Glycyrrhetinic acid derivatives for the treatment of hyperkalemia

Abstract

The present invention provides a compound of formula (I) or a salt thereof: (Formula (I)) wherein X, L, V, R1, R2, R3 and R4 are as defined herein. The claimed compounds inhibit the enzyme type 2 11-hydroxysteroid dehydrogenase (11-HSD2) and are therefore useful for treating hyperkalemia by preventing cortisol from being oxidized to corticosterone and thereby allowing it to occupy the mineralocorticoid receptor, thereby stimulating potassium excretion. #imgabs0#

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 802,210, filed February 7, 2019. The entire contents of the above-cited application are incorporated herein by reference. Technical Field

[0003] This invention relates to compounds that inhibit 11β-hydroxysteroid dehydrogenase 2 and methods for using these compounds to remove potassium from the gastrointestinal tract, including methods for treating hyperkalemia. Background Technology

[0004] Potassium is the most abundant cation in intracellular fluid and plays a crucial role in normal human physiology, particularly in the activation of action potentials in nerve and muscle cells. The total potassium content in the human body is approximately 50 mmol / kg body weight, equivalent to about 3500 mmol of potassium in a 70kg adult. The majority of the body's potassium is intracellular (~98%), with only about 70 mmol (~2%) in the extracellular space. This large difference between intracellular potassium (~120-140 mmol / L) and extracellular potassium (~4 mmol / L) largely determines the resting membrane potential of cells. Therefore, even very small absolute changes in extracellular potassium concentration can have a significant impact on this ratio, and thus a significant impact on the function of excitable tissues (muscles and nerves). Therefore, extracellular potassium levels must be strictly regulated.

[0005] Two independent but cooperative systems are involved in the regulation of potassium homeostasis. One system regulates external potassium homeostasis (the body's equivalence between potassium intake and elimination), while the other regulates internal potassium homeostasis (the distribution between intracellular and extracellular fluid compartments). Intracellular / extracellular homeostasis provides short-term control over changes in serum potassium and is primarily regulated by Na+. + K + The action of the ATPase "pump" is physiologically driven, and the pump utilizes the energy from ATP hydrolysis to reverse the flow of Na+. + and K + The concentration gradient pumps them. Almost all cells possess Na+. + K + -ATPase. The body's potassium balance is controlled through elimination mechanisms via the kidneys and gastrointestinal tract: in healthy kidneys, 90%-95% of the daily potassium load is excreted through the kidneys, with the remainder eliminated in feces.

[0006] Due to the intracellular / extracellular potassium ratio (K i :K e The ratio (K / K ratio) is the main determinant of the resting membrane potential of a cell, therefore K / K ratio is the main determinant of the resting membrane potential of a cell. eSmall changes in serum [K] can profoundly affect 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 crossing the cell membrane and altering the membrane potential, which is the potential difference between the cell's exterior and interior. In addition to active transport, K... + It can also move passively between the extracellular and intracellular compartments. Passive potassium (K) transport is induced by higher serum potassium levels. + Transport overload depolarizes membranes even without stimulation. Excessive serum potassium, known as hyperkalemia, disrupts the membrane potentials in cardiomyocytes that regulate ventricular conduction and contraction. Clinically, the effects of hyperkalemia on cardiac electrophysiology are of great concern, as it can lead to arrhythmias and death. Since most of the body's potassium is maintained through renal excretion, it is expected that the body's ability to control systemic potassium levels will be impaired as kidney function declines.

[0007] Hyperkalemia is defined as a serum potassium level above the normal range, typically >5.0 mmol / L. The one-day mortality rate for moderate hyperkalemia (serum potassium above 6.0 mEq / L) has been reported to be up to 30 times higher than that for patients with serum potassium below 5.5 mEq / L. Severe hyperkalemia (serum K+ at least 6.5 mmol / L) is a potentially life-threatening electrolyte disturbance, reported in 1% to 10% of all hospitalized patients, and constitutes an emergency medical situation requiring immediate treatment. Hyperkalemia is caused by insufficient potassium excretion, and because the kidneys are the primary mechanism for potassium elimination, it commonly affects patients with kidney diseases such as chronic kidney disease (CKD) or end-stage renal disease (ESRD). However, hyperkalemia can also occur in patients with normal kidney function, in which case it remains a life-threatening condition. For example, in hospitalized patients, hyperkalemia is associated with increased mortality in patients with or without CKD. Although chronic kidney disease (CKD) is the most common precipitating condition for hyperkalemia, the mechanisms driving hyperkalemia typically involve a combination of factors, such as increased dietary potassium intake, dysregulation of potassium distribution between the intracellular and extracellular compartments, and abnormal potassium excretion. These mechanisms can be modulated by a variety of factors outside of CKD through causal relationships. These include the presence of other comorbidities, such as type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), or the use of combination therapies that may disrupt potassium homeostasis as a side effect, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) that block the renin-angiotensin-aldosterone system (RAAS).

[0008] Serum potassium can be lowered through two general mechanisms: the first is by transferring potassium intracellularly using agents such as insulin, salbutamol, or sodium bicarbonate. The second is by excreting it from the body via one of four pathways: feces, using potassium-binding resins such as sodium polystyrene sulfonate (Na PSS); urine, using diuretics; blood, using hemodialysis; or peritoneal fluid, using peritoneal dialysis. Apart from Na PSS, medications for treating hyperkalemia such as insulin, diuretics, beta-agonists, and sodium bicarbonate are only used as side effects causing hypokalemia and are not suitable for long-term treatment. Definite therapies require the removal of potassium from the body. Studies have confirmed that lowering serum potassium levels in patients with hyperkalemia actually reduces the risk of death, further confirming the role of excess potassium in mortality risk. While Na PSS is currently the standard of care for potassium reduction in the United States, calcium salts of PSS (Ca PSS) are also widely used in other parts of the world, including in Europe (e.g., Resonium) and Japan.

[0009] Kayexalate / Na PSS is poorly tolerated, leading to a high incidence of GI side effects, including nausea, vomiting, constipation, and diarrhea. Furthermore, Kayexalate (sodium polystyrene sulfonate) is a milled product composed of irregularly shaped particles ranging in size from approximately 1-150 μm, and has a sand-like property in the mouth: it produces a strong foreign body sensation on the palate upon ingestion, which negatively impacts patient adherence. In summary, the physical properties of Kayexalate and its associated side effects contribute to poor adherence and make the drug suboptimal for long-term use. Due to these characteristics, there has long been a need for an optimal drug for long-term use.

[0010] The mineralocorticoid receptor (or MR, MLR, MCR), also known as the aldosterone receptor or nuclear receptor subfamily 3C 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 the cell, interact with the receptor, and lead to signal transduction that affects the expression of specific genes in the cell nucleus. The MR is expressed in many tissues, such as the kidneys, colon, heart, central nervous system (hippocampus), brown adipose tissue, and sweat glands. The ligands aldosterone and cortisol activate the mineralocorticoid receptor in epithelial tissues, promoting potassium excretion. In intact animals, the MR is “protected” from high cortisol concentrations (100-1000 times) by the co-localization of the enzyme 11β-hydroxysteroid dehydrogenase 2 (referred to herein as 11β-HSD2 and HSD2). Therefore, HSD2 prevents MR activation and thus inhibits potassium excretion.

[0011] Therefore, for example in the treatment of hyperkalemia, inhibiting HSD2 to prevent the inactivation of cortisol activation of MR is a promising mechanism for promoting potassium excretion. Summary of the Invention

[0012] In one aspect of the invention, a compound of formula I or a salt thereof is provided:

[0013]

[0014] in,

[0015] 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 -;

[0016] L is a bond, an alkylene group, wherein one or more non-adjacent methylene groups of the alkylene group are replaced by -O-; a divalent aryl or a divalent heteroaryl; or L is an alkylene-Y-alkylene group, wherein Y is O, NR x S, SO, SO2, or a divalent heterocycle; wherein the alkylene group is optionally substituted with OH, -C(O)O-R1, an alkyl group, or an alkyl group substituted with OH or -C(O)O-R1; and wherein the carbon atoms and R atoms of the alkylene group are... x Choose any two elements to form a heterocycle; the condition is that if X is not a bond, then L is not a bond.

[0017] W is either O or S;

[0018] Q is a bond or an alkylene group;

[0019] R1 is H, alkyl, carbocyclic, or heterocyclic, wherein the alkyl group, the carbocyclic ring, and the heterocyclic ring are each optionally substituted with: halogen, OH, amino, oxo, carboxyl, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy, aminocarbonyl, carbocyclic ring optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen, heterocyclic ring optionally substituted with alkyl, oxo, amino, and halogen; and carbocyclic or heterocyclic ring optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen.

[0020] V is -C(O)O-, -C(O)O-(CHR5)-OC(O)-, -C(O)O-(CHR5)-OC(O)-O-, -C(O)N(R5)-, -C(O)N(R5)O-, -NH-C(O)-N(R5)- or NH-S(O) n -;

[0021] R2 is either H or R5;

[0022] R3 is absent or is an alkyl group;

[0023] R4 does not exist; the following are available: H, OH, =O, -R6, -O-R6, -C(O)O-R6, -OC(O)-R6, -OC(O)-O-R6, -OC(O)-NR5R6, -NR5R6, -NR5-C(O)-R6, -NR5-C(O)-O-R6, -NR5-SO2-R6, =NO-R5.

[0024] R5 is H or an alkyl group optionally substituted with a carbocyclic or heterocyclic ring, wherein the carbocyclic and heterocyclic rings are optionally substituted with halogens, OH, oxo groups, and alkyl groups;

[0025] R6 is H, alkyl, carbocyclic, heterocyclic, wherein the alkyl, carbocyclic, and heterocyclic are substituted with: halogen, OH, SH, alkylthio, -S(O)-alkyl, -SO2-alkyl, amino, -NHC(O)-alkyl, oxo, alkyl, carboxyl, acyl, acyloxy, alkoxycarbonyl, a carbocyclic optionally substituted with halogen, OH, amino, or alkyl, or a heterocyclic optionally substituted with halogen, OH, amino, or alkyl; and wherein one or more non-adjacent methylene groups in each of the alkyl groups of R6 are optionally substituted with -O- or -S-.

[0026] R x It is an alkyl group substituted with H, -C(O)O-R1, or optionally substituted with -C(O)O-R1; and

[0027] n is 1 or 2.

[0028] In another aspect of the invention, a composition comprising a compound of formula I and a carrier, diluent or excipient is provided.

[0029] In another aspect of the invention, a method for inhibiting the conversion of cortisol to corticosterone via HSD2 is provided, comprising contacting HSD2 with a compound of formula I.

[0030] In another aspect of the invention, a method for promoting the activation of MR in mammals is provided, comprising administering an effective amount of a compound of formula I to the mammal.

[0031] In another aspect of the invention, a method for reducing potassium levels in the plasma of mammals is provided, comprising administering an effective amount of a compound of formula I to the mammal.

[0032] In another aspect of the invention, a method for promoting the secretion of potassium ions into the colonic lumen of a mammal is provided, comprising administering an effective amount of a compound of formula I to the mammal.

[0033] In another aspect of the invention, a method for treating hyperkalemia in mammals is provided, comprising administering an effective amount of a compound of formula I to the mammal.

[0034] In another aspect of the invention, a method for treating or preventing hyperkalemia in mammals is provided, comprising co-administering a compound of formula I with an inhibitor of the renin-angiotensin-aldosterone system (RAAS). Attached Figure Description

[0035] Figure 1 This study demonstrates the synergistic effect of combined administration of HSD2 inhibitors and NHE3 inhibitors on potassium excretion in feces.

[0036] Figure 2 The study showed that HSD2 inhibition in epithelial cells leads to cortisol activation of the mineralocorticoid receptor (MR), which promotes potassium excretion into the lumen.

[0037] Figure 3 Describe the structure of glycyrrhetinic acid with carbon atom numbers. Detailed Implementation

[0038] Glycyrrhizic acid (or glycyrrhizinic acid) is an extract from the plant licorice, whose name derives from the ancient Greek words 'glykos' (meaning sweet) and 'rhiza' (meaning root). Many prophets and pharaohs were fond of licorice. Eurasian licorice extract has been used in battlefields and deserts, with soldiers and travelers drinking it to suppress thirst during long journeys. The active metabolite glycyrrhetinic acid in Eurasian licorice inhibits HSD2, leading to a cortisol-induced mineralocorticoid effect and a tendency to decrease potassium levels. While glycyrrhetinic acid lowers potassium levels, it is associated with cardiac arrhythmias, hypertension, edema, somnolence, congestive heart failure, hypokalemia, and rhabdomyolysis. Therefore, it is desirable to provide a compound that can promote potassium excretion in patients with hyperkalemia like glycyrrhetinic acid without adverse side effects.

[0039] This invention provides compounds of formula I or salts thereof:

[0040]

[0041] in,

[0042] 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 -;

[0043] L is a bond, an alkylene group, wherein one or more non-adjacent methylene groups of the alkylene group are replaced by -O-; a divalent aryl or a divalent heteroaryl; or L is an alkylene-Y-alkylene group, wherein Y is O, NR x S, SO, SO2, or a divalent heterocycle; wherein the alkylene group is optionally substituted with OH, -C(O)O-R1, an alkyl group, or an alkyl group substituted with OH or -C(O)O-R1; and wherein the carbon atoms and R atoms of the alkylene group are... x Choose any two elements to form a heterocycle; the condition is that if X is not a bond, then L is not a bond.

[0044] W is either O or S;

[0045] Q is a bond or an alkylene group;

[0046] R1 is H, alkyl, carbocyclic, or heterocyclic, wherein the alkyl group, the carbocyclic ring, and the heterocyclic ring are each optionally substituted with: halogen, OH, amino, oxo, carboxyl, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy, aminocarbonyl, carbocyclic ring optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen, heterocyclic ring optionally substituted with alkyl, oxo, amino, and halogen; and carbocyclic or heterocyclic ring optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen.

[0047] V is -C(O)O-, -C(O)O-(CHR5)-OC(O)-, -C(O)O-(CHR5)-OC(O)-O-, -C(O)N(R5)-, -C(O)N(R5)O-, -NH-C(O)-N(R5)- or NH-S(O) n -;

[0048] R2 is either H or R1;

[0049] R3 is absent or is an alkyl group;

[0050] R4 does not exist; the following are available: H, OH, =O, -R6, -O-R6, -C(O)O-R6, -OC(O)-R6, -OC(O)-O-R6, -OC(O)-NR5R6, -NR5R6, -NR5-C(O)-R6, -NR5-C(O)-O-R6, -NR5-SO2-R6, =NO-R5.

[0051] R5 is H or an alkyl group;

[0052] R6 is H, alkyl, carbocyclic, heterocyclic, wherein the alkyl, carbocyclic, and heterocyclic are substituted with: halogen, OH, SH, alkylthio, -S(O)-alkyl, -SO2-alkyl, amino, -NHC(O)-alkyl, oxo, alkyl, carboxyl, acyl, acyloxy, alkoxycarbonyl, a carbocyclic optionally substituted with halogen, OH, amino, or alkyl, or a heterocyclic optionally substituted with halogen, OH, amino, or alkyl; and wherein one or more non-adjacent methylene groups in each of the alkyl groups of R6 are optionally substituted with -O- or -S-.

[0053] R x It is an alkyl group substituted with H, -C(O)O-R1, or optionally substituted with -C(O)O-R1; and

[0054] n is 1 or 2.

[0055] The dashed lines between the 2 and 3 positions of the fused ring system alternately represent single or double bonds. The dashed lines converging inside the fused ring system indicate that R4 (when present) and groups containing -XLC(O)-Q- (and dioxanepentadienone) can be alternately attached to the 3 position (e.g., as in formula Ie) or 4 position (e.g., as in formula Ic) of the fused ring system. Figure 3 The numbering rules for fused rings are illustrated. In one particular embodiment, the compound of the present invention has a dioxanepentadienone group comprising the 4-position of the fused ring system. In one embodiment, after administration of the compound of the present invention to a subject, the ester moiety is metabolized in plasma or liver to an acidic form with lower activity. In another embodiment, the compound of the present invention has HSD2 inhibitory activity equal to or greater than that of glycyrrhetinic acid. In yet another embodiment, the compound of the present invention has HSD2 inhibitory activity greater than that of glycyrrhetinic acid.

[0056] "Acyl" means a substituent containing a carbonyl group represented by the formula -C(O)-R, where R is H, alkyl, carbocyclic, heterocyclic, carbocyclic-substituted alkyl, or heterocyclic-substituted alkyl, wherein the alkyl, alkoxy, carbocyclic, and heterocyclic are as defined herein. Acyl groups include alkylacyl groups (e.g., acetyl), aromatic acyl groups (e.g., benzoyl), and heteroaromatic acyl groups.

[0057] Unless otherwise specified, "alkyl" means 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," "alkylene," etc., the alkyl part can be a saturated hydrocarbon chain, but also includes unsaturated hydrocarbon carbon chains, such as "alkenylamino" and "alkynylamino." Examples of specific alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, n-heptyl, 3-heptyl, 2-methylhexyl, etc. The terms "lower alkyl," "C1-C4 alkyl," and "alkyl with 1 to 4 carbon atoms" are synonyms and used interchangeably, meaning methyl, ethyl, 1-propyl, isopropyl, cyclopropyl, 1-butyl, sec-butyl, or tert-butyl. Unless otherwise specified, the substituted alkyl group may contain, for example, one, two, three, or four substituents that may be the same or different. Examples of substituents, unless otherwise defined, include halogens, amino groups, hydroxyl groups, protected hydroxyl groups, mercapto groups, carboxyl groups, alkoxy groups, nitro groups, cyano groups, amido groups, guanidinyl groups, urea groups, sulfonyl groups, sulfinyl groups, aminosulfonyl groups, alkylsulfonylamino groups, arylsulfonylamino groups, aminocarbonyl groups, acylamino groups, alkoxy groups, acyl groups, acyloxy groups, carbocyclic groups, and heterocyclic groups. Examples of the substituted alkyl groups mentioned above include, but are not limited to: cyanomethyl, nitromethyl, hydroxymethyl, triphenylmethyloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, carboxyethyl, carboxypropyl, alkoxycarbonylmethyl, allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl, ethoxymethyl, tert-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-amino(isopropyl), 2-carbamoyloxyethyl, etc. Alkyl groups may also be substituted with carbocyclic groups. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl, and the corresponding -ethyl, -propyl, -butyl, -pentyl, -hexyl, etc. Substituted alkyl groups include substituted methyl groups, such as those substituted with "C". n -C m The alkyl group is a methyl group substituted with the same substituent as the alkyl group. Examples of substituted methyl groups include groups such as hydroxymethyl, protected hydroxymethyl (e.g., tetrahydropyranoxymethyl), acetoxymethyl, carbamoyloxymethyl, trifluoromethyl, chloromethyl, carboxymethyl, bromomethyl, and iodomethyl. In one embodiment, the alkyl group is saturated. In one embodiment, the alkyl group is unsaturated. In one embodiment, the alkyl group is partially unsaturated.

[0058] "Amidine" refers to the group -C(NH)-NHR, where R is H, alkyl, carbocyclic, heterocyclic, carbocyclic-substituted alkyl, or heterocyclic-substituted alkyl, wherein the alkyl, alkoxy, carbocyclic, and heterocyclic are as defined herein. A specific amidine is -NH-C(NH)-NH2.

[0059] “Amino” means primary amine (i.e., –NH2), secondary amine (i.e., -NRH), and tertiary amine (i.e., -NRR), where R is H, alkyl, carbocyclic, heterocyclic, carbocyclic-substituted alkyl, or heterocyclic-substituted alkyl, wherein the alkyl, alkoxy, carbocyclic, and heterocyclic are as defined herein. Specific secondary and tertiary amines include alkylamines, dialkylamines, arylamines, diarylamines, aralkylamines, and diarylalkylamines, wherein the alkyl group is as defined herein and optionally substituted. Specific secondary and tertiary amines include methylamine, ethylamine, propylamine, isopropylamine, aniline, benzylamine-dimethylamine, diethylamine, dipropylamine, and diisopropylamine.

[0060] As used herein, "amino protecting group" refers to a derivative of a group that is typically used to block or protect the amino group when reacting with other functional groups on a compound. Examples of such protecting groups include urethanes, amides, alkyl and aryl groups, imines, and many N-heteroatom derivatives that can be removed to regenerate the desired amine group. Suitable amino protecting groups (NH-Pg) include acetyl, trifluoroacetyl, tert-butoxycarbonyl ("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 edition, New York: John Wiley & Sons, Inc., 2014. The term "protected amino" refers to an amino group that is substituted with one of the aforementioned amino protecting groups.

[0061] The term "aryl," when used alone or as part of another term, refers to a carbocyclic aromatic group, whether fused or not, having a specified number of carbon atoms, or, if not specified, a maximum of 14 carbon atoms. Specific aryl groups include phenyl, naphthyl, biphenyl, tetraphenyl, etc. (see, for example, Dean, JA.). Lange’s Handbook of Chemistry.13th edition. New York: McGraw-Hill, 1985, Table 7-2). The specific aryl group is phenyl. Substituted phenyl or substituted aryl means a phenyl or aryl group substituted by one, two, three, four or five substituents, for example, substituted by 1-2, 1-3 or 1-4 substituents, unless otherwise specified, selected from halogens (F, Cl, Br, I), hydroxyl, protected hydroxyl, cyano, nitro, alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), benzyloxy, carboxyl, protected carboxyl, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylamino, arylsulfonylaminoalkyl, heterocyclic sulfonylamino, heterocyclic sulfonylaminoalkyl, heterocyclic, aryl or other specified groups. One or more of these substituents, including the methine (CH) and / or methylene (CH2), can be replaced by groups similar to those described above.Examples of the term "substituted phenyl" include, but are not limited to, mono- or di(halogenated)phenyl, 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, etc.; mono- or di(hydroxyphenyl), such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, their protected hydroxyl derivatives, etc.; nitrophenyl, such as 3- or 4-nitrophenyl... Benzylphenyl; cyanophenyl, such as 4-cyanophenyl; mono- or di(lower alkyl)phenyl, such as 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4-(isopropyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl, etc.; mono- or di(alkoxy)phenyl, such as 3,4-dimethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl, 4-(tert-butoxy)phenyl, 3-ethoxy -4-Methoxyphenyl, etc.; 3- or 4-trifluoromethylphenyl; mono- or dicarboxyphenyl or (protected carboxyl)phenyl, such as 4-carboxyphenyl; 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, 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, such as 3-methoxy-4-benzyloxy-6-methylsulfonylamino, 3-methoxy-4-benzyloxy-6-phenylsulfonylamino; and tetrasubstituted phenyl, such as 3-methoxy-4-benzyloxy-5-methyl-6-phenylsulfonylamino. Specific substituted phenyl groups include 2-chlorophenyl, 2-aminophenyl, 2-bromophenyl, 3-methoxyphenyl, 3-ethoxy-phenyl, 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 also be substituted with any of the substituents specified herein, such as one, two, or three substituents, in the same manner as the substituted alkyl group.

[0062] The terms "carbocyclic" and "carbocyclo" (whether used alone or as part of a complex group such as a carbocycloalkyl group) refer to a monocyclic, bicyclic, or tricyclic aliphatic ring having 3 to 14 carbon atoms, for example, having 3 to 7 or 3 to 6 carbon atoms, which can be saturated or unsaturated, aromatic or non-aromatic. Specific saturated carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. One specific saturated carbocycloiden is cyclopropyl. Another specific saturated carbocycloiden is cyclohexyl. Specific unsaturated carbocycloiden are aromatic, such as the previously defined aryl group, such as phenyl. The terms "substituted carbocyclic" and "carbocycloiden" mean these groups substituted with the same substituents as "substituted alkyl".

[0063] As used herein, "carboxyl protecting group" refers to one of the ester derivatives of a carboxylic acid group, which is typically used to block or protect the carboxylic acid group when reacting with other functional groups on a compound. Examples of such carboxylic acid protecting groups include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzyldiphenylmethyl, 4,4'-dimethoxydiphenylmethyl, 2,2',4,4'-tetramethoxydiphenylmethyl, and alkyl groups such as tert-butyl or tert-pentyl. Triphenylmethyl, 4-methoxytriphenylmethyl, 4,4'-dimethoxytriphenylmethyl, 4,4',4”-trimethoxytriphenylmethyl, 2-phenylpropyl-2-yl, trimethylsilyl, tert-butyldimethylsilyl, benzoylmethyl, 2,2,2-trichloroethyl, β-(trimethylsilyl)ethyl, β-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1- (trimethylsilylmethyl)prop-1-en-3-yl, etc. The type of carboxyl protecting group used is not critical, as long as the conditions for subsequent reactions at other positions of the molecule are stable and can be removed at the appropriate time without destroying the rest of the molecule. In particular, it is important to avoid subjecting the carboxyl-protected molecule to strong nucleophilic bases such as lithium hydroxide or NaOH, or to reduction conditions using highly activated metal hydrides such as LiAlH4. Such harsh removal conditions should also be avoided when removing the amino and hydroxyl protecting groups discussed below. Specific carboxyl protecting groups are alkyl (e.g., methyl, ethyl, tert-butyl), allyl, benzyl, and p-nitrobenzyl. Similar carboxyl protecting groups used in cephalosporins, penicillins, and peptides can also be used to protect carboxyl substituents. Further examples of these groups can be found in Greene, TW, and PGMUTS. Protective. Groups in Organic Synthesis, 2nd ed., New York: John Wiley & Sons, Inc., 1991, Chapter 5; Haslam, E. Protective Groups in Organic Chemistry, New York: Plenum Press, 1973, Chapter 5; and Greene, T.W. Protective Groups in Organic Synthesis, New York: John Wiley & Sons, Inc., 1981, Chapter 5. The term "protected carboxyl group" refers to a carboxyl group substituted by one of the aforementioned carboxyl protecting groups.

[0064] "Alkoxycarbonyl" refers to the group -C(=O)OR, where R is an alkyl group. A specific group is C1-C6 alkoxycarbonyl, where R is a C1-C6 alkyl group.

[0065] “Guidane” refers to the group -NH-C(NH)-NHR, where R is hydrogen, alkyl, carbocyclic, heterocyclic, carbocyclic-substituted alkyl, or heterocyclic-substituted alkyl, wherein the alkyl, alkoxy, carbocyclic, and heterocyclic are as defined herein. A specific guanidine is the group -NH-C(NH)-NH2.

[0066] As used herein, a “hydroxyl protecting group” refers to a hydroxyl derivative that is typically used to block or protect the hydroxyl group when reacting with other functional groups on a compound. Examples of such protecting groups include tetrahydropyranoxy, benzoyl, acetoxy, carbamoyloxy, benzyl, and silyl ethers (e.g., TBS, TBDPS). Further examples of these groups can be found in Greene, TW, and PGMUTS. Protective Groups in Organic Synthesis. 2nd edition New York: John Wiley & Sons, Inc. 1991, Chapter 2-3; Haslam, E. Protective Groups in Organic Chemistry. New York: Plenum Press 1973, Chapter 5; and Greene, TW Protective Groups in Organic Synthesis. New York: John Wiley & Sons, Inc. 1981. The term "protected hydroxyl group" refers to a hydroxyl group that is substituted by one of the aforementioned hydroxyl protecting groups.

[0067] The terms “heterocyclic group,” “heterocyclic group,” or “heterocyclic (heterocyclic / heterocycle / heterocyclo)” are used interchangeably, both individually and as part of a complex group such as a heterocyclic alkyl group, and refer to any monocyclic, bicyclic, or tricyclic saturated or unsaturated aromatic (heteroaryl) or non-aromatic ring having a specified number of atoms, typically having 5 to 14 ring atoms, wherein the ring atom is carbon and at least one heteroatom (nitrogen, sulfur, or oxygen), for example, 1 to 4 heteroatoms. Heterocyclic groups include four- to seven-membered cyclic groups containing one, two, or three 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. Nitrogen or sulfur heteroatoms may optionally be oxidized (e.g., SO, SO2), and any nitrogen heteroatom may optionally be quaternized. Specific non-aromatic heterocycles include morpholinyl, pyrrolyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2H-pyranyl, tetrahydropyranyl, thiiranyl, thietanyl, tetrahydrothiobutane, aziridinyl, azetidinyl, 1-methyl-2-pyrrolyl, piperazinyl, and piperidinyl. "Heterocyclic alkyl" refers to a heterocyclic group as defined above, covalently bonded to an alkyl group as defined above. Specific 5-membered heterocycles containing sulfur or oxygen atoms and one to three nitrogen atoms include thiazolyl groups, particularly thiazolyl-2-yl and thiazolyl-2-yl N-oxides; thiadiazolyl groups, particularly 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl; oxazolyl groups, such as oxazol-2-yl; and oxadiazolyl groups, such as 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl. Specific 5-membered heterocycles containing 2 to 4 nitrogen atoms include imidazole groups, such as imidazole-2-yl; triazolyl groups, such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl; and tetrazolyl groups, such as 1H-tetrazole-5-yl. Specific benzo-fused 5-membered heterocycles include benzoxazol-2-yl, benzothiazolyl-2-yl, and benzimidazole-2-yl. Specific 6-membered heterocycles contain one to three nitrogen atoms and optionally sulfur or oxygen atoms, such as pyridinyl groups, like pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; pyrimidinyl groups, like pyrimidin-2-yl and pyrimidin-4-yl; triazine groups, like 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl groups, especially pyridazin-3-yl; and pyrazinyl groups. Pyridine N-oxides and pyridazine N-oxides, as well as pyridinyl, pyrimidin-2-yl, pyrimidin-4-yl, pyridazinyl, and 1,3,4-triazin-2-yl, are specific functional groups.Further examples of substituents in "optionally substituted heterocyclic" heterocycles, as well as the 5- and 6-membered ring systems discussed above, can be found in U.S. Patent No. 4,278,793 to W. Druckheimer et al. In certain embodiments, such optionally substituted heterocyclic groups are substituted with hydroxyl, alkyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, halosubstituted alkyl, amino, cyano, nitro, amido, and guanidinyl groups.

[0068] "Heteroaryl" refers, both alone and as part of a complex group such as a heteroaryl group, to any monocyclic, bicyclic, or tricyclic aromatic ring system having a specified number of atoms, wherein at least one ring is a 5, 6, or 7-membered ring containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur, and in a particular embodiment, at least one heteroatom is nitrogen (Lange's Handbook of Chemistry, ibid.). In one example, a heteroaryl is a five- to six-membered aromatic ring containing one, two, or three heteroatoms selected from nitrogen, oxygen, and sulfur. The definition includes any bicyclic group in which any of the aforementioned heteroaryl rings is fused to a benzene ring. A particular heteroaryl contains either a nitrogen or an oxygen heteroatom. The following ring systems are examples of heteroaryl groups (whether substituted or unsubstituted) represented by the term "heteroaryl": thiophene, furanyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxiadiazolyl, tetrazolyl, thiatriazolyl, oxiatriazolyl, pyridinyl, pyrazinyl, pyridazinyl, thiazidinyl, oxazinyl, triazinyl, thiazidinyl Diazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxthiazinyl, tetraazinyl, thiatriazinyl, oxiatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, tetrazo[1,5-b]pyridazinyl and purine, and benzofused derivatives such as benzoxazolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl and indolyl.The specific "heteroaryl" can be selected from: 1,3-thiazolyl-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazolyl-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazolyl-2-yl, 1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl, 1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 2-hydroxy-1,3,4-triazol-5-yl, 2-carboxy-4-methyl-1,3,4-triazol-5-yl, 2-carboxy-4-methyl-1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl, 2- (hydroxymethyl)-1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 2-mercapto-1,3,4-thiadiazol-5-yl, 2-(methylthio)-1,3,4-thiadiazol-5-yl, 2-amino-1,3,4-thiadiazol-5-yl, 1H-tetrazole-5-yl, 1-methyl-1H-tetrazole-5-yl, 1-(1-(dimethylamino)ethyl-2-yl)-1H-tetrazole-5-yl, 1-(carboxymethyl)-1H-tetrazole-5-yl, 1-(carboxymethyl)-1H-tetrazole-5-yl, 1-(methanesulfonic acid)-1H-tetrazole-5-yl, 1-(methanesulfonic acid)-1H-tetrazole-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, pyridin-2-yl N-oxide, 6-methoxy-2-(n-oxide)-pyridazin-3-yl, 6-hydroxypyridazin-3-yl, 1-methylpyridin-2-yl, 1-methylpyridin-4-yl, 2-hydroxypyrimidin-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-triazine-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazine-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazine-3-yl, 2,5-dihydro-5-oxo-6-methoxy-2-methyl-as-triazine-3-yl, 2,5-dihydro-5-oxo-as-triazine-3-yl, 2,5-dihydro-5-oxo-2-methyl-as-triazine-3-yl, 2,5-dihydro-5-oxo-2,6-dimethyl-as-triazine-3-yl, tetrazolo[1,5-b]pyridazine-6-yl and 8-aminotetrazole[1,5-b]pyridazine-6-yl.The substituent groups for "heteroaryl" include: 4-(carboxymethyl)-5-methyl-1,3-thiazolyl-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazolyl-2-yl, 1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 1H-tetrazole-5-yl, 1-methyl-1H-tetrazole-5-yl, 1-(1-(dimethylamino)ethyl-2-yl)-1H-tetrazole-5-yl, 1-(carboxymethyl)-1H-tetrazole-5-yl, 1-(carboxymethyl)-1H-tetrazole-5-yl, 1-(methylsulfonic acid)-1H-tetrazole-5-yl, 1-(methyl) The compounds are 1,2,3-triazol-5-yl (2-formylmethyl)-5,6-dioxo-4-methyl-as-triazine-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazine-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazine-3-yl, tetrazol[1,5-b]pyridazine-6-yl, and 8-aminotetrazol[1,5-b]pyridazine-6-yl. The heteroaryl groups may be substituted as described with respect to heterocycles.

[0069] "Inhibitor" refers to a compound that reduces or prevents the enzymatic conversion of cortisol to corticosterone via HSD2.

[0070] Unless otherwise specified, "optionally substituted" means that the group may be unsubstituted or, where the valence allows, substituted by one or more (e.g., 0, 1, 2, 3, and / or 4) substituents listed for the group, wherein said substituents may be the same or different. In one embodiment, the optionally substituted group has 1 substituent. In another embodiment, the optionally substituted group has 2 substituents. In yet another embodiment, the optionally substituted group has 3 substituents.

[0071] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" refer to those salts that retain the bioavailability and properties of the free base and are not biologically or otherwise undesirable, forming with inorganic and organic acids. The inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., and the organic acids can be selected from aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, carboxylic acid, and sulfonic acid 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, etc.

[0072] "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. Specifically, base addition salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of the following amines: 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, meglumine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. Specifically, non-toxic organic alkaloids include isopropylamine, diethylamine, ethanolamine, aminobutanetriol, dicyclohexylamine, choline, and caffeine.

[0073] “Thioalkyl” means –SR group, where R is an alkyl, carbocyclic, heterocyclic, carbocyclic-substituted alkyl, or heterocyclic-substituted alkyl, wherein the alkyl, alkoxy, carbocyclic, and heterocyclic are as defined herein. Specific thioalkyl groups are alkylthioalkyl (i.e., –SO2-alkyl), such as methylthioalkyl; arylthioalkyl, such as phenylthioalkyl; aralkylthioalkyl, such as benzylthioalkyl.

[0074] "Sulfinyl" refers to a -SO-R group, where R is hydrogen, alkyl, carbocyclic, heterocyclic, carbocyclic-substituted alkyl, or heterocyclic-substituted alkyl, wherein the alkyl, alkoxy, carbocyclic, and heterocyclic are as defined herein. Specific sulfonyl groups are alkylsulfonyl groups (i.e., -SO-alkyl), such as methylsulfonyl; arylsulfinyl groups, such as phenylsulfinyl; and aralkylsulfinyl groups, such as benzylsulfinyl.

[0075] "Sulfoyl" refers to a –SO2-R group, where R is hydrogen, alkyl, carbocyclic, heterocyclic, carbocyclic-substituted alkyl, or heterocyclic-substituted alkyl, wherein the alkyl, alkoxy, carbocyclic, and heterocyclic are as defined herein. Specific sulfonyl groups are alkylsulfonyl groups (i.e., –SO2-alkyl), such as methylsulfonyl; arylsulfonyl groups, such as phenylsulfonyl; and aralkylsulfonyl groups, such as benzylsulfonyl.

[0076] As used herein, the phrase "and its salts and solvates" means that the compounds of the present invention may exist in the form of one of the salts and solvates or a mixture of the salts and solvates. For example, the compounds of the present invention may be in the form of a specific salt or solvate that is substantially pure, or may be a mixture of two or more salts or solvates.

[0077] In a specific embodiment of the invention, the compound of formula I has a structure defined by formulas Ia-Ip:

[0078]

[0079]

[0080] Wherein X, L, Q, V, R1, R2, R3, and R4 are as defined herein. In a particular embodiment, the compound has a structure according to formula Ia. In a particular embodiment, the compound has a structure according to formula Ib. In a particular embodiment, the compound has a structure according to formula Ic. In a particular embodiment, the compound has a structure according to formula Id. In a particular embodiment, the compound has a structure according to formula Ie. In a particular embodiment, the compound has a structure according to formula If. In a particular embodiment, the compound has a structure according to formula Ig. In a particular embodiment, the compound has a structure according to formula Ih. In a particular embodiment, the compound has a structure according to formula Ii. In a particular embodiment, the compound has a structure according to formula Ij. In a particular embodiment, the compound has a structure according to formula Ik. In a particular embodiment, the compound has a structure according to formula Il. In a particular embodiment, the compound has a structure according to formula Im. In a particular embodiment, the compound has a structure according to formula In. In a particular embodiment, the compound has a structure according to formula Io. In a particular embodiment, the compound has a structure according to formula Ip.

[0081] In a particular embodiment of the invention, the compound of formula I has the structure defined by formula Ia'-If':

[0082]

[0083] Wherein X, L, V, 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'.

[0084] In one embodiment, the compound of the present invention is of any one of Formula I.

[0085] In one implementation, X is a key, -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 X is an alkyl group, either H, -C(O)O-R1, or optionally substituted with -C(O)O-R1; 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 another embodiment, X is -N(R)NH-. x X is -NH-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)2-NH-. In one embodiment, X is -N(R x )-S(O) n - In one embodiment, X is -NH-S(O)-. In another embodiment, X is -NH-S(O)2-.

[0086] W is either O or S. In one implementation, W is O. In another implementation, W is S.

[0087] Q is a bond or an alkylene group. In one embodiment, Q is a bond. In one embodiment, Q is a methylene group. In one embodiment, Q is an ethylene group.

[0088] V is -C(O)O-, -C(O)O-(CHR5)-OC(O)-, -C(O)O-(CHR5)-OC(O)-O-, -C(O)N(R5)-, -C(O)N(R5)O-, -NH-C(O)-N(R5)- or NH-S(O) n -

[0089] 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 an alkyl group. In one embodiment, V is -C(O)O- and R2 is a methyl group. In another embodiment, V is -C(O)O- and R2 is an alkyl group optionally substituted with oxo, acyloxy, alkoxycarbonyl, alkoxyacyloxy, or alkoxycarbonyloxy, a carbocyclic ring optionally substituted with alkyl and oxo, or a heterocyclic ring optionally substituted with alkyl and oxo.

[0090] In one embodiment, V is -C(O)N(R5)-. In one embodiment, V is -C(O)N(R5)- and both R2 and R5 are H. In one embodiment, V is -C(O)N(R5)- and R2 and R5 are independently H and optionally alkyl groups substituted with OH. In one embodiment, V is -C(O)N(R5)- and R5 is H and R2 is hydroxyethyl.

[0091] In one embodiment, V is -C(O)N(R5)O-. In one embodiment, V is -C(O)N(R5)O- and R2 and R5 are independently H or alkyl. In one embodiment, V is -C(O)N(R5)O- and R2 is methyl and R5 is H.

[0092] In one embodiment, V is -NH-C(O)-N(R5)- and R2 and R5 are independently H or alkyl. In one embodiment, V is -NH-C(O)-N(R2)- and R2 is methyl and R5 is H. In one embodiment, V is -NH-C(O)-N(R5)- and both R2 and R5 are H.

[0093] In one implementation, V is NH-S(O) n - In one embodiment, V is NH-S(O)2-. In one embodiment, V is NH-S(O)2- and R2 is an alkyl group. In one embodiment, V is NH-S(O)2- and R2 is a methyl group.

[0094] L is a bond, an alkylene group, wherein one or more non-adjacent methylene groups of the alkylene group are replaced by -O-; a divalent aryl or a divalent heteroaryl; or L is an alkylene-Y-alkylene group, wherein Y is O, NR x S, SO, SO2, or a divalent heterocycle; wherein the alkylene group is optionally substituted with OH, -C(O)O-R1, an alkyl group, or an alkyl group substituted with OH or -C(O)O-R1; and wherein the carbon atoms and R atoms of the alkylene group are... x Choose any two elements to form a heterocycle; the condition is that if X is not a bond, then L is not a bond.

[0095] In one embodiment, L is a bond, an alkylene group, wherein one or more non-adjacent methylene groups of the alkylene group are replaced by -O-. In one embodiment, L is a bond. In one embodiment, L is an alkylene group. In one embodiment, L is an alkylene group. In one embodiment, L is an alkylene group, wherein one or more non-adjacent methylene groups of the alkylene group are replaced by -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-.

[0096] In one embodiment, L is an alkylene-Y-alkylene, where Y is O, NR. x S, SO, SO2, or a divalent heterocycle; wherein the alkylene group is optionally substituted with OH, -C(O)O-R1, an alkyl group, or an alkyl group substituted with OH or -C(O)O-R1; and wherein the carbon atoms and R atoms of the alkylene group are... x The heterocycles can be formed together arbitrarily; the condition is that L is not a bond when X is not a bond. In one embodiment, L is an alkylene-Y-alkylene, where Y is O. In one embodiment, L is an alkylene-Y-alkylene, where Y is NR. x In one embodiment, L is an alkylene-γ-alkylene, where Y is NR. x The carbon of the alkylene group and R xTogether, they form a heterocycle. In one embodiment, L is alkylene-γ-alkylene, where Y is S. In one embodiment, L is alkylene-γ-alkylene, where Y is SO. In one embodiment, L is alkylene-γ-alkylene, where Y is SO2. In one embodiment, L is alkylene-γ-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.

[0097] R1 is H, an alkyl group, a carbocyclic ring, or a heterocyclic ring, wherein the alkyl group, the carbocyclic ring, and the heterocyclic ring are each optionally substituted with: halogen, OH, amino, oxo, carboxyl, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy, aminocarbonyl, a carbocyclic ring optionally substituted with an alkyl group, a haloalkyl group, an oxo, an amino group, or a halogen, a heterocyclic ring optionally substituted with an alkyl group, an oxo, an amino group, or a halogen; and a heterocyclic ring optionally substituted with an alkyl group, a haloalkyl group, an oxo, an amino group, or a halogen. In one embodiment, R1 is H. In one embodiment, R1 is an alkyl group. In one embodiment, R1 is methyl. In one embodiment, R1 is ethyl. In one embodiment, R1 is n-propyl. In one embodiment, R1 is isopropyl. In one embodiment, R1 is cyclohexyl. In one embodiment, R1 is an alkyl group substituted with OH. In one embodiment, R1 is an alkyl group substituted with oxo. In one embodiment, R1 is an alkyl group substituted with a carboxyl group. In one embodiment, R1 is an alkyl group substituted with an acyloxy group. In one embodiment, R1 is an alkyl group substituted with an alkoxycarbonyl group. In one embodiment, R1 is an alkyl group substituted with an alkoxyacyloxy group. In one embodiment, R1 is an alkyl group substituted with an alkoxycarbonyloxy group. In one embodiment, R1 is an alkyl group substituted with an aminocarbonyl group. In one embodiment, R1 is methyl. In one embodiment, R1 is propyl. In one embodiment, R1 is hydroxyethyl.

[0098] In one embodiment, R2 is H or R5. In one embodiment, R2 is H. In one embodiment, R2 is R5. In one embodiment, R2 is methyl. In one embodiment, R2 is tert-butyl. In one embodiment, R2 is diphenylmethyl. In one embodiment, R2 is benzyl.

[0099] R3 is absent or is an alkyl group. In one embodiment, R3 is methyl. In one embodiment, R3 is absent.

[0100] R4 does not exist; it is H, OH, =O, -R6, -O-R6, -C(O)O-R6, -OC(O)-R6, -OC(O)-O-R6, -OC(O)-NR5R6, -NR5R6, -NR5-C(O)-R6, -NR5-C(O)-O-R6, -NR5-SO2-R6, =NO-R5. In one embodiment, R4 is H. In one embodiment, R4 is OH. In one embodiment, R4 is =O. In one embodiment, R4 is -O-R6. In one embodiment, R4 is -C(O)O-R6. In one embodiment, R4 is -OC(O)-R6. In one embodiment, R4 is -OC(O)-O-R6. In one embodiment, R4 is -OC(O)-NR5R6. In one embodiment, R4 is -NR5R6. In one embodiment, R4 is -NR5-SO2-R6. In one embodiment, R4 is =NO-R5. In one embodiment, R4 is as defined and the carbon atom it is attached to is part of a double bond. In one embodiment, R4 is H and the carbon atom it is attached to is not part of a double bond. In one embodiment, R4 is -R6.

[0101] R5 is H or an alkyl group optionally substituted with a carbocyclic or heterocyclic ring, wherein the carbocyclic and heterocyclic rings are optionally substituted with a halogen, OH, oxo, or alkyl group. In one embodiment, R5 is H. In one embodiment, R5 is an alkyl group. In one embodiment, R5 is methyl.

[0102] R6 is H, alkyl, carbocyclic, heterocyclic, wherein the alkyl, carbocyclic, and heterocyclic are substituted with: halogen, OH, SH, alkylthio, -S(O)-alkyl, -SO2-alkyl, amino, -NHC(O)-alkyl, oxo, alkyl, carboxyl, acyl, acyloxy, alkoxycarbonyl, a carbocyclic optionally substituted with halogen, OH, amino, or alkyl, or a heterocyclic optionally substituted with halogen, OH, amino, or alkyl; and wherein one or more non-adjacent methylene groups in each of the alkyl groups of R6 are optionally substituted with -O- or -S-.

[0103] In one embodiment, R6 is H. In one embodiment, R6 is an alkyl group. In one embodiment, R6 is a methyl group.

[0104] In one embodiment, R6 is ethyl. In one embodiment, R6 is cyclopropyl. In one embodiment, R6 is allyl. In one embodiment, R6 is vinyl. In one embodiment, R6 is OH. In one embodiment, R6 is alkoxycarbonyl. In one embodiment, R6 is methoxycarbonyl. In one embodiment, R6 is ethoxycarbonyl. In one embodiment, R6 is amino. In one embodiment, R6 is NH2. In one embodiment, R6 is alkoxy. In one embodiment, R6 is polyalkoxyalkyl. In one embodiment, R6 is oxo. In one embodiment, R6 is alkylthio. In one embodiment, R6 is -S-Me. In one embodiment, R6 is -S-Et.

[0105] In one implementation, R x It is H. In one implementation, R x It is -C(O)O-R1. In one implementation, R x It is an alkyl group. In one embodiment, R x It is an alkyl group that is optionally substituted with -C(O)O-R1.

[0106] In one implementation, 'n' is 1. In another implementation, 'n' is 2.

[0107] In another aspect of the invention, a compound of formula II is provided.

[0108]

[0109] R1, R2, R3, R4, L, X, Q, V, and W are as defined for compounds of Formula I. Furthermore, specific embodiments of Formula II are similar to those specified herein for Formula I. For example, specific embodiments of Formula II include compounds according to Formulas Ia–Ip and Ia'-If', except that the dioxacyclopentadienone ring is saturated.

[0110] In one embodiment, the compounds of the present invention are selected from the group consisting of:

[0111] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2,9-dicarboxylic acid (122-3); (2S,4aS,6aS,6bR) ,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (176-2);

[0112] (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(((5-methyl-2-oxo-1,3-dioxolane-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (178-1); (2S,4aS,6aS,6bR) S,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-(2-(methylthio)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (194-10);

[0113] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-(2-(methanesulfonyl)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid (195-2);

[0114] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((L-valinel)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (196-2);

[0115] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(benzoyloxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (197-2);

[0116] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopropanecarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (198-2);

[0117] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((R)-2-methoxypropionyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (203-2);

[0118] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((S)-2-methoxypropionyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (204-2);

[0119] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(methoxymethoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (205-2);

[0120] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((ethylcarbamoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (206-2);

[0121] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((Butylcarbamoyl)oxy)-2,4a,6a,6b,9,12a-Hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-Eicosyl-2-carboxylic acid (207-2);

[0122] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-10-((pyrrolidine-1-carbonyl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (208-2);

[0123] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-(((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydro-2-carboxylic acid (209-3);

[0124] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-10-(propionyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (211-1);

[0125] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopentanecarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (212-1);

[0126] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-10-((3-(piperidin-1-yl)propionyl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid (215-1);

[0127] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((isopropoxycarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (216-2);

[0128] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,2-difluoroacetoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (223-1);

[0129] (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-9-((2-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)-2-oxoethoxy)methyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (240-8);

[0130] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (243-1);

[0131] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2-hydroxyacetoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (244-1);

[0132] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2-methoxyacetoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (245-1);

[0133] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxadodecanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2- Carboxylic acid (246-3); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (249-5);

[0134] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (252-2);

[0135] (2S,4aS,6aS,6bR,8aR,9R,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (253-4);

[0136] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (254-3);

[0137] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-((((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid (255-2);

[0138] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,2-difluoroacetoxy)-9-(((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid (256-2);

[0139] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-(methoxymethoxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (258-2);

[0140] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxatetradecane-14-acyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (264-1);

[0141] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxatetradecane-14-acyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxolane-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (265-2)

[0142] (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(2-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)-2-oxoethoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (279-2);

[0143] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-amino-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (280-7); (2S, 4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((methoxycarbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (281-3);

[0144] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-10-(valeroyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid (282-2);

[0145] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-(2-(4-methylpiperazin-1-yl)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (283-2);

[0146] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-((3-morpholinopropionyl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid (284-2);

[0147] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-(methanesulfonylamino)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid (285-2);

[0148] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-(((2-morpholinoethyl)carbamoyl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid (286-4);

[0149] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-(2-(methylsulfinyl)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (289-2);

[0150] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((dimethylglycyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (290-2);

[0151] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((acetylglycyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (291-2);

[0152] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetamido-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid;

[0153] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(allyloxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (297-5);

[0154] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(3-methoxy-3-oxopropionamido)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (298-2);

[0155] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4-methoxy-4-oxobutyrylamino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydro-2-carboxylic acid (299-2);

[0156] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((butoxycarbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (300-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-((methoxycarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid (301-2);

[0157] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-((((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (302-3);

[0158] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-((((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid-2,9-dicarboxylic acid (307-2);

[0159] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-(2-methoxyacetoxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid (308-2);

[0160] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,2-difluoroacetamido)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (309-2);

[0161] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopropanecarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (314-4);

[0162] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopropanecarbonyl)oxy)-9-((((5-ethyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid (315-2);

[0163] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-(((5-ethyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydro-2-carboxylic acid (316-1);

[0164] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)-13-oxo-10-(propionyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydro-2-carboxylic acid (317-6); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-((((5-ethyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-10-(propionyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydro-2-carboxylic acid (318-1);

[0165] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)-13-oxo-10-(propionyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (319-1);

[0166] (3S,4S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-4-((((5-ethyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)-4,6a,6b,8a,11,14b-hexamethyl-11-(methylcarbamoyl)-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-eicosyl-3-ylpropionate (320-1);

[0167] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopropanecarbonyl)oxy)-9-((((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid (321-1);

[0168] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)-13-oxo-10-propoxy-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (322-6);

[0169] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-((((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-10-propoxy-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (323-1);

[0170] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (324-3);

[0171] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-((((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (325-1);

[0172] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-((((5-ethyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid (326-1);

[0173] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4,4-difluoropiperidin-1-yl)-9-((((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydro-2-carboxylic acid (327-8);

[0174] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-((((5-ethyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid (326-1);

[0175] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4,4-difluoropiperidin-1-yl)-9-((((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydro-2-carboxylic acid (327-8);

[0176] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-10-(1H-pyrrolo-1-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (328-2);

[0177] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-10-(1H-pyrazol-1-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid;

[0178] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-10-(1H-pyrazol-1-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (330-1);

[0179] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-(5-methyl-1H-pyrazol-1-yl)-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (331-2);

[0180] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-(3-methyl-1H-pyrazol-1-yl)-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (332-2);

[0181] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-((((5-ethyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-10-(propionyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydro-2-carboxylic acid (333-1);

[0182] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (334-8);

[0183] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (335-1);

[0184] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(5-(ethoxycarbonyl)-3-methyl-1H-pyrazol-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (336-2);

[0185] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (337-2);

[0186] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-(4-methyl-1H-pyrazol-1-yl)-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (338-4);

[0187] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-ethyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-10-(4-methyl-1H-pyrazol-1-yl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (339-1);

[0188] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (341-2);

[0189] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2-amino-2-oxoethyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (342-1);

[0190] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (343-3);

[0191] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(allyl(2-methoxy-2-oxoethyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (344-1);

[0192] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((S)-1-methoxy-1-oxopropyl-2-yl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (345-2);

[0193] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-(1-methylcyclopropane-1-carboxamido)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (346-2);

[0194] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-10-(2-oxopyrrolidone-1-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (347-4);

[0195] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-ethyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-((S)-2-(methoxycarbonyl)pyrrolidine-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-eicosylhydrocarboxylic acid (348-11);

[0196] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((S)-2-(methoxycarbonyl)pyrrolidine-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (349-1);

[0197] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-((S)-2-(methoxycarbonyl)pyrrolidine-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-eicosylhydrocarboxylic acid (350-1);

[0198] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-((R)-2-(methoxycarbonyl)pyrrolidine-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-eicosylhydrocarboxylic acid (351-1);

[0199] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((S)-2-(ethoxycarbonyl)pyrrolidine-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (352-1);

[0200] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((R)-2-(ethoxycarbonyl)pyrrolidine-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (353-1);

[0201] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-10-(piperidin-1-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (356-2);

[0202] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4,4-difluoropiperidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (357-7);

[0203] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((R)-3-(ethoxycarbonyl)pyrrolidine-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (358-7);

[0204] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((R)-3-(ethoxycarbonyl)piperidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (359-1)

[0205] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((S)-3-(ethoxycarbonyl)piperidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (360-1);

[0206] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4-(ethoxycarbonyl)piperidin-1-yl)-9-(((5-ethyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (361-1);

[0207] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4-(ethoxycarbonyl)piperidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (362-1);

[0208] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-acetamido-2,4a,6a,6b,9,12a-hexamethyl-10-((((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (363-5);

[0209] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-acetamido-2,4a,6a,6b,9,12a-hexamethyl-10-((((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (363-5);

[0210] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-((R)-5-methyl-2-oxooxazolidine-3-yl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (364-5);

[0211] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,5-dioxoimidazolidine-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (365-8);

[0212] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-((R)-4-methyl-2,5-dioxoimidazolidine-1-yl)-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (366-1);

[0213] 2-(3-((1-PEG 5K -1H-1,2,3-triazol-4-yl)methoxy)-4-nitrobenzyl)9-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxatetradecane-14-acyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2,9-dicarboxylic acid ester (605-2);

[0214] (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-{[(2-oxo-1,3-dioxolane-4-yl)methoxy]carbonyl}-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (compound 700-1);

[0215] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-{[2-(methylthioalkyl)acetyl]oxy}-13-oxo-9-({[2-oxo-5-(prop-2-yl)-2H-1,3-m-dioxacyclopenten-4-yl]methoxy}carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (compound 701-1);

[0216] (2S,4aS,6aS,6bR,8aR,9S,10R,12aS,12bR,14bR)-10-(acetoxy)-2,4a,6a,6b,9,10,12a-heptamethyl-13-oxo-9-({[2-oxo-5-(prop-2-yl)-2H-1,3-m-dioxacyclopenten-4-yl]methoxy}carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (compound 702-1);

[0217] (2S,4aS,6aS,6bR,8aR,9S,10R,12aS,12bR,14bR)-10-(acetoxy)-9-{[(5-ethyl-2-oxo-2H-1,3-m-dioxacyclopenten-4-yl)methoxy]carbonyl}-2,4a,6a,6b,9,10,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (compound 703-1);

[0218] (2S,4aS,6aS,6bR,8aR,9S,10R,12aS,12bR,14bR)-10-(acetoxy)-2,4a,6a,6b,9,10,12a-heptamethyl-9-{[(5-methyl-2-oxo-2H-1,3-m-dioxacyclopenten-4-yl)methoxy]carbonyl}-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (compound 704-1);

[0219] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(acetoxy)-9-{[(5-tert-butyl-2-oxo-2H-1,3-m-dioxacyclopenten-4-yl)methoxy]carbonyl}-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydro-2-carboxylic acid (compound 705-1);

[0220] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(acetoxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-9-{[(2-oxo-5-propyl-2H-1,3-m-dioxacyclopenten-4-yl)methoxy]carbonyl}-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (compound 706-1);

[0221] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(acetoxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-9-{[(2-oxo-5-phenyl-2H-1,3-m-dioxacyclopenten-4-yl)methoxy]carbonyl}-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (compound 707-1);

[0222] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-[(2-methoxyacetyl)oxy]-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-9-({[2-oxo-5-(prop-2-yl)-2H-1,3-m-dioxacyclopenten-4-yl]methoxy}carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (compound 708-1);

[0223] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-[(2-methoxyacetyl)oxy]-2,4a,6a,6b,9,12a-hexamethyl-9-{[(5-methyl-2-oxo-2H-1,3-m-dioxacyclopenten-4-yl)methoxy]carbonyl}-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (compound 709-1);

[0224] (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(2-oxo-2-{[2-oxo-5-(2,5,8-trioxa-11-thiadodecane-12-yl)-2H-1,3-m-dioxacyclopenten-4-yl]methoxy}ethoxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (compound 710-1);

[0225] (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-{[5-(hydroxymethyl)-2-oxo-2H-1,3-m-dioxacyclopenten-4-yl]methoxy}-2-oxoethoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid (compound 711-1);

[0226] (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-{2-[(5-methyl-2-oxo-2H-1,3-m-dioxacyclopenten-4-yl)methoxy]-2-oxoethoxy}-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (compound 712-1); and

[0227] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-[4-(ethoxycarbonyl)-5-methoxy-1H-pyrazol-1-yl]-2,4a,6a,6b,9,12a-hexamethyl-9-{[(5-methyl-2-oxo-2H-1,3-m-dioxacyclopenten-4-yl)methoxy]carbonyl}-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (compound 713-1).

[0228] The compounds of this invention are "soft medicines" whose parent form is an active inhibitor of 11b-HSD2 in the patient's gastrointestinal tract, but is enzymatically converted into inactive or less active metabolites upon plasma ingestion. This effect provides the desired preferential inhibition of HSD2 in the gastrointestinal tract relative to HSD2 in the kidneys. The compounds of this invention disclosed herein were tested in the assays described in Example 112, and HSD2 inhibition was found by measuring the amount of cortisol before and after exposure to human cell lysates or colonic monolayer organoids derived from human colonic tissue. Furthermore, each compound tested was found to be a more potent HSD2 inhibitor than its corresponding metabolite.

[0229] The compounds of the present invention may contain one or more asymmetric or chiral centers. Therefore, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds may employ racemic, diastereomer, or enantiomer as starting materials or intermediates. Diastereomers can be separated by chromatography or crystallization. Similarly, mixtures of enantiomers can be separated using the same techniques or other techniques known in the art. Unless otherwise specified, each asymmetric center may be in an R or S configuration, and both configurations are within the scope of the present invention. All stereoisomers of the compounds described herein, including but not limited to diastereomers, enantiomers, and transisomers, and mixtures thereof, such as racemic mixtures, are intended to be part of the compounds of the present invention.

[0230] It will also be understood that certain compounds of Formula I can be used as intermediates for further compounds of Formula I. Furthermore, it will be understood that the compounds described herein can exist in a non-solventized form as well as in a form solvated with pharmaceutically acceptable solvents such as water, ethanol, etc., and the compounds are intended to include both solvated and non-solventized forms.

[0231] The compounds of the present invention are prepared using standard organic synthesis techniques from commercially available starting materials and reagents. It will be understood that the synthetic procedures used to prepare the compounds of the present invention will depend on the specific substituents present in the compounds and may require various protecting and deprotecting steps standard in organic synthesis, but these may not be shown in the following general scheme. Starting materials are generally available from commercial sources or can be readily prepared using methods well known to those skilled in the art. For example, the compounds of the present invention can be prepared from… Figure 3 The preparation of glycyrrhetinic acid is illustrated. For illustrative purposes, the embodiments herein demonstrate a general method for preparing the compounds of the present invention and key intermediates. Those skilled in the art will understand that other synthetic routes may be employed to synthesize the compounds. While specific starting materials and reagents are described in the embodiments and discussed below, other starting materials and reagents may be substituted to provide various derivatives and / or reaction conditions. Furthermore, many compounds prepared by the methods described below can be further modified using conventional chemical methods well known to those skilled in the art, according to this disclosure. As shown in Scheme I, the compounds of the present invention, wherein -QWC(O)-LX- forms an ester bond -CH2-OC(O)- with dioxacyclopentadienone, can be prepared starting from a carboxylic acid derivative of glycyrrhetinic acid (at the 3- or 4- position) and reacted with, for example, a halodioxacyclopentadienone.

[0232] Option 1

[0233]

[0234] The compound of the present invention, wherein -QWC(O)-LX- forms a bond -CH2-OC(O)-O- with dioxacyclopentadienone, can be prepared according to general scheme 2.

[0235] Option 2

[0236]

[0237] The compound of the present invention, wherein -QWC(O)-LX- forms an amide bond -CH2-OC(O)-NH- with dioxacyclopentadienone, can be prepared as shown in Scheme 3 by reacting an isocyanate at the 3- or 4-position of the fused ring system with a hydroxylated dioxacyclopentadienone.

[0238] Option 3

[0239]

[0240] In the preparation of the compounds of this invention, it may be necessary to protect the distal functional groups of the intermediates (e.g., primary or secondary amines). The need for such protection will vary depending on the nature of the distal functional groups and the conditions of the preparation method. Those skilled in the art can readily determine the need for such protection. For a general description of the protecting groups and their uses, please refer to Greene, TW, and PGMUTS. Greene’s Protective Groups in Organic Synthesis . 4th edition New York: Wiley-Interscience, 2006.

[0241] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter, separated) to the desired homogeneity using techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve many methods, including, for example: reversed-phase and normal-phase; size exclusion; ion exchange; high, medium, and low-pressure liquid chromatography methods and apparatus; small-scale analysis; simulated moving bed (“SMB”) and preparative thin-layer or thick-layer chromatography, as well as small-scale thin-layer and rapid chromatography techniques. Those skilled in the art will apply the techniques most likely to achieve the desired separation.

[0242] Diastereomers and mixtures of enantiomers can be separated into their individual stereoisomers based on their physicochemical differences using methods well known to those skilled in the art (such as chromatography and / or fractional crystallization). Enantiomers can be separated by reacting an enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher acyl chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into their respective pure enantiomers. Enantiomers can also be separated using a chiral HPLC column.

[0243] This invention also includes pharmaceutical compositions or agents containing the compounds of the invention and therapeutically inert carriers, diluents, or excipients, as well as methods for preparing such compositions and agents using the compounds of the invention. Typically, compounds of formula I used in the methods of the invention are formulated by mixing with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dose and concentration used) at ambient temperature and appropriate pH and desired purity. The pH of the formulation depends primarily on the specific use and concentration of the compound, but can be any value in the range of about 3 to about 8. A formulation in an acetate buffer at pH 5 is a suitable embodiment. In one embodiment, the formulation containing the compounds of the invention is sterile. The compounds are typically stored as solid compositions, although lyophilized formulations or aqueous solutions are also acceptable.

[0244] Compositions containing the compounds of the present invention will be formulated, administered, and applied in accordance with good medical practice. Factors to be considered in this case include the specific disorder being treated, the specific mammal being treated, the individual patient's clinical condition, the cause of the disorder, the site of application, the method of administration, the schedule of administration, and other factors known to the physician. The "effective amount" of the compound to be administered will be determined by these considerations and is the minimum amount necessary to inhibit the conversion of cortisol to corticosterone via HSD2. This amount may be below levels that would be toxic to normal cells or the entire mammal.

[0245] The compounds of the present invention may be administered by any suitable manner. In a particular embodiment, the compounds are administered orally. In a particular embodiment, the compounds are administered rectally.

[0246] Generally, the initial pharmaceutically effective amount of each parenteral administration of the compound of the present invention will be in the range of about 0.01-1,000 mg / kg / day, for example, about 0.1 to 100 mg / kg of patient body weight per day, with a typical initial dose range of 0.5 to 50 mg / kg / day. Oral unit dosage forms such as tablets and capsules may contain about 25 to about 1,000 mg of the compound of the present invention. In a particular embodiment, the effective amount is an amount of the compound of the present invention sufficient to increase colonic potassium secretion by about 15 mmol / day. In a particular embodiment, the effective amount is an amount of the compound of the present invention sufficient to increase colonic potassium secretion by about 1 mmol / day. In a particular embodiment, the effective amount is an amount of the compound of the present invention sufficient to increase colonic potassium secretion by about 5 mmol / day. In a particular embodiment, the effective amount is an amount of the compound of the present invention sufficient to increase colonic potassium secretion by about 10 mmol / day. In a particular embodiment, the effective amount is an amount of the compound of the present invention sufficient to increase colonic potassium secretion by about 15 mmol / day. In a particular embodiment, the effective amount is an amount of the compound of the present invention sufficient to increase colonic potassium secretion by about 20 mmol / day.

[0247] The compound can be administered in any convenient form (e.g., 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 the compound of the present invention mixed 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 powder components 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.

[0248] Another formulation can be prepared by mixing the compounds described herein with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, 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 formulation may also include one or more buffers, stabilizers, surfactants, humectants, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light-blocking agents, flow aids, processing aids, colorants, sweeteners, flavorings, diluents, and other known additives that provide an attractive appearance to the pharmaceutical product (i.e., the compound described herein or a pharmaceutical composition thereof) or contribute to the production of the pharmaceutical product (i.e., the formulation).

[0249] In one embodiment, the formulation releases the compound in response to contact with enzymes in the colon (e.g., enzymes produced by intestinal bacteria). Certain starch-based capsule coatings may be used, which are resistant to digestion in the stomach and small intestine, but are degraded by microbial (normal gut flora) enzymes once the dosage form reaches the colon.

[0250] In one embodiment, the compound of the invention is administered orally. In another embodiment, the compound is formulated for colonic delivery. Colonic delivery can be carried out in response to pH, time, microorganisms, and pressure. In one embodiment, the formulation releases the compound in response to colonic pH. The release of the compound is triggered by an increase in pH as the formulation passes through the enteric tract. The formulation is based on polymers that are insoluble at lower pH levels in the stomach and upper small intestine, but soluble at higher pH levels in the distal small intestine; for example, polymers are acrylic and cellulose derivatives that can withstand environments as low as pH 1.2. Suitable enteric polymers include, for example, polyvinyl phthalate (PVAP). Cellulose trimellitate (CAT), hydroxypropyl methyl phthalate (HPMCP) such as HP-50, HP-55, HP-55S, hydroxypropyl methyl succinate (HPMCAS) such as LF, MF or HF grades, methacrylic acid copolymers such as L30D-55, L-1000, L12.5, S-100, S12.5, FS30D, cellulose acetate phthalate (CAP), for example. and shellac, for example 125 or 125N.

[0251] In one aspect of the invention, a method is provided for inhibiting the conversion of cortisol to corticosterone via HSD2, comprising contacting HSD2 with a compound of formula I. In another aspect of the invention, a method is provided for promoting the activation of MR in mammals, comprising administering an effective amount of a compound of formula I to the mammal. In another aspect of the invention, a method is provided for reducing potassium levels in the plasma of mammals, comprising administering an effective amount of a compound of formula I to the mammal. In another aspect of the invention, a method is provided for promoting the secretion of potassium ions into the colonic lumen of mammals, comprising administering an effective amount of a compound of formula I to the mammal.

[0252] In one aspect of the invention, a method for treating and / or preventing hyperkalemia in mammals is provided, comprising administering an effective amount of a compound of formula I to said mammal. Hyperkalemia is particularly common in patients with chronic kidney disease (CKD), hypertension, heart failure, and diabetes. Therefore, in embodiments of the invention, the method for treating and / or preventing hyperkalemia is performed in patients with CKD, hypertension, heart failure, and diabetes. Patients with 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, these drugs can promote potassium retention. Therefore, a method for treating and / or preventing hyperkalemia in mammals is provided, comprising administering a compound of formula I in combination with an inhibitor of the RAAS system. In one embodiment, the RAAS inhibitor is an ACE inhibitor.

[0253] 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 through different mechanisms of action. The compounds of this invention can be administered in a single pharmaceutical composition with other antihyperkalemia agents, or they can be administered alone, and when administered alone, they can be administered simultaneously or sequentially in any order. Such sequential administration can be proximate or spaced apart in time.

[0254] In one embodiment, another anti-hyperkalemia compound is a potassium ion binder, such as a cross-linked polystyrene sulfonate (PSS) polymer resin. In one embodiment, the PSS resin is cross-linked with a divinylbenzene (DVB) copolymer. DVB-crosslinked PSS is the most commonly used drug for controlling hyperkalemia in hospitalized patients. PSS is usually provided in the form of sodium or calcium salts, and it exchanges secreted potassium ions with sodium or calcium ions in the intestinal lumen. This mostly occurs in the colon, which is the site of the highest potassium secretion in the intestine. In one embodiment, an anti-hyperkalemia 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% DVB. In one embodiment, the PSS resin is cross-linked with 1.6% to 1.9% DVB. In one embodiment, the PSS resin is cross-linked with about 1.8% DVB.

[0255] In one implementation scheme, another anti-hyperkalemia agent is Or RDX7675. In another embodiment, another anti-hyperkalemia agent is a fluoroacrylate polymer doped with potassium-bound carboxylate groups, such as patiromer. In one embodiment, another antihyperkalemia agent is insoluble, non-absorbable sodium zirconium silicate, which traps potassium ions within its crystal lattice structure, such as ZS-9. In one implementation, another anti-hyperkalemia agent is cross-linked polyacrylic acid, such as CLP-1001.

[0256] In another aspect of the invention, it was unexpectedly discovered that the combination of HSD2 inhibition and inhibition of sodium-hydrogen exchangers (NHE) synergistically increased potassium excretion in feces. NHE is present in the proximal tubules of the nephrons in the kidneys and in the apical membrane of intestinal epithelial cells. The isoform known as NHE3 is primarily responsible for maintaining sodium homeostasis and is also indirectly associated with buffering blood pH. The NHE3 countertransporter introduces a sodium ion into the cytosol of the cell when the cell ejects a hydrogen ion from the cell into the intestinal lumen and proximal tubules. Figure 1As shown, it has been demonstrated that inhibition of HSD2 and NHE has a synergistic effect on fecal potassium excretion. Therefore, a method for removing potassium from the plasma and / or tissues of a mammal is provided, comprising administering an effective amount of an HSD2 inhibitor or MR agonist to the mammal in combination with a compound that increases the amount of fluid in the colon. A method for removing potassium from the plasma and / or tissues of a mammal is also provided, comprising administering an effective amount of an HSD2 inhibitor or MR agonist to the mammal in combination with a compound that removes sodium from the plasma and / or tissues. A method for removing potassium from the plasma and / or tissues of a mammal is also provided, comprising administering an effective amount of an HSD2 inhibitor or MR agonist to the mammal in combination with a compound that promotes the excretion of sodium into the gastrointestinal tract. In one embodiment, the compound is a laxative that increases the amount of 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... (PEG 3350). In one embodiment, the laxative is lactulose. In one embodiment, the compound is an activator of intestinal guanylate cyclase. In one embodiment, the guanylate cyclase agonist is linaclotide. In one embodiment, the guanylate cyclase agonist is plecanatide. In one embodiment, the compound is an activator of intestinal ClC-2 chloride channels. In one embodiment, the ClC-2 chloride channel activator is lubiprostone.

[0257] Methods for removing potassium from the plasma and / or tissues of mammals are also provided, comprising administering an effective amount of an HSD2 inhibitor or MR agonist to the mammal 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 prior to the NHE inhibitor or MR agonist. In one embodiment, the NHE inhibitor or MR agonist compound is administered prior to the HSD2 inhibitor or MR agonist. In one embodiment, the NHE inhibitor is an NHE3 inhibitor.

[0258] In another aspect of the invention, a pharmaceutical composition comprising an HSD2 inhibitor and an NHE inhibitor is provided. In yet another aspect, a pharmaceutical composition comprising an MR agonist and an NHE inhibitor is provided.

[0259] On the other hand, a method for treating hyperkalemia in mammals is provided, comprising administering an effective amount of an HSD2 inhibitor or an MR agonist to the mammal in combination with an NHE inhibitor. In one embodiment, the NHE inhibitor is an NHE3 inhibitor.

[0260] In one embodiment, the MR agonist is fludrocortisone.

[0261] In another aspect, a method for treating hyperkalemia in mammals is provided, comprising administering an effective amount of an HSD2 inhibitor to the mammal in combination with an NHE inhibitor. In one embodiment, the NHE inhibitor is an NHE3 inhibitor. In another aspect, a composition comprising an HSD2 inhibitor and an NHE inhibitor is provided. In one embodiment, the composition is a pharmaceutical composition. In one embodiment, an effective amount of both the HSD2 inhibitor compound and the 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 analogue 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 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 No. 2004 / 0039001 (WO02 / 020496); 200 5 / 0020612 (WO03 / 055490); 2004 / 0113396 (WO03 / 051866); 2005 / 0020612; 2005 / 0054705; 2008 / 0194621; 2007 / 0225323; 2004 / 0039001; 2004 / 0224965; 2005 / 0113396; 2007 / 0135383; 2007 / 0135385; 2005 / 0244367; 2007 / 0270414; International Publication Number WO WO01 / 072742; WO01 / 021582 (CA2387529); WO97 / 024113 (CA02241531); WO2010078449; WO2014029983; WO2014029984; and European Patent No. EP0744397 (CA2177007); each of which is incorporated herein by reference in its entirety.

[0262] In one embodiment, the NHE inhibitor is a minimally systemic compound, meaning it inhibits NHE in the intestine and is substantially non-bioavailable. In one embodiment, the NHE inhibitor is a compound of formula (I) or (IX):

[0263] NHE-Z

[0264] (I)

[0265]

[0266] in:

[0267] NHE is an NHE-bound small molecule comprising (i) a heteroatom-containing moiety and (ii) a cyclic or heterocyclic scaffold or support moiety directly or indirectly bonded thereto, wherein the heteroatom-containing moiety is selected from substituted guanidine moieties and substituted heterocyclic moieties, and may optionally be fused with the scaffold or support moiety to form a fused bicyclic structure; and,

[0268] Z is a portion having at least one site for linking with NHE-binding small molecules, resulting in an NHE-Z molecule with overall physicochemical properties that make it substantially impermeable or substantially biocompatible throughout the body; and...

[0269] E is an integer with a value of 1 or greater.

[0270] In some embodiments, the total number of freely rotatable bonds in the NHE-Z molecule is at least about 10. In some 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 some 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 some embodiments, the log P of the NHE-Z binding compound is less than about 1 or less than about 0. In some embodiments, the scaffold is a 5- or 6-membered cyclic or heterocyclic moiety. In some embodiments, the scaffold is aromatic.

[0271] In some embodiments, the NHE-binding small molecule scaffold is partially bound to Z, and the compound has the structure of formula (II):

[0272]

[0273] in:

[0274] Z is a core having one or more sites for linking to one or more NHE-binding small molecules, resulting in an NHE-Z molecule with overall physicochemical properties that make it substantially impermeable or substantially biocompatible throughout the body.

[0275] B is the heteroatom-containing part of the NHE-bound small molecule and is selected from the substituted guanidine moiety and the substituted heterocyclic moiety. It may optionally be fused with the scaffold moiety to form a fused bicyclic structure.

[0276] The scaffold is a cyclic or heterocyclic scaffold or support portion of an NHE-bound small molecule, which is directly or indirectly bound to the heteroatom-containing portion B and optionally replaced by one or more additional hydrocarbon or heterohydrocarbon portions.

[0277] X is a bond or a spacer selected from the following: substituted or unsubstituted hydrocarbon or heterohydrocarbon moiety, particularly substituted or unsubstituted C. 1-7 A hydrocarbon or heterohydrocarbon group, and a substituted or unsubstituted saturated or unsaturated cyclic or heterocyclic moiety, which connects B and the support; and

[0278] D and E are integers whose values ​​are 1 or greater, each independently.

[0279] In some embodiments, the compound is an oligomer, a dendritic polymer, or a polymer, and further, wherein Z is a core portion having two or more sites thereon for direct or indirect linkage to multiple NHE-binding small molecules via linking portions L, and the compound has the structure of formula (X):

[0280]

[0281] Where L is a linker for the bond or linker core to the NHE-binding small molecule, and n is an integer of 2 or greater, and further, each NHE-binding small molecule may be the same as or different from each other.

[0282] In some implementations, the NHE-binding small molecule has the structure of formula (IV):

[0283]

[0284] Or its stereoisomers, prodrugs, or pharmaceutically acceptable salts, wherein:

[0285] Each R1, R2, R3, R5 and R9 is independently selected from H, halogen, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8 and -NR7SO2NR8, wherein R7 and R8 are independently selected from H or bonds connecting NHE-binding small molecules to L, provided that at least one of them is a bond connecting NHE-binding small molecules to L;

[0286] R4 is selected from H, C1-C7 alkyl groups, or bonds connecting NHE-linked small molecules to L;

[0287] R6 is absent or selected from H and C1-C7 alkyl groups; and

[0288] Ar1 and Ar2 independently represent aromatic rings or heteroaromatic rings.

[0289] In some implementations, the NHE-binding small molecule has the following structure:

[0290]

[0291] Or its stereoisomers, prodrugs, or pharmaceutically acceptable salts, wherein:

[0292] Each R1, R2, and R3 is independently selected from H, halogen, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, wherein R7 and R8 are independently selected from H or bonds connecting NHE-bound small molecules to L, provided that at least one of them is a bond connecting NHE-bound small molecules to L.

[0293] In some implementations, the NHE-binding small molecule has one of the following structures:

[0294]

[0295] Or its stereoisomers, prodrugs, or pharmaceutically acceptable salts. In some embodiments, L is a polyalkylene glycol linker. In some embodiments, L is a polyethylene glycol linker. In some embodiments, n is 2.

[0296] In some implementations, the core has the following structure:

[0297]

[0298] in:

[0299] X is selected from the following groups: bond, -O-, -NH-, -S-, C 1-6 Alkylene, -NHC(=O)-, -C(=O)NH-, -NHC(=O)NH-, -SO2NH- and -NHSO2-;

[0300] Y is selected from the following groups: key, optional C substitutions. 1-8 Alkylene, optionally substituted aryl, optionally substituted heteroaryl, polyethylene glycol linker, -(CH2) 1-6 O(CH2) 1-6 - and -(CH2) 1-6 NY1(CH2) 1-6 -;and

[0301] Y1 is selected from the group consisting of: hydrogen, C with optional substitution. 1-8 Alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0302] In some implementations, the core is selected from the group consisting of:

[0303]

[0304]

[0305] Where: L is the bond or linker; NHE is the NHE-bound small molecule; and n is a non-zero integer.

[0306] In one implementation, the NHE inhibitor is:

[0307] N,N',N”-(2,2',2”-nitrotris(ethane-2,1-diyl))tris(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0308] 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-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0309] N,N'-(1,4-phenylenebis(methylene))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0310] N,N'-(1,4-phenylenebis(methylene))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0311] N,N'-(butane-1,4-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0312] N,N'-(dodecane-1,12-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0313] N,N',N”,N”'-(3,3',3”,3”'-(butane-1,4-diylbis(azanetriyl))tetra(propane-3,1-diyl))tetra(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0314] N,N'-(butane-1,4-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0315] N,N'-(dodecane-1,12-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0316] N,N',N”-(2,2',2”-nitrotris(ethane-2,1-diyl))tris(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0317] N,N',N”,N”'-(3,3',3”,3”'-(butane-1,4-diylbis(azanetriyl))tetra(propane-3,1-diyl))tetra(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0318] N,N'-(1,4-phenylenebis(methylene))bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0319] 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-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0320] N1,N8-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)octadiamide;

[0321] 2-(N-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl)aminosulfonylamino)ethylphosphonic acid;

[0322] 2-(N-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl)aminosulfonylamino)ethylphosphonic acid;

[0323] N,N'-(butane-1,4-diyl)bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-aminosulfonylphenoxy)phenyl)-2-methylacrylamide];

[0324] N,N'-(1,4-phenylenebis(methylene))bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-aminosulfonylphenoxy)phenyl)-2-methylacrylamide];

[0325] N,N'-(2,2'-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-aminosulfonylphenoxy)phenyl)-2-methylacrylamide];

[0326] 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-aminosulfonylphenoxy)phenyl)-2-methylacrylamide]

[0327] (E)-3-(4-(4-(N-(2-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)aminosulfonyl)phenoxy)-3,5-difluorophenyl)-N-(diaminomethylene)-2-methylacrylamide];

[0328] N,N'-(13-oxo-3,6,9,17,20,23-hexaoxa-12,14-diazapecopentane-1,25-diyl)bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-aminosulfonylphenoxy)phenyl)-2-methylacrylamide];

[0329] N,N'-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,21-diazatriadodecane-1,32-diyl)bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-aminosulfonylphenoxy)phenyl)-2-methylacrylamide];

[0330] N,N'-(2,2'-(2,2'-(2,2'-(2,2'-(4,4'-oxybis(methylene)bis(1H-1,2,3-triazol-4,1-diyl))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[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-aminosulfonylphenoxy)phenyl)-2-methylacrylamide];

[0331] N,N'-(2,2'-(2,2'-(2,2'-(2,2'-(4,4'-oxybis(methylene)bis(1H-1,2,3-triazol-4,1-diyl))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-tetrahydroisoquinoline-4-yl)benzenesulfonamide)

[0332] 1-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4,5-dicarboxylic acid;

[0333] N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0334] N1,N4-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0335] N1,N31-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)-4,7,10,13,16,19,22,25,28-nonoxahexanetradecane-1,31-diamide;

[0336] N1,N31-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)-4,7,10,13,16,19,22,25,28-nonoxatrione-1,31-diamide;

[0337] N,N'-(13-oxo-3,6,9,17,20,23-hexaoxa-12,14-diazapecopentane-1,25-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0338] N1,N31-bis(2-(2-(2-(2-(4-(4-((E)-3-(diaminomethyleneamino)-2-methyl-3-oxopropyl-1-enyl)-2,6-difluorophenoxy)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)-4,7,10,13,16,19,22,25,28-nonoxahexatrione-1,31-diamide;

[0339] N,N'-(13-oxo-3,6,9,17,20,23-hexaoxa-12,14-diazapecopentane-1,25-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0340] N1,N4-bis(20-(4-(4-((E)-3-(diaminomethyleneamino)-2-methyl-3-oxopropyl-1-enyl)-2,6-difluorophenoxy)phenylsulfonylamino)-3,6,9,12,15,18-hexaoxaneeicosuccinyl)-2,3-dihydroxysuccinamide;

[0341] N1,N4-bis(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethyl)-2,3-dihydroxysuccinamide;

[0342] N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-ethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0343] 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))diphenylamine;

[0344] N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0345] N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamino)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0346] N1,N4-bis(1-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamino)-1-oxo-5,8,11-trioxa-2-azatridecane-13-yl)-2,3-dihydroxysuccinamide;

[0347] N1,N2-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)oxalamide;

[0348] N1,N4-bis(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0349] N1,N4-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)succinamide;

[0350] 2,2'-Oxybis(N-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)acetamide);

[0351] (2R,3R)-N1,N4-bis(2-(2-(2-(3-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylamino)-3-oxopropoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0352] N1,N2-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)oxalamide;

[0353] N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)succinamide;

[0354] N1,N3-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)-2,2-dimethylmalonamide;

[0355] N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)-2,2-dimethylmalonamide;

[0356] 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-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0357] 2,2'-(methylazinediyl)bis(N-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)acetamide)tris(2,2,2-trifluoroacetate);

[0358] 5-Amino-N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)isophthalamide tris(2,2,2-trifluoroacetate);

[0359] 2,2'-Oxybis(N-(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)acetamide);

[0360] 5-Bromo-N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)isophthalamide bis(2,2,2-trifluoroacetate);

[0361] N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)-2-hydroxymalondiamide bis(2,2,2-trifluoroacetate);

[0362] N1,N2-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)oxalamide;

[0363] N1,N4-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)succinamide;

[0364] 3,5-Bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethylcarbamoyl)benzenesulfonic acid;

[0365] N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)-5-hydroxyisophthalamide;

[0366] (2R,3R)-N1,N4-bis(3-((3-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)propyl)(methyl)amino)propyl)-2,3-dihydroxysuccinamide;

[0367] 2,2'-Oxybis(N-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)acetamide);

[0368] N1,N3-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)-2,2-dimethylmalonamide;

[0369] N1,N2-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)oxalamide;

[0370] 2,2'-Oxybis(N-(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)acetamide);

[0371] N1,N4-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)succinamide;

[0372] N1,N4-bis(2-(2-(2-(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethyl)succinamide;

[0373] 2,2'-Oxybis(N-(2-(2-(2-(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)acetamide);

[0374] (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-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0375] (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-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0376] N,N'-(butane-1,4-diyl)bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)acetamido)acetamido)acetamide);

[0377] N1,N4-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0378] 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(oxy)bis(ethane-2,1-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0379] (2R,3R)-N1,N4-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0380] N,N'-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,14,19,21-tetraazatridodecane-1,32-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0381] N,N'-(1,1'-(1,4-phenylenebis(azanediyl))bis(1-oxo-5,8,11-trioxa-2-azatridecane-13,1-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0382] (2R,3R)-N1,N4-bis(20-(4-(4-((E)-3-(diaminomethyleneamino)-2-methyl-3-oxopropyl-1-enyl)-2,6-difluorophenoxy)phenylsulfonylamino)-3,6,9,12,15,18-hexaoxaneeicosuccinyl)-2,3-dihydroxysuccinamide;

[0383] (E)-3-(4-(4-(N-(20-amino-3,6,9,12,15,18-hexaoxanetecoyl)aminosulfonyl)phenoxy)-3,5-difluorophenyl)-N-(diaminomethylene)-2-methylacrylamide];

[0384] (2R,3R)-N1,N4-bis(2-(2-(2-(2-(4-(4-((E)-3-(diaminomethyleneamino)-2-methyl-3-oxopropyl-1-enyl)-2,6-difluorophenoxy)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0385] 2,2',2”-N-(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)acetamide);

[0386] N-(32-amino-3,6,9,12,15,18,21,24,27,30-decaoxane-3-dodecyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide;

[0387] N1,N3,N5-tris(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)benzene-1,3,5-tricarboxamide;

[0388] N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)terephthalamide;

[0389] N1,N31-bis(32-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)-3,6,9,12,15,18,21,24,27,30-decoxatridodecyl)-4,7,10,13,16,19,22,25,28-nonoxatridodecane-1,31-diamide;

[0390] 2R,3R)-N1,N4-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0391] N1,N3-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)benzene-1,3-disulfonamide;

[0392] N4,N4'-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)biphenyl-4,4'-disulfonamide;

[0393] (14R,15R)-1-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)-14,15-dihydroxy-13-oxo-3,6,9-trioxa-12-azahexadecane-16-acid;

[0394] (2S,3S)-N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0395] N1,N4-bis(2-(2-(2-(2-(3-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0396] N1,N4-bis(2-(2-(2-(2-(3-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0397] N1,N4-bis(2-(2-(2-(2-(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0398] N1,N4-bis(2-(2-(2-(2-(4-((R or S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0399] N1,N4-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0400] N1,N3-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)isophthalamide;

[0401] (2R,3S)-N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0402] N1,N2-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)phthalamide;

[0403] N1,N4-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)terephthalamide;

[0404] N,N'-(10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecan-1,19-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0405] N1,N4-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)terephthalamide;

[0406] N1,N4-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)terephthalamide;

[0407] N,N'-(10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecan-1,19-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0408] 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-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0409] 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-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0410] 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-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0411] Phenylidene bis(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-tetrahydroisoquinoline-4-yl)benzenesulfonamide;

[0412] (2S,3S)-N1,N4-bis(2-(2-(2-(2-(3-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0413] (2R,3R)-N1,N4-bis(2-(2-(2-(2-(3-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0414] (2S,3S)-N1,N4-bis(2-(2-(2-(2-(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0415] (2R,3R)-N1,N4-bis(2-(2-(2-(2-(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0416] (S or R)-N,N'-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,14,19,21-tetraazatridodecane-1,32-diyl)bis(3-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0417] (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-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0418] N1,N4-bis(2-(2-(2-(2-(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)-terephthalamide;

[0419] N1-(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenylsulfonamide)ethoxy)ethoxy)ethoxy)ethyl)succinamide;

[0420] N,N'-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,14,19,21-tetraazatridodecane-1,32-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0421] N,N'-(1,1'-(1,4-phenylenebis(azanediyl))bis(1-oxo-5,8,11-trioxa-2-azatridecane-13,1-diyl))bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0422] (S or R)-N,N'-(13-oxo-3,6,9,17,20,23-hexaoxa-12,14-diazapecopentane-1,25-diyl)bis(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide);

[0423] (S or R)-N,N'-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,14,19,21-tetraazatridodecane-1,32-diyl)bis(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide); or

[0424] (S or R)-N,N'-(1,1'-(1,4-phenylenebis(azanediyl))bis(1-oxo-5,8,11-trioxa-2-azatridecane-13,1-diyl))bis(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide).

[0425] In one implementation, the NHE inhibitor is:

[0426]

[0427] In some embodiments, the compound has the structure of the following formula (IH):

[0428]

[0429] Or its stereoisomers, prodrugs, or pharmaceutically acceptable salts.

[0430] in:

[0431] (a) n is an integer of 2 or greater;

[0432] (b) The core is a core portion having two or more sites for connecting to two or more NHE-binding small molecule portions;

[0433] (c) L is a linker group connecting the core moiety to two or more NHE-bound small molecule moieties; and

[0434] (d) NHE is the NHE-binding small molecule moiety with the following structure (XI-H):

[0435]

[0436] in:

[0437] Option B is the group consisting of free aryl and heterocyclic groups;

[0438] Each R5 is independently selected from the following groups: hydrogen, halogen, and optionally substituted C. 1–4 Alkyl, optionally substituted C 1–4 Alkoxy, optional substituted C 1–4 Thioalkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, 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 and –SO2NR7R8, wherein R7, R8, and R9 are independently chosen from the group consisting of hydrogen, C 1-4 The group consisting of alkyl groups or bonds connecting the NHE-binding small molecule moiety to L, wherein at least one of them is a bond connecting the NHE-binding small molecule moiety to L.

[0439] R3 and R4 are independently chosen from the following groups: hydrogen, optionally substituted C. 1–4 Alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclic, and optionally substituted heteroaryl; or

[0440] R3 and R4, together with the nitrogen atoms they are bonded to, form optionally substituted 4-8 membered heterocyclic groups; and

[0441] Each R1 is independently selected from the following groups: hydrogen, halogen, and optionally substituted C. 1–6 Alkyl groups and optionally substituted C 1–6 Alkyl group. In some embodiments, n is 2. In some embodiments, L is a polyalkylene glycol linker. In some embodiments, L is a polyethylene glycol linker.

[0442] In some implementations, the core has the following structure:

[0443]

[0444] in:

[0445] X is selected from the following groups: bond, –O–, –NH–, –S–, C. 1–6 Alkylene, –NHC(=O)–, –C(=O)NH–, –NHC(=O)NH–, –SO2NH– and –NHSO2–;

[0446] Y is selected from the following groups: key, optional C substitutions. 1-8 Alkylene, optionally substituted aryl, optionally substituted heteroaryl, polyethylene glycol linker, –(CH2) 1-6 O(CH2) 1-6 – and –(CH2) 1-6 NY1(CH2) 1–6 -;and

[0447] Y1 is selected from the group consisting of: hydrogen, C with optional substitution. 1-8 Alkyl, optionally substituted aryl, or optionally substituted heteroaryl.

[0448] In some implementations, the core is selected from the group consisting of:

[0449]

[0450]

[0451] In some embodiments, the NHE-binding small molecule moiety has the structure of the following formula (XII-H):

[0452]

[0453] in:

[0454] Each R3 and R4 is independently chosen from the group consisting of hydrogen and optionally substituted C. 1–4 Alkyl groups, or R3 and R4, combine with the nitrogen they are bonded to to form optionally substituted 4-8 membered heterocyclic groups;

[0455] Each R1 is independently selected from the following groups: hydrogen, halogen, C 1–6 Alkyl and C 1–6 Halogenated alkyl groups; and

[0456] R5 is selected from the following groups: -SO2-NR7- and -NHC(=O)NH-, where R7 is hydrogen or C.1–4 alkyl.

[0457] In some embodiments, R3 and R4 combine with the nitrogen to which they are bonded to to form an optionally substituted 5- or 6-membered heterocyclic group. In some embodiments, the optionally substituted 5- or 6-membered heterocyclic group is a pyrrolidinyl or piperidinyl group, each substituted with at least one amino or hydroxyl group. In some embodiments, R3 and R4 are independently C 1–4 Alkyl group. In some embodiments, R3 and R4 are methyl groups. In some embodiments, each R1 is independently selected from the group consisting of hydrogen or halogen. In some embodiments, each R1 is independently selected from the group consisting of hydrogen, F, and Cl.

[0458] In some embodiments, the compound has the structure of formula (II):

[0459]

[0460] Or its stereoisomers, prodrugs, or pharmaceutically acceptable salts, wherein:

[0461] (a) NHE is the NHE-binding small molecule moiety with the following structure (AI):

[0462]

[0463] in:

[0464] Each R1, R2, R3, R5, and R9 is independently selected from H, halogens, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, wherein R7 and R8 are independently selected from H, C 1-6 Alkyl, -C 1-6 Alkyl-OH or a bond connecting the NHE-bound small molecule to L, provided that at least one of them is a bond connecting the NHE-bound small molecule to L;

[0465] R4 is selected from H, C1-C7 alkyl groups, or bonds connecting NHE-linked small molecules to L;

[0466] R6 is absent or selected from H and C1-C7 alkyl groups; and

[0467] Ar1 and Ar2 independently represent aromatic rings or heteroaromatic rings;

[0468] (b) The core is the core part with the following structure (BI):

[0469]

[0470] in:

[0471] X is selected from C(X1), N, and N(C). 1-6 alkyl);

[0472] X1 is selected from hydrogen, optionally substituted alkyl groups, and -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 ,

[0473] Each X a and X b Independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl;

[0474] Y is C 1-6 Alkylene;

[0475] When X is CX1, Z is selected from -NZ. a -C(=O)-NZ a -、-C(=O)NZ a -、-NZ a -C(=O)- and heteroaryl groups;

[0476] When X is N or N(C) 1-6 When alkyl), Z is selected from -NZ. a -C(=O)-NZ a -、-NZ a -C(=O)- and heteroaryl groups; and

[0477] Each X c and Z a Independently selected from hydrogen and C 1-6 Alkyl; and

[0478] (c)L is a linker group that connects the core part of the bond or linker to the small molecule part of the NHE.

[0479] In some embodiments, the NHE-binding small molecule moiety has the following structure:

[0480]

[0481] in:

[0482] Each R1, R2, and R3 is independently selected from H, halogens, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, wherein R7 and R8 are independently selected from H, C 1-6 Alkyl, -C 1-6 The alkyl-OH group or the bond connecting the NHE-bound small molecule to L, provided that at least one of them is a bond connecting the NHE-bound small molecule to L.

[0483] In some embodiments, the NHE-binding small molecule moiety has one of the following structures:

[0484]

[0485] In some embodiments, L is a polyalkylene glycol linker. In some embodiments, L is a polyethylene glycol linker. In some embodiments, X is C(X1). In some embodiments, each X c It is hydrogen. In some embodiments, X is N. In some embodiments, each Z a It is hydrogen.

[0486] In some embodiments, the compound has the structure of formula (II):

[0487]

[0488] Or its stereoisomers, prodrugs, or pharmaceutically acceptable salts.

[0489] in:

[0490] (a) NHE is the NHE-binding small molecule moiety with the structure of formula (AI):

[0491]

[0492] in:

[0493] Each R1, R2, R3, R5, and R9 is independently selected from H, halogens, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, wherein R7 and R8 are independently selected from H, C 1-6 Alkyl, -C 1-6 Alkyl-OH or a bond connecting the NHE-bound small molecule to L, provided that at least one of them is a bond connecting the NHE-bound small molecule to L;

[0494] R4 is selected from H, C1-C7 alkyl groups, or bonds connecting NHE-linked small molecules to L;

[0495] R6 is absent or selected from H and C1-C7 alkyl groups; and

[0496] Ar1 and Ar2 independently represent aromatic rings or heteroaromatic rings;

[0497] (b) The core is the core part with the following structure (CI):

[0498]

[0499] in:

[0500] 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.

[0501] X is N;

[0502] Y is C 1-6 Alkylene;

[0503] Z is selected from -NZ a -C(=O)-NZ a -、-C(=O)NZ a -、-NZ a -C(=O)- and heteroaryl groups;

[0504] Each Z a Independently selected from hydrogen and C 1-6 Alkyl; and

[0505] (c)L is a linker group that connects the core part of the bond to the small molecule bound to NHE.

[0506] In some embodiments, the NHE-binding small molecule moiety has the following structure:

[0507]

[0508] in:

[0509] Each R1, R2, and R3 is independently selected from H, halogens, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, wherein R7 and R8 are independently selected from H, C 1-6 Alkyl, -C 1-6 The alkyl-OH group or the bond connecting the NHE-bound small molecule to L, provided that at least one of them is a bond connecting the NHE-bound small molecule to L.

[0510] In some embodiments, the NHE-binding small molecule moiety has one of the following structures:

[0511]

[0512] In another embodiment, the NHE inhibitor is:

[0513]

[0514] and its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers,

[0515] in:

[0516] The linker is -(CHR) 13 ) p -[Y-(CH2) r ] s -ZR 13 -(CH2) t -Z-;

[0517] W is independently S(O)2, C(O), or -(CH2) each time it appears. m -; Z independently represents a bond, C(O) or -C(O)NH- each time it appears;

[0518] Y is independently O, S, NH, N (C1-C3 alkyl) or -C(O)NH- each time it appears;

[0519] 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 from 1 to 2; n is an integer from 1 to 4;

[0520] r and p are independent integers from 0 to 8 each time they appear;

[0521] s is an integer from 0 to 4;

[0522] t is an integer from 0 to 4;

[0523] u is an integer from 0 to 2;

[0524] R 1 and R 2 Independently H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, heterocyclic, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each alkyl, alkenyl, cycloalkenyl, ynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally influenced by one or more halogens, OH, CN, –NO2, oxo, –SR 9 –OR 9 –NHR 9 -NR 9 R 10 –S(O)2N(R) 9 )2–、–S(O)2R 9 –C(O)R 9 –C(O)OR 9 –C(O)NR 9 R 10 –NR 9 S(O)2R 10 -S(O)R 9 -S(O)NR 9 R 10 -NR 8 S(O)R 9 C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, heterocyclic, heterocyclic, aryl, or heteroaryl substituted; or

[0525] R 1 and R 2 Together with the nitrogen atoms attached to them, they can form heterocyclic or heteroaryl groups containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, wherein the heterocyclic or heteroaryl group is optionally bonded by one or more halogens, 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)R9 –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 C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclic, heterocyclic, aryl or heteroaryl substituted;

[0526] R 3 and R 4 Independently halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy or –C(O)NR 9 R 10 ;

[0527] R 5 R 6 R 7 and R 8 Independently, H, halogen, OH, CN, –NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, heterocyclic, aryl, heteroaryl containing 1-5 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 ;

[0528] R 9 and R 10Independently, it is H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, heterocyclic, aryl, or a heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O;

[0529] X is a bond, H, N, O, CR 11 R 12 CR 11 C, -NHC(O)NH- or C3-C6 cycloalkyl;

[0530] R 11 and R 12 Independently, it can be H, C1-C6 alkyl, OH, NH2, CN, or NO2;

[0531] R 13 Each time it appears, it is independently a bond, H, C1-C6 alkyl, C4-C8 cycloalkenyl, C3-C8 cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein each cycloalkenyl, cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally surrounded by one or more R 19 replace;

[0532] R 14 Each time it appears, it is independently H, C1-C6 alkyl, or C1-C6 haloalkyl; or

[0533] R 6 and R 14 Together with the atoms they are attached to, they can independently combine to form 5- to 6-membered heterocyclic groups each time they appear, wherein each C3-C8 cycloalkyl or heterocyclic group is optionally linked by one or more R atoms. 19 Replace; or

[0534] R 13 and R 14 Together with the atoms they are attached to, they can independently combine each time they appear to form C3-C8 cycloalkyl, heterocyclic, aryl, or heteroaryl groups containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each heterocyclic or heteroaryl group is optionally bounded by one or more R atoms. 19 replace;

[0535] R 15 R 16 R 17 and R 18 Each time it appears, it is independently H, OH, NH2, or a C1-C3 alkyl group, wherein the alkyl group is optionally surrounded by one or more R groups. 19 Replace; and

[0536] R 19Each time it appears, it is independently H, OH, NH2, oxo, C1-C6 alkyl, C1-C6H haloalkyl, or C1-C6 alkoxy.

[0537] In one embodiment, the NHE3 inhibitor is a compound according to the preceding formula, under the following conditions:

[0538] (1) When X is H, n is 1;

[0539] (2) When X is a bond, O or CR 11 R 12 When n is 2;

[0540] (3) When n is 3, X is CR 11 Or N;

[0541] (4) When n is 4, X is C;

[0542] (5) At this point, only one of Q or X is -NHC(O)NH-.

[0543] (6)R 1 and R 2 They cannot form pyrroleyl groups together with the nitrogen atoms they are attached to;

[0544] (7) When R 1 and R 2 It is methyl, R 3 and R 4 It is halogen and R 5 and R 8 When it is H, the linker is not

[0545] (8) When R 1 and R 2 Together with the nitrogen atoms they are attached to, they form piperidinyl groups, R 3 and R 4 It is halogen and R 5 and R 8 When it is H, the linker is not or

[0546] (9) When R 1 and R 2 Together with the nitrogen they are attached to, they form a 3-aminopiperidin-1-yl group, R 3 and R 4 It is halogen and R 5 R 6 R 7 and R 8 When it is H, the linker is not

[0547] In one embodiment, the NHE3 compound has a structure according to the following formula:

[0548]

[0549] and its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers, wherein:

[0550] The linker is -(CHR) 8 ) p -[Y-(CH2) r ] s -ZR 8 -(CH2) t -Z-;

[0551] Q is a bond or -NHC(O)NH-; Z is independently a bond, C(O) or -C(O)NH- each time it appears;

[0552] Y is independently O, S, NH, N (C1-C3 alkyl) or -C(O)NH- each time it appears;

[0553] X is a bond, N, O, CR 11 R 12 ,CR 11 C or -NHC(O)NH-;

[0554] n is an integer from 2 to 4;

[0555] r and p are independent integers from 0 to 8 each time they appear;

[0556] s is an integer from 0 to 4;

[0557] t is an integer from 0 to 4;

[0558] u is an integer from 0 to 2;

[0559] R 1 and R 2 Independently halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy or –C(O)NR 9 R 10 ;

[0560] R 3 R 4 R 5 and R 6 Independently, H, halogen, OH, CN, –NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, heterocyclic, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, –SR 9 –OR9 –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 ;

[0561] R 7 Each time it appears, it is independently H, C1-C6 alkyl, or C1-C6 haloalkyl;

[0562] R 8 Each time it appears, it is independently a bond, H, C1-C6 alkyl, C4-C8 cycloalkenyl, C3-C8 cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein each cycloalkenyl, cycloalkyl, heterocyclic, aryl, or heteroaryl is optionally surrounded by one or more R 17 Replace; or

[0563] R 7 and R 8 Together with the atoms they are attached to, they can independently combine each time they appear to form a heterocyclic or heteroaryl group containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each heterocyclic or heteroaryl group is optionally bonded by one or more R atoms. 17 replace;

[0564] R 9 and R 10 Independently, it is H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, heterocyclic, aryl, or a heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O;

[0565] R 11 and R 12 Independently, it can be H, C1-C6 alkyl, OH, NH2, CN, or NO2;

[0566] R 13 R 14 R 15 and R 16 Each time it appears, it is independently H, OH, NH2, or a C1-C3 alkyl group, wherein the alkyl group is optionally surrounded by one or more R groups. 17Replace; and

[0567] R 17 Each time it appears, it is independently H, OH, NH2, oxo, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 alkoxy.

[0568] In one embodiment, the NHE3 inhibitor compound has a structure according to the preceding formula, provided that:

[0569] (1) When X is a bond, O or CR 11 R 12 When n is 2;

[0570] (2) When n is 3, X is CR 11 Or N;

[0571] (3) When n is 4, X is C;

[0572] (4) At this time, only one of Q or X is --NHC(O)NH-;

[0573] (5) When R 1 and R 2 It is chlorine, Q is -NHC(O)NH- and R 3 R 4 R 5 and R 6 When it is H, the linker is not or

[0574] (6) When R 1 and R 2 It is chlorine, Q is -NHC(O)NH- and R 3 R 4 R 5 and R 6 When it is H, the linker is not

[0575] In one embodiment, the NHE3 inhibitor compound has a structure according to the following formula:

[0576] 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-tetrahydroisoquinoline-4-yl)benzenesulfonamide];

[0577] 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-tetrahydroisoquinoline-4-yl)benzenesulfonamide];

[0578] 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-tetrahydroisoquinoline-4-yl)-4-methylbenzenesulfonamide];

[0579] 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-tetrahydroisoquinoline-4-yl)-4-methylbenzenesulfonamide];

[0580] 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-tetrahydroisoquinoline-4-yl)-4-methylbenzenesulfonamide];

[0581] 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-tetrahydroisoquinoline-4-yl)-2-methylbenzenesulfonamide];

[0582] 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-tetrahydroisoquinoline-4-yl)-2-methylbenzenesulfonamide];

[0583] 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-tetrahydroisoquinoline-4-yl)-2-methylbenzenesulfonamide);

[0584] 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-tetrahydroisoquinoline-4-yl)-4-fluorobenzenesulfonamide];

[0585] 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-tetrahydroisoquinoline-4-yl)-4-fluorobenzenesulfonamide;

[0586] 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-tetrahydroisoquinoline-4-yl)-4-fluorobenzenesulfonamide];

[0587] N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide];

[0588] N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide];

[0589] N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide];

[0590] N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-4-methylbenzenesulfonamide];

[0591] N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-4-methylbenzenesulfonamide];

[0592] N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-4-methylbenzenesulfonamide];

[0593] N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-methylbenzenesulfonamide];

[0594] N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[5-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-methylbenzenesulfonamide];

[0595] N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[5-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-methylbenzenesulfonamide];

[0596] N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-4-fluorobenzenesulfonamide];

[0597] N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-4-fluorobenzenesulfonamide];

[0598] N,N'-[(3S,3'S)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-4-fluorobenzenesulfonamide];

[0599] N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide];

[0600] N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide];

[0601] N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide];

[0602] N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-4-methylbenzenesulfonamide];

[0603] N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-4-methylbenzenesulfonamide];

[0604] N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-4-methylbenzenesulfonamide];

[0605] N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[5-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-methylbenzenesulfonamide];

[0606] N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[5-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-methylbenzenesulfonamide];

[0607] N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[5-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-2-methylbenzenesulfonamide];

[0608] N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosan-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-4-fluorobenzenesulfonamide];

[0609] N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-4-fluorobenzenesulfonamide];

[0610] N,N'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)-4-fluorobenzenesulfonamide];

[0611] N,N'-[(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosan-1,20-diyl)bis(piperidine-1,4-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide];

[0612] N,N'-[(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosan-1,20-diyl)bis(piperidine-1,4-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide];

[0613] 1,1'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[N-([3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulfonyl)formamide];

[0614] 1,1'-[(3R,3'R)-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosicosane-1,20-diyl)bis(pyrrolidine-1,3-diyl)]bis[N-([3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulfonyl)formamide];

[0615] 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-tetrahydroisoquinoline-4-yl)phenyl]sulfonyl)piperidine-4-carboxamide];

[0616] 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-tetrahydroisoquinoline-4-yl)phenyl]sulfonyl)piperidine-3-carboxamide];

[0617] N 1 N 18 -Bis([3-(6,8-dichloro-2-dimethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl]sulfonyl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide;

[0618] N,N'-[(3S,3'S)-(6,13-dioxo-5,7,12,14-tetraazaoctadecanoic acid)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide];

[0619] N,N'-[(3S,3'S)-(6,13-dioxo-5,7,12,14-tetraazaoctadecanoic acid)bis(pyrrolidine-1,3-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide];

[0620] 1-[2-(2-[(1-[(3-[(S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-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-tetrahydroisoquinoline-4-yl]phenyl)sulfonyl]piperidin-4-yl)oxy]ethoxy)ethyl]ureoyl)butyl]urea;

[0621] 1-(2-(2-(((R)-1-((3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl)sulfonyl)pyrrolidine-3-yl)oxy)ethoxy)ethyl)-3-(4-(3-(2-(2-(((R)-1-((3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)phenyl)sulfonyl)pyrrolidine-3-yl)oxy)ethoxy)ethyl)ureoyl)butyl)urea;

[0622] 1-(2-[2-([(S)-1-[(3-[(S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl]phenyl)sulfonyl]pyrrolidine-3-yl]oxy)ethoxy]ethyl)-3-(4-[3-(2-[2-([(S)-1-[(3-[(S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl]phenyl)sulfonyl]pyrrolidine-3-yl]oxy)ethoxy]ethyl)ureoyl]butyl)urea;

[0623] 3-[(S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl]-N-[(3R,28R)-28-[(3-[(S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl]phenyl)sulfonamide]-2,29-dimethyl-12,19-dioxo-5,8,23,26-tetraoxa-11,13,18,20-tetraazatriane-3-yl]benzenesulfonamide;

[0624] N,N'-(10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecan-1,19-diyl)bis[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide];

[0625] N,N'-[(3S,3'S)-(7-oxo-3,11-dioxa-6,8-diazatriadecan-1,13-diyl]bis[pyrrolidine-1,3-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl)benzenesulfonamide];

[0626] N 1 N 18 -bis(1-[(3-[(S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl]phenyl)sulfonyl]piperidin-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide;

[0627] N 1 N 18 -bis(1-[(3-[(S)-6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-yl]phenyl)sulfonyl]piperidin-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide; or

[0628] N 1 N 18 -bis(1-[(3-[(S)-6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinoline-4-yl]phenyl)sulfonyl]piperidin-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide.

[0629] In one embodiment of the invention, the NHE3 inhibitor is a compound according to the following formula:

[0630]

[0631] In one embodiment of the invention, the NHE3 inhibitor is a compound according to the following formula:

[0632]

[0633] In one embodiment, the NHE3 inhibitor is one of the following compounds:

[0634] 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0635] 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro,-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0636] 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]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-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0637] 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]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-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0638] 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]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-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0639] 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-fluoro-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]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-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0640] 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]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-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0641] 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]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-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0642] 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]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-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0643] 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonylamino]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-indene-1-yl]oxy]-3-fluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0644] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0645] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0646] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0647] 1-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0648] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0649] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-fluoro-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-fluoro-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0650] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0651] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0652] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-carbamoyl]amino)butyl]urea;

[0653] 1-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0654] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0655] 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino]butyl]urea dihydrochloride;

[0656] 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0657] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0658] 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]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-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0659] 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]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-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0660] 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonylamino]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-indene-1-yl]oxy]-3-fluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-carbamoyl]amino)butyl]urea;

[0661] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]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-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0662] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]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-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0663] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonylamino]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-indene-1-yl]oxy]-3-fluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0664] 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino]butyl]urea;

[0665] 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino]butyl]urea;

[0666] 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0667] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0668] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino]butyl]urea;

[0669] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino]butyl]urea;

[0670] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0671] 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonylamino]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-indene-1-yl]oxy]-3-fluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0672] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]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-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0673] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonylamino]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-indene-1-yl]oxy]-3-fluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0674] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino]butyl]urea;

[0675] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino]butyl]urea;

[0676] 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino]butyl]urea;

[0677] 3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0678] 3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0679] 3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0680] 3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0681] 3-[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea;

[0682] 3-[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea;

[0683] 3-[(4-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-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-indene-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea;

[0684] 3-[(4-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-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-indene-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea;

[0685] 3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]pyrrolidine-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]pyrrolidine-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;

[0686] 3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]pyrrolidine-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]pyrrolidine-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;

[0687] 3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]pyrrolidine-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]pyrrolidine-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;

[0688] 3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]pyrrolidine-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]pyrrolidine-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;

[0689] 1-([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]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-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)carbamoyl]amino]butyl)urea;

[0690] (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-indene-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-2,3,4,5-tetrahydroxyhexamethylenediamide;

[0691] 3-[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]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-indene-1-yl]oxy]benzene)sulfonylamino]butyl]-1H-1,2,3-triazol-4-yl)methyl]carbamoyl]amino)butyl]urea;

[0692] 3-[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]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-indene-1-yl]oxy]benzene)sulfonylamino]hexyl]-1H-1,2,3-triazol-4-yl)methyl]carbamoyl]amino)butyl]urea;

[0693] (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-indene-1-yloxy)phenylsulfonamide]butyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-tetrahydro-[1,3]dioxin[5,4-d][1,3]dioxin-4,8-dicarboxamide;

[0694] (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-indene-1-yloxy)phenylsulfonylamino]hexyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-tetrahydro-[1,3]dioxin[5,4-d][1,3]dioxin-4,8-dicarboxamide;

[0695] 3-[8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]octyl]carbamoyl)amino]butyl]urea;

[0696] 3-[8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]octyl]carbamoyl)amino]butyl]urea;

[0697] 3-[8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]octyl]carbamoyl)amino]butyl]urea;

[0698] 3-[8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]octyl]carbamoyl)amino]butyl]urea;

[0699] 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0700] 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2S)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2S)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0701] 3-[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.1]hept-2-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.1]hept-2-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino]butyl]urea;

[0702] 1-[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.2]oct-2-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.2]oct-2-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino]butyl]urea;

[0703] 3-[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.2.1]oct-8-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.2.1]oct-8-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino]butyl]urea;

[0704] 1-[2-(2-[2-[(4-[[(1S,2S)-2-[9-azabicyclo[3.3.1]non-9-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[9-azabicyclo[3.3.1]non-9-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0705] 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0706] 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0707] 3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0708] 3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino]butyl]urea;

[0709] 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-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)ethoxy]ethoxy]ethyl)aminosulfonyl]phenoxy]-2,3-dihydro-1H-indene-2-yl]-N,N-dimethylpiperazin-1-carboxamide;

[0710] 4-[(1S,2S)-4,6-dichloro-1-[4-[(2-[2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[4-(dimethylcarbamoyl)piperazin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)ethoxy]ethoxy]ethyl)aminosulfonyl]-2-methylphenoxy]-2,3-dihydro-1H-indene-2-yl]-N,N-dimethylpiperazin-1-carboxamide;

[0711] 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[methyl(propyl-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[methyl(propyl-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino]butyl]urea;

[0712] 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-3,5-dimethylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-3,5-dimethylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; hydrochloride;

[0713] 1-[2-(2-[2-[(3-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-2,4-dimethylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3,5-dimethylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0714] 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-2,5-dimethylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-2,5-dimethylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0715] 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-2,5-dimethylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-2,5-dimethylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0716] 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-carbamoyl]amino)butyl]urea; hydrochloride;

[0717] 1-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0718] 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-3,5-difluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-3,5-difluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0719] 4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[26-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy)-3,5-difluorophenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexahexayl]-3,5-difluorobenzenesulfonamide;

[0720] 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0721] 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0722] 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0723] 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0724] 1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]-2-oxopyrrolidone-1-yl]ethoxy]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]-2-oxopyrrolidone-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;

[0725] 1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]-2-oxopyrrolidone-1-yl]ethoxy]ethyl)-3-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonylamino]-2-oxopyrrolidone-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;

[0726] 3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonyl]pyrrolidine-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-indene-1-yl]oxy]benzene)sulfonyl]pyrrolidine-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0727] 3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonyl]pyrrolidine-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-indene-1-yl]oxy]benzene)sulfonyl]pyrrolidine-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0728] 3-[2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-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-indene-1-yl]oxy]benzene)sulfonyl]piperidin-4-yl]oxy)ethoxy]ethyl]carbamoyl)amino]butyl]urea;

[0729] 1-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]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-indene-1-yl]oxy]benzene)sulfonylamino]propoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea; hydrochloride;

[0730] 3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]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-indene-1-yl]oxy]benzene)sulfonylamino]propoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea;

[0731] 3-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]-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-indene-1-yl]oxy]benzene)sulfonylamino]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea dihydrochloride;

[0732] 3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]-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-indene-1-yl]oxy]benzene)sulfonylamino]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea;

[0733] 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonylamino]-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-indene-1-yl]oxy]benzene)sulfonylamino]-2-methylpropoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; hydrochloride;

[0734] 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-2-methoxybenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-2-methoxybenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino]butyl]urea;

[0735] 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-2-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-2-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0736] 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-2-fluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-2-fluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

[0737] 4-([(1S,2S)-2-[(R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy)-N-[26-([4-([(1S,2S)-2-[(R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy)-2-chlorophenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazabihexacoyl]-2-chlorobenzenesulfonamide;

[0738] 4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-3-fluorophenyl]sulfonylamino)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosyl)pyrrolidine-3-yl]-3-fluorobenzenesulfonamide; tetra(trifluoroacetate);

[0739] 4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-3-fluorophenyl]sulfonylamino)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosyl)pyrrolidine-3-yl]-3-fluorobenzenesulfonamide; tetra(trifluoroacetate);

[0740] 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosyl)pyrrolidine-3-yl]benzenesulfonamide; tetra(trifluoroacetate);

[0741] 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosyl)pyrrolidine-3-yl]benzenesulfonamide; tetra(trifluoroacetate);

[0742] 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-3-fluorophenyl)sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosyl)pyrrolidine-3-yl]-3-fluorobenzenesulfonamide; tetra(trifluoroacetate);

[0743] 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-3-fluorophenyl)sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosyl)pyrrolidine-3-yl]-3-fluorobenzenesulfonamide; tetra(trifluoroacetate);

[0744] 4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy)-3-fluorophenyl]sulfonylamino)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosyl)pyrrolidine-3-yl)-3-fluorobenzenesulfonamide; tetra(trifluoroacetate);

[0745] 4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-indene-1-yl]oxy)-3-fluorophenyl]sulfonylamino)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosoetinyl)pyrrolidine-3-yl)-3-fluorobenzenesulfonamide; tetra(trifluoroacetate);

[0746] 4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-indene-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-indene-1-yl]oxy)-3-methylphenyl]sulfonylamino)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosoetin)pyrrolidine-3-yl]-3-methylbenzenesulfonamide; tetra(trifluoroacetate);

[0747] 4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-indene-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-indene-1-yl]oxy)-3-methylphenyl]sulfonylamino)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosoetin)pyrrolidine-3-yl]-3-methylbenzenesulfonamide; tetra(trifluoroacetate);

[0748] 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonylamino)piperidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide;

[0749] 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[(S)-1-(14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonylamino)pyrrolidine-1-yl]-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl)pyrrolidine-3-yl]benzenesulfonamide;

[0750] 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-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-indene-1-yl]oxy)phenyl]sulfonylamino)pyrrolidine-1-yl]-2,13-dimethyl-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl]pyrrolidine-3-yl]benzenesulfonamide;

[0751] N1,N14-bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonylamino)pyrrolid-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;

[0752] N1,N14-bis(2-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonylamino)pyrrolid-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;

[0753] N1,N18-bis(1-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonyl)piperidin-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide;

[0754] 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexahexayl]benzenesulfonamide;

[0755] -([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexahexayl]benzenesulfonamide;

[0756] 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonamide]piperidin-1-yl)-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosyl]piperidin-4-yl)benzenesulfonamide;

[0757] N1,N18-bis([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonyl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide;

[0758] N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonyl)-1-[16-(4-[([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonyl)carbamoyl]piperidin-1-yl)-5,12-dioxo-4,6,11,13-tetraazahexadecyl]piperidin-4-carboxamide;

[0759] 4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazacycloheptane-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazacycloheptane-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosoeyl)pyrrolidine-3-yl]benzenesulfonamide;

[0760] 4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazacycloheptane-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazacycloheptane-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosoeyl)pyrrolidine-3-yl]benzenesulfonamide;

[0761] 4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazacycloheptane-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazacycloheptane-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosoelytyl)pyrrolidine-3-yl]benzenesulfonamide;

[0762] 4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazacycloheptane-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazacycloheptane-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosoeyl)pyrrolidine-3-yl]benzenesulfonamide;

[0763] 4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-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]hept-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicoseroyl)pyrrolidine-3-yl]benzenesulfonamide;

[0764] 4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-indene-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicoseroyl)pyrrolidine-3-yl]benzenesulfonamide;

[0765] 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-indene-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-indene-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosoeyl)pyrrolidine-3-yl]benzenesulfonamide;

[0766] 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-indene-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-indene-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosoeyl)pyrrolidine-3-yl]benzenesulfonamide;

[0767] 4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-indene-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-indene-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosoeyl)pyrrolidine-3-yl]benzenesulfonamide;

[0768] 4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-indene-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-indene-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosoeyl)pyrrolidine-3-yl]benzenesulfonamide;

[0769] 4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-indene-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-indene-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosoeyl)pyrrolidine-3-yl]benzenesulfonamide;

[0770] 4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-indene-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-indene-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosoeyl)pyrrolidine-3-yl]benzenesulfonamide;

[0771] 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonamide)-2-oxopiridine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicoseroyl)-2-oxopiridine-3-yl]benzenesulfonamide;

[0772] 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-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-indene-1-yl]oxy)phenyl]sulfonamide)ethoxy]ethoxy)ethyl]ureo)cyclohexyl]ureo)ethoxy]ethoxy)ethyl]benzenesulfonamide;

[0773] 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[(R)-1-(18-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonylamino)pyrrolidine-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidine-3-yl]benzenesulfonamide;

[0774] 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide;

[0775] N-(2-[2-(2-aminoethoxy)ethoxy]ethyl)-4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)benzenesulfonamide;

[0776] N-[1-(4-aminobutyryl)piperidin-4-yl]-4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide;

[0777] 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-(3-oxo-7,10-dioxa-2,4-diazadodecane-12-yl)benzenesulfonamide;

[0778] 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-(1-[4-(3-methylureo)butyryl]piperidin-4-yl)benzenesulfonamide;

[0779] 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexane-2-yl]benzenesulfonamide;

[0780] 4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonamide)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexane-2-yl]piperidine-1-carboxamide;

[0781] 4-(3-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonylamino)-4-oxobutyl]ureoyl)-N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonyl)butyramide;

[0782] 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[1-(4-[3-(4-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonylamino)piperidin-1-yl]-4-oxobutyl)ureo]butyryl)piperidin-4-yl]benzenesulfonamide;

[0783] 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[19-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonamide)-10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecanyl]benzenesulfonamide;

[0784] 4-([(1S,2S)-6-chloro-4-acylamino-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-acylamino-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazabihexamethyl]benzenesulfonamide;

[0785] 4-([(1S,2S)-4-cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-N-[26-([4-([(1S,2S)-4-cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexahexayl]benzenesulfonamide;

[0786] 1,1'-(butane-1,4-diyl)bis[3-(4-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-yl]-4-oxobutyl)urea];

[0787] 1,1'-(butane-1,4-diyl)bis[3-(4-[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-yl]-4-oxobutyl)urea];

[0788] N,N'-(6,14-dioxo-10-oxa-5,7,13,15-tetraazanonadecan-1,19-diyl)bis[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-formamide];

[0789] N,N'-(6,14-dioxo-10-oxa-5,7,13,15-tetraazanonadecan-1,19-diyl)bis[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-formamide];

[0790] 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-indene-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-indene-1-yl]oxy)phenyl]sulfonylamino)pyrrolidine-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidine-3-yl]benzenesulfonamide;

[0791] 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-indene-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-indene-1-yl]oxy)phenyl]sulfonylamino)pyrrolidine-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidine-3-yl]benzenesulfonamide;

[0792] 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonylamino)piperidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide;

[0793] N1,N14-bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonylamino)pyrrolid-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;

[0794] 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonamide)piperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosyl)piperidin-4-yl]benzenesulfonamide;

[0795] 4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-indene-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-indene-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosoeyl)pyrrolidine-3-yl]benzenesulfonamide;

[0796] N1,N14-bis(2-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy)phenyl]sulfonylamino)pyrrolid-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;

[0797] 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-indene-1-yl]oxy)-1-oxoisoindoline-2-yl]ethoxy)ethyl]urea); and

[0798] 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-indene-1-yl]oxy)-1-oxoisoindoline-2-yl]ethoxy)ethyl]urea).

[0799] Example

[0800] The invention will be more fully understood by referring to the following examples. However, they should not be construed as limiting the scope of the invention. For example, compounds not illustrated can be successfully synthesized by modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art besides those described, and / or by conventionally altering the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered suitable for preparing other compounds described herein.

[0801] 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-eicosylhydrocarboxylic acid (1-9)

[0802]

[0803] 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-octadecylhydrocarboxylic acid (1-2)

[0804] Add (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8, 8a,9,12,12a,12b,13,14b-octadecylhydrobenzyl-2-carboxylate 1-1 (prepared according to the method described in U.S. Patent Application No. 20160151387) (11 g, 15.92 mmol, 1.00 equivalent), tetrakis(triphenylphosphine)palladium(0) (4 g, 3.46 mmol, 0.20 equivalent), THF (250 mL), and water (150 mL). The resulting solution was... Stir for 2 days. Extract the resulting solution with CH2Cl2 (3 × 150 mL) and combine the organic layers. Wash the resulting mixture with brine (3 × 150 mL). Dry the mixture with anhydrous Na2SO4 and concentrate under vacuum. Plugging the residue onto a silica gel column using EtOAc / petroleum ether (1:10) (20 mL). Purify the crude product by rapid preparative HPLC under the following conditions: (CombiFlash-1)C 18 Silica gel; Mobile phase:

[0805] MeCN:water = 100:0; detector: UV 254nm. 1L of product was obtained. This yielded 6.5g (69.6%) 1-2, a pale yellow solid.

[0806] Synthesis of 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-octadecylhydros-2,10-dicarboxylic acid 2-benzyl ester (1-3)

[0807] TEA (3 mL, 5.80 equivalents) was added dropwise to a solution of 1-2 (3 g, 5.11 mmol, 1 equivalent) and DMAP (102.4 mg, 0.84 mmol, 0.10 equivalents) in DMF (30 mL) at 0 °C with stirring. Then, 2-(trimethylsilyl)ethoxymethyl chloride (4.2 mL, 4.8 equivalents) was added dropwise at 0 °C with stirring. The reaction mixture was stirred at room temperature for 1.5 h, then quenched by adding an aqueous solution of K₂CO₃ (50 mL). The mixture was diluted with CH₂Cl₂ (250 mL), washed with brine (3 × 150 mL), dried over (Na₂SO₄), and concentrated under vacuum. The residue was purified by elution with EtOAc / petroleum ether (1:10) using a silica gel column. This yielded 3.5 g (95.5%) of 1-3 as a pale yellow oil.

[0808] 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-eicosylhydrocarboxylic acid (1-4)

[0809] To a 300-mL pressure vessel reactor (40 atm) purged and maintained under an inert hydrogen atmosphere, 1-3 (6.6 g, 9.20 mmol, 1.00 equivalent), Pd / C (1.32 g, 0.20 equivalent), and acetone (150 mL) were added. The reaction mixture was stirred overnight at 50 °C and then concentrated under vacuum. This yielded 4.2 g (73%) of 1-4 as a white solid.

[0810] Synthesis of 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-eicosyl-2,10-dicarboxylic acid 2-benzyl ester (1-5)

[0811] A solution of 1-4 (5.25 g, 8.35 mmol, 1 equivalent), cesium carbonate (4.1 g, 12.58 mmol, 1.5 equivalent), and benzyl bromide (2.86 g, 16.72 mmol, 2 equivalent) in DMF (70 mL) was stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (250 mL) and extracted with CH2Cl2 (2 × 100 mL). The organic layers were combined, dried over (Na2SO4), and concentrated. The residue was purified by elution with EtOAc / petroleum ether (1:10) using a silica gel column. This yielded 6 g (99%) of 1-5 as a grayish-white solid.

[0812] 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-eicosyl-3-carboxylic acid (1-6)

[0813] Hydrogen chloride (4M in dioxane, 30 mL) was added to a 1–5 (5.6 g, 7.79 mmol, 1 equivalent) THF solution (40 mL), and the reaction mixture was stirred at 60 °C for 2 hours. The solution was adjusted to pH 3 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with CH2Cl2 (3 × 100 mL). The organic layers were combined, washed with brine (2 × 150 mL), dried over (Na2SO4), and concentrated. The residue was purified by rapid preparative HPLC under the following conditions: (CombiFlash-1) – column: C 18 Silica gel; mobile phase: MeCN:water = 100:0; detector: UV 254nm. This yielded 3.1 g (68%, 97% purity) L-6 as a white solid. MS (ES, m / z): [M+H] + =589.4; 1 H-NMR (400MHz, chloroform-d): δ0.76(s,4H),0.91(s,5H),1.01-1.21(m,12H),1.2 4-1.49(m,9H),1.56-1.75(m,4H),1.83(td,J=13.6,4.6Hz,1H),1.91-2.1 0(m,5H),2.23(d,J=8.2Hz,1H),2.37(s,1H),2.86(d,J=13.2Hz,1H),5.11 (d,J=12.0Hz,1H),5.23(d,J=12.4Hz,1H),5.57(s,1H),7.30-7.45(m,5H).

[0814] Synthesis of (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-eicosyl-2-carboxylic acid benzyl ester (1-7)

[0815] At room temperature, oxalyl chloride (0.144 mL, 1.70 mmol) was added dropwise to a solution of 1–6 (0.50 g, 0.85 mmol) and DMF (1 drop) in 50 mL of CH2Cl2. The mixture was stirred at room temperature for 1 hour and then evaporated to dryness. This substance was used in subsequent steps without purification.

[0816] Synthesis of (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-eicosyl-2,10-dicarboxylic acid 2-benzyl-10-methyl ester (1-8)

[0817] A solution of 1-7 (200 mg, 0.33 mmol, 1 equivalent) and TEA (0.274 mL, 6 equivalents) in 20 mL of MeOH was stirred overnight at room temperature. The reactants were concentrated under vacuum. This yielded 198 mg (100%) of 1-8 as a pale yellow coarse solid.

[0818] 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-eicosylhydrocarboxylic acid (1-9)

[0819] A solution of 1-8 (198 mg, 0.33 mmol, 1.00 equivalent) and Pd / C (20 mg) in MeOH (40 mL) was placed under a hydrogen atmosphere and stirred at room temperature for 1 hour. The reaction mixture was filtered and concentrated under vacuum. The crude product (200 mg) was purified by preparative HPLC under the following conditions: – Column: XBridge Prep C18 OBD, 190*150 mm, 5 μm; Mobile phase: water (10 mM NH4HCO3 + 0.1% NH4OH) and CH3CN (50.0% CH3CN reached 62.0% within 7 min); Detector: UV 254 / 220 nm. This yielded 111.8 mg (66%) of 1-9 as a pale yellow solid. MS (ES, m / z): [M+H]+ = 513.60; 1 H NMR(400MHz, chloroform-d)δ0.76(d,J=11.2Hz,1H),0.84(s,3H),0.88–0.96(m,4H),0.99–1.0 8(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,2 H),2.37(s,1H),2.82(dt,J=10.4,3.2Hz,1H),3.65(s,3H),5.70(s,1H),9.89(s,1H).

[0820] Example 2 (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(carboxymethoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (78-2)

[0821]

[0822] Synthesis of (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(prop-2-yn-1-yloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid diphenyl methyl ester (76-2)

[0823] 76-1 (prepared as described in Bioorg. Med. Chem. 2010, 18, 433-454) (1.674 g, 2.63 mmol, 1 equivalent), NaHMDS (2.63 mL, 2 equivalents), 3-bromoprop-1-yne (0.45 mL, 2 equivalents), and tetrabutylammonium iodide (486 mg, 1.32 mmol, 0.5 equivalents) in THF (2 mL) was stirred overnight at room temperature. The reactants were diluted with water (30 mL) and extracted with DCM (2 × 50 mL). The extract was dried over (Na2SO4) and concentrated under vacuum. The residue was purified by elution with EtOAc / petroleum ether (1:10) using a silica gel column. This yielded 1.395 g (79%) of 76-2 as a pale yellow solid.

[0824] Synthesize 2-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((diphenylmethyloxy)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-eicosyl-3-yl)oxy)acetic acid (78-1)

[0825] A solution of ruthenium(III) chloride hydrate (20 mg, 0.10 mmol, 6.8 equivalents), 76-2 (100 mg, 0.15 mmol, 1 equivalent), and sodium periodate (150 mg, 0.70 mmol, 5 equivalents) in THF (4 mL) and water (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (2 × 50 mL). The extract was dried over (Na₂SO₄) and concentrated under vacuum. The residue was purified by elution with EtOAc / petroleum ether (1:5) using a silica gel column. This yielded 80 mg (78%) of 78-1 as a white solid.

[0826] Synthesis of (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(carboxymethoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (78-2)

[0827] A solution of 78-1 (148 mg, 0.21 mmol, 1 equivalent) and Pd / C (100 mg) in EtOAc (15 mL) was placed under a hydrogen atmosphere (1 atm) and stirred overnight at room temperature. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 m, 19 x 150 mm; mobile phase: water (0.05% NH4OH) and CH3CN (10.0% CH3CN reached 40.0% within 8 min); detector: UV 254 nm. This yielded 31.1 mg (28%) of 78-2 as a white solid. MS (ES, m / z): [M+H] + =529.40; 1 H NMR(300MHz,MeOH-d4,ppm)δ0.78-0.88(m,7H),0.94-1.08(m,5H),1.16-1. 18(m,9H),1.27(d,J=13.5Hz,1H),1.39-1.51(m,8H),1.56-2.12(m,8H),2. 13-2.26(m,2H),2.47(s,1H),2.76(dt,J=13.5,3.5Hz,1H),2.94(dd,J=11. 7,4.2Hz,1H),3.93(d,J=15.6Hz,1H),4.05(d,J=15.6Hz,1H),5.61(s,1H).

[0828] Example 3 (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (121-2)

[0829]

[0830] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,12aS,12bR,14bR,E)-10-(acetoxyimino)-9-(acetoxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid benzyl ester (120-2)

[0831] 120 was prepared from (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid. -1 (prepared as described in Bioorg. Med. Chem. 2010, 18, 433-454) (1.0 g, 1.7 mmol, 1 equivalent), sodium tetrachloropalladium(II) (0.76 g, 2.04 mmol, 1.2 equivalent), and sodium acetate (0.21 g, 1.36 mmol, 0.8 equivalent) in acetic acid (100 mL) was stirred at room temperature for 72 hours. The reaction mixture was poured onto ice, and the resulting precipitate was collected by filtration and dried under vacuum. DCM (120 mL), acetic anhydride (0.435 g, 3.24 mmol, 1.8 equivalent), TEA (0.364 g, 2.72 mmol, 1.6 equivalent), and DMAP (6 mg, 0.02 equivalent) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water (1 x 300 mL), dried over (Na₂SO₄), and concentrated under vacuum. Add pyridine (0.6 mL) and THF (100 mL), and stir the mixture at room temperature for 15 minutes. Cool the reaction mixture to -78 °C in a dry ice / acetone bath, and slowly add a solution of lead tetraacetate (4.9 g, 8.5 mmol, 5 equivalents) in acetic acid (100 mL). Warm the mixture to room temperature and stir at room temperature for 16 hours. Add a solution of sodium borohydride (60 mg) in 1 N NaOH aqueous solution (50 mL), and continue stirring for 10 minutes. Filter the reaction mixture through diatomaceous earth and extract with DCM (300 mL). Wash the extract with saturated NaHCO3 aqueous solution (3 × 300 mL) and brine (2 × 300 mL), dry to (Na2SO4), and concentrate under vacuum. This yields 1.03 g (88%, crude) 120-2 as a pale yellow solid.

[0832] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,12aS,12bR,14bR,E)-10-(hydroxyimino)-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid benzyl ester (120-3)

[0833] A solution of 120-2 (1.03 g, 1.53 mmol, 1 equivalent) and sodium carbonate (820 mg, 7.74 mmol, 5 equivalents) in MeOH (120 mL) was stirred at room temperature for 16 hours. The reactants were concentrated under vacuum, and the residue was dissolved in DCM (200 mL). The mixture was washed with saturated sodium bicarbonate aqueous solution (2 × 200 mL) and brine (1 × 200 mL) and concentrated under vacuum. This yielded 1.1 g (crude) 120-3 as a yellow solid.

[0834] Synthesis of (2S,4aS,6aS,6bR,8aR,9R,12aS,12bR,14bR)-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid benzyl ester (120-4)

[0835] A solution of 120-3 (1.1 g, 1.87 mmol, 1 equivalent) in 70 mL of THF was added dropwise to a solution of ammonium acetate (3.88 g, 27 equivalents) and titanium(III) chloride (4 mL) in 80 mL of water. The reaction mixture was stirred overnight at room temperature and then partially concentrated under vacuum. The remaining solution was extracted with DCM (200 mL), washed with saturated sodium bicarbonate aqueous solution (1 × 200 mL) and brine (1 × 200 mL), dried over (Na₂SO₄), and concentrated under vacuum. The residue was purified by elution with EtOAc / petroleum ether (1:1) using a silica gel column. This yielded 190 mg (18%) of 120-4 as a white solid.

[0836] Synthesis of (2S,4aS,6aS,6bR,8aR,9R,12aS,12bR,14bR)-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (120-5)

[0837] A solution of 120-4 (100 mg, 0.17 mmol) and Pd / C (20 mg) in EtOAc (15 mL) was placed under a hydrogen atmosphere (1 atm) and stirred at room temperature for 1 hour. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 mm, 19*150 mm; mobile phase: water (0.05% TFA) and MeCN (within 10 min) 20.0% MeCN up to 30.0%; detector: UV 254 nm. This yielded 5.3 mg (6%) of 120-5 as a white solid. MS (ES, m / z): [M+H] + =485.30; 1 H NMR(400MHz,MeOH-d4,ppm): δ0.86(s,3H),0.96(s,3H),1.01-1.09(m,1H),1.13(s,3H),1.19-1.42(m,9H),1.46-1.73(m,8H),1.80-2.08(m,5H), 2.12-2.29(m,1H),2.19-2.48(m,2H),2.48-2.64(m,1H),2.66(s,1H),2. 77-2.98(m,1H),3.35-3.42(m,2H),3.65(d,J=10.8Hz,1H),5.75(s,1H).

[0838] Synthesize (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid benzyl ester (121-1)

[0839] A solution of 120-4 (150 mg, 0.26 mmol, 1 equivalent) and sodium borohydride (40 mg, 1.06 mmol, 4 equivalents) in MeOH (20 mL) was stirred at room temperature for 1 hour. The reaction was quenched by adding water (5 mL) and the mixture was concentrated under vacuum. The residue was diluted with DCM, washed with water and brine, dried over (Na₂SO₄), and concentrated. This yielded 140 mg (93%) of 121-1 as a white solid.

[0840] Synthesize (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (121-2).

[0841] A solution of 121-1 (180 mg, 0.31 mmol) and Pd / C (36 mg) in EtOAc (15 mL) was placed under a hydrogen atmosphere (1 atm) and stirred at room temperature for 1 hour. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 m, 19 x 150 mm; mobile phase: water (0.05% TFA) and MeCN (42.0% MeCN reached 57.0% within 8 min); detector: UV 254 nm. This yielded 37.9 mg (25%) of 121-2 as a white solid. MS (ES, m / z): [M+H] + =487.25; 1 H NMR(400MHz,MeOH-d4,ppm): δ0.72(s,3H),0.86(s,3H),0.97-1.12(m,2H), 1.14-1.33(m,11H),1.37-1.65(m,10H),1.67-1.79(m,2H),1.80-2.03(m,4 H),2.10-2.27(m,2H),2.51(s,1H),2.73(dt,J=13.5,3.6Hz,1H),3.29-3.3 2(m,1H),3.56(d,J=11.0Hz,1H),3.64(dd,J=11.8,4.7Hz,1H),5.60(s,1H).

[0842] Example 4 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid-2,9-dicarboxylic acid (122-3)

[0843]

[0844] Synthesized (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-formyl-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid benzyl ester (122-1)

[0845] A solution of 121-1 (300 mg, 0.52 mmol, 1 equivalent), pH 8.6 phosphate buffer (5 mL), TEMPO (240 mg, 1.54 mmol, 3 equivalents), tetrabutylammonium chloride (0.36 g, 2.5 equivalents), and N-chlorosuccinimide (280 mg, 2.10 mmol, 4 equivalents) in DCM (25 mL) was stirred overnight at 40 °C. The reaction mixture was extracted with DCM (200 mL). The extract was washed with water (1 × 200 mL) and brine (1 × 200 mL), dried over (Na₂SO₄), and concentrated. This yielded 0.4 g (134%, crude) of 122-1 as a yellow semi-solid.

[0846] Synthesis of (3S,4S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-3-hydroxy-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-eicosylhydro-4-carboxylic acid (122-2)

[0847] A solution of 122-1 (400 mg, 0.70 mmol, 1 equivalent), 2-methylbut-2-ene (2 mL), sodium dihydrogen phosphate (0.5 g, 6.00 equivalent), and sodium chlorite (0.38 g, 6.00 equivalent) in water (6 mL) and tert-butanol (12 mL) was stirred at -2 °C for 30 min. The reaction mixture was partially concentrated under vacuum, and the residue was extracted with DCM (200 mL). The extract was washed with brine (1 × 200 mL), dried over (Na₂SO₄), and concentrated under vacuum. This yielded 0.758 g (184%, crude) of 122-2 as a yellow semi-solid.

[0848] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (122-3)

[0849] A solution of 122-2 (225 mg, 0.38 mmol) and Pd / C (45 mg) in EtOAc (16 mL) was placed under a hydrogen atmosphere (1 atm) and stirred at room temperature. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 m, 19 x 150 mm; mobile phase: water (0.05% TFA) and MeCN (38.0% MeCN reached 55.0% within 8 min); detector: UV 254 nm. This yielded 18.5 mg (10%) of 122-3 as a white solid. MS (ES, m / z): [M+H] + =501.20; 1 H NMR (400MHz, MeOH-d4, ppm): δ0.85 (s, 3H), 1.01-1.31 (m, 16H), 1.44 (d, J = 13.4Hz, 7H), 1.54 (d, J = 10.8Hz, 1H), 1.59-1.81 (m, 5 H),1.81-2.01(m,3H),2.10-2.28(m,2H),2.54(s,1H),2.79(dt,J=13.7,3.6Hz,1H),3.99(dd,J=11.8,4.7Hz,1H),5.62(s,1H).

[0850] Example 5 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (176-2)

[0851]

[0852] Synthesis of (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-eicosyl-2,10-dicarboxylic acid 2-benzyl-10-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl) ester (176-1)

[0853] A solution of 1-6 (400 mg, 0.68 mmol, 1 equivalent), potassium iodide (56 mg, 0.5 equivalent), 4-(chloromethyl)-5-methyl-2H-1,3-m-dioxane-2-one (182 mg, 1.23 mmol, 1.8 equivalent), and potassium carbonate (282 mg, 2.04 mmol, 3 equivalent) in DMF (2.5 mL) was stirred at 60 °C for 2 hours. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over (Na2SO4), and concentrated under vacuum. The residue was purified by elution with EtOAc / petroleum ether (1:3) using a silica gel column. This yielded 460 mg (97%) of 176-1 as a pale yellow solid.

[0854] Synthesis of (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (176-2)

[0855] A solution of 176-1 (70 mg) and Pd(OH)2 / C (5.6 mg) in THF (5 mL) was placed under a hydrogen atmosphere (1 atm) and stirred at room temperature for 13 hours. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 m, 19 x 150 mm; mobile phase: water (0.05% TFA) and MeCN (68% phase B reached 77% within 10 min); detector: UV. This yielded 13.2 mg (21.64%) of 176-2 as a white solid. MS (ES, m / z): [M+H] + =611.45; 1H NMR(400MHz,MeOH-d4)δ0.88(d,J=13.9Hz,6H),0.90–0.93(m,1H),0.95–1 .09(m,5H),1.10–1.24(m,9H),1.25–1.30(m,1H),1.31–1.55(m,9H),1.63– 1.80(m,3H),1.81–2.06(m,4H),2.09–2.22(m,5H),2.29(dd,J=13.2,3.2Hz ,1H),2.50(s,1H),2.76(d,J=13.6Hz,1H),4.89–4.99(m,2H),5.57(s,1H).

[0856] Example 6 (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(((5-methyl-2-oxo-1,3-dioxolane-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (178-1)

[0857]

[0858] A solution of 176-1 (110 mg) and Pd(OH)2 / C (11 mg) in THF (10 mL) and EtOH (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC under the following conditions: column: XBridgeShield RP18 OBD, 5 m, 19*150 mm; mobile phase: water (0.05% TFA) and MeCN (5% phase B reaches 84% ​​within 1 min, 93% within 7 min); detector: UV. This yielded 26.4 mg of 178-1 as a white solid. MS (ES, m / z): [M+H] + =613.40; 1H NMR(400MHz,MeOH-d4)δ0.83(s,3H),0.85–0.91(m,4H),0.97–1.09(m,5H),1.13–1.16(m,3H), 1.18–1.19(m,5H),1.21–1.31(m,2H),1.38–1.58(m,12H),1.63–1.78(m,3H),1.79–2.08(m,4H ),2.16(qd,J=12.8,4.4Hz,2H),2.28(dt,J=13.2,4.4Hz,1H),2.51(s,1H),2.77(d,J=13.2Hz, 1H),4.19–4.32(m,1H),4.36–4.50(m,1H),4.91–4.99(m,1H),5.00–5.09(m,1H),5.57(s,1H).

[0859] Example 7 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxatetradecane-14-acyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid-2,9-dicarboxylic acid (190-3)

[0860]

[0861] Synthesis of (3S,4S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-4-formyl-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-eicosicohydrofenozyl-3-yl 2,5,8,11-tetraoxatetradecane-14-ester (190-1)

[0862] EDCI (250 mg, 1.30 mmol, 2.5 equivalences) was added to a solution of 122-1 (300 mg, 0.52 mmol, 1 equivalence), 2,5,8,11-tetraoxatetradecane-14-acid (370 mg, 1.57 mmol, 3 equivalences), and DMAP (130 mg, 1.06 mmol, 2 equivalences) in DCM (20 mL). The reaction mixture was stirred at room temperature for 3 hours, followed by vacuum concentration. The residue was purified by elution with EtOAc / hexane (2:1) using a silica gel column. This yielded 0.2 g (48%) of 190-1 as a yellow semi-solid.

[0863] Synthesis of (3S,4S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-3-((2,5,8,11-tetraoxatetradecane-14-acyl)oxy)-11-((benzyloxy)carbonyl)-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-eicosylhydro-4-carboxylic acid (190-2)

[0864] A solution of 190-1 (200 mg, 0.25 mmol, 1 equivalent), 2-methylprop-1-ene (2 mL), sodium dihydrogen phosphate (0.18 g, 6.00 equivalent), and sodium chlorite (0.14 g, 6.00 equivalent) in tert-butanol (9 mL) and water (3 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum, diluted with DCM, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This yielded 0.2 g (98%) of 190-2 as a yellow solid.

[0865] Example 8 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-(2-(methylthio)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (194-10)

[0866]

[0867] Synthesis of (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid diphenyl methyl ester (194-1)

[0868] Add 76-1 (prepared as described in Bioorg. Med. Chem. 2010, 18, 433-454) (105 g, 165 mmol, 1 equivalent), CH2Cl2 (800 mL), and Dess-Martin periodane (139.8 g, 330 mmol, 2 equivalent) to a 2-L round-bottom flask. Stir the resulting mixture overnight at room temperature. Quench the reaction by adding 300 mL of sodium bicarbonate. Wash the reaction mixture with 3 × 1 L H2O. Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate under vacuum. Recrystallize the crude product from petroleum ether and CH2Cl2 to give 194-1 (100 g, 96%) as a white solid.

[0869] Synthesis of (2S,4aS,6aS,6bR,8aR,12aS,12bR,14bR,E)-10-(hydroxyimino)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid diphenyl methyl ester (194-2)

[0870] Add 194-1 (59.5 g, 93.7 mmol, 1 equivalent), pyridine (1 L), and NH2OH·HCl (23.2 g, 335 mmol, 3.6 equivalent) to a 2 L round-bottom flask. Stir the reaction mixture at 70 °C for 1 hour. Concentrate the reaction mixture under vacuum, dilute with 2 L CH2Cl2, and wash with 4 × 1 L 3N HCl and 1 L brine. Dry the combined organic layers over anhydrous Na2SO4, filter, and concentrate under reduced pressure. Recrystallize the crude product from CH2Cl2 / petroleum ether to give 194-2 (55.1 g, 90%) as a white solid. MS (ES, m / z): [M+1] + =650.15; 1H NMR (300MHz, chloroform-d) δ7.58–7.21(m,10H),6.96(s,1H),5.55(s,1H),5.32(s,1H),3.09(ddd,J=15.5,5.1,3.6Hz,1H),2.90(ddd,J=13.3,5.7,3.6Hz ,1H),2.41–2.21(m,2H),2.12–1.96(m,4H),1.92–1.76(m,1H),1.65(q,J =18.6,16.7Hz,3H),1.56–1.25(m,11H),1.24–0.92(m,16H),0.70(s,3H).

[0871] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,12aS,12bR,14bR,E)-10-(acetoxyimino)-9-(acetoxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid diphenyl methyl ester (194-3)

[0872] Add 194-2 (53.4 g, 82.2 mmol, 1 equivalent), AcOH (400 mL), Ac2O (400 mL), Pd(OAc)2 (3.3 g, 14.8 mmol, 0.18 equivalent), and PhI(OAc)2 (31.8 g, 98.6 mmol, 1.2 equivalent) to a 2-L round-bottom flask. Stir the reaction mixture overnight at 60 °C. Concentrate the reaction mixture, dilute it in CH2Cl2, and then add saturated NaHCO3. 3(水溶液) Wash with brine, dry with anhydrous Na2SO4, filter and concentrate. The residue was purified by silica gel column chromatography by elution with 0-40% EtOAc in petroleum ether to give 194-3 (31.3 g, 51%) as a pale yellow solid (a mixture of isomers, ~6:1 C-23:C-24 acetate).

[0873] Synthesis of (2S,4aS,6aS,6bR,8aR,9R,12aS,12bR,14bR)-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-10,13-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid diphenyl methyl ester (194-4)

[0874] To a 1000-mL round-bottom flask, add diphenylmethyl 194-3 (15 g, 20 mmol), THF (90 mL), MeOH (90 mL), acetone (90 mL), and 2N HCl (90 mL). Stir the reaction mixture overnight at 50 °C. Concentrate the reaction mixture, dilute with CH2Cl2, and wash with 2 × 300 mL saturated NaHCO3 and 2 × 300 mL brine. Dry the organic layer over anhydrous Na2SO4, filter, and concentrate. Dry the solid under reduced pressure in an oven. Apply the residue to a silica gel column using CH2Cl2 / ethyl acetate (4:1) to give 9 g (69%) of 194-4 as a yellow solid (single C-23OH isomer).

[0875] Synthesis of (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-9-(hydroxymethyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid diphenylmethyl ester (194-5)

[0876] At -10 °C, NaBH4 (0.6 g, 17 mmol, 1.1 equivalence) was added in portions to a stirred solution of 194-4 (10 g, 15.4 mmol) in methanol (200 mL). The reaction slurry was stirred at room temperature for 1 hour. After completion, the reaction was quenched with ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was applied to a silica gel column using ethyl acetate (0% to 60% over 30 minutes) / petroleum ether to give 8.4 g (84%) of 194-5 as a white foamy substance (single C-3-β isomer).

[0877] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-formyl-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid diphenyl methyl ester (194-6)

[0878] To a 250-mL round-bottom flask, add 194-5 (4 g, 6.13 mmol), CH2Cl2 (40 mL), pH 8.6 buffer (20 mL), TEMPO (2.87 g, 18.4 mmol, 3 equivalents), TBACl (4.26 g), and NCS (3.2 g, 24 mmol, 3.9 equivalents). Stir the resulting solution at 40 °C for 1.5 h. Cool the reaction mixture and extract with 3 × 50 mL CH2Cl2. Wash the combined organic layers with 2 × 100 mL brine, dry to anhydrous Na2SO4, filter, and concentrate. Plugging the residue onto a silica gel column using ethyl acetate (0-60%) / petroleum ether yields 3.8 g (95%) of 194-6 as a white solid.

[0879] Synthesis of (3S,4S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((diphenylmethyloxy)carbonyl)-3-hydroxy-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-eicosylhydrocarboxylic acid (194-7)

[0880] NaH₂PO₄ (4.4 g, 36.87 mmol, 6 equivalents) was added to a stirred solution of 194-6 (4 g, 6.2 mmol) and 2-methylbut-2-ene (6.6 mL) in water (8.9 mL) and t-BuOH (26.6 mL) at 0 °C. NaClO₂ (3.3 g, 37 mmol, 6 equivalents) was added in portions to the mixture at 0 °C. The reaction slurry was stirred at room temperature for 2 hours. The reaction mixture was extracted with CH₂Cl₂, and the combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give 4 g of crude 194-7 as a pale yellow solid, which was used directly in the next step without further purification.

[0881] Synthesis of (3S,4S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((diphenylmethyloxy)carbonyl)-3-hydroxy-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-eicosylhydrocarboxylic acid (194-8)

[0882] A solution of 194-7 (6.0 g, 9 mmol), K₂CO₃ (3.7 g, 27 mmol, 3 equivalents), and KI (0.75 g, 4.5 mmol, 0.5 equivalents) in DMF was stirred at 60 °C for 2 hours. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution of 2:1 petroleum ether / EtOAc to give 194-8 (6.0 g, 86%) as a pale yellow solid. MS (ES, m / z): [M+1] + =779.00; 1 H NMR (400MHz, chloroform-d) δ7.50–7.29(m,10H),6.95(s,1H),5.54(s,1H),5.04(d,J=13.8Hz,1H),4.80(d,J=13.9Hz,1H),4 .44(s,2H),4.03(dd,J=9.9,6.5Hz,1H),2.98(s,1H),2.88(d,J=19.4Hz,2H),2.79(s,4H),2.40(s,1H),2.22(d,J=6. 6Hz,6H),2.14–1.93(m,4H),1.70(dddd,J=37.5,31.0,16.9,7.4Hz,8H),1.48(d,J=10.1Hz,1H),1.41–1.32(m,6H),1 .27(dd,J=14.6,3.4Hz,1H),1.24–1.10(m,11H),1.08(s,3H),1.04–0.94(m,1H),0.88(d,J=8.8Hz,1H),0.67(s,3H).

[0883] Synthesize (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-(2-(methylthio)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2,9-dicarboxylic acid 2-diphenylmethyl 9-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl) ester (194-9)

[0884] EDCI (250 mg, 1.30 mmol, 5 equivalents) was added to a solution of 194-8 (200 mg, 0.26 mmol, 1 equivalent), 2-(methylthioalkyl)acetic acid (270 mg, 2.54 mmol, 10 equivalents), and DMAP (120 mg, 0.98 mmol, 4 equivalents) in CH2Cl2 (4 mL). The reaction mixture was stirred overnight at room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography using a 1:1 EtOAc:petroleum ether method to give 240 mg (quantitative) of 194-9 as a pale yellow solid.

[0885] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-(2-(methylthio)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (194-10)

[0886] A solution of 194-9 (130 mg, 0.15 mmol, 1 equivalent) and TFA (0.2 mL) in CH2Cl2 (2 mL) was stirred at room temperature for 1 hour. The reactants were concentrated under vacuum, and the residue was purified by preparative HPLC under the following conditions: column: XBridgeShield RP18 OBD, 30*150 mm, 5 μm; mobile phase: water (0.05% TFA) and MeCN (65% phase B reached 75% within 8 minutes); detector: UV. This yielded 24.8 mg (24%) of 194-10 as a grayish-white solid. MS (ES, m / z): [M+H] + =701.10; 1 H-NMR(300MHz,MeOH-d4)δ5.62(s,1H),5.22(dd,J=11.3,5.3Hz,1H),5.04(d,J=13.9Hz,1H),4.91(s,1H),3.15(s,2H),2.85(d,J=13.7Hz,1H), 2.59(s,1H),2.19(d,J=8.2Hz,8H),2.04–1.62(m,9H),1.45(d,J=13.6H z,7H),1.35–1.12(m,14H),1.02(dd,J=29.5,10.7Hz,2H),0.85(s,3H).

[0887] Example 9 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-(2-(methanesulfonyl)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (195-2)

[0888]

[0889] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-(2-(methanesulfonyl)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2,9-dicarboxylic acid 2-diphenylmethyl 9-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl) ester (195-1)

[0890] EDCI (175 mg, 0.91 mmol, 5 equivalents) was added to a solution of 194-8 (140 mg, 0.18 mmol, 1 equivalent), 2-methanesulfonylacetic acid (248 mg, 1.80 mmol, 10 equivalents), and DMAP (84 mg, 0.69 mmol, 4 equivalents) in CH2Cl2 (2.5 mL), and the reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography using EtOAc / petroleum ether (1 / 1). This yielded 160 mg (99%) of 195-1 as a pale yellow solid.

[0891] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-10-(2-(methanesulfonyl)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (195-2)

[0892] A mixture of 195-1 (100 mg, 0.11 mmol, 1 equivalent) and TFA (0.1 mL, 0.01 equivalent) in DCM was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 m, 19 x 150 mm; mobile phase: water (0.05% TFA) and MeCN (50% phase B reached 63% within 13 min); detector: UV. This yielded 195-2 (35.1 mg, 43.06%) as a pale yellow solid. MS (ES, m / z): [M+H] + =732.95; 1 H NMR(300MHz,MeOH-d4)δ5.63(s,1H),5.39–5.26(m,1H),5.05(d,J=13.9Hz,1H ),4.21(s,2H),3.14(d,J=1.0Hz,3H),2.87(d,J=14.0Hz,1H),2.60(s,1H),2. 21(s,5H),1.85(s,6H),1.77(d,J=13.2Hz,1H),1.70(d,J=16.6Hz,2H),1.46( d,J=13.0Hz,7H),1.30(s,4H),1.25–1.13(m,10H),1.00(s,1H),0.86(s,3H).

[0893] Example 10 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((L-valinel)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (196-2)

[0894]

[0895] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((tert-butoxycarbonyl)-L-valine)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2,9-dicarboxylic acid 2-diphenylmethyl 9-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl) ester (196-1)

[0896] EDCI (172.3 mg, 0.90 mmol, 5 equivalents) was added to a solution of 194-8 (140 mg, 0.18 mmol, 1 equivalent), (2S)-2-[[(tert-butoxy)carbonyl]amino]-3-methylbutyric acid (195.2 mg, 0.90 mmol, 5 equivalents), and DMAP (87.8 mg, 0.72 mmol, 4 equivalents) in DCM. The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / EtOAc 1:1) to give 196-1 (170 mg, 96.70%) as a pale yellow solid.

[0897] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((L-valineloyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (196-2)

[0898] A solution of 196-1 (170 mg, 0.17 mmol, 1 equivalent) and TFA (0.15 mL, 2.02 mmol, 12 equivalents) in DCM was stirred at room temperature for 1 hour, followed by vacuum concentration. The crude product was purified by preparative HPLC under the following conditions: column: Xselect CSH OBD, 30*150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 37% B to 65% B over 8 minutes; detector: UV 254 nm, yielding 196-2 (51.5 mg, 41.63%) as a grayish-white solid. MS (ES, m / z): [M+H] + =712.45; 1H NMR(400MHz,MeOH-d4)δ5.63(s,1H),5.43–5.34(m,1H),5.11(d,J=14.0Hz,1H),4.84(d,J=14.0Hz,1H ),3.92(d,J=4.2Hz,1H),2.87(d,J=13.6Hz,1H),2.59(s,1H),2.27-2.12(m,2H),2.21(s,4H),1.98(d, J=10.0Hz,1H),1.87(d,J=9.7Hz,4H),1.80-1.60(m,4H),1.44(d,J=16.3Hz,6H),1.25(d,J=31.4Hz,7H ),1.20(s,3H),1.16(s,3H),1.09(s,1H),1.03(dd,J=7.0,2.9Hz,5H),0.99-0.92(m,1H),0.85(s,3H).

[0899] Example 12 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(benzoyloxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (197-2)

[0900]

[0901] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(benzoyloxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2,9-dicarboxylic acid 2-diphenylmethyl 9-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl) ester (197-1)

[0902] EDCI (175 mg, 0.91 mmol, 5 equivalents) was added to a solution of 194-8 (140 mg, 0.18 mmol, 1 equivalent), benzoic acid (110 mg, 0.90 mmol, 5 equivalents), and DMAP (84 mg, 0.69 mmol, 4 equivalents) in 2.5 mL of DCM. The reaction mixture was stirred overnight at room temperature and then concentrated under vacuum. The residue was purified by elution with EtOAc / petroleum ether (1 / 1) using a silica gel column. This yielded 160 mg (101%) of 197-1 as a pale yellow solid.

[0903] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(benzoyloxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (197-2)

[0904] A solution of 197-1 (160 mg, 0.18 mmol, 1 equivalent) and TFA (0.2 mL, 2.69 mmol, 15 equivalent) in DCM was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum, and the residue was purified by preparative TLC under the following conditions: column: Xselect CSH OBD, 30*150 mm, 5 m; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 37% B to 65% B over 8 minutes; detector: UV 254 nm, yielding 197-2 (27.8 mg, 21.40%) as a grayish-white solid. MS (ES, m / z): [M+H] + =717.00; 1H NMR(300MHz,MeOH-d4)δ8.02–7.88(m,2H),7.63(t,J=7.4Hz,1H),7.49(t,J=7.6Hz,2H),5.6 5(s,1H),5.41(dd,J=11.5,5.1Hz,1H),4.95(s,2H),2.91(d,J=13.9Hz,1H),2.65(s,1H),2.2 5(d,J=14.8Hz,2H),1.97(s,8H),1.85–1.68(m,4H),1.51(s,3H),1.43(d,J=7.6Hz,7H),1.3 4(d,J=12.3Hz,2H),1.27(s,3H),1.20(d,J=6.8Hz,6H),1.06(t,J=13.9Hz,2H),0.87(s,3H).

[0905] Example 13 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopropanecarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (198-2)

[0906]

[0907] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopropanecarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2,9-dicarboxylic acid 2-diphenylmethyl 9-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl) ester (198-1)

[0908] EDCI (250 mg, 1.30 mmol, 5 equivalents) was added to a solution of 194-8 (200 mg, 0.26 mmol, 1 equivalent), cyclopropanecarboxylic acid (220 mg, 2.56 mmol, 10 equivalents), and DMAP (120 mg, 0.98 mmol, 4 equivalents) in DCM (4 mL), and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum, and the residue was purified by elution with EtOAc / petroleum ether (1 / 1) using a silica gel column. This yielded 230 mg (106%) of 198-1 as a pale yellow solid.

[0909] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopropanecarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (198-2)

[0910] A solution of 198-1 (115 mg, 0.14 mmol, 1 equivalent) and TFA (0.15 mL) in DCM (1.5 mL) was stirred at room temperature for 1 hour. The reactants were concentrated under vacuum, and the residue (115 mg) was purified by preparative HPLC under the following conditions: column: Xselect CSH OBD, 30*150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 30% B to 60% B over 8 min; detector: 254 nm. This yielded 26.9 mg (29%) of 198-2 as a grayish-white solid. MS (ES, m / z): [M+H] + =681.20; 1 H NMR(300MHz,MeOH-d4)δ5.62(s,1H),5.14(dd,J=11.5,5.1Hz,1H),5.02(d,J=13.9Hz,1H),4.93(s,1H),2.83(d,J=13.6Hz,1H),2.58(s,1 H),2.20(s,5H),2.01-1.58(m,8H),1.57-1.33(m,10H),1.33-1.13(m,10H),1.07(d,J=12.8Hz,3H),0.95(s,2H),0.87(d,J=13.2Hz,6H).

[0911] Example 14 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((R)-2-methoxypropionyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (203-2)

[0912]

[0913] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((R)-2-methoxypropionyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2,9-dicarboxylic acid 2-diphenylmethyl 9-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl) ester (203-1)

[0914] EDCI (240 mg, 1 mmol, 5 equivalents) was added to a solution of 194-8 (200 mg, 0.2 mmol, 1 equivalent), (2R)-2-methoxypropionic acid (132 mg, 1 mmol, 5 equivalents), and DMAP (132 mg, 0.8 mmol, 4 equivalents) in DCM (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography using EtOAc / petroleum ether (1 / 1). This yielded 150 mg 203-1 as a pale yellow solid.

[0915] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((R)-2-methoxypropionyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (203-2)

[0916] A solution of 203-1 (150 mg, 0.17 mmol, 1 equivalent) and TFA (0.2 mL) in DCM (2 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated and the residue was purified by rapid preparative HPLC to give 47.5 mg (39.20%) of 203-1 as a white solid. MS (ES, m / z): [M+H] + =699; 1 H NMR (300MHz, chloroform-d) δ5.72(s,1H),5.25(dd,J=11.6,5.0Hz,1H),4.99(d,J=13.7Hz,1H),4.69(d,J=13.8Hz,1H),3.79(q,J=6.8Hz,1H),3.34 (s,3H),2.89(d,J=13.7Hz,1H),2.44(s,1H),2.19(s,4H),1.99(s,7H),1.79(s,10H),1.42–1.30(m,14H),1.27–1.15(m,1H),0.82(s,4H).

[0917] Example 15 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((S)-2-methoxypropionyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (204-2)

[0918]

[0919] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((S)-2-methoxypropionyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2,9-dicarboxylic acid 2-diphenylmethyl 9-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl) ester (204-1)

[0920] EDCI (240 mg, 1.2 mmol, 5 equivalents) was added to a solution of 194-8 (200 mg, 0.2 mmol, 1 equivalent), (2S)-2-methoxypropionic acid (132 mg, 1.2 mmol, 5 equivalents), and DMAP (120 mg, 0.8 mmol, 4 equivalents) in DCM (2 mL). The reaction mixture was stirred at 25 °C for 3 hours. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography using EtOAc / petroleum ether (1 / 1). This yielded 150 mg of 204-1 as a pale yellow solid.

[0921] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((S)-2-methoxypropionyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (204-2)

[0922] A solution of 204-1 (150 mg, 0.17 mmol, 1 equivalent) and TFA (0.2 mL, 0.01 equivalent) in DCM (2 mL) was stirred at 25 °C for 2 hours. The reactants were concentrated and the crude product was purified by preparative HPLC under the following conditions: column: Xselect CSH OBD, 30*150 mm, 5 μm; mobile phase: water (0.05% TFA) and MeCN (57% phase B reached 85% within 8 minutes); detector: UV. This produced 204-2 as a white solid. MS (ES, m / z): [M+H] + =699; 1 ¹H NMR (300MHz, chloroform-d) δ 5.72 (s, 1H), 5.26 (dd, J = 11.6, 4.9Hz, 1H), 4.98 (d, J = 13.7Hz, 1H), 4.68 (d, J = 13.8Hz, 1H), 3.79 (t, J = 6.9Hz, 1H), 3.36 (s, 3H), 2.89 (d, J = 13.8Hz, 1H). H),2.45(s,1H),2.19(s,4H),2.00(s,3H),1.87-1.71(m,7H),1.39(s,6H),1.33(d, J=6.9Hz,4H),1.27-1.15(m,12H),1.11(s,3H),1.04(d,J=12.6Hz,1H),0.82(s,4H).

[0923] Example 16 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(methoxymethoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (205-2)

[0924]

[0925] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(methoxymethoxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2,9-dicarboxylic acid 2-diphenylmethyl 9-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl) ester (205-1)

[0926] Bromo(methoxy)methane (0.063 mL, 4.0 equivalents) was added dropwise at 0 °C to a total solution of 194-8 (150 mg, 1 equivalent) and DIEA (0.318 mL, 10.0 equivalents) in DCM (10 mL), and then heated at 60 °C for 1 hour. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography using EtOAc / petroleum ether (1:1). This yielded 178.1 mg (112.38%) of 205-1 as a white crude solid.

[0927] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(methoxymethoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (205-2)

[0928] 205-1 (178.1 mg) and 10% TFA / DCM (10 mL) were stirred at room temperature for 5 hours. The reaction mixture was washed with brine (3 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC under the following conditions: column: Xselect CSH OBD, 30*150 mm, 5 m; mobile phase: water (0.05% TFA) and CH3CN (58% phase B reached 76% within 8 minutes); detector: UV. This yielded 40.0 mg (28%) of 205-2 as a white solid. MS (ES, m / z): [M+H] + =657.25; 1 ¹H NMR (400MHz, chloroform-d) δ 0.85 (s, 4H), 1.01–1.15 (m, 5H), 1.20 (d, J = 12.0 Hz, 6H), 1.26 (s, 4H), 1.33–1.58 (m, 8H), 1.59–1.61 (m, 1H), 1.65–1.70 (m, 2H), 1.72–1.91 (m, 2H), 1.92–2.17 (m, 4H), 2.18–2.20 (m, 1H) ),2.22(s,3H),2.43(s,1H),2.87(d,J=14.0Hz,1H),3.29(s,3H),3.97(dd,J=11.6,4.4Hz,1H),4.52 (d,J=6.8Hz,1H),4.66(d,J=7.2Hz,1H),4.75(d,J=13.6Hz,1H),5.06(d,J=13.6Hz,1H),5.74(s,1H).

[0929] Example 17 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((ethylcarbamoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (206-2)

[0930]

[0931] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((ethylcarbamoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2,9-dicarboxylic acid 2-diphenylmethyl 9-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl) ester (206-1)

[0932] A solution of isocyanate ethane (0.061 mL, 3 equivalents), trimethylchlorosilane (0.111 mL, 5 equivalents), and 194-8 (200 mg, 0.26 mmol) in CH2Cl2 (10 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography using EtOAc / petroleum ether (1:1). This yielded 239.9 mg (quantitative) 206-1 as a white crude solid.

[0933] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((ethylcarbamoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (206-2)

[0934] 206-1 (239.9 mg) and 10% TFA / CH2Cl2 (10 mL) were stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by preparative HPLC under the following conditions: – Column: Xselect CSH OBD, 30*150 mm, 5 μm; Mobile phase: water (0.05% TFA) and MeCN (57% phase B reached 77% within 8 min); Detector: UV. This yielded 65.7 mg (34%) of 206-2 as a white solid. MS (ES, m / z): [M+H] + =684.05; 1H NMR(400MHz,MeOH-d4)δ0.82(s,3H),0.89-0.99(m,1H),1.01-1.04(m,1H),1.09(t,J= 7.2Hz,3H),1.13(s,3H),1.17-1.28(m,11H),1.33-1.48(m,7H),1.61-1.79(m,6H),1. 81-1.90(m,2H),1.95(d,J=10.0Hz,1H),2.11-2.28(m,5H),2.55(s,1H),2.79(d,J=14 .0Hz,1H),2.98-3.17(m,2H),4.89(d,J=14.0Hz,1H),4.95-5.05(m,2H),5.59(s,1H).

[0935] Example 18 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((butylcarbamoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (207-2)

[0936]

[0937] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((butylcarbamoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2,9-dicarboxylic acid 2-diphenylmethyl 9-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl) ester (207-1)

[0938] A solution of 1-isocyanate butane (0.0868 mL, 3 equivalents), TMSCl (0.111 mL, 5 equivalents), and 194-8 (200 mg, 0.26 mmol, 1 equivalent) in CH2Cl2 (10 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography using EtOAc / petroleum ether (1:1). This yielded 256.9 mg (114%) of 207-1 as a white crude solid.

[0939] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((butylcarbamoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (207-2)

[0940] 207-1 (256.9 mg) and 10% TFA / CH2Cl2 (10 mL) were stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum and the crude product was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 m, 19 x 150 mm; mobile phase: water (0.05% TFA) and MeCN (71% phase B reached 72% within 8 minutes); detector: UV. This yielded 28.8 mg (14%) of 207-2 as a grayish-white solid. MS (ES, m / z): [M+H] + =712.05; 1 H NMR(400MHz,MeOH-d4)δ0.85(s,3H),0.94(t,J=7.4Hz,4H),1.07(d,J=13.6Hz ,1H),1.12-1.30(m,14H),1.31-1.59(m,11H),1.63-1.82(m,6H),1.83-1.93(m ,2H),1.96-2.08(m,1H),2.09-2.32(m,5H),2.57(s,1H),2.81(d,J=14.0Hz,1 H),2.97-3.14(m,2H),4.90(d,J=13.6Hz,1H),4.97-5.11(m,2H),5.62(s,1H).

[0941] Example 19 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-10-((pyrrolidine-1-carbonyl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (208-2)

[0942]

[0943] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-10-((pyrrolidine-1-carbonyl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2,9-dicarboxylic acid 2-diphenylmethyl 9-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl) ester (208-1)

[0944] A solution of pyridine (10 mL) containing 194-8 (400 mg), pyrrolidine-1-carbonyl chloride (0.17 mL, 3 equivalents), and DMAP (62.7 mg, 1 equivalent) was stirred at 90 °C for 9 days. The reaction mixture was concentrated and the residue was dissolved in EtOAc. The solution was washed with 1 M HCl (3 × 50 mL) and brine (1 × 50 mL), dried over anhydrous Na2SO4, and concentrated to give 170 mg (38%) of 208-1 as a white solid.

[0945] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-10-((pyrrolidine-1-carbonyl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (208-2)

[0946] 208-1 (170 mg, 1 equivalent) and 10% TFA / CH2Cl2 (10 mL) were stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum and the residue was purified by preparative HPLC under the following conditions: – Column: Xselect CSH OBD, 30*150 mm, 5 m; Mobile phase: water (0.05% TFA) and CH3CN (68% phase B reached 80% within 8 minutes); Detector: UV. This yielded 9.5 mg (6.5%) of 208-2 as a white solid. MS (ES, m / z): [M+H] + =710.20; 1H NMR(400MHz,MeOH-d4)δ0.83(s,3H),0.94-0.99(m,1H),1.04(d,J=13.6Hz,1H),1.15(s,3H), 1.18(s,6H),1.21-1.27(m,6H),1.29-1.36(m,2H),1.38-1.41(m,3H),1.44(s,3H),1.57-1.6 1(m,1H),1.63-1.79(m,6H),1.87(s,6H),1.95(d,J=10.0Hz,1H),2.10-2.15(m,5H),2.56(s, 1H), 2.80 (d, J = 14.0Hz, 1H), 3.13-3.24 (m, 1H), 3.29 (s, 3H), 4.90-5.04 (m, 3H), 5.60 (s, 1H).

[0947] Example 20 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-(((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydro-2-carboxylic acid (209-3)

[0948]

[0949] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2,9-dicarboxylic acid 2-diphenylmethyl 9-((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl) ester (209-1)

[0950] 4-(bromomethyl)-5-isopropyl-1,3-m-dioxacyclopenten-2-one was prepared according to a literature procedure (Sun et al., Tetrahedron Letters, 2002, 43, 1161-1164). A mixture of 2.7 g (1.5 equivalents) of 4-(bromomethyl)-5-isopropyl-1,3-m-dioxacyclopenten-2-one, 3.4 g (3 equivalents) of K₂CO₃, 0.68 g (0.5 equivalents) of KI, and 5.5 g (1 equivalent) of 194-7 in DMF (80 mL) was stirred at 60 °C for 1 hour. The reaction mixture was cooled to room temperature and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography with elution of petroleum ether:EtOAc in a 3:1 ratio to give 209-1 (5.5 g, 83%) as a pale yellow solid. MS (ES, m / z): [M+1] + =806.95; 1 ¹H NMR (400MHz, chloroform-d) δ 7.48–7.28 (m, 10H), 6.95 (s, 1H), 5.54 (s, 1H), 5.07 (d, J = 13.8 Hz, 1H), 4.83 (d, J = 13.8 Hz, 1H), 4.10–3.93 (m, 1H), 3.11–2.94 (m, 2H), 2.94–2.82 (m, 2H), 2.40 (s, 1H), 2.17 –1.93(m,5H),1.91–1.53(m,7H),1.48(d,J=10.6Hz,2H),1.43–1.31(m,6H),1.31–1.22(m,8H) ,1.22–1.11(m,12H),1.08(s,3H),1.00(d,J=13.7Hz,1H),0.90(t,J=10.1Hz,1H),0.67(s,3H).

[0951] Synthesize (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2,9-dicarboxylic acid 2-diphenylmethyl 9-((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl) ester (209-2).

[0952] Add 100 mg (0.12 mmol) of 209-1, 2 mL of CH2Cl2, 29 mg (0.24 mmol, 1.9 equivalences) of DMAP, and 21.2 mg (0.35 mmol, 2.85 equivalences) of AcOH to an 8 mL round-bottom flask, followed by 57 mg (0.3 mmol, 2.4 equivalences) of EDCI. Stir the reaction mixture overnight at room temperature. Concentrate the reaction mixture and feed the residue onto a silica gel column coated with ethyl acetate / petroleum ether (1:1) to give 60 mg (57%) of 209-2 as a white solid.

[0953] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-(((5-isopropyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (209-3)

[0954] Add 209-2 (60 mg, 0.07 mmol), CH2Cl2 (5 mL), and TFA (0.5 mL, 6.7 mmol, 95 equivalence) to a 25 mL round-bottom flask. Stir the reaction slurry at room temperature for 1 hour. Concentrate the resulting mixture and purify the crude product by preparative HPLC under the following conditions: column, XSelect CSH Prep C18 OBD, 5 μm, 19 x 150 mm; mobile phase, water (0.05% TFA) and CH3CN (70% phase B reaches 90% within 8 minutes); detector, UV. This yielded 29.6 mg (61%) of 209-3 as a white solid. The product was tested in the assay described in Example 112, with pIC... 50 Compared to the corresponding acid metabolite (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(acetoxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid, this product exhibits a pIC50 of 7.2. MS (ES, m / z): [M+1] + =683; 1¹H NMR (300 MHz, methanol-d⁴) δ 0.85 (s, 3H), 0.95 (s, 1H), 1.07 (d, J = 13.8 Hz, 1H), 1.18 (d, J = 13.4 Hz, 8H), 1.22–1.34 (m, 9H), 1.45 (d, J = 12.8 Hz, 6H), 1.65–1.83 (m, 5H), 1.88 (dd, J = 12.1, 4.9 Hz, 1H) ),1.96(s,3H),2.09–2.29(m,2H),2.58(s,1H),2.83(d,J=13.7Hz,1H),3.07(h,J=6.9Hz,1H ),4.89(d,J=13.9Hz,1H),5.07(d,J=13.9Hz,1H),5.16(dd,J=11.4,5.2Hz,1H),5.62(s,1H).

[0955] Example 21 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-10-(propionyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (211-1)

[0956]

[0957] The title compound was prepared according to the method used for compound 194-10, starting with 194-8 and propionic acid. The crude product was purified by preparative HPLC under the following conditions: column, X Select CSH OBD, 30*150 mm, 5 μm; mobile phase, water (0.05% TFA) and CH3CN (60% phase B reached 85% within 8 min); detector, UV. 69.7 mg 211-1 was obtained as a white solid. MS (ES, m / z): [M+1] + =669; 1H NMR (300MHz, chloroform-d) δ5.72(s,1H),5.22–5.11(m,1H),4.96(d,J=13.8Hz,1H),4.72(d,J=13.8Hz,1H),2.86(d,J=13.9Hz,1H),2.45(s,1H),2.32– 2.16(m,6H),1.99(s,3H),1.79(s,5H),1.70(d,J=9.9Hz,2H),1.39(s,4 H),1.24(s,3H),1.19(d,J=9.0Hz,12H),1.14–1.03(m,6H),0.83(s,4H).

[0958] Example 22 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopentanecarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (212-1)

[0959]

[0960] The title compound was prepared according to the method used for compound 194-10, starting with 194-8 and cyclopentanoic acid. The crude product was purified by preparative HPLC under the following conditions: column, Kinetex EVO C18, 21.2 x 150; 5 μm; mobile phase, water (0.05% TFA) and CH3CN (70% phase B reached 88% within 8 min); detector, UV. This yielded 66.3 mg 212-1 as a white solid. MS (ES, m / z): [M+1] + =709; 1 H NMR (300MHz, chloroform-d) δ5.72 (s, 1H), 5.14 (dd, J = 10.5, 6.3Hz, 1H), 4.94 (d, J = 13 .8Hz,1H),4.71(d,J=13.8Hz,1H),2.86(d,J=14.0Hz,1H),2.64(q,J=8.0,7.5 Hz,1H),2.44(s,1H),2.18(s,4H),1.99(s,3H),1.82(d,J=8.5Hz,14H),1.39( s,7H),1.27–1.14(m,13H),1.11(s,1H),1.03(d,J=12.7Hz,1H),0.83(s,4H).

[0961] Example 23 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-10-((3-(piperidin-1-yl)propionyl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (215-1)

[0962]

[0963] The title compound was prepared according to the method used for compound 194-10, starting with 194-8 and 3-(piperidin-1-yl)propionic acid. The crude product was purified by preparative HPLC under the following conditions: column, Xselect CSH OBD column 30*150mm 5µm,n; mobile phase, water (0.05% TFA) and ACN (40% phase B reached 53% within 8 min); detector, UV 254nm. This yielded 35.2 mg (33%) 215-1, as a white solid. MS (ES, m / z): [M+1] + =752.43; 1 H NMR (300MHz, chloroform-d) δ11.9(s,1H),5.71(s,1H),5.16(s,1H),4.86(d,J=4.5Hz,2H),3.56(s,3H),3.27(s,6H),2.88(d,J=17.7Hz,3H),2.66(s,2H) ,2.20(s,5H),1.98(s,4H),1.88(d,J=14.0Hz,5H),1.61(d,J=12.0Hz,7 H),1.39(d,J=6.4Hz,9H),1.26–1.14(m,16H),1.12(s,2H),0.82(s,3H).

[0964] Example 24 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((isopropoxycarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (216-2)

[0965]

[0966] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((isopropoxycarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2,9-dicarboxylic acid 2-diphenylmethyl 9-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl) ester (216-1)

[0967] Add 194-8 (200 mg, 0.26 mmol), pyridine (3 mL), DMAP (94.1 mg, 0.77 mmol, 3 equivalents), and isopropyl chloroformate (315 mg, 2.6 mmol, 10 equivalents) to an 8 mL sealed tube at room temperature. Stir the reaction slurry at 60 °C under a nitrogen atmosphere for 6 hours. Add one part of isopropyl chloroformate (315 mg, 2.6 mmol, 10 equivalents) to the mixture at 60 °C. Stir the reaction slurry again at 60 °C for 6 hours. Add a third part of isopropyl chloroformate (315 mg, 2.6 mmol, 10 equivalents) to the reaction mixture at 60 °C. Stir the reaction slurry again at 60 °C for 6 hours, and then concentrate the reaction mixture under vacuum. Purify the residue by preparative TLC (PE / EtOAc 1:1) to give 216-1 (130 mg, 59%) as a pale yellow foam.

[0968] Synthesize (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((isopropoxycarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (216-2).

[0969] Add 130 mg (0.15 mmol, 1 equivalent) of 216-1, 2 mL of CH2Cl2, and 0.2 mL of TFA to a 25 mL round-bottom flask. Stir the resulting solution at room temperature for 30 minutes. Concentrate the resulting mixture. Purify the crude product by preparative HPLC under the following conditions: column, Xselect CSH OBD 30*150 mm, 5 μm; mobile phase, water (0.05% TFA) and CH3CN (64% phase B reaches 87% within 8 minutes); detector, UV. This yielded 40.9 mg (39%) of 216-2 as a white solid. MS (ES, m / z): [M+1] + =698.37; 1 H NMR (400MHz, chloroform-d) δ7.38 (dd, J=17.4, 5.5Hz, 1H), 5.75 (s, 1H), 5.14–4.93 (m, 2H), 4.87–4.7 5(m,2H),2.90(d,J=13.8Hz,1H),2.45(s,1H),2.21(s,4H),2.11–1.90(m,4H),1.87–1.76(m, 3H),1.65(dd,J=12.4,6.5Hz,5H),1.57–1.32(m,9H),1.28(dd,J=6.3,3.4Hz,7H),1.25(d,J= 6.9Hz,7H),1.19(d,J=5.5Hz,5H),1.13(s,4H),1.10–1.00(m,2H),0.85(s,5H),0.09(s,3H).

[0970] Example 25 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,2-difluoroacetoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (223-1)

[0971]

[0972] The title compound was prepared according to the method used for compound 194-10, starting with 194-8 and 2,2-difluoroacetic acid. The crude product was purified by preparative HPLC under the following conditions: column: Xselect CSH OBD 30*150mm, 5m; mobile phase: water (0.05% TFA) and CH3CN (68% phase B reached 80% within 8 min); detector: UV. This yielded 82.1 mg (46%) of 223-1 as a white solid. MS (ES, m / z): [M+H] + =691.15; 1 H NMR(400MHz,MeOH-d4)δ0.83(s,3H),0.97(d,J=7.6Hz,1H),1.05(d,J=13.6Hz,1H),1.14(s,3H),1 .18(d,J=8.4Hz,6H),1.22-1.31(m,5H),1.40(s,4H),1.45(s,3H),1.64-1.80(m,5H),1.82-1.90( m,3H),1.92-2.00(m,1H),2.09-2.29(m,5H),2.57(s,1H),2.88(d,J=10.4Hz,1H),4.88(d,J=14.0 Hz,1H),5.02(d,J=14.0Hz,1H),5.33(dd,J=14.0,5.2Hz,1H),5.61(s,1H),6.05(t,J=53.2Hz,1H).

[0973] Example 26 (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-9-((2-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)-2-oxoethoxy)methyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (240-8)

[0974]

[0975] Synthesize (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-9-((2-(tert-butoxy)-2-oxoethoxy)methyl)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid benzyl ester (240-1).

[0976] Sodium bis(trimethylsilyl)amino (0.5 mL, 2 equivalents) was added to a DMF (5 mL) solution of 121-1 (355 mg, 0.62 mmol, 1 equivalent) and tert-butyl 2-bromoacetate (240.6 mg, 1.24 mmol, 2 equivalents). The reaction slurry was stirred overnight at room temperature, diluted with CH2Cl2 (100 mL), washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column elution with EtOAc / petroleum ether (1:1) to give 300 mg (71%) of 240-1 as a white solid.

[0977] Synthesize 2-(((3S,4R,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-3-hydroxy-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-eicosyl-4-yl)methoxy)acetic acid (240-2)

[0978] 240-1 (300 mg, 0.43 mmol, 1 equivalent) and TFA (1 mL) were mixed in CH2Cl2 (10 mL) at room temperature for 1 hour. The reaction mixture was diluted with CH2Cl2 (100 mL), washed with brine (3 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. This yielded 270 mg (98%) of 240-2 as a yellow solid.

[0979] Synthesize (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-9-((2-methoxy-2-oxoethoxy)methyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid benzyl ester (240-3).

[0980] (Trimethylsilyl)diazomethane (1 mL) was added dropwise to a solution of 240-2 (270 mg, 0.43 mmol, 1 equivalent) of MeOH (5 mL) and CH2Cl2 (10 mL). The reaction slurry was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give 260 mg (94%) of 240-3 as a white solid.

[0981] Synthesis of (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-9-((2-methoxy-2-oxoethoxy)methyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydro-2-carboxylic acid (240-4)

[0982] A solution of 240-3 (270 mg, 0.42 mmol) and Pd / C (20 mg, 10% wt) in EtOAc (30 mL) was stirred in H2 (1 atm) for 2 hours. The reaction mixture was filtered and concentrated to give 216 mg (93%) of 240-4 as a white solid.

[0983] Synthesize (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-9-((2-methoxy-2-oxoethoxy)methyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2-carboxylic acid diphenyl methyl ester (240-5).

[0984] A solution of (diazomethylene)diphenyl (180 mg) in MeOH (20 mL) was added to a solution of 240-4 (216 mg, 1 equivalent) in diethyl ether (10 mL). The reaction slurry was stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography with EtOAc / petroleum ether (1:10) to give 220 mg (79%) of 240-5 as a white solid.

[0985] Synthesize 2-(((3S,4R,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((diphenylmethyloxy)carbonyl)-3-hydroxy-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-eicosyl-4-yl)methoxy)acetic acid (240-6)

[0986] 240-5 (220 mg, 0.30 mmol, 1 equivalent) and lithium hydroxide (73 mg, 3 mmol, 10 equivalent) were mixed in THF (10 mL), H2O (1 mL), and MeOH (1 mL) and stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 4 with 1 M HCl and extracted with CH2Cl2 (2 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give 200 mg (93%) of 240-6 as a white solid.

[0987] Synthesize (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-9-((2-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)-2-oxoethoxy)methyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid diphenyl methyl ester (240-7).

[0988] 240-6 (200 mg, 0.28 mmol, 1 equivalent), 4-(chloromethyl)-5-methyl-2H-1,3-m-dioxane-2-one (84 mg, 0.57 mmol, 2 equivalents), K2CO3 (194 mg, 1.40 mmol, 5 equivalents), and potassium iodide (70 mg, 0.42 mmol, 1.5 equivalents) were mixed in DMF (10 mL) and stirred at 50 °C for 1 hour. The reaction mixture was diluted with CH2Cl2 (100 mL), washed with brine (3 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 200 mg (86%) of 240-7 as a white solid.

[0989] Synthesize (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-9-((2-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)-2-oxoethoxy)methyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (240-8)

[0990] 240-7 (200 mg, 0.24 mmol, 1 equivalent) and TFA (1 mL) were mixed in CH2Cl2 (10 mL) and stirred for 1 hour. The solid was collected by filtration. The resulting mixture was concentrated and the residue was purified by preparative HPLC under the following conditions: - Mobile phase: water (0.05% TFA) and CH3CN (5% phase B for 0 min, 63% for 1 min, and 68% for 8 min); Detector: UV. This yielded 14.5 mg (9%) of 240-8 as a white solid. MS (ES, m / z): [M+H] + =657.25; 1 ¹H NMR (400 MHz, chloroform-d) δ 0.72 (s, 3H), 0.86 (s, 3H), 1.03 (t, J = 15.2 Hz, 2H), 1.13–1.22 (m, 9H), 1.22–1.37 (m, 2H), 1.43 (d, J = 5.6 Hz, 8H), 1.66–1.97 (m, 8H), 2.21 (s, 5H), 2 .51(s,1H),2.73(d,J=13.6Hz,1H),3.39(s,2H),3.72(dd,J=11.8,4.8Hz,1H),4.0 9(d,J=16.8Hz,1H),4.26(d,J=16.8Hz,1H),4.92(s,1H),5.03(s,2H),5.60(s,1H).

[0991] Example 27 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (243-1)

[0992]

[0993] The title compound was prepared according to the method used for compound 194-10, starting with 194-8 and acetic acid. The crude product was purified by preparative HPLC under the following conditions: – Column: XSelect CSH Prep C18 OBD, 5m, 19*150mm; Mobile phase: water (0.05% TFA) and CH3CN (5% phase B held for 0 min, 65% for 1 min, and 85% for 8 min); Detector: UV. This yielded 24.7 mg (20%) of 243-1 as a white solid. MS (ES, m / z): [M+H] + =655.15; 1H NMR (400MHz, methanol-d4) δ0.85 (s, 3H), 0.96 (d, J = 5.6Hz, 1H), 1.06 (d, J = 14.1Hz, 1H) ,1.16–1.29(m,14H),1.36–1.49(m,7H),1.63–1.80(m,6H),1.80–1.92(m,2H),1 .92–2.01(m,4H),2.08–2.08(m,5H),2.55(s,1H),2.78–2.86(m,1H),4.89(d,J= 13.9Hz, 1H), 5.03 (d, J = 14.0Hz, 1H), 5.15 (dd, J = 11.7, 4.9Hz, 1H), 5.62 (s, 1H).

[0994] Example 28 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2-hydroxyacetoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (244-1)

[0995]

[0996] The title compound was prepared according to the method used for compound 194-10, starting with 194-8 and 2-[(4-methoxyphenyl)methoxy]acetic acid. The crude product was purified by preparative HPLC under the following conditions: – Column: XBridge Prep C18OBD, 19*150mm, 5m; Mobile phase: water (0.05% TFA) and CH3CN (35% phase B reached 90% within 7 min); Detector: UV. This yielded 25.8 mg (28%) of 244-1 as a white solid. MS (ES, m / z): [M+H] + =671.35; 1 H NMR (400MHz, methanol-d4) δ0.85 (s, 3H), 0.95 (s, 1H), 1.06 (d, J = 14.0Hz, 1H), 1.15 (s, 3H),1.17–1.27(m,10H),1.27(d,J=8.0Hz,1H),1.33–1.524(m,7H),1.61–2.00(m ,9H),2.20(s,5H),2.58(s,1H),2.80–2.88(m,1H),3.96–4.11(m,2H),4.87(d,J =13.9Hz, 1H), 5.06 (d, J = 14.0Hz, 1H), 5.26 (dd, J = 11.7, 5.0Hz, 1H), 5.62 (s, 1H).

[0997] Example 29 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2-methoxyacetoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (245-1)

[0998]

[0999] The title compound was prepared according to the method used for compound 194-10, starting with 194-8 and 2-methoxyacetic acid. The crude product was purified by preparative HPLC under the following conditions: – Column: XSelect CSH Prep C18 OBD, 5m, 19*150mm; Mobile phase: water (0.05% TFA) and CH3CN (holds 5% phase B within 0 min, reaches 62% within 1 min, and 82% within 8 min); Detector: UV. This yielded 25.9 mg (19%) 245-1, as a white solid. MS (ES, m / z): [M+H]+ =685.15; 1 H NMR (400MHz, methanol-d4) δ0.85 (s, 3H), 1.06 (d, J = 14.1Hz, 1H), 1.00–1.10 (m, 1H), 1.10–1.30(m,14H),1.35–1.51(m,7H),1.61–2.08(m,9H),2.09–2.28(m,5H),2 .59(s,1H),2.80–2.88(m,1H),3.39(s,3H),3.97(d,J=1.3Hz,2H),4.88(d,J=1 4.0Hz,1H),5.05(d,J=13.9Hz,1H),5.27(dd,J=11.8,5.0Hz,1H),5.62(s,1H).

[1000] Example 30 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxadodecanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydro-2-carboxylic acid (246-3)

[1001]

[1002] Synthesis of 2-(2-(2-methoxyethoxy)ethoxy)ethyl(4-nitrophenyl)carbonate (246-1)

[1003] A solution of 2-[2-(2-methoxyethoxy)ethoxy]ethane-1-ol (3.0 g, 18.3 mmol, 1 equivalent), p-nitrobenzene chloroformate (4.4 g, 20.4 mmol, 1.1 equivalent), and Et3N (5 mL, 36 mmol, 2 equivalent) in CH2Cl2 (20 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography with EtOAc / petroleum ether (1:1) to give 4.2 g (67%) of 246-1 as a clear liquid.

[1004] Synthesize (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxadodecanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2,9-dicarboxylic acid 2-diphenylmethyl 9-((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl) ester (246-2)

[1005] A solution of 194-8 (150 mg, 0.19 mmol, 1 equivalent), 246-1 (640 mg, 1.9 mmol, 10 equivalents), and DMAP (94 mg, 0.77 mmol, 4 equivalents) in THF (8 mL) was stirred at 50 °C for 24 hours. The reaction mixture was diluted with CH2Cl2 (300 mL), washed with brine (3 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by elution with EtOAc / petroleum ether (1:1) through a silica gel column to give 156 mg (84%) of 246-2 as a yellow oil.

[1006] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxadodecanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (246-3)

[1007] A solution of 246-2 (156 mg, 0.16 mmol, 1 equivalent) and TFA (1 mL) in CH2Cl2 (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by preparative HPLC under the following conditions: column, XBridgePrep C18 OBD, 19*150 mm, 5 μm; mobile phase: water (0.05% TFA) and CH3CN (35% phase B reached 90% within 7 min); detector: UV. This yielded 21.5 mg (16%) of 246-3 as a white solid. MS (ES, m / z): [M+H] + =803.20; 1H NMR (400MHz, methanol-d4) δ0.85 (s, 3H), 0.98 (d, J = 9.2Hz, 1H), 1.06 (d, J = 14.1Hz, 1H) ,1.13–1.25(m,14H),1.44(d,J=18.2Hz,7H),1.61–1.93(m,8H),1.97(d,J=9.6H z,1H),2.11–2.37(m,5H),2.58(s,1H),2.81–2.89(m,1H),3.38(s,3H),3.52–3. 61(m,2H),3.61–3.73(m,8H),4.12–4.30(m,2H),4.91–5.07(m,3H),5.62(s,1H).

[1008] Example 31 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosylhydrocarboxylic acid (249-5)

[1009]

[1010] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-eicosyl-2,9-dicarboxylic acid 2-diphenylmethyl-9-methyl ester

[1011] (249-1) (trimethylsilyl)diazomethane (1 mL) was added to a solution of 194-7 (200 mg, 0.30 mmol, 1 equivalent) in...

Claims

1. A compound of formula I or a salt thereof: in, X is a bond, -O- or -N(R x )-; L is a bond or a C1-C6 alkylene group; W is O; Q is C1-C6 alkylene; R1 is H or C1-C6 alkyl; V is -C(O)O- or -C(O)N(R5)-; R2 is H; R3 is absent or is a C1-C6 alkyl group; R4 does not exist and is H, OH, =O, -R6, -O-R6, -C(O)O-R6, -OC(O)-R6, - OC(O)-O-R6, -OC(O)-NR5R6, -NR5R6, -NR5-C(O)-R6, -NR5-C(O)-O-R6, -NR5-SO2-R6 or =NO-R5; R5 is H or C1-C6 alkyl; R6 is H, C1-C6 alkyl, carbocycle or heterocycle, wherein the C1-C6 alkyl, the carbocycle and the heterocycle are optionally substituted by halogen, OH, SH, C1-C6 alkylthio, -S(O)-C1-C6 alkyl, -SO2-C1-C6 alkyl, amino, -NHC(O)-C1-C6 alkyl, oxo, C1-C6 alkyl, carboxyl, acyl, acyloxy, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, carbocycle optionally substituted by C1-C6 alkyl or heterocycle optionally substituted by C1-C6 alkyl; and wherein one or more non-adjacent methylene groups in each of the C1-C6 alkyl groups of R6 are optionally replaced by -O- or -S-; R x is H; and in: The carbocyclic ring has 3 to 6 carbon atoms, and The heterocyclic ring has 5 to 14 ring atoms, wherein the ring atoms are carbon and 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur.

2. The compound or salt thereof according to claim 1, wherein the compound has structure Ib or Ic:

3. The compound or salt thereof according to claim 1, wherein V is -C(O)-O-.

4. The compound or salt thereof according to claim 1, wherein R1 is methyl, ethyl or isopropyl. The compound or a salt thereof according to claim 1 , wherein X and L are both bonds. The compound or salt thereof according to claim 1, wherein R3 is methyl.

7. The compound or salt thereof according to claim 1, wherein R4 is -OC(O)-R6 and R6 is C1-C6 alkyl, carbocycle or heterocycle; wherein the C1-C6 alkyl is optionally substituted by hydroxyl, halogen, carboxyl, C1-C6 alkoxy, C1-C6 alkylthio, amino, NHC(O)-C1-C6 alkyl, heterocycle optionally substituted by C1-C6 alkyl; and the carbocycle and the heterocycle are optionally substituted by halogen, hydroxyl and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted by hydroxyl, halogen, carboxyl; and wherein one or more non-adjacent methylene groups are replaced by -O-.

8. The compound or salt thereof according to claim 1, wherein R4 is NH2, C1-C6 alkoxy or OH.

9. The compound or salt thereof according to claim 1, wherein R4 is R6 and R6 is phenyl optionally substituted by C1-C6 alkoxy.

10. The compound or salt thereof according to claim 1, wherein R4 is R6 and R6 is a heterocycle optionally substituted by halogen, C1-C6 alkyl, oxo and C1-C6 alkoxycarbonyl.

11. The compound or salt thereof according to claim 1, wherein R4 is -NHC(O)-R6.

12. The compound or salt thereof according to claim 1, wherein R4 is -NHC(O)-O-R6.

13. The compound or salt thereof according to claim 1, wherein R4 is -OC(O)-O-R6.

14. The compound or salt thereof according to claim 1, wherein R4 is O-R6.

15. The compound or salt thereof according to claim 1, wherein R4 is -NR5R6.

16. The compound or salt thereof according to claim 1, wherein R4 is -OC(O)-R6 and R6 is methyl, ethyl or cyclopropyl.

17. A compound or a salt thereof, wherein the compound is selected from: (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2,9-dicarboxylic acid (122-3); (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (176-2); (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(((5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (178-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(2-(methylthio)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (194-10); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(2-(methylsulfonyl)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (195-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((L-valyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (196-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(benzoyloxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (197-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopropanecarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (198-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((R)-2-methoxypropanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (203-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((S)-2-methoxypropanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (204-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(methoxymethoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (205-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((ethylcarbamoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (206-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((butylcarbamoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (207-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-((pyrrolidine-1-carbonyl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (208-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (209-3); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-(propionyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (211-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopentanecarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentahydro-2-carboxylic acid (212-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-((3-(piperidin-1-yl)propanoyl)oxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (215-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((isopropoxycarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (216-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,2-difluoroacetyloxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (223-1); (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-9-((2-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)-2-oxoethoxy)methyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (240-8); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (243-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2-hydroxyacetoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (244-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2-methoxyacetoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (245-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxadodecanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoyl-2-carboxylic acid (246-3); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (249-5); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (252-2); (2S,4aS,6aS,6bR,8aR,9R,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (253-4); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (254-3); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-((((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (255-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,2-difluoroacetyloxy)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (256-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(methoxymethoxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (258-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxatetradecane-14-yl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (264-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxatetradecane-14-yl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (265-2); (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-(2-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)-2-oxoethoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (279-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-amino-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (280-7); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((methoxycarbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (281-3); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-(pentanoyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (282-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(2-(4-methylpiperazin-1-yl)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (283-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-((3-morpholinopropanoyl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (284-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(methylsulfonylamino)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (285-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(((2-morpholinoethyl)carbamoyl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (286-4); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(2-(methylsulfinyl)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (289-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((dimethylglycyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (290-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((acetylglycyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (291-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetamido-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid; (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(allyloxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (297-5); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(3-methoxy-3-oxopropionylamino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (298-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4-methoxy-4-oxobutyrylamino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (299-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((butoxycarbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (300-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-((methoxycarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (301-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (302-3); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (307-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(2-methoxyacetoxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (308-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,2-difluoroacetylamino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (309-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopropanecarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (314-4); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopropanecarbonyl)oxy)-9-((((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (315-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-(((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (316-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-13-oxo-10-(propionyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (317-6); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-((((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-10-(propionyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (318-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-13-oxo-10-(propionyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (319-1); (3S,4S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-4-((((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-4,6a,6b,8a,11,14b-hexamethyl-11-(methylcarbamoyl)-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosapent-3-ylpropanoate (320-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((cyclopropanecarbonyl)oxy)-9-((((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (321-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-13-oxo-10-propoxy-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (322-6); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-((((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-10-propoxy-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (323-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-9-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (324-3); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-((((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (325-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-((((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (326-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4,4-difluoropiperidin-1-yl)-9-((((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (327-8); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-acetoxy-9-((((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (326-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4,4-difluoropiperidin-1-yl)-9-((((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (327-8); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-(1H-pyrrol-1-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (328-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-(1H-pyrazol-1-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid; (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-10-(1H-pyrazol-1-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (330-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-(5-methyl-1H-pyrazol-1-yl)-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (331-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-(3-methyl-1H-pyrazol-1-yl)-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (332-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-((((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-10-(propionyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (333-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (334-8); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (335-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(5-(ethoxycarbonyl)-3-methyl-1H-pyrazol-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (336-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (337-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-(4-methyl-1H-pyrazol-1-yl)-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (338-4); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-10-(4-methyl-1H-pyrazol-1-yl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (339-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (341-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2-amino-2-oxoethyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (342-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2-methoxy-2-oxoethyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (343-3); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(allyl(2-methoxy-2-oxoethyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (344-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((S)-1-methoxy-1-oxopropyl-2-yl)amino)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (345-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(1-methylcyclopropane-1-carboxamido)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (346-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-(2-oxopyrrolidin-1-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (347-4); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-((S)-2-(methoxycarbonyl)pyrrolidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (348-11); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((S)-2-(methoxycarbonyl)pyrrolidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (349-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-((S)-2-(methoxycarbonyl)pyrrolidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (350-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-((R)-2-(methoxycarbonyl)pyrrolidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (351-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((S)-2-(ethoxycarbonyl)pyrrolidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (352-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((R)-2-(ethoxycarbonyl)pyrrolidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (353-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-10-(piperidin-1-yl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (356-2); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4,4-difluoropiperidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (357-7); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((R)-3-(ethoxycarbonyl)pyrrolidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (358-7); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((R)-3-(ethoxycarbonyl)piperidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (359-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((S)-3-(ethoxycarbonyl)piperidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (360-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4-(ethoxycarbonyl)piperidin-1-yl)-9-(((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (361-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(4-(ethoxycarbonyl)piperidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (362-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-acetamido-2,4a,6a,6b,9,12a-hexamethyl-10-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (363-5); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-acetamido-2,4a,6a,6b,9,12a-hexamethyl-10-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)oxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (363-5); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-((R)-5-methyl-2-oxooxazolidin-3-yl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (364-5); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,5-dioxoimidazolidin-1-yl)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (365-8); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-((R)-4-methyl-2,5-dioxoimidazolidin-1-yl)-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (366-1); 2-(3-((1-PEG 5K 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)(2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxatetradecane-14-yl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2,9-dicarboxylate (605-2); (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-{[(2-oxo-1,3-dioxolan-4-yl)methoxy]carbonyl}-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (Compound 700-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-10-{[2-(methylsulfanyl)acetyl]oxy}-13-oxo-9-({[2-oxo-5-(propan-2-yl)-2H-1,3-dioxol-4-yl]methoxy}carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (Compound 701-1); (2S,4aS,6aS,6bR,8aR,9S,10R,12aS,12bR,14bR)-10-(acetoxy)-2,4a,6a,6b,9,10,12a-heptamethyl-13-oxo-9-({[2-oxo-5-(propan-2-yl)-2H-1,3-dioxol-4-yl]methoxy}carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (Compound 702-1); (2S,4aS,6aS,6bR,8aR,9S,10R,12aS,12bR,14bR)-10-(acetyloxy)-9-{[(5-ethyl-2-oxo-2H-1,3-dioxol-4-yl)methoxy]carbonyl}-2,4a,6a,6b,9,10,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (Compound 703-1); (2S,4aS,6aS,6bR,8aR,9S,10R,12aS,12bR,14bR)-10-(acetyloxy)-2,4a,6a,6b,9,10,12a-heptamethyl-9-{[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methoxy]carbonyl}-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (Compound 704-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(acetyloxy)-9-{[(5-tert-butyl-2-oxo-2H-1,3-dioxol-4-yl)methoxy]carbonyl}-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (Compound 705-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(acetyloxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-9-{[(2-oxo-5-propyl-2H-1,3-dioxol-4-yl)methoxy]carbonyl}-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (Compound 706-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(acetyloxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-9-{[(2-oxo-5-phenyl-2H-1,3-dioxol-4-yl)methoxy]carbonyl}-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (Compound 707-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-[(2-methoxyacetyl)oxy]-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-9-({[2-oxo-5-(propan-2-yl)-2H-1,3-dioxol-4-yl]methoxy}carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (Compound 708-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-[(2-methoxyacetyl)oxy]-2,4a,6a,6b,9,12a-hexamethyl-9-{[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methoxy]carbonyl}-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (Compound 709-1); (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-10-(2-oxo-2-{[2-oxo-5-(2,5,8-trioxa-11-thiadodecane-12-yl)-2H-1,3-dioxol-4-yl]methoxy}ethoxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid (Compound 710-1); (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-(2-{[5-(hydroxymethyl)-2-oxo-2H-1,3-dioxol-4-yl]methoxy}-2-oxoethoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (Compound 711-1); (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-{2-[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methoxy]-2-oxoethoxy}-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (Compound 712-1); and (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-[4-(ethoxycarbonyl)-5-methoxy-1H-pyrazol-1-yl]-2,4a,6a,6b,9,12a-hexamethyl-9-{[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methoxy]carbonyl}-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (Compound 713-1). 18 . Use of the compound or salt thereof according to claim 1 in the preparation of a medicament for inhibiting the conversion of cortisol to corticosterone via 11β-HSD2.

19. Use of a compound according to any one of claims 1 to 17 or a salt thereof for the preparation of a medicament for treating a disease or condition mediated by the conversion of Cortisol to corticosterone via 11β-HSD2.

20. Use of the compound or salt thereof according to any one of claims 1 to 17 for preparing a medicament for promoting secretion of potassium ions into the colon lumen of a mammal.

21. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 17 and a pharmaceutically acceptable carrier, diluent or excipient.

22. Use of a compound according to any one of claims 1 to 17 in the preparation of a medicament for treating a condition, disease or disorder mediated by 11[beta]-HSD2.

23. Use of a compound according to any one of claims 1 to 17 in the preparation of a medicament for the treatment of hyperkalemia.

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