Glycyrrhetinic acid derivatives for treatment of hyperkalemia

Abstract

The present invention provides compounds of Formula (I) or salts thereof: (Formula (I)) wherein X, L, V, R1, R2, R3 and R4 are as defined herein. The claimed compounds inhibit the enzyme type 2 11-hydroxysteroid dehydrogenase (11-HSD2) and thus stimulate potassium excretion by preventing cortisol from being oxidized to corticosterone and thus making it occupy the mineralocorticoid receptor, and are useful in the treatment of hyperkalemia. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese patent application No. 202080023794.7 (application date: February 6, 2020, invention name: Glycyrrhetinic acid derivatives for the treatment of hyperkalemia).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 62 / 802,210, filed February 7, 2019. The entire contents of the above-referenced application are incorporated herein by reference. Technical Field

[0004] The present invention relates to compounds that inhibit 11β-hydroxysteroid dehydrogenase 2 and methods of using these compounds to eliminate potassium from the gastrointestinal tract, including methods of treating hyperkalemia. Background Art

[0005] Potassium is the most abundant cation in intracellular fluid and plays a crucial role in normal human physiology, particularly in the firing 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 approximately 3500 mmol of potassium in a 70 kg adult. Most of the body's potassium is intracellular (~98%), with only approximately 70 mmol (~2%) confined to the extracellular space. This large difference between intracellular potassium (~120-140 mmol / L) and extracellular potassium (~4 mmol / L) largely determines the cell's resting membrane potential. Therefore, even very small absolute changes in extracellular potassium concentration can have a significant impact on this ratio and, therefore, on the function of excitable tissues (muscles and nerves). Therefore, extracellular potassium levels are tightly regulated.

[0006] Two independent yet collaborative systems are involved in the regulation of potassium homeostasis: one regulates external potassium balance (the body's balance between potassium intake and potassium elimination), while the other regulates internal potassium balance (distribution between intracellular and extracellular fluid compartments). The intracellular / extracellular balance 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 by the energy of ATP hydrolysis against the Na + and K + Almost all cells have Na + , K + -ATPase. The body's potassium balance is controlled by elimination mechanisms via the kidneys and the gastrointestinal tract: in healthy kidneys, 90%-95% of the daily potassium load is excreted by the kidneys, the remainder is eliminated in the feces.

[0007] Since the intracellular / extracellular potassium ratio (K i :K e ratio) is the main determinant of the cell's resting membrane potential, so K e Small changes in potassium (i.e., serum [K]) can have profound effects on the function of electrically active tissues such as muscles and nerves. Potassium and sodium ions drive action potentials in nerve and muscle cells by actively crossing the cell membrane and changing the membrane potential, which is the electrical potential difference between the outside and inside of the cell. In addition to active transport, K + It can also move passively between the extracellular and intracellular compartments. Passive K + Transporter overload depolarizes membranes in the absence of stimulation. Excess serum potassium, termed hyperkalemia, disrupts the membrane potential in cardiomyocytes that regulate ventricular conduction and contraction. Clinically, the effects of hyperkalemia on cardiac electrophysiology are of greatest concern because they can lead to arrhythmias and death. Because the majority of body potassium is maintained through renal excretion, it is expected that the ability to control systemic potassium will be impaired as renal function declines.

[0008] Hyperkalemia is defined as a serum potassium level above the normal range, usually >5.0 mmol / L. Moderate hyperkalemia (serum potassium above 6.0 mEq / L) has been reported to have a 1-day mortality rate as high as 30 times that of patients with serum potassium below 5.5 mEq / L. Severe hyperkalemia (serum K+ of at least 6.5 mmol / L) is a potentially life-threatening electrolyte disturbance that has been reported in 1% to 10% of all hospitalized patients and constitutes a medical emergency requiring immediate treatment. Hyperkalemia is caused by insufficient potassium excretion, and because the kidneys are the primary mechanism of potassium excretion, hyperkalemia typically affects patients with kidney disease such as chronic kidney disease (CKD) or end-stage renal disease (ESRD). However, patients with normal renal function can also experience episodes of hyperkalemia, 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 CKD is the most common precipitating condition for hyperkalemia, the mechanisms driving hyperkalemia generally involve a combination of factors, such as increased dietary potassium intake, disturbances in potassium distribution between intracellular and extracellular compartments, and abnormal potassium excretion. These mechanisms can be modulated by a variety of factors that are causally independent of CKD. These include the presence of other comorbidities, such as type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), or the use of co-medications that may disrupt potassium homeostasis as a side effect, such as blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).

[0009] Serum potassium can be lowered through two general mechanisms: the first is by shifting potassium within cells through the use of agents such as insulin, albuterol, or sodium bicarbonate. The second is by excreting it from the body through one of four routes: feces, using potassium-binding resins such as sodium polystyrene sulfonate (NaPSS); urine, using diuretics; blood, using hemodialysis; or peritoneal fluid, using peritoneal dialysis. With the exception of NaPSS, medications used to treat hyperkalemia, such as insulin, diuretics, beta-agonists, and sodium bicarbonate, only cause hypokalemia as a side effect and are not suitable for long-term treatment. Definitive therapy requires removing potassium from the body. Studies have demonstrated that lowering serum potassium levels in patients with hyperkalemia actually reduces the risk of death, further solidifying the role of excess potassium in mortality risk. While NaPSS is the current standard of care for potassium reduction in the United States, the calcium salt of PSS (CaPSS) is also commonly used in other parts of the world, including in Europe (e.g., Resonium) and Japan.

[0010] Kayexalate / Na PSS is poorly tolerated, resulting in a high incidence of GI side effects, including nausea, vomiting, constipation, and diarrhea. In addition, Kayexalate (sodium polystyrene sulfonate) is a ground product composed of irregularly shaped particles ranging in size from about 1-150 μm and has sand-like properties in the human mouth: it produces a strong foreign body sensation on the palate when ingested, and this sensation is detrimental to patient compliance. Overall, the physical properties of Kayexalate and the associated side effects lead to poor compliance and make the drug suboptimal for long-term use. Due to these properties, there has been a long-standing need to provide an optimal medication for long-term use.

[0011] The mineralocorticoid receptor (or MR, MLR, MCR), also known as the aldosterone receptor or nuclear receptor subfamily 3 group C member 2 (NR3C2), is a protein encoded by the NR3C2 gene gene located on chromosome 4q31.1-31.2 in humans. The MR is a receptor with equal affinity for mineralocorticoids and glucocorticoids (including cortisol). It belongs to the nuclear receptor family, in which ligands diffuse into 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 kidney, colon, heart, central nervous system (hippocampus), brown adipose tissue, and sweat glands. Activation of the mineralocorticoid receptor in epithelial tissues by the ligands aldosterone and cortisol promotes potassium excretion. In intact animals, the MR is "protected" from the effects of higher (100-1000-fold) concentrations of cortisol by co-localization of the enzyme 11β-hydroxysteroid dehydrogenase 2 (referred to herein as 11β-HSD2 and HSD2). HSD2 therefore prevents MR activation and thus inhibits potassium excretion.

[0012] Therefore, inhibition of HSD2 to prevent the inactivation of cortisol-activated MR is a promising mechanism to promote potassium excretion, for example in the treatment of hyperkalemia. Summary of the Invention

[0013] In one aspect of the present invention, there is provided a compound of formula I or a salt thereof:

[0014]

[0015] in,

[0016] 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 -;

[0017] 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 group or a divalent heteroaryl group; 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 and R x optionally taken together to form a heterocycle; provided that when X is not a bond, then L is not a bond;

[0018] W is O or S;

[0019] Q is a bond or an alkylene group;

[0020] R1 is H, alkyl, carbocycle, or heterocycle, wherein each of the alkyl, carbocycle, and heterocycle is optionally substituted with halogen, OH, amino, oxo, carboxyl, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy, aminocarbonyl, carbocycle optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen, heterocycle optionally substituted with alkyl, oxo, amino, and halogen; and carbocycle or heterocycle optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen;

[0021] 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 -;

[0022] R2 is H or R5;

[0023] R3 is absent or is an alkyl group;

[0024] R4 is absent 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, =NO-R5;

[0025] R5 is H or alkyl optionally substituted by carbocyclic or heterocyclic rings, wherein said carbocyclic rings and said heterocyclic rings are optionally substituted by halogen, OH, oxo and alkyl;

[0026] R6 is H, alkyl, carbocycle, heterocycle, wherein said alkyl, said carbocycle and said heterocycle are substituted by halogen, OH, SH, alkylthio, -S(O)-alkyl, -SO2-alkyl, amino, -NHC(O)-alkyl, oxo, alkyl, carboxyl, acyl, acyloxy, alkoxycarbonyl, carbocycle optionally substituted by halogen, OH, amino or alkyl, or heterocycle optionally substituted by halogen, OH, amino or alkyl; and wherein one or more non-adjacent methylene groups in each of said alkyl groups of R6 are optionally replaced by -O- or -S-;

[0027] R x is H, -C(O)O-R1, or alkyl optionally substituted with -C(O)O-R1; and

[0028] n is 1 or 2.

[0029] In another aspect of the present invention, a composition comprising a compound of Formula I and a carrier, diluent, or excipient is provided.

[0030] In another aspect of the present invention, a method of inhibiting the conversion of Cortisol to corticosterone by HSD2 is provided, comprising contacting HSD2 with a compound of formula I.

[0031] In another aspect of the present invention, a method for promoting MR activation in a mammal is provided, comprising administering an effective amount of a compound of formula I to the mammal.

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

[0034] In another aspect of the present invention, a method for treating hyperkalemia in a mammal is provided, comprising administering an effective amount of a compound of Formula I to the mammal.

[0035] In another aspect of the present invention, there is provided a method of treating or preventing hyperkalemia in a mammal comprising co-administering a compound of Formula I and an inhibitor of the renin-angiotensin-aldosterone system (RAAS). BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 A synergistic effect of combined administration of an HSD2 inhibitor and an NHE3 inhibitor on potassium excretion in feces was shown.

[0037] Figure 2 HSD2 inhibition in epithelial cells was shown to allow Cortisol to activate the mineralocorticoid receptor (MR), which promotes potassium excretion into the lumen.

[0038] Figure 3 Describe the structure of glycyrrhetinic acid with carbon atom numbering.

[0039] Figure 4 Describe the structure of formula (II). DETAILED DESCRIPTION

[0040] Glycyrrhizin (or glycyrrhizic acid, glycyrrhizic acid / glycyrrhizinic acid) is an extract of the plant called licorice, which derives its name from the ancient Greek words 'glykos' (meaning sweet) and 'rhiza' (meaning root). Many prophets and pharaohs were addicted to licorice. Licorice extracts have been used on battlefields and in deserts, with soldiers and travelers drinking them to suppress thirst during long journeys. The active metabolite in licorice, glycyrrhetinic acid, inhibits HSD2, resulting in a cortisol-induced mineralocorticoid effect and a tendency for potassium levels to decrease. Although glycyrrhetinic acid lowers potassium levels, it is associated with abnormal heart rhythms, hypertension, edema, drowsiness, 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 the adverse side effects.

[0041] The present invention provides a compound of formula I or a salt thereof:

[0042]

[0043] in,

[0044] 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 -;

[0045] 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 group or a divalent heteroaryl group; 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 and R x optionally taken together to form a heterocycle; provided that when X is not a bond, then L is not a bond;

[0046] W is O or S;

[0047] Q is a bond or an alkylene group;

[0048] R1 is H, alkyl, carbocycle, or heterocycle, wherein each of the alkyl, carbocycle, and heterocycle is optionally substituted with halogen, OH, amino, oxo, carboxyl, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy, aminocarbonyl, carbocycle optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen, heterocycle optionally substituted with alkyl, oxo, amino, and halogen; and carbocycle or heterocycle optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen;

[0049] 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 -;

[0050] R2 is H or R1;

[0051] R3 is absent or is an alkyl group;

[0052] R4 is absent 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, =NO-R5;

[0053] R5 is H or alkyl;

[0054] R6 is H, alkyl, carbocycle, heterocycle, wherein said alkyl, said carbocycle and said heterocycle are substituted by halogen, OH, SH, alkylthio, -S(O)-alkyl, -SO2-alkyl, amino, -NHC(O)-alkyl, oxo, alkyl, carboxyl, acyl, acyloxy, alkoxycarbonyl, carbocycle optionally substituted by halogen, OH, amino or alkyl, or heterocycle optionally substituted by halogen, OH, amino or alkyl; and wherein one or more non-adjacent methylene groups in each of said alkyl groups of R6 are optionally replaced by -O- or -S-;

[0055] R x is H, -C(O)O-R1, or alkyl optionally substituted with -C(O)O-R1; and

[0056] n is 1 or 2.

[0057] The dashed line between the 2- and 3-positions of the fused ring system alternately represents a single bond or a double bond. The dashed lines converging within the fused ring system indicate that R4 (when present) and groups comprising -XLC(O)-Q- (and dioxolone) can be alternately attached at the 3-position (e.g., as in Formula 1e) or the 4-position (e.g., as in Formula 1c) of the fused ring system. Figure 3 The fused ring numbering convention is shown in . In a specific embodiment, the compounds of the present invention have a dioxolone-containing group pendant from the 4-position of the fused ring system. In one embodiment, after administration of the compounds of the present invention to a subject, the ester moiety is metabolized in plasma or liver to the less active acid form. In another embodiment, the compounds of the present invention have HSD2 inhibitory activity equal to or greater than that of glycyrrhetinic acid. In another embodiment, the compounds of the present invention have HSD2 inhibitory activity greater than that of glycyrrhetinic acid.

[0058] "Acyl" means a carbonyl-containing substituent represented by the formula -C(O)-R, wherein R is H, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, wherein alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. Acyl includes alkanoyl (e.g., acetyl), aroyl (e.g., benzoyl), and heteroaroyl.

[0059] 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 portion 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 of 1 to 4 carbon atoms" are synonymous and used interchangeably to refer to methyl, ethyl, 1-propyl, isopropyl, cyclopropyl, 1-butyl, sec-butyl or tert-butyl. Unless otherwise specified, a substituted alkyl group may contain, for example, one, two, three or four substituents which may be the same or different. Examples of substituents are, unless otherwise defined, halogen, amino, hydroxy, protected hydroxy, mercapto, carboxyl, alkoxy, nitro, cyano, amidino, guanidino, urea, sulfonyl, sulfinyl, aminosulfonyl, alkylsulfonylamino, arylsulfonylamino, aminocarbonyl, acylamino, alkoxy, acyl, acyloxy, carbocycle and heterocycle. Examples of the above-mentioned substituted alkyl groups include, but are not limited to, cyanomethyl, nitromethyl, hydroxymethyl, trityloxymethyl, 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, and the like. Alkyl groups may also be substituted with carbocyclic groups. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl, as well as the corresponding -ethyl, -propyl, -butyl, -pentyl, -hexyl, and the like. Substituted alkyl groups include substituted methyl groups, such as those substituted with "substituted C n -C m 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.

[0060] "Amidine" means the group -C(NH)-NHR, where R is H, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, wherein alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. A specific amidine is -NH-C(NH)-NH2.

[0061] "Amino" refers to primary amines (i.e., -NH2), secondary amines (i.e., -NRH), and tertiary amines (i.e., -NRR), where R is H, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, where alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. Specific secondary and tertiary amines include alkylamines, dialkylamines, arylamines, diarylamines, aralkylamines, and diaralkylamines, where alkyl is as defined herein and is optionally substituted. Specific secondary and tertiary amines include methylamine, ethylamine, propylamine, isopropylamine, aniline, benzylamine, dimethylamine, diethylamine, dipropylamine, and diisopropylamine.

[0062] As used herein, "amino protecting group" refers to a derivative of a group that is typically used to block or protect an amino group when reacting on other functional groups on a compound. Examples of such protecting groups include carbamates, amides, alkyl and aryl groups, imines, and many N-heteroatom derivatives that can be removed to regenerate the desired amine group. Suitable amino protecting groups (NH-Pg) include acetyl, trifluoroacetyl, tert-butoxycarbonyl ("Boc"), benzyloxycarbonyl ("CBz"), and 9-fluorenylmethyleneoxycarbonyl ("Fmoc"). Additional examples of these groups are found in Wuts. 格林的保护基 《有机合成中的保护基》 5th edition. New York: John Wiley & Sons, Inc., 2014. The term "protected amino" refers to an amino group substituted with one of the above-mentioned amino-protecting groups.

[0063] "Aryl" when used alone or as part of another term means a carbocyclic aromatic group, whether or not fused, having the number of carbon atoms specified, or if no number of carbon atoms is specified, up to 14 carbon atoms. Particular aryl groups are phenyl, naphthyl, biphenyl, naphthacene, and the like (see, e.g., Dean, JA, ed. 兰氏化学手册 《化学手册》13th ed. New York: McGraw-Hill, 1985, Table 7-2). Specific aryl is phenyl. Substituted phenyl or substituted aryl means phenyl or aryl substituted with one, two, three, four or five substituents, for example, 1-2, 1-3 or 1-4 substituents, wherein the substituents are selected from halogen (F, Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), benzyloxy, carboxyl, protected carboxyl, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylamino, arylsulfonylaminoalkyl, heterocyclylsulfonylamino, heterocyclylsulfonylaminoalkyl, heterocyclyl, aryl or other specified groups unless otherwise specified. One or more methine (CH) and / or methylene (CH2) groups in these substituents may be substituted with groups similar to those described above.Examples of the term "substituted phenyl" include, but are not limited to, mono- or di-(halo)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, and the like; mono- or di-(hydroxy)phenyl, such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, protected hydroxy derivatives thereof, and the like; nitrophenyl, such as 3- or 4-nitrophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl, and the like; phenyl; cyanophenyl, for example 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, for example 3,4-dimethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4-(1-chloromethyl)benzyloxy-phenyl, 3-ethoxyphenyl, 4-(isopropyloxy)phenyl, 4-(tert-butoxy)phenyl, 3-ethoxy -4-methoxyphenyl; 3- or 4-trifluoromethylphenyl; mono- or di-carboxyphenyl or (protected carboxy)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, 3-methoxy-4-(1-chloromethyl)benzyloxy-6-methylsulfonylaminophenyl. Fused aryl rings may also be substituted in the same manner as substituted alkyl groups with any of the substituents specified herein, for example, 1, 2, or 3 substituents.

[0064] "Carbocyclyl," "carbocyclic," "carbocycle," and "carbocyclo," alone and when used as part of a complex group such as carbocycloalkyl, refer to a monocyclic, bicyclic, or tricyclic aliphatic ring having 3 to 14 carbon atoms, for example, 3 to 7 carbon atoms or 3 to 6 carbon atoms, which may be saturated or unsaturated, aromatic or non-aromatic. Specific saturated carbocyclic groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. One specific saturated carbocyclic group is cyclopropyl. Another specific saturated carbocyclic group is cyclohexyl. Specific unsaturated carbocyclic groups are aromatic, for example, aryl groups as previously defined, such as phenyl. The terms "substituted carbocyclyl" and "carbocycle" refer to these groups substituted with the same substituents as "substituted alkyl."

[0065] As used herein, a "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 while reactions are carried out on other functional groups on the compound. Examples of such carboxylic acid protecting groups include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, alkyl groups such as tert-butyl or tert-amyl, Trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylpropan-2-yl, trimethylsilyl, tert-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, β-(trimethylsilyl)ethyl, β-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1- (trimethylsilylmethyl)prop-1-ene-3-yl and other moieties. The type of carboxyl protecting group used is not critical, as long as the derivatized carboxylic acid is stable to the conditions of subsequent reactions at other positions on the molecule and can be removed at the appropriate time without damaging the rest of the molecule. In particular, it is important not to subject the carboxyl protected molecule to the reducing conditions of strong nucleophilic bases such as lithium hydroxide or NaOH, or to highly activated metal hydrides such as LiAlH4. Such harsh removal conditions should also be avoided when removing the amino protecting groups and hydroxy protecting groups discussed below. Specific carboxylic acid protecting groups are alkyl (e.g., methyl, ethyl, tert-butyl), allyl, benzyl and p-nitrobenzyl. Similar carboxyl protecting groups used in the fields of cephalosporins, penicillins and peptides can also be used to protect carboxyl substituents. Additional examples of these groups are found in Greene, TW and PGM Wuts. 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, TW Protective Groups in Organic Synthesis. New York: John Wiley & Sons, Inc. 1981, Chapter 5. The term "protected carboxyl" refers to a carboxyl group substituted with one of the above-mentioned carboxyl protecting groups.

[0066] "Alkoxycarbonyl" means a group -C(=O)OR, where R is an alkyl group. A specific group is C1-C6 alkoxycarbonyl, where the R group is a C1-C6 alkyl group.

[0067] "Guanidine" means the group -NH-C(NH)-NHR, where R is hydrogen, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, wherein alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. A specific guanidine is the group -NH-C(NH)-NH2.

[0068] As used herein, a "hydroxy protecting group" refers to a derivative of a hydroxy group that is typically used to block or protect the hydroxy group while reactions are performed on other functional groups on the compound. Examples of such protecting groups include tetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, and silyl ethers (e.g., TBS, TBDPS). Additional examples of these groups are found in Greene, TW, and PGM Wuts. 《有机合成中的保护基》 2nd edition New York: John Wiley & Sons, Inc. 1991, Chapter 2-3; Haslam, E. 有机化学中的保护基 《有机化学中的保护基》 New York: Plenum Press 1973, Chapter 5; and Greene, TW 保护基 《有机合成中的保护基》 New York: John Wiley & Sons, Inc. 1981. The term "protected hydroxy" refers to a hydroxy group substituted with one of the above-described hydroxy protecting groups.

[0069] "Heterocyclic group," "heterocyclyl" or "heterocyclic / heterocycle / heterocyclo" are used interchangeably, both alone and as part of a complex group such as heterocycloalkyl, and refer to any monocyclic, bicyclic or tricyclic saturated or unsaturated aromatic (heteroaryl) or non-aromatic ring having the specified number of atoms, typically having 5 to about 14 ring atoms, wherein the ring atoms are carbon and at least one heteroatom (nitrogen, sulfur or oxygen), e.g., 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, a 5-membered ring has 0 to 2 double bonds, and a 6- or 7-membered ring has 0 to 3 double bonds. The nitrogen or sulfur heteroatom may be optionally oxidized (e.g., SO, SO2), and any nitrogen heteroatom may be optionally quaternized. Specific non-aromatic heterocycles are morpholinyl (morpholino), pyrrolidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2H-pyranyl, tetrahydropyranyl, thiiranyl, thietanyl, tetrahydrothietanyl, aziridinyl, azetidinyl, 1-methyl-2-pyrrolyl, piperazinyl, and piperidinyl. "Heterocycloalkyl" is a heterocyclic group as defined above covalently bonded to an alkyl group as defined above. Specific five-membered heterocycles containing sulfur or oxygen atoms and one to three nitrogen atoms include thiazolyl, particularly thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, particularly 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, such as oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl. Specific five-membered heterocycles containing two to four nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as 1H-tetrazol-5-yl. Specific benzo-fused five-membered heterocycles include benzoxazol-2-yl, benzothiazol-2-yl, and benzimidazol-2-yl. Particular six-membered heterocycles contain one to three nitrogen atoms and optionally sulfur or oxygen atoms, for example pyridyl, such as pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; pyrimidinyl, such as pyrimidin-2-yl and pyrimidin-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. 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 particular groups.Further examples of "optionally substituted heterocyclic" substituents, as well as the 5- and 6-membered ring systems discussed above, can be found in U.S. Pat. No. 4,278,793 to W. Druckheimer et al. In certain embodiments, such optionally substituted heterocyclic groups are substituted with hydroxy, alkyl, alkoxy, acyl, halo, mercapto, oxo, carboxyl, acyl, halo-substituted alkyl, amino, cyano, nitro, amidino, and guanidino.

[0070] "Heteroaryl," alone and when used as part of a complex group such as heteroaralkyl, refers to any monocyclic, bicyclic, or tricyclic aromatic ring system having the specified number of atoms, wherein at least one ring is a 5-, 6-, or 7-membered ring containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur, and in certain embodiments, at least one heteroatom is nitrogen (Lange's Handbook of Chemistry, supra). 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. Included in the definition are any bicyclic groups in which any of the above heteroaryl rings is fused to a benzene ring. Specific heteroaryl groups contain nitrogen or oxygen heteroatoms. The following ring systems are examples of heteroaryl (whether substituted or unsubstituted) groups represented by the term "heteroaryl": thiophenyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thia Diazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, tetrazo[1,5-b]pyridazinyl and purinyl, as well as benzo-fused derivatives such as benzoxazolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl and indolyl.Particular "heteroaryl" groups may be selected from: 1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl, 1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 2-hydroxy-1,3,4-triazol-5-yl, 2-carboxy-4-methyl-1,3,4-triazol-5-yl, 2-carboxy-4-methyl-1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl, 2- (Hydroxymethyl)-1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 2-mercapto-1,3,4-thiadiazol-5-yl, 2-(methylthio)-1,3,4-thiadiazol-5-yl, 2-amino-1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 1-(1-(dimethylamino)ethane-2-yl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(methylsulfonate)-1H-tetrazol-5-yl, 1-(methylsulfonate)-1H-tetrazol-5-yl, 2-methyl-1H-tetrazol -5-yl, 1,2,3-triazol-5-yl, 1-methyl-1,2,3-triazol-5-yl, 2-methyl-1,2,3-triazol-5-yl, 4-methyl-1,2,3-triazol-5-yl, 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-triazine -3-yl, 2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-methoxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-2,6-dimethyl-as-triazin-3-yl, tetrazolo[1,5-b]pyridazin-6-yl and 8-aminotetrazolo[1,5-b]-pyridazin-6-yl.Alternative groups to "heteroaryl" include: 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 1-(1-(dimethylamino)ethane-2-yl)-1H-tetrazol-5-yl, 1-(carboxymethyl)-1H-tetrazol-5-yl, 1-(methylsulfonic acid)-1H-tetrazol-5-yl, 1-(methylamino)ethane-2-yl)-1H-tetrazol-5-yl. The heteroaryl groups are optionally substituted as described for the heterocycles.

[0071] "Inhibitor" means a compound that reduces or prevents the enzymatic conversion of Cortisol to corticosterone by HSD2.

[0072] Unless otherwise specified, "optionally substituted" means that the group can be unsubstituted or, where valence permits, substituted with one or more (e.g., 0, 1, 2, 3, and / or 4) of the substituents listed for the group, wherein the substituents can 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 another embodiment, the optionally substituted group has 3 substituents.

[0073] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" refers to those salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, which retain the biological effectiveness and properties of the free bases and are not biologically or otherwise undesirable, and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and organic acids selected from the group consisting of aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0074] "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases, such as sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. In particular, base addition salts are ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, meglumine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. In particular, the organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline and caffeine.

[0075] "Sulfanyl" means a -SR group, where R is alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, wherein alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. Specific sulfanyl groups are alkylsulfanyl (i.e., -SO2-alkyl), such as methylsulfanyl; arylsulfanyl, such as phenylsulfanyl; and aralkylsulfanyl, such as benzylsulfanyl.

[0076] "Sulfinyl" means a -SO-R group, where R is hydrogen, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, wherein alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. Specific sulfonyl groups are alkylsulfonyl (i.e., -SO-alkyl), such as methylsulfonyl; arylsulfinyl, such as phenylsulfinyl; and aralkylsulfinyl, such as benzylsulfinyl.

[0077] "Sulfonyl" means a -SO2-R group, where R is hydrogen, alkyl, carbocycle, heterocycle, carbocycle-substituted alkyl, or heterocycle-substituted alkyl, wherein alkyl, alkoxy, carbocycle, and heterocycle are as defined herein. Specific sulfonyl groups are alkylsulfonyl (i.e., -SO2-alkyl), such as methylsulfonyl; arylsulfonyl, such as phenylsulfonyl; and aralkylsulfonyl, such as benzylsulfonyl.

[0078] As used herein, the phrase "and salts and solvates thereof" means that the compounds of the present invention may exist in the form of one of salts and solvates or in the form of a mixture of salts and solvates. For example, the compounds of the present invention may be in the form of substantially pure one specific salt or solvate, or may be a mixture of two or more salt or solvate forms.

[0079] In certain embodiments of the present invention, the compound of Formula I has the structure defined by Formulas Ia-Ip:

[0080]

[0081]

[0082] wherein X, L, Q, V, R1, R2, R3, and R4 are as defined herein. In a specific embodiment, the compound has a structure according to Formula Ia. In a specific embodiment, the compound has a structure according to Formula Ib. In a specific embodiment, the compound has a structure according to Formula Ic. In a specific embodiment, the compound has a structure according to Formula Id. In a specific embodiment, the compound has a structure according to Formula Ie. In a specific embodiment, the compound has a structure according to Formula If. In a specific embodiment, the compound has a structure according to Formula Ig. In a specific embodiment, the compound has a structure according to Formula Ih. In a specific embodiment, the compound has a structure according to Formula Ii. In a specific embodiment, the compound has a structure according to Formula Ij. In a specific embodiment, the compound has a structure according to Formula Ik. In a specific embodiment, the compound has a structure according to Formula Il. In a specific embodiment, the compound has a structure according to Formula Im. In a specific embodiment, the compound has a structure according to Formula In. In a specific embodiment, the compound has a structure according to Formula Io. In a specific embodiment, the compound has a structure according to Formula Ip.

[0083] In certain embodiments of the present invention, the compound of Formula I has the structure defined by Formula Ia'-If':

[0084]

[0085] wherein X, L, V, R1, R2, R3, R4 and R5 are as defined herein. In a specific embodiment, the compound has a structure according to Formula Ib'. In a specific embodiment, the compound has a structure according to Formula Ic'. In a specific embodiment, the compound has a structure according to Formula Id'. In a specific embodiment, the compound has a structure according to Formula If'.

[0086] In one embodiment, the compound of the present invention is any one of Formula I

[0087] In one embodiment, X is a bond, -O-, -N(R x )-、-C(O)N(R x )-、-N(R x )-C(O)-、-S(O) n -N(R x )-or-N(R x )-S(O) n -; where R x is H, -C(O)O-R1 or alkyl 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 one embodiment, X is -N(R x )-C(O)-. In one embodiment, X is -NH-C(O)-. In one embodiment, X is -S(O) n -N(R x )-. In one embodiment, X is -S(O)-NH-. In one embodiment, X is -S(O)2-NH-. In one embodiment, X is -N(R x )-S(O) n -. In one embodiment, X is -NH-S(O)-. In one embodiment, X is -NH-S(O)2-.

[0088] W is O or S. In one embodiment, W is O. In another embodiment, W is S.

[0089] 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.

[0090] 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 -.

[0091] In one embodiment, V is -C(O)O-. In one embodiment, V is -C(O)O- and R2 is H. In one embodiment, V is -C(O)O- and R2 is a prodrug group. In one embodiment, V is -C(O)O- and R2 is alkyl. In one embodiment, V is -C(O)O- and R2 is methyl. In another embodiment, V is -C(O)O- and R2 is alkyl optionally substituted with oxo, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy, carbocycle optionally substituted with alkyl and oxo, and heterocycle optionally substituted with alkyl and oxo.

[0092] In one embodiment, V is -C(O)N(R5)-. In one embodiment, V is -C(O)N(R5)- and R2 and R5 are both H. In one embodiment, V is -C(O)N(R5)- and R2 and R5 are independently H and alkyl optionally substituted with OH. In one embodiment, V is -C(O)N(R5)- and R5 is H and R2 is hydroxyethyl.

[0093] 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.

[0094] 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 R2 and R5 are both H.

[0095] In one embodiment, 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 alkyl. In one embodiment, V is NH-S(O)2- and R2 is methyl.

[0096] 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 group or a divalent heteroaryl group; 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 and R x optionally taken together to form a heterocycle; provided that when X is not a bond, then L is not a bond;

[0097] 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-.

[0098] In one embodiment, L is alkylene-Y-alkylene, 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 and R x and L are optionally taken together to form a heterocycle; provided that when X is not a bond, then L is not a bond. In one embodiment, L is alkylene-Y-alkylene, wherein Y is O. In one embodiment, L is alkylene-Y-alkylene, wherein Y is NR x In one embodiment, L is alkylene-Y-alkylene, wherein Y is NR x , wherein 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.

[0099] R1 is H, alkyl, carbocycle, or heterocycle, wherein each of the alkyl, carbocycle, and heterocycle is optionally substituted with halogen, OH, amino, oxo, carboxyl, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy, aminocarbonyl, carbocycle optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen, heterocycle optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen; and heterocycle optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen. In one embodiment, R1 is H. In one embodiment, R1 is alkyl. In one embodiment, R1 is methyl. In one embodiment, R1 is ethyl. In one embodiment, R1 is n-propyl. In one embodiment, R1 is isopropyl. In one embodiment, R1 is cyclohexyl. In one embodiment, R1 is alkyl substituted with OH. In one embodiment, R1 is alkyl substituted with oxo. In one embodiment, R1 is alkyl substituted with carboxyl. In one embodiment, R1 is alkyl substituted with acyloxy. In one embodiment, R1 is alkyl substituted with an alkoxycarbonyl group. In one embodiment, R1 is alkyl substituted with an alkoxyacyloxy group. In one embodiment, R1 is alkyl substituted with an alkoxycarbonyloxy group. In one embodiment, R1 is alkyl substituted with an aminocarbonyl group. In one embodiment, R1 is methyl. In one embodiment, R1 is propyl. In one embodiment, R1 is hydroxyethyl.

[0100] 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 benzhydryl. In one embodiment, R2 is benzyl.

[0101] R3 is absent or is alkyl. In one embodiment, R3 is methyl. In one embodiment, R3 is absent.

[0102] R4 is absent 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, =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 to which it is attached is part of a double bond. In one embodiment, R4 is H and the carbon to which it is attached is not part of a double bond. In one embodiment, R4 is -R6.

[0103] R5 is H or alkyl optionally substituted by carbocyclic or heterocyclic ring, wherein the carbocyclic ring and the heterocyclic ring are optionally substituted by halogen, OH, oxo and alkyl. In one embodiment, R5 is H. In one embodiment, R5 is alkyl. In one embodiment, R5 is methyl.

[0104] R6 is H, alkyl, carbocycle, heterocycle, wherein the alkyl, the carbocycle and the heterocycle are substituted by halogen, OH, SH, alkylthio, -S(O)-alkyl, -SO2-alkyl, amino, -NHC(O)-alkyl, oxo, alkyl, carboxyl, acyl, acyloxy, alkoxycarbonyl, carbocycle optionally substituted by halogen, OH, amino or alkyl, or heterocycle optionally substituted by halogen, OH, amino or alkyl; and wherein one or more non-adjacent methylene groups in each of the alkyl groups of R6 are optionally replaced by -O- or -S-.

[0105] In one embodiment, R6 is H. In one embodiment, R6 is alkyl. In one embodiment, R6 is methyl.

[0106] 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.

[0107] In one embodiment, R x is H. In one embodiment, R x In one embodiment, R x In one embodiment, R x is alkyl optionally substituted with -C(O)O-R1.

[0108] In one embodiment, 'n' is 1. In another embodiment, 'n' is 2.

[0109] In another aspect of the present invention, there is provided a compound of formula II

[0110]

[0111] wherein 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, Ia'-If', except that the dioxolone ring is saturated.

[0112] In one embodiment, the compound of the present invention is selected from the group consisting of:

[0113] (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-2-carboxylic acid (176-2);

[0114] (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-2-carboxylic acid (178-1); (2S,4aS,6a S,6bR,8aR,9S,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-(2-(methylthio)acetoxy)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydroquinone-2-carboxylic acid (194-10);

[0115] (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-icosahydroquinone-2-carboxylic acid (195-2);

[0116] (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-icosahydroquinone-2-carboxylic acid (196-2);

[0117] (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-icosahydroquinone-2-carboxylic acid (197-2);

[0118] (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-icosahydroquinone-2-carboxylic acid (198-2);

[0119] (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-icosahydroquinone-2-carboxylic acid (203-2);

[0120] (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-icosahydro-2-carboxylic acid (204-2);

[0121] (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-icosahydroquinone-2-carboxylic acid (205-2);

[0122] (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-icosahydroquinone-2-carboxylic acid (206-2);

[0123] (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-icosahydroquinone-2-carboxylic acid (207-2);

[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-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-icosahydroquinone-2-carboxylic acid (208-2);

[0125] (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-icosahydroquinone-2-carboxylic acid (209-3);

[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-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-icosahydroquinone-2-carboxylic acid (211-1);

[0127] (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-icosahydroquinone-2-carboxylic acid (212-1);

[0128] (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-icosahydroquinone-2-carboxylic acid (215-1);

[0129] (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-icosahydroquinone-2-carboxylic acid (216-2);

[0130] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,2-difluoroacetoxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydroquinone-2-carboxylic acid (223-1);

[0131] (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-icosahydroquinone-2-carboxylic acid (240-8);

[0132] (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-icosahydroquinone-2-carboxylic acid (243-1);

[0133] (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-icosahydroquinone-2-carboxylic acid (244-1);

[0134] (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-icosahydroquinone-2-carboxylic acid (245-1);

[0135] (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-icosahydro-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-icosahydro-2-carboxylic acid (249-5);

[0136] (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-icosahydroquinone-2-carboxylic acid (252-2);

[0137] (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-icosahydroquinone-2-carboxylic acid (253-4);

[0138] (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-icosahydroquinone-2-carboxylic acid (254-3);

[0139] (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-icosahydroquinone-2-carboxylic acid (255-2);

[0140] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,2-difluoroacetoxy)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydroquinone-2-carboxylic acid (256-2);

[0141] (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-icosahydroquinone-2-carboxylic acid (258-2);

[0142] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxatetradec-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-icosahydroquinone-2-carboxylic acid (264-1);

[0143] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((2,5,8,11-tetraoxatetradec-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-2-carboxylic acid (265-2)

[0144] (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-icosahydroquinone-2-carboxylic acid (279-2);

[0145] (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-2-carboxylic 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-icosahydroquinone-2-carboxylic acid (281-3);

[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-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-icosahydroquinone-2-carboxylic acid (282-2);

[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-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-icosahydroquinone-2-carboxylic acid (283-2);

[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-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-icosahydro-2-carboxylic acid (284-2);

[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-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-icosahydroquinone-2-carboxylic acid (285-2);

[0150] (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-icosahydroquinone-2-carboxylic acid (286-4);

[0151] (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-icosahydroquinone-2-carboxylic acid (289-2);

[0152] (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-icosahydroquinone-2-carboxylic acid (290-2);

[0153] (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-icosahydroquinone-2-carboxylic acid (291-2);

[0154] (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-icosahydroquinone-2-carboxylic acid;

[0155] (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-icosahydroquinone-2-carboxylic acid (297-5);

[0156] (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-icosahydroquinone-2-carboxylic acid (298-2);

[0157] (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-icosahydroquinone-2-carboxylic acid (299-2);

[0158] (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-icosahydroquinone-2-carboxylic acid (300-1); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-((methoxycarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydroquinone-2-carboxylic acid (301-2);

[0159] (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-icosahydroquinone-2-carboxylic acid (302-3);

[0160] (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);

[0161] (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-icosahydroquinone-2-carboxylic acid (308-2);

[0162] (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(2,2-difluoroacetamido)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydroquinone-2-carboxylic acid (309-2);

[0163] (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-icosahydroquinone-2-carboxylic acid (314-4);

[0164] (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-icosahydroquinone-2-carboxylic acid (315-2);

[0165] (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-icosahydroquinone-2-carboxylic acid (316-1);

[0166] (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-icosahydroquinone-2-carboxylic acid (317-6); (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-((((5-ethyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-10-(propionyloxy)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydroquinone-2-carboxylic acid (318-1);

[0167] (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-icosahydroquinone-2-carboxylic acid (319-1);

[0168] (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-icosahydroquinone-3-ylpropanoate (320-1);

[0169] (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-icosahydroquinone-2-carboxylic acid (321-1);

[0170] (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-icosahydroquinone-2-carboxylic acid (322-6);

[0171] (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-2-carboxylic acid (323-1);

[0172] (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-icosahydroquinone-2-carboxylic acid (324-3);

[0173] (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-icosahydroquinone-2-carboxylic acid (325-1);

[0174] (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-icosahydroquinone-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-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-icosahydro-2-carboxylic acid (327-8);

[0176] (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-icosahydroquinone-2-carboxylic acid (326-1);

[0177] (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-icosahydro-2-carboxylic acid (327-8);

[0178] (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-icosahydroquinone-2-carboxylic acid (328-2);

[0179] (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-icosahydroquinone-2-carboxylic acid;

[0180] (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-icosahydroquinone-2-carboxylic acid (330-1);

[0181] (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-icosahydroquinone-2-carboxylic acid (331-2);

[0182] (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-icosahydroquinone-2-carboxylic acid (332-2);

[0183] (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-icosahydroquinone-2-carboxylic acid (333-1);

[0184] (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-icosahydroquinone-2-carboxylic acid (334-8);

[0185] (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-icosahydroquinone-2-carboxylic acid (335-1);

[0186] (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-icosahydroquinone-2-carboxylic acid (336-2);

[0187] (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-icosahydroquinone-2-carboxylic acid (337-2);

[0188] (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-icosahydroquinone-2-carboxylic acid (338-4);

[0189] (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-icosahydroquinone-2-carboxylic acid (339-1);

[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-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-icosahydroquinone-2-carboxylic acid (341-2);

[0191] (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-icosahydroquinone-2-carboxylic acid (342-1);

[0192] (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-icosahydroquinone-2-carboxylic acid (343-3);

[0193] (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-icosahydroquinone-2-carboxylic acid (344-1);

[0194] (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-icosahydroquinone-2-carboxylic acid (345-2);

[0195] (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-icosahydroquinone-2-carboxylic acid (346-2);

[0196] (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-icosahydroquinone-2-carboxylic acid (347-4);

[0197] (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-icosahydroquinone-2-carboxylic acid (348-11);

[0198] (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-icosahydroquinone-2-carboxylic acid (349-1);

[0199] (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-icosahydroquinone-2-carboxylic acid (350-1);

[0200] (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-icosahydroquinone-2-carboxylic acid (351-1);

[0201] (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-icosahydroquinone-2-carboxylic acid (352-1);

[0202] (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-icosahydroquinone-2-carboxylic acid (353-1);

[0203] (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-icosahydroquinone-2-carboxylic acid (356-2);

[0204] (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-icosahydro-2-carboxylic acid (357-7);

[0205] (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-icosahydroquinone-2-carboxylic acid (358-7);

[0206] (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-icosahydroquinone-2-carboxylic acid (359-1)

[0207] (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-icosahydroquinone-2-carboxylic acid (360-1);

[0208] (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-icosahydroquinone-2-carboxylic acid (361-1);

[0209] (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-icosahydroquinone-2-carboxylic acid (362-1);

[0210] (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-icosahydroquinone-2-carboxylic acid (363-5);

[0211] (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-icosahydroquinone-2-carboxylic acid (363-5);

[0212] (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-icosahydro-2-carboxylic acid (364-5);

[0213] (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-icosahydroquinone-2-carboxylic acid (365-8);

[0214] (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-icosahydroquinone-2-carboxylic acid (366-1);

[0215] 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-tetraoxatetradec-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-icosahydro-2,9-dicarboxylate (605-2);

[0216] (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-icosahydroquinone-2-carboxylic acid (Compound 700-1);

[0217] (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-icosahydroquinone-2-carboxylic acid (Compound 701-1);

[0218] (2S,4aS,6aS,6bR,8aR,9S,10R,12aS,12bR,14bR)-10-(acetyloxy)-2,4a,6a,6b,9,10,12a-heptamethyl-13-oxo-9-({[2-oxo-5-(propan-2-yl)-2H-1,3-dioxol-4-yl]methoxy}carbonyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydroquinone-2-carboxylic acid (Compound 702-1);

[0219] (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-icosahydro-2-carboxylic acid (Compound 703-1);

[0220] (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-icosahydroquinone-2-carboxylic acid (Compound 704-1);

[0221] (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-icosahydroquinone-2-carboxylic acid (Compound 705-1);

[0222] (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-icosahydroquinone-2-carboxylic acid (Compound 706-1);

[0223] (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-icosahydroquinone-2-carboxylic acid (Compound 707-1);

[0224] (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-icosahydroquinone-2-carboxylic acid (Compound 708-1);

[0225] (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-icosahydro-2-carboxylic acid (Compound 709-1);

[0226] (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-thiadodec-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-icosahydroquinone-2-carboxylic acid (Compound 710-1);

[0227] (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-icosahydroquinone-2-carboxylic acid (Compound 711-1);

[0228] (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-icosahydroquinone-2-carboxylic acid (Compound 712-1); and

[0229] (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-icosahydro-2-carboxylic acid (Compound 713-1).

[0230] The compounds of the present invention are "soft drugs" in that their parent form is an active inhibitor of 11b-HSD2 in the patient's gastrointestinal tract, but upon ingestion into plasma, they are enzymatically converted to inactive or less active metabolites. This effect provides the desired preferential inhibition of HSD2 in the gastrointestinal tract relative to HSD2 in the kidney. The compounds disclosed herein were tested in the assay described in Example 112 and found to inhibit HSD2 by measuring the amount of cortisol before and after exposure to human cell lysates or colonic monolayer organoids derived from human colon tissue. Furthermore, each compound tested was found to be a more potent HSD2 inhibitor than its corresponding metabolite.

[0231] The compounds of the present invention may contain one or more asymmetric or chiral centers. Thus, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds may employ racemates, diastereomers, or enantiomers as starting materials or intermediates. The diastereomeric compounds may be separated by chromatography or crystallization. Similarly, enantiomeric mixtures may be separated using the same techniques or other techniques known in the art. Unless otherwise specified, each asymmetric center may be in the R or S configuration, and both configurations are within the scope of the present invention. All stereoisomeric forms of the compounds described herein, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof, such as racemic mixtures, are intended to be part of the compounds of the present invention.

[0232] It will also be understood that certain compounds of Formula I may serve as intermediates for further compounds of Formula I. It will be further understood that the compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and that the compounds are intended to include both solvated and unsolvated forms.

[0233] 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 employed to prepare the compounds of the present invention will depend on the specific substituents present in the compound and may require various protection and deprotection steps that are standard in organic synthesis but which may not be shown in the following general schemes. The starting materials are generally available from commercial sources or are readily prepared using methods well known to those skilled in the art. For example, the compounds of the present invention may be prepared from Figure 3 The preparation of glycyrrhetinic acid shown in the scheme is shown. For illustrative purposes, the schemes herein show general methods for preparing the compounds of the present invention and key intermediates. It will be understood by those skilled in the art that other synthetic routes can be used to synthesize the compounds. Although specific starting materials and reagents are described in the schemes and discussed below, other starting materials and reagents can be substituted to provide various derivatives and / or reaction conditions. In addition, according to the present disclosure, many of the compounds prepared by the following methods can be further modified using conventional chemical methods well known to those skilled in the art. As shown in Scheme 1, compounds of the present invention in which -QWC(O)-LX- forms an ester bond -CH2-OC(O)- with a dioxolone can be prepared starting from a carboxylic acid derivative of glycyrrhetinic acid (at the 3- or 4-position) and reacted with, for example, a halogenated dioxolone.

[0234] Solution 1

[0235]

[0236] Compounds of the invention wherein -QWC(O)-LX- forms a bond -CH2-OC(O)-O- with the dioxolone can be prepared according to General Scheme 2.

[0237] Option 2

[0238]

[0239] Compounds of the invention in which -QWC(O)-LX- forms an amide bond -CH2-OC(O)-NH- with a dioxolone can be prepared as shown in Scheme 3 starting by reacting an isocyanate at the 3- or 4-position of the fused ring system with a hydroxylated dioxolone.

[0240] Option 3

[0241]

[0242] In preparing the compounds of the present invention, it may be necessary to protect distal functional groups (e.g., primary or secondary amines, etc.) of intermediates. The need for such protection will vary depending on the nature of the distal functional group and the conditions of the preparation process. The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their uses, see Greene, TW, and PGM Wuts. 格林的 《有机合成中的保护基》 . 4th edition New York: Wiley-Interscience, 2006.

[0243] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired product of each step or series of steps is separated and / or purified (hereinafter separated) to the desired uniformity by 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: reverse 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 or thick layer chromatography, as well as small-scale thin layer and flash chromatography techniques. One skilled in the art will apply the techniques most likely to achieve the desired separation.

[0244] Diastereomers and enantiomeric mixtures can be separated into their individual stereoisomers based on their physicochemical differences by methods well known to those skilled in the art (e.g., by chromatography and / or fractional crystallization). Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated by using a chiral HPLC column.

[0245] The present invention also includes pharmaceutical compositions or medicaments containing the compound of the present invention and treatment inert carriers, diluents or excipients, and methods for preparing such compositions and medicaments using the compound of the present invention. Conventionally, the compound of the formula I used in the inventive method is prepared by mixing with a physiologically acceptable carrier (that is, a carrier nontoxic to the recipient under dosage and concentration used) at ambient temperature and suitable pH and required purity. The pH of the preparation depends primarily on the specific use and concentration of the compound, but can be any value in the range of approximately 3 to approximately 8. The preparation in the acetate buffer of pH 5 is a suitable embodiment. In one embodiment, the preparation comprising the compound of the present invention is sterile. Conventionally, the compound will be stored as a solid composition, although lyophilized formulations or the aqueous solution are also acceptable.

[0246] Compositions comprising the compounds of the present invention will be formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of administration, the method of administration, the administration schedule, and other factors known to practitioners. The "effective amount" of the compound to be administered will be determined by such considerations and is the minimum amount necessary to inhibit the conversion of cortisol to corticosterone via HSD2. This amount may be below an amount that would be toxic to normal cells or the entire mammal.

[0247] The compounds of the present invention may be administered by any suitable means. In certain embodiments, the compounds are administered orally. In certain embodiments, the compounds are administered rectally.

[0248] Generally, the initial pharmaceutically effective amount of a compound of the invention per parenteral dose 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 dosage range of 0.5 to 50 mg / kg / day. Oral unit dosage forms such as tablets and capsules may contain from about 25 to about 1000 mg of a compound of the invention. In a specific embodiment, the effective amount is an amount of a compound of the invention sufficient to increase colonic potassium secretion by about 15 mmol / day. In a specific embodiment, the effective amount is an amount of a compound of the invention sufficient to increase colonic potassium secretion by about 1 mmol / day. In a specific embodiment, the effective amount is an amount of a compound of the invention sufficient to increase colonic potassium secretion by about 5 mmol / day. In a specific embodiment, the effective amount is an amount of a compound of the invention sufficient to increase colonic potassium secretion by about 10 mmol / day. In a specific embodiment, the effective amount is an amount of a compound of the invention sufficient to increase colonic potassium secretion by about 15 mmol / day. In a specific embodiment, the effective amount is an amount of a compound of the invention sufficient to increase colonic potassium secretion by about 20 mmol / day.

[0249] The compound can be administered in any convenient administration form, such as tablets, capsules, solutions, dispersions, suspensions, syrups, suppositories, gels, emulsions, and the like. An example of a suitable oral dosage form is a tablet containing about 25 mg, 50 mg, 100 mg, 250 mg, or 500 mg of a compound of the invention 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 powdered ingredients are first mixed together and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment.

[0250] Another formulation can be prepared by mixing a compound 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 in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light-shielding agents, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents, diluents and other known additives that provide an elegant appearance of the drug (i.e., a compound described herein or a pharmaceutical composition thereof) or facilitate the production of a pharmaceutical product (i.e., a medicament).

[0251] In one embodiment, the formulation releases the compound in response to contact with enzymes of the colon (e.g., enzymes produced by enteric bacteria). Certain starch-based capsule coatings can be used that are resistant to digestion in the stomach and small intestine, but are degraded by microbial (normal intestinal flora) enzymes once the dosage form reaches the colon.

[0252] In one embodiment, the compound of the present invention is administered orally. In another embodiment, the compound is formulated for colonic delivery. Colonic delivery can be implemented in response to pH time, microorganisms and pressure. In one embodiment, the formulation releases the compound in response to colonic pH. As the formulation passes through the GI tract, the release of the compound is triggered by an increase in pH. The formulation is based on a polymer that is insoluble at lower pH in the stomach and upper small intestine, but soluble at higher pH in the distal small intestine, for example, a polymer that can withstand environments as low as pH ~ 1.2, such as acrylic acid and cellulose derivatives. Suitable enteric polymers include polyvinyl acetate phthalate (PVAP) such as Cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP) such as HP-50, HP-55, HP-55S, hydroxypropyl methylcellulose acetate succinate (HPMCAS) such as LF grade, MF grade or HF grade, methacrylic acid copolymer such as L100-55, L30D-55, L-1000, L12.5, S-100, S12.5, FS30D, Cellulose acetate phthalate (CAP) e.g. and shellac e.g. 125 or 125N.

[0253] In one aspect of the present invention, a method for inhibiting the conversion of cortisol to corticosterone by HSD2 is provided, comprising contacting HSD2 with a compound of Formula I. In another aspect of the present invention, a method for promoting MR activation in a mammal is provided, comprising administering to the mammal an effective amount of a compound of Formula I. In another aspect of the present invention, a method for reducing the potassium level in the plasma of a mammal is provided, comprising administering to the mammal an effective amount of a compound of Formula I. In another aspect of the present invention, a method for promoting the secretion of potassium ions into the colonic lumen of a mammal is provided, comprising administering to the mammal an effective amount of a compound of Formula I.

[0254] In one aspect of the present invention, there is provided a method for treating and / or preventing hyperkalemia in a mammal, comprising administering an effective amount of a compound of Formula I to the mammal. Hyperkalemia is particularly frequent in patients with chronic kidney disease (CKD), hypertension, heart failure, and diabetes. Therefore, in an embodiment of the present invention, the method for treating and / or preventing hyperkalemia is carried out in patients with CKD hypertension, heart failure, and diabetes. Patients suffering from these conditions are often treated with certain classes of drugs, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), or other inhibitors of the renin-angiotensin-aldosterone system (RAAS), in order to regulate blood pressure. However, such drugs promote potassium retention. Therefore, there is provided a method for treating and / or preventing hyperkalemia in a mammal, comprising administering a compound of Formula I in combination with an inhibitor of the RAAS system. In one embodiment, the RAAS inhibitor is an ACE inhibitor.

[0255] The compounds described herein, and their stereoisomers, diastereomers, enantiomers, tautomers, and pharmaceutically acceptable salts, can be used alone or in combination with other antihyperkalemic agents that work by different mechanisms of action. The compounds of the present invention can be administered with other antihyperkalemic agents in a single pharmaceutical composition, or can be administered separately, and when administered separately, they can be administered simultaneously or sequentially in any order. Such sequential administration can be close in time or remote in time.

[0256] In one embodiment, another anti-hyperkalemic compound is a potassium ion binder, such as a cross-linked polystyrene sulfonate (PSS) polymer resin. In one embodiment, the PSS resin is cross-linked with a divinylbenzene (DVB) copolymer. DVB-cross-linked PSS is the most commonly used drug for controlling hyperkalemia in hospitalized patients. PSS is usually provided in the form of a sodium salt or a calcium salt, and it exchanges secreted potassium ions with sodium ions 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-hyperkalemic 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.

[0257] In one embodiment, the other antihyperkalemic agent is In another embodiment, another antihyperkalemic agent is a fluoroacrylate polymer incorporating potassium-binding carboxylate groups, such as patiromer In one embodiment, another antihyperkalemic agent is an insoluble, non-absorbable sodium zirconium silicate, which traps potassium ions within its lattice structure, e.g. In one embodiment, the other antihyperkalemic agent is a cross-linked polyacrylic acid, such as CLP-1001.

[0258] In another aspect of the present invention, it was unexpectedly discovered that HSD2 inhibition in combination with inhibition of the sodium-hydrogen exchanger (NHE) synergistically increases potassium excretion into the feces. NHEs are present in the tubules proximal to the nephrons of the kidney and in the apical membrane of the enterocytes of the intestine. The isoform known as NHE3 is primarily responsible for maintaining sodium homeostasis and is also indirectly involved in buffering blood pH. The NHE3 antiporter imports a sodium ion into the cytosol of the cell while the cell ejects a hydrogen ion from the cell into the lumen of the intestinal lumen and the lumen of the proximal tubules. Figure 1As shown in , it has been shown that when HSD2 and NHE are inhibited, there is a synergistic effect on fecal potassium excretion. Therefore, a method of removing potassium from the plasma and / or tissues of a mammal is provided, comprising administering to the mammal an effective amount of an HSD2 inhibitor or MR agonist in combination with a compound that increases the amount of fluid in the colon. Also provided is a method of removing potassium from the plasma and / or tissues of a mammal, comprising administering to the mammal an effective amount of an HSD2 inhibitor or MR agonist in combination with a compound that removes sodium from the plasma and / or tissues. Also provided is a method of removing potassium from the plasma and / or tissues of a mammal, comprising administering to the mammal an effective amount of an HSD2 inhibitor or MR agonist in combination with a compound that promotes sodium excretion into the gastrointestinal tract. In one embodiment, the compound is a laxative that increases fluid in the colon. In one embodiment, the laxative is bisacodyl. In one embodiment, the laxative is picosulfate. In one embodiment, the laxative is MgOH. In one embodiment, the laxative is (PEG 3350). In one embodiment, the laxative is lactulose. In one embodiment, the compound is an activator of intestinal guanylate cyclase. In one embodiment, the guanylate cyclase agonist is linaclotide. In one embodiment, the guanylate cyclase agonist is plecanatide. In one embodiment, the compound is an activator of the intestinal ClC-2 chloride channel. In one embodiment, the ClC-2 chloride channel activator is lubiprostone.

[0259] Also provided are methods for depleting potassium from the plasma and / or tissues of a mammal, comprising administering to the mammal an effective amount of an HSD2 inhibitor or MR agonist in combination with an NHE inhibitor. In one embodiment, the HSD2 inhibitor or MR agonist and the NHE inhibitor compound are administered simultaneously. In one embodiment, the HSD2 or MR agonist and the NHE inhibitor compound are administered sequentially. In one embodiment, the HSD2 inhibitor or MR agonist is administered before the NHE inhibitor or MR agonist. In one embodiment, the NHE inhibitor or MR agonist compound is administered before the HSD2 inhibitor or MR agonist. In one embodiment, the NHE inhibitor or MR agonist compound is administered before the HSD2 inhibitor or MR agonist. In one embodiment, the NHE inhibitor is an NHE3 inhibitor.

[0260] In another aspect of the present invention, a pharmaceutical composition comprising an HSD2 inhibitor and an NHE inhibitor is provided. In another aspect, a pharmaceutical composition comprising an MR agonist and an NHE inhibitor is provided.

[0261] In another aspect, a method of treating hyperkalemia in a mammal is provided, comprising administering to the mammal an effective amount of an HSD2 inhibitor or MR agonist in combination with an NHE inhibitor. In one embodiment, the NHE inhibitor is an NHE3 inhibitor.

[0262] In one embodiment, the MR agonist is fludrocortisone.

[0263] In another aspect, a method for treating hyperkalemia in a mammal is provided, comprising administering to the mammal an effective amount of an HSD2 inhibitor in combination with an NHE inhibitor. In one embodiment, the NHE inhibitor is an NHE3 inhibitor. In another aspect, a composition comprising an HSD2 inhibitor and an NHE inhibitor is provided. In one embodiment, the composition is a pharmaceutical composition. In one embodiment, an effective amount of an HSD2 inhibitor compound and an NHE inhibitor compound are present. In one embodiment, the composition further comprises a pharmaceutically acceptable carrier, excipient, and / or diluent. In one embodiment, the HSD2 inhibitor is glycyrrhetinic acid or an analog thereof. In one embodiment, the HSD2 inhibitor is glycyrrhetinic acid. In one embodiment, the HSD2 inhibitor is glycyrrhetinic acid. 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 Nos. 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 No. WO 01 / 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.

[0264] In one embodiment, the NHE inhibitor is a minimally systemic compound, i.e., 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):

[0265] NHE-Z

[0266] (I)

[0267]

[0268] in:

[0269] NHE is an NHE-binding small molecule comprising (i) a heteroatom-containing moiety, and (ii) a cyclic or heterocyclic scaffold or supporting moiety directly or indirectly bound thereto, the heteroatom-containing moiety being selected from a substituted guanidino moiety and a substituted heterocyclic moiety, which may be optionally fused to the scaffold or supporting moiety to form a fused bicyclic structure; and,

[0270] Z is a moiety having at least one site thereon for attachment to an NHE-binding small molecule, the resulting NHE-Z molecule having overall physicochemical properties rendering it substantially impermeable or substantially systemically non-bioavailable; and,

[0271] E is an integer with a value of 1 or greater.

[0272] In certain embodiments, the total number of freely rotatable bonds in the NHE-Z molecule is at least about 10. In certain embodiments, the total number of hydrogen bond donors in the NHE-Z molecule is at least about 5. In certain embodiments, the total number of hydrogen bond acceptors in the NHE-Z molecule is at least about 10. In certain embodiments, the total number of hydrogen bond donors and hydrogen bond acceptors in the NHE-Z molecule is at least about 10. In certain embodiments, the Log P of the NHE-Z binding compound is at least about 5. In certain embodiments, the log P of the NHE-Z binding compound is less than about 1 or less than about 0. In certain embodiments, the scaffold is a 5-membered or 6-membered cyclic or heterocyclic moiety. In certain embodiments, the scaffold is aromatic.

[0273] In some embodiments, the scaffold of the NHE-binding small molecule is bound to moiety Z, and the compound has a structure of formula (II), such as Figure 4 described.

[0274] in:

[0275] Z is a core having thereon one or more sites for attachment to one or more NHE-binding small molecules, the resulting NHE-Z molecule having overall physicochemical properties rendering it substantially impermeable or substantially systemically non-bioavailable;

[0276] B is a heteroatom-containing moiety of the NHE-binding small molecule and is selected from a substituted guanidinyl moiety and a substituted heterocyclic moiety, which may be optionally fused to the scaffold moiety to form a fused bicyclic structure;

[0277] The scaffold is a cyclic or heterocyclic scaffold or supporting portion of the NHE-binding small molecule, which is directly or indirectly bound to the heteroatom-containing moiety B and is optionally substituted with one or more additional hydrocarbyl or heterohydrocarbyl moieties;

[0278] X is a bond or a spacer moiety selected from the group consisting of a substituted or unsubstituted hydrocarbon or heteroalkyl moiety, in particular a substituted or unsubstituted C 1-7 a hydrocarbyl or heterohydrocarbyl group, and a substituted or unsubstituted saturated or unsaturated cyclic or heterocyclic moiety, which links B and the scaffold; and

[0279] D and E are integers each independently having a value of 1 or greater.

[0280] In some embodiments, the compound is an oligomer, dendrimer, or polymer, and further, wherein Z is a core moiety having two or more sites thereon for attachment to multiple NHE-binding small molecules, directly or indirectly through a linker moiety L, the compound having a structure of Formula (X):

[0281]

[0282] wherein L is a bond or a linker connecting the core to the NHE-binding small molecule, and n is an integer of 2 or greater, and further wherein each NHE-binding small molecule may be the same as or different from each other.

[0283] In some embodiments, the NHE-binding small molecule has the structure of Formula (IV):

[0284]

[0285] or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, wherein:

[0286] Each of 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 a bond connecting the NHE-binding small molecule to L, with the proviso that at least one is a bond connecting the NHE-binding small molecule to L;

[0287] R4 is selected from H, C1-C7 alkyl or a bond connecting the NHE-bound small molecule and L;

[0288] R6 is absent or selected from H and C1-C7 alkyl; and

[0289] Ar1 and Ar2 independently represent an aromatic ring or a heteroaromatic ring.

[0290] In certain embodiments, the NHE-binding small molecule has the following structure:

[0291]

[0292] or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, wherein:

[0293] Each of 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 a bond connecting the NHE-binding small molecule to L, with the proviso that at least one is a bond connecting the NHE-binding small molecule to L.

[0294] In some embodiments, the NHE-binding small molecule has one of the following structures:

[0295]

[0296] or a stereoisomer, prodrug, or pharmaceutically acceptable salt thereof. In certain embodiments, L is a polyalkylene glycol linker. In certain embodiments, L is a polyethylene glycol linker. In some embodiments, n is 2.

[0297] In certain embodiments, the core has the following structure:

[0298]

[0299] in:

[0300] X is selected from the group consisting of: a bond, -O-, -NH-, -S-, C 1-6 Alkylene, -NHC(=O)-, -C(=O)NH-, -NHC(=O)NH-, -SO2NH- and -NHSO2-;

[0301] Y is selected from the group consisting of: a bond, an optionally substituted C 1-8 Alkylene, optionally substituted aryl, optionally substituted heteroaryl, polyethylene glycol linker, -(CH2) 1-6 O(CH2) 1-6 - and -(CH2) 1-6 NY1(CH2) 1-6 -;and

[0302] Y1 is selected from the group consisting of hydrogen, optionally substituted C 1-8 alkyl, optionally substituted aryl or optionally substituted heteroaryl.

[0303] In some embodiments, the core is selected from the group consisting of:

[0304]

[0305]

[0306] wherein: L is a bond or linking moiety; NHE is an NHE-binding small molecule; and n is a non-zero integer.

[0307] In one embodiment, the NHE inhibitor is:

[0308] N,N',N"-(2,2',2"-nitrilotris(ethane-2,1-diyl))tris(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0309] N,N'-(2,2'-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

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

[0311] N,N'-(1,4-phenylenebis(methylene))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

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

[0313] N,N'-(Dodecane-1,12-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0314] N,N',N",N"'-(3,3',3",3"'-(butane-1,4-diylbis(azanetriyl))tetrakis(propane-3,1-diyl))tetrakis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

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

[0316] N,N'-(Dodecane-1,12-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0317] N,N',N"-(2,2',2"-nitrilotris(ethane-2,1-diyl))tris(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0318] N,N',N",N"'-(3,3',3",3"'-(butane-1,4-diylbis(azanetriyl))tetrakis(propane-3,1-diyl))tetrakis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0319] N,N'-(1,4-phenylenebis(methylene))bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0320] N,N'-(2,2'-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0321] N1,N8-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)suberamide;

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

[0323] 2-(N-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)sulfamoylamino)ethylphosphonic acid;

[0324] N,N′-(Butane-1,4-diyl)bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide];

[0325] N,N′-(1,4-phenylenebis(methylene))bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide];

[0326] N,N'-(2,2'-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide];

[0327] N,N'-(2,2'-(2,2'-oxybis(ethane-2,1-diyl)bis(oxy))bis(ethane-2,1-diyl))bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide]

[0328] (E)-3-(4-(4-(N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-3,5-difluorophenyl)-N-(diaminomethylene)-2-methylacrylamide];

[0329] N,N′-(13-oxo-3,6,9,17,20,23-hexaoxa-12,14-diazapentacosane-1,25-diyl)bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide];

[0330] N,N'-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,21-diazadotriacontane-1,32-diyl)bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide];

[0331] N,N'-(2,2'-(2,2'-(2,2'-(2,2'-(4,4'-oxybis(methylene)bis(1H-1,2,3-triazole-4,1-diyl))bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis[(E)-N-(diaminomethylene)-3-(3,5-difluoro-4-(4-sulfamoylphenoxy)phenyl)-2-methylacrylamide];

[0332] N,N'-(2,2'-(2,2'-(2,2'-(2,2'-(4,4'-oxybis(methylene)bis(1H-1,2,3-triazole-4,1-diyl))bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide)

[0333] 1-(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazole-4,5-dicarboxylic acid;

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

[0335] N1,N4-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

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

[0337] N1,N31-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)-4,7,10,13,16,19,22,25,28-nonaoxatriacontane-1,31-diamide;

[0338] N,N'-(13-oxo-3,6,9,17,20,23-hexaoxa-12,14-diazapentacosane-1,25-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0339] N1,N31-bis(2-(2-(2-(2-(4-(4-((E)-3-(diaminomethyleneamino)-2-methyl-3-oxoprop-1-enyl)-2,6-difluorophenoxy)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)-4,7,10,13,16,19,22,25,28-nonaoxatriacontane-1,31-diamide;

[0340] N,N'-(13-oxo-3,6,9,17,20,23-hexaoxa-12,14-diazapentacosane-1,25-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0341] N1,N4-bis(20-(4-(4-((E)-3-(diaminomethyleneamino)-2-methyl-3-oxoprop-1-enyl)-2,6-difluorophenoxy)phenylsulfonylamino)-3,6,9,12,15,18-hexaoxaeicosyl)-2,3-dihydroxysuccinamide;

[0342] N1,N4-bis(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonylamino)ethyl)-2,3-dihydroxysuccinamide;

[0343] N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0344] 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;

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

[0346] N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamino)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0347] N1,N4-bis(1-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamino)-1-oxo-5,8,11-trioxa-2-azatridecan-13-yl)-2,3-dihydroxysuccinamide;

[0348] N1,N2-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)oxamide;

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

[0350] N1,N4-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)succinamide;

[0351] 2,2'-oxybis(N-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)acetamide);

[0352] (2R,3R)-N1,N4-bis(2-(2-(2-(3-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamino)-3-oxopropoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0353] N1,N2-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)oxamide;

[0354] N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)succinamide;

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

[0356] N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)-2,2-dimethylmalonamide;

[0357] 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(oxy)bis(ethane-2,1-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0358] 2,2'-(Methylazanediyl)bis(N-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)acetamide)tris(2,2,2-trifluoroacetate);

[0359] 5-amino-N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)isophthalamide tris(2,2,2-trifluoroacetate);

[0360] 2,2'-oxybis(N-(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)acetamide);

[0361] 5-Bromo-N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)isophthalamide bis(2,2,2-trifluoroacetate);

[0362] N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)-2-hydroxymalonamide bis(2,2,2-trifluoroacetate);

[0363] N1,N2-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)oxamide;

[0364] N1,N4-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)succinamide;

[0365] 3,5-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethylcarbamoyl)benzenesulfonic acid;

[0366] N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)-5-hydroxyisophthalamide;

[0367] (2R,3R)-N1,N4-bis(3-((3-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)propyl)(methyl)amino)propyl)-2,3-dihydroxysuccinamide;

[0368] 2,2'-oxybis(N-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)acetamide);

[0369] N1,N3-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)-2,2-dimethylmalonamide;

[0370] N1,N2-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)oxamide;

[0371] 2,2'-oxybis(N-(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)acetamide);

[0372] N1,N4-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)succinamide;

[0373] N1,N4-bis(2-(2-(2-(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)succinamide;

[0374] 2,2'-oxybis(N-(2-(2-(2-(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)acetamide);

[0375] (S or R)-N,N'-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis(3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0376] (S or R)-N,N'-(2,2'-(2,2'-(2,2'-(1,4-phenylenebis(azanediyl))bis(oxymethylene)bis(azanediyl)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(3-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0377] N,N'-(Butane-1,4-diyl)bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonylamino)acetamido)acetamido)acetamide);

[0378] N1,N4-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0379] 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-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0380] (2R,3R)-N1,N4-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0381] N,N'-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,14,19,21-tetraazadotriacontane-1,32-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0382] N,N'-(1,1'-(1,4-phenylenebis(azanediyl))bis(1-oxo-5,8,11-trioxa-2-azatridecane-13,1-diyl))bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0383] (2R,3R)-N1,N4-bis(20-(4-(4-((E)-3-(diaminomethyleneamino)-2-methyl-3-oxoprop-1-enyl)-2,6-difluorophenoxy)phenylsulfonylamino)-3,6,9,12,15,18-hexaoxaeicosyl)-2,3-dihydroxysuccinamide;

[0384] (E)-3-(4-(4-(N-(20-amino-3,6,9,12,15,18-hexaoxaeicosyl)sulfamoyl)phenoxy)-3,5-difluorophenyl)-N-(diaminomethylene)-2-methylacrylamide];

[0385] (2R,3R)-N1,N4-bis(2-(2-(2-(2-(4-(4-((E)-3-(diaminomethyleneamino)-2-methyl-3-oxoprop-1-enyl)-2,6-difluorophenoxy)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0386] 2,2',2"-Nitrilotris(N-(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)acetamide);

[0387] N-(32-amino-3,6,9,12,15,18,21,24,27,30-decaoxatriacontacyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide;

[0388] N1,N3,N5-tris(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)benzene-1,3,5-tricarboxamide;

[0389] N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)terephthalamide;

[0390] N1,N31-bis(32-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonylamino)-3,6,9,12,15,18,21,24,27,30-decaoxatriacontyl)-4,7,10,13,16,19,22,25,28-nonaoxatriacontane-1,31-diamide;

[0391] 2R,3R)-N1,N4-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0392] N1,N3-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)benzene-1,3-disulfonamide;

[0393] N4,N4′-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)biphenyl-4,4′-disulfonamide;

[0394] (14R,15R)-1-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonylamino)-14,15-dihydroxy-13-oxo-3,6,9-trioxa-12-azahexadecane-16-oic acid;

[0395] (2S,3S)-N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

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

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

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

[0399] N1,N4-bis(2-(2-(2-(2-(4-((R or S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0400] N1,N4-bis(2-(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0401] N1,N3-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)isophthalamide;

[0402] (2R,3S)-N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0403] N1,N2-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)phthalamide;

[0404] N1,N4-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)terephthalamide;

[0405] 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-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

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

[0407] N1,N4-bis(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)terephthalamide;

[0408] N,N'-(10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecan-1,19-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0409] N,N'-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0410] N,N'-(2,2'-(2,2'-(2,2'-(1,4-phenylenebis(azanediyl))bis(oxymethylene)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-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0411] N,N'-(10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosane-1,26-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0412] Phenylenebis(azanediyl))bis(oxymethylene)bis(azanediyl)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(oxy)bis(ethane-2,1-diyl))bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide;

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

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

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

[0416] (2R,3R)-N1,N4-bis(2-(2-(2-(2-(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide;

[0417] (S or R)-N,N'-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,14,19,21-tetraazadotriacontane-1,32-diyl)bis(3-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0418] (S or R)-N,N'-(1,1'-(1,4-phenylenebis(azanediyl))bis(1-oxo-5,8,11-trioxa-2-azatridecan-13,1-diyl))bis(3-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0419] N1,N4-bis(2-(2-(2-(2-(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonylamino)ethoxy)ethoxy)ethoxy)ethyl)-terephthalamide;

[0420] N1-(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)succinamide;

[0421] N,N'-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,14,19,21-tetraazadotriacontane-1,32-diyl)bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0422] N,N'-(1,1'-(1,4-phenylenebis(azanediyl))bis(1-oxo-5,8,11-trioxa-2-azatridecan-13,1-diyl))bis(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0423] (S or R)-N,N'-(13-oxo-3,6,9,17,20,23-hexaoxa-12,14-diazapentacosane-1,25-diyl)bis(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide);

[0424] (S or R)-N,N'-(13,20-dioxo-3,6,9,24,27,30-hexaoxa-12,14,19,21-tetraazadotriacontane-1,32-diyl)bis(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide); or

[0425] (S or R)-N,N'-(1,1'-(1,4-phenylenebis(azanediyl))bis(1-oxo-5,8,11-trioxa-2-azatridecan-13,1-diyl))bis(4-((S or R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide).

[0426] In one embodiment, the NHE inhibitor is:

[0427]

[0428] In some embodiments, the compound has the structure of the following Formula (IH):

[0429]

[0430] or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,

[0431] in:

[0432] (a) n is an integer of 2 or greater;

[0433] (b) the core is a core portion having two or more sites thereon for attachment of two or more NHE-binding small molecule moieties;

[0434] (c) L is a bond or a linker connecting the core moiety to two or more NHE-binding small molecule moieties; and

[0435] (d) NHE is an NHE-binding small molecule moiety having the structure of the following formula (XI-H):

[0436]

[0437] in:

[0438] B is selected from the group consisting of aryl and heterocyclic groups;

[0439] Each R5 is independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1–4 Alkyl, optionally substituted C 1–4 Alkoxy, optionally substituted C 1–4 thioalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, 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 selected from the group consisting of hydrogen, C 1-4 an alkyl group or a bond connecting an NHE-binding small molecule moiety to L, provided that at least one is a bond connecting an NHE-binding small molecule moiety to L;

[0440] R3 and R4 are independently selected from the group consisting of hydrogen, optionally substituted C 1–4 alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; or

[0441] R3 and R4 together with the nitrogen to which they are bound form an optionally substituted 4-8 membered heterocyclyl; and

[0442] Each R1 is independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1–6 Alkyl and optionally substituted C 1–6 In some embodiments, n is 2. In certain embodiments, L is a polyalkylene glycol linker. In certain embodiments, L is a polyethylene glycol linker.

[0443] In certain embodiments, the core has the following structure:

[0444]

[0445] in:

[0446] X is selected from the group consisting of: a bond, –O–, –NH–, –S–, C 1–6 Alkylene, –NHC(=O)–, –C(=O)NH–, –NHC(=O)NH–, –SO2NH–, and –NHSO2–;

[0447] Y is selected from the group consisting of: a bond, an optionally substituted C 1-8 Alkylene, optionally substituted aryl, optionally substituted heteroaryl, polyethylene glycol linker, –(CH2) 1-6 O(CH2) 1-6 – and – (CH2) 1-6 NY1(CH2) 1–6 -;and

[0448] Y1 is selected from the group consisting of hydrogen, optionally substituted C 1-8 alkyl, optionally substituted aryl or optionally substituted heteroaryl.

[0449] In some embodiments, the core is selected from the group consisting of:

[0450]

[0451] In certain 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 selected from the group consisting of hydrogen and optionally substituted C 1–4 alkyl, or R3 and R4 together with the nitrogen to which they are bound form an optionally substituted 4-8 membered heterocyclic group;

[0455] Each R1 is independently selected from the group consisting of hydrogen, halogen, C 1–6 Alkyl and C 1–6 haloalkyl; and

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

[0457] In some embodiments, R3 and R4 together with the nitrogen to which they are bound form an optionally substituted 5 or 6 membered heterocyclic group. In certain embodiments, the optionally substituted 5 or 6 membered heterocyclic group is pyrrolidinyl or piperidinyl. In certain embodiments, the optionally substituted 5 or 6 membered heterocyclic group is pyrrolidinyl or piperidinyl, each substituted with at least one amino or hydroxyl group. In some embodiments, R3 and R4 are independently C 1–4 In some embodiments, R3 and R4 are methyl. 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 certain embodiments, the compound has the structure of Formula (II):

[0459]

[0460] or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, wherein:

[0461] (a) NHE is an NHE-binding small molecule moiety having the structure of the following formula (AI):

[0462]

[0463] in:

[0464] Each of 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, C 1-6 Alkyl, -C 1-6 Alkyl-OH or a bond connecting an NHE-bound small molecule to L, provided that at least one is a bond connecting an NHE-bound small molecule to L;

[0465] R4 is selected from H, C1-C7 alkyl or a bond connecting the NHE-bound small molecule and L;

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

[0467] Ar1 and Ar2 independently represent an aromatic ring or a heteroaromatic ring;

[0468] (b) Core is a core portion having a structure of the following formula (B1):

[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, -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 heterocyclyl, optionally substituted heterocyclylalkyl, 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;

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

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

[0478] (c) L is a bond or a linker connecting the core moiety to the NHE-binding small molecule moiety.

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

[0480]

[0481] in:

[0482] Each of 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, C 1-6 Alkyl, -C 1-6 Alkyl-OH or a bond connecting an NHE-bound small molecule to L, provided that at least one is a bond connecting an 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 certain embodiments, L is a polyethylene glycol linker. In some embodiments, X is C(X1). In some embodiments, each X c In certain embodiments, X is N. In certain embodiments, each Z a It's hydrogen.

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

[0487]

[0488] or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,

[0489] in:

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

[0491]

[0492] in:

[0493] Each of 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, C1-6 Alkyl, -C 1-6 Alkyl-OH or a bond connecting an NHE-bound small molecule to L, provided that at least one is a bond connecting an NHE-bound small molecule to L;

[0494] R4 is selected from H, C1-C7 alkyl or a bond connecting the NHE-bound small molecule and L;

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

[0496] Ar1 and Ar2 independently represent an aromatic ring or a heteroaromatic ring;

[0497] (b) Core is a core portion having a structure of the following formula (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;

[0504] Each Z a independently selected from hydrogen and C 1-6 alkyl; and

[0505] (c) L is a bond or a linker that connects the core moiety to the NHE-binding small molecule.

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

[0507]

[0508] in:

[0509] Each of 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, C 1-6 Alkyl, -C 1-6 Alkyl-OH or a bond connecting an NHE-bound small molecule to L, provided that at least one is a bond connecting an NHE-bound small molecule to L.

[0510] In certain 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 pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers thereof,

[0515] in:

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

[0517] W is independently at each occurrence S(O)2, C(O) or -(CH2) m -; Z is independently at each occurrence a bond, C(O) or -C(O)NH-;

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

[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 independently at each occurrence an integer from 0 to 8;

[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 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more halogen, OH, CN, -NO2, oxo, -SR 9 、–OR 9 ,–NHR 9 、-NR 9 R 10 、–S(O)2N(R 9 )2–、–S(O)2R 9 ,–C(O)R 9 、–C(O)OR 9 ,–C(O)NR 9 R 10 ,–NR 9 S(O)2R 10 、-S(O)R 9 、-S(O)NR 9 R 10 、-NR 8 S(O)R 9 , C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, heterocycle, aryl or heteroaryl substituted; or

[0525] R 1 and R 2 Together with the nitrogen to which they are attached, they can form a heterocyclic or heteroaryl group containing 1 to 5 heteroatoms selected from the group consisting of N, S, P and O, wherein the heterocyclic or heteroaryl group is optionally substituted by one or more halogen, OH, CN, -NO2, oxo, -SR 9 、–OR 9 ,–NHR 9 、-NR 9 R 10 、–S(O)2N(R 9 )2–、–S(O)2R 9 ,–C(O)R 9 、–C(O)OR 9 ,–C(O)NR 9 R 10 ,–NR 9 S(O)2R10 、-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, heterocyclyl, heterocycle, aryl or heteroaryl substituted;

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

[0527] R 5 、R 6 、R 7 and R 8 are independently H, halogen, OH, CN, –NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 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 10 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1-5 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 are independently H, C1-C6 alkyl, OH, NH2, CN or NO2;

[0531] R 13 is independently at each occurrence a bond, H, C1-C6 alkyl, C4-C8 cycloalkenyl, C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each cycloalkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally replaced by one or more R 19 replace;

[0532] R 14 is independently H, C1-C6 alkyl or C1-C6 haloalkyl at each occurrence; or

[0533] R 6 and R 14 Together with the atoms to which they are attached, they may independently combine at each occurrence to form a 5- to 6-membered heterocyclyl, wherein each C3-C8 cycloalkyl or heterocyclyl is optionally replaced by one or more R 19 replace; or

[0534] R 13 and R 14 Together with the atoms to which they are attached, they may independently combine at each occurrence to form a C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each heterocyclyl or heteroaryl is optionally substituted by one or more R 19 replace;

[0535] R 15 、R 16 、R 17 and R 18 is independently H, OH, NH2 or C1-C3 alkyl at each occurrence, wherein said alkyl is optionally substituted by one or more R 19 replace; and

[0536] R 19 is independently at each occurrence H, OH, NH2, oxo, C1-C6 alkyl, C1-C6H haloalkyl, C1-C6 alkoxy.

[0537] In one embodiment, the NHE3 inhibitor is a compound according to the preceding formula, with the proviso that:

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

[0539] (2) When X is a bond, O or CR 11 R12 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) In this case, only one of Q or X is -NHC(O)NH-,

[0543] (6)R 1 and R 2 Together with the nitrogen to which they are attached they cannot form a pyrrolidinyl group;

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

[0545] (8) When R 1 and R 2 Together with the nitrogen to which they are attached, they form a piperidinyl group, R 3 and R 4 is a halogen and R 5 and R 8 When H is present, the linker is not or

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

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

[0548]

[0549] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers and tautomers thereof, 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 at each occurrence a bond, C(O) or -C(O)NH-;

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

[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 independently at each occurrence an integer from 0 to 8;

[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 are 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 are independently H, halogen, OH, CN, –NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 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 ;

[0561] R 7 is independently H, C1-C6 alkyl or C1-C6 haloalkyl at each occurrence;

[0562] R 8 is independently at each occurrence a bond, H, C1-C6 alkyl, C4-C8 cycloalkenyl, C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each cycloalkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally replaced by one or more R 17 replace; or

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

[0564] R 9 and R 10 are independently H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O;

[0565] R 11 and R 12 are independently H, C1-C6 alkyl, OH, NH2, CN or NO2;

[0566] R 13 、R 14 、R 15 and R 16 is independently H, OH, NH2 or C1-C3 alkyl at each occurrence, wherein said alkyl is optionally substituted by one or more R 17 replace; and

[0567] R 17 is independently at each occurrence 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, with the proviso that:

[0569] (1) When X is a bond, O or CR 11 R12 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) In this case, only one of Q or X is --NHC(O)NH-;

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

[0574] (6) When R 1 and R 2 is chlorine, Q is -NHC(O)NH- and R 3 、R 4 、R 5 and R 6 When H is present, 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-tetrahydroisoquinolin-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-tetrahydroisoquinolin-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-tetrahydroisoquinolin-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-tetrahydroisoquinolin-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-tetrahydroisoquinolin-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-tetrahydroisoquinolin-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-tetrahydroisoquinolin-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-tetrahydroisoquinolin-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-tetrahydroisoquinolin-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-tetrahydroisoquinolin-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-tetrahydroisoquinolin-4-yl)-4-fluorobenzenesulfonamide];

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0611] N,N′-[(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosane-1,20-diyl)bis(piperidin-1,4-diyl)]bis[3-(6-chloro-2,8-dimethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide];

[0612] N,N′-[(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaeicosane-1,20-diyl)bis(piperidin-1,4-diyl)]bis[3-(6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide];

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

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

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

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

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

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

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

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

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

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

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

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

[0627] N 1 ,N18 -bis(1-[(3-[(S)-6-chloro-8-cyano-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]phenyl)sulfonyl]piperidin-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide; or

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

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

[0630]

[0631] In one embodiment of the present 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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonylamino]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-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]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-inden-1-yl]oxy]-3-fluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonylamino]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-inden-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonylamino]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-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]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-inden-1-yl]oxy]-3-fluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonylamino]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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonylamino]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-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]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-inden-1-yl]oxy]-3-fluorobenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonylamino]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-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

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

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

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

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

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

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

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

[0685] 3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]pyrrolidin-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-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]pyrrolidin-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-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]pyrrolidin-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-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]pyrrolidin-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-inden-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-inden-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-inden-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-2,3,4,5-tetrahydroxyadipamide;

[0691] 3-[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-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-inden-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-inden-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-inden-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-inden-1-yloxy)phenylsulfonamide]butyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-tetrahydro-[1,3]dioxino[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-inden-1-yloxy)phenylsulfonylamino]hexyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-tetrahydro-[1,3]dioxino[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-inden-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-inden-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-inden-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-inden-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-inden-1-yl]oxy]benzene)sulfonylamino]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-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-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonylamino]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-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]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-inden-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonylamino]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-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

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

[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-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)ethoxy]ethoxy]ethyl)sulfamoyl]-2-methylphenoxy]-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperazine-1-carboxamide;

[0711] 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonylamino]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3,5-difluorophenyl]sulfonylamino)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]-3,5-difluorobenzenesulfonamide;

[0720] 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]-2-oxopyrrolidin-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-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonylamino]-2-oxopyrrolidin-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-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;

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

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

[0729] 1-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)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-inden-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-inden-1-yl]oxy]benzene)sulfonylamino]propyloxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonylamino]propyloxy]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-inden-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-inden-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-inden-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-inden-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-inden-1-yl]oxy]benzene)sulfonylamino]-2-methylpropyloxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonylamino]-2-methylpropyloxy]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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-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-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-2-[(R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy)-2-chlorophenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]-2-chlorobenzenesulfonamide;

[0738] 4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide; tetrakis(trifluoroacetate);

[0739] 4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide; tetrakis(trifluoroacetate);

[0740] 4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; tetrakis(trifluoroacetate);

[0741] 4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; tetrakis(trifluoroacetate);

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

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

[0744] 4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)-3-fluorobenzenesulfonamide; tetrakis(trifluoroacetate);

[0745] 4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)-3-fluorobenzenesulfonamide; tetrakis(trifluoroacetate);

[0746] 4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamide; tetrakis(trifluoroacetate);

[0747] 4-([(1S,2S)-6-Chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-Chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamide; tetrakis(trifluoroacetate);

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

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

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

[0751] N1,N14-bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonylamino)pyrrolidin-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-inden-1-yl]oxy)phenyl]sulfonylamino)pyrrolidin-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-inden-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-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide;

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

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

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

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

[0759] 4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;

[0760] 4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;

[0761] 4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;

[0762] 4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;

[0763] 4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;

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

[0765] 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;

[0766] 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;

[0767] 4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;

[0768] 4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;

[0769] 4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;

[0770] 4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;

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

[0772] 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[2-(2-[2-(3-[(1r,4r)-4-(3-[2-(2-[2-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)ethoxy]ethoxy)ethyl]ureido)cyclohexyl]ureido)ethoxy]ethoxy)ethyl]benzenesulfonamide;

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

[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-inden-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-inden-1-yl]oxy)-N-(3-oxo-7,10-dioxa-2,4-diazadodec-12-yl)benzenesulfonamide;

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

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

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

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

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

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

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

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

[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-inden-1-yl]oxy)-3,4-dihydroisoquinolin-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-inden-1-yl]oxy)-3,4-dihydroisoquinolin-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-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide];

[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-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide];

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

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

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

[0793] N1,N14-bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonylamino)pyrrolidin-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-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)piperidin-4-yl]benzenesulfonamide;

[0795] 4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;

[0796] N1,N14-bis(2-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonylamino)pyrrolidin-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-inden-1-yl]oxy)-1-oxoisoindolin-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-inden-1-yl]oxy)-1-oxoisoindolin-2-yl]ethoxy)ethyl]urea).

[0799] Example

[0800] The present invention will be more fully understood by reference to the following examples. However, they should not be construed as limiting the scope of the present invention. For example, the synthesis of compounds not illustrated can be successfully performed by modifications apparent to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and / or by routinely varying 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-icosahydro-2-carboxylic 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-octahydroquinone-3-carboxylic acid (1-2)

[0804] To a 1-L pressure tank reactor (10 atm) purged and maintained with a CO inert atmosphere was added (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-octahydroquinone-2-carboxylic acid benzyl ester 1-1 (prepared according to the method described in U.S. Patent Application No. 20160151387) (11 g, 15.92 mmol, 1.00 equiv), tetrakis(triphenylphosphine)palladium(0) (4 g, 3.46 mmol, 0.20 equiv), THF (250 mL) and water (150 mL). The resulting solution was stirred at 400 °C for 1 h. The resulting solution was extracted with CH2Cl2 (3×150 mL) and the organic layers were combined. The resulting mixture was washed with brine (3×150 mL). The mixture was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was applied to a silica gel column using EtOAc / petroleum ether (1:10) (20 mL). The crude product was purified by flash preparative HPLC under the following conditions: (CombiFlash-1) C 18 Silica gel; mobile phase:

[0805] MeCN:water=100:0; detector: UV 254 nm. 1 L of product was obtained. This yielded 6.5 g (69.6%) of 1-2 as a light 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-octahydroquinone-2,10-dicarboxylic acid 2-benzyl ester (1-3)

[0807] TEA (3 mL, 5.80 eq) was added dropwise to a DMF (30 mL) solution of 1-2 (3 g, 5.11 mmol, 1 eq) and DMAP (102.4 mg, 0.84 mmol, 0.10 eq) at 0°C with stirring. 2-(Trimethylsilyl)ethoxymethyl chloride (4.2 mL, 4.8 eq) was then added dropwise at 0°C with stirring. The reaction was stirred at room temperature for 1.5 hours and then quenched by the addition of aqueous K2CO3 solution (50 mL). The mixture was diluted with CHCl (250 mL), washed with brine (3×150 mL), dried over (Na2SO4) and concentrated in vacuo. The residue was purified by eluting with EtOAc / petroleum ether (1:10) on a silica gel column. This yielded 3.5 g (95.5%) of 1-3 as a light 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-icosahydroquinone-2-carboxylic acid (1-4)

[0809] To a 300-mL pressure tank reactor (40 atm) purged and maintained with an inert atmosphere of hydrogen was added 1-3 (6.6 g, 9.20 mmol, 1.00 equiv), Pd / C (1.32 g, 0.20 equiv), and acetone (150 mL). The reaction was stirred at 50° C. overnight and then concentrated in vacuo. This 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-icosapentaenoic acid-2,10-dicarboxylic acid 2-benzyl ester (1-5)

[0811] A solution of 1-4 (5.25 g, 8.35 mmol, 1 eq), cesium carbonate (4.1 g, 12.58 mmol, 1.5 eq), and benzyl bromide (2.86 g, 16.72 mmol, 2 eq) in DMF (70 mL) was stirred at 60° C. for 2 hours. The reaction 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 silica gel column eluting with EtOAc / petroleum ether (1:10). This yielded 6 g (99%) of 1-5 as an off-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-icosahydro-3-carboxylic acid (1-6)

[0813] Hydrogen chloride (4M in dioxane, 30 mL) was added to a solution of 1-5 (5.6 g, 7.79 mmol, 1 equivalent) in THF (40 mL), and the reaction was stirred at 60 ° C for 2 hours. The solution was adjusted to pH = 3 with aqueous sodium bicarbonate solution (saturated). 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 flash preparative HPLC under the following conditions: (CombiFlash-1)-column: C 18Silica gel; mobile phase: MeCN: water = 100:0; detector: UV 254 nm. This yielded 3.1 g (68%, 97% purity) of 1-6 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-icosahydroquinone-2-carboxylic acid benzyl ester (1-7)

[0815] 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 CH2Cl2 (50 mL) at room temperature. The mixture was stirred at room temperature for 1 hour and then evaporated to dryness. The material was used in the next step without purification.

[0816] Synthesis of 2-benzyl 10-methyl (2S,4aS,6aS,6bR,8aS,10S,12aS,12bR,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2,10-dicarboxylate (1-8)

[0817] A solution of 1-7 (200 mg, 0.33 mmol, 1 eq) and TEA (0.274 mL, 6 eq) in MeOH (20 mL) was stirred at room temperature overnight. The reaction was concentrated in vacuo. This yielded 198 mg (100%) of 1-8 as a pale yellow crude 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-icosahydro-2-carboxylic acid (1-9)

[0819] A solution of 1-8 (198 mg, 0.33 mmol, 1.00 equiv) 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 was filtered and concentrated in vacuo. The crude product (200 mg) was purified by preparative HPLC under the following conditions: – Column: XBridge Prep C18 OBD, 190*150 mm, 5 m; Mobile phase: water (10 mM NH4HCO3 + 0.1% NH4OH) and CH3CN (50.0% CH3CN reached 62.0% in 7 minutes); Detector: UV 254 / 220 nm. This produced 111.8 mg (66%) of 1-9 as a light 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-icosapentaenoic acid-2-carboxylic 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-icosapentaenoic acid-2-carboxylic acid diphenylmethyl ester (76-2)

[0823] A solution of 76-1 (prepared as described in Bioorg. Med. Chem. 2010, 18, 433-454) (1.674 g, 2.63 mmol, 1 eq), NaHMDS (2.63 mL, 2 eq), 3-bromoprop-1-yne (0.45 mL, 2 eq), and tetrabutylammonium iodide (486 mg, 1.32 mmol, 0.5 eq) in THF (2 mL) was stirred at room temperature overnight. The reaction was diluted with water (30 mL) and extracted with DCM (2×50 mL). The extract was dried over (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:10). This yielded 1.395 g (79%) of 76-2 as a light yellow solid.

[0824] Synthesis of 2-(((3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzhydryloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydroquinone-3-yl)oxy)acetic acid (78-1)

[0825] A solution of ruthenium(III) chloride hydrate (20 mg, 0.10 mmol, 6.8 equiv), 76-2 (100 mg, 0.15 mmol, 1 equiv), sodium periodate (150 mg, 0.70 mmol, 5 equiv) in THF (4 mL) and water (1 mL) was stirred at room temperature for 2 hours. The reaction was diluted with water (20 mL) and extracted with DCM (2×50 mL). The extract was dried over (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by eluting with EtOAc / petroleum ether (1:5) on 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-icosahydroquinone-2-carboxylic acid (78-2)

[0827] A solution of 78-1 (148 mg, 0.21 mmol, 1 equiv) and Pd / C (100 mg) in EtOAc (15 mL) was placed under a hydrogen atmosphere (1 atm) and stirred at room temperature overnight. The reaction was filtered and concentrated in vacuo. The residue was purified by preparative HPLC under the following conditions: - Column: XBridge Shield RP18 OBD, 5 m, 19*150 mm; Mobile phase: water (0.05% NH4OH) and CH3CN (10.0% CH3CN to 40.0% in 8 minutes); 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-icosapentaenoic acid-2-carboxylic 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-icosahydroquinone-2-carboxylic acid benzyl ester (120-2)

[0831] 120 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-icosapentaenoic acid -1 (prepared as described in Bioorg. Med. Chem. 2010, 18, 433-454) (1.0 g, 1.7 mmol, 1 equivalent), sodium tetrachloropalladate (II) (0.76 g, 2.04 mmol, 1.2 equivalents) and sodium acetate (0.21 g, 1.36 mmol, 0.8 equivalents) in acetic acid (100 mL) was stirred at room temperature for 72 hours. The reactants were poured onto ice, the resulting precipitate was collected by filtration and dried under vacuum. DCM (120 mL), acetic anhydride (0.435 g, 3.24 mmol, 1.8 equivalents), TEA (0.364 g, 2.72 mmol, 1.6 equivalents) and DMAP (6 mg, 0.02 equivalents) were added and the mixture was stirred at room temperature for 1 hour. The reactants were washed with water (1x300 mL), dried over (Na2SO4) and concentrated in vacuo. Pyridine (0.6 mL) and THF (100 mL) were added, and the mixture was stirred at room temperature for 15 minutes. The reactants were cooled to -78 ° C in a dry ice / acetone bath, and a solution of lead tetraacetate (4.9 g, 8.5 mmol, 5 equivalents) in acetic acid (100 mL) was slowly added. The mixture was allowed to warm to room temperature and stirred at room temperature for 16 hours. A solution of sodium borohydride (60 mg) in 1N NaOH aqueous solution (50 mL) was added and stirring was continued for 10 minutes. The reactants were filtered through celite and extracted with DCM (300 mL). The extracts were washed with saturated NaHCO3 aqueous solution (3×300 mL) and brine (2×300 mL), dried over (Na2SO4) and concentrated in vacuo. This produced 1.03 g (88%, crude) of 120-2 as a light 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-icosahydroquinone-2-carboxylic acid benzyl ester (120-3)

[0833] A solution of 120-2 (1.03 g, 1.53 mmol, 1 eq) and sodium carbonate (820 mg, 7.74 mmol, 5 eq) in MeOH (120 mL) was stirred at room temperature for 16 hours. The reaction was concentrated in vacuo and the residue was dissolved in DCM (200 mL). The mixture was washed with saturated aqueous sodium bicarbonate solution (2 × 200 mL) and brine (1 × 200 mL) and concentrated in vacuo. This produced 1.1 g (crude) of 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-icosapentaenoic acid-2-carboxylic acid benzyl ester (120-4)

[0835] A solution of 120-3 (1.1 g, 1.87 mmol, 1 eq) in THF (70 mL) was added dropwise to a solution of ammonium acetate (3.88 g, 27 eq) and titanium (III) chloride (4 mL) in water (80 mL). The reaction was stirred at room temperature overnight and then partially concentrated under vacuum. The remaining solution was extracted with DCM (200 mL), washed with saturated aqueous sodium bicarbonate solution (1×200 mL) and brine (1×200 mL), dried over (Na2SO4) and concentrated in vacuo. The residue was purified by eluting with EtOAc / petroleum ether (1:1) on a silica gel column. This produced 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-icosapentaenoic acid-2-carboxylic 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 was filtered and concentrated in vacuo. The residue was purified by preparative HPLC under the following conditions: - Column: XBridge Shield RP18OBD, 5 mm, 19*150 mm; Mobile phase: water (0.05% TFA) and MeCN (in 10 minutes) 20.0% MeCN 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] 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-icosahydroquinone-2-carboxylic acid benzyl ester (121-1)

[0839] A solution of 120-4 (150 mg, 0.26 mmol, 1 eq) and sodium borohydride (40 mg, 1.06 mmol, 4 eq) 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 in vacuo. 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] 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-icosahydro-2-carboxylic 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 was filtered and concentrated in vacuo. The residue was purified by preparative HPLC under the following conditions: - Column: XBridge Shield RP18OBD, 5m, 19*150mm; Mobile phase: water (0.05% TFA) and MeCN (42.0% MeCN to 57.0% in 8 minutes); Detector: UV 254nm. This produced 37.9 mg (25%) of 121-2 as a white solid. MS (ES, m / z): [M+H] + =487.25; 1 H NMR (400 MHz, MeOH-d 4, ppm): 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,4H),2.10-2. 27(m,2H),2.51(s,1H),2.73(dt,J=13.5,3.6Hz,1H),3.29-3.32(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-icosapentaenoic acid-2,9-dicarboxylic acid (122-3)

[0843]

[0844] 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-icosahydroquinone-2-carboxylic acid benzyl ester (122-1)

[0845] A solution of 121-1 (300 mg, 0.52 mmol, 1 eq), pH 8.6 phosphate buffer (5 mL), TEMPO (240 mg, 1.54 mmol, 3 eq), tetrabutylammonium chloride (0.36 g, 2.5 eq), and N-chlorosuccinimide (280 mg, 2.10 mmol, 4 eq) in DCM (25 mL) was stirred at 40° C. overnight. The reaction was extracted with DCM (200 mL). The extract was washed with water (1×200 mL) and brine (1×200 mL), dried over Na 2 SO 4 , 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-icosapentaenoic acid-4-carboxylic acid (122-2)

[0847] A solution of 122-1 (400 mg, 0.70 mmol, 1 eq), 2-methylbut-2-ene (2 mL), sodium dihydrogen phosphate (0.5 g, 6.00 eq) and sodium chlorite (0.38 g, 6.00 eq) in water (6 mL) and tert-butanol (12 mL) was stirred at -2°C for 30 minutes. The reaction was partially concentrated under vacuum and the residue was extracted with DCM (200 mL). The extract was washed with brine (1 x 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-icosapentaenoic acid-2,9-dicarboxylic 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 was filtered and concentrated in vacuo. The residue was purified by preparative HPLC under the following conditions: - Column: XBridge Shield RP18 OBD, 5 m, 19*150 mm; Mobile phase: water (0.05% TFA) and MeCN (38.0% MeCN to 55.0% in 8 minutes); 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-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 (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-icosapentaenoic acid-2,10-dicarboxylic acid 2-benzyl 10-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester (176-1)

[0853] A solution of 1-6 (400 mg, 0.68 mmol, 1 eq), potassium iodide (56 mg, 0.5 eq), 4-(chloromethyl)-5-methyl-2H-1,3-dioxol-2-one (182 mg, 1.23 mmol, 1.8 eq) and potassium carbonate (282 mg, 2.04 mmol, 3 eq) in DMF (2.5 mL) was stirred at 60 ° C for 2 hours. The reaction was diluted with EtOAc, washed with water and brine, dried over (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:3). This yielded 460 mg (97%) of 176-1 as a light 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-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 (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 was filtered and concentrated. The residue was purified by preparative HPLC under the following conditions: - Column: XBridge Shield RP18 OBD, 5 m, 19*150 mm; Mobile phase: water (0.05% TFA) and MeCN (68% phase B to 77% in 10 minutes); 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-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-2-carboxylic 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 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 reached 84% in 1 minute and 93% in 7 minutes); 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-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-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-icosahydro-3-yl-2,5,8,11-tetraoxatetradecanoate-14-oate (190-1)

[0862] EDCI (250 mg, 1.30 mmol, 2.5 eq) was added to a solution of 122-1 (300 mg, 0.52 mmol, 1 eq), 2,5,8,11-tetraoxatetradecane-14-oic acid (370 mg, 1.57 mmol, 3 eq) and DMAP (130 mg, 1.06 mmol, 2 eq) in DCM (20 mL). The reaction was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was purified by eluting with EtOAc / hexane (2:1) on 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-tetraoxatetradec-14-yl)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-icosahydro-4-carboxylic acid (190-2)

[0864] A solution of 190-1 (200 mg, 0.25 mmol, 1 eq), 2-methylprop-1-ene (2 mL), sodium dihydrogen phosphate (0.18 g, 6.00 eq) and sodium chlorite (0.14 g, 6.00 eq) in tert-butanol (9 mL) and water (3 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, diluted with DCM, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. 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-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-2-carboxylic 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-icosapentaenoic acid-2-carboxylic acid diphenylmethyl ester (194-1)

[0868] To a 2-L round-bottom flask was added 76-1 (prepared as described in Bioorg. Med. Chem. 2010, 18, 433-454) (105 g, 165 mmol, 1 eq), CHCl (800 mL), and Dess-Martin periodinane (139.8 g, 330 mmol, 2 eq). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of 300 mL of sodium bicarbonate. The reaction mixture was washed with 3 × 1 L of H2O. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was recrystallized from petroleum ether and CHCl to afford 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-icosahydroquinone-2-carboxylic acid diphenylmethyl ester (194-2)

[0870] To a 2-L round-bottom flask was added 194-1 (59.5 g, 93.7 mmol, 1 eq), pyridine (1 L), and NH2OH·HCl (23.2 g, 335 mmol, 3.6 eq). The reaction slurry was stirred at 70°C for 1 hour. The reaction mixture was concentrated in vacuo, diluted with 2 L of CHCl2, and washed with 4 × 1 L of 3N HCl and 1 L of brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was recrystallized from CHCl2 / petroleum ether to afford 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-icosahydroquinone-2-carboxylic acid diphenylmethyl ester (194-3)

[0872] To a 2-L round-bottom flask was added 194-2 (53.4 g, 82.2 mmol, 1 eq), AcOH (400 mL), Ac2O (400 mL), Pd(OAc)2 (3.3 g, 14.8 mmol, 0.18 eq) and PhI(OAc)2 (31.8 g, 98.6 mmol, 1.2 eq). The reaction slurry was stirred at 60 °C overnight. The reaction mixture was concentrated, diluted in CH2Cl2, and washed with saturated NaHCO 3(水溶液) The residue was purified by column chromatography on silica gel with 0-40% EtOAc in petroleum ether to afford 194-3 (31.3 g, 51%) as a light yellow solid (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-icosapentaenoic acid-2-carboxylic acid diphenylmethyl ester (194-4)

[0874] To a 1000-mL round-bottom flask was added benzhydryl 194-3 (15 g, 20 mmol), THF (90 mL), MeOH (90 mL), acetone (90 mL), and 2N HCl (90 mL). The reaction slurry was stirred at 50°C overnight. The reaction mixture was concentrated, diluted with CHCl, and washed with 2×300 mL of saturated NaHCO and 2×300 mL of brine. The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The solid was dried in an oven under reduced pressure. The residue was applied to a silica gel column with CHCl / ethyl acetate (4:1) to afford 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-icosapentaenoic acid-2-carboxylic acid diphenylmethyl ester (194-5)

[0876] To a stirred solution of 194-4 (10 g, 15.4 mmol) in methanol (200 mL) was added NaBH4 (0.6 g, 17 mmol, 1.1 equivalents) in portions at -10 ° C. 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 with ethyl acetate (0% to 60% in 30 minutes) / petroleum ether to give 8.4 g (84%) of 194-5 as a white foam (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-icosahydroquinone-2-carboxylic acid diphenylmethyl ester (194-6)

[0878] To a 250-mL round-bottom flask was added 194-5 (4 g, 6.13 mmol), CHCl (40 mL), pH 8.6 buffer (20 mL), TEMPO (2.87 g, 18.4 mmol, 3 equiv), TBACl (4.26 g), and NCS (3.2 g, 24 mmol, 3.9 equiv). The resulting solution was stirred at 40°C for 1.5 hours. The reaction mixture was cooled and extracted with 3×50 mL of CHCl. ​​The combined organic layers were washed with 2×100 mL of brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was applied to a silica gel column with ethyl acetate (0-60%) / petroleum ether to afford 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-((benzhydryloxy)carbonyl)-3-hydroxy-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydro-4-carboxylic acid (194-7)

[0880] 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) was added NaH2PO4 (4.4 g, 36.87 mmol, 6 equiv) at 0°C. To the above mixture was added NaClO2 (3.3 g, 37 mmol, 6 equiv) in portions at 0°C. The reaction slurry was stirred at room temperature for 2 hours. The reaction mixture was extracted with CHCl2, 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 light 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-((benzhydryloxy)carbonyl)-3-hydroxy-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydro-4-carboxylic acid (194-8)

[0882] A solution of 194-7 (6.0 g, 9 mmol), K2CO3 (3.7 g, 27 mmol, 3 equiv) and KI (0.75 g, 4.5 mmol, 0.5 equiv) in DMF was stirred at 60°C for 2 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 eluting with 2:1 petroleum ether / EtOAc to give 194-8 (6.0 g, 86%) as a light 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] Synthesis of (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-icosapentaenoic acid-2,9-dicarboxylic acid 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester (194-9)

[0884] EDCI (250 mg, 1.30 mmol, 5 eq) was added to a solution of 194-8 (200 mg, 0.26 mmol, 1 eq), 2-(methylsulfanyl)acetic acid (270 mg, 2.54 mmol, 10 eq) and DMAP (120 mg, 0.98 mmol, 4 eq) in CHCl (4 mL). The reaction was stirred at room temperature overnight and concentrated in vacuo. The residue was purified on a silica gel column using 1:1 EtOAc: petroleum ether to afford 240 mg (quantitative) of 194-9 as a light 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-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-icosahydroquinone-2-carboxylic acid (194-10)

[0886] A solution of 194-9 (130 mg, 0.15 mmol, 1 eq) and TFA (0.2 mL) in CH2Cl2 (2 mL) was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and the residue was purified by preparative HPLC under the following conditions: Column: XBridgeShield RP18 OBD, 30*150 mm, 5 m; Mobile phase: Water (0.05% TFA) and MeCN (65% Phase B to 75% in 8 minutes); Detector: UV. This yielded 24.8 mg (24%) of 194-10 as an off-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-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-2-carboxylic 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-(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-2,9-dicarboxylic acid 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester (195-1)

[0890] EDCI (175 mg, 0.91 mmol, 5 eq) was added to a solution of 194-8 (140 mg, 0.18 mmol, 1 eq), 2-methanesulfonylacetic acid (248 mg, 1.80 mmol, 10 eq) and DMAP (84 mg, 0.69 mmol, 4 eq) in CHCl (2.5 mL) and the reaction was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel column purification using EtOAc / petroleum ether (1 / 1). This yielded 160 mg (99%) of 195-1 as a light 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-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-icosahydroquinone-2-carboxylic acid (195-2)

[0892] A mixture of 195-1 (100 mg, 0.11 mmol, 1 eq) and TFA (0.1 mL, 0.01 eq) in DCM was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions: - Column: XBridge Shield RP18 OBD, 5 m, 19*150 mm; Mobile phase: Water (0.05% TFA) and MeCN (50% phase B to 63% in 13 minutes); Detector: UV. This yielded 195-2 (35.1 mg, 43.06%) as a light 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-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-2-carboxylic acid (196-2)

[0894]

[0895] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((tert-butoxycarbonyl)-L-valyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2,9-dicarboxylic acid 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester (196-1)

[0896] EDCI (172.3 mg, 0.90 mmol, 5 equiv) was added to a DCM solution of 194-8 (140 mg, 0.18 mmol, 1 equiv), (2S)-2-[[(tert-butoxy)carbonyl]amino]-3-methylbutanoic acid (195.2 mg, 0.90 mmol, 5 equiv) and DMAP (87.8 mg, 0.72 mmol, 4 equiv). The reaction was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / EtOAc 1:1) to give 196-1 (170 mg, 96.70%) as a light yellow solid.

[0897] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((L-valyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (196-2)

[0898] A solution of 196-1 (170 mg, 0.17 mmol, 1 eq) and TFA (0.15 mL, 2.02 mmol, 12 eq) in DCM was stirred at room temperature for 1 hour and then concentrated in vacuo. The crude product was purified by preparative HPLC 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 in 8 minutes; Detector: UV 254 nm, to afford 196-2 (51.5 mg, 41.63%) as an off-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-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-icosahydroquinone-2-carboxylic 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-icosapentaenoic acid-2,9-dicarboxylic acid 2-benzyl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester (197-1)

[0902] EDCI (175 mg, 0.91 mmol, 5 eq) was added to a solution of 194-8 (140 mg, 0.18 mmol, 1 eq), benzoic acid (110 mg, 0.90 mmol, 5 eq) and DMAP (84 mg, 0.69 mmol, 4 eq) in DCM (2.5 mL). The reaction was stirred at room temperature overnight and then concentrated in vacuo. The residue was purified by eluting with EtOAc / petroleum ether (1 / 1) on a silica gel column. This yielded 160 mg (101%) of 197-1 as a light 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-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-icosahydroquinone-2-carboxylic acid (197-2)

[0904] A solution of 197-1 (160 mg, 0.18 mmol, 1 eq) and TFA (0.2 mL, 2.69 mmol, 15 eq) in DCM was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo, and the residue was purified by preparative TLC under the following conditions: Column: Xselect CSH OBD, 30 x 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, to afford 197-2 (27.8 mg, 21.40%) as an off-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-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)

[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-icosapentaenoic-2,9-dicarboxylic acid 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester (198-1)

[0908] EDCI (250 mg, 1.30 mmol, 5 eq) was added to a solution of 194-8 (200 mg, 0.26 mmol, 1 eq), cyclopropanecarboxylic acid (220 mg, 2.56 mmol, 10 eq) and DMAP (120 mg, 0.98 mmol, 4 eq) in DCM (4 mL) and the reaction was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was purified by eluting with EtOAc / petroleum ether (1 / 1) on a silica gel column. This yielded 230 mg (106%) of 198-1 as a light 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-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-icosahydroquinone-2-carboxylic acid (198-2)

[0910] A solution of 198-1 (115 mg, 0.14 mmol, 1 equiv) and TFA (0.15 mL) in DCM (1.5 mL) was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and the residue (115 mg) was purified by preparative HPLC 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: 30% B to 60% B in 8 minutes; Detector: 254 nm. This yielded 26.9 mg (29%) of 198-2 as an off-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-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-2-carboxylic acid (203-2)

[0912]

[0913] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((R)-2-methoxypropanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic-2,9-dicarboxylic acid 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester (203-1)

[0914] EDCI (240 mg, 1 mmol, 5 equivalents) was added to a DCM (2 mL) 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) and the reaction was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the residue was purified by a silica gel column using EtOAc / petroleum ether (1 / 1). This produced 150 mg of 203-1 as a light yellow solid.

[0915] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((R)-2-methoxypropanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydroquinone-2-carboxylic acid (203-2)

[0916] A solution of 203-1 (150 mg, 0.17 mmol, 1 eq) and TFA (0.2 mL) in DCM (2 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated and the residue was purified by flash preparative HPLC to give 47.5 mg (39.20%) of 203-1 as a white solid. MS (ES, m / z): [M+H] + =699; 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-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-2-carboxylic acid (204-2)

[0918]

[0919] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((S)-2-methoxypropanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic-2,9-dicarboxylic acid 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester (204-1)

[0920] EDCI (240 mg, 1.2 mmol, 5 equiv) was added to a solution of 194-8 (200 mg, 0.2 mmol, 1 equiv), (2S)-2-methoxypropionic acid (132 mg, 1.2 mmol, 5 equiv) and DMAP (120 mg, 0.8 mmol, 4 equiv) in DCM (2 mL) and the reaction was stirred at 25 ° C for 3 hours. The mixture was concentrated in vacuo and the residue was purified by a silica gel column using EtOAc / petroleum ether (1 / 1). This gave 150 mg of 204-1 as a light yellow solid.

[0921] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(((S)-2-methoxypropanoyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydroquinone-2-carboxylic acid (204-2)

[0922] A solution of 204-1 (150 mg, 0.17 mmol, 1 eq) and TFA (0.2 mL, 0.01 eq) in DCM (2 mL) was stirred at 25°C for 2 hours. The reaction was concentrated and the crude product 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 MeCN (57% Phase B to 85% in 8 minutes); Detector: UV. This yielded 204-2 as a white solid. MS (ES, m / z): [M+H] + =699; 1 H NMR (300 MHz, chloroform-d) δ 5.72 (s, 1H), 5.26 (dd, J = 11.6, 4.9 Hz, 1H), 4.98 (d, J = 13.7 Hz, 1H), 4.68 (d, J = 13.8 Hz, 1H), 3.79 (t, J = 6.9 Hz, 1H), 3.36 (s, 3H), 2.89 (d, J = 13.8 Hz, 1 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-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 (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-icosapentaenoic acid-2,9-dicarboxylic acid 2-benzyl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester (205-1)

[0926] Bromo(methoxy)methane (0.063 mL, 4.0 eq) was added dropwise to a solution of 194-8 (150 mg, 1 eq) and DIEA (0.318 mL, 10.0 eq) in DCM (10 mL) at 0°C, followed by heating at 60°C for 1 hour. The reaction was concentrated and the residue was purified by silica gel column with 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-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-icosahydroquinone-2-carboxylic 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 in vacuo. 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 to 76% in 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 H NMR (400 MHz, chloroform-d) δ 0.85 (s, 4H), 1.01-1.15 (m, 5H), 1.20 (d, J = 12.0 Hz, 6H), 1.26 (s, 4H), 1.33-1.58 (m, 8H), 1.59-1.61 (m, 1H), 1.65-1.70 (m, 2H), 1.72-1.91 (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-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)

[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-icosapentaenoic-2,9-dicarboxylic acid 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester (206-1)

[0932] A solution of isocyanatoethane (0.061 mL, 3 equivalents), trimethylsilyl chloride (0.111 mL, 5 equivalents) and 194-8 (200 mg, 0.26 mmol) in CHCl (10 mL) was stirred at room temperature overnight. The reaction was concentrated in vacuo and the residue was purified by silica gel column purification using EtOAc / petroleum ether (1:1). This yielded 239.9 mg (quantitative) of 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-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-icosahydroquinone-2-carboxylic 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 was concentrated 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 MeCN (57% Phase B to 77% in 8 minutes); 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-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)

[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-icosapentaenoic-2,9-dicarboxylic acid 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester (207-1)

[0938] A solution of 1-isocyanatobutane (0.0868 mL, 3 eq), TMSCl (0.111 mL, 5 eq) and 194-8 (200 mg, 0.26 mmol, 1 eq) in CHCl (10 mL) was stirred at room temperature overnight. The reaction was concentrated in vacuo and the residue was purified by silica gel column purification 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-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-icosahydroquinone-2-carboxylic 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 was concentrated in vacuo 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% to 72% of phase B in 8 minutes); Detector: UV. This yielded 28.8 mg (14%) of 207-2 as an off-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-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-2-carboxylic 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-icosapentaenoic acid-2,9-dicarboxylic acid 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester (208-1)

[0944] A solution of 194-8 (400 mg), pyrrolidine-1-carbonyl chloride (0.17 mL, 3 eq.), and DMAP (62.7 mg, 1 eq.) in pyridine (10 mL) 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 1M HCl (3 x 50 mL) and brine (1 x 50 mL), dried over anhydrous Na2SO4, and concentrated to afford 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-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-2-carboxylic 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 in vacuo, and the residue was purified by preparative HPLC under the following conditions: Column: Xselect CSH OBD, 30 x 150 mm, 5 m; Mobile phase: Water (0.05% TFA) and CH3CN (68% phase B to 80% in 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-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 (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-icosapentaenoic acid-2,9-dicarboxylic acid 2-benzyl 9-((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methyl) ester (209-1)

[0950] 4-(Bromomethyl)-5-isopropyl-1,3-dioxol-2-one was prepared according to the literature procedure (Sun et al., Tetrahedron Letters, 2002, 43, 1161-1164). A mixture of 4-(bromomethyl)-5-isopropyl-1,3-dioxol-2-one (2.7 g, 1.5 eq), K2CO3 (3.4 g, 3 eq), KI (0.68 g, 0.5 eq) and 194-7 (5.5 g, 1 eq) 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 eluting with 3:1 petroleum ether:EtOAc to give 209-1 (5.5 g, 83%) as a light yellow solid. MS (ES, m / z): [M+1] + =806.95; 1 H NMR (400 MHz, chloroform-d) δ7.48–7.28 (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] Synthesis of (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-icosapentaenoic acid-2,9-dicarboxylic acid 2-benzhydryl 9-((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methyl) ester (209-2).

[0952] To an 8-mL round-bottom flask was added 209-1 (100 mg, 0.12 mmol), CH2Cl2 (2 mL), DMAP (29 mg, 0.24 mmol, 1.9 equiv), AcOH (21.2 mg, 0.35 mmol, 2.85 equiv), followed by EDCI (57 mg, 0.3 mmol, 2.4 equiv). The reaction slurry was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:1) to afford 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-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-icosahydroquinone-2-carboxylic acid (209-3)

[0954] To a 25-mL round-bottom flask was added 209-2 (60 mg, 0.07 mmol), CH2Cl2 (5 mL) and TFA (0.5 mL, 6.7 mmol, 95 equiv). The reaction slurry was stirred at room temperature for 1 hour. The resulting mixture was concentrated and the crude product was purified by preparative HPLC under the following conditions: column, XSelect CSH Prep C18 OBD, 5 μm, 19*150 mm; mobile phase, water (0.05% TFA) and CH3CN (70% phase B to 90% in 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 and compared with pIC 50 This product exhibited a pIC50 of 7.2 compared to 5.9 for the corresponding acid metabolite (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-(acetyloxy)-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydroquinone-2,9-dicarboxylic acid. MS (ES, m / z): [M+1] + =683; 1H 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-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)

[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 x 150 mm, 5 μm; mobile phase, water (0.05% TFA) and CH3CN (60% phase B to 85% over 8 minutes); detector, UV. 69.7 mg of 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-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)

[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*150; 5 μm; mobile phase, water (0.05% TFA) and CH3CN (70% phase B to 88% in 8 minutes); detector, UV. This yielded 66.3 mg of 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-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-2-carboxylic 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)propanoic acid. The crude product was purified by preparative HPLC under the following conditions: column, Xselect CSH OBD Column 30*150mm 5um,n; mobile phase, water (0.05% TFA) and ACN (40% phase B to 53% in 8 minutes); detector, UV 254nm. This yielded 35.2 mg (33%) of 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-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)

[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-icosapentaenoic acid-2,9-dicarboxylic acid 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester (216-1)

[0967] To an 8 mL sealed tube at room temperature were added 194-8 (200 mg, 0.26 mmol), pyridine (3 mL), DMAP (94.1 mg, 0.77 mmol, 3 equiv), and isopropyl chloroformate (315 mg, 2.6 mmol, 10 equiv). The reaction slurry was stirred at 60°C under a nitrogen atmosphere for 6 hours. An additional portion of isopropyl chloroformate (315 mg, 2.6 mmol, 10 equiv) was added to the above mixture at 60°C. The reaction slurry was stirred at 60°C for an additional 6 hours. A third portion of isopropyl chloroformate (315 mg, 2.6 mmol, 10 equiv) was added to the reaction mixture at 60°C. The reaction slurry was stirred at 60°C for an additional 6 hours, and the reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC (PE / EtOAc 1:1) to afford 216-1 (130 mg, 59%) as a light yellow foam.

[0968] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-((isopropoxycarbonyl)oxy)-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydroquinone-2-carboxylic acid (216-2)

[0969] To a 25-mL round-bottom flask were added 216-1 (130 mg, 0.15 mmol, 1 equiv), CH2Cl2 (2 mL), and TFA (0.2 mL). The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated. The crude product was purified by preparative HPLC under the following conditions: column, Xselect CSH OBD 30*150 mm, 5 μm; mobile phase, water (0.05% TFA) and CH3CN (64% phase B to 87% in 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-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 (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*150 mm, 5 m; Mobile phase: Water (0.05% TFA) and CH3CN (68% Phase B to 80% in 8 minutes); 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-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)

[0974]

[0975] Synthesis of (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-icosahydroquinone-2-carboxylic acid benzyl ester (240-1)

[0976] Sodium bis(trimethylsilyl)amide (0.5 mL, 2 eq) was added to a solution of 121-1 (355 mg, 0.62 mmol, 1 eq) and tert-butyl 2-bromoacetate (240.6 mg, 1.24 mmol, 2 eq) in DMF (5 mL). The reaction slurry was stirred at room temperature overnight, diluted with CH2Cl2 (100 mL), washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:1) to afford 300 mg (71%) of 240-1 as a white solid.

[0977] Synthesis of 2-(((3S,4R,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-3-hydroxy-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosyl)methoxy)acetic acid (240-2)

[0978] 240-1 (300 mg, 0.43 mmol, 1 eq) 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] 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-icosapentaenoic acid-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 equiv) in MeOH (5 mL) and CHCl (10 mL). The reaction slurry was stirred at room temperature for 2 h. The reaction mixture was concentrated to afford 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-icosahydro-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 under H2 (1 atm) for 2 h. The reaction mixture was filtered and concentrated to afford 216 mg (93%) of 240-4 as a white solid.

[0983] 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-icosapentaenoic acid-2-carboxylic acid diphenylmethyl 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 eluting with EtOAc / petroleum ether (1:10) to afford 220 mg (79%) of 240-5 as a white solid.

[0985] Synthesis of 2-(((3S,4R,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzhydryloxy)carbonyl)-3-hydroxy-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosyl)methoxy)acetic acid (240-6)

[0986] 240-5 (220 mg, 0.30 mmol, 1 eq) and lithium hydroxide (73 mg, 3 mmol, 10 eq) 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 1M HCl and extracted with CH2Cl2 (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to afford 200 mg (93%) of 240-6 as a white solid.

[0987] Synthesis of (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-9-((2-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)-2-oxoethoxy)methyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydroquinone-2-carboxylic acid diphenylmethyl ester (240-7)

[0988] 240-6 (200 mg, 0.28 mmol, 1 eq), 4-(chloromethyl)-5-methyl-2H-1,3-dioxol-2-one (84 mg, 0.57 mmol, 2 eq), K2CO3 (194 mg, 1.40 mmol, 5 eq) and potassium iodide (70 mg, 0.42 mmol, 1.5 eq) 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 afford 200 mg (86%) of 240-7 as a white solid.

[0989] Synthesis of (2S,4aS,6aS,6bR,8aR,9R,10S,12aS,12bR,14bR)-10-hydroxy-2,4a,6a,6b,9,12a-hexamethyl-9-((2-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)-2-oxoethoxy)methyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (240-8)

[0990] 240-7 (200 mg, 0.24 mmol, 1 equiv) 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 (maintaining 5% phase B in 0 minutes, reaching 63% in 1 minute, and reaching 68% in 8 minutes); Detector: UV. This yielded 14.5 mg (9%) of 240-8 as a white solid. MS (ES, m / z): [M+H] + =657.25; 1 H NMR (400 MHz, chloroform-d) δ 0.72 (s, 3H), 0.86 (s, 3H), 1.03 (t, J = 15.2 Hz, 2H), 1.13–1.22 (m, 9H), 1.22–1.37 (m, 2H), 1.43 (d, J = 5.6 Hz, 8H), 1.66–1.97 (m, 8H), 2.21 (s, 5H), 2 .51(s,1H),2.73(d,J=13.6Hz,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-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-icosahydroquinone-2-carboxylic 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 (maintaining 5% phase B over 0 minutes, reaching 65% over 1 minute, and reaching 85% over 8 minutes); 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-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 (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 C18 OBD, 19*150 mm, 5 m; Mobile phase: Water (0.05% TFA) and CH3CN (35% Phase B to 90% over 7 minutes); 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-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 (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 (maintaining 5% phase B in 0 minutes, reaching 62% in 1 minute, and reaching 82% in 8 minutes); Detector: UV. This yielded 25.9 mg (19%) of 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-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-icosahydroquinone-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]ethan-1-ol (3.0 g, 18.3 mmol, 1 eq), p-nitrophenyl chloroformate (4.4 g, 20.4 mmol, 1.1 eq), and Et3N (5 mL, 36 mmol, 2 eq) in C2Cl2 (20 mL) was stirred at room temperature for 1 hour. The reaction was concentrated and the residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:1) to afford 4.2 g (67%) of 246-1 as a clear liquid.

[1004] 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-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoyl-2,9-dicarboxylic acid 2-benzhydryl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester (246-2)

[1005] A solution of 194-8 (150 mg, 0.19 mmol, 1 eq), 246-1 (640 mg, 1.9 mmol, 10 eq), and DMAP (94 mg, 0.77 mmol, 4 eq) in THF (8 mL) was stirred at 50° C. for 24 h. 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 silica gel column eluting with EtOAc / petroleum ether (1:1) to afford 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-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-icosahydroquinone-2-carboxylic acid (246-3)

[1007] A solution of 246-2 (156 mg, 0.16 mmol, 1 equiv) 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 m; mobile phase: water (0.05% TFA) and CH3CN (35% phase B to 90% in 7 minutes); 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-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 (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-icosapentaenoic-2,9-dicarboxylic acid 2-benzyl 9-methyl ester

[1011] (249-1)(trimethylsilyl)diazomethane (1 mL) was added to a solution of 194-7 (200 mg, 0.30 mmol, 1 eq) in CH2Cl2 (5 mL) and MeOH (2.5 mL). The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated to afford 200 mg (98%) of 249-1 as a white solid.

[1012] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic-2,9-dicarboxylic acid 2-benzhydryl 9-methyl ester (249-2)

[1013] Sodium hydride (100 mg, 4.17 mmol, 14 equiv) was added portionwise to a solution of 249-1 (200 mg, 0.29 mmol, 1 equiv) and iodomethane (0.5 mL, 8.03 mmol) in THF (10 mL) at room temperature. The reaction slurry was stirred at 50 ° C overnight and then quenched by adding water. The reaction mixture was washed with EtOAc (3×50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:1) to give 180 mg (88%) of 249-2 as a white solid.

[1014] Synthesis of (3S,4S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzhydryloxy)carbonyl)-3-methoxy-4,6a,6b,8a,11,14b-hexamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydro-4-carboxylic acid (249-3)

[1015] A slurry of 249-2 (180 mg, 0.26 mmol, 1 eq) and lithium iodide (100 mg, 0.75 mmol, 2.9 eq) in pyridine (5 mL) was stirred at 125° C. for 2 days. The reaction mixture was diluted with CH2Cl2, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:1) to afford 110 mg (62%) of 249-3 as a yellow solid.

[1016] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2,9-dicarboxylic acid 2-benzyl 9-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) ester (249-4)

[1017] A solution of 249-3 (110 mg, 0.16 mmol, 1 eq), 4-(chloromethyl)-5-methyl-2H-1,3-dioxol-2-one (150 mg, 1.0 mmol, 6.3 eq), KCO (150 mg, 1.1 mmol, 6.7 eq), and potassium iodide (50 mg, 0.30 mmol, 1.9 eq) in DMF (10 mL) was stirred at 50° C. for 1 hour. The reaction mixture was diluted with CHCl (100 mL), washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column eluting with EtOAc / petroleum ether (1:1) to afford 100 mg (78%) of 249-4 as a white solid.

[1018] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-9-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydroquinone-2-carboxylic acid (249-5)

[1019] A solution of 249-4 (150 mg, 0.19 mmol, 1 equiv) 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: Mobile phase: water (0.05% TFA) and CH3CN (66% phase B to 74% in 8 minutes); Detector: UV. This yielded 38.3 mg (32%) of 249-5 as a white solid. MS (ES, m / z): [M+H] + =627.55; 1H NMR(400MHz, methanol-d4)δ0.85(s,3H),0.90(d,J=9.8Hz,1H),0.96–1.29(m,15H),1.44(d,J=8.1Hz,5H),1.54(t,J=13.0Hz,2H),1.60–1.99(m,6H), 2.22(s,5H),2.54(s,1H),2.83(d,J=13.8Hz,1H),3.26(s,3H),3.64(dd ,J=11.8,4.2Hz,1H),4.92(s,1H),5.13(d,J=14.0Hz,1H),5.61(s,1H).

[1020] Example 32 (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-9-(((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2-carboxylic acid (252-2)

[1021]

[1022] Synthesis of (2S,4aS,6aS,6bR,8aR,9S,10S,12aS,12bR,14bR)-10-methoxy-2,4a,6a,6b,9,12a-hexamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosapentaenoic acid-2,9-dicarboxylic acid 2-benzyl 9-((5-isopropyl-2-oxo-1,3-dioxol-4-yl)methyl) ester (252-1)

[1023] A solution of 249-3 (300 mg, 0.44 mmol, 1 e...

Claims

1. A compound of formula I or a salt thereof: in, 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 -; 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 group or a divalent heteroaryl group; 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 and R x optionally taken together to form a heterocycle; provided that when X is not a bond, then L is not a bond; W is O or S; Q is a bond or an alkylene group; R1 is H, alkyl, carbocycle, or heterocycle, wherein each of the alkyl, carbocycle, and heterocycle is optionally substituted with halogen, OH, amino, oxo, carboxyl, acyloxy, alkoxycarbonyl, alkoxyacyloxy, alkoxycarbonyloxy, aminocarbonyl, carbocycle optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen, heterocycle optionally substituted with alkyl, oxo, amino, and halogen; and carbocycle or heterocycle optionally substituted with alkyl, haloalkyl, oxo, amino, and halogen; V is -C(O)O-, -C(O)O-(CHR5)-OC(O)-, -C(O)O-(CHR5)-OC(O)-O-, -C(O)O-(CH2) n -Y-, -C(O)N(R5)-, -C(O)N(R5)-O-, -NH-C(O)-N(R5)- or NH-S(O) n -; wherein Y is a divalent heterocyclic ring optionally substituted by alkyl, halogen, OH, amino, carboxyl and oxo; R2 is H or R5; R3 is absent or is an 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, =NO-R5; R5 is H or alkyl optionally substituted by carbocyclic or heterocyclic rings, wherein said carbocyclic rings and said heterocyclic rings are optionally substituted by halogen, OH, oxo and alkyl; R6 is H, alkyl, carbocycle, heterocycle, wherein said alkyl, said carbocycle and said heterocycle are substituted by halogen, OH, SH, alkylthio, -S(O)-alkyl, -SO2-alkyl, amino, -NHC(O)-alkyl, oxo, alkyl, carboxyl, acyl, acyloxy, alkoxycarbonyl, carbocycle optionally substituted by halogen, OH, amino or alkyl, or heterocycle optionally substituted by halogen, OH, amino or alkyl; and wherein one or more non-adjacent methylene groups in each of said alkyl groups of R6 are optionally replaced by -O- or -S-; R x is H, -C(O)O-R1, or alkyl optionally substituted with -C(O)O-R1; and n is 1 or 2.

2. The compound according to claim 1, having any one of the following structures: Ia-Io: Or formula Ia'-If':

3. A compound according to claim 1 or claim 2, wherein V is -C(O)-O- and R2 is H.

4. The compound of claim 1 or claim 2, wherein R1 is methyl, ethyl or isopropyl. The compound according to claim 1 , wherein X and L are both bonds.

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

7. A compound according to any one of claims 1 to 6, wherein R3 is H.

8. A compound according to any one of claims 1 to 7, wherein R4 is -OC(O)-R6 and R6 is alkyl, carbocycle or heterocycle; wherein the alkyl is optionally substituted by hydroxy, halogen, carboxyl, alkoxy, alkylthio, amino, NHC(O)-alkyl, heterocycle optionally substituted by alkyl; and the carbocycle and the heterocycle are optionally substituted by halogen, hydroxy and alkyl, wherein the alkyl is optionally substituted by hydroxy, halogen, carboxyl; and wherein one or more non-adjacent methylene groups are replaced by -O-.

9. The compound according to any one of claims 1 to 7, wherein R4 is NH2, alkoxy, OH, =NO-alkyl, =N-OH.

10. A compound according to any one of claims 1 to 7, wherein R4 is R6 and R6 is phenyl optionally substituted with alkoxy.

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