 mg, 0.02 mmol, 0.10 equiv), and TEA (0.047 mL, 1.50 equiv) were added. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with DCM / MeOH (20:1). This gave 140 mg (91%) of 7-1 as a white solid.

[0141] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(1H-imidazol-1-yl)ethoxy)carbonyl)-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 (7-2). To a 50 mL round-bottom flask purged and maintained under an inert atmosphere of H was placed 7-1 (140 mg, 0.20 mmol, 1.00 equiv), THF (10 mL), and Pd / C (14 mg). The resulting solution was stirred overnight at room temperature. The solid was filtered off. The resulting mixture was concentrated under vacuum. The crude product (120 mg) was purified by preparative HPLC using the following conditions: column, XBridge Prep C18 OBD column, 19 x 150 mm 5 um; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O) and ACN (ACN 30.0% to 66.0% in 7 min); detector, UV 254 / 220 nm. 67.4 mg of product was obtained. This resulted in 67.4 mg (55%) of 7-2 as a white solid. MS (ES, m / z): [M+H] + = 593.40; 1 H NMR (400 MHz, MeOH-d4): δ 0.69 (s, 3H), 0.71-0.75 (m, 4H), 0.80 (s, 3H), 0.84-0.98 (m, 2H), 1.04-1.09 (m, 9H), 1.10-1.21 (m, 2H), 1.27-1.30 (m, 3H), 1.31- 1.32 (m, 4H), 1.35-1.38 (m, 1H), 1.49-1.58 (m, 1H), 1.58-1.69 (m, 2H), 1.70-1.90 (m, 4H), 1.99- 2.19 (m, 3H), 2.39 (s, 1H), 2.64 (d, J = 13.6 Hz, 1H), 4.20-4.33 (m, 4H), 5.49 (s, 1H), 6.87 (s, 1H), 7.07 (s, 1H), 7.69 (s, 1H).

[0142] Example 8 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-morpholinoethoxy)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 (8-2) [ka] Synthesis of 2-benzyl 10-(2-morpholinoethyl)(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 (8-1). In a 25 mL round-bottom flask, add 1-7 (137 mg, 0.23 mmol, 1.00 equiv), DCM (10 mL), 2-(morpholinoethyl)- (4-yl)ethan-1-ol (59 mg, 0.45 mmol, 2.00 equiv.), DMAP (3 mg, 0.02 mmol, 0.10 equiv.), and TEA (0.047 mL, 1.50 equiv.) were added. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with DCM / MeOH (20:1). This gave 151 mg (95%) of 8-1 as a white solid.

[0143] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-morpholinoethoxy)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 (8-2). To a 50 mL round-bottom flask purged and maintained under an inert atmosphere of H was placed 8-1 (151 mg, 0.22 mmol, 1.00 equiv), THF (10 mL), and Pd / C (15 mg). The resulting solution was stirred overnight at room temperature. The solid was filtered off. The resulting mixture was concentrated under vacuum. The crude product (150 mg) was purified by preparative HPLC using the following conditions: column, XBridge Prep C18 OBD column, 19 x 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (ACN 30.0% to 66.0% in 7 min); detector, UV 254 / 220 nm. 28.6 mg of product was obtained. This resulted in 28.6 mg (22%) of 8-2 as a white solid. MS (ES, m / z): [M+H] + = 612.70; 1 H NMR (300 MHz, chloroform-d): δ 0.49-0.98 (m, 8H), 1.02 (s, 4H), 1.09 -1.28 (m, 10H), 1.29-1.48 (m, 8H), 1.49-1.75 (m, 4H), 1.77-2.12 (m, 5H), 2.20 (d, J = 12.9 Hz, 2H), 2.37 (s, 1H), 2.44-2.75 (m, 6H), 2.83 (d, J = 13.5 Hz, 1H), 3.72 (s, 4H), 4.00-4.70 (m, 2H), 5.70 (s, 1H).

[0144] Example 9 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-((((R)-quinuclidin-3-yl)oxy)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 (10-2) [ka] Synthesis of 2-benzyl 10-((R)-quinuclidin-3-yl)(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 (10-1). A 25 mL round-bottom flask was charged with 1-7 (154 mg, 0.25 mmol, 1.00 equiv), DCM (10 mL), (3R)-1-azabicyclo[2.2.2]octan-3-ol (65 mg, 0.51 mmol, 2.02 equiv), DMAP (3 mg, 0.02 mmol, 0.10 equiv), and TEA (0.053 mL, 1.50 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography with DCM / MeOH (10:1). The column was loaded with 10-1, which gave 72 mg (41%) of 10-1 as a crude white solid.

[0145] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-((((R)-quinuclidin-3-yl)oxy)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 (10-2). A 100 mL round-bottom flask purged and maintained under an inert atmosphere of H was charged with 10-1 (72 mg, 0.10 mmol, 1.00 equiv), MeOH (10 mL), THF (10 mL), and Pd / C (7 mg). The resulting solution was stirred overnight at room temperature. The solid was filtered off. The resulting mixture was concentrated under vacuum. The crude product (50 mg) was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19×150 mm; mobile phase, water (0.05% TFA) and ACN (ACN 40.0% to 54.0% in 8 minutes); detector, UV 254 nm. 11.3 mg of product was obtained. This resulted in 11.3 mg (18%) of 10-2 as a white solid. MS (ES, m / z): [M+H] + = 608.40; 1 H NMR (400 MHz, MeOH-d4): δ 0.84-1.93 (m, 4H), 0.95 (s, 3H), 0.99 -1.12 (m, 5H), 1.16-1.23 (m, 9H), 1.24-1.38 (m, 2H), 1.39-1.53 ​​(m, 8H), 1.54-1.65 (m, 1H), 1.68-1.80 (m, 3H), 1.81-2.05 (m, 6H), 2.06-2.19 (m, 2H), 2.20-2.29 (m, 2H), 2.31-2.41 (m, 2H), 2.53 (s, 1H), 2.82 (dt, J = 13.2, 3.4 Hz, 1H), 3.21-3.30 (m, 2H), 3.38-3.44 (m, 2H), 3.78 (ddd, J = 14.0, 8.7, 2.1 Hz, 1H), 5.12 (dt, J = 7.8, 3.5 Hz, 1H), 5.61 (s, 1H).

[0146] Example 10 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-((2-(pyridin-2-yl)ethoxy)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 (11-2) [ka] Synthesis of 2-benzyl 10-(2-(pyridin-2-yl)ethyl)(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 (11-1). A 25 mL round-bottom flask was charged with 1-7 (154 mg, 0.25 mmol, 1.00 equiv.), DCM (10 mL), 2-(pyridin-2-yl)ethan-1-ol (63 mg, 0.51 mmol, 2.00 equiv.), DMAP (3 mg, 0.02 mmol, 0.10 equiv.), and TEA (0.053 mL, 1.50 equiv.). The resulting solution was stirred overnight at room temperature. The resulting mixture was then cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was loaded onto a silica gel column with EtOAc / petroleum ether (1:1), which gave 217 mg (123%) of 11-1 as a crude white solid.

[0147] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-((2-(pyridin-2-yl)ethoxy)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 (11-2). A 25 mL round-bottom flask was charged with 11-1 (176 mg, 0.25 mmol, 1.00 equiv), MeOH (10 mL), THF (10 mL), and Pd / C (18 mg). The resulting solution was stirred overnight at room temperature. The solid was filtered off. The resulting mixture was concentrated under vacuum. The crude product (150 mg) was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19×150 mm; mobile phase, water (0.05% TFA) and ACN (ACN 40.0% to 55.0% in 8 min); detector, UV 254 nm. 35.8 mg of product was obtained. This resulted in 35.8 mg (23%) of 11-2 as a white solid. MS (ES, m / z): [M] + = 604.35; 1 H NMR (400 MHz, MeOH-d4): δ 0.77 (s, 3H), 0.79-0.90 (m, 7H), 0.91 -1.01 (m, 1H), 1.03-1.10 (m, 1H), 1.17 (d, J = 14.4 Hz, 9H), 1.25-1.33 (m, 1H), 1.37-1.50 (m, 9H), 1.58- 1.82 (m, 3H), 1.82-2.08 (m, 4H), 2.09-2.30 (m, 3H), 2.49 (s, 1H), 2.75 (dt, J = 13.6, 3.5 Hz, 1H), 3.39 (t, J = 6.2 Hz, 2H), 4.50 (t, J = 6.2 Hz, 2H), 5.60 (s, 1H), 7.87 (t, J = 6.8 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 8.45 (td, J = 8.0, 1.6 Hz, 1H), 8.75 (dd, J = 6.0, 0.8 Hz, 1H).

[0148] Example 11 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-amino-2-oxoethoxy)carbonyl)-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 (12-2) [ka] Synthesis of 10-(2-amino-2-oxoethyl) 2-benzyl (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 (12-1). In a 50 mL round-bottom flask, 1-6 (59 mg, 0.10 mmol, 1 equiv), DMF (5 mL, 0.07 mmol, 0.683 equiv), TBAI (18 mg, 0.05 mmol, 0.486 equiv), 2-chloro- The resulting solution was stirred at 65° C. for 2 hours. The resulting solution was diluted with 30 mL of DCM. The resulting mixture was washed with 2×15 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solid was filtered off. The resulting mixture was concentrated. The residue was applied to a silica gel column with EA. This gave 50 mg (77.26%) of 12-1 as a white solid.

[0149] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-amino-2-oxoethoxy)carbonyl)-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 (12-2). A 100 mL round-bottom flask purged and maintained with an inert atmosphere of H was charged with 12-1 (200 mg, 0.31 mmol, 1 equiv.), MeOH (10 mL, 0.31 mmol, 1.008 equiv.), and Pd / C (20 mg, 0.19 mmol, 0.607 equiv.). The resulting solution was stirred at room temperature for 1 h. The solid was filtered off. The crude product was purified by preparative HPLC (2#-Analyse HPLC-SHIMADZU (HPLC-10)) using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% TFA) and ACN (phase B 5% to 54% in 1 min, to 68% in 7 min); detector, UV 254 nm. This yielded 84.6 mg (49.16%) of 12-2 as a white solid. MS (ES, m / z): [M+H] + =556.46; 1 H-NMR (400 MHz, MeOH-d4): δ 0.82-0.96 (m, 7H), 0.99-1.08 (m, 5H), 1.13-1.19 (m, 9H), 1.23 (d, J = 3.2 Hz, 1H), 1.40-1.49 (m, 8H), 1.55-1.60 (m, 1H), 1.67-1.76 (m, 3H), 1.83-2.00 (m, 4H), 2.15-2.19 (m, 2H), 2.35 (d, J = 0.4 Hz, 1H), 2.50 (s, 1H), 2.78 (d, J = 1.6 Hz, 1H), 4.51 (q, J = 4.8 Hz, 2H), 5.58 (s, 1H).

[0150] Example 12 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((carboxymethoxy)carbonyl)-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 (13-3) [ka] Synthesis of 2-benzyl 10-(2-methoxy-2-oxoethyl)(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 (13-1). A 50 mL round-bottom flask was charged with 1-6 (590 mg, 1.00 mmol, 1.00 equiv), acetone (20 mL), TEA (510 mg, 5.04 mmol, 5.00 equiv), and methyl 2-chloroacetate (440 mg, 4.05 mmol, 4.00 equiv). The resulting solution was heated for 4 h. The mixture was refluxed. The resulting mixture was concentrated under vacuum. The resulting solid was washed with 3×10 mL of hexane. This gave 600 mg (91%) of 13-1 as a white solid.

[0151] Synthesis of 2-(((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-carbonyl)oxy)acetic acid (13-2). A 50 mL round-bottom flask was charged with benzyl 13-1 (600 mg, 0.91 mmol, 1.00 equiv), THF (10 mL), water (10 mL), and LiOH.HO (190 mg, 4.52 mmol, 5.00 equiv). The resulting solution was stirred at room temperature for 3 h. The resulting solution was diluted with 30 mL of water. The pH of the solution was adjusted to 2-3 with 1.0 M hydrogen chloride. The resulting solution was extracted with 3 × 30 mL of DCM, and the organic layers were combined. The resulting mixture was washed with 1 × 40 mL of water and 1 × 40 mL of saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This yielded 520 mg (89%) of 13-2 as a white solid.

[0152] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((carboxymethoxy)carbonyl)-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 (13-3). A 100 mL round-bottom flask was charged with 13-2 (150 mg, 0.23 mmol, 1 equiv.), EA (16 mL), and Pd / C (4.9 mg, 0.05 mmol, 0.199 equiv.). H2 (g) was introduced into the flask. The resulting solution was stirred overnight at room temperature. The solid was filtered off. The resulting mixture was concentrated. The crude product (130 mg) was purified by preparative HPLC using the following conditions: column, XBridge Prep C18 OBD column, 19 x 150 mm 5 um; mobile phase, water (0.05% TFA) and ACN (phase B 5% to 62% in 1 min, to 76% in 7 min); detector, uv. The product was obtained. This gave 89.2 mg (69.09%) of 13-3 as a white solid. MS (ES, m / z): [M+H] + = 557.30; 1 H NMR (400 MHz, MeOH-d4): δ 0.84 (s, 3H), 0.85-0.89 (m, 1H), 0.93 (s, 3H), 0.95-1.09 (m, 2H), 1.10 (s, 3H), 1.17 (t, J = 4.5 Hz, 9H), 1.20-1.30 (m, 1H), 1.38-1.62 (m, 9H), 1.63-1.79 (m, 3H), 1.80-2.09 (m, 4H), 2.10-2.28 (m, 2H), 2.33 (q, J = 5.5 Hz, 1H), 2.51 (s, 1H), 2.78 (d, J = 13.2 Hz, 1H), 4.58 (q, J = 13.2 Hz, 2H), 5.58 (s, 1H).

[0153] Example 13 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethoxy)carbonyl)-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 (14-1) [ka] A 100 mL round-bottom flask was charged with 13-1 (125 mg, 0.19 mmol, 1 equiv.), EA (12 mL), and Pd / C (25 mg, 0.23 mmol, 1.242 equiv.). H2 (g) was introduced into the above. The resulting solution was stirred overnight at room temperature. The solid was filtered off. The resulting mixture was concentrated. The crude product (100 mg) was purified by preparative HPLC using the following conditions: column, XBridge Prep C18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% TFA) and ACN (phase B 66% to 83% in 8 min); detector, uv. The product was obtained. This yielded 127.6 mg (118.20%) of 14-1 as a white solid. MS (ES, m / z): [M+H] + = 571.30; 1 H NMR (400 MHz, MeOH-d4) δ: 0.84 (s, 3H), 0.85-0.89 (m, 1H), 0.93 (s, 3H), 0.98-1.31 (m, 16H), 1.32-1.59 (m, 9H), 1.65-1.79 (m, 3H), 1.80-2.04 (m, 4H), 2.08-2.27 (m, 2H), 2.51 (s, 1H), 2.78 (d, J = 13.2 Hz, 1H), 3.73 (s, 3H), 4.62 (q, J = 14.5 Hz, 2H), 5.58 (s, 1H).

[0154] Example 14 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(tert-butoxy)-2-oxoethoxy)carbonyl)-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 (15-2) [ka] Synthesis of 2-benzyl 10-(2-(tert-butoxy)-2-oxoethyl)(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 (15-1). A 100 mL round-bottom flask was charged with 1-6 (295 mg, 0.50 mmol, 1 equiv), DMF (5 mL, 0.07 mmol), TBAI (92 mg, 0.25 mmol, 0.497 equiv), K2CO3 (83 mg, 0.60 mmol, 1.199 equiv), and tert-butyl 2-chloroacetate (91 mg, 0.60 mmol, 1.206 equiv). The resulting solution was stirred at 65 °C for 2 h. The resulting solution was diluted with 50 mL of DCM. The resulting mixture was washed with 2 × 15 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solid was filtered off. The resulting mixture was concentrated. The residue was dissolved in 1:3 EtOAc / petroleum ether. This gave 200 mg (56.79%) of 15-1 as a yellow oil.

[0155] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(tert-butoxy)-2-oxoethoxy)carbonyl)-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 (15-2). A 100 mL round-bottom flask purged and maintained with an inert atmosphere of H2 was charged with benzyl 15-1 (200 mg, 0.28 mmol, 1 equiv.), MeOH (10 mL, 0.31 mmol), and Pd / C (30 mg, 0.28 mmol). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The crude product was purified by preparative HPLC (2#-Analyse HPLC-SHIMADZU (HPLC-10)) using the following conditions: Column: XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; Mobile phase: water (0.05% TFA) and ACN (from 5% to 80% of phase B in 1 min, to 90% in 7 min); Detector: UV 254 nm. The product was obtained. This yielded 21 mg (12.04%) of 15-2 as a white solid. MS (ES, m / z): [M+H] + =613.40; 1 H-NMR (400 MHz, MeOH-d4): δ 0.72-0.99 (m, 8H), 1.00-1.29 (m, 15H), 1.32-1.59 (m, 17H), 1.63-1.68 (m, 4H), 1.91-2.17 (m, 5H), 2.20-2.27 (m, 1H), 2.29 (d, J = 1.6 Hz, 1H), 2.38 (s, 1H), 2.84 (d, J = 1.6 Hz, 1H), 4.47 (q, J = 5.6Hz, 2H), 5.71 (s, 1H).

[0156] Example 15 (2S,4aS,6aS,6bR,8aR,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,9,12,12a,12b,13,14b-octadecahydropicene-2-carboxylic acid (27-2) [ka] Synthesis of 2-benzyl 10-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 (27-1). (Trimethylsilyl)diazomethane in ether (2 M) was added dropwise to 1-2 (100 mg, 0.170 mmol) in MeOH (3 mL) until the yellow color persisted (approximately 1.2 mmol added). The reaction was stirred at room temperature for 30 min and then evaporated to give 27-1 (0.1 g, quantitative) as a white solid.

[0157] (2S,4aS,6aS,6bR,8aR,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,9,12,12 Synthesis of a,12b,13,14b-octadecahydropicene-2-carboxylic acid (27-2). A 100 mL round-bottom flask purged and maintained under an inert atmosphere of hydrogen (1 atm) was charged with 27-1 (100 mg, 0.17 mmol, 1.00 equiv.), MeOH (25 mL), and Pd / C (20 mg). The resulting solution was stirred overnight at room temperature. The solid was filtered off. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% TFA) and ACN (ACN 70.0% to 82.0% in 7 min); detector, UV 254 nm. This yielded 25.7 mg (30%) of 27-2 as a white solid. MS (ES, m / z): [M+H] + = 511.25; 1 H-NMR (400 MHz, MeOH-d4, ppm): δ 0.73-0.83 (m, 3H), 0.91-0.97 (m, 1H), 1.03-1.17 (m, 15H), 1.18-1.23 (m, 2H), 1.28-1.35 (m, 6H), 1.41-1.52 (m, 2H), 1.53-1.69 (m, 3H), 1.71-1.93 (m, 4H), 2.03-2.18 (m, 2H), 2.45 (s, 1H), 3.15-3.21(m, 1H), 3.58 (s, 3H), 5.54 (s, 1H), 6.76 (d, J = 2.0 Hz, 1H).

[0158] Example 16 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)carbamoyl)-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 (29-2) [ka] Synthesis of benzyl (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)carbamoyl)-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 (29-1). A 250 mL round-bottom flask was charged with methyl 2-aminoacetate hydrochloride (540 mg, 4.30 mmol, 3.00 equiv), DCM (60 mL), TEA (0.59 mL, 3.00 equiv), and a solution of PH-RDX-013-291-4 (860 mg, 1.42 mmol, 1.00 equiv) in DCM (30 mL). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo. This yielded 900 mg (96%) of 29-1 as a white solid.

[0159] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)carbamoyl)-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 (29-2). A 250 mL round-bottom flask was charged with 29-1 (500 mg, 0.76 mmol, 1.00 equiv), EtOAc (15 mL), MeOH (15 mL), and Pd / C (50 mg). Hydrogen (1 atm) was introduced into the flask. The resulting solution was stirred at room temperature for 1 hour. The solid was filtered off. The resulting mixture was concentrated under vacuum. The residue was dissolved in 8 mL of THF-MeOH (1:1). The crude product was purified by preparative HPLC with the following conditions: column, XBridge Shield RP18 OBD column, 5 um, 19 x 150 mm; mobile phase, water (0.05% TFA) and ACN (ACN 52.0% to 70.0% in 8 minutes); detector, UV 254 nm. This gave 284.1 mg (66%) of 29-2 as a white solid. MS-PH (ES, m / z): [M+H]+ = 570.30; 1 H NMR (400 MHz, MeOH-d4, ppm): δ 0.74 (s, 3H), 0.76 (s, 1H), 0.83 (s, 3H), 0.90-0.95 (m, 2H), 0.97 (s, 3H), 1.06 (s, 6H), 1.08 (s, 3H), 1.16 (d, J = 13.6 Hz, 1H), 1.27-1.29 (m, 4H), 1.31 (s, 3H), 1.34-1.38 (m, 2H), 1.56-1.67 (m, 3H), 1.77 (d, J = 13.6 Hz, 2H), 1.85-1.92 (m, 2H), 1.98-2.06 (m, 2H), 2.11-2.15 (m, 1H), 2.40 (s, 1H), 2.67-2.71 (m, 1H), 3.61 (s, 3H), 3.75 (d, J = 17.6 Hz, 1H), 3.85 (d, J = 17.2 Hz, 1H), 5.49 (s, 1H).

[0160] Example 17 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10- ((カルボキシメチル)カルバモイル)-2,4a,6a,6b,9,9,12a-ヘプタメチル-13-オキソ-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,1 1,12,12a,12b,13,14b-イコサヒドロピセン-2-カルボン acid (30-3)

change

[0161] 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-carbonyl)glycine (30-2). A 100 mL round-bottom flask was charged with 30-1 (1.19 g, 1.70 mmol, 1.00 equiv), DCM (10 mL), and trifluoroacetic acid (10 mL). The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The resulting mixture was washed with 2×100 mL of n-hexane, which gave 1.0 g (91%) of 30-2 as an off-white solid.

[0162] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((carboxymethyl)carbamoyl)-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 (30-3). A 100 mL round-bottom flask was charged with 30-2 (560 g, 848.62 mmol, 1.00 equiv), Pd / C (50 mg), and THF (30 mL). Hydrogen (1 atm) was introduced. The resulting solution was stirred at room temperature for 1 h. The solid was filtered off. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Prep OBD C18 column, 19 x 250 mm, 5 μm; mobile phase, water (0.05% TFA) and ACN (ACN 45.0% to 65.0% in 8 min); detector, UV 254 nm. This gave 289 mg of 30-3 as a white solid. MS (ES, m / z): [M+H] + = 556.30; 1 H NMR (300 MHz, MeOH-d4, ppm): δ 0.87 (s, 3H), 0.90 (s, 1H), 0.96 (s, 3H), 1.02 (d, J = 14.0 Hz, 2H), 1.10 (s, 3H), 1.19 (s, 3H), 1.20 (s, 3H), 1.22 (s, 3H), 1.28 (d, J = 14.4 Hz, 1H), 1.40-1.56 (m, 9H), 1.67-2.22 (m, 10H), 2.50 (s, 1H), 2.78 (dt, J = 13.4 Hz, 3.3 Hz, 1H), 3.82 (d, J = 17.4 Hz, 1H), 3.92 (d, J = 17.4 Hz, 1H), 5.58 (s, 1H).

[0163] Example 18 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)(methyl)carbamoyl)-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 (31-2) [ka] Benzyl(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)(methyl)carbamoyl)-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,1 Synthesis of 3,14b-icosahydropicene-2-carboxylate (31-1). A 100 mL round-bottom flask was charged with methyl 2-(methylamino)acetate hydrochloride (172 mg, 1.23 mmol, 3.00 equiv.), DCM (15 mL), TEA (0.171 mL, 3.00 equiv.), and a solution of 1-7 (250 mg, 0.41 mmol, 1.00 equiv.) in DCM (5 mL). The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. This yielded 0.25 g (90%) of 31-1 as an off-white solid.

[0164] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)(methyl)carbamoyl)-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 (31-2). A 100 mL round-bottom flask was charged with 31-1 (250 mg, 0.37 mmol, 1.00 equiv), MeOH (15 mL), and Pd / C (25 mg). Hydrogen (1 atm) was introduced to the flask. The resulting solution was stirred at room temperature for 1 h. The solid was filtered off. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19×150 mm; mobile phase, water (0.05% TFA) and ACN (ACN 58.0% to 74.0% in 8 min); detector, UV 254 nm. This gave 28.6 mg (13%) of 31-2 as a white solid. MS (ES, m / z): [M+H] + = 584.35; 1 H NMR (400 MHz, MeOH-d4, ppm): δ 0.84 (s, 3H), 0.92 (s, 3H), 0.93-0.98 (m, 2H), 1.05 (s, 3H), 1.06-1.08 (m, 1H), 1.15 (d, J = 4.0 Hz, 3H), 1.17 (s, 3H), 1.19 (d, J = 2.4 Hz, 3H), 1.26 (d, J = 12.0 Hz, 1H), 1.33 - 1.43 (m, 5H), 1.45 (s, 3H), 1.48-1.49 (m, 1H), 1.69-1.79 (m, 3H), 1.84-1.90 (m, 2H), 1.92-2.03 (m, 2H), 2.18-2.21 (m, 2H), 2.54 (s, 1H), 2.74-2.80 (m, 2H), 2.93 (s, 1H), 3.19 (s, 2H), 3.70 (s, 3H), 3.98 (d, J = 17.2 Hz, 1H), 4.23 (d, J = 17.2 Hz, 1H), 5.55 (s, 1H).

[0165] Example 19 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((R)-2-(methoxycarbonyl)pyrrolidine-1-carbonyl)-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 (33-2) [ka] Methyl((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, Synthesis of 7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicene-3-carbonyl)-D-prolinate (33-1). A 100 mL round-bottom flask was charged with (2R)-pyrrolidine-2-carboxylic acid hydrochloride (245 mg, 1.62 mmol, 3.00 equiv.), DCM (15 mL), TEA (0.206 mL, 3.00 equiv.), and a solution of 1-7 (300 mg, 0.49 mmol, 1.00 equiv.) in DCM (5 mL). The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. This yielded 320 mg (93%) of 33-1 as a white solid.

[0166] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((R)-2-(methoxycarbonyl)pyrrolidine-1-carbonyl)-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 (33-2). A 100 mL round-bottom flask was charged with 33-1 (320 mg, 0.46 mmol, 1.00 equiv), EtOAc (20 mL), and Pd / C (32 mg). Hydrogen (1 atm) was added to the flask. The resulting solution was stirred overnight at room temperature. The solid was filtered off. The resulting mixture was concentrated under vacuum. The residue was dissolved in 8 mL of MeOH. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O) and ACN (ACN 35.0% to 65.0% in 8 min); detector, UV 254 nm. This yielded 26 mg (9%) of 33-2 as a white solid. MS (ES, m / z): [M+H] + = 610.4; 1 H NMR (400 MHz, MeOH-d4, ppm): δ 0.86 (s, 3H), 0.93 (s, 1H), 0.97 (s, 3H), 1.00 (s, 3H), 1.05-1.09 (m, 2H), 1.17 (s, 3H), 1.18 (s, 3H), 1.21 (s, 3H), 1.27 (d, J = 14.3 Hz, 1H), 1.35 -1.45 (m, 4H), 1.47 (s, 3H), 1.48-1.51 (m, 2H), 1.65-1.87 (m, 3H), 1.90-2.03 (m, 7H), 2.05-2.26 (m, 3H), 2.51-2.55 (m, 2H), 2.81 (dt, J = 13.4, 3.3 Hz, 1H), 3.71-3.76 (m, 5H), 4.44 (dd, J = 8.6, 3.8 Hz, 1H), 5.62 (s, 1H).

[0167] Example 20 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1,5-dimethoxy-1,5-dioxopentan-2-yl)carbamoyl)-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 (35-2) [ka] Dimethyl ((3S, 4aS, 6aR, 6bS, 8aS, 11S, 12aR, 14aR, Synthesis of (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-carbonyl)-L-glutamate (35-1). A 250 mL round-bottom flask was charged with 1,5-dimethyl(2S)-2-aminopentanedioate hydrochloride (261 mg, 1.23 mmol, 3.00 equiv), DCM (15 mL), TEA (0.171 mL, 3.00 equiv), and a solution of 1-7 (250 mg, 0.41 mmol, 1.00 equiv) in DCM (5 mL). The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. This afforded 250 mg (81%) of 35-1 as an off-white solid.

[0168] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1,5-dimethoxy-1,5-dioxopentan-2-yl)carbamoyl)-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 (35-2). A 100 mL round-bottom flask was charged with 35-1 (250 mg, 0.34 mmol, 1.00 equiv.), EtOAc (20 g, 226.99 mmol, 677.32 equiv.), and Pd / C (30 mg). Hydrogen (1 atm) was introduced to the above. The resulting solution was stirred at room temperature for 1 hour. The solid was filtered off. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% TFA) and ACN (ACN 53.0% to 71.0% in 8 min); detector, UV 254 nm. This gave 33.3 mg (15%) of 35-2 as a white solid. MS (ES, m / z): [M+H] + = 656.35; 1 H NMR (300 MHz, Chloroform-d, ppm): δ 0.75 (d, J = 11.1 Hz, 1H), 0.84 (s, 3H), 0.91 (s, 3H), 0.97 (s, 1H), 1.02 (s, 1H), 1.05 (s, 3H), 1.14 (s, 3H), 1.19 (s, 3H), 1.23 (s, 3H), 1.24-1.30 (m, 1H), 1.33-1.49 (m, 9H), 1.59-1.68 (m, 3H), 1.83-2.07 (m, 7H), 2.17-2.22 (m, 2H), 2.24-2.49 (m, 3H), 2.86 (d, J = 13.5, 1H), 3.68 (s, 3H), 3.75 (s, 3H), 4.60-4.64 (m, 1H), 5.71 (s, 1H), 6.28 (d, J = 7.5 Hz, 1H).

[0169] Example 21 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((R)-1,4-dimethoxy-1,4-dioxobutan-2-yl)carbamoyl)-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 (37-2) [ka] Dimethyl ((3S, 4aS, 6aR, 6bS, 8aS, 11S, 12aR, 14aR, Synthesis of (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-carbonyl)-D-aspartate (37-1). A 100 mL round-bottom flask was charged with 1,4-dimethyl(2R)-2-aminobutanedioate hydrochloride (201 mg, 1.02 mmol, 1.00 equiv.), DCM (20 mL), and TEA (0.353 mL, 5.00 equiv.). The resulting solution was stirred at room temperature for 0.5 h. This was then followed by the dropwise addition of a solution of 1-7 (309 mg, 0.51 mmol, 1.00 equiv) in DCM (10 mL) with stirring at room temperature. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo. This gave 372 mg (100%) of 37-1 as a pale yellow crude solid.

[0170] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((R)-1,4-dimethoxy-1,4-dioxobutan-2-yl)carbamoyl)-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 (37-2). A 100 mL round-bottom flask purged and maintained with an inert atmosphere of H was charged with 37-1 (372 mg, 0.51 mmol, 1.00 equiv), MeOH (10 mL), THF (10 mL), and Pd / C (37 mg). The resulting solution was stirred overnight at room temperature. The solids were filtered off. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% TFA) and ACN (ACN 5.0% to 56.0% in 1 min, to 72.0% in 7 min); detector, UV 254 nm. This yielded 206 mg (63%) of 37-2 as a white solid. MS (ES, m / z): [M+H] + = 642; 1 H NMR (400 MHz, MeOH-d 4, ppm): δ 0.84 (s, 4H), 0.91 (s, 3H), 0.95 -1.00 (m, 5H), 1.13-1.21 (m, 9H), 1.25 (d, J = 13.2 Hz, 1H), 1.38-1.52 (m, 9H), 1.62-1.81 (m, 3H), 1.82-2.04 (m, 4H), 2.05-2.26 (m, 3H), 2.49 (s, 1H), 2.72-2.86 (m, 2H), 2.95 (dd, J = 16.4, 5.2 Hz, 1H), 3.65 (s, 3H), 3.72 (s, 3H), 4.76 (dd, J = 8.0, 5.6 Hz, 1H), 5.58 (s, 1H).

[0171] Example 22 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-methoxy-1-oxopropan-2-yl)carbamoyl)-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 (39-2) [ka] Benzyl(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-methoxy-1-oxopropan-2-yl)carbamoyl Synthesis of (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 (39-1). A 100 mL round-bottom flask was charged with methyl (2S)-2-aminopropanoate hydrochloride (172 mg, 1.23 mmol, 2.993 equiv.), DCM (15 mL), TEA (0.171 mL, 1.23 mmol, 2.988 equiv.), and a solution of 1-7 (250 mg, 0.41 mmol, 1 equiv.) in DCM (5 mL). The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated. This yielded 250 mg (90.11%) of PH-RDX-013-455-1 as a pale yellow solid.

[0172] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-methoxy-1-oxopropan-2-yl)carbamoyl)-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 (39-2). A 100 mL round-bottom flask was charged with 39-1 (250 mg, 0.37 mmol, 1.00 equiv), MeOH (25 mL), and Pd / C (25 mg). Hydrogen (1 atm) was introduced into the flask. The resulting solution was stirred at room temperature for 1 hour. The solid was filtered off. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19×150 mm; mobile phase, water (0.05% TFA) and ACN (ACN 53.0% to 71.0% in 8 minutes); detector, UV 254 nm. This gave 31.7 mg (15%) of 39-2 as a white solid. (ES, m / z): [M+H] + = 584.35; 1 H NMR (300 MHz, chloroform-d, ppm): δ 0.77 (d, J = 11.7 Hz, 1H), 0.87 (s, 3H), 0.95 (s, 3H), 1.09 (s, 3H), 1.17 (s, 3H), 1.22 (s, 3H), 1.26 (s, 3H), 1.29-1.32 (m, 1H), 1.32-1.51 (m, 11H), 1.59-1.79 (m, 3H), 1.83-2.07 (m, 9H), 2.19 (d, J = 10.5, 1H), 2.37 (s, 1H), 2.86 (d, J = 13.5 Hz, 1H), 3.75 (s, 3H), 4.56-4.66 (m, 1H), 5.71 (s, 1H), 5.95 (d, J = 7.2 Hz, 1H).

[0173] Example 23 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl)carbamoyl)-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 (41-2) [ka] Benzyl(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl)carbamoyl)-2,4a,6a,6b,9,9,12a-heptamethyl-13 Synthesis of -oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (41-1). A 100 mL round-bottom flask was charged with methyl (2S)-2-amino-3-hydroxypropanoate hydrochloride (211 mg, 1.36 mmol, 2.00 equiv.), DCM (20 mL), and TEA (0.283 mL, 3.00 equiv.). The resulting solution was stirred at room temperature for 0.5 h. This was followed by the dropwise addition of a solution of 1-7 (412 mg, 0.68 mmol, 1.00 equiv.) in DCM (10 mL) with stirring at room temperature. The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. This yielded 468 mg (100%) of 41-1 as a crude pale yellow solid.

[0174] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl)carbamoyl)-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 (41-2). A 100 mL round-bottom flask purged and maintained with an inert atmosphere of H was charged with 41-1 (468 mg, 0.68 mmol, 1.00 equiv), MeOH (20 mL), THF (10 mL), and Pd / C (50 mg). The resulting solution was stirred overnight at room temperature. The solids were filtered off. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% TFA) and ACN (ACN 45.0% to 63.0% in 8 min); detector, UV 254 nm. This yielded 283 mg (70%) of 41-2 as a white solid. MS (ES, m / z): [M+H] + = 600.40; 1 H NMR (400 MHz, MeOH-d4, ppm): δ 0.81-0.89 (m, 4H), 0.91 (s, 3H), 0.95-1.07 (m, 2H), 1.10 (s, 3H), 1.13-1.20 (m, 9H), 1.20-1.30 (m, 1H), 1.40 (s, 3H), 1.43-1.52 (m, 5H), 1.61-1.79 (m, 3H), 1.80-2.08 (m, 4H), 2.09-2.29 (m, 3H), 2.50 (s, 1H), 2.78 (dt, J = 13.2, 3.2 Hz, 1H), 3.34 (s, 1H), 3.72 (s, 3H), 3.78 (dd, J = 11.2, 4.8 Hz, 1H), 3.88 (dd, J = 11.2, 4.8 Hz, 1H), 4.40-4.57 (m, 1H), 5.58 (s, 1H), 7.87 (d, J = 7.7 Hz, 1H).

[0175] Example 24 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-(1H-imidazol-1-yl)ethoxy)-2-oxoethyl)carbamoyl)-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 (44-2) [ka] Benzyl (2S, 4aS, 6aS, 6bR, 8aS, 10S, 12aS, 12bR, 1 Synthesis of (4bR)-10-((2-(2-(1H-imidazol-1-yl)ethoxy)-2-oxoethyl)carbamoyl)-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 (44-1). A 100 mL round-bottom flask was charged with EDCI (53.4 mg, 0.28 mmol, 1.50 equiv), DCM (15 mL), and DMAP (113 mg, 0.92 mmol, 5.00 equiv). The resulting solution was stirred at room temperature for 1 h. 30-2 (120 mg, 0.19 mmol, 1.00 equiv) was added. The resulting solution was reacted with stirring at 55° C. for an additional 1 h. 2-(1H-imidazol-1-yl)ethan-1-ol (83 mg, 0.74 mmol, 4.00 equiv) was added. The resulting solution was reacted with stirring at 55° C. overnight. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with DCM / MeOH (9:1). This gave 85 mg (62%) of 44-1 as an off-white solid.

[0176] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-(1H-imidazol-1-yl)ethoxy)-2-oxoethyl)carbamoyl)-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 (44-2). A 100 mL round-bottom flask was charged with 44-1 (125 mg, 0.17 mmol, 1.00 equiv), MeOH (20 mL), and Pd / C (30 mg). To the above was introduced hydrogen (1 atm). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The solid was filtered off. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 um, 19 x 150 mm; mobile phase, water (0.05% TFA) and ACN (ACN 32.0% to 50.0% in 8 minutes); detector, UV 254 nm. This gave 108.9 mg (99%) of 44-2 as a white solid. MS (ES, m / z): [M+H] + = 650.45; 1 H NMR (400 MHz, MeOH-d4, ppm): δ 0.84 (s, 3H), 0.85 (s, 1H), 0.91 (s, 3H), 0.94-0.99 (m, 1H), 1.04 (s, 3H), 1.05-1.07 (m, 1H), 1.15 (s, 3H), 1.17 (s, 3H), 1.19 (s, 3H), 1.26 (d, J = 13.8 Hz, 1H), 1.37-1.48 (m, 9H), 1.66-1.75 (m, 3H), 1.83-2.19 (m, 7H), 2.49 (s, 1H), 2.78 (dt, J = 13.4 Hz, 3.3 Hz, 1H), 3.87-3.91 (m, 2H), 4.51-4.55 (m, 4H), 5.58 (s, 1H), 7.56 (s, 1H), 7.69 (s, 1H), 8.20 (t, J = 5.8 Hz, 1H), 8.98 (s, 1H).

[0177] Example 25 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-hydroxyethoxy)-2-oxoethyl)carbamoyl)-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 (45-2) [ka] Synthesis of benzyl (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-(benzyloxy)ethoxy)-2-oxoethyl)carbamoyl)-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 (45-1). In a 100 mL round-bottom flask, add EDCI (44 mg, 0.23 mmol, 1.50 equiv.), DCM (15 mL), and DMAP (95 mg, 0.78 mmol, 5.00 equiv.). The resulting solution was stirred at room temperature for 1 hour. 30-2 (100 mg, 0.15 mmol, 1.00 equiv.) was added. The resulting solution was reacted at 55° C. with stirring for an additional 1 hour. 2-(benzyloxy)ethan-1-ol (0.088 mL, 4.00 equiv.) was added. The resulting solution was reacted at 55° C. with stirring overnight. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with DCM / MeOH (9:1). This gave 95 mg (79%) of 45-1 as an off-white solid.

[0178] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(2-hydroxyethoxy)-2-oxoethyl)carbamoyl)-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 (45-2). A 100 mL round-bottom flask was charged with 45-1 (120 mg, 0.15 mmol, 1.00 equiv), THF (10 mL), MeOH (10 mL), and Pd / C (30 mg). To the above was introduced hydrogen (1 atm). The resulting solution was stirred at room temperature for 2 days. The solid was filtered off. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 um, 19 x 150 mm; mobile phase, water (0.05% TFA) and ACN (ACN 42.0% to 61.0% in 8 minutes); detector, UV 254 nm. This gave 58.8 mg (64%) of 45-2 as a white solid. MS (ES, m / z): [M+H] + = 600.35; 1 H NMR (300 MHz, MeOH-d4ppm): δ 0.83 (s, 3H), 0.86 (s, 1H), 0.92 (s, 3H), 0.96-1.01 (m, 2H), 1.07 (s, 3H), 1.15 (s, 3H), 1.17 (s, 3H), 1.19 (s, 3H), 1.25 (d, J = 13.9 Hz, 1H), 1.40-1.52 (m, 9H), 1.71 (t, J = 13.4 Hz, 3H), 1.81-2.03 (m, 4H), 2.07-2.24 (m, 3H), 2.50 (s, 1H), 2.79 (dt, J = 13.2 Hz, 3.3 Hz, 1H), 3.71-3.74 (m, 2H), 3.88 (d, J = 17.4 Hz, 1H), 3.99 (d, J = 17.4 Hz, 1H), 4.17-4.20 (m, 2H), 5.58 (s, 1H).

[0179] Example 26 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-(2-morpholinoethoxy)-2-oxoethyl)carbamoyl)-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 (46-2) [ka] Synthesis of benzyl (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-(2-morpholinoethoxy)-2-oxoethyl)carbamoyl)-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 (46-1). A 100 mL round-bottom flask was charged with EDCI (53.4 mg, 0.28 mmol, 1.50 equiv), DCM (15 mL), and DMAP (226 mg, 1.85 mmol, 10.00 equiv). The resulting solution was stirred at room temperature for 1 h. 30-2 (120 mg, 0.19 mmol, 1.00 equiv) was added. The resulting solution was reacted at 55° C. with stirring for an additional 1 h. 2-(morpholin-4-yl)ethan-1-ol (0.09 mL, 4.00 equiv) was added. The resulting solution was reacted at 55° C. with stirring for an additional 2 days. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with DCM / MeOH (9:1). This gave 125 mg (89%) of 46-1 as an off-white solid.

[0180] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-(2-morpholinoethoxy)-2-oxoethyl)carbamoyl)-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 (46-2). A 100 mL round-bottom flask was charged with 46-1 (160 mg, 0.21 mmol, 1.00 equiv), MeOH (15 mL), and Pd / C (30 mg). Hydrogen was introduced (1 atm). The resulting solution was stirred at room temperature for 1 hour. The solid was filtered off. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19×150 mm; mobile phase, water (0.05% TFA) and ACN (ACN 32.0% to 50.0% in 8 minutes); detector, UV 254 nm. This gave 77.2 mg (55%) of 46-2 as a white solid. MS (ES, m / z): [M+H] + = 669.45; 1 H NMR (300 MHz, MeOH-d4, ppm) δ 0.87 (s, 3H), 0.92 (s, 1H), 0.96 (s, 3H), 1.02-1.07 (m, 2H), 1.09 (s, 3H), 1.16 (s, 3H), 1.17 (s, 3H), 1.19 (s, 3H), 1.29 (d, J = 14.3 Hz, 1H), 1.40 -1.56 (m, 10H), 1.73 (t, J = 13.5 Hz, 3H), 1.82-2.10 (m, 4H), 2.14-2.29 (m, 3H), 2.50 (s, 1H), 2.80 (dt, J = 13.3 Hz, 3.3 Hz, 1H), 3.53 (t, J = 5.0 Hz, 4H), 3.72-4.20 (m, 6H), 4.53 (q, J = 4.6 Hz, 2H), 5.58 (s, 1H).

[0181] Example 27 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo- 10-(((pivaloyloxy)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 (47-2) [ka] Synthesis of 2-benzyl 10-((pivaloyloxy)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 (47-1). A 100 mL round-bottom flask was charged with 1-6 (100 mg, 0.17 mmol, 1 equiv.), DMF (5 mL, 0.07 mmol), chloromethyl 2,2-dimethylpropanoate (30 mg, 0.20 mmol, 1.173 equiv.), TBAI (30 mg, 0.08 mmol, 0.478 equiv.), and K2CO3 (28 mg, 0.20 mmol, 1.193 equiv.). The resulting solution was stirred at 65 °C for 2 h. The resulting solution was diluted with 30 mL of DCM. The resulting mixture was washed with 2 × 15 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solid was filtered off. The resulting mixture was concentrated. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:3). This gave 65 mg (54.45%) of 47-1 as a yellow oil.

[0182] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(((pivaloyloxy)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 (47-2). A 100 mL round-bottom flask purged and maintained under an inert atmosphere of H2 (1 atm) was charged with 47-1 (300 mg, 0.43 mmol, 1 equiv.), MeOH (10 mL, 0.31 mmol, 0.733 equiv.), and Pd / C (30 mg, 0.662 equiv.). The resulting solution was stirred at room temperature for 1 h. The solid was filtered off. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% TFA) and ACN (from 5% to 80% of phase B in 1 min, to 95% in 7 min); detector, UV 254 nm. This yielded 47.6 mg (18.25%) of 47-2 as a white solid. MS (ES, m / z): [M+H] + = 613.46; 1 H NMR (400 MHz, MeOH-d4, ppm): δ 0.83-0.89 (m, 7H), 1.00-1.06 (m, 5H), 1.15-1.19 (m, 18H), 1.22-1.29 (m, 3H), 1.40-1.51(m, 8H), 1.65-1.68 (m, 3H), 1.82-1.98 (m, 3H), 2.14-2.29 (m, 3H), 2.50 (s, 1H), 2.77 (d, J = 13.6 Hz, 1H), 5.58 (s, 1H), 5.69 (d, J = 5.6 Hz, 1H), 5.78 (d, J = 5.6 Hz, 1H).

[0183] Example 28 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((((isopropoxycarbonyl)oxy)methoxy)carbonyl )-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 (48-2) [ka] Synthesis of 2-benzyl 10-(((isopropoxycarbonyl)oxy)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 (48-1). A 100 mL round-bottom flask was charged with 1-6 (300 mg, 0.51 mmol, 1 equiv.), DMF (5 mg, 0.07 mmol, 0.134 equiv.), chloromethylpropan-2-yl carbonate (93 mg, 0.61 mmol, 1.196 equiv.), KCO (84 mg, 0.61 mmol, 1.193 equiv.), and TBAI (90 mg, 0.24 mmol, 0.478 equiv.). The resulting solution was stirred at 65 °C for 2 h. The resulting solution was diluted with 50 mL of DCM. The resulting mixture was washed with 2 × 25 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solid was filtered off. The resulting mixture was concentrated. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:3). This gave 200 mg (55.69%) of 48-1 as a white solid.

[0184] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((((isopropoxycarbonyl)oxy)methoxy)carbonyl)-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 (48-2). A 100 mL round-bottom flask purged and maintained under an inert atmosphere of H2 (1 atm) was charged with 48-1 (300 mg, 0.43 mmol, 1 equiv.), MeOH (10 mL, 0.31 mmol, 0.733 equiv.), and Pd / C (30 mg, 0.662 equiv.). The resulting solution was stirred at room temperature for 1 h. The solid was filtered off. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% TFA) and ACN (phase B 5% to 74% in 1 min, to 88% in 7 min); detector, UV 254 nm. This yielded 148.2 mg (56.64%) of 48-2 as a white solid. MS (ES, m / z): [M+H] + = 615.40; 1 H NMR (400 MHz, MeOH-d4, ppm): δ 0.83-0.89 (m, 7H), 0.97-1.06 (m, 5H), 1.13-1.23 (m, 16H), 1.40-1.53 ​​(m, 9H), 1.66-2.03 (m, 7H), 2.11-2.30 (m, 3H), 2.50 (s, 1H), 2.77 (d, J = 13.2 Hz, 1H), 4.84-4.90 (m, 1H), 5.58 (s, 1H), 5.68 (d, J = 5.6 Hz, 1H), 5.75 (d, J = 5.6 Hz, 1H).

[0185] Example 29 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-((isopropoxycarbonyl)oxy)ethoxy )carbonyl)-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 (49-2) [ka] Synthesis of 2-benzyl 10-(1-((isopropoxycarbonyl)oxy)ethyl)(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 (49-1). A 100 mL round-bottom flask was charged with 1-6 (400 mg, 0.68 mmol, 1.00 equiv), 1-chloroethylpropan-2-yl carbonate (135.8 mg, 0.82 mmol, 1.20 equiv), TBAI (125 mg, 0.89 mmol, 0.50 equiv), potassium methane peroxoate (112 mg, 0.80 mmol, 1.20 equiv), and DMF (15 mL). The resulting solution was stirred at room temperature for 2 h. The resulting solution was extracted with 3 × 150 mL of DCM, and the organic layers were combined. The resulting mixture was washed with 2 × 250 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:3). This yielded 450 mg of the mixed stereoisomers. Further purification by preparative SFC and collection of the earlier eluting peak gave 180 mg of 49-1.

[0186] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((S)-1-((isopropoxycarbonyl)oxy)ethoxy)carbonyl)-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 (49-2). 49-1, Pd / C (40 mg), and MeOH (20 mL) were placed in a 100 mL round-bottom flask and hydrogen (1 atm) was introduced. The resulting solution was stirred overnight at room temperature. The solid was filtered off. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions: mobile phase, water (0.05% TFA) and ACN (5.0% to 80.0% ACN in 1 min, to 90.0% in 7 min); detector, UV 254 nm. This yielded 87.6 mg (56%) of 49-2. MS (ES, m / z): [M+H] + = 629.4; 1 H NMR (400 MHz, MeOH-d4, ppm): δ 0.82 (s, 4H), 0.91 (s, 3H), 0.96 -1.11 (m, 5H), 1.15-1.28 (m, 9H), 1.28-1.36 (m, 7H), 1.33-1.58 (m, 12H), 1.71-1.82 (m, 3H), 1.82-2.02 (m, 2H), 2.10-2.25 (m, 3H), 2.53 (s, 1H), 2.80 (dt, J = 13.6, 3.6 Hz, 1H), 4.89 (d, J = 6.4 Hz, 1H), 5.60 (s, 1H), 6.73 (q, J = 5.4 Hz, 1H).

[0187] Example 30 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((R)-1-((isopropoxycarbonyl)oxy)ethoxy)carbonyl)-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 (50-2) [ka] Synthesis of 2-benzyl 10-((R)-1-((isopropoxycarbonyl)oxy)ethyl)(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 (50-1). The slower eluting peak in the purification of 49-1 was collected to give 150 mg of 50-1.

[0188] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-(((R)-1-((isopropoxycarbonyl)oxy)ethoxy)carbonyl)-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 (50-2). A 100 mL round-bottom flask was charged with 50-1 (150 mg, 0.21 mmol, 1.00 equiv), Pd / C (40 mg), and MeOH (20 mL) and charged with H (1 atm). The resulting solution was stirred overnight at room temperature. The solid was filtered off. The crude product was purified by preparative HPLC using the following conditions: mobile phase, water (0.05% TFA) and ACN (ACN 5.0% to 80.0% in 1 min, to 90.0% in 7 min); detector, UV 254 nm. This gave 79 mg (60%) of 50-2 as a white solid. MS (ES, m / z): [M+H] + = 629.93; 1 H NMR (400 MHz, MeOH-d4, ppm): δ 0.78-0.93 (m, 7H), 0.95-1.15 (m, 5H), 1.15-1.21 (m, 9H), 1.21-1.33 (m, 7H), 1.33-1.56 (m, 12H), 1.60-1.80 (m, 3H), 1.83-2.02 (m, 4H), 2.06-2.25 (m, 3H), 2.52 (s, 1H), 2.79 (dt, J = 13.4, 3.6 Hz, 1H), 4.86 (d, J = 1.8 Hz, 1H), 5.60 (s, 1H), 6.75 (q, J = 5.4 Hz, 1H).

[0189] Example 31 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(diethylamino)-2-oxoethoxy)carbonyl)-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 (51-2) [ka] 2-Benzyl 10-(2-(diethylamino)-2-oxoethyl) (2S,4aS, Synthesis of (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 (51-1). A 100 mL round-bottom flask was charged with 1-6 (589 mg, 1.00 mmol, 1 equiv.), DMF (10 mg, 0.14 mmol), TBAI (185 mg, 0.501 equiv.), KCO (165 mg, 1.19 mmol, 1.194 equiv.), and 2-chloro-N,N-diethylacetamide (180 mg, 1.20 mmol, 1.203 equiv.). The resulting solution was stirred at 65 °C for 2 h. The resulting mixture was concentrated. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:3). This gave 600 mg (85.45%) of 51-1 as a white solid.

[0190] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-10-((2-(diethylamino)-2-oxoethoxy)carbonyl)-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 (51-2). A 100 mL round-bottom flask purged and maintained under an inert atmosphere of H2 (1 atm) was charged with 51-1 (200 mg, 0.28 mmol, 1 equiv.), MeOH (10 mL, 0.31 mmol), and Pd / C (30 mg, 0.1 equiv.). The resulting solution was stirred overnight at room temperature. The solid was filtered off. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% TFA) and ACN (from 5% to 66% of phase B in 1 min, to 80% in 7 min); detector, UV 254 nm. This yielded 91.4 mg (52.43%) of 51-2 as a white solid. MS (ES, m / z): [M+H] + = 612.55; 1 H NMR (400 MHz, MeOH-d4, ppm): δ 0.84-0.98 (m, 4H), 0.93-1.01 (m, 3H), 1.04-1.10 (m, 2H), 1.10-1.18 (m, 15H), 1.21-1.27 (m, 4H), 1.38-1.48 (m, 8H), 1.57-1.60 (m, 1H), 1.61-1.75 (m, 3H), 1.76-2.03 (m, 4H), 2.15-2.19 (m, 2H), 2.34 (d, J = 13.2 Hz, 1H), 2.51 (s, 1H), 2.77 (d, J = 13.2 Hz, 1H), 3.30-3.40 (m, 4H), 4.76 (s, 2H), 5.58 (s, 1H).

[0191] Example 32 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-morpholino-2-oxoethoxy)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 (52-2) [ka] 2-Benzyl 10-(2-morpholino-2-oxoethyl)(2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9 Synthesis of 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 (52-1). A 100 mL round-bottom flask was charged with 13-2 (150 mg, 0.23 mmol, 1 equiv.), DMF (15 mL), HATU (0.2 g, 0.47 mmol, 2.041 equiv.), morpholine (0.06 mL, 3 equiv.), and DIPEA (0.08 mL, 0.48 mmol, 2.087 equiv.). The resulting solution was stirred at room temperature for 2 h. The resulting solution was extracted with 500 mL of DCM. The resulting mixture was washed with 500 mL of water (1 × 500 mL). The resulting mixture was washed with 1×500 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solid was filtered off. This gave 200 mg (120.46%, crude) of 52-1 as a white solid.

[0192] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-morpholino-2-oxoethoxy)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 (52-2). In a 100 mL round-bottom flask, 52-1 (200 mg, 0.28 mmol, 1 equiv.), EA (16 mL), and Pd / C (5.9 mg, 0.06 mmol, 0.198 equiv.) were placed. To the above was introduced H2(g). The resulting solution was stirred overnight at room temperature. The solid was filtered off. The resulting mixture was concentrated. The crude product was purified by preparative HPLC with the following conditions: column, XBridge Prep OBD C18 column, 19 x 250 mm, 5 μm; mobile phase, water (0.05% TFA) and ACN (from 5% to 60% phase B in 2 min, to 75% in 8 min); detector, UV. This yielded 56.7 mg (32.43%) of 52-2 as a white solid. MS (ES, m / z): [M+H] + = 626.45; 1 H NMR (300 MHz, MeOH-d4, ppm): 0.85 (s, 3H), 0.89-1.00 (m, 4H), 1.02-1.31 (m, 15H), 1.33-1.52 (m, 8H), 1.52-1.64 (m, 1H), 1.63-1.80 (m, 3H), 1.81-2.08 (m, 4H), 2.09-2.27 (m, 2H), 2.28-2.42 (m, 1H), 2.52 (s, 1H), 2.72-2.88 (m, 1H), 3.42-3.61 (m, 4H), 3.62-3.78 (m, 4H), 4.80-4.86 (m, 2H), 5.58 (s, 1H).

[0193] Example 33 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)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 (53-2) [ka] Synthesis of 2-benzyl 10-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)(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 (53-1) A 100 mL round-bottom flask was charged with 13-2 (150 mg, 0.23 mmol, 1 equiv), DMF (15 mL), HATU (180 mg, 0.47 mmol, 2.041 equiv), 1-methylpiperazine (0.077 mL, 3 equiv), and DIPEA (0.08 mL, 0.48 mmol, 2.087 equiv). The resulting solution was stirred at room temperature for 2 h. The resulting solution was extracted with 200 mL of DCM. The resulting mixture was washed with 1 × 200 mL of water. The resulting mixture was washed with 1 × 200 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solid was filtered off. This yielded 150 mg (88.73%) of 53-1 as a white semi-solid.

[0194] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-((2-(4-methylpiperazin-1-yl)-2-oxoethoxy)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 (53-2). A 100 mL round-bottom flask was charged with 53-1 (150 mg, 0.21 mmol, 1 equiv.), EA (16 mL), and Pd / C (4.4 mg, 0.201 equiv.). To the above was introduced H2(g). The resulting solution was stirred overnight at room temperature. The solid was filtered off. The resulting mixture was concentrated. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Prep OBD C18 column, 19 x 250 mm, 5 um; mobile phase, water (0.05% TFA) and ACN (phase B 41% to 59% in 8 min); detector, UV 254 nm. This gave 85.8 mg (65.27%) of 53-2 as a white solid. MS (ES, m / z): [M+H] + = 639.45; 1 H NMR (300 MHz, MeOH-d4, ppm): 0.79-1.00 (m, 8H), 1.02-1.15 (m, 5H), 1.15-1.22 (m, 9H), 1.23-1.35 (m, 2H), 1.36-1.51 (m, 8H), 1.52-1.64 (m, 2H), 1.73 (t, J = 13.5 Hz, 3H), 1.80-2.27 (m, 7H), 2.32-2.46 (m, 1H), 2.52 (s, 1H), 2.70-2.88 (m, 1H), 2.95 (s, 3H), 3.20-3.28 (m, 1H), 3.34 -3.47 (m, 2H), 3.52-4.09 (m, 3H), 5.58 (s, 1H).

[0195] Example 34 (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)amino)-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 (54-2) [ka] Benzyl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)amino)-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-isobenzofuran Synthesis of sahydropicene-2-carboxylate (54-2). A 50 mL round-bottom flask was charged with 54-1 (prepared according to the method described in Bioorg. Med. Chem. 2010, 18, 433-454) (100 mg, 0.18 mmol, 1.00 equiv.), CHCN (5 mL), methyl 2-bromoacetate (55 mg, 0.36 mmol, 2.00 equiv.), and potassium carbonate (74 mg, 0.54 mmol, 3.00 equiv.). The resulting solution was stirred overnight at 60 °C. The resulting solution was extracted with 3 × 20 mL of EtOAc, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silica gel column with EtOAc / petroleum ether (1 / 2). The collected fractions were combined and concentrated under vacuum. This yielded 100 mg (89%) of 54-2 as a white solid.

[0196] Synthesis of (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)amino)-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 (54-3). A 50 mL round-bottom flask was charged with 54-2 (160 mg, 0.25 mmol, 1.00 equiv), Pd / C (80 mg), and MeOH (5 mL) under a hydrogen atmosphere. The resulting solution was stirred at room temperature for 2 h. The solid was filtered off. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19×150 mm; mobile phase, water (0.05% TFA) and ACN (ACN 30.0% to 48.0% in 8 min); detector, UV 254 nm. This gave 30.7 mg (22%) of 54-3 as an off-white solid. MS (ES, m / z): [M+H] + = 542.45; 1 H NMR (300 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.15 (s, 1H), 5.42 (s, 1H), 4.22 - 3.94 (m, 3H), 3.77 (s, 3H), 2.85 (s, 1H), 2.67 (d, J = 13.3 Hz, 1H), 2.36 (s, 1H), 2.07 (dd, J = 11.7, 5.5 Hz, 2H), 1.93 - 1.49 (m, 7H), 1.35 (s, 8H), 1.11 (d, J = 9.4 Hz, 7H), 1.04 (d, J = 2.6 Hz, 6H), 0.97 (d, J = 13.7 Hz, 2H), 0.85 (s, 4H), 0.76 (s, 3H).

[0197] Example 35 (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(bis(2-methoxy-2-oxoethyl)amino)-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 (56-2) [ka] Dimethyl 2,2'-(((3S,4aR,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- Synthesis of (icosahydropicen-3-yl)azanediyl)diacetate (56-1). A 50 mL round-bottom flask was charged with 54-1 (100 mg, 0.18 mmol, 1.00 equiv), 2-bromomethyl acetate (273 mg, 1.78 mmol, 10.00 equiv), ACN (10 mL), and potassium carbonate (370 mg, 2.68 mmol, 15.00 equiv). The resulting solution was stirred overnight at 60 °C. The resulting solution was extracted with 3 × 20 mL of EtOAc, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silica gel column with EtOAc / petroleum ether (1 / 2). The collected fractions were combined and concentrated under vacuum. This yielded 105 mg (84%) of 56-1 as a white solid.

[0198] Synthesis of (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(bis(2-methoxy-2-oxoethyl)amino)-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 (56-2). A 25 mL round-bottom flask purged and maintained under an inert atmosphere of H was charged with 56-1 (80 mg, 0.11 mmol, 1.00 equiv), MeOH (5 mL), and Pd / C (80 mg). The resulting solution was stirred at room temperature for 2 h. The solid was filtered off. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19×150 mm; mobile phase, water (0.05% TFA) and ACN (ACN 67.0% to 80.0% in 8 min); detector, UV 254 nm. This gave 36.8 mg (53%) of 56-2 as a white solid. MS (ES, m / z): [M+H] + = 614; 1 H NMR (300 MHz, MeOH-d4) δ 5.55 (s, 1H), 3.71 (d, J = 12.1 Hz, 10H), 2.78 (d, J = 13.3 Hz, 1H), 2.43 (s, 2H), 2.22 - 2.05 (m, 2H), 1.91 (s, 1H), 1.82 (d, J = 13.7 Hz, 4H), 1.70 (d, J = 13.3 Hz, 1H), 1.58 (s, 1H), 1.38 (d, J = 4.9 Hz, 7H), 1.25 (d, J = 6.8 Hz, 1H), 1.23 - 1.07 (m, 10H), 1.02 (d, J = 14.5 Hz, 6H), 0.80 (d, J = 2.6 Hz, 7H).

[0199] Example 36 2,2'-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-carboxy-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)azanediyl)diacetic acid (57-2) [ka] Dibenzyl 2,2'-(((3S,4aR,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 Synthesis of (icosahydropicen-3-yl)azanediyl)diacetate (57-1). A 250 mL round-bottom flask was charged with 54-1 (500 mg, 0.89 mmol, 1.00 equiv), CHCN (50 mL), potassium carbonate (1.85 g, 13.39 mmol, 15.00 equiv), and 2-bromobenzyl acetate (1.42 g, 6.20 mmol, 10.00 equiv). The resulting solution was stirred overnight at 60 °C. Potassium carbonate (0.92 g, 7.50 equiv) and 2-bromobenzyl acetate (0.71 mg, 5.00 equiv) were added. The resulting solution was allowed to react at 60 °C for an additional 6 h with stirring. The resulting mixture was concentrated under vacuum. The residue was dissolved in 100 mL of DCM. The resulting mixture was washed with 1 × 100 mL of water. The solid was dried in an oven under reduced pressure. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:5). This gave 380 mg (50%) of 57-1 as a pale yellow oil.

[0200] Synthesis of 2,2'-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-carboxy-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)azanediyl)diacetic acid (57-2). A 100 mL round-bottom flask was charged with 57-1 (466 mg, 0.54 mmol, 1.00 equiv), THF (30 mL), and Pd / C (50 mg). Hydrogen was introduced into the flask. The resulting solution was stirred overnight at room temperature. The solid was filtered off. The resulting mixture was concentrated under vacuum. The residue was dissolved in 10 mL of MeOH. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Prep OBD C18 column, 19 x 250 mm, 5 μm; mobile phase, water (0.05% TFA) and ACN (ACN 32.0% to 55.0% in 8 min); detector, UV 254 nm. This resulted in 263.9 mg (83%) of PH-RDX-013-431-0 as a white solid. MS (ES, m / z): [M+H] + = 586.35; 1 H NMR (300 MHz, MeOH-d4, ppm): δ 0.87 (s, 3H), 0.95 (s, 1H), 1.00 (s, 3H), 1.08 (d, J = 13.6 Hz, 1H), 1.15 (s, 3H), 1.17 (s, 3H), 1.20 (s, 3H), 1.26 (s, 3H), 1.31-1.39 (m, 2H), 1.38-1.59 (m, 8H), 1.65-2.26 (m, 10H), 2.51 (s, 1H), 2.89-2.97 (m, 2H), 3.97 (d, J = 3.3 Hz, 4H), 5.59 (s, 1H).

[0201] Example 37 (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-methoxy-2,2-dimethyl-3-oxopropanamido)-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 (58-2) [ka] Benzyl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-methoxy-2,2-dimethyl-3-oxopropanamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4, Synthesis of 4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate (58-1). A 25 mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with 3-methoxy-2,2-dimethyl-3-oxopropanoic acid (26 mg, 0.18 mmol, 1.00 equiv), DMF (5 mL), 54-1 (100 mg, 0.18 mmol, 1.00 equiv), DIEA (65 mg, 0.50 mmol, 3.00 equiv), and HATU (102 mg, 0.27 mmol, 1.50 equiv). The resulting solution was stirred at room temperature for 1 h. The resulting solution was extracted with 3 × 10 mL of EtOAc, and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column with EtOAc / petroleum ether (1 / 2). The collected fractions were combined and concentrated in vacuo to give 110 mg (90%) of 58-1 as a white solid.

[0202] Synthesis of (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-methoxy-2,2-dimethyl-3-oxopropanamido)-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 (58-2). A 50 mL round-bottom flask purged and maintained under an inert atmosphere of H was charged with 58-1 (50 mg, 0.07 mmol, 1.00 equiv), MeOH (10 mL), and Pd / C (25 mg). The resulting solution was stirred at room temperature for 1 h. The solid was filtered off. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19×150 mm; mobile phase, water (0.05% TFA) and ACN (ACN 60.0% to 78.0% in 8 min); detector, UV 254 nm. This gave 12.3 mg (28%) of 58-2 as a white solid. MS (ES, m / z): [M+H] + = 598; 1 H NMR (300 MHz, MeOH-d4) δ 0.81 - 0.98 (m, 12H), 1.06 (d, J = 14.2 Hz, 2H), 1.13 - 1.33 (m, 12H), 1.43 (q, J = 4.6, 4.1 Hz, 14H), 1.71 (dd, J = 27.4, 13.7 Hz, 4H), 1.81 - 1.98 (m, 3H), 2.20 (s, 2H), 2.52 (s, 1H), 2.77 (d, J = 13.7 Hz, 1H), 3.72 (s, 6H), 5.59 (s, 1H), 7.11 (d, J = 9.6 Hz, 1H).

[0203] Example 38 (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-methoxy-2-oxoacetamido)-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 (60-2) [ka] Benzyl(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-methoxy-2-oxoacetamido)-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-isobenzofuran Synthesis of dropicene-2-carboxylate (60-1). A 50 mL round-bottom flask was charged with 54-1 (90 mg, 0.16 mmol, 1 equiv.), DCM (4 mL, 0.05 mmol, 0.293 equiv.), and DIEA (45.7 mg, 0.35 mmol, 2.2 equiv.). This was followed by the dropwise addition of methyl 2-chloro-2-oxoacetate (21.7 mg, 0.18 mmol, 1.1 equiv.) with stirring. The resulting solution was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum. This yielded 110 mg (105.94%) of 60-1 as a crude yellow solid.

[0204] Synthesis of (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-methoxy-2-oxoacetamido)-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 (60-2). A 25 mL round-bottom flask purged and maintained with an inert atmosphere of H was charged with 60-1 (104 mg, 0.16 mmol, 1 equiv.), MeOH (5 mg, 0.16 mmol, 0.969 equiv.), and Pd / C (50 mg, 0.47 mmol, 2.918 equiv.). The resulting solution was stirred at room temperature for 2.5 hours. The solids were filtered off. The resulting mixture was concentrated. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% TFA) and ACN (phase B 58% to 72% in 8 minutes); detector, UV. This yielded 45.5 mg (50.84%) of 60-2 as a white solid. MS (ES, m / z): [M+H] + = 555.76; 1 H NMR (300 MHz, DMSO-d6) δ 12.18 (s, 1H), 8.30 (d, J = 9.7 Hz, 1H), 5.41 (s, 1H), 3.77 (s, 3H), 3.57 (ddd, J = 13.2, 9.6, 4.1 Hz, 1H), 2.63 (d, J = 13.4 Hz, 1H), 2.41 (s, 1H), 2.08 (q, J = 9.8, 6.6 Hz, 2H), 1.79 (d, J = 13.5 Hz, 3H), 1.69 (d, J = 7.0 Hz, 3H), 1.53 (d, J = 13.2 Hz, 1H), 1.46 - 1.16 (m, 9H), 1.17 - 0.95 (m, 13H), 0.81 - 0.73 (m, 9H).

[0205] Example 39 (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-methoxy-3-oxopropanamido)-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 (62-2) [ka] Synthesis of benzyl (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-methoxy-3-oxopropanamido)-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 (62-1). In a 100 mL round-bottom flask, add 54-1 (500 mg, 0.89 mmol, 1 equiv.), methyl 3-chloro-3-oxopropanamide, and 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. Lopanoate (243.9 mg, 1.79 mmol, 2 equiv.), TEA (271.1 mg, 2.68 mmol, 3 equiv.), and CHCl (10 mL, 0.12 mmol, 0.132 equiv.) were added. The resulting solution was stirred at room temperature for 1 h. The residue was applied to a silica gel column with EtOAc / petroleum ether (1:1). This gave 439 mg (74.49%) of 62-1 as a white solid.

[0206] Synthesis of (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-methoxy-3-oxopropanamido)-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 (62-2). A 100 mL round-bottom flask purged and maintained with an inert atmosphere of H was charged with 62-1 (439 mg, 0.67 mmol, 1 equiv.), THF (200 mg, 2.77 mmol, 4.169 equiv.), MeOH (10 mL, 0.31 mmol, 0.469 equiv.), and Pd / C (10 mL). The resulting solution was stirred at room temperature for 1 hour. The solid was filtered off. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% TFA) and ACN (from 5% to 56% of phase B in 1 min, to 70% in 7 min); detector, UV. This yielded 61.4 mg (16.20%) of 62-2 as a white solid. MS (ES, m / z): [M+H] + = 570; 1 H NMR (300 MHz, MeOH-d4) δ 5.59 (s, 1H), 3.72 (s, 4H), 3.35 (s, 2H), 2.77 (dt, J = 13.4, 3.7 Hz, 1H), 2.53 (s, 1H), 2.18 (ddd, J = 19.3, 13.0, 4.5 Hz, 2H), 2.01 - 1.61 (m, 7H), 1.59 - 1.34 (m, 9H), 1.33 - 1.13 (m, 11H), 1.07 (d, J = 14.9 Hz, 2H), 0.98 - 0.81 (m, 10H).

[0207] Example 40 (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-methoxy-4-oxobutanamido)-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 (64-2) [ka] Synthesis of benzyl (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-methoxy-4-oxobutanamido)-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 (64-1). A 25 mL round-bottom flask was charged with 4-methoxy-4-oxobutanoic acid (28 mg, 0.21 mmol, 1.00 equiv), 54-1 (120 mg, 0.21 mmol, 1.00 equiv), DMF (5 mL), DIEA (78 mg, 0.60 mmol, 3.00 equiv), and HATU (122 mg, 0.32 mmol, 1.50 equiv). The resulting solution was stirred at room temperature for 1 h. The resulting solution was extracted with 3 x 20 mL of EtOAc, and the combined organic layers were dried over anhydrous sodium sulfate. The mixture was then evaporated and concentrated in vacuo. The residue was loaded onto a silica gel column with EtOAc / petroleum ether (1 / 2). The collected fractions were combined and concentrated in vacuo. This gave 140 mg (98%) of 64-1 as a white solid.

[0208] Synthesis of (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-methoxy-4-oxobutanamido)-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 (64-2). A 50 mL round-bottom flask purged and maintained under an inert atmosphere of H was charged with 64-1 (50 mg, 0.07 mmol, 1.00 equiv), MeOH (5 mL), and Pd / C (25 mg). The resulting solution was stirred at room temperature for 1 h. The solid was filtered off. The crude product was purified by recrystallization from ACN, which gave 39.9 mg (92%) of 64-2 as a white solid. MS (ES, m / z): [M+H] + = 584; 1 H NMR (300 MHz, MeOH-d4) δ 0.81 - 0.96 (m, 10H), 0.99 - 1.20 (m, 11H), 1.20 - 1.58 (m, 11H), 1.59 - 1.82 (m, 4H), 1.82 - 2.08 (m, 3H), 2.08 - 2.33 (m, 2H), 2.42 - 2.72 (m, 5H), 2.75 (dq, J = 12.1, 5.0, 4.2 Hz, 1H), 3.67 (s, 4H), 5.65 (s, 1H).

[0209] Example 41 (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((E)-4-methoxy-4-oxobut-2-enamido)-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 (66-2) [ka] Synthesis of benzyl (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((E)-4-methoxy-4-oxobut-2-enamido)-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 (66-1). An 8 mL round-bottom flask was charged with (2E)-4-methoxy-4-oxobut-2-enoic acid (66.48 mg, 0.51 mmol, 1.20 equiv.), 54-1 (200 mg, 0.36 mmol, 1.00 equiv.), DIEA (220.13 mg, 1.70 mmol, 4.00 equiv.), DMF (2 mL), and HATU (343 mg, 0.90 mmol, 1.50 equiv.). The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with EtOAc / petroleum ether (100:1). This gave 200 mg (83%) of 66-1 as a yellow solid.

[0210] (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((E)-4-methoxy-4-oxobut-2-enamido)-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-isopropyl Synthesis of cosahydropicene-2-carboxylic acid (66-2). A 100 mL round-bottom flask was charged with 66-1 (250 mg, 0.37 mmol, 1.00 equiv), THF (10 mL), water (5 mL), sodium hydroxide (90 mg, 2.25 mmol, 6.00 equiv), and MeOH (10 mL). The resulting solution was stirred at 60 °C for 4 days. The residue was applied to a silica gel column with EtOAc / petroleum ether (0-35%). This gave 31.8 mg (15%) of 66-2 as a white solid. MS (ES, m / z): [M+H] + = 582; 1H NMR (300 MHz, MeOH-d4) δ 8.26 (d, J = 9.7 Hz, 1H), 7.08 (d, J = 15.4 Hz, 1H), 6.69 (d, J = 15.4 Hz, 1H), 5.59 (s, 1H), 3.71 (s, 4H), 3.35 (s, 2H), 2.79 (d, J = 13.5 Hz, 1H), 2.57 - 2.50 (m, 1H), 2.16 (t, J = 12.3 Hz, 2H), 2.04 - 1.61 (m, 6H), 1.56 - 1.38 (m, 8H), 1.38 - 1.21 (m, 2H), 1.21 - 0.80 (m, 20H).

[0211] Example 42 (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-carboxy-3-methylbutanamide)-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 (68-3) [ka] Synthesis of benzyl (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-methoxy-3,3-dimethyl-4-oxobutanamido)-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 (68-1). A 25 mL round-bottom flask was charged with 54-1 (150 mg, 0.27 mmol, 1 equiv.), DMF (2 mL, 0.03 mmol, 0.102 equiv.), 4-methoxy-3,3-dimethyl-4-oxobutanoic acid (51.5 mg, 0.32 mmol, 1.2 equiv.), DIEA (138.5 mg, 1.07 mmol, 4.0 equiv.), and HATU (152.8 mg, 0.40 mmol, 1.5 equiv.). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with EA. The resulting mixture was washed with brine ×. The residue was applied to a silica gel column with EtOAc / petroleum ether. This yielded 170 mg (90.38%) of 68-1 as an off-white solid.

[0212] 4-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,1 Synthesis of 4bS)-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-icosahydropicen-3-yl)amino)-2,2-dimethyl-4-oxobutanoic acid (68-2). A 25 mL round-bottom flask was charged with 68-1 (100 mg, 0.14 mmol, 1 equiv), MeOH (5 mL, 49.40 mmol, 346.760 equiv), THF (5 mL, 24.69 mmol, 173.289 equiv), HO (2 mL, 111.02 mmol, 779.31 equiv), and LiOH.HO (54 mg, 1.29 mmol, 9.033 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The pH of the solution was adjusted to 5–6 with HCl. The resulting solution was extracted with 3×100 mL of EtOAc. The residue was applied onto a silica gel column with DCM / MeOH. This afforded 80 mg (81.63%) of 68-2 as a white solid.

[0213] Synthesis of (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(3-carboxy-3-methylbutanamido)-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 (68-3). A 25 mL round-bottom flask purged and maintained with an inert atmosphere of H was charged with 68-2 (80 mg, 0.12 mmol, 1 equiv.), MeOH (5 mL, 0.16 mmol, 1.342 equiv.), and Pd / C (40 mg, 0.38 mmol, 3.232 equiv.). The resulting solution was stirred at room temperature for 2 hours. The solid was filtered off. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O) and ACN (phase B 48% to 73% in 8 minutes); detector, UV. This yielded 14.1 mg (20.28%) of 68-3 as a white solid. MS (ES, m / z): [M+H] + = 598; 1 H NMR (300 MHz, MeOH-d4) δ 5.61 (s, 1H), 3.64 - 3.53 (m, 1H), 2.74 (d, J = 13.6 Hz, 1H), 2.51 (s, 3H), 2.28 - 2.09 (m, 2H), 1.91 (dd, J = 24.4, 10.9 Hz, 3H), 1.81 - 1.60 (m, 2H), 1.43 (d, J = 10.2 Hz, 8H), 1.24 (d, J = 1.8 Hz, 8H), 1.16 (d, J = 4.3 Hz, 11H), 1.05 (d, J = 14.1 Hz, 2H), 0.96 - 0.81 (m, 11H).

[0214] Example 43 (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(4-methoxy-3,3-dimethyl-4-oxobutanamido)-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 (69-1) [ka] A 25 mL round-bottom flask purged and maintained with an inert atmosphere of H was charged with 68-1 (116 mg, 1 equiv.), MeOH (10 mL), and Pd / C (100 mg). The solution was stirred at room temperature for 2 hours. The solid was filtered off. The resulting mixture was concentrated. The crude product was purified by preparative HPLC using the following conditions: column, XBridge Prep C18 OBD column 19 x 150 nm 5 um C-0013; mobile phase, water (0.05% TFA) and ACN (phase B 61% to 81% in 8 minutes); detector, UV. This resulted in 16.5 mg of 69-1 as a white solid. MS (ES, m / z): [M+H] + = 612; 1 H NMR (300 MHz, MeOH-d4) δ 5.59 (s, 1H), 3.68 (s, 3H), 3.53(s,1H), 2.75 (d, J = 12.8 Hz, 1H), 2.52 (d, J = 5.4 Hz, 3H), 2.18 (s, 2H), 1.98 - 1.81 (m, 3H), 1.70 (dd, J = 27.6, 13.7 Hz, 4H), 1.43 (d, J = 10.0 Hz, 10H), 1.33 - 1.12 (m, 16H), 1.05 (d, J = 13.5 Hz, 2H), 0.90 - 0.80 (m, 9H).

[0215] Example 44 (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)sulfonamido)-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 (70-2) [ka] Synthesis of benzyl (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)sulfonamido)-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 (70-1). A 100 mL round-bottom flask was charged with 54-1 (500 mg, 0.89 mmol, 1 equiv.), methyl 2-(chlorosulfonyl)acetate (308.3 mg, 1.79 mmol, 2 equiv.), TEA (271.1 mg, 2.68 mmol, 3 equiv.), CHCl (15 mL, 235.95 mmol, 264.181 equiv.), and DMAP (11 mg, 0.09 mmol, 0.101 equiv.). The resulting solution was stirred overnight at room temperature. The residue was applied to a silica gel column with EtOAc / pe...

Claims

[Claim 1] The invention as depicted in the drawings.

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