Compounds useful for treating gastrointestinal disorders

Abstract

To provide a method for treating a disease. [Solution] This disclosure relates to compounds and methods for treating disorders associated with fluid retention or salt overload, such as heart failure (particularly congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. This disclosure also relates to compounds and methods for treating hypertension. This disclosure also relates to compounds and methods for treating gastrointestinal disorders, including treating or relieving pain associated with gastrointestinal disorders.

Description

[Technical Field]

[0001] This application claims priority and benefit of U.S. Provisional Patent Application No. 62 / 444,335 filed 9 January 2017 and U.S. Provisional Patent Application No. 62 / 541,097 filed 4 August 2017, which are incorporated herein by reference in whole.

[0002] Field of Invention This disclosure relates to indan derivatives that are substantially active in the gastrointestinal tract to inhibit NHE-mediated antiportation of sodium and hydrogen ions, and to the use of such compounds in the treatment of gastrointestinal disorders, including the treatment of disorders associated with fluid retention or salt overload, and the treatment or relief of pain associated with gastrointestinal disorders. [Background technology]

[0003] Disorders associated with fluid retention and salt overload According to the American Heart Association, more than 5 million Americans suffer from heart failure, with an estimated 550,000 cases of congestive heart failure (CHF) occurring annually (Schocken, DD et al., Prevention of heart failure: a scientific statement from the American Heart Association Councils on Epidemiology and Prevention, Clinical Cardiology, Cardiovascular Nursing, and High Blood Pressure). Research; Quality of Care and Outcomes Research Interdisciplinary Working Group; and Functional Genomics and Translational Biology Interdisciplinary Working Group: Circulation, v.117, no.19, p.2544-2565 (2008). The clinical syndrome of congestive heart failure occurs when cardiac dysfunction prevents adequate perfusion of peripheral tissues. The most common type of heart failure leading to CHF is systolic heart failure, resulting from impaired contractility of the myocardial layer. The main cause of CHF is ischemic coronary artery disease, with or without infarction. Long-term hypertension can lead to CHF, especially if not adequately controlled.

[0004] In patients with CHF, neurohumoral compensatory mechanisms (i.e., the sympathetic nervous system and the renin-angiotensin system) are activated in an attempt to maintain normal circulation. The renin-angiotensin system is activated in response to decreased cardiac output, resulting in elevated levels of renin, angiotensin II, and aldosterone in the plasma. As the volume of blood in the heart increases, cardiac output increases proportionally until the heart can no longer expand further. In heart failure, contractility is reduced, so the heart works at higher volumes and higher filling pressures to maintain output. Filling pressure can eventually rise to levels that cause fluid leakage into the lungs and congestion symptoms (e.g., edema, shortness of breath). All of these symptoms are related to fluid and salt retention, and this chronic fluid and salt overload further contributes to disease progression.

[0005] Adherence to medication plans and dietary sodium restrictions is a crucial element of self-management in patients with heart failure, potentially extending lifespan, shortening hospital stays, and improving quality of life. Physicians often recommend that individuals with heart failure maintain a salt intake of less than 2.3g per day and less than 2g per day. Since many people consume significantly more than this, those with congestive heart failure will likely need to find ways to reduce their dietary salt intake.

[0006] Several drug therapies are currently available for patients suffering from CHF. For example, diuretics may be used or administered to reduce congestion by reducing volume, and consequently filling pressure, to below the filling pressure that leads to pulmonary edema. By counteracting volume increase, diuretics reduce cardiac output; however, fatigue and dizziness may replace CHF symptoms. One class or type of diuretic currently used is thiazides. Thiazides inhibit the transport of NaCl to the kidneys, thereby preventing Na reabsorption in the cortical dilution segment at the endpoint of the loop of Henle and the proximal part of the distal tubule. However, these drugs are not effective if the glomerular filtration rate (GFR) is less than 30 ml / min. In addition, thiazides, and even other diuretics, can cause hypokalemia. Another class or type of diuretic currently used is loop diuretics (e.g., furosemide). These are the most potent diuretics and are particularly effective in treating pulmonary edema. Loop diuretics inhibit the NaKCl transport system and therefore prevent the reabsorption of Na in the Loop of Henle.

[0007] Patients with persistent edema despite high-dose diuretics are either diuretic-resistant or may become so. Diuretic resistance can be due to insufficient drug utilization. In patients with renal failure, which has a high incidence in the CHF population, endogenous acids compete with loop diuretics such as furosemide for organic acid secretion pathways in the nephron tubular lumen. Therefore, higher doses or continuous infusions are required to achieve sufficient drug entry into the nephrons. However, recent meta-analyses have increased awareness of the long-term risks of long-term diuretic use in the treatment of CHF. For example, a recent study (Ahmed et al., Int J Cardiol. 2008 April 10;125(2):246-253) showed that long-term diuretic use was associated with a significant increase in mortality and length of hospital stay in elderly outpatients with heart failure receiving angiotensin-converting enzyme inhibitors and diuretics.

[0008] Angiotensin-converting enzyme ("ACE") inhibitors are another example of a drug therapy that can be used to treat congestive heart failure. ACE inhibitors cause vasodilation by blocking the renin-angiotensin-aldosterone system. Abnormally low cardiac output can lead to a renal response by releasing renin, which then converts angiotensinogen to angiotensin I. ACE converts angiotensin I to angiotensin II. Angiotensin II stimulates the thirst center in the hypothalamus, causing vasoconstriction, thus increasing blood pressure and venous return. Angiotensin II also leads to the release of aldosterone, resulting in sodium reabsorption and the simultaneous passive reabsorption of body fluids, which then leads to an increase in blood volume. ACE inhibitors block this compensatory system and improve cardiac function by reducing systemic and pulmonary vascular tolerance. ACE inhibitors have shown life-prolonging effects and have traditionally been a treatment option for CHF. However, because ACE inhibitors lower aldosterone and potassium secretion, one of the side effects of their use is hyperkalemia. In addition, ACE inhibitors have been shown to induce acute renal failure in certain categories of CHF patients (see, for example, CSCruz et al., Incidence and Predictors of Development of Acute Renal Failure Related to the Treatment of Congestive Heart Failure with ACE Inhibitors, Nephron Clin. Pract., v.105, no.2, pp c77-c83 (2007)).

[0009] Patients with end-stage renal disease (ESRD), i.e., stage 5 chronic renal failure, must undergo hemodialysis three times a week. The near-absence of kidney function and the ability to excrete salt and fluids leads to significant weight fluctuations because fluids and salts are produced in the body (Natri). Fluid overload is characterized by weight gain between dialysis sessions. High fluid overload is also exacerbated by cardiac dysfunction, specifically CHF. Dialysis is used to remove uremic toxins and to regulate salt and fluid homeostasis. However, symptomatic dialysis-induced hypotension (SIH) can occur when a patient is overdialyzed. SIH is observed in approximately 15%–25% of the ESRD population (Davenport, A., C. Cox, and R. Thuraisingham, Blood pressure control and symptomatic intradialytic hypotension in diabetic haemodialysis patients: a cross-sectional survey; Nephron Clin. Pract., v.109, no.2, p.c65–c71 (2008)). As with patients with hypertension and CHF, dietary restrictions on salt and fluids are highly recommended, but low-salt foods are not palatable and are therefore rarely followed.

[0010] The causes of primary or "essential" hypertension are unclear. However, several observations point to the kidneys as a major factor. The strongest data on excessive salt intake and hypertension came from INTERSALT, a cross-sectional study of over 10,000 participants. For individuals, a significant, positive, independent linear relationship was found between 24-hour sodium excretion and systolic blood pressure. Higher 24-hour urinary sodium excretion in individuals was found to be associated with higher systolic / diastolic blood pressure of 6–3 / 3–0 mmHg on average. Primary hypertension is a typical example of a complex, multifactorial, and polygeneic phenotype. All of these monogenic hypertension syndromes are substantially limited to mutant genes involving the acquisition of function of various components of the renin-angiotensin-aldosterone system, resulting in excessive renal sodium retention. In a broad sense, these syndromes are characterized by increased renal sodium reabsorption resulting from a primary defect in the sodium transport system or stimulation of mineralocorticoid receptor activity (Altun, B., and M. Arici, 2006, Salt and Blood pressure: time to challenge; Cardiology, v.105, no.1, pp.9-16 (2006). In the last 30 years, a great many controlled studies have been conducted on hypertensive subjects to determine whether sodium reduction lowers established hypertension. Meta-analyses of these studies have clearly shown a significant reduction in blood pressure in hypertensive patients.

[0011] In end-stage liver disease (ESLD), fluid retention is common as ascites, edema, or pleural exudation due to cirrhosis, resulting from a disruption of the extracellular fluid volume regulation mechanism. Fluid retention is the most common complication of ESLD, occurring in approximately 50% of patients within 10 years of diagnosis of cirrhosis. This complication significantly worsens the quality of life for patients with cirrhosis and is associated with a poor prognosis. The 1-year and 5-year survival rates are 85% and 56%, respectively (Kashani et al., Fluid retention in cirrhosis: pathophysiology). and management; QJM, v.101, no.2, p.71-85 (2008). The most accepted theory is that the initial event in ascites production in patients with cirrhosis is sinusoidal hypertension. Portal hypertension, due to increased sinusoidal pressure, activates vasodilatory mechanisms. In advanced stages of cirrhosis, arteriolar vasodilation leads to insufficient filling of systemic arterial lumen. This event induces a decrease in arterial pressure through a reduction in effective blood volume. As a result, activation of the renin-angiotensin-aldosterone system, baroreceptors in the sympathetic nervous system, and non-osmolar release of antidiuretic hormone occur, restoring normal blood homeostasis. These events lead to further retention of renal sodium and body fluid. Visceral vasodilation increases visceral lymphatic production beyond the capacity of the lymphatic transport system, inducing lymphatic leakage into the abdominal cavity. Persistent renal sodium and fluid retention, along with increased visceral vascular permeability and lymphatic leakage into the abdominal cavity, plays a major role in persistent ascites production.

[0012] Thiazolidinediones (TZDs), such as rosiglitazone, are used to treat type 2 diabetes. It is a peroxisome proliferator-activated receptor (PPAR) gamma agonist and is widely prescribed. Unfortunately, fluid retention is the most common and serious side effect of TZDs and is the leading cause of treatment discontinuation. The incidence of TZD-induced fluid retention ranges from 7% in monotherapy to 15% in combination with insulin (Yan, T., Soodvilai, S., PPAR Research volume 2008, article ID 943614). The mechanism of such side effects is not fully understood, but it may be related to the renal reabsorption of sodium and fluids. However, TZD-induced fluid retention is resistant to loop diuretics or thiazide diuretics, and the combination of peroxisome proliferator-activated receptor (PPAR) alpha and PPAR gamma agonists, which has been proposed to reduce such fluid overload, is associated with major adverse cardiovascular events.

[0013] Considering the above, it is recognized that salt and fluid retention contribute to the morbidity and mortality of many diseases, including heart failure (especially congestive heart failure), chronic kidney disease, end-stage renal disease, and liver disease. It is also accepted that salt and fluid retention are risk factors for hypertension. Therefore, there is a clear need for medications that, when administered to patients who need them, reduce sodium retention, fluid retention, or both. Such medications should not interfere with, or otherwise exacerbate, the renal mechanisms of fluid / Na homeostasis.

[0014] One option for treating excessive fluid overload is to induce diarrhea. Diarrhea can be induced by several medications, including laxatives such as sorbitol, polyethylene glycol, bisacodyl, and phenolphthalein. Sorbitol and polyethylene glycol induce osmotic diarrhea along with low levels of secreted electrolytes; thus, their usefulness in removing sodium salts from the GI tube is limited. The mechanism of action of phenolphthalein is not clearly established, but it is thought to be caused by inhibition of Na / K ATPase and Cl / HCO3 anion exchanger, as well as stimulation of electrogenic anion secretion (see, e.g., Eherer, AJ, C. Anta, Ana, J. Porter, and J. Fordtran, 1993, Gastroenterology, v.104, no.4, pp.1007-1012). However, some laxatives, such as phenolphthalein, are not viable options for the long-term treatment of fluid overload due to their potential carcinogenic risks in humans. Furthermore, laxatives are irritating and have been shown to cause mucosal damage, making long-term use undesirable. Therefore, it should be recognized that inducing chronic diarrhea as part of an attempt to control salt and fluid overload is an undesirable mode of treatment for many patients. Thus, for any medication utilizing GI tubes for this purpose to provide practical benefits, diarrhea must be controlled.

[0015] One method for treating mild diarrhea is the administration of liquid-absorbing polymers, such as the natural plant fiber plantain. Polymer materials, more specifically hydrogel polymers, can also be used to remove bodily fluids from the digestive (GI) tract. The use of such polymers is described, for example, in U.S. Patents 4,470,975 and 6,908,609, the entirety of which is incorporated herein by reference for any relevant and consistent purpose. However, for such polymers to efficiently remove a significant amount of bodily fluid, they must preferably resist the static and osmotic pressure range present in the GI tract. Many mammals, including humans, do so by producing soft feces with a water content of about 70%, and by transporting bodily fluids against the high water pressure resistance imposed by the fecal mass. Several studies have shown that the pressure required to dehydrate feces from approximately 80% to 60% is approximately 500 kPa to 1000 kPa (i.e., approximately 5 to 10 atm) (e.g., McKie, AT, W. Powrie, and RJ Naftalin, 1990, Am J Physiol, v.258, no.3 Pt 1). See pp.G391-G394; Bleakman, D., and RJ Naftalin, 1990, Am J Physiol, v.258, no.3 Pt 1, p.G377-G390; Zammit, PS, M. Mendizabal, and RJ Naftalin, 1994, J Physiol, v.477(Pt 3), p.539-548.). However, the static pressure measured in the lumen is usually about 6 kPa to about 15 kPa. The fairly high pressure required to dehydrate feces is essentially due to the osmotic process, not to the mechanical process brought about by muscle force. Osmotic pressure arises from the active transport of salts through the colonic mucosa, ultimately resulting in hypertonic fluid absorption. The osmotic gradient produced drives the fluid from the lumen to the serosal side of the mucosa. For example, liquid-absorbing polymers such as those described in U.S. Patent Nos. 4,470,975 and 6,908,609 may not be able to withstand such pressure. Such polymers disintegrate in a normal colon where the salt absorption process is intact, and thus can remove a moderate amount of bodily fluids and, by extension, salt.

[0016] Synthetic polymers that bind to sodium are also described. For example, ion exchange polymer resins such as Dowex-type cation exchange resins have been known since around the 1950s. However, with the exception of Kayexalate® (or Kionex®), a polystyrene sulfonate approved for the treatment of hyperkalemia, cation exchange resins have very limited drug applications, at least partially, due to their limited capacity and weak cation binding selectivity. In addition, during the ion exchange process, the resin releases stoichiometric amounts of exogenous cations (e.g., H, K, Ca), which may then potentially lead to acidosis (H), hyperkalemia (K), or contribute to vascular calcification (Ca). Such resins may also cause constipation.

[0017] Gastrointestinal disorders Constipation is characterized by infrequent bowel movements and difficulty in passing stool, and becomes chronic when a patient experiences specific symptoms discontinuously for more than 12 weeks within a 12-month period. Chronic constipation is idiopathic if it is not caused by another disease or medication use. An evidence-based approach to the management of chronic constipation in North America (Brandt et al., 2005, Am.J. Gastroenterol. 100(Suppl.1):S5-S21) revealed a prevalence of approximately 15% in the general population. Constipation is more commonly reported in women, older adults, non-white individuals, and lower-class individuals.

[0018] Irritable bowel syndrome (IBS) is a common GI disorder associated with changes in motility, secretory, and visceral sensation. A variety of clinical symptoms characterize this disorder, including frequency and form of bowel movements, abdominal pain, and bloating. While the recognition of IBS clinical symptoms is not yet fully defined, it is currently common to refer to diarrhea-predominant IBS (D-IBS) and constipation-predominant IBS (C-IBS), where D-IBS is defined as the continuous passage of loose or watery stools, and C-IBS as a group of dysfunctions that result in difficult, infrequent, or seemingly incomplete bowel movements. The pathophysiology of IBS is not fully understood, but several mechanisms have been suggested. Visceral hypersensitivity is often considered to play a major etiological role and has been proposed as a more useful biological marker for distinguishing IBS from other causes of abdominal pain. Recent clinical trials (Posserud, I. et al., Gastroenterology, 2007;133:1113-1123) compared IBS patients with visceral hypersensitivity testing (balloon inflation) and healthy subjects. It was found that 61% of IBS patients had altered visceral sensations as measured by pain and discomfort thresholds. Other reviews have documented the role of visceral hypersensitivity in abdominal pain, a sign of various gastrointestinal disorders (Akbar, A et al, Aliment.Pharmaco.Ther., 2009, 30, 423-435; Bueno et al., Neurogastroenterol Motility (2007) 19 (suppl.1), 89-119). Colonic and rectal distension is associated with movement. It has been widely used as a tool for evaluating visceral sensation in research on objects and humans. The type of stress used to induce visceral sensation varies depending on the model (e.g., Eutamen, H Neurogastroenterol Motil. 2009). Aug 25. (See [Electronic version available before printing]), stress such as partial restraint stress (PRS) is a relatively mild, non-ulcer-inducing model that is considered to be more representative of IBS settings.

[0019] Constipation is commonly observed in older adults, particularly in osteoporosis patients who require calcium supplements. While calcium supplements have been shown to be beneficial in restoring bone density in osteoporosis patients, adherence to them is poor due to calcium-induced constipation.

[0020] Opioid-induced constipation (OIC), also known as opioid-induced bowel dysfunction or opioid bowel dysfunction (OBD), is a common adverse effect associated with opioid therapy. While OIC is commonly described as constipation, it is a collection of adverse gastrointestinal (GI) effects, including abdominal cramps, bloating, and gastroesophageal reflux. Cancer patients may also experience disease-related constipation, which is usually exacerbated by opioid therapy. However, OIC is not limited to cancer patients. A recent study of patients receiving opioid therapy for non-cancer-derived pain found that approximately 40% of patients experienced opioid-related constipation (<3 complete bowel movements per week), compared to 7.6% in the control group. Among those requiring laxative therapy, only 46% of opioid-treated patients (compared to 84% of the control group) reported achieving the desired treatment outcome for >50% of the time (Pappagallo, 2001, Am.J.Surg. 182(5A Suppl.):11S-18S).

[0021] Some patients with chronic idiopathic constipation can be successfully managed with lifestyle changes, dietary changes, and increased fluid and fiber intake, and these are generally the first measures to be tried. For patients who do not respond to these methods, physicians typically recommend laxatives, many of which are available over-the-counter. Over-the-counter laxatives are deemed ineffective in about half of patients (Johanson and Kralstein, 2007, Aliment. Pharmacol. Ther. 25(5):599-608). Other treatment options currently prescribed or in clinical development for treating chronic constipation, including IBS and OIC, include, for example, Chang et al., 2006, Curr. Teat. Options Gastroenterol. 9(4):314-323; Gershon and Tack, 2007, Gastroenterology 132(1):397-414; and Hammerle and This is described in Surawicz, 2008, World J. Gastroenterol. 14(17):2639-2649. Such treatments include, but are not limited to, serotonin receptor ligands, chloride channel activators, opioid receptor antagonists, guanylate cyclase receptor agonists, and nucleotide P2Y(2) receptor agonists. Many of these treatment options are inadequate, as they may be habit-forming or ineffective in some patients, may cause long-term side effects, or are simply not the best option.

[0022] Na + / H + NHE exchange inhibitors The primary function of the GI tube is to maintain water / sodium homeostasis by absorbing virtually all the water and sodium it is exposed to. The epithelial layer covering the apical surface of the mammalian colon is a typical electrolyte transport epithelium, which can move large amounts of salt and water in both directions across the mucosa. For example, on a daily basis, the GI tube processes approximately 9 liters of body fluid and approximately 800 meq of sodium (e.g., Zachos et al., Molec). See the physiology of intestinal Na+ / H+ exchange; Annu. Rev. Physiol., v. 67, pp. 411-443 (2005). Only about 1.5 liters of this fluid and about 150 meq of this sodium come from oral intake; rather, the majority of the fluid (e.g., about 7.5 liters) and sodium (about 650 meq) are secreted via the GI organ as part of the digestive contents. Therefore, the GI duct is a viable target for regulating systemic sodium and fluid levels.

[0023] Numerous general overviews have been published regarding the physiological, secretory, and / or absorption mechanisms of the GI tract (see, for example, Kunzelmann et al., Electrolyte transport in the mammalian colon: mechanisms and implications for disease; Physiol. Rev., v.82, no.1, p.245-289 (2002); Geibel, JP; Secretion and absorption by colonic crypts; Annu. Rev. Physiol, v.67, p.471-490 (2005); Zachos et al., previously cited; Kiela, PR et al., Apical NA+ / H+ exchangers in the mammalian gastrointestinal tract; J. Physiol. Pharmacol., v.57 Suppl.7, p.51-79 (2006)). The two main mechanisms of Na absorption are electroneutral transport and electromotive transport. Electroneutral transport is essentially Na + / H + This is due to antiport NHE (e.g., NHE-3) and is responsible for most of the Na absorption. Electrogenic transport is provided by epithelial sodium channels ("ENaC"). Electroneutral transport is mainly located in the ileum and proximal colon, while electrogenic transport is located in the distal colon.

[0024] Plasma membrane NHE contributes to the regulation of intracellular pH and volume, intercellular absorption of NaCl and NaHCO3, and the maintenance of fluid balance, particularly in the kidneys, intestines, gallbladder, and salivary glands, performed by epithelial cells, as well as the regulation of systemic pH. Literature exists on the role of systemic NHE and its clinical interventions for treating ischemia-reperfusion-related injuries for cardioprotection or renal protection. Nine isoforms of NHE have been identified (Kiela, PRet al.; Apical NA+ / H+ exchangers in the Mammalian gastrointestinal tract; J. Physiol. Pharmacol., v. 57 Suppl 7, p. 51-79 (2006)), of which NHE-2, NHE-3, and NHE-8 are expressed on the apical side of the GI duct, with NHE-3 providing a greater contribution to transport. Separately, Cl-dependent NHE has been identified in rat cell foves, although it has not yet been identified. In addition, many studies have been directed towards the identification of NHE inhibitors. The main targets of such studies have been NHE-1 and NHE-3. Small molecule NHE inhibitors include, for example, 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 Application Publication No. 2004 / 0039001 (WO02 / 020496); U.S. Patent Application Publication No. 2005 / 0020612 (WO03 / 055490); U.S. Patent Application Publication No. 20 04 / 0113396 (WO03 / 051866); 2005 / 0020612; 2005 / 0054705; 2008 / 0194621; 2007 / 0225323; 2004 / 0039001; 2004 / 0224965; 2005 / Patent No. 0113396; Patent No. 2007 / 0135383; Patent No. 2007 / 0135385; Patent No. 2005 / 0244367; Patent No. 2007 / 0270414; International Publication WO01 / 072742; WO01 / 021582 (Canadian Patent No. CA2387529); WO97 / 0241 These are described in 13 (Canadian Patent No. 02241531) and European Patent No. 0744397 (Canadian Patent No. 2177007); all of these are incorporated herein by reference in their entirety for all relevant and consistent purposes.

[0025] However, as recently disclosed in WO2010 / 078449, such studies have failed to develop or recognize the value or importance of NHE inhibitors that are not absorbed (i.e., not systemic) and target the gastrointestinal tract. Such inhibitors could be used in the treatment of GI tract disorders, including the treatment or relief of disorders associated with fluid retention and salt overload, and pain associated with gastrointestinal disorders. Such inhibitors are particularly advantageous because they can be delivered with a low risk of systemic on-target or off-target effects (e.g., little to no risk of renal impairment or other systemic effects). Therefore, although the aforementioned field has advanced, there is still a need in the art for novel compounds to be used in the treatment of gastrointestinal disorders, including disorders associated with fluid retention and salt overload, and pain associated with gastrointestinal disorders. The present invention satisfies this need and provides further relevant benefits. [Prior art documents] [Patent Documents]

[0026] [Patent Document 1] U.S. Patent No. 4,470,975 [Patent Document 2] U.S. Patent No. 6,908,609 [Patent Document 3] International Publication No. 2010 / 078449 [Overview of the Initiative] [Means for solving the problem]

[0027] In short, the present invention relates to compounds that are substantially active in the gastrointestinal tract to inhibit NHE-mediated antiportation of sodium and hydrogen ions, and to the use of such compounds in the treatment of gastrointestinal disorders, including the treatment of disorders associated with fluid retention and salt overload, and the treatment or relief of pain associated with gastrointestinal disorders.

[0028] Compound of formula I: [Chemical formula] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof [wherein, the linker is -R 13 -(CHR 13 ) p -[Y-(CH2) r s -Z-R 13 -(CH2) t -Z-; X is a bond, H, N, O, CR 11 R 12 , CR 11 , C, -NHC(O)NH-, -(CHR 13 ) p - or C3-C6 cycloalkyl; W is, each time it appears, independently, S(O)2, C(O), or -(CH2) m -; Z is, each time it appears, independently, a bond, C(O), or -C(O)NH-; Y is, each time it appears, independently, O, S, NH, N(C1-C3 alkyl), or -C(O)NH-; Q is a bond, NH, -C(O)NH-, -NHC(O)NH-, -NHC(O)N(CH3)-, or -NHC(O)NH-(CHR 13 ); m is an integer from 1 to 2; n is an integer from 1 to 4; r and p are, each time they appear, independently, integers from 0 to 8; s is an integer from 0 to 4; t is an integer from 0 to 4; u is an integer from 0 to 2; R 1 and R 2 ​Each is a heteroaryl compound independently containing 1 to 5 heteroatoms selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, N, S, P, and O, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more halogens, OH, CN, -NO2, oxo, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 -S(O)2N(R 9 )2-, -S(O)2R 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 9 R 10 , -NR 9 S(O)2R 10 ,-S(O)R 9 -S(O)NR 9 R 10 , -NR 8 S(O)R 9 , optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, heterocyclic, aryl, or heteroaryl; or R 1 and R 2 These may form a heterocyclyl or heteroaryl group containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, together with the nitrogen to which they are bonded, thereafter the heterocyclyl or heteroaryl group may contain one or more halogens, OH, CN, -NO2, oxo, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 -S(O)2N(R 9 )2-, -S(O)2R 9 , -C(O)R 9 , -C(O)OR 9-C(O)NR 9 R 10 , -NR 9 S(O)2R 10 ,-S(O)R 9 -S(O)NR 9 R 10 , -NR 9 S(O)R 10 , optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, heterocyclic, aryl, or heteroaryl; R 3 and R 4 These are independently halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -C(O)NR 9 R 10 and; R 5 , R 6 , R 7 , and R 8 These are heteroaryls and -SRs, which independently contain 1 to 5 heteroatoms selected from the group consisting of H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, N, S, P, and O. 9 , -OR 9 , -NHR 9 , -NR 9 R 10 -S(O)2N(R 9 )2-, -S(O)2R 9 , -C(O)R 9 , -C(O)OR 9 , -NR 9 S(O)2R 10 ,-S(O)R 9 -S(O)NR 9 R 10 , -NR 8 S(O)R 9 and; R 9 and R 10is 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, R 11 and R 12 are independently H, C1-C6 alkyl, OH, NH2, CN, or NO2; R 13 is, each time it appears, independently a bond, H, C1-C6 alkyl, C4-C8 cycloalkenyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R 19 ; R 14 is, each time it appears, independently H, C1-C6 alkyl, or C1-C6 haloalkyl; or R 6 and R 14 may combine together with the atoms to which they are attached to independently form a 5-6 membered heterocyclyl each time it appears, where each C3-C8 cycloalkyl, or heterocyclyl is optionally substituted with one or more R 19 ; or R 13 and R 14 may combine together with the atoms to which they are attached to independently form a C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O each time it appears, where each heterocyclyl or heteroaryl is optionally substituted with one or more R 19 ; R 15 、R 16 、R 17 、and R 18Each instance is independently H, OH, NH2, or C1-C3 alkyl, where the alkyl is one or more R 19 It is optionally replaced by; and R 19 Each of these is independently H, OH, NH2, oxo, C1-C6 alkyl, C1-C6H haloalkyl, or C1-C6 alkoxy; however: (1) If X is H, then n is 1; (2) X is bonded, O, or CR 11 R 12 If so, then n is 2; (3) When n is 3, X is CR 11 or N; (4) If n is 4, then X is C; (5) In this case, only one of Q or X is -NHC(O)NH- (6)R 1 and R 2 They must not form pyrrolidinyl with the nitrogen to which they are bound; (7)R 1 and R 2 is methyl, and R 3 and R 4 is a halogen, and R 5 and R 8 If H, the linker is [ka] isn't it; (8)R 1 and R 2 Together with the nitrogen to which they are bound, they form piperidinyl, R 3 and R 4 is a halogen, and R 5 and R 8 If H, the linker is [ka] not; and (9)R 1 and R2 However, together with the nitrogen to which they are bound, they form 3-aminopiperidine-1-yl, R 3 and R 4 is a halogen, and R 5 , R 6 , R 7 , and R 8 If H, the linker is [ka] isn't it [This is conditional upon].

[0029] In another embodiment, a pharmaceutical composition is provided comprising the compound described above, or its stereoisomer, a pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier, diluent or additive. The pharmaceutical composition treats diseases or disorders associated with fluid retention or salt overload. It may be effective for treatment. Pharmaceutical compositions may contain the compounds of the present invention for use in the treatment of diseases described herein. Compositions may contain at least one compound of the present invention and a pharmaceutically acceptable carrier.

[0030] Another aspect of the present invention relates to a method for inhibiting NHE-mediated antiportation of sodium and hydrogen ions. The method comprises administering a pharmaceutically effective amount of a compound or pharmaceutical composition described herein to a mammal in need thereof.

[0031] In another embodiment, a method is provided for treating disorders associated with fluid retention or salt overload. The method comprises administering a pharmaceutically effective amount of the compound or pharmaceutical composition described above to a mammal in need.

[0032] The present invention further provides compounds that can inhibit NHE-mediated antiportation of sodium and hydrogen ions. The efficacy-safety profile of the compounds of the present invention can be improved compared to other known NHE-3 inhibitors. In addition, the technology also applies, but is not limited to, heart failure (such as congestive heart failure), chronic kidney disease, end-stage renal disease, hypertension, essential hypertension, primary hypertension, salt-sensitive hypertension, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention, gastrointestinal motility disorders, irritable bowel syndrome, chronic constipation, chronic idiopathic constipation, chronic constipation occurring in patients with cystic fibrosis, chronic constipation occurring in patients with chronic kidney disease, and calcium-induced constipation occurring in patients with osteoporosis. Opioid-induced constipation, functional gastrointestinal disorders, Parkinson's disease, multiple sclerosis, gastroesophageal reflux disease, functional heartburn, indigestion, functional dyspepsia, non-ulcerative dyspepsia, gastroparesis, chronic pseudo-obstruction, Crohn's disease, ulcerative colitis and related diseases known as inflammatory bowel syndrome, pseudo-obstruction of the colon, gastric ulcer, infectious diarrhea, cancer (colorectal), "leaky gut syndrome," cystic fibrosis gastrointestinal disease, multiple organ failure, microscopic colitis, necrotizing pancolitis, allergies - atopic dermatitis, food allergies Allergies, infections (respiratory), acute inflammation (e.g., sepsis, systemic inflammatory response syndrome), chronic inflammation (arthritis), obesity-induced metabolic diseases (e.g., non-alcoholic steatohepatitis, type 1 diabetes, type 2 diabetes, cardiovascular disease), kidney disease, diabetic nephropathy, cirrhosis, non-alcoholic steatohepatitis, non-alcoholic fatty acid liver disease, steatosis, primary sclerosing cholangitis, primary biliary cholangitis, portal hypertension, autoimmune diseases (e.g., type 1 diabetes, celiac-associated PTH, ankylosing spine) It has the advantage of being usable for several different types of diseases, including inflammation, lupus, alopecia areata, rheumatoid arthritis, polymyalgia rheumatica, fibromyalgia, chronic fatigue syndrome, Sjögren's syndrome, vitiligo, thyroiditis, vasculitis, urticaria (hives), Raynaud's syndrome, schizophrenia, autism spectrum disorder, hepatic encephalopathy, intestinal bacterial overgrowth, and chronic alcoholism, secondary hyperparathyroidism (PTH), celiac disease, and hyperphosphatemia. Additional features and advantages of this technology will become apparent to those skilled in the art by reading the detailed description of the invention below. [Brief explanation of the drawing]

[0033] [Figure 1] NHE3-independent changes in intracellular pH (pHi) have been shown to modulate transepithelial electrical resistance in enteroileal monolayer cultures. Changes in pHi and transepithelial electrical resistance (TEER) with (A, B) nigericin and (C, D) BAM15 (3 μM) and FCCP (3 μM) were compared in monolayer cultures with known NHE3 inhibitors tenapanor and vehicle (DMSO) controls. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs DMSO. [Figure 2] A dose-dependent decrease in urinary albumin excretion has been demonstrated. [Modes for carrying out the invention]

[0034] A first aspect of the present invention relates to the following compound: [ka] The pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, or tautomers thereof [wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 15 , R 16 , R 17 , R 18 [, n, u, X, and linker are described herein as follows]. Details of the present invention are described below in the accompanying description. Methods and substances similar to or equivalent to those described herein may be used in the practice or testing of the present invention, and examples of such methods and substances are described below. Other features, subjects, and advantages of the present invention are evident from the specification and claims. In the specification and the accompanying claims, singular nouns also include plural nouns unless otherwise specified in the context. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention pertains. All patents and publications referenced herein are incorporated herein by reference in their entirety.

[0035] Definition: Unless the context otherwise requires, throughout this specification and the claims, the term “comprise” and its variations, such as “comprises” and “comprising,” should be interpreted in an open and comprehensive sense, including, but not limited to, “comprise.”

[0036] The articles “a” and “an” are used in this disclosure to refer to one or more (i.e., at least one) grammatical objects of that article. For example, “an element” means one or more elements.

[0037] In this disclosure, the terms “and / or” are used to mean either “and” or “or” unless otherwise indicated.

[0038] Throughout this specification, any reference to “one embodiment” or “an embodiment” means that certain features, structures, or characteristics described in relation to that embodiment are included in at least one embodiment of the present invention. Therefore, the occurrences of the phrases “in one embodiment” or “in another embodiment” in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, certain features, structures, or characteristics may be combined in one or more embodiments in any preferred manner.

[0039] "Amino" refers to the -NH2 radical.

[0040] "Cyano" refers to the -CN radical.

[0041] "Hydroxy" or "hydroxyl" refers to the -OH radical.

[0042] "Imino" refers to the =NH substituent.

[0043] "Nitro" refers to the -NO2 radical.

[0044] "Oxo" refers to an =O substituent.

[0045] "Thioxo" refers to the =S substituent.

[0046] As used herein, the term “substituted” means any of the above groups (i.e., alkyl, alkylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl) in which at least one hydrogen atom is replaced by a bond to a non-hydrogen atom, e.g., halogen atoms, e.g., F, Cl, Br, and I; oxygen atoms in groups such as hydroxyl, alkoxy, alkoxy, hydroxyl, hydroxylalkyl, and ester groups; sulfur atoms in groups such as thiol, thioalkyl, sulfonyl, and sulfoxide groups; nitrogen atoms in groups such as amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide, and enamine; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and a bond to another heteroatom in various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by higher-order bonds (e.g., double or triple bonds) with heteroatoms such as oxygen in oxo, carbonyl, carboxyl, and ester groups, as well as nitrogen in imines, oximes, hydrazones, and nitrile groups. For example, "Substituted" means that one or more hydrogen atoms are replaced by -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h -OC(=O)NR g R h , -OR g , -SR g -SOR g , -SO2R g , -OSO2Rg , -SO2OR g ,=NSO2R g , and -SO2NR g R h Contains any of the above groups that are replaced by -C(=O)R. "Substituted (substituted)" also means that one or more hydrogen atoms are replaced by -C(=O)R g , -C(=O)OR g -C(=O)NR g R h -CH2SO2R g -CH2SO2NR g R h -(CH2CH2O) 2~10 R g This means any of the above bases that are replaced by R. g and R h These are the same or different, independently of hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituting" further means any of the above groups in which one or more hydrogen atoms are replaced by bonding with amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. In addition, each of the above substituents may be optionally substituted with one or more of the above substituents.

[0047] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) may (but does not need to) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group may be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have substituents other than hydrogen. For example, this could be along the chain. At any point, it may be bonded to a halogen atom, a hydroxyl group, or any other substituent as described herein. Thus, the term “optionally substituted” means that a given chemical moiety may contain other functional groups, but does not necessarily have any further functional groups.

[0048] "Alkyl" consists only of carbon and hydrogen atoms, and is saturated or unsaturated (i.e., contains one or more double and / or triple bonds), and has 1 to 12 carbon atoms (C1 to C1). 12 This refers to linear or branched hydrocarbon chain radicals having 1 to 8 carbon atoms (C1-C8 alkyl) or 1 to 6 carbon atoms (C1-C6 alkyl) and being bonded to the rest of the molecule by single bonds, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl, propa-1-enyl, buta-1-enyl, penta-1-enyl, penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless otherwise specifically stated herein, alkyl groups may be optionally substituted.

[0049] "alkoxy" is the formula -OR a (In the formula, R a This refers to a radical (which is an alkyl radical containing 1 to 12 carbon atoms as defined above). Unless otherwise specifically stated herein, the alkoxy group may be optionally substituted.

[0050] An "alkenyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in its chain. The double bond of an alkenyl group may or may not be conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group may be unsubstituted or substituted. An alkenyl may be straight-chain or branched as defined herein.

[0051] "Alkynyl" refers to a straight-chain or branched-chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. The "alkynyl" group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propanyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. The alkynyl group may be unsubstituted or substituted.

[0052] The term "cycloalkyl" refers to a monocyclic or polycyclic saturated carbocyclic ring containing 3 to 18 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl. C3-C8 cycloalkyl groups are cycloalkyl groups containing 3 to 8 carbon atoms. Cycloalkyl groups may be condensed (e.g., decalin) or cross-linked (e.g., norbornane).

[0053] The term "cycloalkenyl" refers to a monocyclic, non-aromatic unsaturated carbon ring containing 4 to 18 carbon atoms. Examples of cycloalkenyl groups, though not limited to them, include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and norborenyl. C4-C8 cycloalkenyls are cycloalkenyl groups containing 4 to 8 carbon atoms.

[0054] The term "heterocyclyl," "heterocycloalkyl," or "heterocyclic" refers to a ring containing carbon and a heteroatom selected from oxygen, phosphorus, nitrogen, or sulfur, and having a ring carbon or heteroatom. This refers to monocyclic or polycyclic 3- to 24-membered rings that do not have delocalized π electrons (aromaticity) shared between the tetraatoms. Heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl. Heterocyclyl or heterocycloalkyl rings may be condensed or crosslinked, and may be, for example, bicyclic rings.

[0055] As used herein, the term "halo" or "halogen" means a fluoro, chloro, bromo, or iodine group.

[0056] The term "carbonyl" refers to a functional group consisting of a carbon atom double-bonded to an oxygen atom. In this specification, it may be abbreviated as "oxo," C(O), or C=O.

[0057] The term "aryl" refers to a cyclic aromatic hydrocarbon group having one or two aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. If two aromatic rings (such as bicyclic) are present, the aromatic rings of the aryl group may be bonded at a single point (e.g., biphenyl) or fused together (e.g., naphthyl). The aryl group may be optionally substituted at any point of bond with one or more substituents, e.g., one to five substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -O-C1~C6 alkyl, -C1~C6 alkyl, -OC2~C6 alkenyl, -OC2~C6 alkynyl, -C2~C6 alkenyl, -C2~C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)C1~C6 alkyl, -C(O)C1~C6 alkyl, -OC(O)OC1~C6 alkyl, -NH2, -NH(C1~C6 alkyl), -N(C1~C6 alkyl)2, -S(O)2-C1~C6 alkyl, -S(O)NHC1~C6 alkyl, and -S(O)N(C1~C6 alkyl)2. Substituents may be optionally substituted themselves. Furthermore, if two fused rings are present, the aryl group as defined herein may have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoanurenyl.

[0058] Unless specifically defined otherwise, “heteroaryl” means a monovalent monocyclic or polycyclic aromatic radical comprising 5 to 24 ring atoms, with one or more ring heteroatoms selected from N, S, P, and O, and the remaining ring atoms being C. Heteroaryl as defined herein also means a bicyclic heteroaromatic group in which the heteroatoms are selected from N, S, P, and O. Aromatic radicals are optionally substituted independently with one or more substituents as described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranil, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3- [c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanil, thiochromanil, teto Lahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanil, quinolinyl, isoquinolinyl, 1,6-naphthilidinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthilidinyl, thieno[2,3-b]pyradinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyridinyl, tetrahydropyrrolo[1,2-a]pyridinyl, 3,4-dihydro-2H-1□ 2-Pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridine-2-one, flo[3,2-c]pyridinyl, flo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiadinyl, benzoxazolyl, benzoisoxazolyl, flo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthilidinyl, flo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4] These include riazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazole-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and their derivatives. Furthermore, if two fused rings are present, the heteroaryl groups as defined herein may have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzooxanyl.

[0059] The term "prodrug" refers to a compound that can be converted to the bioactive compound of the present invention under physiological conditions or by solvolysis. Therefore, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of the compound of the present invention. A prodrug may be inactive when administered to a target requiring it, but is converted to the active compound of the present invention in vivo. Typically, prodrugs are rapidly converted in vivo, for example, by hydrolysis in the blood, to yield the parent compound of the present invention. Prodrug compounds often offer advantages in mammalian vivo, such as solubility, histocompatibility, or delayed release (see Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). For further discussion of prodrugs, see Higuchi, et al., ACSSymposium Series, Vol. 14, and Bioreversible Carriers. This information is available in *In Drug Design*, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0060] The term “prodrug” also means any covalent carrier that releases the active compound of the present invention in vivo when such a prodrug is administered to a mammalian subject. Prodrugs of the compounds of the present invention can be prepared by modifying functional groups present in the compounds of the present invention in such a way that the modified form is cleaved into the parent compound of the present invention by routine operation or in vivo. Prodrugs include compounds of the present invention in which a hydroxy, amino, or mercapto group is cleaved when the prodrug of the compound of the present invention is administered to a mammalian subject, and is attached to any group that forms a free hydroxy, free amino, or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, The compounds of the present invention include alcohol derivatives such as acetic acid, formic acid, and benzoic acid, or amide derivatives of amine functional groups.

[0061] The present invention as disclosed herein also means encompassing in vivo metabolites of the disclosed compounds. Such products may arise, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily by enzymatic processes. Accordingly, the present invention includes compounds produced by processes comprising administering the compounds of the present invention to mammals for a sufficient time to obtain their metabolites. Typically, such products are identified by administering a detectable dose of the radiolabeled compound of the present invention to animals such as rats, mice, guinea pigs, monkeys, or humans for a sufficient time for metabolism to occur, and then isolating the converted products from urine, blood, or other biological samples.

[0062] "Stable compound" and "stable structure" refer to a compound that is robust enough to survive isolation from a reaction mixture to a usable purity and to be formulated into an effective therapeutic agent.

[0063] "Pharmacologically acceptable carriers, diluents or additives" include, but are not limited to, any adjuvants, carriers, additives, fluidizers, sweeteners, diluents, preservatives, colorants, flavor enhancers, surfactants, humectants, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers approved by the U.S. Food and Drug Administration as acceptable for use in human or animal.

[0064] "Pharmacologically acceptable salts" include both acid and base addition salts.

[0065] "Pharmacologically acceptable acid addition salts" are those that maintain the biological efficacy and properties of the free base, are not biologically or otherwise undesirable, and are not limited to, inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids, for example, for example, not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, gas This refers to salts formed with lactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucoic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0066] "Pharmacologically acceptable base addition salts" refer to salts that retain the biological efficacy and properties of a free acid without any biological or other undesirable aspects. These salts are prepared by adding an inorganic or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and base ion exchange resins, e.g. Examples include ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, benetamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, and salts of polyamine resins. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0067] Crystallization often results in solvates of the compounds of the present invention. As used herein, the term “solvate” refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more molecules of a solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and as corresponding solvated forms. The compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may simply retain foreign water or be a mixture of water and some foreign solvent.

[0068] "Pharmaceutical composition" refers to a formulation of the compound of the present invention with a medium generally accepted in the art for delivering the biologically active compound to a mammal, such as a human. Such a medium may include any pharmaceutically acceptable carrier, diluent, or additive for that purpose.

[0069] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers, and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined with respect to amino acids as (R)- or (S)- or (D)- or (L)- in terms of absolute stereochemistry. The present invention means that all such possible isomers, as well as their racemic and optically pure forms, are included. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). Where a compound described herein contains an olefinic double bond or other geometrically asymmetric centers, and unless otherwise specified, such compound is intended to include both E and Z geometric isomers. Similarly, all tautomers are also intended to be included.

[0070] A "stereoisomer" refers to a compound made from the same atoms bonded together by the same bonds, but possessing different three-dimensional structures and being incompatible. This invention aims to introduce various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers that are mirror images of each other and whose molecules cannot be superimposed.

[0071] A "tautomer" refers to a proton shift from one atom in a molecule to another atom in the same molecule. This invention includes tautomers of any of the aforementioned compounds.

[0072] In accordance with this disclosure, the compounds described herein are designed to be substantially active or localized in the lumen of the gastrointestinal tract of human or animal subjects. The term “gastrointestinal lumen” is used herein interchangeably with the term “lumen” and refers to the space or cavity within the gastrointestinal tract (also known as the GI duct, or intestine) demarcated by the apical membrane of the GI epithelial cells of the subject. Some embodiments In this state, the compound is not absorbed through the epithelial cell layer of the GI tubule (also known as GI epithelium). "Gastrointestinal mucosa" refers to the layer(s) of cells that separate the lumen of the gastrointestinal tract from the rest of the body, and includes the mucosa of the stomach and intestines, such as the mucosa of the small intestine. "Gastrointestinal epithelial cells" or "intestinal epithelial cells," as used herein, refers to any epithelial cells on the surface of the gastrointestinal mucosa facing the lumen of the gastrointestinal tract, including, for example, gastric epithelial cells, intestinal epithelial cells, colonic epithelial cells, etc.

[0073] The "subject" is human, but may also be animals that require treatment with the compounds of this disclosure, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cattle, pigs, horses, etc.) and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0074] As used herein, “substantially systemically unbiogenic” and / or “substantially impermeable” (and variations thereof) generally refer to situations in which a statistically significant amount, and in some embodiments essentially all, of the compounds of this disclosure (including NHE inhibitory small molecules) remain in the gastrointestinal lumen. For example, according to one or more embodiments of this disclosure, at least about 70%, about 80%, about 90%, about 95%, about 98%, about 99%, or even about 99.5% of the compounds remain in the gastrointestinal lumen. In such cases, localization to the gastrointestinal lumen means reducing the net movement of epithelial cells through the gastrointestinal lamina, for example, by both intercellular and paracellular transport, and even by active and / or passive transport. In such embodiments, the compounds are prevented from net permeating the gastrointestinal epithelial cell lamina in intercellular transport, for example, across the apical membrane of small intestinal epithelial cells. The compounds in these embodiments can also have their net permeability inhibited via "tight junctions" in paracellular transport between gastrointestinal epithelial cells lining the lumen.

[0075] In this regard, it should be noted that in a particular embodiment, the compound is essentially not absorbed at all by the GI tube or the lumen of the gastrointestinal tract. As used herein, the terms “substantially impermeable” or “substantially systemically unbiogenic” refer to embodiments in which any detectable amount of absorption, permeation, or systemic exposure of the compound is not detectable by means of means commonly known in the Art.

[0076] However, in this regard, in alternative embodiments, “substantially impermeable” or “substantially systemically unbiogenic” means that “substantially impermeable” or “substantially systemically unbiogenic” means that the compound provides or enables somewhat limited absorption in the GI tube and, more specifically, intestinal epithelium (e.g., some detectable amount of absorption, e.g., at least about 0.1%, 0.5%, 1% or more and about 30%, 20%, 10%, less than 5%, etc.), with the absorption range being, for example, about 1% to 30% or 5% to 20%; otherwise, “substantially impermeable” or “substantially systemically unbiogenic” means that less than about 20% of the administered compound (e.g., about 15%, about 10%, or even less than about 5%, and e.g., about 0.5%, or more than 1%) is eliminated by the liver (i.e., hepatic extraction) and / or kidneys (i.e., renal excretion).

[0077] In accordance with this disclosure and as further detailed below herein, sodium ions (Na) in the gastrointestinal tract, and more specifically in the gastrointestinal epithelium. + ) and hydrogen ions (H + Inhibition of NHE-mediated antiports of ) has been found to be a potent approach to treating various disorders associated with or potentially resulting from fluid retention and / or salt overload, and / or disorders such as heart failure (particularly congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and / or peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. More specifically, inhibition of NHE-mediated antiports of sodium and hydrogen ions in the GI tube has been found to increase fecal sodium excretion and efficiently lower systemic levels of sodium and fluid. This, in turn, leads to, for example, This improves the clinical condition of patients suffering from CHF, ESRD / CKD, and / or liver disease. Furthermore, it has been found that such treatment can be optionally enhanced by the co-administration of other beneficial compounds or compositions, such as liquid absorbent polymers. Liquid absorbent polymers can be optimally selected because they do not block or negatively interfere with the mechanism of action of the co-administered NHE inhibitor compound.

[0078] In addition, as will be further detailed below in this specification, sodium ions (Na) in the gastrointestinal tract, and more specifically in the gastrointestinal epithelium. + ) and hydrogen ions (H + Inhibition of NHE-mediated antiports of sodium and hydrogen ions has been found to be a potent technique for treating hypertension associated with or potentially resulting from fluid retention and / or salt overload. More specifically, inhibition of NHE-mediated antiports of sodium and hydrogen ions in the GI tube has been found to increase fecal excretion of sodium and efficiently lower systemic levels of sodium and body fluids. This, in turn, improves the clinical condition of patients suffering from hypertension. Such treatment can be optionally enhanced by the co-administration of other beneficial compounds or compositions, such as liquid absorbent polymers. Liquid absorbent polymers can be optimally selected because they do not block or negatively interfere with the mechanism of action of the co-administered NHE inhibitor.

[0079] In addition, as will be further detailed below in this specification, sodium ions (Na) in the gastrointestinal tract, and more specifically in the gastrointestinal epithelium. + ) and hydrogen ions (H +It has been further found that inhibition of NHE-mediated antiport is a potent approach to treating a variety of gastrointestinal disorders, including the treatment or relief of pain associated with gastrointestinal disorders, and more specifically, the restoration of appropriate fluid secretion in the intestines and the improvement of pathological conditions encountered in constipated states. The applicant further recognizes that by blocking sodium ion reabsorption, the compounds of the present disclosure restore fluid homeostasis in the GI tubule, particularly in situations where fluid secretion / absorption is altered to result in constipated states and GI discomfort, generally leading to a high degree of fecal dehydration, low gastrointestinal motility, and / or delayed transit time. It has been further found that such treatment can be optionally enhanced by co-administration of other beneficial compounds or compositions, such as liquid absorbent polymers. Liquid absorbent polymers can be optimally selected because they do not block or otherwise negatively interfere with the mechanism of action of the co-administered NHE inhibitor compounds.

[0080] Due to the presence of NHE in other organs or tissues in the body, the methods of this disclosure utilize the use of compounds and compositions that are preferably highly selective or localized and therefore act substantially in the gastrointestinal tract without exposure to other tissues or organs. In this way, any systemic effects can be minimized (whether they are on-target or off-target). It should be noted that, as used herein and as further elaborated elsewhere, “substantially active in the gastrointestinal tract” generally refers to compounds that are substantially systemically unbiovable and / or substantially impermeable to the epithelial cell layer, and more specifically to the epithelial cells of the gastrointestinal tract. Furthermore, it should be noted that, as used herein and as further elaborated elsewhere, “substantially impermeable” more specifically includes compounds that are impermeable to the epithelial cell layer, and more specifically to the gastrointestinal epithelium (or epithelial layer). “Gastrointestinal epithelial cells” refers to the membrane tissue covering the inner surface of the gastrointestinal tract. Therefore, by being substantially impermeable, compounds have a very limited ability to be transported through gastrointestinal epithelial cells and thus come into contact with other internal organs (e.g., brain, heart, liver, etc.). Typical mechanisms by which compounds can be transported through gastrointestinal epithelial cells are by intercellular transport (transcellular transport of substances mediated by passive or active transport across both the apical and basolateral membranes) and / or by paracellular transport, in which substances move between epithelial cells via highly limited structures usually known as "tight junctions". That is the case.

[0081] While we do not wish to be bound by any particular theory, it is thought that the NHE inhibitors of this disclosure (e.g., NHE-3, -2, and / or -8 inhibitors) act to reduce paracellular permeability of the intestine through distinct and unique mechanisms. NHE3 is highly expressed at the apical end of the gastrointestinal tract and links luminal Na absorption to intracellular proton secretion. Inhibition of NHE3 by the NHE inhibitors of this disclosure (e.g., NHE-3, -2, and / or -8 inhibitors) results in intracellular proton accumulation. NHE3 inhibition accompanied by intracellular proton retention modulates tight junctions between cells, reducing paracellular permeability, which can be measured by increased transepithelial electrical resistance.Increased paracellular and / or transcellular permeability of the intestine is, but is not limited to, gastrointestinal motility disorders, irritable bowel syndrome, chronic constipation, chronic idiopathic constipation, chronic constipation occurring in patients with cystic fibrosis, chronic constipation occurring in patients with chronic kidney disease, calcium-induced constipation occurring in patients with osteoporosis, opioid-induced constipation, multiple sclerosis-induced constipation, Parkinson's disease-induced constipation, functional gastrointestinal disorders, gastroesophageal reflux disease, functional heartburn, indigestion, functional Indigestion, non-ulcerative dyspepsia, gastroparesis, chronic pseudo-obstruction, Crohn's disease, ulcerative colitis and related diseases known as inflammatory bowel syndrome, pseudo-obstruction of the colon, gastric ulcer, infectious diarrhea, cancer (colorectal), "leaky gut syndrome," cystic fibrosis gastrointestinal disease, multiple organ failure, microscopic colitis, necrotizing pancolitis, allergies - atopic dermatitis, food allergies, infections (respiratory tract), acute inflammation (e.g., sepsis, systemic inflammatory response syndrome), chronic NHE inhibition is observed in many diseases, including inflammatory bowel disorders (arthritis), obesity-induced metabolic diseases (e.g., non-alcoholic fatty liver disease, type 1 diabetes, type 2 diabetes, cardiovascular disease), kidney diseases, diabetic nephropathy, cirrhosis, non-alcoholic fatty acid liver disease, steatosis, primary sclerosing cholangitis, primary biliary cholangitis, portal hypertension, autoimmune diseases (e.g., type 1 diabetes, ankylosing spondylitis, lupus, alopecia areata, rheumatoid arthritis, polymyalgia rheumatica, fibromyalgia, chronic fatigue syndrome, Sjögren's syndrome, vitiligo, thyroiditis, vasculitis, urticaria, Raynaud's syndrome), schizophrenia, autism spectrum disorder, hepatic encephalopathy, small intestinal bacterial overgrowth, and chronic alcoholism. Therefore, NHE inhibition is expected to provide therapeutic effects in these diseases by reducing paracellular and / or transcellular permeability in the intestines.

[0082] Accordingly, in some embodiments, the present disclosure provides a method for reducing the paracellular permeability of the intestine. In some embodiments, the method for reducing the paracellular permeability of the intestine includes the administration of an NHE3 inhibitor. In some embodiments, inhibition of NHE3 results in the accumulation of intracellular protons. In some embodiments, the reduction in paracellular permeability is due to an increase in intracellular protons that is independent of and unaccompanied by NHE3 inhibition. In other words, an increase in intracellular protons unaccompanied by NHE3 inhibition results in a reduction in paracellular permeability. Accordingly, the present disclosure provides a method for reducing paracellular permeability, which includes an increase in intracellular protons. In some embodiments, the present disclosure provides a method for treating a disease associated with paracellular permeability, which includes administering an agent that increases intracellular protons in tight junctions, thereby reducing paracellular permeability, and thus treating the disease. Non-exclusive examples of such diseases include Crohn's disease, ulcerative colitis and related disorders known as inflammatory bowel syndrome, pseudo-obstruction of the colon, gastric ulcer, infectious diarrhea, cancer (colorectal), "leaky gut syndrome," cystic fibrosis gastrointestinal disease, multiple organ failure, microscopic colitis, necrotizing pancolitis, allergies - atopic dermatitis, food allergies, infections (respiratory), acute inflammation (e.g., sepsis, systemic inflammatory response syndrome), chronic inflammation (arthritis), obesity-induced metabolic diseases (e.g., non-alcoholic fatty liver disease, type 1 diabetes, type 2 diabetes, cardiovascular disease), and kidney disease. Diseases include diabetic nephropathy, cirrhosis, non-alcoholic fatty liver disease, non-alcoholic fatty acid liver disease, steatosis, primary sclerosing cholangitis, primary biliary cholangitis, portal hypertension, autoimmune diseases (e.g., type 1 diabetes, ankylosing spondylitis, lupus, alopecia areata, rheumatoid arthritis, polymyalgia rheumatica, fibromyalgia, chronic fatigue syndrome, Sjögren's syndrome, vitiligo, thyroiditis, vasculitis, urticaria, Raynaud's syndrome), schizophrenia, autism spectrum disorder, hepatic encephalopathy, small intestinal bacterial overgrowth, and chronic alcoholism.

[0083] In some embodiments, the present disclosure provides methods for modulating intestinal transcellular permeability. In some embodiments, the method for modulating intestinal transcellular permeability includes the administration of an NHE3 inhibitor. In some embodiments, inhibition of NHE3 results in transcellular substance transport mediated by passive or active transport across both the apical and basolateral membranes. Thus, the present invention provides a method for modulating transcellular permeability, comprising mediating the passive or active transport of substances across both the apical and basolateral membranes. In some embodiments, the present invention provides a method for treating a disease associated with transcellular permeability, comprising administering an agent that mediates the passive or active transport of substances across both the apical and basolateral membranes of a cell, thereby modulating transcellular permeability and thus treating the disease. Non-limiting examples of such disorders include gastrointestinal motility disorders, irritable bowel syndrome, chronic constipation, chronic idiopathic constipation, chronic constipation in patients with cystic fibrosis, chronic constipation in patients with chronic kidney disease, calcium-induced constipation in patients with osteoporosis, opioid-induced constipation, multiple sclerosis-induced constipation, Parkinson's disease-induced constipation, functional gastrointestinal disorders, gastroesophageal reflux disease, functional heartburn, indigestion, functional dyspepsia, non-ulcerative dyspepsia, gastroparesis, and chronic pseudo-obstruction of the intestines.

[0084] Therefore, the compounds of this disclosure do not need to be absorbed and are therefore essentially not systemically bioavailable at all (e.g., they do not permeate gastrointestinal epithelial cells at all), or they do not exhibit detectable concentrations of the compounds in serum. Alternatively, the compounds may (i) be rapidly eliminated in the liver (i.e., hepatic extract) via first-pass metabolism, exhibiting some detectable permeability to the epithelial cell layer and more specifically to GI duct epithelial cells, but less than about 20% of the administered compound (e.g., about 15%, about 10%, or even less than about 5%, and more specifically to GI duct epithelial cells, but less than about 20% of the administered compound (e.g., about 15%, about 10%, or even less than about 5%, and more specifically to GI duct epithelial cells, but less than about 20% of the administered compound (i.e., about 15%, about 10%, or even less than about 5%, and more than about 0.5%, or more than 1%), but less than some detectable permeability to the epithelial cell layer and more specifically to GI duct epithelial cells, but less than about 20% of the administered compound (i.e., hepatic extract).

[0085] The compounds can also be removed from circulation into bile without change by bile drainage. Therefore, the compounds of this disclosure cannot exhibit detectable concentrations in bile. Alternatively, the compounds may exhibit some detectable concentrations in bile, more specifically in the epithelial cells of the bile ducts and gallbladder, of 10 μM, less than 1 μM, less than 0.1 μM, less than 0.01 μM, or about less than 0.001 μM.

[0086] In this regard, it should be further noted that, as used herein, “substantially systemically unbiogenic” generally means that the compound cannot be detected in the systemic circulation of an animal or human after oral administration. For biocompatible compounds, it should be transported through the gastrointestinal epithelial cells (i.e., substantially permeable as defined above), transported to the liver via the portal circulation, avoid substantial metabolism in the liver, and then transported into the systemic circulation.

[0087] While we do not wish to be bound by any particular theory, the NHE inhibitors of this disclosure (e.g., NHE-3, -2, and / or -8 inhibitors) are thought to act through distinct and unique mechanisms, resulting in the retention of fluids and ions in the GI tubules (and stimulation of fecal excretion) rather than stimulating increased secretion of fluids and ions. For example, lubiprostone (Amitiza® Sucampo / Takeda) is a bicyclic fatty acid prostaglandin E1 analog that activates type 2 chloride channels (ClC-2) and increases the secretion of chloride-rich fluids from the serosal membrane of the GI tubules to the mucosal side (see, e.g., Pharmacological Reviews for Amitiza®, NDA package). Linaclotide (MD-1100 acetate, Microbia / F Orest Labs) is a 14-amino acid peptide analog of the endogenous hormone guanylin, which indirectly activates the cystic fibrosis membrane conductance regulator (CFTR), thereby inducing the secretion of fluids and electrolytes into the GI ducts (see, e.g., Li et al., J. Exp. Med., vol. 202 (2005), pp. 975-986). The substantially impermeable NHE inhibitor compound of this disclosure acts to inhibit the reuptake of salts and fluids rather than to promote secretion. Since the GI ducts process approximately 9 liters of fluid and approximately 800 meq of sodium daily, NHE inhibition is expected to enable the removal of substantial amounts of systemic fluids and sodium, thereby reabsorbing edema and resolving CHF symptoms.

[0088] I. Substantially impermeable or substantially systemically unbiogenic NHE inhibitors In one embodiment, the compounds of the present disclosure generally have the following formula (I): [ka] and also represented by its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers. [In the formula, The linker is -(CHR 13 ) p -[Y-(CH2) r ] s -ZR 13 -(CH2) t -Z- is; Each instance of W is independently S(O)2, C(O), or -(CH2). m -and; Z is, independently, a bond, C(O), or -C(O)NH- each time it appears; Y is independently O, S, NH, N(C1-C3 alkyl), or -C(O)NH- each time it appears; Q is a bond, NH, -C(O)NH-, -NHC(O)NH-, -NHC(O)N(CH3)-, or -NHC(O)NH-(CHR 13 ) and; m is an integer between 1 and 2; n is an integer between 1 and 4; r and p are, independently, integers between 0 and 8 each time they appear; s is an integer between 0 and 4; t is an integer between 0 and 4; u is an integer between 0 and 2; R 1 and R 2 Each is a heteroaryl compound independently containing 1 to 5 heteroatoms selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, N, S, P, and O, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more halogens, OH, CN, -NO2, oxo, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 -S(O)2N(R 9 )2-, -S(O)2R 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 9 R 10 , -NR 9 S(O)2R 10 ,-S(O)R 9 -S(O)NR 9 R 10 , -NR 8 S(O)R 9 , optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, heterocyclic, aryl, or heteroaryl; or R 1 and R 2 These may form a heterocyclyl or heteroaryl group containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, together with the nitrogen to which they are bonded, thereafter the heterocyclyl or heteroaryl group may contain one or more halogens, OH, CN, -NO2, oxo, -SR9 , -OR 9 , -NHR 9 , -NR 9 R 10 -S(O)2N(R 9 )2-, -S(O)2R 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 9 R 10 , -NR 9 S(O)2R 10 ,-S(O)R 9 -S(O)NR 9 R 10 , -NR 9 S(O)R 10 , optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, heterocyclic, aryl, or heteroaryl; R 3 and R 4 These are independently halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -C(O)NR 9 R 10 and; R 5 , R 6 , R 7 , and R 8 These are heteroaryls and -SRs, which independently contain 1 to 5 heteroatoms selected from the group consisting of H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, N, S, P, and O. 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)R9 -S(O)NR 9 R 10 , -NR 8 S(O)R 9 and; R 9 and R 10 Each is independently a heteroaryl compound containing H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O. X is a bond, H, N, O, CR 11 R 12 CR 11 , C, -NHC(O)NH-, or C3-C6 cycloalkyl; R 11 and R 12 These are independently H, C1-C6 alkyl, OH, NH2, CN, or NO2; R 13 Each instance is independently a bond, H, C1-C6 alkyl, C4-C8 cycloalkenyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more R 19 It is replaced by an optional choice; R 14 Each instance is independently either H, C1-C6 alkyl, or C1-C6 haloalkyl; or R 6 and R 14 These may combine with the atoms to which they are bonded to form a 5-6 membered heterocycline independently each time they appear, where each C3-C8 cycloalkyl or heterocycline has one or more R 19 It is either optionally replaced; or R 13 and R 14These may combine with the atoms to which they are bonded to form a heteroaryl that, each time it appears, independently contains 1 to 5 heteroatoms selected from the group consisting of C3-C8 cycloalkyl, heterocyclyl, aryl, or N, S, P, and O, where each heterocyclyl or heteroaryl contains 1 or more R 19 It is replaced by an optional choice; R 15 , R 16 , R 17 , and R 18 Each instance is independently H, OH, NH2, or a C1-C3 alkyl group, and the alkyl group contains one or more R groups. 19 It is replaced by an optional choice; R 19 Each of these is independently H, OH, NH2, oxo, C1-C6 alkyl, C1-C6H haloalkyl, and C1-C6 alkoxy, however: (1) If X is H, then n is 1; (2) X is bonded, O, or CR 11 R 12 If so, then n is 2; (3) When n is 3, X is CR 11 or N; (4) If n is 4, then X is C; (5) In this case, only one of Q or X is -NHC(O)NH- (6)R 1 and R 2 They must not form pyrrolidinyl with the nitrogen to which they are bound; (7)R 1 and R 2 is methyl, and R 3 and R 4 is a halogen, and R 5 and R 8 If H, the linker is [ka] isn't it; (8)R 1and R 2 Together with the nitrogen to which they are bound, they form piperidinyl, R 3 and R 4 is a halogen, and R 5 and R 8 If H, the linker is [ka] not; or (9)R 1 and R 2 However, together with the nitrogen to which they are bound, they form 3-aminopiperidine-1-yl, R 3 and R 4 is a halogen, and R 5 , R 6 , R 7 , and R 8 If H, the linker is [ka] isn't it [This is conditional upon].

[0089] In one embodiment, the NHE inhibitor compound of formula (I) has overall physicochemical properties that make them substantially impermeable or substantially systemically unbiogenic.

[0090] In one embodiment, the compound of the present invention is of formula I' [ka] Having a structure or a pharmaceutically acceptable salt thereof [In the formula, The linker is -R 13 -(CHR 13 ) p -[Y-(CH2) r ] s -ZR 13 -(CH2) t -Z- is; X is a bond, H, N, O, CR 11 R 12 CR11 , C, -NHC(O)NH-, -(CHR 13 ) p -or C3-C6 cycloalkyl; Each instance of W is independently S(O)2, C(O), or -(CH2). m - and ; Z is, independently, a bond, C(O), or -C(O)NH- each time it appears; Y is independently O, S, NH, N(C1-C3 alkyl), or -C(O)NH- each time it appears; Q is a bond, NH, -C(O)NH-, -NHC(O)NH-, -NHC(O)N(CH3)-, or -NHC(O)NH-(CHR 13 ) and; m is an integer between 1 and 2; n is an integer between 1 and 4; r and p are, independently, integers between 0 and 8 each time they appear; s is an integer between 0 and 4; t is an integer between 0 and 4; u is an integer between 0 and 2; R 1 and R 2 Each is a heteroaryl compound independently containing 1 to 5 heteroatoms selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, N, S, P, and O, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more halogens, OH, CN, -NO2, oxo, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 -S(O)2N(R 9 )2-, -S(O)2R 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 9 R 10 , -NR9 S(O)2R 10 ,-S(O)R 9 -S(O)NR 9 R 10 , -NR 8 S(O)R 9 , optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, heterocyclic, aryl, or heteroaryl; or R 1 and R 2 These may form a heterocyclyl or heteroaryl group containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, together with the nitrogen to which they are bonded, thereafter the heterocyclyl or heteroaryl group may contain one or more halogens, OH, CN, -NO2, oxo, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 -S(O)2N(R 9 )2-, -S(O)2R 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 9 R 10 , -NR 9 S(O)2R 10 ,-S(O)R 9 -S(O)NR 9 R 10 , -NR 9 S(O)R 10 , optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, heterocyclic, aryl, or heteroaryl; R 3 and R 4 These are independently halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -C(O)NR 9 R 10 and; R5 , R 6 , R 7 , and R 8 These are heteroaryls and -SRs, which independently contain 1 to 5 heteroatoms selected from the group consisting of H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, N, S, P, and O. 9 , -OR 9 , -NHR 9 , -NR 9 R 10 -S(O)2N(R 9 )2-, -S(O)2R 9 , -C(O)R 9 , -C(O)OR 9 , -NR 9 S(O)2R 10 ,-S(O)R 9 -S(O)NR 9 R 10 , -NR 8 S(O)R 9 and; R 9 and R 10 Each is independently a heteroaryl compound containing H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O. R 11 and R 12 These are independently H, C1-C6 alkyl, OH, NH2, CN, or NO2; R 13 Each instance is independently a bond, H, C1-C6 alkyl, C4-C8 cycloalkenyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more R 19 It is replaced by an optional choice; R 14Each instance is independently either H, C1-C6 alkyl, or C1-C6 haloalkyl; or R 6 and R 14 These may combine with the atoms to which they are bonded to form a 5-6 membered heterocycline independently each time they appear, where each C3-C8 cycloalkyl or heterocycline has one or more R 19 It is either optionally replaced; or R 13 and R 14 These may combine with the atoms to which they are bonded to form a heteroaryl that, each time it appears, independently contains 1 to 5 heteroatoms selected from the group consisting of C3-C8 cycloalkyl, heterocyclyl, aryl, or N, S, P, and O, where each heterocyclyl or heteroaryl contains 1 or more R 19 It is replaced by an optional choice; R 15 , R 16 , R 17 , and R 18 Each instance is independently H, OH, NH2, or a C1-C3 alkyl group, and the alkyl group contains one or more R groups. 19 It is replaced by an optional choice; R 19 Each of these is independently H, OH, NH2, oxo, C1-C6 alkyl, C1-C6H haloalkyl, or C1-C6 alkoxy.

[0091] It should be noted that in many of the structures illustrated herein, not all possible linkages or connections are shown in every example. However, this should not be taken as restrictive. Rather, it should be understood that the NHE inhibitory molecule is linked or connected in several ways (e.g., by binding or linkers) so that the resulting NHE inhibitory compound is suitable for use (i.e., substantially impermeable in the GI tube or substantially systemically unbiogenic).

[0092] In other embodiments, the polyvalent NHE inhibitor compound may be in oligomeric or polymeric form. It should be noted that the repeating units in each formula (I) generally encompass repeating units of various polymer embodiments, including linear, branched, and dendritic repeating units, which may be optionally produced by the methods described herein. In each polymer, or more generally in polyvalent embodiments, each repeating unit may be the same or different, and may or may not be linked via the "X" portion by a linker, and the linker, if present, may be the same or different. In this regard, it should be noted that, as used herein, "polyvalent" refers to a molecule having multiple (e.g., 2, 4, 6, 8, 10 or more) NHE inhibitory molecules.

[0093] In one embodiment of the present invention, the linker is a heterocyclyl-(CHR) 13 ) p -[Y-(CH2) r ] s -In another embodiment of the present invention, the linker is, but is not limited to, [ka] It can be represented by:

[0094] In another embodiment, the linker is, but is not limited to, [ka] It can be represented by:

[0095] In some embodiments of the present invention, R 1 and R 2 is a C1-C6 alkyl group. In some embodiments, R 1 and R 2 It is methyl.

[0096] In addition, in other embodiments of the compound of formula I, R 1 and R 2These may, together with the nitrogen to which they are bound, form a heterocyclyl or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O. In some embodiments of the compounds of formula I, R 1 and R 2 However, the heterocyclyl or heteroaryl formed with the nitrogen to which they are bound consists of one or more H, halogens, and -NR 9 R 10 , or optionally substituted with C1-C6 alkyl groups.

[0097] In other embodiments of the compound of formula I, R 1 and R 2 They may form a heterocycle together with the nitrogen to which they are bonded. In some embodiments of the compounds of formula I, R 1 and R 2 However, the heterocycles they form together with the nitrogen atoms to which they are bonded are optionally substituted with one or more oxos. In other embodiments of the compounds of formula I, R 1 and R 2 They may also form piperidine or piperazine together with the nitrogen to which they are bound. In further embodiments of the compounds of formula I, piperidine or piperazine may have one or more oxo, halogen, -NR 9 R 10 or optionally substituted with C1-C6 alkyl groups. In one particular embodiment, piperazine is substituted with methyl groups.

[0098] In some embodiments of the compound of formula I, R 9 and R 10 is a C1-C6 alkyl group. In other embodiments, R 9 and R 10 is methyl. In some embodiments of the compound of formula I, R 3 R is a halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 haloalkoxy. In some embodiments of the compounds of formula I, R 3 is a halogen, CN, or C1-C6 alkyl. In one embodiment, R3 is CN. In some embodiments, R 3 It is F, Cl, CN, or methyl.

[0099] In some embodiments of the compound of formula I, R 4 is a halogen or a C1-C6 alkyl group. In some embodiments of the compounds of formula I, R 4 is F, Cl, or methyl. In one embodiment, R 3 is CN, and R 4 It is Cl.

[0100] In other embodiments of the compound of formula I, R 5 is H, halogen, C1-C6 alkyl, or OR 9 In another embodiment, R 5 It is H, F, or methyl.

[0101] In another embodiment of the present invention, R 6 , R 7 , and R 8 is H, a halogen, or a C1-C6 alkyl group. In another embodiment, R 6 , R 7 , and R 8 All are H. If the halogen or alkyl substituent is R 6 It is built into R 5 , R 7 and R 8 Compounds of the present invention in which each of the following is H have been observed to show low interaction with cytochrome enzymes. Therefore, in one embodiment, R 5 , R 7 and R 8 These are H and R respectively. 6 is halogen or C 1~6 It is alkyl. In one embodiment, R 5 , R 7 and R 8 These are H and R respectively. 6 In one embodiment, R 5 , R 7 and R 8 These are H and R respectively. 6But that's me.

[0102] In another embodiment of the compound of formula I, Q is -NHC(O)NH-. In a particular embodiment, Q is -NHC(O)NH- and the linker is -heterocyclyl-(CHR 13 ) p -[Y-(CH2) r ] s -In one particular embodiment, Q is -NHC(O)NH- and the linker is -heterocyclyl-(CHR 13 ) p -[Y-(CH2) r ] s - and u is 0. In a particular embodiment, Q is -NHC(O)NH- and the linker is -heterocyclyl-(CHR 13 ) p -[Y-(CH2) r ] s -, u is 0, and n is 2. In a particular embodiment, Q is -NHC(O)NH-, and the linker is -heterocyclyl-(CHR 13 ) p -[Y-(CH2) r ] s -, u is 0, n is 2, and X is -(CHR 13 ) p -or C3-C6 cycloalkyl. In another embodiment, Q is a bond.

[0103] In one embodiment of the compound of formula I, R 15 , R 16 , R 17 , and R 18 All of them are H. In one embodiment of the compound of formula I, R 15 and R 17 is H. In one embodiment of the compound of formula I, R 16 and R 18 is OH. In another embodiment of the compound of formula I, R 15 and R 17 H is R 16 and R 18 It is OH.

[0104] In one embodiment of the compound of formula I, Y is O, r is 2, and s is 1. In another embodiment, Y is O, r is 2, and s is 2. In some embodiments, s is 0. In some embodiments, Z is C(O).

[0105] In some embodiments of the compound of formula I, R 13 R is H, C1-C6 alkyl, heterocyclyl, or heteroaryl. In some embodiments of the compounds of formula I, R 13 The heterocyclyl or heteroaryl is one or more R 19 It is optionally replaced by R. In some embodiments, 13 This is one or more R 19 It is a heterocycline that is optionally substituted with R. In some embodiments, 19 It is an oxo compound. In some embodiments, n is 2. In other embodiments of the compound of formula I, n is 3 or 4.

[0106] In one embodiment of the present invention, the compound of formula I is of formula Ia or Ia': [ka] It holds.

[0107] In one embodiment of the present invention, the compound of formula I is of formula Ib or Ib': [ka] has [In the formula, The ring Het is R 1 and R 2 This indicates that together with the nitrogen to which they are bonded, they may form a heterocyclyl or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where the heterocyclyl or heteroaryl group may contain one or more halogens, OH, CN, -NO2, oxo, -SR 9 , -OR9 , -NHR 9 , -NR 9 R 10 -S(O)2N(R 9 )2-, -S(O)2R 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 9 R 10 , -NR 9 S(O)2R 10 ,-S(O)R 9 -S(O)NR 9 R 10 , -NR 9 S(O)R 10 [Optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, heterocyclic, aryl, or heteroaryl compounds.]

[0108] In one embodiment of the present invention, the compound of formula I is of formula Ic or Ic': [ka] [In the formula, Het B represents a heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of C3-C8 cycloalkyl, heterocyclyl, aryl, or N, S, P and O, where each heterocyclyl or heteroaryl contains 1 or more R 19 [It is replaced by an optional selection.]

[0109] In one embodiment of the present invention, the compound of formula I is of formula Id or Id': [ka] [wherein Het represents a C4-C8 cycloalkenyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl R] 13 Here, each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more R 19[It is replaced by an optional selection.]

[0110] In one embodiment of the present invention, the compound of formula I is of formula Ie or Ie': [ka] [wherein the formula, ring Het A is R 1 and R 2 However, together with the nitrogen to which they are bonded, they may form a heterocyclyl or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where the heterocyclyl or heteroaryl group may contain one or more halogens, OH, CN, -NO2, oxo, or -SR. 9 , -OR 9 , -NHR 9 , -NR 9 R 10 -S(O)2N(R 9 )2-, -S(O)2R 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 9 R 10 , -NR 9 S(O)2R 10 ,-S(O)R 9 -S(O)NR 9 R 10 , -NR 9 S(O)R 10 , optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, heterocyclic, aryl, or heteroaryl; Het represents C4-C8 cycloalkenyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl. 13 Here, each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more R 19 [It is replaced by an optional selection.]

[0111] One embodiment of the present invention includes a compound of formula I, formula If or If': [ka] It holds.

[0112] In one embodiment of the present invention, the compound of formula I is formula Ig or Ig': [ka] It holds.

[0113] In one embodiment of the present invention, the compound of formula I is of formula Ih or Ih': [ka] [In the formula, Het is R 6 and R 14 This indicates that, together with the atoms to which they are bonded, they independently form a 5-6 member heterocycline each time they appear.

[0114] In one embodiment of the present invention, the compound of formula I is of formula Ii or Ii': [ka] It holds.

[0115] In other embodiments, the compound of formula I includes, but is not limited to, the following: 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl ]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl ]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 1-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden [1-yl]oxy]-3-methylbenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 1-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea dihydrochloride; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-4-methyl-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-4-methyl-2,3-dihydro-1H-indene-1-yl]oxy]-3-fluorobenzene) Sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3 -[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy)eth [L]-1-[4-([[2-(2[2[(4[[(1S,2S)-2[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy )ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-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]pyrrolidine-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl] Oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]pyridine-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]pyrrolidine-3-yl]methoxy]pyridine-2-yl)methyl]carbamoyl]amino)butyl]urea; 3-[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridine-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]pyrrolidine-3-yl]methoxy]pyridine-2-yl)methyl]carbamoyl]amino)butyl]urea; 3-[(4-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]pyridine-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]pyrrolidine-3-yl]methoxy]pyridine-2-yl)methyl]carbamoyl]amino)butyl]urea; 3-[(4-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]pyridine-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]pyrrolidine-3-yl]methoxy]pyridine-2-yl)methyl]carbamoyl]amino)butyl]urea; 3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]pyrrolidine-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)sulfonamide]pyrrolidine-1-yl]ethoxy]ethyl)cal Bamoylaminobutyl urea; 3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]pyrrolidine-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)sulfonamide]pyrrolidine-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea; 3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]pyrrolidine-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)sulfonamide]pyrrolidine-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea; 3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]pyrrolidine-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)sulfonamide]pyrrolidine-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea; 1-([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazole-4-yl]methyl)-3-(4-[[([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazole-4-yl]methyl)carbamoyl]amino]butyl)urea; (2R,3S,4R,5S)-N 1 ,N 6 -Bis([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazole-4-yl]methyl)-2,3,4,5-tetrahydroxyhexanediamide; 3-[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]butyl]-1H-1,2,3-triazole-4-yl)methyl]-1-[4-([[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]butyl]-1H-1,2,3-triazole-4-yl)methyl]carbamoyl]amino)butyl]urea; 3-[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]hexyl]-1H-1,2,3-triazole-4-yl)methyl]-1-[4-([[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]hexyl]-1H-1,2,3-triazole-4-yl)methyl]carbamoyl]amino)butyl]urea; (4R,4aS,8S,8aR)-N 4 ,N 8 -bis([1-(4-[4-((1S,2 S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenyl sulfonamide]butyl)-1H-1,2,3-triazole-4-yl]methyl)-2,2,6,6-tetramethyltetrahydro-[1,3]dioxyno[5,4-d][1,3]dioxin-4,8-dicarboxamide; (4R,4aS,8S,8aR)-N 4 ,N 8-Bis([1-(6-[4-((1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenylsulfonamide]hexyl)-1H-1,2,3-triazole-4-yl]methyl)-2,2,6,6-tetramethyl-tetrahydro-[1,3]dioxyno[5,4-d][1,3]dioxin-4,8-dicarboxamide; 3-[8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]octyl]carbamoyl)amino]butyl]urea; 3-[8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]octyl]carbamoyl)amino]butyl]urea; 3-[8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]octyl]carbamoyl)amino]butyl]urea; 3-[8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]octyl]carbamoyl)amino]butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2R)-2-methylpiperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2R)-2-methylpiperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2S)-2-methylpiperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2S)-2-methylpiperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.1]heptan-2-yl]-4,6-dichloro-2,3-dihydro-1H-indene- 1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.1]heptan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 1-[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.2]octane-2-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.2]octane-2-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.2.1]octane-8-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.2.1]octane-8-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 1-[2-(2-[2-[(4-[[(1S,2S)-2-[9-azabicyclo[3.3.1]nonane-9-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[9-azabicyclo[3.3.1]nonane-9-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazine-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazine-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl] [Lu]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazine-1-yl)-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazine-1-yl)-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy ]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)ethoxy]ethoxy]ethyl)sulfamoyl]phenoxy]-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperazin-1-carboxamide; 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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)ethoxy]ethoxy]ethyl)sulfamoyl]-2-methylphenoxy]-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperazin-1-carboxamide; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)buty Urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene) sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene) sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; hydrochloride; 1-[2-(2-[2-[(3-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,4-dimethylbenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[( 4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopipette Lysine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; hydrochloride; 1-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-difluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-difluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3,5-difluorophenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]-3,5-difluorobenzenesulfonamide; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]-2-oxopyrrolidine-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)sulfonamide]-2-oxopyrrolidine-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea; 1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]-2-oxopyrrolidine-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)sulfonamide]-2-oxopyrrolidine-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea; 3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidine-3-yl]oxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidine-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidine-3-yl]oxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidine-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonyl]piperidine-4-yl]oxy)ethoxy]ethyl]-1-[4-[([2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-indene-1-yl]oxy]benzene)sulfonyl]piperidine-4-yl]oxy)ethoxy]ethyl]carbamoyl)amino]butyl]urea; 1-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]propoxy]ethoxy]ethyl)-3-(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]propoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea; hydrochloride; 3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]propoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R )-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]propoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea; 3-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]-3-methylbutoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea dihydrochloride; 3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]-3-methylbutoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea; 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]-2-methylpropoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]-2-methylpropoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; hydrochloride; 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamide]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 4-([(1S,2S)-2-[(R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-2-[(R)-3-aminopiperidine-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy)-2-chlorophenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9 ,11,16,18-tetraazahexacosyl]-2-chlorobenzenesulfonamide; 4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidine-3-yl]-3-fluorobenzenesulfonamide; tetra(trifluoroacetate); 4-([(1S,2S)-4,6-dichloro-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]-3-fluorobenzenesulfonamide; tetra(trifluoroacetate); 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; tetra(trifluoroacetate); 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; tetra(trifluoroacetate); 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]-3-fluorobenzenesulfonamide; tetra(trifluoroacetate); 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]-3-fluorobenzenesulfonamide; tetra(trifluoroacetate); 4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl)-3-fluorobenzenesulfonamide; tetra(trifluoroacetate); 4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl)-3-fluorobenzenesulfonamide; tetra(trifluoroacetate); 4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidine-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)piperidine-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-3-methylphenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]-3-methylbenzenesulfonamide; tetra(trifluoroacetate); 4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidine-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)piperidine-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-3-methylphenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]-3-methylbenzenesulfonamide; tetra(trifluoroacetate); 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)piperidine-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidine-4-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-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-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-2,13-dimethyl-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl]pyrrolidine-3-yl]benzenesulfonamide; N 1 ,N 14 -Bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide; N 1 ,N 14 -Bis(2-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide; N 1 ,N 18-Bis(1-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)piperidine-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide; -([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide]piperidine-1-yl)-7,14-dioxo-3,18-dioxazycosyl]piperidine-4-yl)benzenesulfonamide; N 1 ,N 18-Bis([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide; N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-1-[16-(4-[([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)carbamoyl]piperidine-1-yl)-5,12-dioxo-4,6,11,13-tetraazahexadecyl]piperidine-4-carboxamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[( S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-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]heptane-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-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]heptane-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-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-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-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-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazine-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-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazi [N-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-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazine-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-dimethylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazine-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-dimethylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-2-oxopiperidine-1-yl]-7,14-dioxo-3,18-dioxazycosyl)-2-oxopiperidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[2-(2-[2-(3-[(1r,4r)-4-(3-[2-(2-[2-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)ethoxy]ethoxy)ethyl]ureido)cyclohexyl]ureido)ethoxy]ethoxy)ethyl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(18-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide; N-(2-[2-(2-aminoethoxy)ethoxy]ethyl)-4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide; N-[1-(4-aminobutanoyl)piperidine-4-yl]-4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-(3-oxo-7,10- Dioxa-2,4-diazadodecane-12-yl)benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-(1-[4-(3-methylureido)butanoyl]piperidine-4-yl)benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexane-2-yl]benzenesulfonamide; 4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexane-2-yl]piperidine-1-carboxamide; 4-(3-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-4-oxobutyl]ureido)-N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)butanamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(4-[3-(4-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)piperidine-1-yl]-4-oxobutyl)ureido]butanoyl)piperidine-4-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[19-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecyl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-amide-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-amide-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide; 4-([(1S,2S)-4-cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-4-cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide; 1,1'-(butane-1,4-diyl)bis[3-(4-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-yl]-4-oxobutyl)urea]; 1,1'-(butane-1,4-diyl)bis[3-(4-[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-yl]-4-oxobutyl)urea]; N,N'-(6,14-dioxo-10-oxa-5,7,13,15-tetraazanonna) Decane-1,19-diyl)bis[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide]; N,N'-(6,14-dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide]; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-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-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-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-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)piperidine-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidine-4-yl]benzenesulfonamide; N 1 ,N 14-Bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)piperidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)piperidine-4-yl]benzenesulfonamide; 4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazine-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-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; N 1 ,N 14 -Bis(2-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-2-o Xoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide; 1,1'-(butane-1,4-diyl)bis(3-[2-(2-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindorin-2-yl]ethoxy)ethyl]urea); and 1,1'-(butane-1,4-diyl)bis(3-[2-(2-[5-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindorin-2-yl]ethoxyethyl]urea). (1S,2S)-1-(4-{[(3S)-1-[2-(2-{[(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-4-carboxy-6-chloro-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)-1-hydroxy-1λ 4 -Pyrrolidine-1-yl]ethoxyethyl)carbamoyl]amino}butyl)carbamoyl]amino}ethoxy)ethyl]-1-hydroxy-1λ 4 -Pyrrolidine-3-yl]sulfamoyl}phenoxy)-6-chloro-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-indene-4-carboxylic acid; 3-(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}(2,3,5,6- 2 H4)Benzenesulfonamide)Pyrrolidine-1-yl]ethoxyethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}(2,3,5,6- 2 H4)Benzene sulfonamide)Pyrrolidine-1-yl]ethoxyethyl)Carbamoyl]amino}(1,1,2,2,3,3,4,4- 2 H8) Butyl) Urea; 3-(2-{2-[2-(4-{[(1S,2S)-4-cyano-6-methyl-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-4-cyano-6-methyl-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea; 3-(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)urea; N-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]-2-oxoethyl}-2-({[4-({[({2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]-2-oxoethyl}carbamoyl)methyl]carbamoyl}amino)butyl]carbamoyl}amino)acetamide; 3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxybenze (Benzesulfonamide)ethoxy]ethoxy}ethyl)-1-[(1s,4s)-4-{[(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)ethoxy]ethoxy}ethyl)carbamoyl]amino}cyclohexyl]urea; 1,3-Bis(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)ethoxy]ethoxy}ethyl)urea; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[19-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecyl]benzenesulfonamide; 3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)ethoxy]ethoxy}ethyl)-1-[(1r,4r)-4-{[(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)ethoxy]ethoxy}ethyl)carbamoyl]amino}cyclohexyl]urea; 3-(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]ethoxy}ethyl)carbamoyl]amino}(1,1,2,2,3,3,4,4- 2 H8) Butyl) Urea; 3-{4-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]-4-oxobutyl}-1-{4-[({4-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]-4-oxobutyl}carbamoyl)amino]butyl}urea; 3-{4-[4-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy}benzenesulfonamide)piperidine-1-yl]-4-oxobutyl}-1-{4-[({4-[4-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-indene-1-yl]oxy}benzenesulfonamide)piperidine-1-yl]-4-oxobutyl}carbamoyl)amino]butyl}urea; N-{2-[(3R)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]-2-oxoethyl}-2-({[4-({[({2-[(3R)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]-2-oxoethyl}carbamoyl)methyl]carbamoyl}amino)butyl]carbamoyl}amino)acetamide; 3-(2-{2-[4-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)piperidine-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[4-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)piperidine-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)urea; 3-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]-2-oxoethyl}-1-{4-[({2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]-2-oxoethyl}carbamoyl)amino]butyl}urea; and (3S)-N-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonyl)-1-[2-(2-{[(4-{[(2-{2-[(3S)-3-[(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonyl)carbamoyl]pyrrolidine-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)carbamoyl]amino}ethoxy)ethyl]pyrrolidine-3-carboxamide.

[0116] In other embodiments, W is S(O)2, C(O), or -(CH2) m -. In other embodiments, W is S(O)2. In other embodiments, W is C(O). In other embodiments, W is -(CH2)2-. In other embodiments, W is -(CH2)-.

[0117] In some embodiments, Y is O, S, NH, N(C1-C3 alkyl), or -C(O)NH-. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is NH. In some embodiments, Y is N(C1-C3 alkyl). In some embodiments, Y is -C(O)NH-. In some embodiments, Y is O, S, NH, or N(C1-C3 alkyl). In some embodiments, Y is O, S, or NH. In some embodiments, Y is O or S.

[0118] In some embodiments, Q is a bond, NH, -C(O)NH-, -NHC(O)NH-, -NHC(O)N(CH3)-, or -NHC(O)NH-(CHR 13) is. In some embodiments, Q is a bond, NH, -C(O)NH-, -NHC(O)NH-, or -NHC(O)N(CH3)-. In some embodiments, Q is a bond, NH, -C(O)NH-, or -NHC(O)NH-. In some embodiments, Q is a bond, NH, or -C(O)NH-. In some embodiments, Q is a bond or NH. In some embodiments, Q is a bond. In some embodiments, Q is -NHC(O)NH-. In some embodiments, Q is -C(O)NH-. In some embodiments, Q is -NHC(O)N(CH3)-. In some embodiments, Q is -NHC(O)NH-(CH3)-. 13 )

[0119] In some embodiments, R 1 and R 2 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R 1 and R 2 R is independently H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, or aryl. In some embodiments, R 1 and R 2 R is independently H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, or heterocyclyl. In some embodiments, R 1 and R 2 Independently, are H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R 1 and R 2R is independently H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl. In some embodiments, R 1 and R 2 R is independently H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, or C2-C6 alkynyl. In some embodiments, R 1 and R 2 R is independently H, C1-C6 alkyl, C2-C6 alkenyl, or C4-C8 cycloalkenyl. In some embodiments, R 1 and R 2 R is independently H, C1-C6 alkyl, or C2-C6 alkenyl. In some embodiments, R 1 and R 2 R is independently H or C1-C6 alkyl. In some embodiments, R 1 and R 2 These are independently H, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is one or more halogens, OH, CN, -NO2, oxo, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 -S(O)2N(R 9 )2-, -S(O)2R 9 , -C(O)R 9 , -C(O)OR 9 -C(O)NR 9 R 10 , -NR 9 S(O)2R 10 ,-S(O)R 9 -S(O)NR 9 R 10 , -NR 8 S(O)R 9They are optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, heterocyclic, aryl, or heteroaryl compounds.

[0120] In another embodiment, R 3 This refers to halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -C(O)NR 9 R 10 In one embodiment, R 3 is a halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 haloalkoxy. In one embodiment, R 3 is a halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl. In one embodiment, R 3 is a halogen, OH, CN, C1-C6 alkyl, or C1-C6 alkoxy. In one embodiment, R 3 R is a halogen, OH, CN, or C1-C6 alkyl. 3 is a halogen, OH, or CN. In one embodiment, R 3 is a halogen or OH. In one embodiment, R 3 It is a halogen. 3 is OH. In one embodiment, R 3 is CN. In one embodiment, R 3 is a C1-C6 alkyl group. In one embodiment, R 3 is a C1-C6 alkoxy. In one embodiment, R 3 is a C1-C6 haloalkyl group. In one embodiment, R 3 is a C1-C6 haloalkoxy. In one embodiment, R 3 is -C(O)NR 9 R 10 That is the case.

[0121] In another embodiment, R 4This refers to halogens, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -C(O)NR 9 R 10 In one embodiment, R 4 is a halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 haloalkoxy. In one embodiment, R 4 is a halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl. In one embodiment, R 4 is a halogen, OH, CN, C1-C6 alkyl, or C1-C6 alkoxy. In one embodiment, R 4 R is a halogen, OH, CN, or C1-C6 alkyl. 3 , It is logen, OH, or CN. In one embodiment, R 4 is a halogen or OH. In one embodiment, R 4 It is a halogen. 3 is OH. In one embodiment, R 4 is CN. In one embodiment, R 4 is a C1-C6 alkyl group. In one embodiment, R 4 is a C1-C6 alkoxy. In one embodiment, R 4 is a C1-C6 haloalkyl group. In one embodiment, R 4 is a C1-C6 haloalkoxy. In one embodiment, R 4 is -C(O)NR 9 R 10 That is the case.

[0122] In one embodiment, R 5 , R 6 , R 7 , and R 8These are heteroaryls and -SRs, which independently contain 1 to 5 heteroatoms selected from the group consisting of H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, N, S, P, and O. 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 In one embodiment, R 5 , R 6 , R 7 , and R 8 These are heteroaryls and -SRs, which independently contain 1 to 5 heteroatoms selected from the group consisting of H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, N, S, P, and O. 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 In one embodiment, R 5 , R 6 , R 7 , and R 8These are heteroaryls and -SRs, which independently contain 1 to 5 heteroatoms selected from the group consisting of H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, N, S, P, and O. 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 In one embodiment, R 10 , R 5 , R 6 , R 7 , and R 8 These are heteroaryls and -SRs, which independently contain 1 to 5 heteroatoms selected from the group consisting of H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, N, S, P, and O. 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 In one embodiment, R 5 , R 6 , R 7 , and R 8 These are heteroaryls and -SRs, which independently contain 1 to 5 heteroatoms selected from the group consisting of H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, N, S, P, and O. 9 , -OR 9 , -NHR 9 , -NR9 R 10 -S(O)2N(R 9 )2-, -S(O)2R 9 , -C(O)R 9 In one embodiment, R 5 , R 6 , R 7 , and R 8 These are heteroaryls and -SRs, which independently contain 1 to 5 heteroatoms selected from the group consisting of H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, N, S, P, and O. 9 , -OR 9 , -NHR 9 , -NR 9 R 10 -S(O)2N(R 9 )2-, -S(O)2R 9 In one embodiment, R 5 , R 6 , R 7 , and R 8 These are heteroaryls and -SRs, which independently contain 1 to 5 heteroatoms selected from the group consisting of H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, N, S, P, and O. 9 , -OR 9 , -NHR 9 , -NR 9 R 10 -S(O)2N(R 9 )2-. In one embodiment, R 5 , R 6 , R 7 , and R 8 These are independently H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cyclo Heteroaryls containing 1 to 5 heteroatoms selected from the group consisting of alkyl, heterocyclyl, aryl, N, S, P, and O, -SR 9 , -OR9 , -NHR 9 , -NR 9 R 10 In one embodiment, R 5 , R 6 , R 7 , and R 8 These are heteroaryls and -SRs, which independently contain 1 to 5 heteroatoms selected from the group consisting of H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, N, S, P, and O. 9 , -OR 9 , -NHR 9 In one embodiment, R 5 , R 6 , R 7 , and R 8 These are heteroaryls and -SRs, which independently contain 1 to 5 heteroatoms selected from the group consisting of H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, N, S, P, and O. 9 , -OR 9 In one embodiment, R 5 , R 6 , R 7 , and R 8 These are heteroaryls and -SRs, which independently contain 1 to 5 heteroatoms selected from the group consisting of H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, N, S, P, and O. 9 In one embodiment, R 5 , R 6 , R 7 , and R 8In one embodiment, R is a heteroaryl compound containing 1 to 5 heteroatoms selected from the group consisting of H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, aryl, or N, S, P, and O. 5 , R 6 , R 7 , and R 8 R is independently H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heterocyclyl, or aryl. In one embodiment, R 5 , R 6 , R 7 , and R 8 R is independently H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, or heterocyclyl. In one embodiment, R 5 , R 6 , R 7 , and R 8 R is independently H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, C2-C6 alkynyl, or C3-C8 cycloalkyl. In one embodiment, R 5 , R 6 , R 7 , and R 8 R is independently H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C4-C8 cycloalkenyl, or C2-C6 alkynyl. In one embodiment, R 5 , R 6 , R 7 , and R 8 R is independently H, halogen, OH, CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, or C4-C8 cycloalkenyl. In one embodiment, R 5 , R 6 , R 7 , and R 8R is independently H, halogen, OH, CN, -NO2, C1-C6 alkyl, or C2-C6 alkenyl. In one embodiment, R 5 , R 6 , R 7 , and biR 8 R is independently H, halogen, OH, CN, -NO2, or C1-C6 alkyl. In one embodiment, R 5 , R 6 , R 7 , and R 8 R is independently H, halogen, OH, CN, or -NO2. In one embodiment, R 5 , R 6 , R 7 , and R 8 R is independently H, halogen, OH, or CN. In one embodiment, R 5 , R 6 , R 7 , and R 8 R is independently H, halogen, or OH. In one embodiment, R 5 , R 6 , R 7 , and R 8 These are independently either H or a halogen.

[0123] In one embodiment, R 15 , R 16 , R 17 , and R 18 Each instance is independently H, OH, NH2, or C1-C3 alkyl. In a further embodiment, R 15 , R 16 , R 17 , and R 18 Each instance is independently H, OH, or NH2. In a further embodiment, R 15 , R 16 , R 17 , and R 18 Each instance is independently either H or OH. In a further embodiment, R 16 , R 17 , and R 18Each instance is independently H, OH, NH2, or C1-C3 alkyl, where the alkyl is one or more R 19 It is being replaced by an optional choice.

[0124] In one embodiment, X is a bond, H, N, O, CR 11 R 12 CR 11 , C, -NHC(O)NH-, or C3-C6 cycloalkyl. In one embodiment, X is a bond, H, N, O, CR 11 R 12 CR 11 , C, or -NHC(O)NH-. In one embodiment, X is a bond, H, N, O, CR 11 R 12 CR 11 , or C. In one embodiment, X is a bond, H, N, O, CR 11 R 12 , or CR 11 In one embodiment, X is a bond, H, N, O, or CR. 11 R 12 In one embodiment, X is a bond, H, N, or O. X is a bond, H, or N. In one embodiment, X is a bond or H. In one embodiment, X is a bond. In another embodiment, X is H and n is 1. In another embodiment, if n is 3, X is N. In another embodiment, X is O and n is 2. In another embodiment, X is CR 11 R 12 And n is 2. In another embodiment, X is CR 11 In another embodiment, X is C and n is 3. In another embodiment, X is -NHC(O)NH-. In yet another embodiment, X is C3-C6 cycloalkyl.

[0125] In some embodiments, R 14 is H, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R 14 is H or C1-C6 alkyl. In some embodiments, R 14H is H. In some embodiments, R 14 is a C1-C6 alkyl group. In some embodiments, R 14 These are C1-C6 haloalkyl groups.

[0126] In another embodiment, R 6 and R 14 These may combine with the atoms to which they are bonded to form a 5-6 member heterocycline. In other embodiments, R 6 and R 14 These may combine with the atoms to which they are bonded to form a 5-6 member heterocycline independently each time they appear, where the heterocycline is composed of one or more R 19 It is being replaced by an optional choice.

[0127] In other embodiments, R 13 and R 14 These may combine with the atoms to which they are bonded to to independently form a C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl group each time they appear. In other embodiments, R 13 and R 14 These may combine with the atoms to which they are bonded to to form, independently each time they appear, a C3-C8 cycloalkyl, heterocyclyl, or aryl group. In some embodiments, R 13 and R 14 These may combine with the atoms to which they are bonded to, independently forming a C3-C8 cycloalkyl or heterocycline each time they appear. In some embodiments, R 13 and R 14 These may combine with the atoms to which they are bonded to form a C3-C8 cycloalkyl group independently each time they appear. In some embodiments, R 13 and R 14 These may combine with the atoms to which they are bonded, independently forming heterocyclines each time they appear. In some embodiments, R 13 and R 14These may combine with the atoms to which they are bonded, independently forming aryl groups each time they appear. In some embodiments, R 13 and R 14 These atoms may combine with the atoms to which they are bonded, independently forming heteroaryl groups each time they appear.

[0128] In other embodiments, R 13 and R 14 These may combine with the atoms to which they are bonded to to independently form a C3-C8 cycloalkyl, heterocyclyl, aryl, or heteroaryl each time they appear, where each heterocyclyl or heteroaryl is one or more R 19 It is optionally replaced by R. In other embodiments, 13 and R 14 These may combine with the atoms to which they are bonded to to independently form a C3-C8 cycloalkyl, heterocyclyl, or aryl group each time they appear, where each heterocyclyl group may have one or more R 19 It is replaced by an optional choice. In some embodiments, R 13 and R 14 These may combine with the atoms to which they are bonded to to independently form a C3-C8 cycloalkyl or heterocycline each time they appear, where each heterocycline is composed of one or more R 19 It is optionally replaced by R. In some embodiments, 13 and R 14 These may combine with the atoms to which they are bonded to form a C3-C8 cycloalkyl group independently each time they appear. In some embodiments, R 13 and R 14 These may combine with the atoms to which they are bonded, independently forming heterocyclines each time they appear, where each heterocycline is composed of one or more R atoms. 19 It is optionally replaced by R. In some embodiments, 13 and R 14These may combine with the atoms to which they are bonded, independently forming aryl groups each time they appear. In some embodiments, R 13 and R 14 These may combine with the atoms to which they are bonded to, independently forming heteroaryls each time they appear, where each heteroaryl is one or more R 19 It is being replaced by an optional choice.

[0129] In some embodiments, u is 0, 1, or 2. In some embodiments, u is 0 or 1. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2.

[0130] In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0131] In some embodiments, s is 0, 1, 2, 3, or 4. In some embodiments, s is 0, 1, 2, or 3. In some embodiments, s is 0, 1, or 2. In some embodiments, s is 0 or 1. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. In some embodiments, s is 4.

[0132] In some embodiments, r is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, r is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, r is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, r is 0, 1, 2, 3, 4, or 5. In some embodiments, r is 0, 1, 2, 3, or 4. In some embodiments, r is 0, 1, 2, or 3. In some embodiments, r is 0, 1, or 2. In some embodiments, r is 0 or 1. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. In some embodiments, r is 6. In some embodiments, r is 7. In some embodiments, r is 8.

[0133] In some embodiments, p is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, p is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, p is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, p is 0, 1, 2, 3, 4, or 5. In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is , 6. In some embodiments, p is 7. In some embodiments, p is 8.

[0134] In designing and preparing substantially impermeable or substantially systemically unbiogenic NHE inhibitor compounds of the present invention that can be used for the treatments detailed in this disclosure.

[0135] In another embodiment, compounds of the present invention having long hydrocarbon functional groups may spontaneously decompose in an intramolecular manner, resulting in an increased enthalpy barrier for interaction with a desired biological target. Therefore, when designing the "X" and linker moieties, they should be designed to be resistant to hydrophobic decomposition. For example, the rigidity of the structure can be increased by introducing conformational constraints such as rigid monocyclic, bicyclic, or polycyclic structures into the "X" and linker moieties. Alternatively, unsaturated bonds such as alkenes and alkynes may be introduced. Such modifications can ensure that the NHE inhibitor compound is accessible for effective binding to its target. Furthermore, the hydrophilicity of the linker can be improved by adding hydrogen bond donor or acceptor motifs, or ionic motifs such as amines that are protonated in the GI tube or acids that are deprotonated. Such modifications will increase the hydrophilicity of the "X" and linker moieties and help prevent hydrophobic decomposition. Furthermore, such modifications will also contribute to the impermeability of the resulting compound by increasing the tPSA.

[0136] Those skilled in the art can consider various functional groups that enable easy and specific bonding between the "X" moiety and / or the linker and the rest of the molecule of the compound of formula I. These functional groups may include electrophiles that can react with a nucleophilic group and / or nucleophiles that can react with the electrophilic "X" and the linker moiety. Similarly, the NHE inhibitory compound of formula I may be derivatized, for example, using a boronic acid group. The NHE inhibitory compound of formula I may also contain an olefin via olefin double decomposition chemistry, or an alkyne or azide that can react with other suitable "X" and linker via [2+3] cycloaddition.

[0137] Those skilled in the art should note that several "X" and linker moieties can be envisioned that can be functionalized using suitable electrophiles or nucleophiles. The following is a series of such compounds selected based on several design considerations, including solubility, steric effects, and the ability to confer or match a desirable structure-activity relationship. However, it should be further noted that the structures provided below and above are for illustrative purposes only and should not be viewed in an restrictive sense.

[0138] Exemplary electrophilic and nucleophilic linker portions include, but are not limited to, the examples and linker portions illustrated below:

[0139] [ka] In each of the embodiments described, the linking portion, or linker, may also be, for example, a chemical bond or other portion which may be hydrophilic and / or hydrophobic. In one embodiment, the linking portion may be, for example, a polymer portion grafted onto a polymer backbone using a living free radical polymerization technique known in the art.

[0140] In another embodiment, the "X" portion exemplified in the compound of formula I may also include, but is not limited to, an ether portion, an ester portion, a sulfide portion, a disulfide portion, an amine portion, an aryl portion, an alkoxyl portion, and the following: [ka] [ka] [In the formula, bond breakage (i.e., wavy bonds that penetrate them, [ka] Those having ( ) are, when n>1, connection points to the rest of the molecule of formula I, where the connection points can be made using chemical and functional groups known in the field of medicinal chemistry; furthermore, each p', q', r' and s' is about 0 to about 48, about 0 to about 36 , or an independently selected integer in the range of about 0 to about 24, or about 0 to about 16. In some cases, each p, q, r and s may be an independently selected integer in the range of about 0 to 12. In addition, R' may be a substituent moiety generally selected from moieties including halides, hydroxyls, amines, thiols, ethers, carbonyls, carboxyls, esters, amides, carbocyclics, heterocyclics, and combinations thereof.

[0141] Alternatively, the "X" portion of Equation I may be a dendrimer defined as a repeatedly branched molecule (see, for example, JMJ Frechet, DATomalia, Dendriers and Other Dendritic Polymers, John Wiley & Sons, Ltd., NY, NY, 2001), as shown below: [ka]

[0142] In this method, the remaining NHE inhibitor molecules are attached via a linker to one, several, or optionally all of the terminals of the dendrimer. In another method, the dendrimer constituent units exemplified above are called dendrons, and the remaining NHE inhibitor molecules are attached to one, several, or optionally all of the terminals of the dendrons as "X" portions. The number of generations described herein is typically about 0 to 6 and about 0 to 3 (generations are defined, for example, in JMJ Frechet, DATomalia, Dendriers and Other Dendritic Polymers, John Wiley & Sons, Ltd., NY, NY). Dendrimer and / or dendron structures are well known in the art and include, for example, those shown or illustrated in (i) JMJ Frechet, DATomalia, Dendriers and Other Dendritic Polymers, John Wiley & Sons, Ltd., NY, NY; (ii) George R Newkome, Charles N. Moorefield and Fritz Vogtle, Dendriers and Dendrons: Concepts, Syntheses, Applications, VCH Verlagsgesellschaft Mbh; and (iii) Boas, U., Christensen, JB, Heegaard, PMH, Dendrimers in Medicine and Biotechnology: New Molecular Tools, Springer, 2006.

[0143] In another method, the "X" portion may be a polymer portion or an oligomer portion. The polymer or oligomer may be considered independently, and may include repeating units consisting of repeating portions selected from any of the above, which are substituted with alkyl (e.g., -CH2-), substituted alkyl (e.g., -CHR-, (where R is hydroxyl)), alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, aryl, heterocyclic, amine, ether, sulfide, disulfide, hydrazine, and oxygen, sulfur, sulfonyl, phosphonyl, hydroxyl, alkoxyl, amine, thiol, ether, carbonyl, carboxyl, ester, amide, alkyl, alkenyl, alkynyl, aryl, heterocyclic, or combinations thereof. In yet another method, the "X" portion may include repeating units resulting from the polymerization of ethylene monomers (e.g., ethylene monomers listed elsewhere in this specification).

[0144] Preferred polymers for polymer moieties useful in constructing polyvalent, substantially impermeable, or substantially systemically bioavailable NHE inhibitor compounds for use in the various treatment methods disclosed herein can be prepared by any preferred technique such as free radical polymerization, condensation polymerization, addition polymerization, ring-opening polymerization, and / or derivatized from naturally occurring polymers such as sugar polymers. Furthermore, in some embodiments, any of these polymer moieties may be functionalized.

[0145] Examples of polysaccharides useful in the preparation of such compounds include, but are not limited to, plant or animal-derived materials, including cellulose materials, hemicellulose, alkylcellulose, hydroxyalkylcellulose, carboxymethylcellulose, sulfoethylcellulose, starch, xylan, amylopectin, chondroitin, hyaluronic acid, heparin, guar, xanthan gum, mannan, galactomannan, chitin, and / or chitosan. More preferred are polymeric portions that do not decompose or decompose significantly under the physiological conditions of the GI tube, at least in some cases (e.g., carboxymethylcellulose, chitosan, and sulfoethylcellulose).

[0146] When using free radical polymerization, the polymer moiety can be prepared from various classes of monomers, including, for example, acrylic acid, methacrylic acid, styrene acid, vinyl acid, and dienoic acid. Typical examples are listed below: styrene, substituted styrene, alkyl acrylate, substituted alkyl acrylate, alkyl methacrylate, substituted alkyl methacrylate, acrylonitrile, methacrylonitrile, acrylamide, methacrylamide, N-alkylacrylamide, N-alkylmethacrylamide, N,N-dialkylacrylamide, N,N-dialkylmethacrylamide, isoprene, butadiene, ethylene, vinyl acetate, and combinations thereof. Functionalized forms of these monomers may be used, or any of these monomers may be used as comonomers together with other monomers. For example, certain monomers or comonomers that can be used in this disclosure include methyl methacrylate, ethyl methacrylate, propyl methacrylate (all isomers), butyl methacrylate (all isomers), 2-ethylhexyl methacrylate, isobomyl methacrylate, methacrylic acid, benzyl methacrylate, phenyl methacrylate, methacrylonitrile, α-methylstyrene, methyl acrylate, ethyl acrylate, propyl acrylate (all isomers), butyl acrylate (all isomers), 2-ethylhexyl acrylate, isobomyl acrylate, acrylic acid, acrylic acid Benzyl, phenyl acrylate, acrylonitrile, styrene, glycidyl methacrylate, 2-hydroxyethyl methacrylate, hydroxypropyl methacrylate (all isomers), hydroxybutyl methacrylate (all isomers), N,N-dimethylaminoethyl methacrylate, N,N-diethylaminoethyl methacrylate, triethylene glycol methacrylate, itaconic anhydride, itaconic acid, glycidyl acrylate, 2-hydroxyethyl acrylate, hydroxypropyl acrylate (all isomers), hydroxybutyl acrylate (all isomers), N,N-dimethylaminoethyl methacrylate Diethylaminoethyl, N,N-diethylaminoethyl acrylate, triethylene glycol acrylate, methacrylamide, N-methylacrylamide, N,N-dimethylacrylamide, N-tert-butylmethacrylamide, NN-butylmethacrylamide, N-methylolmethacrylamide, N-ethylolmethacrylamide, N-tert-butylacrylamide, NN-butylacrylamide, N-methylolacrylamide, N-ethylolacrylamide, 4-acrylomorpholine, vinyl benzoate (all isomers), diethylamino This includes styrene (all isomers), α-methylvinylbenzoic acid (all isomers), diethylamino α-methylstyrene (all isomers), p-vinylbenzenesulfonic acid, sodium p-vinylbenzenesulfonate, alkoxy and alkylsilane functional monomers, maleic anhydride, N-phenylmaleimide, N-butylmaleimide, butadiene, isoprene, chloroprene, ethylene, vinyl acetate, vinylformamide, allylamine, vinylpyridine (all isomers), fluorinated acrylates, methacrylates, and combinations thereof. Furthermore, main-chain heteroatom polymer moieties containing polyethyleneimines and polyethers, such as polyethylene oxide and polypropylene oxide, and their copolymers, may also be used.

[0147] In a particular embodiment, the polymer to which the NHE inhibitory molecule is attached, or a part thereof, is a polyol (e.g., a polymer having repeating hydroxyl-substituted alkyl units such as -CH(OH)-). Polyols such as monosaccharides and disaccharides, with or without reducing or reducible end groups, may be good candidates for introducing further functional groups that can make the compound substantially impermeable.

[0148] In a particular embodiment, the NHE inhibitor molecule is attached to one or both ends of the polymer chain. More specifically, another alternative approach to the multivalent embodiments of this disclosure involves the following general exemplary structure: [ka] A polymer (e.g., a polymer or oligomer) having part: [ka] [ka] [ka] [ka] Regarding this matter, examples, designs, and / or constructions may be made as described.

[0149] It is understood that any embodiment of the compounds of the present invention as described above, and any specific substituents described herein in such compounds as described above, may be independently combined with other embodiments and / or substituents of such compounds to form embodiments of the present invention not specifically described above. In addition, it is understood that in instances where the list of substituents is enumerated for any specific substituent in a particular embodiment and / or claim, each individual substituent may be removed from that particular embodiment and / or claim, and the remaining list of substituents is considered to be within the scope of the present invention. Furthermore, it is understood that combinations of substituents and / or modifications of the given formulas are permissible only if such contributions result in a stable compound.

[0150] B. Transparency In this regard, it should be noted that in various embodiments, the ability of a compound to become substantially systemically unbiodable depends on the compound's charge, size, and / or other physicochemical parameters (e.g., polar surface area, the number of hydrogen bond donors and / or acceptors therein, the number of freely rotatable bonds, etc.). More specifically, it should be noted that the absorption characteristics of a compound can be selected by applying the laws of pharmacodynamics, for example, by applying Lipinski's Law, also known as the "Rule of Five." Rather than a law, it is a set of guidelines, but Lipinski has shown that small molecule drugs having (i) molecular weight, (ii) multiple hydrogen bond donors, (iii) multiple hydrogen bond acceptors, and / or (iv) water / octanol partition coefficient (Moriguchi Log P) above a certain threshold generally do not show significant systemic concentrations (i.e., are generally not absorbed to a significant degree) (e.g., Lipinski et al., Advanced Drug Delivery Research, cited by reference). See ews, 46, 2001 3-26). Therefore, a compound that is substantially systemically unbiovable (e.g., a substantially systemically unbiovable NHE inhibitor) can be designed to have a molecular structure that exceeds one or more Lipinski thresholds (see also Lipinski et al., Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings, Adv. Drug Delivery Reviews, 46:3-26(2001); and Lipinski, Drug-like Properties and See also the Causes of Poor Solubility and Poor Permeability, J. Pharm. & Toxicol. Methods, 44:235-249 (2000). In some embodiments, for example, the substantially impermeable or substantially systemically unbiogenic NHE inhibitory compounds of this disclosure are characterized by: (i) about 500 Da, about 1000 Da, about 2500 Da, about 5000 Da, about 10,000 Da or more MW (unsalted form of the compound); (ii) about 5, about 10, about 15 or more NH and / or OH and / or other potential hydrogen bond donors; (iii) about 5, about 10, about 15 or more O atoms and / or N atoms and / or other potential hydrogen bond acceptors; and / or (iv) about 10 5 It can be constructed to feature one or more of the Moriguchi distribution coefficients that are greater than (i.e., Log P greater than approximately 5, approximately 6, or approximately 7), or alternatively, less than approximately 10 (i.e., Log P less than 1 or even less than 0).

[0151] In addition to the above parameters, the molecular polar surface area (i.e., "PSA"), which can be characterized as the surface belonging to polar atoms, is well correlated with passive transport across membranes and has thus also been shown to enable prediction of drug transport properties. It has been successfully applied to the prediction of intestinal absorption and Caco2 cell monolayer permeation (for details of the Caco2 cell monolayer permeation test, see, for example, Example 31 of U.S. Patent No. 6,737,423, the entire content of which is incorporated herein by reference for all relevant consistent purposes, and in particular, see the description of the Caco2 model presented in the text of Example 31, which can also be applied to the evaluation or testing of the compounds of the present disclosure). PSA is expressed in Å2 (square angstroms) and is calculated from a three-dimensional molecular representation. Fast calculation methods are currently available using desktop computers and commercially available chemical graphic tool packages such as ChemDraw (see, for example, Ertl et al., Journal of Medicinal Chemistry, 2000, 43, 3714-3717, the entire content of which is extended herein by reference for all relevant consistent purposes). The term "topological PSA" (tPSA) has been created for this fast calculation method. tPSA is well correlated with human absorption data for common drugs (see, for example, Table 1 below):

Table 1

[0152] Due to exceptions to Lipinski's "rules" or the tPSA model, the permeation properties of the compounds of the present disclosure can be experimentally screened. For example, the permeability coefficient can be determined by methods known to those skilled in the art, including, for example, those by Caco-2 cell permeability assays and / or those using artificial membranes as models of gastrointestinal epithelial cells (as described above, for example, for an explanation of the Caco-2 model, see U.S. Patent No. 6,737,423, Example 31, which is incorporated herein by reference). Synthetic membranes impregnated with, for example, lecithin and / or dodecane can be used as models of the gastrointestinal mucosa to mimic the net permeation properties of the gastrointestinal mucosa. Using this membrane, a section containing the compound of the present disclosure can be separated from a section that monitors the permeation rate. Also, a parallel artificial membrane permeability assay (PAMPA) can be performed. Such in vitro measurement methods can reasonably indicate the actual permeability in vivo (for example, see Wohnsland et al., J. Med. Chem., 2001, 44:923-930; Schmidt et al., Millipore Corp. Application Note, 2002, n AN1725EN00, and n AN1728EN00, which are incorporated herein by reference).

[0153] Thus, in some embodiments, the compounds used in the methods of the present disclosure have a permeability coefficient P of less than about 100×10 -6 cm / s, or less than about 10×10 -6 cm / s, or less than about 1×10 -6 cm / s, or less than about 0.1×10 -6 cm / s when measured using means known in the art appIt may have (for example, the permeability experiment described in Wohnsland et al., J.Med.Chem., 2001, 44.923-930, the contents of which are incorporated herein by reference).

[0154] As described above, in accordance with this disclosure, NHE inhibitory compounds are modified as described above to inhibit net absorption through the intestinal epithelial cell layer, making the resulting compound substantially systemically unbiogenic. In various embodiments, the compounds of this disclosure are substantially impermeable or substantially systemically unbiogenic. More specifically, the NHE inhibitor is a dimer, polymer, or polymer moiety such that the resulting compound is substantially impermeable or substantially systemically unbiogenic. The dimers, polymers, or polymers may have molecular weights of about 500 daltons (Da), about 1000 Da, about 2500 Da, about 5000 Da, or more than about 10,000 Da, and in particular may have molecular weights in the range of about 1000 daltons (Da) to about 500,000 Da, or in the range of about 5000 to about 200,000 Da, and may have molecular weights high enough to essentially hinder any net absorption of the compound through the intestinal epithelial cell layer.

[0155] C. Sustained inhibitory effect In other embodiments, substantially impermeable or substantially systemically unbiogenic NHE inhibitory compounds used in the treatment methods of this disclosure may also exhibit a sustained inhibitory effect. This effect occurs when the inhibitory effect of a compound at a specific concentration (e.g., its inhibitory concentration, IC, or a higher concentration) in equilibrium with epithelial cells does not return to baseline even after the compound is depleted by simple washing of the luminal contents (i.e., sodium transport without inhibitor).

[0156] This effect can be interpreted as a result of tight binding of the NHE inhibitor compound to the NHE protein on the apical side of intestinal epithelial cells. This binding can be considered to be an apparent irreversible effect, where, after contact of the compound with intestinal epithelial cells and subsequent washing and removal of the cells, sodium transport flow remains significantly lower than in the control without the compound. This sustained inhibitory effect has a clear advantage in maintaining drug activity in the GI duct even when the residence time of the active substance in the upper GI duct is short, and when the enterobiliary recirculation process is not effective in replenishing the compound concentration near the site of action.

[0157] Such sustained inhibitory effects offer clear advantages not only in terms of patient medication adherence but also in limiting drug exposure within the GI (Ground Intake) zone.

[0158] Sustained effects can be determined using in vitro methods; for example, a cell line expressing an NHE transport factor is divided into different vials and treated with an NHE inhibitor compound and a sodium solution, and the rate of sodium uptake is measured. The cells in one set of vials are washed for varying durations to remove the inhibitor, and the measurement of sodium uptake is repeated after washing. Compounds that maintain their inhibitory effect after multiple / long washing steps (compared to the inhibitory effect measured in an unwashed vial) are sustained inhibitors. Sustained effects can also be characterized ex vivo by using an inversion bag technique, where Na transport is monitored using cleaved fragments of GI perfused with a solution containing the inhibitor, and the bath is immediately washed with a buffer solution without the inhibitor. Furthermore, sustained effects can be characterized in vivo by observing the time required for sodium equilibrium to return to normal after the inhibitor treatment is interrupted. A limitation of the above method is apical cells. The problem lies in the fact that (and therefore, apical NHE transport factors) are shed after 3-4 days, which is the typical metabolic turnover time for intestinal epithelial cells. Sustained effects can be achieved by increasing the residence time of the active compound on the apical surface of intestinal epithelial cells; this can be achieved by designing an NHE antiport inhibitor using several NHE inhibitor molecules or oligomers (as used herein, "several" typically means at least about 2, about 4, or about 6 or more). An example of such a structure in relation to an analogue of the antibiotic vancomycin is shown in Griffin et al., J.Am.Chem.Soc., 2003, 125, 6517-6531. Alternatively, the compound may contain a group that contributes to increasing affinity to intestinal epithelial cells in order to increase contact time with the surface of intestinal epithelial cells. Such a group is referred to as "mucosal adhesion." More specifically, the "X" and linker portions can be replaced with such mucosal adhesive groups as polyacrylate, partially deacetylated chitosan, or polyalkylene glycol (see also Patil, SB et al., Curr. Drug. Deliv., 2008, Oct. 5(4), pp. 312-8).

[0159] Compounds of the present invention, in which a cyano group is incorporated at the 4-position of the indane ring system of Formula I, unexpectedly showed superior sustained inhibition of NHE3 in the cell-based assay described in Example 181 of this specification, compared to compounds in which other groups are incorporated at the 4- and 6-positions. For example, compounds incorporating 4-cyano and 6-chloro groups demonstrated superior sustained inhibition compared to similar compounds having a 4,6-dichloro-substituted indane ring system. See the following table. The following compound pairs differ only in the substituent at the 4-position (either chloro (X-Cl) or cyano (X-CN)): (A-Cl) 3-(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)urea; and (A-CN) 3-(2-{2-[(3R)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3R)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)urea. (B-Cl) N-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]-2-oxoethyl}-2-({[4-({[({2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]-2-oxoethyl}carbamoyl)methyl]carbamoyl}amino)butyl]carbamoyl}amino)acetamide; and (B-CN) N-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrroridine-1-yl]-2-oxoethyl}-2-({[4-({[({2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide) Pyrrolidine-1-yl]-2-oxoethyl}carbamoyl)methyl]carbamoyl}amino)butyl]carbamoyl}amino)acetamide. (C-Cl) 3-(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamide)pyrrolidine-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamide)pyrrolidine-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)urea; and (C-CN) 3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea. (C-Cl) 3-(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamide)pyrrolidine-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamide)pyrrolidine-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)urea; and (C-CN) 3-(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamide)pyrrolidine-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamide)pyrrolidine-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)urea. (D-Cl) 3-(2-{2-[2-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamide)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-fluorobenzenesulfonamide)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea; and (D-CN) 3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamide)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-fluorobenzenesulfonamide)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea. (E-Cl) 3-(2-{2-[2-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)ethoxy]ethoxy }ethyl)carbamoyl]amino}butyl)urea; and (E-CN) 3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea. (F-Cl) 3-(2-{2-[2-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-methylbenzenesulfonamide)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-methylbenzenesulfonamide)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea; and (F-CN) 3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-methylbenzenesulfonamide)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-methylbenzenesulfonamide)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea. (G-Cl) 3-(2-{2-[2-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)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}benzenesulfonamide)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea; and (G-CN) 3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)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}benzenesulfonamide)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea. [Table 9]

[0160] Therefore, one embodiment of the present invention provides a compound having a structure according to any one of formulas (I') and (Ia') to (Ii').

[0161] D.GI enzyme resistance The compounds used in the treatment methods of this disclosure are substantially systemically unbiovable and / or exhibit sustained inhibitory effects, and therefore, it is desirable to maintain hydrolytic conditions that allow these compounds to spread into the upper GI tubules during their long residence time in the intestine. In such embodiments, the compounds of this disclosure are resistant to enzymatic metabolism. For example, the administered compounds are resistant to the activity of P450 enzymes, glucrosyltransferases, sulfotransferases, glutathione S-transferases, etc., in the intestinal mucosa, as well as to the activity of gastric enzymes (e.g., gastric lipases and pepsin), pancreatic enzymes (e.g., trypsin, triglyceride pancreatic lipase, phospholipase A2, endonucleases, nucleotidases, and alpha-amylases), and brush-edge enzymes (e.g., alkaline phosphatases, glycosidases, and proteases) commonly known in the art.

[0162] The compounds used in the methods of this disclosure are also resistant to metabolism by the gut microbiota; that is, the compounds are not substrates for enzymes produced by the microbiota. In addition, the compounds administered according to the methods of this disclosure may be substantially inactive to the gastrointestinal microbiota and do not interrupt bacterial growth or survival. As a result, in various embodiments herein, the minimum inhibitory concentration (or "MIC") to the GI microbiota is preferably about 15 μg / ml, about 30 μg / ml, about 60 μg / ml, about 120 μg / ml, or even greater than about 240 μg / ml, and in various embodiments the MIC is, for example, about 16 to about 32 μg / ml, or about 64 to about 128 μg / ml, or greater than about 256 μg / ml.

[0163] For those skilled in the pharmaceutical chemistry industry, metabolic stability can be achieved in several ways. For example, a functional group susceptible to oxidation via P450 can be modified by removing a halogen or other functional group. Protection can be achieved by blocking metabolic sites using [a specific method]. Alternatively, protection against oxidation can generally be provided by adding electron-withdrawing groups to the conjugate system to reduce the electrophilicity of the compound. Proteolytic stability can be achieved by avoiding secondary amide bonds or by incorporating other modifications that alter stereochemically or otherwise prevent the drug from being recognized as a substrate by metabolic enzymes.

[0164] E. Sodium and / or fluid excretion In various embodiments of this disclosure, one or more of the NHE inhibitory compounds detailed herein may, when administered alone or in combination with one or more additional pharmaceutically active compounds or agents (e.g., liquid absorbent polymers) to patients in need, act to increase the patient's daily fecal sodium excretion by at least about 20, about 30 mmol, about 40 mmol, about 50 mmol, about 60 mmol, about 70 mmol, about 80 mmol, about 90 mmol, about 100 mmol, about 125 mmol, or about 150 mmol or more, and it should also be noted that the increase is, for example, within the range of about 20 to about 150 mmol / day, or about 25 to about 100 mmol / day, or about 30 to about 60 mmol / day.

[0165] In addition, or by other means, in various embodiments of the present disclosure, one or more of the NHE inhibitory compounds detailed herein, when administered alone or in combination with one or more additional pharmaceutically active compounds or agents (e.g., liquid absorbent polymers) to patients in need, can act to increase a patient's daily fluid outflow by at least about 100 ml, about 200 ml, about 300 ml, about 400 ml, about 500 ml, about 600 ml, about 700 ml, about 800 ml, about 900 ml, or about 1000 ml or more, and it should also be noted that the increase is, for example, within the range of about 100 to about 1000 ml / day, or about 150 to about 750 ml / day, or about 200 to about 500 ml / day (assuming isotonic fluids).

[0166] FC max and IC 50 In various embodiments of this disclosure, one or more of the NHE inhibitor compounds detailed herein, when administered to a patient in need at a dose resulting in an increase of at least 10% in fecal moisture content, either alone or in combination with one or more additional pharmaceutically active compounds or agents (e.g., liquid absorbent polymers), results in IC at NHE-3. 50 Lower, more specifically, IC 50It is less than approximately 10 times (10 times), and more specifically, IC 50 C is less than approximately 100 × (100 times) of max It should also be noted that it has [this characteristic].

[0167] In addition, or by other means, in various embodiments of this disclosure, one or more of the NHE inhibitor compounds detailed herein, when administered alone or in combination with one or more additional pharmaceutically active compounds or agents (e.g., liquid absorbent polymers) to a patient in need, results in a C level of approximately 10 ng / ml, approximately 7.5 ng / ml, approximately 5 ng / ml, approximately 2.5 ng / ml, approximately 1 ng / ml, or less than approximately 0.5 ng / ml. max It may have C max It should also be noted that, for example, these ranges from approximately 1 ng / ml to approximately 10 ng / ml, or from approximately 2.5 ng / ml to approximately 7.5 ng / ml.

[0168] In addition, or by other means, in various embodiments of this disclosure, one or more of the NHE inhibitory compounds detailed herein, when administered alone or in combination with one or more additional pharmaceutically active compounds or agents (e.g., liquid absorbent polymers) to a patient in need, yields an IC50 of about 10 μM, about 7.5 μM, about 5 μM, about 2.5 μM, about 1 μM, or less than about 0.5 μM. 50 It may have an IC 50 It should also be noted that, for example, the range is approximately 1 μM to 10 μM, or approximately 2.5 μM to 7.5 μM. That is the case.

[0169] In addition, or otherwise, in various embodiments of this disclosure, one or more of the NHE inhibitory compounds detailed herein, when administered to a patient in need, result in at least about 10, about 50, about 100, about 250, about 500, about 750, or about 1000 ICs. 50 :C max Ratio (here, IC 50 and C max It should also be noted that they may have (expressed in the same units).

[0170] In addition, or otherwise, in various embodiments of this disclosure, one or more of the NHE inhibitor compounds detailed herein, when administered orally to a patient in need, within the therapeutic range or concentration, C max The maximum concentration of a compound detected in serum, defined as the NHE inhibitory concentration IC of the compound, is 50 It should also be noted that it is lower than. As stated above, when used herein, IC 50 This is defined as a quantitative measure indicating the concentration of a compound required to inhibit 50% of NHE-mediated Na / H antiport activity in a cell-based assay.

[0171] III. Pharmaceutical Compositions and Treatment Methods A. Compositions and Methods 1. Fluid retention and / or salt overload disorder Another aspect of the present invention relates to a method for inhibiting NHE-mediated antiportation of sodium and hydrogen ions. The method comprises administering a pharmaceutically effective amount of a compound or pharmaceutical composition of formula I to a mammal requiring it. In one embodiment, the method comprises administering a pharmaceutically effective amount of compound Ia, Ib, Ic, Id, Ie, If, Ig, Ih, or Ii or a combination thereof to a mammal requiring it.

[0172] Another aspect of the present invention relates to a method for treating disorders associated with fluid retention or salt overload. The method comprises administering a pharmaceutically effective amount of a compound or pharmaceutical composition of formula I to a mammal in need. In one embodiment, the method for treating a disorder associated with fluid retention or salt overload comprises administering a pharmaceutically effective amount of compound Ia, Ib, Ic, Id, Ie, If, Ig, Ih, or Ii or a combination thereof to a mammal in need.

[0173] In one embodiment, a method is provided for treating a disorder selected from the group consisting of heart failure (such as congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention, the method comprising administering a pharmaceutically effective amount of the compound or pharmaceutical composition described above to a mammal in need thereof. In another embodiment, the disorders are not limited to, but include: gastrointestinal motility disorders, irritable bowel syndrome, chronic constipation, chronic idiopathic constipation, chronic constipation occurring in patients with cystic fibrosis, chronic constipation occurring in patients with chronic kidney disease, calcium-induced constipation occurring in patients with osteoporosis, opioid-induced constipation, functional gastrointestinal disorders, gastroesophageal reflux disease, functional heartburn, indigestion, functional indigestion, non-ulcerative indigestion, gastroparesis, chronic intestinal pseudo-obstruction, Crohn's disease, ulcerative colitis and related diseases referred to as inflammatory bowel syndrome, colonic pseudo-obstruction, gastric ulcer, infectious diarrhea, cancer (colorectal), "leaky gut syndrome," cystic fibrosis gastrointestinal disorders, multiple organ failure, microscopic colitis, necrotizing Panentitis, allergies - atopic dermatitis, food allergies, infections (respiratory), acute inflammation (e.g., sepsis, systemic inflammatory response syndrome), chronic inflammation (arthritis), obesity-induced metabolic diseases (e.g., non-alcoholic steatohepatitis, type 1 diabetes, type 2 diabetes, cardiovascular disease), kidney disease, diabetic nephropathy, cirrhosis, non-alcoholic steatohepatitis, non-alcoholic fatty acid liver disease, steatosis, primary sclerosing cholangitis, primary biliary cholangitis, portal hypertension, autoimmune diseases (e.g., type 1 diabetes, ankylosing spondylitis, lupus, alopecia areata, rheumatoid arthritis, polymyalgia rheumatica, fibromyalgia, chronic fatigue syndrome, Sjögren's syndrome, vitiligo, thyroiditis, vasculitis, urticaria These include measles (urticaria), Raynaud's syndrome, schizophrenia, autism spectrum disorder, hepatic encephalopathy, and chronic alcoholism.

[0174] Another embodiment provides a method for treating hypertension, comprising administering a pharmaceutically effective amount of the compound or pharmaceutical composition described above to a mammal in need thereof.

[0175] In a further embodiment, the method includes administering a pharmaceutically effective amount of the compound to a mammal to increase the daily fecal excretion of sodium and / or body fluids of the mammal. In a further embodiment, the method includes administering a pharmaceutically effective amount of the compound to a mammal to increase the daily fecal excretion of at least about 30 mmol of sodium and / or at least about 200 ml of body fluids of the mammal. In a further embodiment, the fecal excretion of sodium and / or body fluids of the mammal is increased without introducing another type of cation in a stoichiometric or near-stoichiometric manner via an ion exchange process. In a further embodiment, the method further includes administering to a mammal a liquid absorbent polymer that absorbs fecal fluid resulting from the use of a compound that is substantially active in the gastrointestinal tract to inhibit NHE-mediated antiportation of sodium and hydrogen ions.

[0176] In further embodiments, the compound or composition is administered to treat hypertension. In further embodiments, the compound or composition is administered to treat hypertension associated with dietary salt intake. In further embodiments, administration of the compound or composition allows mammals to consume more palatable food. In further embodiments, the compound or composition is administered to treat fluid overload. In further embodiments, fluid overload is associated with congestive heart failure. In further embodiments, fluid overload is associated with end-stage renal disease. In further embodiments, fluid overload is associated with peroxisome proliferator-activated receptor (PPAR) gamma agonist therapy. In further embodiments, the compound or composition is administered to treat sodium overload. In further embodiments, the compound or composition is administered to reduce weight gain between dialysis in ESRD patients. In further embodiments, the compound or composition is administered to treat edema. In further embodiments, edema is caused by chemotherapy, premenstrual fluid overload, or pre-eclampsia.

[0177] In further embodiments, the compound or composition is administered to treat gastric ulcers. In further embodiments, the compound or composition is administered to treat infectious diarrhea. In further embodiments, the compound or composition is administered to treat colorectal cancer. In further embodiments, the compound or composition is administered to treat leaky gut syndrome. In further embodiments, the compound or composition is administered to treat cystic fibrosis gastrointestinal disease. In further embodiments, the compound or composition is administered to treat multiple organ failure. In further embodiments, the compound or composition is administered to treat microscopic colitis. In further embodiments, the compound or composition is administered to treat necrotizing pancolitis. In further embodiments, the compound or composition is administered to treat atopic dermatitis. In further embodiments, the compound or composition is administered to treat food allergies. In further embodiments, the compound or composition is administered to treat respiratory infections. In further embodiments, the compound or composition is administered to treat acute inflammation (e.g., sepsis, systemic inflammatory response syndrome). In further embodiments, the compound or composition is administered to treat chronic inflammation (e.g., arthritis). In further embodiments, the compound or composition is administered to treat obesity-induced metabolic diseases (e.g., non-alcoholic steatohepatitis, type 1 diabetes, type 2 diabetes, cardiovascular disease). In further embodiments, the compound or composition is administered to treat renal disease. In one embodiment, the compound or composition is administered to treat diabetic nephropathy. In a further embodiment, the compound or composition is administered to treat cirrhosis. In a further embodiment, the compound or composition is administered to treat fatty liver disease. In a further embodiment, the compound or composition is administered to treat non-alcoholic fatty acid liver disease. In a further embodiment, the compound or composition is administered to treat steatosis. In a further embodiment, the compound or composition is administered to treat primary sclerosing cholangitis. In a further embodiment, the compound or composition is administered to treat primary biliary cholangitis. In a further embodiment, the compound or composition is administered to treat portal hypertension. In further embodiments, the compound or composition is administered to treat autoimmune diseases (e.g., type 1 diabetes, ankylosing spondylitis, lupus, alopecia areata, rheumatoid arthritis, polymyalgia rheumatica, fibromyalgia, chronic fatigue syndrome, Sjögren's syndrome, vitiligo, thyroiditis, vasculitis, urticaria, or Raynaud's syndrome). In further embodiments, the compound or composition is administered to treat schizophrenia. In further embodiments, the compound or composition is administered to treat autism spectrum disorder. In further embodiments, the compound or composition is administered to treat hepatic encephalopathy. In further embodiments, the compound or composition is administered to treat chronic alcoholism.

[0178] In further embodiments, the compound or composition is administered orally, by rectal suppositories, or by enema.

[0179] In further embodiments, the method includes administering a pharmaceutically effective amount of the compound or composition in combination with one or more additional pharmaceutically active compounds or agents. In further embodiments, one or more additional pharmaceutically active compounds or agents are selected from the group consisting of diuretics, cardiotonic glycosides, ACE inhibitors, angiotensin-2 receptor antagonists, aldosterone antagonists, aldosterone synthase inhibitors, renin inhibitors, calcium channel blockers, beta-blockers, alpha-blockers, central alpha-agonists, vasodilators, anticoagulants, antiplatelet agents, lipid-lowering agents, and peroxisome proliferator-activated receptor (PPAR) gamma agonists. In further embodiments, the diuretics are selected from the group consisting of potent loop diuretics, benzothiadiazide diuretics, potassium-sparing diuretics, and osmotic diuretics. In further embodiments, a pharmaceutically effective amount of the compound or composition and one or more additional pharmaceutically active compounds or agents are administered as part of a single pharmaceutical formulation. In further embodiments, a pharmaceutically effective amount of the compound or composition and one or more additional pharmaceutically active compounds or agents are administered as individual pharmaceutical formulations. In further embodiments, the individual pharmaceutical formulations are administered sequentially. In further embodiments, the individual pharmaceutical formulations are administered simultaneously.

[0180] Another embodiment provides a method for treating a gastrointestinal disorder, comprising administering a pharmaceutically effective amount of the compound or pharmaceutical composition described above to a mammal in need thereof.

[0181] In further embodiments, the gastrointestinal disorder is gastrointestinal motility disorder. In further embodiments, the gastrointestinal disorder is irritable bowel syndrome. In further embodiments, the gastrointestinal disorder is chronic constipation. In further embodiments, the gastrointestinal disorder is chronic idiopathic constipation. In further embodiments, the gastrointestinal disorder is chronic constipation occurring in patients with cystic fibrosis. In further embodiments, the gastrointestinal disorder is opioid-induced constipation. In further embodiments, the gastrointestinal disorder is functional gastrointestinal disorder. In further embodiments, the gastrointestinal disorder is selected from the group consisting of chronic intestinal pseudo-obstruction and colonic pseudo-obstruction. In further embodiments, the gastrointestinal disorder is Crohn's disease. In further embodiments, the gastrointestinal disorder is ulcerative colitis. In further embodiments, the gastrointestinal disorder is a disease referred to as inflammatory bowel disease. In further embodiments In a further embodiment, the gastrointestinal disorder is associated with chronic kidney disease (stage 4 or 5). In a further embodiment, the gastrointestinal disorder is constipation induced by calcium supplements. In a further embodiment, the gastrointestinal disorder is constipation, and the constipation to be treated is associated with the use of therapeutic drugs. In a further embodiment, the gastrointestinal disorder is constipation, and the constipation to be treated is associated with neuropathic disorders. In a further embodiment, the gastrointestinal disorder is constipation, and the constipation to be treated is postoperative constipation (postoperative ileus). In a further embodiment, the gastrointestinal disorder is constipation, and the constipation to be treated is idiopathic (functional constipation or delayed-pass constipation). In further embodiments, the gastrointestinal disorder is constipation, and the constipation to be treated is associated with neuropathic, metabolic, or endocrine disorders (e.g., diabetes mellitus, renal failure, hypothyroidism, hyperthyroidism, hypocalcemia, multiple sclerosis, Parkinson's disease, spinal cord lesions, neurofibromatosis, autonomic neuropathy, Chagas disease, Hirschsprung's disease, or cystic fibrosis). In further embodiments, the gastrointestinal disorder is constipation, and the constipation to be treated is by the use of drugs selected from analgesics (e.g., opioids), antihypertensives, anticonvulsants, antidepressants, antispasmodics, and antipsychotics.

[0182] In other embodiments, gastrointestinal disorders include gastric ulcers, infectious diarrhea, cancer (colorectal), "leaky gut syndrome," cystic fibrosis gastrointestinal disease, multiple organ failure, microscopic colitis, necrotizing pancolitis, allergies - atopy, food allergies, infections (respiratory), acute inflammation (e.g., sepsis, systemic inflammatory response syndrome), chronic inflammation (arthritis), obesity-induced metabolic diseases (e.g., non-alcoholic steatohepatitis, type 1 diabetes, type 2 diabetes, cardiovascular disease), kidney disease, diabetic nephropathy, cirrhosis, and non-alcoholic diseases. It is associated with steatohepatitis, non-alcoholic fatty acid liver disease, steatosis, primary sclerosing cholangitis, primary biliary cholangitis, portal hypertension, autoimmune diseases (e.g., type 1 diabetes, ankylosing spondylitis, lupus, alopecia areata, rheumatoid arthritis, polymyalgia rheumatica, fibromyalgia, chronic fatigue syndrome, Sjögren's syndrome, vitiligo, thyroiditis, vasculitis, urticaria (hives), or Raynaud's syndrome), schizophrenia, autism spectrum disorder, hepatic encephalopathy, intestinal bacterial overgrowth, or chronic alcoholism.

[0183] Another embodiment provides a method for treating irritable bowel syndrome, comprising administering a pharmaceutically effective amount of the compound or pharmaceutical composition described above to a mammal in need thereof.

[0184] In further embodiments of the above embodiments, the compound or composition is administered to treat or alleviate pain associated with gastrointestinal disorders. In further embodiments, the compound or composition is administered to treat or alleviate visceral hypersensitivity associated with gastrointestinal disorders. In further embodiments, the compound or composition is administered to treat or alleviate inflammation of the gastrointestinal tract. In further embodiments, the compound or composition is administered to reduce gastrointestinal transit time.

[0185] The compounds of the present invention inhibit transient receptor potential cation channel subfamily C, member 6 (TRPC6). Therefore, the compounds of the present invention are useful for treating diseases, disorders, and conditions mediated by abherent TRPC6 activity, such as cardiac hypertrophic renal disease, and in particular glomerular disease.

[0186] In further embodiments, the compound or composition is administered orally or by rectal suppositories.

[0187] In further embodiments, the method includes administering a pharmaceutically effective amount of the compound or composition in combination with one or more additional pharmaceutically active compounds or agents. In further embodiments, the one or more additional pharmaceutically active agents or compounds are analgesic peptides or agents. In further embodiments, the one or more additional pharmaceutically active agents The agent or compound is selected from the group consisting of laxatives selected from bulking laxatives (e.g., psyllium husk (Metamucil)), methylcellulose (Citrucel), polycarbophil, dietary fiber, apple, stool softeners / surfactants (e.g., Doxart, Colace, Diocto), wettable powders or osmotic regulators (e.g., sodium dibasic phosphate, magnesium citrate, magnesium hydroxide (magnesia milk), magnesium sulfate (Epsom salt), sodium dihydrogen phosphate, sodium biphosphate), and hyperosmolar agents (e.g., glycerin suppositories, sorbitol, lactulose, and polyethylene glycol (PEG)). In further embodiments, a pharmaceutically effective amount of the compound or composition, and one or more additional pharmaceutically active compounds or agents are administered as part of a single pharmaceutical formulation. In further embodiments, a pharmaceutically effective amount of the compound or composition, and one or more additional pharmaceutically active compounds or agents are administered as individual pharmaceutical formulations. In further embodiments, the individual pharmaceutical formulations are administered sequentially. In further embodiments, the individual pharmaceutical preparations are administered simultaneously.

[0188] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition comprises a compound of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, or Ii and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition described herein can be used to inhibit NHE-mediated antiportation of sodium and hydrogen ions. In yet another embodiment, the pharmaceutical composition described herein can be used to treat disorders associated with fluid retention or salt overload.

[0189] Pharmaceutical compositions or formulations that can be used pursuant to this disclosure for the treatment of various disorders associated with fluid retention and / or salt overload in the gastrointestinal tract (e.g., hypertension, heart failure (particularly congestive heart failure), chronic kidney disease, end-stage renal disease, hepatic disease, and / or peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention) generally comprise substantially impermeable or substantially systemically unbiogenic NHE inhibitor compounds of this disclosure, as well as a variety of other optional components (e.g., pharmaceutically acceptable additives) as further elaborated below herein. Accordingly, compounds used in the treatment methods of this disclosure, as well as pharmaceutical compositions containing them, can be administered alone or as part of a treatment protocol or plan that includes the administration or use of other beneficial compounds (as further elaborated elsewhere herein). In some specific embodiments, NHE inhibitor compounds, including any pharmaceutical composition containing them, are administered together with a liquid absorbent polymer (as more fully described below).

[0190] Subjects “requiring treatment” or “requiring NHE inhibition” using the compounds of this disclosure include subjects having diseases and / or conditions that can be treated with substantially impermeable or substantially systemically unbiogenic NHE inhibitor compounds, with or without liquid absorbent polymers, to achieve beneficial therapeutic and / or prophylactic outcomes. Beneficial outcomes include reduced symptom severity or delayed symptom onset, increased lifespan, and / or faster or more complete resolution of the disease or condition. For example, subjects requiring treatment may have: hypertension; salt-sensitive hypertension that may result from dietary salt intake; risk of cardiovascular disorders resulting from hypertension (e.g., myocardial infarction, congestive heart failure, etc.); heart failure resulting in fluid or salt overload (e.g., congestive heart failure); chronic kidney disease resulting in fluid or salt overload; end-stage renal disease resulting in fluid or salt overload; liver disease resulting in fluid or salt overload; peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention; or edema resulting from congestive heart failure or end-stage renal disease. In various embodiments, subjects requiring treatment typically show signs of hypervolume resulting from salt and fluid retention, which are common features of congestive heart failure, renal failure, or cirrhosis. The occurrence of shortness of breath, edema, ascites, or weight gain between dialysis may also indicate fluid overload. Retention and salt retention may occur. Other examples of subjects who would benefit from the above treatment include those with congestive heart failure and hypertension, and in particular, those who are resistant to diuretic treatments, i.e., those with very few available treatment options. Subjects who “require treatment” also include those with hypertension, salt-sensitive blood pressure, and systolic / diastolic blood pressure higher than approximately 130-139 / 85-89 mmHg.

[0191] Administration of NHE inhibitor compounds, with or without liquid absorbent polymers, may be beneficial for patients placed on a “salt-free” diet plan (i.e., 60–100 mmol of Na per day) to liberalize their diet while maintaining a neutral or slightly negative sodium balance (i.e., total salt uptake is less than or equal to secreted salt). In this context, “liberating their diet” means that the treated patient can add salt to their diet to make it more palatable or / or diversify their diet with salt-containing foods, thereby maintaining a good nutritional status while improving their quality of life.

[0192] The treatment methods described herein can also save patients with chemotherapy-related edema, premenstrual fluid overload, and pre-eclampsia (pregnancy-induced hypertension).

[0193] Accordingly, it should be noted that the Disclosure further relates to methods of treatment, including the administration of the compounds of the Disclosure or pharmaceutical compositions containing such compounds. Such methods may include, for example, a method of treating hypertension, which includes administering to a patient a substantially impermeable or substantially systemically unbiogenic NHE inhibitor compound or a pharmaceutical composition containing the same. The method may be for reducing fluid overload associated with heart failure (in particular congestive heart failure), which includes administering to a patient a substantially impermeable or substantially systemically unbiogenic NHE inhibitor compound or a pharmaceutical composition containing the same. The method may be for reducing fluid overload associated with end-stage renal disease, which includes administering to a patient a substantially impermeable or substantially systemically unbiogenic NHE inhibitor compound or a composition containing the same. The method described above may be for reducing fluid overload associated with peroxisome proliferator-activated receptor (PPAR) gamma agonist therapy, and the method includes administering to a patient a substantially impermeable or substantially systemically unbiogenic NHE inhibitor compound, or a composition containing the same. In addition, or otherwise, the method may be for reducing the activity of intestinal NHE transporters in a patient, and the method includes administering to a patient a substantially impermeable or substantially systemically unbiogenic NHE inhibitor compound, or a composition containing the same.In another embodiment, the diseases to be treated include, but are not limited to, heart failure (such as congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention, gastrointestinal motility disorders, irritable bowel syndrome, chronic constipation, chronic idiopathic constipation, chronic constipation occurring in patients with cystic fibrosis, chronic constipation occurring in patients with chronic kidney disease, calcium-induced constipation occurring in patients with osteoporosis, opioid-induced constipation, functional gastrointestinal disorders, gastroesophageal reflux disease, functional heartburn, indigestion, functional indigestion, non-ulcerative indigestion, gastroparesis, chronic intestinal pseudo-obstruction, Crohn's disease, ulcerative colitis and related diseases referred to as inflammatory bowel syndrome, colonic pseudo-obstruction, and gastric Ulcers, infectious diarrhea, cancer (colorectal), "leaky gut syndrome," cystic fibrosis gastrointestinal diseases, multiple organ failure, microscopic colitis, necrotizing pancolitis, allergies - atopic dermatitis, food allergies, infections (respiratory tract), acute inflammation (e.g., sepsis, systemic inflammatory response syndrome), chronic inflammation (arthritis), obesity-induced metabolic diseases (e.g., non-alcoholic steatohepatitis, type 1 diabetes, type 2 diabetes, cardiovascular disease), kidney disease, diabetic nephropathy, cirrhosis, non-alcoholic steatohepatitis, non-alcoholic fatty acid liver disease, steatosis, primary sclerosing cholangitis, primary biliary cholangitis, portal hypertension, autoimmune diseases (e.g., type 1 diabetes, ankylosing spondylitis, lupus, alopecia areata, rheumatoid arthritis, polymyalgia rheumatica, linea). This includes visceral myalgia, chronic fatigue syndrome, Sjögren's syndrome, vitiligo, thyroiditis, vasculitis, urticaria (hives), Raynaud's syndrome, schizophrenia, autism spectrum disorder, hepatic encephalopathy, small intestinal bacterial overgrowth, and chronic alcoholism.

[0194] 2. Gastrointestinal disorders Another aspect of the present invention relates to a method for treating gastrointestinal disorders. The method comprises administering a pharmaceutically effective amount of a compound or pharmaceutical composition of formula I to a mammal in need. In one embodiment, the method for treating gastrointestinal disorders comprises administering a pharmaceutically effective amount of compound Ia, Ib, Ic, Id, Ie, If, Ig, Ih, or Ii or a combination thereof to a mammal in need.

[0195] Pharmaceutical compositions or formulations that can be used pursuant to this disclosure for the treatment of various gastrointestinal disorders, including the treatment or relief of pain associated with gastrointestinal disorders, comprise substantially impermeable or substantially systemically unbiogenic NHE inhibitor compounds of this disclosure, as well as a variety of other optional components (e.g., pharmaceutically acceptable excipients) as further elaborated below herein. Accordingly, the compounds used in the treatment methods of this disclosure, as well as pharmaceutical compositions containing them, can be administered alone or as part of a therapeutic protocol or plan that includes the administration or use of other beneficial compounds (as further elaborated elsewhere herein). In some specific embodiments, NHE inhibitor compounds, comprising any pharmaceutical composition containing an NHE inhibitor compound, are administered together with a liquid absorbent polymer (as fully described below).

[0196] Subjects “requiring treatment” or “requiring NHE inhibition” using the compounds of this disclosure include subjects having diseases and / or conditions that can be treated with substantially impermeable or substantially systemically unbiogenic NHE inhibitor compounds, with or without liquid absorbent polymers, to achieve beneficial therapeutic and / or prophylactic outcomes. Beneficial outcomes include reduced symptom severity or delayed symptom onset, increased lifespan, and / or faster or more complete resolution of the disease or condition. For example, those requiring treatment are suffering from gastrointestinal disorders; patients may have gastrointestinal motility disorders, irritable bowel syndrome, chronic constipation, chronic idiopathic constipation, chronic constipation occurring in patients with cystic fibrosis, chronic constipation occurring in patients with chronic kidney disease, calcium-induced constipation occurring in patients with osteoporosis, opioid-induced constipation, functional gastrointestinal disorders, gastroesophageal reflux disease, functional heartburn, indigestion, functional indigestion, non-ulcerative indigestion, gastroparesis, chronic intestinal pseudo-obstruction, Crohn's disease, ulcerative colitis and related diseases known as inflammatory bowel syndrome, colonic pseudo-obstruction, gastric ulcer, infectious diarrhea, cancer (colorectal), "leaky gut syndrome," cystic fibrosis gastrointestinal disorders, multiple organ failure, microscopic colitis, necrotizing pancolitis, atopic dermatitis, food allergies, infections (respiratory tract), acute inflammation (e.g., dysentery). The patient suffers from a disorder selected from the group consisting of (e.g., rheumatoid arthritis, systemic inflammatory response syndrome), chronic inflammation (arthritis), obesity-induced metabolic diseases (e.g., non-alcoholic steatohepatitis, type 1 diabetes mellitus, type 2 diabetes mellitus, cardiovascular disease), renal disease, diabetic nephropathy, cirrhosis, non-alcoholic steatohepatitis, non-alcoholic fatty acid liver disease, steatosis, primary sclerosing cholangitis, primary biliary cholangitis, portal hypertension, autoimmune diseases (e.g., type 1 diabetes mellitus, ankylosing spondylitis, lupus, alopecia areata, rheumatoid arthritis, polymyalgia rheumatica, fibromyalgia, chronic fatigue syndrome, Sjögren's syndrome, vitiligo, thyroiditis, vasculitis, urticaria (hives), Raynaud's syndrome), schizophrenia, autism spectrum disorder, hepatic encephalopathy, small intestinal bacterial overgrowth, and chronic alcoholism.

[0197] In various preferred embodiments, the constipation to be treated is associated with the use of therapeutic drugs; neuropathic disorders; postoperative constipation (postoperative ileus); gastrointestinal disorders; idiopathic (functional constipation or delayed-transit constipation); neuropathic, metabolic or endocrine disorders (e.g., diabetes, renal failure, hypothyroidism, hyperthyroidism, hypocalcemia, multiple sclerosis, Parkinson's disease, spinal cord lesions, neurofibromatosis, autonomic neuropathy, Chagas disease, Hirsutism It is associated with conditions such as Jüsprung's disease or cystic fibrosis. Constipation may also be a result of surgery (postoperative ileus) or due to the use of medications such as analgesics (e.g., opioids), antihypertensives, anticonvulsants, antidepressants, antispasmodics, and antipsychotics.

[0198] In other embodiments, constipation may be associated with gastric ulcers, infectious diarrhea, cancer (colorectal), "leaky gut syndrome," cystic fibrosis gastrointestinal diseases, multiple organ failure, microscopic colitis, necrotizing pancolitis, atopic dermatitis, food allergies, infections (respiratory tract), acute inflammation (e.g., sepsis, systemic inflammatory response syndrome), chronic inflammation (arthritis), obesity-induced metabolic diseases (e.g., non-alcoholic fatty liver disease, type 1 diabetes, type 2 diabetes, cardiovascular disease), kidney disease, diabetic nephropathy, cirrhosis, and non-alcoholic lipids. It is associated with fatty liver disease, non-alcoholic fatty acid liver disease, steatosis, primary sclerosing cholangitis, primary biliary cholangitis, portal hypertension, autoimmune diseases (e.g., type 1 diabetes, ankylosing spondylitis, lupus, alopecia areata, rheumatoid arthritis, polymyalgia rheumatica, fibromyalgia, chronic fatigue syndrome, Sjögren's syndrome, vitiligo, thyroiditis, vasculitis, urticaria, Raynaud's syndrome), schizophrenia, autism spectrum disorder, hepatic encephalopathy, small intestinal bacterial overgrowth, and chronic alcoholism.

[0199] Accordingly, it should be noted that the Disclosure further relates to methods of treatment, including the administration of the compounds of the Disclosure or pharmaceutical compositions containing such compounds. Such methods may include, for example, a method for increasing gastrointestinal motility in a patient, which includes administering to the patient a substantially impermeable or substantially unbiogenic NHE inhibitor compound or a pharmaceutical composition containing the same. In addition, or otherwise, such methods may be for reducing the activity of intestinal NHE transporters in a patient, which includes administering to the patient a substantially impermeable or substantially unbiogenic NHE inhibitor compound or a pharmaceutical composition containing the same. In addition, or otherwise, the method may be for treating gastrointestinal disorders, gastrointestinal motility disorders, irritable bowel syndrome, calcium-induced constipation in patients with osteoporosis, chronic constipation occurring in patients with cystic fibrosis, chronic constipation occurring in patients with chronic kidney disease, functional gastrointestinal disorders, gastroesophageal reflux disease, functional heartburn, indigestion, functional dyspepsia, non-ulcerative dyspepsia, gastroparesis, chronic pseudo-obstruction of the intestine, pseudo-obstruction of the colon, Crohn's disease, ulcerative colitis, or inflammatory bowel disease, and the method may include administering, orally or by rectal suppositories, an antagonist of intestinal NHE, and more specifically, substantially impermeable or substantially unbiogenic NHE inhibitor compounds, or a pharmaceutical composition containing the same. In addition, or otherwise, the method may be for treating or relieving pain, including visceral pain, pain associated with gastrointestinal disorders or pain associated with several other disorders, and the method includes administering to a patient a substantially impermeable or substantially unbiogenic NHE inhibitor compound, or a pharmaceutical composition containing the same. In addition, or otherwise, the method may be for treating inflammation of the gastrointestinal tract, including inflammation, for example, inflammation associated with gastrointestinal disorders or infections or several other disorders, and the method includes administering to a patient a substantially impermeable or substantially unbiogenic NHE inhibitor compound, or a pharmaceutical composition containing the same.

[0200] 3. Metabolic disorders Pharmaceutical compositions or formulations that can be used pursuant to this disclosure for the treatment of various metabolic disorders, including type 2 diabetes mellitus (T2DM), metabolic syndromes, and / or symptoms associated with such disorders, generally comprise substantially impermeable or substantially systemically unbiogenic NHE inhibitor compounds of this disclosure, as well as various other optional components (e.g., pharmaceutically acceptable excipients) as further elaborated below herein. Accordingly, compounds used in the treatment methods of this disclosure, and pharmaceutical compositions comprising them, may be administered alone or as part of a treatment protocol or plan that includes the administration or use of other beneficial compounds (as further elaborated elsewhere herein). In another embodiment, the pharmaceutical composition is used for non-alcoholic steatohepatitis, type 1 and 2 diabetes mellitus, and It can be used to treat other metabolic diseases such as cardiovascular diseases.

[0201] Obesity is becoming a global epidemic. In the United States, approximately two-thirds of the population is overweight (BMI 25-29.9) or obese (BMI ≥ 30) (Ogden, CL et al, “Prevalence of overweight and obesity in the united states, 1999-2004” JAMA 2006, 295, 1549-1555). Obesity is a major risk factor for developing diabetes and related complications, including cardiovascular disease and chronic kidney disease (CKD). In the United States, the prevalence of T2DM is increasing dramatically. The American Diabetes Association (ADA) estimates that more than 23 million Americans aged 20 and over have diabetes, and that T2DM accounts for nearly 95% of these cases. The World Health Organization (WHO) estimates that there are nearly 170 million people worldwide with diabetes (Campbell, RK, “Type 2 diabetes: where we are today: an overview of disease burden, current treatments, and treatment strategies,” Journal of the American Pharmacists Association 2009, 49(5), S3-S9).

[0202] Obesity is also a major risk factor for the development of metabolic syndromes, and subsequently, chronic kidney disease (CKD). Previously known as Syndrome X, multiple metabolic disorders, metabolic disorders, and other names, metabolic syndromes consist of an accumulation of metabolic abnormalities including abdominal obesity, hypertriglyceridemia, low levels of high-density lipoprotein (HDL) cholesterol, elevated blood pressure (BP), and elevated fasting glucose or diabetes (Townsend, R et al. “Metabolic Syndrome, Components, and Cardiovascular Disease Prevalence in Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study” American Journal of Nephrology 2011, 33, 477-484). Metabolic syndromes are common in patients with CKD and are important risk factors for the onset and progression of CKD.

[0203] Hemodynamic factors appear to play a significant role in obesity-induced renal dysfunction. Hypertension, closely associated with obesity, appears to be a major cause of renal dysfunction in obese patients (Wahba, I et al. “Obesity and obesity-initiated metabolic syndrome: mechanical links to chronic kidney disease” Clinical Journal of the American Society of Nephrology 2007, 2, 550-562). Studies in animals and humans have shown that obesity is associated with increased glomerular filtration rate (GFR) and increased renal blood flow. This may result from afferent arteriole dilation as a result of proximal salt reabsorption, coupled with efferent renal arteriole stenosis as a result of elevated angiotensin II levels. These effects may contribute to ultrafiltration, glomerular hypertrophy, and late focal segmental glomerulosclerosis. Despite elevated glomerular filtration rate (GFR) in obese individuals, urinary sodium excretion in response to saline loading is often delayed, and individuals exhibit abnormal pressure natriuresis, indicating greedy proximal tubular sodium reabsorption. In addition, increased fat distribution leads to increased intraperitoneal pressure, which can result in compression of the renal veins, and therefore increased renal venous pressure and decreased renal perfusion. Increased fat can lead to increased renal interstitial fluid through various mechanisms, stimulating renal sodium retention and thereby contributing to hypertension (Wahba_2007).

[0204] Considering the above, either bypass the kidneys or use a mechanism that does not depend on normal renal function, There is a need in the art for agents that can eliminate sodium and body fluids from subjects. Subjects with metabolic diseases, including T2DM and metabolic syndromes, are humans, but may also be animals requiring treatment with the compounds of this disclosure, such as companion animals (e.g., dogs, cats), livestock (e.g., cattle, pigs, horses), and laboratory animals (e.g., rats, mice, guinea pigs).

[0205] Accordingly, the compounds used in the treatment methods of this disclosure, and furthermore, pharmaceutical compositions containing them, may be administered alone or as part of a combination therapy or plan that includes the administration or use of other therapeutic compounds related to the treatment of metabolic disorders such as T2DM and metabolic syndromes. In some specific embodiments, an NHE inhibitor compound is administered together with a liquid absorbent polymer, including any pharmaceutical composition containing the compound.

[0206] 3. Protein excretion in urine The compounds described herein have been shown to reduce urinary protein (e.g., albumin) excretion in a dose-dependent manner. Figure 2 shows the effects of two NHE3 inhibitors, NHE3-1 and NHE3-2, and the compounds of this disclosure on urinary albumin excretion in rats. Thus, another aspect of the present invention relates to a method for reducing urinary protein excretion and disorders associated with increased urinary protein excretion in mammals. The method comprises administering a pharmaceutically effective amount of a compound or pharmaceutical composition of formula I to a mammal in need. In one embodiment, a method for treating disorders associated with increased urinary protein excretion comprises administering a pharmaceutically effective amount of compound Ia, Ib, Ic, Id, Ie, If, Ig, Ih, or Ii or a combination thereof to a mammal in need. In one embodiment, the protein is albumin.

[0207] B. Combination therapy 1. Fluid retention and / or salt overload disorder As described above, the compounds described herein can be used alone or in combination with other agents. For example, the compounds can be administered together with diuretics (i.e., potent loop diuretics, benzothiadiazide diuretics, potassium-sparing diuretics, osmotic diuretics), cardiac glycosides, ACE inhibitors, angiotensin-2 receptor antagonists, aldosterone antagonists, aldosterone synthase inhibitors, renin inhibitors, calcium channel blockers, beta-blockers, alpha-blockers, central alpha-agonists, vasodilators, anticoagulants, antiplatelet agents, lipid-lowering agents, peroxisome proliferator-activated receptor (PPAR) gamma agonists or compounds, or together with liquid absorbent polymers as described more fully below. The agents can be covalently bound to the compounds described herein, or they may be separate agents administered together with or sequentially with the compounds described herein in combination therapy.

[0208] Combination therapy can be achieved by separately formulating and administering two or more drugs, for example, a substantially impermeable or substantially systemically unbiogenic NHE inhibitor compound as described herein, and a diuretic, cardiac glycoside, ACE inhibitor, angiotensin-2 receptor antagonist, aldosterone antagonist, aldosterone synthase inhibitor, renin inhibitor, calcium channel blocker, beta-blocker, alpha-blocker, central alpha-agonist, vasodilator, anticoagulant, antiplatelet agent, or compound, or by administering two or more drugs in a single formulation. Other combinations are also included in combination therapy. For example, two drugs can be formulated together and administered in combination with a separate formulation containing a third drug. In combination therapy, two or more drugs may be administered simultaneously, but this is not always necessary. For example, the first drug (or combination of drugs) may be administered several minutes, several hours, several days, or several weeks before the second drug (or combination of drugs) is administered. Therefore, two or more drugs should be mixed with each other within a few minutes, or mixed with each other in groups of 1, 2, 3, 6. They may be administered within 9, 12, 15, 18, or 24 hours, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, or 9 weeks or more of each other. In some cases, even longer intervals are possible. In many cases, it is desirable, but not necessarily, that two or more drugs used in combination therapy be present in the patient's body at the same time.

[0209] Combination therapy may include two or more administrations of one or more drugs used in combination. For example, when drug X and drug Y are used in combination, they can be administered one or more times in any combination sequentially, for example, in the order of XYX, XXY, YXY, YYX, XXYY, etc.

[0210] The compounds described herein can be used in combination therapy with diuretics. Useful diuretics include, for example, potent loop diuretics [furosemide (Lasix), ethacrine (Edecrin), bumetanide (Bumex)], benzothiadiazide diuretics [hydrochlorothiazide (Hydrodiuril), chlorothiazide (Diuril), chlorthalidone (Hygroton), benzthiazide (Aguapres), bendroflumethiazide (Naturetin), meticlothiazide (Aguatensen), polythiazide ( These include diuretics such as Renese, indapamide (Lozol), cyclothiazide (Anhydron), hydroflumethiazide (Diucardin), metrazone (Diulo), quinetazone (Hydromox), and trichlormethiazide (Naqua), potassium-sparing diuretics such as spironolactone (Aldactone), triamterene (Dyrenium), and amyloride (Midamor), and osmotic diuretics such as mannitol (Osmitrol). Various classes of diuretics are known and described in the literature.

[0211] Cardiac glycosides (cardinolides) or other digitalis preparations can be administered concurrently with the compounds of this disclosure. Useful cardiac glycosides include, for example, digitoxin (Crystodigin), digoxin (Lanoxin), or deslanoside (Cedilanid-D). Various classes of cardiac glycosides have been documented in the literature.

[0212] Angiotensin-converting enzyme inhibitors (ACE inhibitors) can be administered concurrently with the compounds disclosed herein. Useful ACE inhibitors include, for example, captopril (Capoten), enalapril (Vasotec), and lisinopril (Prinivil). Various classes of ACE inhibitors have been documented in the literature.

[0213] Angiotensin-2 receptor antagonists (also known as AT1 antagonists, angiotensin receptor blockers, or ARBs) can be administered concurrently with the compounds disclosed herein. Useful angiotensin-2 receptor antagonists include, for example, candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), telmisartan (Micardis), and valsartan (Diovan). Various classes of angiotensin-2 receptor antagonists have been described in the literature.

[0214] Calcium channel blockers, for example, amlodipine (Norvasc, Lotrel), bepridil (Vascor), diltiazem (Cardizem, Tiazac), felodipine (Plendil), nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine (Sular), verapamil (Calan, Isoptin, Verelan), and for example, European Patent No. 625162B1, U.S. Patent No. 5,364,842, U.S. Patent No. 5,587,454, U.S. Patent No. 5,824,645, U.S. Patent No. 5,859,186, U.S. Patent No. 5,994,305, U.S. Patent No. 6,087,091, U.S. Patent No. 6,136,786, WO93 / 131 Related compounds described in 28A1, European Patent No. 1336409A1, European Patent No. 835126A1, European Patent No. 835126B1, U.S. Patent No. 5,795,864, U.S. Patent No. 5,891,849, U.S. Patent No. 6,054,429, and WO97 / 01351A1 (the entirety of which is incorporated herein by reference for any relevant and consistent purpose) may be used in conjunction with the compounds of this disclosure.

[0215] Beta-blockers can be administered concurrently with the compounds of this disclosure. Useful beta-blockers include, for example, acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol / hydrochlorothiazide (Ziac), bisoprolol (Zebeta), carteolol (Cartrol), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), and timolol (Blocadren). Various classes of beta-blockers have been documented in the literature.

[0216] PPAR gamma agonists, such as thiazolidinediones (also known as glitazone), can be administered concurrently with the compounds of this disclosure. Useful PPAR agonists include, for example, rosiglitazone (Avandia), pioglitazone (Actos), and riboglitazone.

[0217] Aldosterone antagonists can be administered concurrently with the compounds of this disclosure. Particularly useful aldosterone antagonists include, for example, eplerenone, spironolactone, and canrenone.

[0218] Renin inhibitors can be administered concurrently with the compounds of this disclosure. A particularly useful renin inhibitor is, for example, aliskiren.

[0219] Alpha-blockers can be administered concurrently with the compounds of this disclosure. Useful alpha-blockers include, for example, doxazosin mesylate (Cardura), prazosin hydrochloride (Minipress), prazosin and polythiazide (Minizide), and terazosin hydrochloride (Hytrin). Various classes of alpha-blockers have been described in the literature.

[0220] Central alpha agonists can be administered concurrently with the compounds of this disclosure. Useful central alpha agonists include, for example, clonidine hydrochloride (Catapres), clonidine hydrochloride and chlorthalidone (Clorpres, Combipres), guanabenz acetate (Wytensin), guanfacine hydrochloride (Tenex), methyldopa (Aldomet), methyldopa and chlorothiazide (Aldochlor), and methyldopa and hydrochlorothiazide (Aldoril). Various classes of central alpha agonists have been described in the literature.

[0221] Vasodilators can be administered concurrently with the compounds of this disclosure. Useful vasodilators include, for example, isosorbide dinitrate (Isordil), nesiritide (Natrecor), hydralazine (Apresoline), nitrate / nitroglycerin, and minoxidil (Loniten). Various classes of vasodilators have been described in the literature.

[0222] Anticoagulants can be administered concurrently with the compounds disclosed herein. Useful anticoagulants include, for example, warfarin (coumadin) and heparin. Various classes of anticoagulants are described in the literature.

[0223] Antiplatelet agents can be administered concurrently with the compounds disclosed herein. Useful antiplatelet agents include, for example, cyclooxygenase inhibitors (aspirin), adenosine diphosphate (ADP) receptor inhibitors [clopidogrel (Plavix), ticlopidine (Ticlid)], phosphodiesterase inhibitors [cilostazol (Pletal)], glycoprotein IIB / IIIA inhibitors [abcisimab (ReoPro), eptifivatide (Integrilin), tirofiban (Aggrastat), defibrotide], and adenosine reuptake inhibitors [dipyridamole (Persantine)]. Various classes of antiplatelet agents are described in the literature.

[0224] Lipid-lowering agents can be administered concurrently with the compounds of this disclosure. Useful lipid-lowering drugs include, for example, statins (HMG CoA reductase inhibitors) [atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altoprev), pravastatin (Pravachol), rosuvastatin calcium (Crestor), simvastatin (Zocor)], selective cholesterol absorption inhibitors [ezetimibe (Zetia)], resins (bile acid inhibitors or bile acid binders) [cholestyramine (Questran, Questran Light, Prevalite, Locholest, Locholest Light), colestipol (Colestid), coleseveram hydrochloride (WelChol)], fibrates (fibric acid derivatives) [genfibrozil (Lopid), fenofibrate (Antara, Lofibra, Tricor, and Triglide), clofibrate (Atromid-S)], and niacin (nicotinic acid). Various classes of lipid-lowering drugs are described in the literature.

[0225] The compounds of this disclosure can be used in combination with peptides or peptide analogs that activate guanylate cyclase receptors in the intestine, resulting in an increase in intracellular messenger 2 or cyclic guanosine monophosphate (cGMP), along with increased secretion of chloride and bicarbonate into the intestinal lumen and associated increased fluid secretion. Examples of such peptides include linaclotide (MD-1100 acetate), the endogenous hormones guanylin and uroguanilin, and intestinal bacterial peptides (ST peptides) of the thermostable enterotoxin family, as well as those described herein by reference in their entirety for any relevant and consistent purpose, U.S. Patents 5,140102, 5,489670, 5969097, WO2006 / 001931A2, WO2008 / 002971A2, WO2008 / 106429A2, US2008 / 0227685A1 and U.S. Patent 7,041786.

[0226] The compounds of this disclosure can be used in combination with type II chloride channel agonists such as Lubiprostone and other related compounds described in U.S. Patent No. 6,414,016, which is incorporated herein by reference for any relevant and consistent purpose.

[0227] The compounds described herein can be used in combination therapy with drugs used to treat obesity, T2DM, metabolic syndromes, and other conditions. Useful drugs include insulin; insulin secretagogues such as sulfonylurea; glucose-lowering agents such as metformin; peroxisome proliferator-activated receptor γ (PPARγ) activators such as thiazolidinedione; dipeptidyl peptidase-4 inhibitors such as sitagliptin; and incretin-based drugs including synthetic incretin mimetic substances such as liraglutide and exenatide; alpha-glucosidase inhibitors such as acarbose; and glinides such as repaglinide and nateglinide.

[0228] The compounds of this disclosure can be used in combination with P2Y2 receptor agonists, such as those described herein in their entirety for any relevant and consistent purpose, including those described herein by reference, European Patent No. 1196396B1 and U.S. Patent No. 6624150.

[0229] Other drugs include natriuretic peptides such as nesiritide, recombinant brain natriuretic peptide (BNP), and atrial natriuretic peptide (ANP). Vasopressin receptor antagonists such as tolvaptan and conivaptan, as well as phosphate binders such as Renagel, Lenreva, Foslo, and Fosrenol, may be administered concurrently. Other drugs include phosphate transport inhibitors (US Patent Nos. 4,806,532; 6,355,823; 6,787,528; 7,119,120; 7,109,184; US Patent Application Publication Nos. 2007 / 021509; 2006 / 0280719; 2006 / 0217426; International Patent Application Publications WO2001 / 005398, WO2001 / 087294, WO2001 This includes patents such as WO2002 / 028353, WO2003 / 048134, WO2003 / 057225, WO2003 / 080630, WO2004 / 085448, WO2004 / 085382; European Patent Nos. 1465638 and 1485391; and Japanese Patent No. 2007131532), or phosphate transport antagonists such as nicotinamide.

[0230] 2. Gastrointestinal disorders As previously described, the compounds described herein can be used alone or in combination with other agents. For example, the compounds can be administered together with analgesic peptides or compounds. The analgesic peptides or compounds may be covalently bonded to the compounds described herein, or they may be other agents administered together with or sequentially with the compounds described herein in combination therapy.

[0231] Combination therapy can be achieved by administering two or more drugs, for example, a substantially impermeable or substantially unbiogenic NHE inhibitor compound described herein, each formulated and administered separately, and an analgesic peptide or compound, or by administering two or more drugs in a single formulation. Other combinations are also included in combination therapy. For example, two drugs may be formulated together and administered with another formulation containing a third drug. Two or more drugs in combination therapy may be administered simultaneously, but this is not required. For example, the administration of the first drug (or combination of drugs) may be minutes, hours, days, or weeks before the administration of the second drug (or combination of drugs). Therefore, two or more drugs may be administered to each other within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, or 9 weeks or more of each other. In some cases, even longer intervals are possible. In many cases, it is desirable that the two or more drugs used in combination therapy be present in the patient's body at the same time, but this is not always necessary.

[0232] Combination therapy may also include two or more administrations of one or more drugs used in the combination. For example, when drug X and drug Y are used in combination, they can be administered one or more times in any combination, in any order, such as XYX, XXY, YXY, YYX, XXYY, etc.

[0233] The compounds described herein can be used in combination therapy with analgesics, such as analgesic compounds or analgesic peptides. Optionally, analgesics can be covalently bonded to the compounds described herein. Useful analgesics include, for example, calcium channel blockers, 5HT3 agonists (e.g., MCK-733), and 5HT4 agonists (e.g., tegaserodone, plutonium). These include calopride, 5HT1 receptor antagonists, opioid receptor agonists (loperamide, fedotodin, and fentanyl), NK1 receptor antagonists, CCK receptor agonists (e.g., roxiglumide), NK1 receptor antagonists, NK3 receptor antagonists, norepinephrine-serotonin reuptake inhibitors (NSR1), vanilloid and canavanoid receptor agonists, and sialorphine. Various classes of analgesics are described in the literature.

[0234] Opioid receptor antagonists and agonists can be administered concurrently with the compounds of the Disclosure, or they can be linked to the compounds of the Disclosure, for example, by covalent bonding. For example, opioid receptor antagonists such as naloxone, naltrexone, methylnalozone, nalmefene, cipridim, beta-fnaltrexamine, naloxonazine, naltrindol, and nor-binaltolfimine are considered useful in the treatment of opioid-induced constipation (OIC). It may also be useful to formulate this type of opioid antagonist in delayed or sustained-release formulations such that the initial release of the antagonist occurs in the mid-small intestine, terminal small intestine, and / or ascending colon. Such antagonists are described in U.S. Patent No. 6,734,188 (WO01 / 32180 A2), the entirety of which is incorporated herein by reference for any relevant and consistent purpose. Enkephalin pentapeptide (HOE825; Tyr-D-Lys-Gly-Phe-L-homoserine) is an agonist of μ- and γ-opioid receptors and is thought to be useful for increasing intestinal motility (Eur. J. Pharm., 219:445, 1992), and this peptide can be used in conjunction with the compounds of this disclosure. Trimebutine, which is thought to bind to the mu / delta / kappa-opioid receptor, activate the release of motilin, and modulate the release of gastrin, vasoactive intestinal peptides, gastrin, and glucagon, is also useful. κ-opioid receptor agonists such as phedotodin, ketocyclazosine, and compounds described in US2005 / 0176746 (WO03 / 097051A2), whose entire contents are incorporated herein by reference for any relevant and consistent purpose, can be used in conjunction with or linked to the compounds of this disclosure. In addition, μ-opioid receptor agonists such as morphine, diphenyl oxilate, flacaefamide (H-Tyr-D-Ala-Phe(F)-Phe-NH2; the entire contents of which are disclosed in WO01 / 019849A1, which is incorporated herein by reference for any relevant and consistent purpose) and loperamide may be used.

[0235] Tyr-Arg (kyotorphin) is a dipeptide that acts by stimulating the release of met-enkephalin to produce an analgesic effect (J. Biol. Chem. 262:8165, 1987). Kyotorphin can be used with or linked to the compounds of this disclosure. CCK receptor agonists such as cerulein, derived from amphibians and other species, are useful analgesics that can be used with or linked to the compounds of this disclosure.

[0236] Conotoxin peptides are a broad class of analgesic peptides, NMDA receptors, or nicotinic receptors that act on voltage-gated Ca channels. These peptides can be used with or ligated to the compounds of this disclosure.

[0237] A peptide analog of thymurin (U.S. Patent No. 7,309,690 or French Patent No. 2830451, whose entire contents are incorporated herein by reference for any relevant and consistent purpose) has analgesic activity and can be used in conjunction with or linked to the compounds of the present disclosure.

[0238] Roxiglumide and Dexroxiglumide (R isomer of roxiglumide) (the entirety of which is incorporated herein by reference for any relevant and consistent purpose of the U.S. Patent) CCK (CCKa or CCKb) receptor antagonists, including those specified in Patent No. 5,130,474 or WO88 / 05774, have analgesic activity and can be used in conjunction with or linked to the compounds of this disclosure.

[0239] Other useful analgesics include 5-HT4 agonists such as tegaserod / zelnom and rilexapride. Such agonists are described in European Patent No. 1321142A1, WO03 / 053432A1, European Patent No. 505322A1, European Patent No. 505322B1, European Patent No. 507672A1, European Patent No. 507672B1, U.S. Patent No. 5,510,353 and U.S. Patent No. 5,273,983, the entirety of which is incorporated herein by reference for any relevant and consistent purpose.

[0240] Diconotides and calcium channel blockers, such as those described herein, in their entirety incorporated herein by reference for any relevant and consistent purpose, including, for example, European Patent No. 625162B1, U.S. Patent No. 5,364,842, U.S. Patent No. 5,587,454, U.S. Patent No. 5,824,645, U.S. Patent No. 5,859,186, U.S. Patent No. 5,994,305, U.S. Patent No. 6,087,091, U.S. Patent No. 6,136,786, WO93 / 13128A1, European Patent No. 1336409A1, European Patent No. 835126A1, European Patent No. 835126B1, U.S. Patent No. 5,795,864, U.S. Patent No. 5,891,849, U.S. Patent No. 6,054,429, and WO97 / 01351A1.

[0241] Various antagonists of NK-1, NK-2, and NK-3 receptors (see Giardina et al., 2003 Drugs 6:758 for an overview) can be used with or linked to the compounds of this disclosure.

[0242] NK1 receptor antagonists such as aprepitant (Merck & Co Inc.), bofopitant, ezropitant (Pfizer, Inc.), R-673 (Hoffmann-La Roche Ltd), SR-14033, and related compounds described herein, for example, European Patent No. 873753A1, U.S. Patent Application Publication No. 20010006972A1, U.S. Patent Publication No. 20030109417A1, and WO01 / 52844A1, whose entire contents are incorporated herein by reference for any relevant and consistent purpose, may be used with or linked to the compounds of this disclosure.

[0243] NK-2 receptor antagonists such as napadutant (Menarini Ricerche SpA), saledutant (Sanofi-Synthelabo), SR-144190 (Sanofi-Synthelabo), and UK-290795 (Pfizer Inc) may be used with or linked to the compounds of this disclosure.

[0244] Osanatant (Sanofi-Synthelabo), Tarnetant, and NK3 receptor antagonists such as WO02 / 094187 A2, European Patent No. 876347A1, WO97 / 21680A1, U.S. Patent No. 6,277,862, WO98 / 11090, WO95 / 28418, WO97 / 19927, and Boden et al. (J Med.Chem.39:1664-75, 1996), whose entire contents are incorporated herein by reference for any relevant and consistent purpose, may be used with or linked to the compounds of this disclosure.

[0245] Norepinephrine-serotonin reuptake inhibitors, such as milnacipran and related compounds described in WO03 / 077897A1, which are incorporated herein by reference for any relevant and consistent purpose, may be used in conjunction with the compounds of this disclosure, or in combination with them. They can be connected.

[0246] Vanilloid receptor antagonists, such as albanil and related compounds described in WO01 / 64212A1, whose entire contents are incorporated herein by reference for any relevant and consistent purpose, may be used with or linked to the compounds of this disclosure.

[0247] The compound may be used in combination therapy with a phosphodiesterase inhibitor (an example of such an inhibitor can be found in U.S. Patent No. 6,333,354, the entirety of which is incorporated herein by reference for any relevant and consistent purpose).

[0248] The aforementioned compounds can be used alone or in combination therapy to treat disorders associated with chloride or bicarbonate secretion that can induce constipation, such as cystic fibrosis.

[0249] Alternatively, the aforementioned compounds can be used alone or in combination therapy to treat calcium-induced constipation. Constipation is commonly observed in elderly populations, particularly in osteoporosis patients who must take calcium supplements. While calcium supplements are beneficial in osteoporosis patients for restoring bone density, their associated constipation has been shown to lead to poor adherence.

[0250] The compounds of this disclosure can be used in combination with opioids. While the use of opioids is primarily directed toward pain relief, a prominent side effect is impaired GI, such as constipation. These drugs act by binding to opioid receptors found primarily in the central nervous system and the gastrointestinal tract. Receptors in these two organ systems mediate both beneficial effects and undesirable side effects (e.g., decreased bowel motility and subsequent constipation). Opioids suitable for use typically belong to one of the following exemplary classes: natural opioids, which are alkaloids found in poppy resin, including morphine, codeine, and thebaine; semi-synthetic opioids made from natural opioids such as hydromorphone, hydrocodone, oxycodone, oxymorphone, desomorphine, diacetylmorphine (heroin), nicomorphine, dipropanoylmorphine, benzylmorphine, and ethylmorphine; fully synthetic opioids such as fentanyl, pethidine, methadone, tramadol, and propoxyfene; and endogenous opioid peptides that are naturally produced in the body, such as endorphins, enkephalins, dynorphins, and endomorphine.

[0251] The compounds of this disclosure, used alone or in combination therapy, can alleviate GI impairment faced by patients with renal failure (stages 3–5). Constipation is the second most frequently reported symptom in patients in this category (Murtagh et al., 2006; Murtagh et al., 2007a; Murtagh et al., 2007b). Though not bound by theory, renal failure is thought to involve stimulation of intestinal sodium reabsorption (Hatch and Freel, 2008). Overall or partial inhibition of such transport by administration of the compounds of this disclosure may have a therapeutic effect of improving GI transit and relieving abdominal pain. In this regard, the compounds disclosed herein include angiotensin modulators: angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril, enalopril, lisinopril, ramipril) and angiotensin II receptor antagonists (also known as AT1 antagonists, angiotensin receptor blockers, or ARBs); diuretics such as loop diuretics (e.g., furosemide, bumetanide), thiazide diuretics (e.g., hydrochlorothiazide, chlorthalidone, chlorthiazide) and potassium-sparing diuretics: amiloride; beta-blockers: bisoprolol, carvedilol, nebivolol, and sustained-release metoprolol; cardiac stimulants: digoxin, dobutamine; phosphodiesterates such as milrinone. Vasopressin receptor inhibitors; vasodilators: isosorbide dinitrate / hydrazine combination; aldosterone receptor antagonists: spironolactone, eplerenone; natriuretic peptides: nesiritide, recombinant brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP); vasopressin receptor antagonists: tolvaptan and conivaptan; phosphate binders (Lenagel, Lenreva, Foslo, Fosrenol); the entire contents of which are incorporated herein by reference for any relevant and consistent purpose are U.S. Patents 4,806,532, 6,355,823, 6,787,528, WO2001 / 005398, WO2001 / 0872. It can be used in combination with phosphate transport inhibitors or phosphate transport antagonists (nicotinamides), such as those described in 94, WO2001 / 082924, WO2002 / 028353, WO2003 / 048134, WO2003 / 057225, U.S. Patent No. 7,119120, European Patent No. 1,465638, U.S. Patent Application Publication No. 2007 / 021509, WO2003 / 080630, U.S. Patent No. 7,109184, U.S. Patent Application Publication No. 2006 / 0280719, European Patent No. 1,485391, WO2004 / 085448, WO2004 / 085382, U.S. Patent Application Publication No. 2006 / 0217426, and Japanese Patent No. 2007 / 131532.

[0252] The compounds of this disclosure can be used in combination with peptides or peptide analogs that activate guanylate cyclase receptors in the intestines, resulting in an increase in intracellular messenger 2 or cyclic guanosine monophosphate (cGMP), along with increased chloride and bicarbonate secretion into the intestinal lumen and associated fluid secretion. Examples of such peptides include linaclotide (MD-1100 acetate), the endogenous hormones guanylin and uroguanylin, and the thermostable enterotoxin family of intestinal bacterial peptides (ST peptides), as well as U.S. Patents 5,140102, 5,489670, 5969097, WO2006 / 001931A2, WO2008 / 002971A2, WO2008 / 106429A2, U.S. Patent Application Publication 2008 / 0227685A1 and U.S. Patent Application Publication 7,041786, the entire contents of which are incorporated herein by reference for any relevant and consistent purpose.

[0253] The compounds of this disclosure can be used in combination with type II chloride channel agonists such as Amitiza (rubiprostone) and other related compounds described in U.S. Patent No. 6,414,016, which is incorporated herein by reference for any relevant and consistent purpose.

[0254] The compounds of this disclosure can be used in combination with P2Y2 receptor agonists, such as those described herein in their entirety for any relevant and consistent purpose, including those described herein by reference, European Patent No. 1196396B1 and U.S. Patent No. 6624150.

[0255] The compounds of this disclosure can be used in combination with bulking laxatives, such as stool softeners / surfactants like psyllium husk (Metamucil), methylcellulose (Citrucel), polycarbophil, dietary fiber, apple, and doxate (Colace, Diocto); wettable powders (isotonic agents) such as dibasic sodium phosphate, magnesium citrate, magnesium hydroxide (magnesia milk), magnesium sulfate (Epsom salt), monobasic sodium phosphate, and sodium biphosphate; and osmotic agents such as glycerin suppositories, sorbitol, lactulose, and polyethylene glycol (PEG). The compounds of this disclosure can also be used in combination with agents that stimulate intestinal peristalsis, such as bisacodyl tablets (Dulcolax), casanthranol, senna, and aloin derived from aloe vera.

[0256] In one embodiment, the compounds disclosed herein do not substantially affect the gastric residence time. In other words, it has no significant effect on gastric emptying time and promotes gastrointestinal transit, and more specifically, transit through the colon. More specifically, the compounds of the present invention restore colonic transit without side effects associated with delayed gastric emptying time, such as nausea. GI and colonic transit, e.g., Burton DD, Camilleri M, Mullan BP et al., J. Nucl. Med., 1997;38:1807-1810; Cremonini F, Mullan BP, Camilleri M et al., Aliment. Pharmacol. Ther., 2002; 16:1781-1790; AR,Gastroenterology,1992;103:36-42;Bouras EP,Camilleri M,Burton DD et al.,Gastroenterology,2001;120:354-360;Coulie B,Szarka LA,Camilleri M et The measurement is performed in patients using the methods reported in al., Gastroenterology, 2000;119:41-50; Prather CM, Camilleri M, Zinsmeister AR, et al., Gastroenterology, 2000;118:463-468; and Camilleri M, McKinzie S, Fox J et al., Clin. Gastroenterol. Hepatol., 2004;2:895-904.

[0257] C. Polymer combination therapy The NHE inhibitor compounds described herein can be administered to patients in need with a liquid absorbent polymer ("FAP"). Intestinal liquid absorbent polymers useful for administration according to embodiments of this disclosure can be orally administered in combination with non-absorbable NHE inhibitors (e.g., NHE-3 inhibitors) to allow absorption of intestinal fluid resulting from the action of sodium transport inhibitors. Such polymers swell in the colon and bind to body fluids, giving the stool a consistency acceptable to the patient. The liquid absorbent polymers described herein can be selected from polymers having laxative properties, also known as bulking agents (i.e., polymers that retain some intestinal fluid in the stool, providing a higher degree of hydration to the stool and facilitating its passage). Optionally, the liquid absorbent polymer can also be selected from pharmaceutical polymers with antidiarrheal properties, i.e., agents that maintain some consistency in the stool to avoid watery stools or potential incontinence.

[0258] The ability of polymers to maintain a specific consistency in feces with a high liquid content can be characterized by their "water retention capacity." Wenzl et al. (Determinants of decreased fecal consistency in patients with diarrhea; Gastroenterology, v.108, no.6, p.1729-1738 (1995)) studied the determinants controlling fecal consistency in patients with diarrhea and found that they narrowly correlate with the water retention capacity of feces. Water retention capacity is determined as the water content of a given feces that achieves a specific level of consistency after centrifuging a specific number of grams of reconstituted fecal material (corresponding to the consistency of the "formed feces"). Although not bound by any particular theory, it was found that the water retention capacity of feces increases with the intake of a specific polymer having a given liquid absorption profile. More specifically, it was found that the water retention capacity of the polymer correlates with its liquid absorption capacity (AUL) under load; and even more specifically, the AUL of the polymer exceeds 15 g of isotonic liquid per gram of polymer under a static pressure of 5 kPa or 10 kPa.

[0259] The FAP used in the treatment method of this disclosure also has an isotonic liquid absorption capacity of at least about 10 g, about 15 g, about 20 g, or about 25 g per g of polymer at a static pressure of about 5 kPa or about 10 kPa, and may have a liquid absorption capacity of about 20 g, about 25 g or more, as determined by means commonly known in the art. In addition, or by other means, the FAP has a minimum consistency in the fecal material, and in some embodiments, when the non-water-soluble solid fraction of the feces is 10% to 20%, and the polymer concentration is 1% to 5% of the weight of the feces, The polymer may be given a consistency graded "soft" on the scale described in the following test methods. The determination of the non-water-soluble solid fraction of feces is described in Wenz et al. The polymer may be uncharged or have a low charge density (e.g., 1-2 meq / gr). Alternatively, or in addition, the polymer can be delivered directly to the colon using known delivery methods to avoid premature bloating in the esophagus.

[0260] In one embodiment of this disclosure, FAP is a “superabsorbent” polymer (i.e., a lightly crosslinked, partially neutralized polyelectrolyte hydrogel, similar to those used in infant diapers, feminine hygiene products, agricultural additives, etc.). The superabsorbent polymer can be prepared from a lightly crosslinked polyacrylic acid hydrogel. The expansion of the polymer is driven by two effects: (i) the entropy of hydration and mixing of the polymer backbone and (ii) the osmotic pressure arising from counterions (e.g., Na ions) within the gel. The swelling ratio of the gel at equilibrium is controlled by the elastic resistance inherent in the polymer network and by the chemical potential of the bath solution; i.e., the background electrolyte will de-expand at higher salt concentrations because it reduces the apparent charge density on the polymer and decreases the difference in free ion concentration between the inside and outside of the gel that drives the osmotic pressure. The swelling ratio SR (liquid (g) per gram of dry polymer, synonymous with "liquid absorbency") can vary from 1000 in pure water to 30 in a 0.9% NaCl solution, which is used as a substitute for physiological saline (i.e., isotonic). SR may increase with the degree of neutralization and decrease with the crosslink density. Generally, SR decreases with the applied load, which depends on the gel's strength, i.e., the degree of reduction, which is dependent on the crosslink density. The salt concentration within the gel may be lower than that in the external solution as a result of the Donnan effect due to the internal potential.

[0261] The liquid-absorbing polymer may include liquid-absorbing crosslinked polyacrylic acids, such as those prepared from α,β-ethylene unsaturated monomers, including monocarboxylic acids, polycarboxylic acids, acrylamides, and their derivatives. These polymers may have repeating units of acrylic acid, methacrylic acid, metal salts of acrylic acid, acrylamide, and acrylamide derivatives (e.g., 2-acrylamido-2-methylpropanesulfonic acid), and various combinations of such repeating units as copolymers. Such derivatives include acrylic acid polymers containing hydrophilic grafts of polymers such as polyvinyl alcohol. Examples of suitable polymers and processes for preparing such polymers, including gel polymerization processes, are incorporated herein by reference for any relevant and consistent purposes, U.S. Patent Nos. 3,997,484; 3,926,891; 3,935,099; 4,090,013; 4,093,776; 4,340,706; 4,446,261; 4,683,274; and 4 Disclosed in Patent Nos. 459,396; Nos. 4,708,997; Nos. 4,076,663; Nos. 4,190,562; Nos. 4,286,082; Nos. 4,857,610; Nos. 4,985,518; Nos. 5,145,906; Nos. 5,629,377 and Nos. 6,908,609 (see also Buchholz, FLand Graham, AT, “Modern Superabsorbent Polymer Technology,” John Wiley & Sons (1998), which is also incorporated herein by reference for all relevant and consistent purposes). A preferred class of polymers for therapy in combination with NHE inhibitors is polyelectrolytes.

[0262] The degree of crosslinking may vary considerably depending on the specific polymer material; however, in many applications, the superabsorbent polymer in question is only lightly crosslinked, i.e., the degree of crosslinking is such that the polymer can still absorb more than 10 times its weight in physiological saline (i.e., 0.9% salt water). For example, such polymers typically contain less than about 0.2 mol% of the crosslinking agent.

[0263] In some embodiments, the FAPs used for treatment are calcium carbophyl (registration number: 9003-97-8, also known as Carbopol EX-83) and Carbopol 934P.

[0264] In some embodiments, the liquid-absorbing polymer is prepared by a high internal emulsification ("HIPE") process. The HIPE process induces a polymer buoyancy slab having a very large porous fraction (about 100 μm) of internally connected large voids (i.e., an open-cell structure). This technique produces a flexible and collapsible buoyancy material with exceptional intake pressure and liquid absorption (see U.S. Patents 5,650,222; 5,763,499 and 6,107,356, incorporated herein by reference for all relevant consistent purposes). The polymer is hydrophobic and therefore its surface should be modified to be moistened with aqueous liquids. This is achieved by post-treating the buoyancy material with a surfactant to reduce interfacial tension. These materials are claimed to be less conforming to load, i.e., they do not de-expand much under static pressure.

[0265] In some embodiments, liquid absorbent gels are prepared by aqueous free radical polymerization of acrylamide or its derivatives, a crosslinking agent (e.g., methylene-bis-acrylamide), and a free radical redox initiation system in water. This material is obtained as a slab. Typically, the swelling ratio of crosslinked polyacrylamide at low crosslinking densities (e.g., 2%-4% when expressed as wt% of methylene-bis-acrylamide) is 25-40 (F. Horkay, Macromolecules, 22, pp. 2007-09 (1989)). The expansion properties of these polymers have been widely studied and are essentially the same as those of crosslinked polyacrylic acid at high salt concentrations. Under these conditions, osmotic pressure is zero due to the presence of counterions, and expansion is controlled by the free energy of mixing and the elastic energy of the network. In other words, a crosslinked polyacrylamide gel with the same crosslinking density as neutralized polyacrylic acid would exhibit the same swelling ratio (i.e., liquid absorption properties), and it is thought to have similar de-expansion properties under pressure as a crosslinked polymer electrolyte with a high salt content (e.g., 1 M). The properties of a neutral hydrogel (e.g., swelling) would not be sensitive to a saline environment as long as the polymer remains in good solvent conditions. While not bound by any particular theory, it is assumed that the liquid contained within the gel has the same salt composition as the surrounding liquid (i.e., there is no salt distribution due to the Donnan effect).

[0266] Another subclass of liquid-absorbing polymers that can be used is hydrogel material containing N-alkylacrylamide polymers (e.g., N-isopropylacrylamide (NIPAM)). The corresponding aqueous poly-NIPAM hydrogel exhibits a temperature transition at approximately 35°C. Above this temperature, the hydrogel may collapse. The mechanism is generally reversible, and when the temperature returns to room temperature, the gel re-expands to its original swelling ratio. This makes it possible to produce nanoparticles by emulsion polymerization (R. Pelton, Advances in Colloid and Interface Science, 85, pp.1-33, (2000)). The expansion characteristics of poly-NIPAM nanoparticles below the transition temperature have been reported, and are similar to those reported for poly-NIPAM bulk gels and equivalent to those found for polyacrylamide (i.e., 30-50 g / g) (W. McPhee, Journal of Colloid and Interface Science, 156, pp.24-30 (1993); and K. Oh, Journal of Applied Polymer Science, 69, pp. 109-114 (1997)).

[0267] In some embodiments, FAP used in combination with NHE inhibitors for treatment is used for the treatment of obesity (J. Chen, Journal of Controlled Release, 65, pp. 73-82 (2000)), or for the delivery of protein in the stomach. This is a superporous gel that can delay void discharge. A polyacrylic acid-based SAP with a macroporous structure may also be used. Macroporous SAP and superporous gels differ in that the porous structure remains almost intact in the dry state for superporous gels, while it disappears during drying for macroporous SAPs. Although the preparation methods differ, both methods use a foaming agent (e.g., a carbonate that generates CO2 bubbles during polymerization). The typical swelling ratio SR of superporous materials is about 10. Superporous gels retain a large internal pore volume in the dry state.

[0268] Macroporous hydrogels can also be formed using a method that induces polymer phase separation using a non-solvent. This polymer may be poly-NIPAM, and the non-solvent used may be glucose (see, e.g., Z. Zhang, J. Org. Chem., 69, 23 (2004)) or NaCl (see, e.g., Cheng et al., Journal of Biomedical Materials Research - Part A, Vol. 67, Issue 1, 1 October 2003, Pages 96-103). Phase separation induced by the presence of NaCl results in an increase in the swelling ratio. These materials are preferred if the swelling ratio of the material, the SR is maintained in a salt isotonic solution, and the gel does not collapse under load. The "service" temperature should be shifted below body temperature, for example, by diluting the NIPAM in a polymer having monomers that lack a transition temperature phenomenon.

[0269] In some embodiments, the liquid-absorbing polymer can be selected from certain natural polymers, such as those containing a carbohydrate moiety. In one preferred embodiment, such a carbohydrate-containing hydrogel is non-digestible and has a low fraction of soluble material and a high fraction of gel-forming material. In some embodiments, the liquid-absorbing polymer is selected from xanthan gum, guar, welane, hemicellulose, alkylcellulose, hydroalkylcellulose, carboxyalkylcellulose, carrageenan, dextran, hyaluronic acid, and agarose. In one preferred embodiment, the gel-forming polymer is plantain. Plantain (or "Ispacula") is a common name used for several members of the genus Plantago, whose seeds are commercially used in the manufacture of rubber cement. The liquid-absorbing polymer is found in the gel-forming fraction of plantain, namely, the neutral sugar copolymer of arabinose (25%) and xylose (75%) described in U.S. Patents No. 6,287,609; No. 7,026,303; No. 5,126,150; No. 5,445,831; No. 7,014,862; No. 4,766,004; No. 4,999,200, respectively, which are incorporated herein by reference for any relevant and consistent purpose, as well as the trade name Metamucil (The Procter and It is found in over-the-counter psyllium-containing medications, such as those sold under the name of Gamble. Psyllium-containing dosage forms are also suitable for chewing, as the chewing action disintegrates the tablet into smaller, separate particles before swallowing, but undergoes minimal gelation in the mouth, resulting in an acceptable texture and good aesthetics that are understandable to patients.

[0270] The psyllium-containing dosage forms contain physically distinct units suitable as unit dosage forms for human subjects and other mammals, each containing a predetermined amount of active material (e.g., gel-forming polysaccharides) calculated to produce the desired therapeutic effect. Suitable solid oral dosage forms for this composition include tablets, pills, capsules, lozenges, chewable tablets, troches, cachets, pellets, wafers, and the like.

[0271] In some embodiments, FAP is a polysaccharide particle whose polysaccharide component includes xylose and arabinose. The ratio of xylose to arabinose may be at least about 3:1 by weight, as described in U.S. Patents 6,287,609; 7,026,303 and 7,014,862, each incorporated herein for any relevant and consistent purpose.

[0272] The liquid absorbent polymers described herein can be used in combination with NHE inhibitors or pharmaceutical compositions containing them. NHE inhibitors and FAPs may be administered together with other agents, including those described under the heading "Combination Therapies," without departing from the scope of this disclosure. As described above, NHE inhibitors may be administered alone without the use of liquid absorbent polymers to resolve symptoms without causing severe diarrhea or fluid secretion into the feces, which may require the co-administration of liquid absorbent polymers.

[0273] The liquid absorbent polymers described herein can be selected so as not to induce any substantial interaction with NHE inhibitor compounds or pharmaceutical compositions containing them. Where used herein, “substantial interaction” generally means that co-administration of the FAP polymer does not substantially alter (i.e., substantially decrease or substantia...

Claims

1. 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]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)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamide]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[(4-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidine-3-yl]methoxy]pyridine-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]pyrrolidine-3-yl]methoxy]pyridine-2-yl)methyl]carbamoyl]amino)butyl]urea; 3-[(4-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrroridine-3-yl]methoxy]pyridine-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]pyrrolidine-3-yl]methoxy]pyridine-2-yl)methyl]carbamoyl]amino)butyl]urea; 3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]pyrrolidine-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)sulfonamide]pyrrolidine-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea; 3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]pyrrolidine-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)sulfonamide]pyrrolidine-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea; 1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamide]-2-oxopyrrolidine-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)sulfonamide]-2-oxopyrrolidine-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]-3-fluorobenzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]-3-fluorobenzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)piperidine-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidine-4-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-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-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-2,13-dimethyl-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl]pyrrolidine-3-yl]benzenesulfonamide; N1,N14-bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide; N1,N14-bis(2-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide; N1,N18-bis(1-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)piperidine-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide]piperidine-1-yl)-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl]piperidine-4-yl)benzenesulfonamide; N1,N18-bis([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide; N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-1-[16-(4-[([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)carbamoyl]piperidine-1-yl)-5,12-dioxo-4,6,11,13-tetraazahexadecyl]piperidine-4-carboxamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-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]heptane-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-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]heptane-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-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-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-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-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazine-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-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazine-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-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazine-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-dimethylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazine-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-dimethylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-2-oxopiperidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)-2-oxopiperidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-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-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)ethoxy]ethoxy)ethyl]ureido)cyclohexyl]ureido)ethoxy]ethoxy)ethyl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(18-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(4-[3-(4-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)piperidine-1-yl]-4-oxobutyl)ureido]butanoyl)piperidine-4-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[19-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecyl]benzenesulfonamide; 4-([(1S,2S)-4-cyano-6-methyl-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-4-cyano-6-methyl-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide; 1,1'-(butane-1,4-diyl)bis[3-(4-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-yl]-4-oxobutyl)urea]; 1,1'-(butane-1,4-diyl)bis[3-(4-[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-yl]-4-oxobutyl)urea]; N,N'-(6,14-dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide]; N,N'-(6,14-dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide]; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-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-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-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-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidine-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)piperidine-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidine-4-yl]benzenesulfonamide; N1,N14-bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)piperidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)piperidine-4-yl]benzenesulfonamide; 1,1'-(butane-1,4-diyl)bis(3-[2-(2-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindorin-2-yl]ethoxy)ethyl]urea); 1,1'-(butane-1,4-diyl)bis(3-[2-(2-[5-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindorin-2-yl]ethoxy)ethyl]urea). 3-(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}(2,3,5,6-2H4)benzenesulfonamide)pyrrolidine-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}(2,3,5,6-2H4 )Benzene sulfonamide)pyrrolidine-1-yl]ethoxyethyl)carbamoyl]amino}(1,1,2,2,3,3,4,4-2H8)butyl)urea; 3-(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]ethoxy}ethyl)carbamoyl]amino}(1,1,2,2,3,3,4,4-2H8)butyl)urea; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-2-oxoazepan-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)-2-oxoazepan-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[2-(2-[2-(3-[(1s,4s)-4-(3-[2-(2-[2-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)ethoxy]ethoxy)ethyl]ureido)cyclohexyl]ureido)ethoxy]ethoxy)ethyl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(18-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidine-3-yl]benzenesulfonamide; (S)-N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-1-(20-[(S)-3-[([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)carbamoyl]pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-carboxamide; (R)-N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-1-(20-[(R)-3-[([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)carbamoyl]pyrrolidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)pyrrolidine-3-carboxamide, An oral pharmaceutical composition comprising a compound selected from the group consisting of a pharmaceutically acceptable salt thereof.

2. The oral pharmaceutical composition according to claim 1, wherein the compound is in the form of a free base.

3. The oral pharmaceutical composition according to claim 1, wherein the compound is a free base compound of 3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea.

4. The oral pharmaceutical composition according to claim 1, wherein the compound is a free base compound of N-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]-2-oxoethyl}-2-({[4-({[({2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidine-1-yl]-2-oxoethyl}carbamoyl)methyl]carbamoyl}amino)butyl]carbamoyl}amino)acetamide.

5. The oral pharmaceutical composition according to claim 1, wherein the compound is a free base compound of 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(4-[3-(4-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)piperidine-1-yl]-4-oxobutyl)ureido]butanoyl)piperidine-4-yl]benzenesulfonamide.

6. The oral pharmaceutical composition according to claim 1, wherein the compound is a free base compound of 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(18-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazine-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidine-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidine-3-yl]benzenesulfonamide.

7. The oral pharmaceutical composition according to claim 1, wherein the compound is a free base compound of 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazine-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)piperidine-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazycosyl)piperidine-4-yl]benzenesulfonamide.

8. The oral pharmaceutical composition according to any one of claims 1 to 7, wherein the oral pharmaceutical composition is a tablet.

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