Compounds useful for treating gastrointestinal tract disorders

Abstract

To provide methods for the treatment of disorders.SOLUTION: The present disclosure is directed to compounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist- induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders.SELECTED DRAWING: Figure 2

Description

[Technical field]

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

[0002] FIELD OF THEINVENTION The present disclosure relates to indan derivatives that are substantially active in the gastrointestinal tract to inhibit NHE-mediated antiport of sodium and hydrogen ions, and 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 alleviation of pain associated with gastrointestinal disorders. [Background technology]

[0003] Disorders associated with fluid retention and salt overload According to the American Heart Association, over 5 million Americans suffer from heart failure, and an estimated 550,000 cases of congestive heart failure (CHF) occur each year (Schocken, D. D. 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 due to contractile dysfunction of the myocardium. The main cause of CHF is due to ischemic coronary artery disease with or without infarction. Long-term hypertension, especially if not well controlled, can lead to CHF.

[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 reduced cardiac output, resulting in increased plasma renin, angiotensin II, and aldosterone levels. As blood volume in the heart increases, cardiac output increases proportionately until the heart cannot expand any further. In heart failure, contractility is reduced so the heart operates at higher volumes and higher filling pressures to maintain output. Filling pressures can eventually rise to levels that cause fluid leakage into the lungs and congestive symptoms (e.g., edema, shortness of breath). All of these symptoms are related to volume and salt retention, and this chronic fluid and salt overload further contributes to disease progression.

[0005] Compliance with medication regimens and dietary sodium restriction is an important component of self-management in patients with heart failure and may increase life expectancy, reduce hospital stays, and improve quality of life. Doctors often recommend that people with heart failure maintain a salt intake of less than 2.3g per day and no more than 2g per day. Many people consume significantly more than this, so people with congestive heart failure may need to find ways to reduce their dietary salt intake.

[0006] For patients suffering from CHF, several drug therapies currently exist. For example, diuretics may be used or administered to relieve congestion by reducing the volume and, therefore, the filling pressure below the filling pressure that results in pulmonary edema. By countering the volume increase, diuretics reduce cardiac output; however, fatigue and dizziness may replace CHF symptoms. Currently used diuretic classes or types include thiazides. Thiazides inhibit the transport of NaCl to the kidney, thereby preventing Na reabsorption in the cortical dilution segments at the terminal portion of the loop of Henle and the proximal portion of the distal tubule. However, these drugs are not effective when the glomerular filtration rate (GFR) is less than 30 ml / min. In addition, thiazides, as well as other diuretics, may result in hypokalemia. Currently used diuretic classes or types also include 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, thus preventing Na reabsorption in the loop of Henle.

[0007] Patients with persistent edema despite receiving high doses of diuretics are or may become diuretic resistant. Diuretic resistance may be due to insufficient utilization of the drug. In patients with renal failure, which has a high incidence in the CHF population, endogenous acid competes with loop diuretics such as furosemide for the organic acid secretion pathway in the tubular lumen of the nephron. Thus, higher doses or continuous infusions are required to achieve sufficient drug entry into the nephron. However, recent meta-analyses have led to increased awareness of the long-term risks of long-term use of diuretics 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 hospitalization in ambulatory elderly patients with heart failure receiving angiotensin-converting enzyme inhibitors and diuretics.

[0008] Angiotensin-converting enzyme ("ACE") inhibitors are an example of another 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 result in a response of the renal system by releasing renin, which then converts angiotensinogen to angiotensin I. ACE converts angiotensin I to angiotensin II. Angiotensin II stimulates the hypothalamic thirst center, causing vasoconstriction, thus increasing blood pressure and venous return. Angiotensin II also causes the release of aldosterone, which causes reabsorption of Na and the concomitant passive reabsorption of fluid, 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 resistance. ACE inhibitors have shown survival benefits and were traditionally the treatment of choice for CHF. However, one of the side effects of their use is hyperkalemia, since ACE inhibitors reduce aldosterone, a K-secreting hormone. In addition, ACE inhibitors have been shown to induce acute renal failure in certain categories of CHF patients (see, for example, C.S.Cruz 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 results in large fluctuations in weight because fluids and salts are produced by the body (sodium 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 also to regulate salt and fluid homeostasis. However, symptomatic intradialytic hypotension (SIH) can occur when patients are overdialyzed. SIH is demonstrated 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 in hypertensive and CHF patients, salt and fluid dietary restriction is highly recommended, but is rarely followed due to low palatability of low-salt foods.

[0010] The cause of primary or "essential" hypertension is elusive. However, several observations point to the kidney as a major contributing factor. The strongest data on excess salt intake and hypertension come from INTERSALT, a cross-sectional study of over 10,000 participants. For individuals, a significant, positive, independent linear relationship between 24-hour sodium excretion and systolic blood pressure was found. Higher individual 24-hour urinary sodium excretion was found to be associated with higher systolic / diastolic blood pressure of 6-3 / 3-0 mmHg on average. Primary hypertension is a classic example of a complex, multifactorial, and polygenic trait. All of these monogenic hypertension syndromes are virtually confined to mutated genes involving gain of function of various components of the renin-angiotensin-aldosterone system, resulting in excess renal sodium retention. Broadly speaking, these syndromes are characterized by a primary defect in the sodium transport system or increased renal sodium reabsorption that occurs via stimulation of mineralocorticoid receptor activity (Altun, B., and M. Arici, 2006, Salt and (Blood Pressure: Time to Challenge; Cardiology, v. 105, no. 1, p. 9-16 (2006)). A large number of controlled studies have been conducted in hypertensive subjects over the last 30 years to determine whether sodium reduction reduces established hypertension. Meta-analyses of these studies have clearly demonstrated a significant reduction in blood pressure in hypertensive patients.

[0011] In end-stage liver disease (ESLD), fluid accumulation as ascites, edema, or pleural effusion due to cirrhosis is common and results from a disturbance in the extracellular fluid volume regulation. Fluid retention is the most common complication of ESLD, occurring in approximately 50% of patients within 10 years of the diagnosis of cirrhosis. This complication significantly worsens the quality of life of patients with cirrhosis and is associated with a poor prognosis. The 1- 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 claims that the initial event in ascites production in patients with cirrhosis is sinusoidal hypertension. Portal hypertension due to increased sinusoidal pressure activates vasodilator mechanisms. In advanced stages of cirrhosis, arteriolar vasodilation leads to underfilling of the systemic arterial vascular space. This event induces a fall in arterial pressure through a decrease in effective blood volume. This results in activation of the renin-angiotensin-aldosterone system, the baroreceptors of the sympathetic nervous system, and nonosmotic release of antidiuretic hormone, restoring normal blood homeostasis. These events result in further retention of renal sodium and fluid. Splanchnic vasodilation exceeds the capacity of the lymphatic transport system, increasing splanchnic lymph production and inducing lymphatic leakage into the peritoneal cavity. Persistent renal sodium and fluid retention, along with increased splanchnic vascular permeability along with lymphatic leakage into the peritoneal cavity, play a major role in the persistent production of ascites.

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

[0013] In view of the above, it is recognized that salt and fluid retention contributes to morbidity and mortality in many diseases, including heart failure (particularly congestive heart failure), chronic kidney disease, end stage renal disease, liver disease, etc. It is also accepted that salt and fluid retention is a risk factor for hypertension. Thus, there is a clear need for pharmaceutical agents that, when administered to a patient in need, result in a reduction in sodium retention, fluid retention, or both. Such pharmaceutical agents do not engage or otherwise exacerbate the renal mechanisms of fluid / Na homeostasis.

[0014] One option to consider for treating excessive fluid overload is to induce diarrhea. Diarrhea can be induced by several agents, including laxatives such as sorbitol, polyethylene glycol, bisacodyl, and phenolphthalein. Sorbitol and polyethylene glycol induce osmotic diarrhea with low levels of secreted electrolytes; thus, their usefulness in removing sodium salts from the GI tract is limited. The mechanism of action of phenolphthalein has not been clearly established, but it is believed to inhibit Na / K ATPase and Cl / HCO 3It is believed to be caused by inhibition of anion exchangers as well as stimulation of electrogenic anion secretion (see, e.g., Eherer, AJ, CA Santa Ana, J. Porter, and JS Fordtran, 1993, Gastroenterology, v. 104, no. 4, p. 1007-1012). However, some laxatives, such as phenolphthalein, are not viable options for long-term treatment of fluid overload due to the potential risk of carcinogenicity in humans. Furthermore, laxatives have been shown to be irritating and to cause mucosal damage, which precludes their long-term use. It should therefore also be recognized that the induction of chronic diarrhea as part of an attempt to control salt and fluid overload is an undesirable treatment modality for many patients. Thus, any pharmaceutical that utilizes the GI tract for this purpose would need to control diarrhea in order to be of practical benefit.

[0015] One approach to treat mild diarrhea is the administration of liquid-absorbing polymers, such as the natural plant fiber psyllium. Polymeric materials, more specifically hydrogel polymers, can also be used to remove fluid from the gastrointestinal (GI) tract. The use of such polymers is described, for example, in U.S. Patent Nos. 4,470,975 and 6,908,609, the entire contents of which are incorporated herein by reference for all relevant consistent purposes. However, for such polymers to effectively remove significant amounts of fluid, they must desirably resist the hydrostatic and osmotic pressure ranges present in the GI tract. Many mammals, including humans, do so by producing soft feces with a water content of about 70% and transporting fluid against the high hydraulic resistance imposed by the fecal mass. Several studies have shown that the pressure required to dehydrate feces from about 80% to about 60% is about 500 kPa to about 1000 kPa (i.e., about 5 to about 10 atm) (e.g., McKie, A.T., W. Powrie, and R.J. Naftalin, 1990, Am J Physiol, v.258, no.3 Pt 1). , p. 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 rather high pressures required to dehydrate feces are essentially due to osmotic processes and not to mechanical processes brought about by muscular forces. Osmotic pressure arises from the active transport of salts across the colonic mucosa, ultimately resulting in hypertonic fluid absorption. The osmotic gradient produced drives fluid from the lumen to the serosal side of the mucosa. For example, liquid-absorbing polymers such as those described in U.S. Patents 4,470,975 and 6,908,609 may not be able to sustain such pressures.Such polymers would collapse in a normal colon where the salt absorption process is intact, thus allowing removal of an adequate amount of fluid, and thereby salt.

[0016] Synthetic polymers that bind sodium have also been described. Ion exchange polymer resins, such as Dowex-type cation exchange resins, have been known since about the 1950s. However, except for Kayexalate™ (or Kionex™), a polystyrene sulfonate approved for the treatment of hyperkalemia, cation exchange resins have very limited use as drugs, at least in part due to their limited capacity and weak cation binding selectivity. In addition, during the ion exchange process, the resins liberate stoichiometric amounts of exogenous cations (e.g., H, K, Ca), which can then potentially lead to acidosis (H), hyperkalemia (K), or contribute to vascular calcification (Ca). Such resins can also lead to constipation.

[0017] Gastrointestinal disorders Constipation is characterized by infrequent and difficult passage of stool and becomes chronic when a patient suffers from the specific symptoms for more than 12 non-consecutive weeks within a 12-month period. Chronic constipation is idiopathic if it is not due to other diseases or the use of medications. 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 that the prevalence is approximately 15% in the general population. Constipation is more commonly reported in women, older adults, non-whites, and lower-class individuals.

[0018] Irritable bowel syndrome (IBS) is a common GI disorder associated with alterations in motility, secretion, and visceral sensation. A variety of clinical symptoms characterize the disorder, including frequency and form of stool, abdominal pain, and distension. The clinical manifestations of IBS have yet to be defined, but it is now common to refer to it as diarrhea-predominant IBS (D-IBS) and constipation-predominant IBS (C-IBS), where D-IBS is defined as the continuous passage of loose or watery stool, and C-IBS is defined as a group of functional disorders that present as difficult, infrequent, or apparently incomplete defecation. The pathophysiology of IBS is not fully understood, but several mechanisms have been suggested. Visceral hypersensitivity is often thought to play a major pathogenetic role and has been proposed to be a more useful biological marker to distinguish IBS from other causes of abdominal pain. In a recent clinical trial (Posserud, I. et al., Gastroenterology, 2007; 133: 1113-1123), visceral hypersensitivity tests (balloon distention) were performed on IBS patients and compared with healthy controls. 61% of IBS patients were found to have altered visceral perception as measured by pain and discomfort thresholds. Other reviews have documented the role of visceral hypersensitivity in abdominal pain, which is indicative 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 distention is associated with increased motility and dysphagia. It has been widely used as a tool to evaluate visceral sensation in animal and human studies. 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 publication ahead of print]), and stress such as partial restraint stress (PRS) are relatively mild, non-ulcerogenic models that are thought to be more representative of the IBS setting.

[0019] Constipation is common in the elderly population, especially in osteoporosis patients who must take calcium supplements. Calcium supplements have been shown to be beneficial for restoring bone density in osteoporosis patients, but compliance is poor due to calcium-induced constipating effects.

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

[0021] Some patients suffering from chronic idiopathic constipation can be successfully treated with lifestyle modifications, dietary changes, and increased fluid and fiber intake, and these treatments are typically tried first. For patients who fail to respond to these approaches, physicians typically recommend laxatives, many of which are available over the counter. The use of over the counter laxatives is judged to be ineffective by approximately 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, are described, for example, in Chang et al., 2006, Curr. Treat. Options Gastroenterol. 9(4):314-323; Gershon and Tack, 2007, Gastroenterology 132(1):397-414; and Hammerle and 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 because they are addictive and ineffective in some patients, may cause long-term side effects, or are otherwise suboptimal.

[0022] Na + / H + Exchange (NHE) inhibitors The primary function of the GI tract is to maintain water / Na homeostasis by absorbing virtually all water and Na to which it is exposed. The epithelial layer covering the apical surface of the mammalian colon is a typical electrolyte-transporting epithelium, which can move large amounts of salt and water in both directions across the mucosa. For example, each day, the GI tract processes about 9 liters of fluid and about 800 meq of Na (e.g., Zachos et al., Molec (See, for example, Annu. Rev. Physiol., v. 67, p. 411-443 (2005)). Only about 1.5 liters of this fluid and about 150 meq of this sodium result from oral intake; rather, most fluid (e.g., about 7.5 liters) and sodium (about 650 meq) are secreted through the GI tract as part of the digesta. Thus, the GI tract is a viable target for regulating whole body sodium and fluid levels.

[0023] Many reviews have been published regarding the physiology of the GI tract and the mechanisms of secretion and / or absorption (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., supra; 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 electrogenic transport. Electroneutral transport essentially transports Na + / H + It is due to antiport NHE (e.g., NHE-3) and is responsible for most of the Na absorption. Electrogenic transport is provided by the epithelial sodium channel ("ENaC"). Electroneutral transport is located mainly in the ileum and proximal colon, while electrogenic transport is located in the distal colon.

[0024] The plasma membrane NHE regulates intracellular pH and volume, NaCl and NaHCO 3 NHE contributes to the intercellular absorption of NA+ and the maintenance of fluid balance, which is carried out by epithelial cells, particularly in the kidney, intestine, gallbladder, and salivary glands, as well as the regulation of systemic pH. There is a literature directed to the role and clinical intervention of systemic NHE to treat injuries associated with ischemia and reperfusion for cardioprotection or renal protection. Nine isoforms of NHE have been identified (Kiela, PR et 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 in the apical side of the GI tract, with NHE-3 providing the greater contribution to transport. Another, yet to be identified, Cl-dependent NHE has been identified in the crypts of rat cells. In addition, much research has been directed at identifying inhibitors of NHE. The primary targets of such research have been NHE-1 and NHE-3. Small molecule NHE inhibitors are described, for example, in U.S. Pat. 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 (WO 94 / 026709); 6,399,824 (WO 02 / 024637); U.S. Patent Application Publication No. 2004 / 0039001 (WO 02 / 020496); 2005 / 0020612 (WO 03 / 055490); 04 / 0113396 (WO03 / 051866); 2005 / 0020612; 2005 / 0054705; 2008 / 0194621; 2007 / 0225323; 2004 / 0039001; 2004 / 0224965; 2005 / 0113396; 2007 / 0135383; 2007 / 0135385; 2005 / 0244367; 2007 / 0270414; International Publication No. WO01 / 072742; WO01 / 021582 (Canadian Patent No. CA2387529); WO97 / 0241 13 (Canadian Patent No. 02241531) and European Patent No. 0744397 (Canadian Patent No. 2177007); all of which are incorporated herein by reference in their entirety for all relevant consistent purposes.

[0025] However, as recently disclosed in WO2010 / 078449, such research has failed to develop or recognize the value or importance of NHE inhibitors that are not absorbed (i.e., not systemically) and target the gastrointestinal tract. Such inhibitors can be utilized in the treatment of GI tract disorders, including the treatment of disorders associated with fluid retention and salt overload, and the treatment or alleviation of pain associated with gastrointestinal disorders. Such inhibitors are particularly advantageous because they can be delivered with low risk of systemic on-target or off-target effects (e.g., with little or no risk of kidney damage or other systemic effects). Thus, despite advances in the field, there remains a need in the art for novel compounds for use in the treatment of gastrointestinal disorders, including disorders associated with fluid retention and salt overload, and the treatment or alleviation of pain associated with gastrointestinal disorders. The present invention fulfills this need and provides further related advantages. [Prior art documents] [Patent documents]

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

[0027] Briefly, the present invention relates to compounds that are substantially active in the gastrointestinal tract to inhibit NHE-mediated antiport of sodium and hydrogen ions, and 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 alleviation of pain associated with gastrointestinal disorders.

[0028] Compounds of Formula I: [ka] or a pharma- ceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof. [In the formula, The linker is -R 13 -(CHR 13 ) p -[Y-(CH 2 ) r ] s -ZR 13 -(CH 2 ) t -Z-; X is a bond, H, N, O, or CR 11 R 12 , C.R. 11 , C, -NHC(O)NH-, -(CHR 13 ) p - or C 3 ~C 6 is cycloalkyl; Each occurrence of W is independent of S(O). 2 , C(O), or -(CH 2 ) m - and; Z is, independently at each occurrence, a bond, C(O), or -C(O)NH-; Each occurrence of Y is independently O, S, NH, N(C 1 ~C 3 alkyl), or -C(O)NH-; Q is a bond, NH, -C(O)NH-, -NHC(O)NH-, -NHC(O)N(CH 3 )-, or -NHC(O)NH-(CHR 13 ) and; m is an integer from 1 to 2; n is an integer from 1 to 4; r and p, independently at each occurrence, are integers from 0 to 8; s is an integer from 0 to 4; t is an integer from 0 to 4; u is an integer from 0 to 2; R 1and R 2 are independently, H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more halogen, OH, CN, -NO 2 , Oxo, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 -, -S(O) 2 R 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 9 R 10 , -NR 9 S(O) 2 R 10 , -S(O)R 9 , -S(O)NR 9 R 10 , -NR 8 S(O)R 9 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 optionally substituted with cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl; or R 1 and R2 may together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P and O, wherein said heterocyclyl or heteroaryl group may further comprise one or more halogen, OH, CN, -NO 2 , Oxo, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 -, -S(O) 2 R 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 9 R 10 , -NR 9 S(O) 2 R 10 , -S(O)R 9 , -S(O)NR 9 R 10 , -NR 9 S(O)R 10 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 optionally substituted with cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl; R 3 and R 4 are independently halogen, OH, CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Haloalkoxy, or -C(O)NR 9 R 10 and; R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 -, -S(O) 2 R 9 , -C(O)R 9 , -C(O)OR 9 , -NR 9 S(O) 2 R 10 , -S(O)R 9 , -S(O)NR 9 R 10 , -NR 8 S(O)R 9 and; R 9 and R 10 are independently, H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 is a cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; R11 and R 12 are independently, H, C 1 ~C 6 Alkyl, OH, NH 2 , CN, or NO 2 and; R 13 are independently for each occurrence a bond, H, or C. 1 ~C 6 Alkyl, C 4 ~C 8 Cycloalkenyl, C 3 ~C 8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl where each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R 19 is optionally replaced by; R 14 are independently defined for each occurrence: H, C 1 ~C 6 Alkyl, or C 1 ~C 6 is haloalkyl; or R 6 and R 14 may combine together with the atom to which they are attached to form, independently at each occurrence, a 5- to 6-membered heterocyclyl, where each C 3 ~C 8 Cycloalkyl or heterocyclyl can be one or more R 19 is optionally replaced by; or R 13 and R 14 are combined with the atoms to which they are attached, and each occurrence is 3 ~C 8 may form a cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where each heterocyclyl or heteroaryl may be selected from one or more R 19 is optionally replaced by; R 15 , R 16 , R17 , and R 18 are independently H, OH, NH 2 , or C 1 ~C 3 alkyl, wherein said alkyl is selected from one or more R 19 is optionally substituted with; and R 19 are independently H, OH, NH 2 , Oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 H haloalkyl, C 1 ~C 6 Although alkoxy; however: (1) If X is H, then n is 1; (2) X is a bond, O, or CR 11 R 12 then n is 2; (3) If n is 3, X is CR 11 or N; (4) When n is 4, X is C; (5) wherein only one of Q or X is -NHC(O)NH-; (6)R 1 and R 2 together with the nitrogen to which they are attached must not form a pyrrolidinyl; (7)R 1 and R 2 is methyl and R 3 and R 4 is a halogen and R 5 and R 8 When is H, the linker is [ka] isn't it; (8)R 1 and R 2 together with the nitrogen to which they are attached form a piperidinyl, and R 3 and R 4 is a halogen and R5 and R 8 When is H, the linker is [ka] is not; and (9)R 1 and R 2 together with the nitrogen to which they are attached form 3-aminopiperidin-1-yl, R 3 and R 4 is a halogen and R 5 , R 6 , R 7 , and R 8 When is H, the linker is [ka] isn't it [Provided that:

[0029] In another aspect, there is provided a pharmaceutical composition comprising a compound as described above, or a stereoisomer, pharma- ceutically acceptable salt or prodrug thereof, and a pharma- ceutically acceptable carrier, diluent or excipient. The pharmaceutical composition is useful for treating a disease or disorder associated with fluid retention or salt overload. The pharmaceutical composition may include the compound of the present invention for use in treating the diseases described herein. The composition may include at least one compound of the present invention and a pharmaceutically acceptable carrier.

[0030] Another aspect of the invention relates to a method for inhibiting NHE-mediated antiport of sodium and hydrogen ions, the method comprising administering to a mammal in need thereof a pharma- ceutical effective amount of a compound or pharmaceutical composition described herein.

[0031] In another aspect, there is provided a method for treating a disorder associated with fluid retention or salt overload, comprising administering to a mammal in need thereof a pharma- ceutical effective amount of a compound or pharmaceutical composition as described above.

[0032] The present invention further provides compounds that can inhibit the NHE-mediated antiport of sodium and hydrogen ions.The efficacy-safety profile of the compounds of the present invention can be improved relative to other known NHE-3 inhibitors.In addition, the present technology also provides, but is not limited to, the treatment of 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 disorder, irritable bowel syndrome, chronic constipation, chronic idiopathic constipation, chronic constipation occurring in cystic fibrosis patients, chronic constipation occurring in chronic kidney disease patients, calcium-induced constipation occurring in osteoporosis patients, Opioid-induced constipation, functional gastrointestinal disorders, Parkinson's disease, multiple sclerosis, gastroesophageal reflux disease, functional heartburn, indigestion, functional dyspepsia, non-ulcer dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, Crohn's disease, ulcerative colitis and related disorders called inflammatory bowel syndrome, colonic pseudo-obstruction, gastric ulcers, infectious diarrhea, cancer (colorectal), "leaky gut syndrome", cystic fibrosis gastrointestinal disease, multiple organ failure, microscopic colitis, necrotizing enterocolitis, allergies-atopy, food allergies Allergies, infections (respiratory), acute inflammation (e.g., sepsis, systemic inflammatory response syndrome), chronic inflammation (arthritis), obesity-induced metabolic diseases (e.g., nonalcoholic steatohepatitis, type I diabetes, type II diabetes, cardiovascular disease), kidney disease, diabetic kidney disease, cirrhosis, nonalcoholic steatohepatitis, nonalcoholic fatty acid liver disease, steatosis, primary sclerosing cholangitis, primary biliary cholangitis, portal hypertension, autoimmune diseases (e.g., type 1 diabetes, celiac secondary PTH, ankylosing spine Advantageously, it can be used for several different types of diseases, including rheumatoid arthritis, lupus, alopecia areata, rheumatoid arthritis, polymyalgia rheumatica, fibromyalgia, chronic fatigue syndrome, Sjogren's syndrome, vitiligo, thyroiditis, vasculitis, urticaria (hives), Raynaud's syndrome, schizophrenia, autism spectrum disorder, hepatic encephalopathy, small intestinal bacterial overgrowth, and chronic alcoholism, secondary hyperparathyroidism (PTH), celiac disease, hyperphosphatemia, etc. Additional features and advantages of the present technology will become apparent to those skilled in the art upon reading the detailed description of the invention below. [Brief description of the drawings]

[0033] [Figure 1] NHE3-independent changes in intracellular pH (pHi) have been shown to modulate transepithelial electrical resistance in intestinal ileal monolayer cultures. Changes in pHi and transepithelial electrical resistance (TEER) with (A, B) nigericin and (C, D) BAM15 (3 μM) and FCCP (3 μM) are compared to the known NHE3 inhibitor tenapanor and vehicle (DMSO) control in monolayer cultures. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 vs DMSO. [Diagram 2] A dose-dependent decrease in urinary albumin excretion has been demonstrated. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] A first aspect of the present invention relates to a compound of the formula: [ka] The present invention relates to a pharma- ceutically acceptable salt, prodrug, solvate, hydrate, isomer, or tautomer thereof, 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 the linker are as described herein]. The details of the present invention are described in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, examples of methods and materials are described below. Other features, objects, and advantages of the present invention are apparent from the specification and claims. In the specification and the appended claims, the singular form includes the plural form unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. All patents and publications cited herein are incorporated by reference in their entirety.

[0035] Definition: Unless the context otherwise requires, throughout this specification and claims, the term "comprise" and its variations, such as "comprises" and "comprising," are to be interpreted in their open and inclusive sense, such as "including, but not limited to."

[0036] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0037] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated.

[0038] Throughout this specification, reference to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0039] "Amino" is -NH 2 Refers to radicals.

[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" is -NO 2 Refers to radicals.

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

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

[0046] The term "substituted" as used herein 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 has been replaced by a non-hydrogen atom, including, but not limited to: halogen atoms, e.g., F, Cl, Br, and I; oxygen atoms in groups such as hydroxyl, alkoxy, and ester groups; sulfur atoms in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and bonds to other heteroatoms in various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms have been replaced by a higher order bond (e.g., a double or triple bond) to a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imine, oxime, hydrazone, and nitrile. For example, "substituted" means that one or more hydrogen atoms have been 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 SO 2 R h , -OC(=O)NR g R h , -OR g , -SR g , -SOR g , -SO 2 Rg , -OSO 2 R g , -SO 2 OR g , =NSO 2 R g , and -SO 2 NR g R h "Substituted" also includes any of the above groups replaced with one or more hydrogen atoms by -C(=O)R. g , -C(=O)OR g , -C(=O)NR g R h , -CH 2 SO 2 R g , -CH 2 SO 2 NR g R h , -(CH 2 CH 2 O) 2~10 R g In the above, R g and R h are the same or different and are independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" further refers to any of the above groups in which one or more hydrogen atoms are replaced by a bond to an 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 group. In addition, each of the above-mentioned substituents may be optionally substituted with one or more of the above-mentioned substituents.

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

[0048] "Alkyl" refers to an alkyl group consisting solely of carbon and hydrogen atoms, saturated or unsaturated (i.e., containing one or more double and / or triple bonds), and having from 1 to 12 carbon atoms (C 1 ~C 12 alkyl), 1 to 8 carbon atoms (C 1 ~C 8 alkyl) or 1 to 6 carbon atoms (C 1 ~C 6 "alkyl") and refers to a straight or branched hydrocarbon chain radical attached to the remainder of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, alkyl groups may be optionally substituted.

[0049] "Alkoxy" means a group of the formula -OR a (In the formula, R arefers to a radical of the formula: (wherein R is an alkyl radical, as defined above, containing 1 to 12 carbon atoms). Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted.

[0050] "Alkenyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. Alkenyl can be straight or branched, as defined herein.

[0051] "Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "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. Alkynyl groups can be unsubstituted or substituted.

[0052] The term "cycloalkyl" means 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. 3 ~C 8 Cycloalkyl is a cycloalkyl group containing from 3 to 8 carbon atoms. The cycloalkyl groups can be fused (e.g., decalin) or bridged (e.g., norbornane).

[0053] The term "cycloalkenyl" means a monocyclic, non-aromatic unsaturated carbocyclic ring containing from 4 to 18 carbon atoms. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and norborenyl. 4 ~C 8 Cycloalkenyl is a cycloalkenyl group containing 4 to 8 carbon atoms.

[0054] The terms "heterocyclyl" or "heterocycloalkyl" or "heterocycle" refer to a ring system that contains carbon and heteroatoms selected from oxygen, phosphorus, nitrogen, or sulfur and has ring carbon or heterocyclic ring members. It refers to a monocyclic or polycyclic 3-24 membered ring in which there is no shared delocalized π electron (aromaticity) between heteroatoms. 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 fused or bridged, e.g., bicyclic rings.

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

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

[0057] The term "aryl" refers to a cyclic aromatic hydrocarbon group having one to two aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When containing two aromatic rings (such as bicyclic), the aromatic rings of the aryl group may be attached at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may be optionally substituted at any point of attachment with one or more substituents, e.g., 1 to 5 substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -OC. 1 ~C 6 Alkyl, -C 1 ~C 6 Alkyl, -OC 2 ~C 6 Alkenyl, -OC 2 ~C 6 Alkynyl, -C 2 ~C 6 Alkenyl, -C 2 ~C 6 Alkynyl, -OH, -OP(O)(OH) 2 , -OC(O)C 1 ~C 6 Alkyl, -C(O)C 1 ~C 6 Alkyl, -OC(O)OC 1 ~C 6 Alkyl, -NH 2 , -NH(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , -S(O) 2 -C 1 ~C 6 Alkyl, -S(O)NHC 1 ~C 6 Alkyl, and -S(O)N(C 1 ~C 6 Alkyl) 2The substituents may themselves be optionally substituted. Furthermore, when containing two fused rings, the aryl groups defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

[0058] Unless specifically defined otherwise, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, S, P, and O, with 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. The aromatic radicals are optionally substituted independently with one or more substituents 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, benzopyranyl, 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, chromanyl, thiochromanyl, tetrahydropyridine ... lahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, 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]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1 2-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[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]thiazinyl Examples of heteroaryl groups include riazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-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 derivatives thereof. Furthermore, when containing two fused rings, the heteroaryl groups as defined herein may have an unsaturated or partially saturated ring fused to 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 dihydrobenzoxanyl.

[0059] "Prodrug" is meant to indicate a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. Thus, the term "prodrug" refers to a metabolic precursor of a compound of the invention that is pharma- ceutically acceptable. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention. Prodrugs are typically rapidly converted in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs can be found in Higuchi, et al., ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0060] The term "prodrug" is also meant to include any covalently bonded carrier that releases the active compound of the present invention in vivo when such 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 to the parent compound of the present invention, either by routine manipulation or in vivo. Prodrugs include compounds of the present invention in which a hydroxy, amino or mercapto group is bonded to any group that is cleaved to form a free hydroxy, free amino or free mercapto group, respectively, when a prodrug of the compound of the present invention is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, Included are acetate, formate and benzoate derivatives of alcohols or amide derivatives of amine functional groups in the compounds of the invention.

[0061] The invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily by enzymatic processes. Thus, the invention includes compounds produced by a process that includes administering a compound of the invention to a mammal for a sufficient time to obtain its metabolic products. Typically, such products are identified by administering a detectable dose of a radiolabeled compound of the invention to an animal, such as a rat, mouse, guinea pig, monkey, or human, for a sufficient time for metabolism to occur, and isolating the conversion products from urine, blood, or other biological samples.

[0062] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0063] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, without limitation, any adjuvant, carrier, excipient, fluidity enhancer, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicity agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0064] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0065] "Pharmaceutically acceptable acid addition salts" refer to those which retain the biological effectiveness and properties of the free base and which are not biologically or otherwise undesirable, and which are formed from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as, but 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, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galectin, glycerin, glycerol ... It refers to salts formed with lactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic 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, and the like.

[0066] "Pharmaceutically acceptable base addition salt" refers to salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are the 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 basic 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, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, salts of polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0067] Crystallization often results in a solvate of the compound of the present invention. As used herein, the term "solvate" refers to an aggregate that includes 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 compound of the present invention may exist as a hydrate, including a monohydrate, a dihydrate, a hemihydrate, a sesquihydrate, a trihydrate, a tetrahydrate, and also as a corresponding solvate form. The compound of the present invention may be a true solvate, but in other cases, the compound of the present invention may simply retain extraneous water or may be a mixture of water and some extraneous solvent.

[0068] A "pharmaceutical composition" refers to a formulation of a compound of the invention with a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal, e.g., a human. Such a vehicle includes any pharma- ceutically acceptable carrier, diluent, or excipient therefor.

[0069] The compounds of the present invention, or pharma- ceutically acceptable salts thereof, may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be de?ned in terms of absolute stereochemistry as to amino acids as (R)- or (S)- or (D)- or (L)-. The present invention is meant to include all such possible isomers, as Well as their racemic and optically pure forms. 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, e.g., chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemates (or racemates of salts or derivatives) using, e.g., chiral high performance liquid chromatography (HPLC). Where the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers, as well as all tautomeric forms.

[0070] "Stereoisomers" refer to compounds made up of the same atoms joined by the same bonds but with different three-dimensional structures and are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0071] "Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The invention includes tautomers of any of the above compounds.

[0072] In accordance with the present disclosure, the compounds described herein are designed to be substantially active or localized in the gastrointestinal lumen of a human or animal subject. The term "gastrointestinal lumen" is used interchangeably herein with the term "lumen" and refers to the space or cavity within the gastrointestinal tract (GI tract, which may also be called the intestine) bounded by the apical membrane of the GI epithelial cells of a subject. In some embodiments, the compound is not absorbed through the epithelial cell layer of the GI tract (also known as the GI epithelium). "Gastrointestinal mucosa" refers to the layer or layers of cells that separate the lumen of the gastrointestinal tract from the rest of the body, including the mucosa of the stomach and intestine, such as the mucosa of the small intestine. "Gastrointestinal epithelial cells" or "intestinal epithelial cells," as used herein, refer to any epithelial cell on the surface of the gastrointestinal mucosa that faces the lumen of the gastrointestinal tract, including, for example, gastric epithelial cells, intestinal epithelial cells, colonic epithelial cells, etc.

[0073] A "subject" is a human, but may also be an animal in need of treatment with a compound of the present disclosure, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0074] As used herein, "substantially systemically non-bioavailable" and / or "substantially impermeable" (and variations thereof) generally refer to a situation in which a statistically significant amount, and in some embodiments essentially all, of the disclosed compounds (including NHE-inhibiting small molecules) remain in the gastrointestinal lumen. For example, according to one or more embodiments of the present disclosure, at least about 70%, about 80%, about 90%, about 95%, about 98%, about 99%, or even about 99.5% of the compound remains in the gastrointestinal lumen. In such cases, localization to the gastrointestinal lumen refers to a reduction in net movement through the gastrointestinal layer of epithelial cells, for example, by both paracellular and paracellular transport, as well as by active and / or passive transport. The compound in such embodiments is prevented from net permeation of the gastrointestinal epithelial cell layer in paracellular transport, for example, through the apical membrane of epithelial cells of the small intestine. The compounds in these embodiments are also prevented from net permeation through "tight junctions" in paracellular transport between gastrointestinal epithelial cells lining the lumen.

[0075] In this regard, it should be noted that in one particular embodiment, the compound is essentially not absorbed at all by the GI tract or gastrointestinal lumen. As used herein, the terms "substantially impermeable" or "substantially systemically non-bioavailable" refer to embodiments in which no detectable amount of absorption or penetration or systemic exposure of the compound is detected using means commonly known in the art.

[0076] However, in this regard, it should be further noted that in alternative embodiments, "substantially impermeable" or "substantially systemically non-bioavailable" provides or allows for more or less limited absorption in the GI tract, 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 less than about 30%, 20%, 10%, 5%, etc.), with the absorption range being, for example, about 1%-30% or 5%-20%, etc.; otherwise stated, "substantially impermeable" or "substantially non-bioavailable" refers to a compound that exhibits some detectable permeability to the epithelial cell layer in the GI tract of less than about 20% of the administered compound (e.g., about 15%, about 10%, or even less than about 5%, and for example, more than about 0.5% or 1%), but is eliminated by the liver (i.e., hepatic extraction) and / or kidney (i.e., renal excretion).

[0077] In accordance with the present disclosure, and as further detailed herein below, the concentration of sodium ions (Na ions) in the gastrointestinal tract, and more specifically, in the gastrointestinal epithelium, is increased by 100%. + ) and hydrogen ions (H + Inhibition of NHE-mediated antiport of sodium ions and hydrogen ions in the GI tract has been found to be a powerful approach to the treatment of various disorders that are associated with or may result 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 antiport of sodium ions and hydrogen ions in the GI tract has been found to increase fecal excretion of sodium, effectively lowering systemic levels of sodium and fluid. This, in turn, can be used to treat, for example, , improve the clinical condition of patients suffering from CHF, ESRD / CKD and / or liver disease. It has also been found that, optionally, such treatment can be enhanced by the co-administration of other beneficial compounds or compositions, such as, for example, a fluid-absorbing polymer. The fluid-absorbing polymer can be optimally selected because it does not block or otherwise negatively interfere with the mechanism of action of the co-administered NHE-inhibiting compound.

[0078] In addition, and as described in further detail herein below, the concentration of sodium ions (Na ions) in the gastrointestinal tract, and more specifically in the gastrointestinal epithelium, is increased. + ) and hydrogen ions (H + It has further been found that inhibition of NHE-mediated antiport of .) is a powerful approach to the treatment of hypertension associated with or resulting from fluid retention and / or salt overload. More specifically, it has been found that inhibition of NHE-mediated antiport of sodium ions and hydrogen ions in the GI tract increases fecal excretion of sodium, effectively lowering the systemic levels of sodium and fluid. This in turn improves the clinical condition of patients suffering from hypertension. Such treatment can be optionally augmented by the co-administration of other beneficial compounds or compositions, such as, for example, a liquid-absorbing polymer. The liquid-absorbing polymer can be optimally selected because it does not block or otherwise negatively interfere with the mechanism of action of the co-administered NHE-inhibiting compound.

[0079] In addition, and as described in further detail herein below, the concentration of sodium ions (Na ions) in the gastrointestinal tract, and more specifically in the gastrointestinal epithelium, is increased. + ) and hydrogen ions (H +It has further been found that inhibition of NHE-mediated antiport of ) is a powerful approach to the treatment of various gastrointestinal disorders, including the treatment or alleviation of pain associated with gastrointestinal disorders, and more specifically, the restoration of appropriate fluid secretion in the intestine and the amelioration of pathological conditions encountered in constipated states. Applicant further recognizes that by blocking sodium ion reabsorption, the compounds of the present disclosure restore fluid homeostasis in the GI tract, particularly in situations where fluid secretion / absorption is altered to result in constipated states and GI discomfort, which generally result in high degrees of fecal dehydration, low gastrointestinal motility, and / or delayed transit time. It has further been found that such treatment can be optionally enhanced by the co-administration of other beneficial compounds or compositions, such as, for example, a fluid-absorbing polymer. The fluid-absorbing polymer can be optimally selected because it does not block or otherwise negatively interfere with the mechanism of action of the co-administered NHE-inhibiting compound.

[0080] Due to the presence of NHE in other organs or tissues in the body, the methods of the present disclosure employ the use of compounds and compositions that are desirably 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 (whether they are on-target or off-target) can be minimized. Thus, as used herein and as further detailed elsewhere herein, it should be noted that "substantially active in the gastrointestinal tract" generally refers to compounds that are substantially systemically non-bioavailable and / or substantially impermeable to epithelial cell layers, and more specifically, epithelial cells of the GI tract. Furthermore, as used herein and as further detailed elsewhere herein, it should be noted that "substantially impermeable" more specifically encompasses compounds that are impermeable to epithelial cell layers, and more specifically, gastrointestinal epithelium (or epithelial layer). "Gastrointestinal epithelial cells" refers to the membrane tissue that covers the inner surface of the gastrointestinal tract. Thus, by being substantially impermeable, compounds have a very limited ability to be transported across 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 across gastrointestinal epithelial cells are by paracellular movement (transcellular material transfer mediated by passive or active transport across both the apical and basolateral membranes) and / or by paracellular movement, whereby materials are transferred between epithelial cells, usually via highly restrictive structures known as "tight junctions". It is.

[0081] Without wishing to be bound by any particular theory, it is believed that the NHE inhibitor compounds of the present disclosure (e.g., NHE-3, -2 and / or -8 inhibitors) act to reduce intestinal paracellular permeability through separate and distinct mechanisms. NHE3 is expressed at high levels at the apical surface of the digestive tract and couples luminal Na absorption to secretion of intracellular protons. Inhibition of NHE3 by the NHE inhibitor compounds of the present disclosure (e.g., NHE-3, -2 and / or -8 inhibitors) results in the accumulation of intracellular protons. NHE3 inhibition, accompanied by retention of intracellular protons, modulates tight junctions between cells, reducing paracellular permeability, which can be measured by an increase in transepithelial electrical resistance.Increased intestinal paracellular and / or transcellular permeability may be associated with, 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, dyspepsia, functional Dyspepsia, Non-ulcer Dyspepsia, Gastroparesis, Chronic Intestinal Pseudo-obstruction, Crohn's Disease, Ulcerative Colitis and related disorders called Inflammatory Bowel Syndrome, Colonic Pseudo-obstruction, Gastric Ulcers, Infectious Diarrhea, Cancer (Colorectal), "Leaky Gut Syndrome", Cystic Fibrosis Gastrointestinal Disease, Multiple Organ Failure, Microscopic Colitis, Necrotizing Enterocolitis, Allergy-Atopy, Food Allergy, Infection (Respiratory), Acute Inflammation (e.g., Sepsis, Systemic Inflammatory Response Syndrome), Chronic Inflammation Since NHE inhibition has been observed in many diseases, including chronic inflammation (arthritis), obesity-induced metabolic diseases (e.g., nonalcoholic steatohepatitis, type I diabetes, type II diabetes, cardiovascular disease), renal disease, diabetic kidney disease, cirrhosis, nonalcoholic steatohepatitis, nonalcoholic 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, Sjogren's syndrome, vitiligo, thyroiditis, vasculitis, urticaria (hives), Raynaud's syndrome), schizophrenia, autism spectrum disorder, hepatic encephalopathy, small intestinal bacterial overgrowth, and chronic alcoholism, it is expected that NHE inhibition may provide a therapeutic benefit in these diseases by decreasing paracellular and / or transcellular permeability in the intestine.

[0082] Thus, in some embodiments, the present disclosure provides a method for reducing intestinal paracellular permeability. In some embodiments, the method for reducing intestinal paracellular permeability comprises administering an NHE3 inhibitor. In some embodiments, the inhibition of NHE3 results in the accumulation of intracellular protons. In some embodiments, the reduction in paracellular permeability is due to the increase in intracellular protons independent of and without NHE3 inhibition. In other words, the increase in intracellular protons without NHE3 inhibition results in the reduction in paracellular permeability. Thus, the method for reducing paracellular permeability comprises the increase in intracellular protons. In some embodiments, the present disclosure provides a method for treating a disease associated with paracellular permeability, comprising administering an agent that increases intracellular protons at tight junctions, thereby reducing paracellular permeability and thus treating the disease. Non-limiting examples of such diseases include Crohn's disease, ulcerative colitis and related disorders referred to as inflammatory bowel syndrome, colonic pseudo-obstruction, gastric ulcers, infectious diarrhea, cancer (colorectal), "leaky gut syndrome", cystic fibrosis gastrointestinal disease, multiple organ failure, microscopic colitis, necrotizing enterocolitis, allergy-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 I diabetes, type II diabetes, cardiovascular disease), renal Diseases, diabetic kidney disease, cirrhosis, nonalcoholic steatohepatitis, nonalcoholic 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, Sjogren's syndrome, vitiligo, thyroiditis, vasculitis, urticaria (hives), Raynaud's syndrome), schizophrenia, autism spectrum disorder, hepatic encephalopathy, small intestinal bacterial overgrowth, and chronic alcoholism.

[0083] In some embodiments, the present disclosure provides a method for modulating intestinal transcellular permeability. In some embodiments, the method for modulating intestinal transcellular permeability comprises administering an NHE3 inhibitor. In some embodiments, the inhibition of NHE3 results in transcellular material movement mediated by passive or active transport through both apical and basolateral membranes. Thus, the method for modulating transcellular permeability comprises mediating passive or active transport of material through both apical and basolateral membranes. In some embodiments, the present disclosure provides a method for treating a disease associated with transcellular permeability, comprising administering an agent that mediates passive or active transport of material through both apical and basolateral membranes of cells, 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 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, dyspepsia, functional dyspepsia, non-ulcer dyspepsia, gastroparesis, and chronic intestinal pseudo-obstruction.

[0084] Thus, the compounds of the present disclosure may not be absorbed, and therefore are essentially not systemically bioavailable at all (e.g., do not penetrate gastrointestinal epithelial cells at all), or they do not show detectable concentrations of the compounds in serum.Alternatively, the compounds may (i) show some detectable permeability to epithelial cell layers and more specifically GI tract epithelial cells of less than about 20% (e.g., less than about 15%, about 10%, or even less than about 5%, and for example, more than about 0.5%, or 1%) of the compounds administered, but are rapidly eliminated in the liver (i.e., hepatic extraction) via first-pass metabolism; and / or (ii) show some detectable permeability to epithelial cell layers and more specifically GI tract epithelial cells of less than about 20% (e.g., less than about 15%, about 10%, or even less than about 5%, and for example, more than about 0.5%, or 1%) of the compounds administered, but are then rapidly eliminated in the kidney (i.e., renal extraction).

[0085] Compounds can also be removed unchanged from circulation into bile by biliary excretion.Therefore, compounds of the present disclosure can not show detectable concentrations in bile.Alternatively, said compounds can show some detectable concentrations of 10 μM, less than 1 μM, less than 0.1 μM, less than 0.01 μM or less than about 0.001 μM in bile, more particularly in bile duct and gallbladder epithelial cells.

[0086] In this regard, it should be further noted that "substantially systemically non-bioavailable" as used herein generally refers to the inability to detect the compound in the systemic circulation of an animal or human following oral administration of the compound. For a compound to be bioavailable, it must be transported across the gastrointestinal epithelial cells (i.e., be substantially permeable as defined above), transported via the portal circulation to the liver, avoid substantial metabolism in the liver, and then transported to the systemic circulation.

[0087] Without wishing to be bound by any particular theory, it is believed that the NHE inhibitor compounds (e.g., NHE-3, -2 and / or -8 inhibitors) of the present disclosure act via separate and distinct mechanisms, resulting in retention of fluids and ions in the GI tract (and stimulation of fecal excretion) rather than stimulating increased secretion of said fluids and ions. For example, lubiprostone (Amitiza® Sucampo / Takeda) is a bicyclic fatty acid prostaglandin E1 analogue that activates type 2 chloride channels (ClC-2) and increases chloride-rich fluid secretion from the serosal to the mucosal side of the GI tract (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 transmembrane conductance regulator (CFTR), thereby inducing fluid and electrolyte secretion into the GI tract (see, e.g., Li et al., J. Exp. Med., vol. 202 (2005), pp. 975-986). The substantially impermeable NHE inhibitor compounds of the present disclosure act to inhibit salt and fluid reuptake rather than promoting secretion. Because the GI tract processes approximately 9 liters of fluid and approximately 800 meq of Na daily, it is predicted that NHE inhibition could allow substantial total body fluid and sodium removal to reabsorb edema and resolve CHF symptoms.

[0088] I. Substantially Impermeable or Substantially Systemically Non-Bioavailable NHE Inhibitor Compounds In one embodiment, the compounds of the present disclosure generally have the following formula (I): [ka] and pharma- ceutically acceptable salts, prodrugs, solvates, hydrates, isomers, and tautomers thereof. [In the formula, The linker is -(CHR 13 ) p -[Y-(CH 2 ) r ] s -ZR 13 -(CH 2 ) t -Z-; Each occurrence of W is independent of S(O). 2 , C(O), or -(CH 2 ) m - and; Z is, independently at each occurrence, a bond, C(O), or -C(O)NH-; Each occurrence of Y is independently O, S, NH, N(C 1 ~C 3 alkyl), or -C(O)NH-; Q is a bond, NH, -C(O)NH-, -NHC(O)NH-, -NHC(O)N(CH 3 )-, 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, independently at each occurrence, are integers from 0 to 8; s is an integer from 0 to 4; t is an integer from 0 to 4; u is an integer from 0 to 2; R 1 and R 2 are independently, H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more halogen, OH, CN, -NO 2 , Oxo, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 -, -S(O) 2 R 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 9 R 10 , -NR 9 S(O) 2 R 10 , -S(O)R 9 , -S(O)NR 9 R 10 , -NR 8 S(O)R9 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 optionally substituted with cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl; or R 1 and R 2 may together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P and O, wherein said heterocyclyl or heteroaryl group may further comprise one or more halogen, OH, CN, -NO 2 , Oxo, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 -, -S(O) 2 R 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 9 R 10 , -NR 9 S(O) 2 R 10 , -S(O)R 9 , -S(O)NR 9 R 10 , -NR 9 S(O)R 10 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8optionally substituted with cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl; R 3 and R 4 are independently halogen, OH, CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Haloalkoxy, or -C(O)NR 9 R 10 and; R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 -, -S(O) 2 R 9 , -C(O)R 9 , -C(O)OR 9 , -NR 9 S(O) 2 R 10 , -S(O)R 9 , -S(O)NR 9 R 10 , -NR 8 S(O)R 9 and; R9 and R 10 are independently, H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 is a cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; X is a bond, H, N, O, or CR 11 R 12 , C.R. 11 , C, -NHC(O)NH-, or C 3 ~C 6 is cycloalkyl; R 11 and R 12 are independently, H, C 1 ~C 6 Alkyl, OH, NH 2 , CN, or NO 2 and; R 13 are independently for each occurrence a bond, H, or C. 1 ~C 6 Alkyl, C 4 ~C 8 Cycloalkenyl, C 3 ~C 8 cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R 19 is optionally replaced by; R 14 are independently defined for each occurrence: H, C 1 ~C 6 Alkyl, or C 1 ~C 6 is haloalkyl; or R 6 and R 14may combine together with the atom to which they are attached to form, independently at each occurrence, a 5- to 6-membered heterocyclyl, where each C 3 ~C 8 Cycloalkyl or heterocyclyl can be one or more R 19 is optionally replaced by; or R 13 and R 14 are combined with the atoms to which they are attached, and each occurrence is 3 ~C 8 may form a cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where each heterocyclyl or heteroaryl may be selected from one or more R 19 is optionally replaced by; R 15 , R 16 , R 17 , and R 18 are independently H, OH, NH 2 , or C 1 ~C 3 alkyl, said alkyl being selected from one or more R 19 is optionally replaced by; R 19 are independently H, OH, NH 2 , Oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 H haloalkyl, C 1 ~C 6 Although it is an alkoxy, however: (1) If X is H, then n is 1; (2) X is a bond, O, or CR 11 R 12 then n is 2; (3) If n is 3, X is CR 11 or N; (4) When n is 4, X is C; (5) wherein only one of Q or X is -NHC(O)NH-; (6)R 1 and R 2 together with the nitrogen to which they are attached must not form a pyrrolidinyl; (7)R 1 and R 2 is methyl and R 3 and R 4 is a halogen and R 5 and R 8 When is H, the linker is [ka] isn't it; (8)R 1 and R 2 together with the nitrogen to which they are attached form a piperidinyl, and R 3 and R 4 is a halogen and R 5 and R 8 When is H, the linker is [ka] is not; or (9)R 1 and R 2 together with the nitrogen to which they are attached form 3-aminopiperidin-1-yl, R 3 and R 4 is a halogen and R 5 , R 6 , R 7 , and R 8 When is H, the linker is [ka] isn't it [Provided that:

[0089] In one embodiment, the NHE-inhibiting compounds of formula (I) have overall physicochemical properties that render them substantially impermeable or substantially systemically non-bioavailable.

[0090] In one embodiment, the compound of the invention has formula I' [ka] or a pharma- ceutically acceptable salt thereof. [In the formula, The linker is -R 13 -(CHR 13 ) p -[Y-(CH 2 ) r ] s -ZR 13 -(CH 2 ) t -Z-; X is a bond, H, N, O, or CR 11 R 12 , C.R. 11 , C, -NHC(O)NH-, -(CHR 13 ) p - or C 3 ~C 6 is cycloalkyl; Each occurrence of W is independent of S(O). 2 , C(O), or -(CH 2 ) m -And ; Z is, independently at each occurrence, a bond, C(O), or -C(O)NH-; Each occurrence of Y is independently O, S, NH, N(C 1 ~C 3 alkyl), or -C(O)NH-; Q is a bond, NH, -C(O)NH-, -NHC(O)NH-, -NHC(O)N(CH 3 )-, or -NHC(O)NH-(CHR 13 ) and; m is an integer from 1 to 2; n is an integer from 1 to 4; r and p, independently at each occurrence, are integers from 0 to 8; s is an integer from 0 to 4; t is an integer from 0 to 4; u is an integer from 0 to 2; R 1 and R 2 are independently, H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from the group consisting of one or more halogen, OH, CN, -NO 2 , Oxo, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 -, -S(O) 2 R 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 9 R 10 , -NR 9 S(O) 2 R 10 , -S(O)R 9 , -S(O)NR 9 R 10 , -NR 8 S(O)R 9 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 optionally substituted with cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl; or R 1 and R 2 may together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P and O, wherein said heterocyclyl or heteroaryl group may further comprise one or more halogen, OH, CN, -NO 2 , Oxo, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 -, -S(O) 2 R 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 9 R 10 , -NR 9 S(O) 2 R 10 , -S(O)R 9 , -S(O)NR 9 R 10 , -NR 9 S(O)R 10 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 optionally substituted with cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl; R 3 and R 4 are independently halogen, OH, CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Haloalkoxy, or -C(O)NR9 R 10 and; R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 -, -S(O) 2 R 9 , -C(O)R 9 , -C(O)OR 9 , -NR 9 S(O) 2 R 10 , -S(O)R 9 , -S(O)NR 9 R 10 , -NR 8 S(O)R 9 and; R 9 and R 10 are independently, H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8is a cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; R 11 and R 12 are independently, H, C 1 ~C 6 Alkyl, OH, NH 2 , CN, or NO 2 and; R 13 are independently for each occurrence a bond, H, or C. 1 ~C 6 Alkyl, C 4 ~C 8 Cycloalkenyl, C 3 ~C 8 cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R 19 is optionally replaced by; R 14 are independently defined for each occurrence: H, C 1 ~C 6 Alkyl, or C 1 ~C 6 is haloalkyl; or R 6 and R 14 may combine together with the atom to which they are attached to form, independently at each occurrence, a 5- to 6-membered heterocyclyl, where each C 3 ~C 8 Cycloalkyl or heterocyclyl can be one or more R 19 is optionally replaced by; or R 13 and R 14 are combined with the atoms to which they are attached, and each occurrence is 3 ~C 8 may form a cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where each heterocyclyl or heteroaryl may be selected from one or more R19 is optionally replaced by; R 15 , R 16 , R 17 , and R 18 are independently H, OH, NH 2 , or C 1 ~C 3 alkyl, said alkyl being selected from one or more R 19 is optionally replaced by; R 19 are independently H, OH, NH 2 , Oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 H haloalkyl, C 1 ~C 6 [alkoxy].

[0091] It should be noted that in many structures illustrated herein, various linkages or bonds are not all shown in each example.However, this should not be considered in a limiting sense.Rather, it should be understood that NHE inhibitory molecules are linked or connected in some way (e.g., by bond or linker) so that the resulting NHE inhibitory compound is suitable for use (i.e., substantially impermeable in GI tract or substantially systemically non-bioavailable).

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

[0093] In one embodiment of the invention, the linker is -heterocyclyl-(CHR 13 ) p -[Y-(CH 2 ) r ] s In another embodiment of the invention, the linker is, but is not limited to, [ka] It can be represented by:

[0094] In another embodiment, the linker may be, 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 C 1 ~C 6 In some embodiments, R 1 and R 2 is methyl.

[0096] In another embodiment of the compound of formula I, R1 and R 2 may be taken together with the nitrogen to which they are attached to form a heterocyclyl or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O. In some embodiments of the compounds of Formula I, R 1 and R 2 However, the heterocyclyl or heteroaryl formed together with the nitrogen to which they are attached may contain one or more H, halogen, -NR 9 R 10 , or C 1 ~C 6 Optionally substituted with alkyl.

[0097] In another embodiment of the compound of formula I, R 1 and R 2 may be taken together with the nitrogen to which they are attached to form a heterocycle. In some embodiments of the compounds of formula I, R 1 and R 2 In another embodiment of the compound of formula I, R 1 and R 2 may also form a piperidine or piperazine together with the nitrogen to which they are attached. In further embodiments of the compounds of formula I, the piperidine or piperazine may be one or more of oxo, halogen, -NR 9 R 10 , or C 1 ~C 6 It is optionally substituted with alkyl, hi one particular embodiment, the piperazine is substituted with methyl.

[0098] In some embodiments of the compound of formula I, R 9 and R 10 is C 1 ~C 6 In another embodiment, R 9 and R 10 is methyl. In some embodiments of the compound of formula I, R 3 is halogen, CN, C 1 ~C6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, or C 1 ~C 6 In some embodiments of the compounds of formula I, R 3 is halogen, CN, or C 1 ~C 6 In one embodiment, R 3 is CN. In some embodiments, R 3 is F, Cl, CN, or methyl.

[0099] In some embodiments of the compound of formula I, R 4 is halogen or C 1 ~C 6 In some embodiments of the compound of formula I, R 4 is F, Cl, or methyl. In one embodiment, R 3 is CN and R 4 is Cl.

[0100] In another embodiment of the compound of formula I, R 5 H, halogen, C 1 ~C 6 Alkyl, or OR 9 In yet another embodiment, R 5 is H, F, or methyl.

[0101] In another embodiment of the present invention, R 6 , R 7 , and R 8 is H, halogen, or C1-C6 alkyl. 6 , R 7 , and R 8 are all H. Halogen or alkyl substituents are R 6 It is built into R 5 , R 7 and R 8Compounds of the invention in which R is each H have been observed to exhibit low interaction with cytochrome enzymes. 5 , R 7 and R 8 are H and R, respectively. 6 is halogen or C 1~6 In one embodiment, R 5 , R 7 and R 8 are H and R, respectively. 6 is F. In one embodiment, R 5 , R 7 and R 8 are H and R, respectively. 6 But it's Me.

[0102] In another embodiment of the compound of formula I, Q is -NHC(O)NH-. In one particular embodiment, Q is -NHC(O)NH- and the linker is -heterocyclyl-(CHR 13 ) p -[Y-(CH 2 ) r ] s In one particular embodiment, Q is -NHC(O)NH- and the linker is -heterocyclyl-(CHR 13 ) p -[Y-(CH 2 ) r ] s - and u is 0. In one particular embodiment, Q is -NHC(O)NH- and the linker is -heterocyclyl-(CHR 13 ) p -[Y-(CH 2 ) r ] s -, u is 0 and n is 2. In one particular embodiment, Q is -NHC(O)NH- and the linker is -heterocyclyl-(CHR 13 ) p -[Y-(CH 2 ) r ] s -, u is 0, n is 2, and X is -(CHR 13 ) p - or C3 ~C 6 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 are all 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 In another embodiment of the compound of formula I, R 15 and R 17 is H and R 16 and R 18 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 , H, C 1 ~C 6 In some embodiments of the compounds of formula I, R 13 The heterocyclyl or heteroaryl of 19 In some embodiments, R 13 is one or more R 19 In some embodiments, R is a heterocyclyl optionally substituted with 19 is oxo. In some embodiments, n is 2. In other embodiments of the compounds of formula I, n is 3 or 4.

[0106] In one embodiment of the invention, the compound of formula I has formula Ia or Ia': [ka] has.

[0107] In one embodiment of the invention, the compound of formula I has formula Ib or Ib': [ka] have [In the formula, The ring Het is R 1 and R 2 may together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P and O, wherein the heterocyclyl or heteroaryl group is selected from one or more of halogen, OH, CN, -NO 2 , Oxo, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 -, -S(O) 2 R 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 9 R 10 , -NR 9 S(O) 2 R 10 , -S(O)R 9 , -S(O)NR 9 R 10 , -NR 9 S(O)R 10 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8optionally substituted with cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl.

[0108] In one embodiment of the invention, the compound of formula I has formula Ic or Ic': [ka] wherein Het B is C 3 ~C 8 represents a cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where each heterocyclyl or heteroaryl is selected from one or more R 19 [optionally replaced by ].

[0109] In one embodiment of the invention, the compound of formula I has formula Id or Id': [ka] wherein Het is C 4 ~C 8 Cycloalkenyl, C 3 ~C 8 R represents cycloalkyl, heterocyclyl, aryl, or heteroaryl 13 where each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R 19 [optionally replaced by ].

[0110] In one embodiment of the invention, the compound of formula I has formula Ie or Ie': [ka] wherein ring Het A is R 1 and R 2may together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P and O, wherein the heterocyclyl or heteroaryl group may further comprise one or more of halogen, OH, CN, -NO 2 , Oxo, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 -, -S(O) 2 R 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 9 R 10 , -NR 9 S(O) 2 R 10 , -S(O)R 9 , -S(O)NR 9 R 10 , -NR 9 S(O)R 10 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 optionally substituted with cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl; Het is C 4 ~C 8 Cycloalkenyl, C 3 ~C 8 R represents cycloalkyl, heterocyclyl, aryl, or heteroaryl 13 where each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is selected from one or more R 19 [optionally replaced by ].

[0111] In one embodiment of the invention, the compound of formula I has the formula If or If': [ka] has.

[0112] In one embodiment of the invention, the compound of formula I has formula Ig or Ig': [ka] has.

[0113] In one embodiment of the invention, the compound of formula I has formula Ih or Ih': [ka] [Wherein: Het is R 6 and R 14 represent, independently for each occurrence, together with the atom to which they are attached, a 5- or 6-membered heterocyclyl.

[0114] In one embodiment of the invention, the compound of formula I has formula Ii or Ii': [ka] has.

[0115] In other embodiments, compounds of formula I include, but are not limited to, the following: 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl ]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl ]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 1-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl ]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4 -[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden 1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 1-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea dihydrochloride; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2, 3-Dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene) sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3 -[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl yl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy )ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl] Oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea; 3-[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea; 3-[(4-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea; 3-[(4-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea; 3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)cal Bamoyl]amino]butyl)urea; 3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea; 3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea; 3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea; 1-([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-3-(4-[[([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)carbamoyl]amino]butyl)urea; (2R, 3S, 4R, 5S)-N 1 ,N 6 -bis([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-2,3,4,5-tetrahydroxyhexanediamide; 3-[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)methyl]-1-[4-([[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)methyl]carbamoyl]amino)butyl]urea; 3-[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]hexyl]-1H-1,2,3-triazol-4-yl)methyl]-1-[4-([[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]hexyl]-1H-1,2,3-triazol-4-yl)methyl]carbamoyl]amino)butyl]urea; (4R, 4aS, 8S, 8aR)-N 4 ,N 8 -Bis([1-(4-[4-((1S,2 S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenyl sulfonamido]butyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-tetrahydro-[1,3]dioxino[5,4-d][1,3]dioxine-4,8-dicarboxamide; (4R, 4aS, 8S, 8aR)-N 4 ,N 8-bis([1-(6-[4-((1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenylsulfonamido]hexyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-tetrahydro-[1,3]dioxino[5,4-d][1,3]dioxine-4,8-dicarboxamide; 3-[8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea; 3-[8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea; 3-[8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea; 3-[8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2S)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2S)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.1]heptan-2-yl]-4,6-dichloro-2,3-dihydro-1H-indene- 1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.1]heptan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 1-[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.2]octan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.2]octan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.2.1]octan-8-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.2.1]octan-8-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 1-[2-(2-[2-[(4-[[(1S,2S)-2-[9-azabicyclo[3.3.1]nonan-9-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[9-azabicyclo[3.3.1]nonan-9-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl 3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([ ... ]-3-Methylbenzene)sulfonamido]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)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)ethoxy]ethoxy]ethyl)sulfamoyl]phenoxy]-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperazine-1-carboxamide; 4-[(1S,2S)-4,6-dichloro-1-[4-[(2-[2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[4-(dimethylcarbamoyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)ethoxy]ethoxy]ethyl)sulfamoyl]-2-methylphenoxy]-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperazine-1-carboxamide; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyric acid 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;hydrochloride; 1-[2-(2-[2-[(3-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,4-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[( 4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidine Lysin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;hydrochloride; 1-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-difluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-difluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3,5-difluorophenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]-3,5-difluorobenzenesulfonamide; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([ [2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea; 1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea; 3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]piperidin-4-yl]oxy)ethoxy]ethyl]-1-[4-[([2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]piperidin-4-yl]oxy)ethoxy]ethyl]carbamoyl)amino]butyl]urea; 1-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-3-(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea;hydrochloride; 3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R )-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea; 3-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea dihydrochloride; 3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea; 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-2-methylpropoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-2-methylpropoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;hydrochloride; 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 4-([(1S,2S)-2-[(R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-2-[(R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy)-2-chlorophenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9 ,11,16,18-tetraazahexacosyl]-2-chlorobenzenesulfonamide;4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide;tetra(trifluoroacetate); 4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamido; tetra(trifluoroacetate); 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; tetra(trifluoroacetate); 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; tetra(trifluoroacetate); 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide; tetra(trifluoroacetate); 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide; tetra(trifluoroacetate); 4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)-3-fluorobenzenesulfonamide; tetra(trifluoroacetate); 4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)-3-fluorobenzenesulfonamide; tetra(trifluoroacetate); 4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamido; tetra(trifluoroacetate); 4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamido; tetra(trifluoroacetate); 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)piperidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidin-1-yl]-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl)pyrrolidin-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-[(2S,13S)-14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidin-1-yl]-2,13-dimethyl-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl]pyrrolidin-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]sulfonamido)pyrrolidin-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]sulfonamido)pyrrolidin-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-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)piperidin-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide; -([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido]piperidin-1-yl)-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl]piperidin-4-yl)benzenesulfonamide; 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]piperidin-1-yl)-5,12-dioxo-4,6,11,13-tetraazahexadecyl]piperidine-4-carboxamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(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)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[( S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; 4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazabicosyl)pyrrolidin-3-yl]benzenesulfonamide; 4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazabicosyl)pyrrolidin-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazine phenyl]sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-2-oxopiperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)-2-oxopiperidin-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[2-(2-[2-(3-[(1r,4r)-4-(3-[2-(2-[2-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)ethoxy]ethoxy)ethyl]ureido)cyclohexyl]ureido)ethoxy]ethoxy)ethyl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(18-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide; N-(2-[2-(2-aminoethoxy)ethoxy]ethyl)-4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide; N-[1-(4-aminobutanoyl)piperidin-4-yl]-4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-(3-oxo-7,10- Dioxa-2,4-diazadodecan-12-yl)benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-(1-[4-(3-methylureido)butanoyl]piperidin-4-yl)benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-yl]benzenesulfonamide; 4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-yl]piperidine-1-carboxamide; 4-(3-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-4-oxobutyl]ureido)-N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)butanamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(4-[3-(4-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-4-oxobutyl)ureido]butanoyl)piperidin-4-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[19-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecyl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-amido-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-amido-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide; 4-([(1S,2S)-4-cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-4-cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide; 1,1'-(butane-1,4-diyl)bis[3-(4-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinolin-2(1H)-yl]-4-oxobutyl)urea]; 1,1'-(butane-1,4-diyl)bis[3-(4-[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinolin-2(1H)-yl]-4-oxobutyl)urea]; N,N'-(6,14-dioxo-10-oxa-5,7,13,15-tetraazanona 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-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(18-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(18-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)piperidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide; N 1 ,N 14-bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide; 4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)piperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)piperidin-4-yl]benzenesulfonamide; 4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; N 1 ,N 14 -Bis(2-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-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-oxoisoindolin-2-yl]ethoxy)ethyl]urea; and 1,1'-(butane-1,4-diyl)bis(3-[2-(2-[5-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindolin-2-yl]ethoxy)ethyl]urea). (1S,2S)-1-(4-{[(3S)-1-[2-(2-{[(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-4-carboxy-6-chloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)-1-hydroxy-1λ 4 -pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)carbamoyl]amino}ethoxy)ethyl]-1-hydroxy-1λ 4 -pyrrolidin-3-yl]sulfamoyl}phenoxy)-6-chloro-2-[(3R)-3-methylpiperazin-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-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}(2,3,5,6- 2 H 4 )benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}(2,3,5,6- 2 H 4 )benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)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-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-4-cyano-6-methyl-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea; 3-(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)urea; N-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}-2-({[4-({[({2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}carbamoyl)methyl]carbamoyl}amino)butyl]carbamoyl}amino)acetamide; 3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzene benzenesulfonamido)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}benzenesulfonamido)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}benzenesulfonamido)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}benzenesulfonamido)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}benzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}cyclohexyl]urea; 3-(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}(1,1,2,2,3,3,4,4- 2 H 8 )Butyl)urea; 3-{4-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-4-oxobutyl}-1-{4-[({4-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-4-oxobutyl}carbamoyl)amino]butyl}urea; 3-{4-[4-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)piperidin-1-yl]-4-oxobutyl}-1-{4-[({4-[4-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)piperidin-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}benzenesulfonamido)pyrrolidin-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}benzenesulfonamido)pyrrolidin-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-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)piperidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[4-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)piperidin-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}benzenesulfonamido)pyrrolidin-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}benzenesulfonamido)pyrrolidin-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]pyrrolidin-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 -(CH 2 ) m In another embodiment, W is S(O). 2 In another embodiment, W is C(O). In another embodiment, W is -(CH 2 ) 2 In other embodiments, W is -(CH 2 )-.

[0117] In some embodiments, Y is O, S, NH, N(C 1 ~C 3 In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is NH. In some embodiments, Y is N(C 1 ~C 3 In some embodiments, Y is -C(O)NH-. In some embodiments, Y is O, S, NH, or N(C 1 ~C 3 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(CH 3 )-, or -NHC(O)NH-(CHR13 In some embodiments, Q is a bond, NH, -C(O)NH-, -NHC(O)NH-, or -NHC(O)N(CH 3 )-. 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)NH-. In some embodiments, Q is -NHC(O)N(CH 3 In some embodiments, Q is -NHC(O)NH-(CHR 13 ).

[0119] In some embodiments, R 1 and R 2 are independently, H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R 1 and R 2 are independently, H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 In some embodiments, R is cycloalkyl, heterocyclyl, or aryl. 1 and R 2 are independently, H, C 1 ~C 6Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 In some embodiments, R is cycloalkyl, or heterocyclyl. 1 and R 2 are independently, H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 In some embodiments, R is cycloalkyl, heterocyclyl, aryl, or heteroaryl. 1 and R 2 are independently, H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, or C 3 ~C 8 In some embodiments, R 1 and R 2 are independently, H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, or C 2 ~C 6 In some embodiments, R is alkynyl. 1 and R 2 are independently, H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, or C 4 ~C 8In some embodiments, R 1 and R 2 are independently, H, C 1 ~C 6 Alkyl, or C 2 ~C 6 In some embodiments, R is alkenyl. 1 and R 2 are independently H or C 1 ~C 6 In some embodiments, R 1 and R 2 are independently, H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from the group consisting of one or more halogen, OH, CN, -NO 2 , Oxo, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 -, -S(O) 2 R 9 , -C(O)R 9 , -C(O)OR 9 , -C(O)NR 9 R 10 , -NR 9 S(O) 2 R 10 , -S(O)R 9 , -S(O)NR 9 R 10 , -NR 8 S(O)R 9 , C 1 ~C 6 Alkyl, C2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 Optionally substituted with cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl.

[0120] In another embodiment, R 3 are halogens, OH, CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Haloalkoxy, or -C(O)NR 9 R 10 In one embodiment, R 3 are halogens, OH, CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, or C 1 ~C 6 In one embodiment, R 3 are halogens, OH, CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, or C 1 ~C 6 In one embodiment, R 3 are halogens, OH, CN, C 1 ~C 6 Alkyl, or C 1 ~C 6 In one embodiment, R 3 is a halogen, OH, CN, or C 1 ~C 6 It is an alkyl group. 3 is halogen, OH, or CN. In one embodiment, R3 is halogen or OH. In one embodiment, R 3 is a halogen. 3 is OH. In one embodiment, R 3 is CN. In one embodiment, R 3 is C 1 ~C 6 In one embodiment, R 3 is C 1 ~C 6 In one embodiment, R 3 is C 1 ~C 6 In one embodiment, R 3 is C 1 ~C 6 In one embodiment, R 3 is -C(O)NR 9 R 10 It is.

[0121] In another embodiment, R 4 are halogens, OH, CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Haloalkoxy, or -C(O)NR 9 R 10 In one embodiment, R 4 are halogens, OH, CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, or C 1 ~C 6 In one embodiment, R 4 are halogens, OH, CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, or C 1 ~C 6In one embodiment, R 4 are halogens, OH, CN, C 1 ~C 6 Alkyl, or C 1 ~C 6 In one embodiment, R 4 is a halogen, OH, CN, or C 1 ~C 6 It is an alkyl group. 3 Ha, ha In one embodiment, R is an alkylene, OH, or CN. 4 is halogen or OH. In one embodiment, R 4 is a halogen. 3 is OH. In one embodiment, R 4 is CN. In one embodiment, R 4 is C 1 ~C 6 In one embodiment, R 4 is C 1 ~C 6 In one embodiment, R 4 is C 1 ~C 6 In one embodiment, R 4 is C 1 ~C 6 In one embodiment, R 4 is -C(O)NR 9 R 10 It is.

[0122] In one embodiment, R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 -, -S(O) 2 R 9 , -C(O)R 9 , -C(O)OR 9 , -NR 9 S(O) 2 R 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 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 -, -S(O) 2 R 9 , -C(O)R 9 , -C(O)OR 9 , -NR 9 S(O) 2 R10 , -S(O)R 9 , -S(O)NR 9 R 10 In one embodiment, R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 -, -S(O) 2 R 9 , -C(O)R 9 , -C(O)OR 9 , -NR 9 S(O) 2 In one embodiment, R 10 , R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 -, -S(O) 2 R 9 , -C(O)R 9 , -C(O)OR 9 In one embodiment, R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 -, -S(O) 2 R 9 , -C(O)R 9 In one embodiment, R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 -, -S(O) 2 R 9 In one embodiment, R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 , -S(O) 2 N(R 9 ) 2 In one embodiment, R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 Cyclo alkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, -SR 9 , -OR 9 , -NHR 9 , -NR 9 R 10 In one embodiment, R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, -SR 9 , -OR 9 , -NHR 9 In one embodiment, R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, -SR 9 , -OR 9In one embodiment, R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, -SR 9 In one embodiment, R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 is a cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O. In one embodiment, R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8In one embodiment, R is cycloalkyl, heterocyclyl, or aryl. 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, C 3 ~C 8 In one embodiment, R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, C 2 ~C 6 Alkynyl, or C 3 ~C 8 In one embodiment, R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 4 ~C 8 Cycloalkenyl, or C 2 ~C 6 In one embodiment, R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6Alkyl, C 2 ~C 6 Alkenyl, or C 4 ~C 8 In one embodiment, R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, -NO 2 , C 1 ~C 6 Alkyl, or C 2 ~C 6 In one embodiment, R is an alkenyl. 5 , R 6 , R 7 , and BiR 8 are independently H, halogen, OH, CN, -NO 2 , or C 1 ~C 6 In one embodiment, R 5 , R 6 , R 7 , and R 8 are independently H, halogen, OH, CN, or -NO 2 In one embodiment, R 5 , R 6 , R 7 , and R 8 is independently H, halogen, OH, or CN. In one embodiment, R 5 , R 6 , R 7 , and R 8 is independently H, halogen, or OH. In one embodiment, R 5 , R 6 , R 7 , and R 8 are independently H or halogen.

[0123] In one embodiment, R 15 , R 16 , R 17 , and R 18 are independently H, OH, NH 2 , or C 1 ~C 3In a further embodiment, R 15 , R 16 , R 17 , and R 18 is independently H, OH, or NH 2 In a further embodiment, R 15 , R 16 , R 17 , and R 18 is independently at each occurrence H or OH. In a further embodiment, R 16 , R 17 , and R 18 are independently H, OH, NH 2 , or C 1 ~C 3 alkyl, wherein said alkyl is selected from one or more R 19 is optionally replaced by

[0124] In one embodiment, X is a bond, H, N, O, CR 11 R 12 , C.R. 11 , C, -NHC(O)NH-, or C 3 ~C 6 In one embodiment, X is a bond, H, N, O, CR 11 R 12 , C.R. 11 , C, or -NHC(O)NH-. In one embodiment, X is a bond, H, N, O, CR 11 R 12 , C.R. 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 12In 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, when 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 and n is 3. In another embodiment, X is C and n is 4. In another embodiment, X is -NHC(O)NH-. In another embodiment, X is C 3 ~C 6 It is cycloalkyl.

[0125] In some embodiments, R 14 , H, C 1 ~C 6 Alkyl, or C 1 ~C 6 In some embodiments, R 14 is H or C 1 ~C 6 In some embodiments, R 14 is H. In some embodiments, R 14 is C 1 ~C 6 In some embodiments, R 14 is C 1 ~C 6 It is haloalkyl.

[0126] In yet another embodiment, R 6 and R 14 may combine with the atoms to which they are attached to form a 5- to 6-membered heterocyclyl. 6 and R 14 may be combined together with the atom to which they are attached to form, independently at each occurrence, a 5- to 6-membered heterocyclyl, wherein said heterocyclyl is selected from one or more R 19 is optionally replaced by

[0127] In other embodiments, R 13 and R 14 are combined with the atoms to which they are attached, and each occurrence is 3 ~C 8 In another embodiment, R 13 and R 14 are combined with the atoms to which they are attached, and each occurrence is 3 ~C 8 In some embodiments, R 13 and R 14 are combined with the atoms to which they are attached, and each occurrence is 3 ~C 8 In some embodiments, R 13 and R 14 are combined with the atoms to which they are attached, and each occurrence is 3 ~C 8 In some embodiments, R 13 and R 14 may, independently at each occurrence, combine with the atom to which they are attached to form a heterocyclyl. 13 and R 14 may, independently at each occurrence, combine with the atom to which they are attached to form aryl. 13 and R 14 may be combined together with the atom to which they are attached to form, independently at each occurrence, heteroaryl.

[0128] In other embodiments, R 13 and R 14 are combined with the atoms to which they are attached, and each occurrence is 3 ~C 8cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each heterocyclyl or heteroaryl may be selected from one or more R 19 In another embodiment, R 13 and R 14 are combined with the atoms to which they are attached, and each occurrence is 3 ~C 8 cycloalkyl, heterocyclyl, or aryl, where each heterocyclyl may be selected from one or more R 19 is optionally replaced with In some embodiments, R 13 and R 14 are combined with the atoms to which they are attached, and each occurrence is 3 ~C 8 cycloalkyl or heterocyclyl, where each heterocyclyl may be one or more R 19 In some embodiments, R 13 and R 14 are combined with the atoms to which they are attached, and each occurrence is 3 ~C 8 In some embodiments, R 13 and R 14 may be combined together with the atom to which they are attached to form, independently at each occurrence, a heterocyclyl, where each heterocyclyl may be selected from one or more R 19 In some embodiments, R 13 and R 14 may, independently at each occurrence, combine with the atom to which they are attached to form aryl. 13 and R 14 may be combined together with the atom to which they are attached to form, independently at each occurrence, heteroaryl, where each heteroaryl is selected from one or more R 19 is optionally replaced by

[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 creating substantially impermeable or substantially systemically non-bioavailable NHE inhibitor compounds of the invention that can be utilized for the treatments detailed in this disclosure.

[0135] In another embodiment, compounds of the present invention with long hydrocarbon functional groups may collapse on their own in an intramolecular manner, resulting in an increase in the enthalpy barrier for interaction with the desired biological target. Therefore, when designing the "X" and linker moieties, they are designed to be resistant to hydrophobic collapse. For example, conformational constraints such as rigid monocyclic, bicyclic or polycyclic rings can be introduced into the "X" and linker moieties to increase the rigidity of the structure. Also, or 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 with 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 tract, or acids that are deprotonated. Such modifications will help to increase the hydrophilicity of the "X" and linker moieties and prevent hydrophobic collapse. Furthermore, such modifications will also contribute to the impermeability of the compound obtained by increasing tPSA.

[0136] Those skilled in the art can consider various functional groups that allow for easy and specific attachment of the "X" moiety and / or linker to the remainder of the molecule of the compound of formula I. These functional groups may include electrophiles that can react with nucleophilic groups and / or nucleophiles that can react with electrophilic "X" and linker moieties. Similarly, the NHE inhibitor compounds of formula I may be derivatized with, for example, boronic acid groups. The NHE inhibitor compounds of formula I may also contain alkynes or azides that can react with olefins via olefin metathesis chemistry, or with other suitable "X" and linkers via [2+3] cycloaddition.

[0137] It should be noted that one of ordinary skill in the art can envision several "X" and linker moieties that can be functionalized with suitable electrophiles or nucleophiles. Shown below is a series of such compounds that were selected based on several design considerations, including solubility, steric effects, and the ability to impart or match favorable structure-activity relationships. In this regard, however, it should be further noted that the structures provided below and above are merely for illustrative purposes and therefore should not be viewed in a limiting sense.

[0138] Exemplary electrophilic and nucleophilic linker moieties include, but are not limited to, the linker moieties illustrated in the Examples and below:

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

[0140] In another embodiment, the "X" moieties exemplified in the compounds of formula I may also include ether moieties, ester moieties, sulfide moieties, disulfide moieties, amine moieties, aryl moieties, alkoxyl moieties, and the like, including, but not limited to, the following: [ka] [ka] [Wherein bond breaking (i.e., wavy bonds passing through them, [ka] When n>1, p', q', r', and s' are each an attachment point to the remainder of the molecule of formula I, wherein said attachment points can be made using chemistry and functional groups known in the art of medicinal chemistry; and each p', q', r', and s' are each an attachment point to the remainder of the molecule of formula I, wherein ... said attachment points can be made using chemistry and functional groups known in the art of medicinal chemistry; or an independently selected integer ranging from about 0 to about 24, or from about 0 to about 16. In some cases, each p, q, r, and s can be an independently selected integer ranging from about 0 to 12. Additionally, R' can be a substituent moiety typically selected from moieties including halides, hydroxyls, amines, thiols, ethers, carbonyls, carboxyls, esters, amides, carbocycles, heterocycles, and combinations thereof.

[0141] In another approach, the "X" moiety of formula I may be a dendrimer, defined as a recursively branched molecule (see, e.g., J. M. J. Frechet, DATomalia, Dendrimers and Other Dendritic Polymers, John Wiley & Sons, Ltd. NY, NY, 2001), as shown below: [ka]

[0142] In this approach, the remainder of the NHE inhibitor molecule is attached to one, several or optionally all of the termini of the dendrimer via a linker. In another approach, the dendrimer building blocks named dendrons and exemplified above are used as "X" moieties to which the remainder of the NHE inhibitor molecule is attached to one, several or optionally all of the termini of the dendron. The generation number herein is typically about 0 to about 6, and about 0 to about 3 (generations are defined, for example, in JMJ Frechet, DA Tomaria, Dendrimers 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 exemplified in: (i) JMJ Frechet, DA Tomaria, Dendrimers and Other Dendritic Polymers, John Wiley & Sons, Ltd. NY, NY; (ii) George R Newkome, Charles N. Moorefield and Fritz Vogtle, Dendrimers 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 approach, the "X" moiety may be a polymeric or oligomeric moiety. A polymer or oligomer may each be considered independently, which may include alkyl (e.g., -CH 2-), substituted alkyl (e.g., -CHR-, where, for example, R is hydroxy), alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, aryl, heterocyclic, amine, ether, sulfide, disulfide, hydrazine, as well as repeating moieties selected from any of the foregoing substituted with moieties including oxygen, sulfur, sulfonyl, phosphonyl, hydroxyl, alkoxyl, amine, thiol, ether, carbonyl, carboxyl, ester, amide, alkyl, alkenyl, alkynyl, aryl, heterocyclic, as well as combinations thereof. In yet another approach, the "X" moiety may include repeating units resulting from the polymerization of ethylene monomers (such as the ethylene monomers listed elsewhere herein below).

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

[0145] Examples of polysaccharides useful in preparing such compounds include plant or animal derived materials, including, but not limited to, cellulosic materials, hemicelluloses, alkylcelluloses, hydroxyalkylcelluloses, carboxymethylcelluloses, sulfoethylcelluloses, starches, xylans, amylopectins, chondroitins, hyaluronic acid, heparins, guar, xanthan, mannans, galactomannans, chitins, and / or chitosans. More preferred, at least in some cases, are polymeric moieties that do not degrade or do not significantly degrade under the physiological conditions of the GI tract, such as, for example, carboxymethylcelluloses, chitosans, and sulfoethylcelluloses.

[0146] When free radical polymerization is used, the polymer portion can be prepared from various classes of monomers including, for example, acrylic acid, methacrylic acid, styrenic acid, vinyl acid, and dienoic acid, representative examples of which are: styrene, substituted styrene, alkyl acrylates, substituted alkyl acrylates, alkyl methacrylates, substituted alkyl methacrylates, acrylonitrile, methacrylonitrile, acrylamide, methacrylamide, N-alkyl acrylamide, N-alkyl methacrylamide, N,N-dialkyl acrylamide, N,N-dialkyl methacrylamide, isoprene, butadiene, ethylene, vinyl acetate, and combinations thereof. Functionalized versions of these monomers may be used, and any of these monomers may be used as comonomers with other monomers. For example, specific monomers or comonomers that can be used in the present 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-Dimethyl acrylate ethylaminoethyl, N,N-diethylaminoethyl acrylate, triethylene glycol acrylate, methacrylamide, N-methylacrylamide, N,N-dimethylacrylamide, N-tert-butylmethacrylamide, N-butylmethacrylamide, N-methylolmethacrylamide, N-ethylolmethacrylamide, N-tert-butylacrylamide, N-butylacrylamide, N-methylolacrylamide, N-ethylolacrylamide, 4-acryloylmorpholine, vinyl benzoate (all isomers), diethylamino Included are styrene (all isomers), α-methylvinylbenzoic acid (all isomers), diethylamino α-methylstyrene (all isomers), p-vinylbenzenesulfonic acid, p-vinylbenzenesulfonic acid sodium salt, 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. Main chain heteroatom polymeric moieties may also be used, including polyethyleneimines and polyethers, such as polyethylene oxide and polypropylene oxide, as well as copolymers thereof.

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

[0148] In one particular embodiment, the NHE inhibitor molecule is attached to one or both ends of the polymer chain. More specifically, in another alternative approach to the multivalent embodiments of the present disclosure, the polymer chain is attached to the following general exemplary structure: [ka] A macromolecule (e.g., a polymer or oligomer) having the moiety: [ka] [ka] [ka] [ka] may be illustrated, designed and / or constructed as described.

[0149] It is understood that any embodiment of the compounds of the invention as described above, and any specific substituents described herein in such compounds as described above, can be independently combined with other embodiments and / or substituents of such compounds to form embodiments of the invention not specifically described above.In addition, in the event that a list of substituents is recited for any particular substituent in a particular embodiment and / or claim, it is understood that each individual substituent may be removed from the particular embodiment and / or claim, and the remaining list of substituents is considered to be within the scope of the invention.Furthermore, it is understood that in this description, combinations of substituents and / or variables of the shown formula are only permitted if such contributions result in stable compounds.

[0150] B. Transparency In this regard, it should be noted that in various embodiments, the ability of a compound to be substantially systemically non-bioavailable is based on the charge, size, and / or other physicochemical parameters of the compound (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 rule, also known as the "rule of five." Although not a rule but rather a set of guidelines, 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 coefficients (Moriguchi Log P) greater than certain thresholds generally do not exhibit significant systemic concentrations (i.e., generally are not absorbed to a significant extent) (e.g., Lipinski et al., Advanced Drug Delivery Review, incorporated by reference). ews, 46, 2001 3-26). Thus, substantially systemically non-bioavailable compounds (e.g., substantially systemically non-bioavailable NHE inhibitor compounds) can be designed to have molecular structures that exceed 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, J. Pharm. & Toxicol. Methods, 44:235-249 (2000)). In some embodiments, for example, a substantially impermeable or substantially systemically non-bioavailable NHE inhibiting compound of the present disclosure can be prepared by a method comprising administering to a subject a compound having the following characteristics: (i) a MW (non-salt form of the compound) of greater than about 500 Da, about 1000 Da, about 2500 Da, about 5000 Da, about 10,000 Da, or more; (ii) a total number of NH and / or OH and / or other potential hydrogen bond donors of greater than about 5, about 10, about 15, or more; (iii) a total number of O atoms and / or N atoms and / or other potential hydrogen bond acceptors of greater than about 5, about 10, about 15, or more; and / or (iv) a total number of about 10 5 (i.e., a Log P of greater than about 5, about 6, about 7, etc.), or alternatively less than about 10 (i.e., a Log P of less than 1, or even 0).

[0151] In addition to the above parameters, molecular polar surface area (i.e., "PSA"), which can be characterized as the surface belonging to polar atoms, is also a descriptor that has been shown to correlate well with passive transport through membranes and thus allows prediction of transport properties of drugs. It has been successfully applied to predict intestinal absorption and Caco2 cell monolayer permeation (for details of Caco2 cell monolayer permeation studies, see, for example, Example 31 of U.S. Pat. No. 6,737,423, the entire contents of which are incorporated herein by reference for all relevant consistent purposes, and in particular, the description of the Caco2 model presented in the text of Example 31, which can be applied, for example, to the evaluation or testing of compounds of the present disclosure). PSA is expressed in Å2 (Angstroms squared) and is calculated from a three-dimensional molecular representation. Fast computational methods are now available using desktop computers and commercially available chemical graphic tool packages such as ChemDraw (see, e.g., Ertl et al., Journal of Medicinal Chemistry, 2000, 43, 3714-3717, the entire contents of which are incorporated herein by reference for all relevant consistent purposes). The term "topological PSA" (tPSA) has been coined for this fast computational method. tPSA correlates well with human absorption data for common drugs (see, e.g., Table 1 below): [Table 1] (Source: Ertl et al., J. Med. Chem., 2000, 43:3714-3717). Thus, in some preferred embodiments, the compounds of the present disclosure are substantially impermeable or substantially systemically non-bioavailable (as defined elsewhere herein) with a thickness of about 100 Å. 2 , about 120 Å 2 , about 130 Å 2 , or about 140 Å 2 , and in some instances, about 150 Å 2 , about 200Å 2 , about 250Å 2 , about 270Å 2 , about 300Å2 , about 400 Å 2 , or about 500 Å 2 Compounds of the present disclosure can be constructed to exhibit tPSA values ​​greater than

[0152] Since there are exceptions to Lipinski's "rule" or tPSA model, the permeability properties of the compounds of the present disclosure can be experimentally screened. Permeability coefficients can be determined by methods known to those skilled in the art, including, for example, by Caco-2 cell permeability assay and / or by using artificial membranes as models of gastrointestinal epithelial cells (see, for example, U.S. Patent No. 6,737,423, Example 31, incorporated herein by reference, for a description of the Caco-2 model, as described above). Synthetic membranes that mimic the net permeability properties of gastrointestinal mucosa, for example, impregnated with lecithin and / or dodecane, can be used as models of gastrointestinal mucosa. The membranes can be used to separate the compartments that contain the compounds of the present disclosure from the compartments that monitor the permeation rate. Parallel artificial membrane permeability assays (PAMPA) can also be performed. Such in vitro measurements can provide a reasonable indication of actual permeability in vivo (see, e.g., 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 potency of about 100×10 -6 Less than cm / s, or about 10×10 -6 Less than cm / s, or about 1×10 -6 Less than cm / s, or about 0.1×10 -6 Permeability coefficient P in less than cm / s app(e.g., the permeability experiments 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, according to the present disclosure, NHE inhibitor compound is modified as described above to inhibit net absorption through intestinal epithelial cell layer, and the obtained compound is substantially not bioavailable in the whole body.In various embodiments, the compound of the present disclosure is substantially impermeable or substantially not bioavailable in the whole body.More specifically, NHE inhibitor is a dimer, a multimer, a polymer moiety, so that the obtained compound is substantially impermeable or substantially not bioavailable in the whole body. The dimers, multimers or polymers may have a molecular weight of about 500 Daltons (Da), about 1000 Da, about 2500 Da, about 5000 Da, greater than about 10,000 Da or more, and in particular may have a molecular weight 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 a molecular weight high enough to essentially prevent any net absorption of the compound across the intestinal epithelial cell layer.

[0155] C. Sustained inhibitory effect In other embodiments, the substantially impermeable or substantially systemically non-bioavailable NHE inhibitor compounds utilized in the disclosed treatment methods may additionally exhibit a sustained inhibitory effect, manifested when the inhibitory action of a particular concentration of the compound (e.g., at or above its inhibitory concentration, IC) in equilibrium with epithelial cells does not return to baseline after depletion of the compound by simple washing of the luminal contents (i.e., sodium transport without the inhibitor).

[0156] This effect can be interpreted as the result of the tight binding of NHE inhibitory compound to NHE protein at the intestinal apical side of intestinal epithelial cells.This binding can be considered as being apparently irreversible, since after compound is contacted with intestinal epithelial cells and then washed away, the sodium transport flux is still significantly lower than in control without compound.This sustained inhibitory effect has the distinct advantage of maintaining drug activity in the GI tract, even when the residence time of active substance in the upper GI tract is short, and when the enterobiliary recirculation process is not effective to replenish compound concentration near the site of action.

[0157] Such a sustained inhibitory effect has clear advantages not only in terms of patient compliance but also in limiting drug exposure within the GI tract.

[0158] The sustained effect can be determined using in vitro methods; in one case, a cell line expressing an NHE transporter is split into different vials and treated with an NHE inhibitor compound and sodium solution to measure the rate of sodium uptake. The cells in one set of vials are washed for various times 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 (when compared to the inhibitory effect measured in a vial without washing) are sustained inhibitors. The sustained effect can also be characterized ex vivo by using the everted pouch technique, where Na transport is monitored using excised segments of the GI perfused with a solution containing the inhibitor, followed immediately by flushing the bath with a buffer solution without the inhibitor. The sustained effect can also be characterized in vivo by observing the time it takes for the sodium balance to return to normal when the inhibitor treatment is discontinued. A limitation of the method is that the apical cells The main advantage of this approach lies in the fact that the NHE transporter (and thus the apical NHE transporter) is shed after 3-4 days, which is the typical turnover time of intestinal epithelial cells. A sustained effect can be achieved by increasing the residence time of the active compound at the apical surface of the intestinal epithelial cells; this can be obtained by designing the NHE antiport inhibitor with several NHE inhibitor molecules or oligomers ("several" as used herein typically means at least about 2, about 4, about 6 or more). An example of such a structure in the context of analogues of the antibiotic vancomycin is given in Griffin et al., J.Am.Chem.Soc., 2003, 125, 6517-6531. Alternatively, the compound contains a group that contributes to increasing its affinity for intestinal epithelial cells to increase the contact time with the intestinal epithelial cell surface. Such a group is referred to as "mucoadhesive". More specifically, "X" and the linker moiety can be substituted by such mucoadhesive 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 incorporating a cyano group at the 4-position of the indane ring system of formula I unexpectedly exhibited superior and more persistent inhibition of NHE3 in the cell-based assay described in Example 181 herein, compared to compounds incorporating other groups at the 4- and 6-positions. For example, compounds incorporating 4-cyano and 6-chloro groups demonstrated superior and more persistent inhibition compared to similar compounds with 4,6-dichloro substituted indane ring systems. 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-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-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-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3R)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)urea. (B-Cl) N-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}-2-({[4-({[({2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-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-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide)pyrrolidin-1-yl]-2-oxoethyl}-2-({[4-({[({2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamide) Pyrrolidin-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-fluorobenzenesulfonamido)pyrrolidin-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-fluorobenzenesulfonamido)pyrrolidin-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)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)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-fluorobenzenesulfonamido)pyrrolidin-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-fluorobenzenesulfonamido)pyrrolidin-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-fluorobenzenesulfonamido)pyrrolidin-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-fluorobenzenesulfonamido)pyrrolidin-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-fluorobenzenesulfonamido)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-fluorobenzenesulfonamido)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-fluorobenzenesulfonamido)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-fluorobenzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea. (E-Cl) 3-(2-{2-[2-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)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)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)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-methylbenzenesulfonamido)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-methylbenzenesulfonamido)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-methylbenzenesulfonamido)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-methylbenzenesulfonamido)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}benzenesulfonamido)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}benzenesulfonamido)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}benzenesulfonamido)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}benzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea. [Table 9]

[0160] Thus, in one embodiment of the present invention, there is provided a compound having a structure according to any one of formulas (I') and (Ia')-(Ii').

[0161] D. GI enzyme resistance It is also desirable that the compounds used in the treatment methods of the present disclosure are substantially systemically non-bioavailable and / or exhibit sustained inhibitory effects, so that during their long residence time in the intestine, these compounds sustain the hydrolysis conditions that prevail in the upper GI tract.In such embodiments, the compounds of the present disclosure are resistant to enzymatic metabolism.For example, the compounds administered are resistant to the activity of P450 enzymes, glucurosyltransferases, sulfotransferases, glutathione S-transferases, etc. in the intestinal mucosa, as well as the activity of gastric enzymes (e.g., gastric lipase, and pepsin), pancreatic enzymes (e.g., trypsin, triglyceride pancreatic lipase, phospholipase A2, endonucleases, nucleotidases, and alpha-amylases), and brush border enzymes (e.g., alkaline phosphatase, glycosidases, and proteases) commonly known in the art.

[0162] The compounds used in the methods of the present disclosure are also resistant to metabolism by the gut flora; i.e., the compounds are not substrates for enzymes produced by the flora. In addition, the compounds administered according to the methods of the present disclosure may be substantially inactive against the gastrointestinal flora and do not disrupt bacterial growth or survival. As a result, in various embodiments herein, the minimum inhibitory concentration (or "MIC") against the GI flora is desirably greater than about 15 μg / ml, about 30 μg / ml, about 60 μg / ml, about 120 μg / ml, or even 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] Those skilled in the art of medicinal chemistry will appreciate that metabolic stability can be achieved in several ways. Functional groups susceptible to oxidation via P450s can be modified, for example, by removing halogens or other functional groups. Alternatively, electron-withdrawing groups can be added to the conjugate system to generally provide protection against oxidation by reducing the electrophilicity of the compound. Proteolytic stability can be achieved by avoiding secondary amide bonds or by incorporating stereochemical changes or other modifications that otherwise prevent the drug from being recognized as a substrate by metabolic enzymes.

[0164] E. Sodium and / or fluid output It should also be noted that in various embodiments of the disclosure, one or more of the NHE inhibitor compounds detailed herein, when administered to a patient in need thereof, either alone or in combination with one or more additional pharmacologic active compounds or agents (e.g., liquid-absorbing polymers, etc.), can act to increase the patient's daily fecal sodium output by at least about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 125, about 150 mmol or more, e.g., 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] Additionally or alternatively, it should be noted that in various embodiments of the present disclosure, one or more of the NHE inhibitor compounds detailed herein, when administered alone or in combination with one or more additional pharma- ceutical active compounds or agents (e.g., fluid-absorbing polymers, etc.) to a patient in need thereof, can act to increase the patient's daily fluid output 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, about 1000 ml or more, e.g., 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 the present disclosure, one or more of the NHE inhibitor compounds detailed herein, when administered to a patient in need thereof at a dose that results in an increase in fecal moisture content of at least 10%, alone or in combination with one or more additional pharmacologic active compounds or agents (e.g., liquid-absorbing polymers, etc.), inhibits IC at NHE-3. 50 Lower, more specifically, IC 50and, even more specifically, less than about 10× (10-fold) of the IC 50 C is less than about 100 × (100 times) max It should also be noted that

[0167] Additionally or alternatively, in various embodiments of the present disclosure, one or more of the NHE inhibitor compounds detailed herein, when administered to a patient in need thereof, alone or in combination with one or more additional pharmacologic active compounds or agents (e.g., liquid-absorbing polymers, etc.), provide a C of less than about 10 ng / ml, about 7.5 ng / ml, about 5 ng / ml, about 2.5 ng / ml, about 1 ng / ml, or about 0.5 ng / ml. max and C max It should also be noted that, for example, the concentration is within the range of about 1 ng / ml to about 10 ng / ml, or about 2.5 ng / ml to about 7.5 ng / ml.

[0168] Additionally or alternatively, in various embodiments of the disclosure, one or more of the NHE inhibitor compounds detailed herein have an IC of less than about 10 μM, about 7.5 μM, about 5 μM, about 2.5 μM, about 1 μM, or about 0.5 μM when administered alone or in combination with one or more additional pharma- ceutical active compounds or agents (e.g., liquid-absorbing polymers, etc.) to a patient in need thereof. 50 The IC may have 50 It should also be noted that, for example, is in the range of about 1 μM to about 10 μM, or about 2.5 μM to about 7.5 μM. It is.

[0169] Additionally or alternatively, in various embodiments of the disclosure, one or more of the NHE inhibitor compounds detailed herein have an IC of at least about 10, about 50, about 100, about 250, about 500, about 750, or about 1000 when administered to a patient in need thereof. 50 :C max Ratio (where IC 50 and C max It should also be noted that the σ may have the same units.

[0170] Additionally or alternatively, in various embodiments of the present disclosure, one or more of the NHE inhibitor compounds detailed herein, when administered orally within a therapeutic range or concentration to a patient in need thereof, inhibits C max The maximum compound concentration detected in serum is defined as the NHE inhibitory concentration IC 50 As noted above, as used herein, IC 50 is defined as a quantitative measure indicating the concentration of a compound required to inhibit 50% of the NHE-mediated Na / H antiport activity in a cell-based assay.

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

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

[0173] In one embodiment, there is provided a method 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, comprising administering to a mammal in need thereof a pharma- ceutical effective amount of a compound or pharmaceutical composition as described above. In another embodiment, the disorder includes, but is not limited to, gastrointestinal motility disorders, irritable bowel syndrome, chronic constipation, chronic idiopathic constipation, chronic constipation occurring in cystic fibrosis patients, chronic constipation occurring in chronic kidney disease patients, calcium-induced constipation occurring in osteoporosis patients, opioid-induced constipation, functional gastrointestinal disorders, gastroesophageal reflux disease, functional heartburn, dyspepsia, functional dyspepsia, non-ulcer dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, Crohn's disease, ulcerative colitis and a related disorder called inflammatory bowel syndrome, colonic pseudo-obstruction, gastric ulcers, infectious diarrhea, cancer (colorectal), "leaky gut syndrome", cystic fibrosis gastrointestinal disease, multiple organ failure, microscopic colitis, necrotizing Enterocolitis, Allergy-Atopy, Food Allergy, Infection (Respiratory), Acute Inflammation (e.g., Sepsis, Systemic Inflammatory Response Syndrome), Chronic Inflammation (Arthritis), Obesity-Induced Metabolic Disease (e.g., Nonalcoholic Steatohepatitis, Type I Diabetes, Type II Diabetes, Cardiovascular Disease), Kidney Disease, Diabetic Kidney Disease, Cirrhosis, Nonalcoholic Steatohepatitis, Nonalcoholic Fatty Acid Liver Disease, Steatosis, Primary Sclerosing Cholangitis, Primary Biliary Cholangitis, Portal Hypertension, Autoimmune Disease (e.g., Type 1 Diabetes, Ankylosing Spondylitis, Lupus, Alopecia Areata, Rheumatoid Arthritis, Rheumatic Polymyalgia, Fibromyalgia, Chronic Fatigue Syndrome, Sjogren's Syndrome, Vitiligo, Thyroiditis, Vasculitis, These include measles (hives), Raynaud's syndrome, schizophrenia, autism spectrum disorder, hepatic encephalopathy, and chronic alcoholism.

[0174] In another embodiment, there is provided a method for treating hypertension comprising administering to a mammal in need thereof a pharma- ceutical effective amount of a compound or pharmaceutical composition as described above.

[0175] In a further embodiment, the method comprises administering to the mammal a pharma- ceutical effective amount of the compound to increase the mammal's daily fecal output of sodium and / or bodily fluid. In a further embodiment, the method comprises administering to the mammal a pharma- ceutical effective amount of the compound to increase the mammal's daily fecal output of at least about 30 mmol of sodium and / or at least about 200 ml of bodily fluid. In a further embodiment, the mammal's fecal output of sodium and / or bodily fluid is increased in a stoichiometric or near stoichiometric manner via an ion exchange process without introducing another type of cation. In a further embodiment, the method further comprises administering to the mammal a fluid-absorbing polymer that absorbs fecal fluid resulting from the use of a compound substantially active in the gastrointestinal tract to inhibit NHE-mediated antiport of sodium and hydrogen ions.

[0176] In a further embodiment, the compound or composition is administered to treat hypertension. In a further embodiment, the compound or composition is administered to treat hypertension associated with dietary salt intake. In a further embodiment, administration of the compound or composition allows the mammal to consume a more palatable diet. In a further embodiment, the compound or composition is administered to treat fluid overload. In a further embodiment, the fluid overload is associated with congestive heart failure. In a further embodiment, the fluid overload is associated with end stage renal disease. In a further embodiment, the fluid overload is associated with peroxisome proliferator-activated receptor (PPAR) gamma agonist therapy. In a further embodiment, the compound or composition is administered to treat sodium overload. In a further embodiment, the compound or composition is administered to reduce interdialytic weight gain in ESRD patients. In a further embodiment, the compound or composition is administered to treat edema. In a further embodiment, the edema is due to chemotherapy, premenstrual fluid overload, or preeclampsia.

[0177] In a further embodiment, the compound or composition is administered to treat gastric ulcers. In a further embodiment, the compound or composition is administered to treat infectious diarrhea. In a further embodiment, the compound or composition is administered to treat cancer (colorectal). In a further embodiment, the compound or composition is administered to treat "leaky gut syndrome". In a further embodiment, the compound or composition is administered to treat cystic fibrosis gastrointestinal disease. In a further embodiment, the compound or composition is administered to treat multiple organ failure. In a further embodiment, the compound or composition is administered to treat microscopic colitis. In a further embodiment, the compound or composition is administered to treat necrotizing enterocolitis. In a further embodiment, the compound or composition is administered to treat atopy. In a further embodiment, the compound or composition is administered to treat food allergies. In a further embodiment, the compound or composition is administered to treat respiratory infections. In a further embodiment, the compound or composition is administered to treat acute inflammation (e.g., sepsis, systemic inflammatory response syndrome). In a further embodiment, the compound or composition is administered to treat chronic inflammation (e.g., arthritis). In a further embodiment, the compound or composition is administered to treat obesity-induced metabolic disease (e.g., non-alcoholic steatohepatitis, type I diabetes, type II diabetes, cardiovascular disease). In a further embodiment, the compound or composition is administered to treat renal disease. Further embodiments In an embodiment, the compound or composition is administered to treat diabetic kidney disease. 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 steatohepatitis. 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 an autoimmune disease (e.g., type 1 diabetes, ankylosing spondylitis, lupus, alopecia areata, rheumatoid arthritis, polymyalgia rheumatica, fibromyalgia, chronic fatigue syndrome, Sjogren's syndrome, vitiligo, thyroiditis, vasculitis, urticaria (hives), 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 a further embodiment, the compound or composition is administered orally, by rectal suppository, or by enema.

[0179] In a further embodiment, the method comprises administering a pharmacologic effective amount of the compound or composition in combination with one or more additional pharmacologic active compounds or agents. In a further embodiment, the one or more additional pharmacologic active compounds or agents are selected from the group consisting of 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, and peroxisome proliferator-activated receptor (PPAR) gamma agonist agents. In a further embodiment, the diuretic is selected from the group consisting of high-potency loop diuretics, benzothiadiazide diuretics, potassium-sparing diuretics, and osmotic diuretics. In a further embodiment, the pharmacologic effective amount of the compound or composition and one or more additional pharmacologic active compounds or agents are administered as part of a single pharmaceutical formulation. In a further embodiment, a pharma- ceutical effective amount of the compound or composition and one or more additional pharma- ceutical active compounds or agents are administered as separate pharmaceutical formulations. In a further embodiment, the separate pharmaceutical formulations are administered sequentially. In a further embodiment, the separate pharmaceutical formulations are administered simultaneously.

[0180] In another embodiment, there is provided a method for treating a gastrointestinal disorder, comprising administering to a mammal in need thereof a pharma- ceutical effective amount of a compound or pharmaceutical composition as described above.

[0181] In a further embodiment, the gastrointestinal disorder is a gastrointestinal motility disorder. In a further embodiment, the gastrointestinal disorder is irritable bowel syndrome. In a further embodiment, the gastrointestinal disorder is chronic constipation. In a further embodiment, the gastrointestinal disorder is chronic idiopathic constipation. In a further embodiment, the gastrointestinal disorder is chronic constipation that occurs in cystic fibrosis patients. In a further embodiment, the gastrointestinal disorder is opioid-induced constipation. In a further embodiment, the gastrointestinal disorder is a functional gastrointestinal disorder. In a further embodiment, the gastrointestinal disorder is selected from the group consisting of chronic intestinal pseudo-obstruction and colonic pseudo-obstruction. In a further embodiment, the gastrointestinal disorder is Crohn's disease. In a further embodiment, the gastrointestinal disorder is ulcerative colitis. In a further embodiment, the gastrointestinal disorder is a disease referred to as inflammatory bowel disease. In a further embodiment, 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 a therapeutic drug. In a further embodiment, the gastrointestinal disorder is constipation and the constipation to be treated is associated with a neuropathic disorder. In a further embodiment, the gastrointestinal disorder is constipation and the constipation to be treated is post-operative constipation (post-operative ileus). In a further embodiment, the gastrointestinal disorder is constipation and the constipation to be treated is idiopathic (functional constipation or slow transit constipation). In a further embodiment, the gastrointestinal disorder is constipation and the constipation to be treated is associated with a neuropathic, metabolic or endocrine disorder (e.g., diabetes, renal failure, hypothyroidism, hyperthyroidism, hypocalcemia, multiple sclerosis, Parkinson's disease, spinal cord pathology, neurofibromatosis, autonomic neuropathy, Chagas' disease, Hirschsprung's disease or cystic fibrosis, etc.). In a further embodiment, the gastrointestinal disorder is constipation and the constipation to be treated is due to the use of a drug selected from analgesics (e.g., opioids), antihypertensives, anticonvulsants, antidepressants, antispasmodics and antipsychotics.

[0182] In other embodiments, the gastrointestinal disorder is gastric ulcer, infectious diarrhea, cancer (colorectal), "leaky gut syndrome", cystic fibrosis gastrointestinal disease, multiple organ failure, microscopic colitis, necrotizing enterocolitis, allergy-atopy, food allergy, infection (respiratory), acute inflammation (e.g., sepsis, systemic inflammatory response syndrome), chronic inflammation (arthritis), obesity-induced metabolic disease (e.g., non-alcoholic steatohepatitis, type I diabetes, type II diabetes, cardiovascular disease), renal disease, diabetic kidney disease, cirrhosis, non-alcoholic fatty liver disease, chronic obstructive pulmonary disease, chronic kidney disease, chronic obstructive pulmonary disease, chronic myocardial infarction ... associated with chronic steatohepatitis, nonalcoholic 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, Sjogren's syndrome, vitiligo, thyroiditis, vasculitis, urticaria (hives), or Raynaud's syndrome), schizophrenia, autism spectrum disorder, hepatic encephalopathy, small intestinal bacterial overgrowth, or chronic alcoholism.

[0183] In another embodiment, there is provided a method for treating irritable bowel syndrome, comprising administering to a mammal in need thereof a pharma- ceutical effective amount of a compound or pharmaceutical composition as described above.

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

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

[0186] In a further embodiment, the compound or composition is administered orally or by rectal suppository.

[0187] In a further embodiment, the method comprises administering a pharma- ceutical effective amount of the compound or composition in combination with one or more additional pharma- ceutical active compounds or agents. In a further embodiment, the one or more additional pharma- ceutical active agents or compounds are analgesic peptides or agents. In a further embodiment, the one or more additional pharma- ceutical active agents are The agent or compound is selected from the group consisting of laxatives selected from bulk-forming laxatives (e.g., psyllium husk (Metamucil)), methylcellulose (Citrucel), polycarbophil, dietary fiber, apple, stool softeners / surfactants (e.g., Docusate, Colace, Diocto), hydrating or osmolality adjusting agents (e.g., sodium phosphate dibasic, magnesium citrate, magnesium hydroxide (milk of magnesia), magnesium sulfate (which is an Epsom salt), sodium dihydrogen phosphate, sodium biphosphate), and hyperosmolality agents (e.g., glycerin suppositories, sorbitol, lactulose, and polyethylene glycol (PEG)). In a further embodiment, a pharmacologic effective amount of the compound or composition and one or more additional pharmacologic active compounds or agents are administered as part of a single pharmaceutical formulation. In a further embodiment, a pharmacologic effective amount of the compound or composition and one or more additional pharmacologic active compounds or agents are administered as separate pharmaceutical formulations. In a further embodiment, the separate pharmaceutical formulations are administered sequentially. In a further embodiment, 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 pharma- ceutically 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 pharma- ceutically acceptable carrier. In another embodiment, the pharmaceutical composition described herein can be used to inhibit NHE-mediated antiport of sodium and hydrogen ions. In 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 according to the present 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, liver disease, and / or peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention) generally comprise a substantially impermeable or substantially systemically non-bioavailable NHE-inhibiting compound of the present disclosure, as well as a variety of other optional components (e.g., pharma- ceutically acceptable additives, etc.) as further detailed herein below. Thus, the compounds used in the treatment methods of the present disclosure, as well as pharmaceutical compositions comprising same, 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 detailed elsewhere herein). In certain embodiments, the NHE-inhibiting compound, including any pharmaceutical composition comprising the compound, is administered together with a fluid-absorbing polymer (as more fully described below).

[0190] A subject "in need of treatment" with a compound of the present disclosure or a subject "in need of NHE inhibition" includes a subject having a disease and / or condition that can be treated with a substantially impermeable or substantially systemically non-bioavailable NHE inhibiting compound, with or without a liquid-absorbing polymer, to achieve a beneficial therapeutic and / or prophylactic outcome. Beneficial outcomes include reduced severity or delayed onset of symptoms, increased longevity and / or more rapid or more complete resolution of the disease or condition. For example, the subject in need of treatment may suffer from hypertension; salt-sensitive hypertension, which may result from dietary salt intake; risk of cardiovascular disorders (e.g., myocardial infarction, congestive heart failure, etc.) resulting from hypertension; heart failure (e.g., congestive heart failure) resulting in fluid or salt overload; 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, the subject in need of treatment typically exhibits signs of hypervolemia resulting from salt and fluid retention, which is a common feature of congestive heart failure, renal failure, or liver cirrhosis. Fluid retention may also be indicated by the occurrence of shortness of breath, edema, ascites, or weight gain between dialysis. Retention and salt retention appear.Other examples of subjects who may benefit from the treatment are subjects suffering from congestive heart failure and hypertensive patients, and in particular subjects who are resistant to treatment with diuretics, i.e., patients who have very few available treatment options.Subjects "in need of treatment" also include subjects with hypertension, salt-sensitive blood pressure, and subjects with systolic / diastolic blood pressure higher than about 130-139 / 85-89 mmHg.

[0191] Administration of an NHE-inhibiting compound with or without administration of a fluid-absorbing polymer may be beneficial for patients who have been placed on a "no salt" diet plan (i.e., 60-100 mmol Na per day) to liberalize their diet while maintaining a neutral or slightly negative sodium balance (i.e., total intake of salt is less than or equal to secreted salt). In that context, "liberalizing their diet" means that the patient being treated can add salt to their diet to make it more palatable and / or diversify their diet with foods that contain salt, thus maintaining good nutritional status while improving their quality of life.

[0192] The treatment methods described herein may also help patients with chemotherapy-related edema, premenstrual fluid overload and preeclampsia (pregnancy-induced hypertension).

[0193] Therefore, it should be noted that the present disclosure further relates to a method of treatment comprising administering the compound of the present disclosure or a pharmaceutical composition comprising such a compound. Such a method may include, for example, a method of treating hypertension, comprising administering to a patient a substantially impermeable or substantially systemically non-bioavailable NHE inhibitor compound or a pharmaceutical composition comprising the same. The method may be for reducing fluid overload associated with heart failure (particularly congestive heart failure), comprising administering to a patient a substantially impermeable or substantially systemically non-bioavailable NHE inhibitor compound or a pharmaceutical composition comprising the same. The method may be for reducing fluid overload associated with end-stage renal disease, comprising administering to a patient a substantially impermeable or substantially systemically non-bioavailable NHE inhibitor compound or a composition comprising the same. The method may be for reducing fluid overload associated with peroxisome proliferator-activated receptor (PPAR) gamma agonist therapy, the method comprising administering to the patient a substantially impermeable or substantially systemically non-bioavailable NHE inhibitor compound, or a composition comprising the same. Additionally or alternatively, the method may be for reducing intestinal NHE transporter activity in the patient, the method comprising administering to the patient a substantially impermeable or substantially systemically non-bioavailable NHE inhibitor compound, or a composition comprising 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, dyspepsia, functional dyspepsia, non-ulcer dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, Crohn's disease, ulcerative colitis and related disorders referred to as inflammatory bowel syndrome, colonic pseudo-obstruction, gastrointestinal dysbiosis, ... Ulcers, infectious diarrhea, cancer (colorectal), "leaky gut syndrome", cystic fibrosis gastrointestinal disease, multiple organ failure, microscopic colitis, necrotizing enterocolitis, allergy-atopy, food allergy, infection (respiratory), acute inflammation (e.g., sepsis, systemic inflammatory response syndrome), chronic inflammation (arthritis), obesity-induced metabolic disease (e.g., non-alcoholic steatohepatitis, type I diabetes, type II diabetes, cardiovascular disease), renal disease, diabetic kidney disease, 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, streptococcus aureus, fibromyalgia. These include fibromyalgia, chronic fatigue syndrome, Sjogren'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 a disorder associated with the digestive tract, comprising administering to a mammal in need thereof a pharmacologic effective amount of a compound or pharmaceutical composition of formula I. In one embodiment, the method for treating a disorder associated with the digestive tract comprises administering to a mammal in need thereof a pharmacologic effective amount of compound Ia, Ib, Ic, Id, Ie, If, Ig, Ih, or Ii, or a combination thereof.

[0195] The pharmaceutical compositions or formulations that can be used according to the present disclosure for the treatment of various gastrointestinal disorders, including the treatment or alleviation of pain associated with gastrointestinal disorders, include the substantially impermeable or substantially systemically non-bioavailable NHE inhibitor compounds of the present disclosure, as well as various other optional components (e.g., pharma- ceutically acceptable additives, etc.) as further detailed herein below.Thus, the compounds used in the treatment methods of the present disclosure, as well as pharmaceutical compositions that include 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 detailed elsewhere herein).In some specific embodiments, the NHE inhibitor compounds, including any pharmaceutical compositions that include NHE inhibitor compounds, are administered together with a liquid-absorbing polymer (as more fully described below).

[0196] A subject "in need of treatment" with a compound of the present disclosure or a subject "in need of NHE inhibition" includes a subject having a disease and / or condition that can be treated with a substantially impermeable or substantially systemically non-bioavailable NHE inhibiting compound, with or without a liquid-absorbing polymer, to achieve a beneficial therapeutic and / or prophylactic outcome. Beneficial outcomes include reduced severity or delayed onset of symptoms, increased longevity and / or more rapid or more complete resolution of the disease or condition. For example, the subject in need of treatment is suffering from a gastrointestinal disorder; the patient may be suffering from a gastrointestinal motility disorder, irritable bowel syndrome, chronic constipation, chronic idiopathic constipation, chronic constipation occurring in cystic fibrosis patients, chronic constipation occurring in chronic kidney disease patients, calcium-induced constipation occurring in osteoporosis patients, opioid-induced constipation, functional gastrointestinal disorder, gastroesophageal reflux disease, functional heartburn, dyspepsia, functional dyspepsia, non-ulcer dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, Crohn's disease, ulcerative colitis and a related disorder called inflammatory bowel syndrome, colonic pseudo-obstruction, gastric ulcers, infectious diarrhea, cancer (colorectal), "leaky gut syndrome", cystic fibrosis gastrointestinal disease, multiple organ failure, microscopic colitis, necrotizing enterocolitis, atopy, food allergies, infections (respiratory), acute inflammation (e.g., ulcerative colitis, bronch ... In one embodiment, the patient is suffering from a disorder selected from the group consisting of: diabetes mellitus, systemic inflammatory response syndrome, chronic inflammation (arthritis), obesity-induced metabolic disease (e.g., nonalcoholic steatohepatitis, type I diabetes, type II diabetes, cardiovascular disease), kidney disease, diabetic kidney disease, cirrhosis, nonalcoholic steatohepatitis, nonalcoholic fatty acid liver disease, steatosis, primary sclerosing cholangitis, primary biliary cholangitis, portal hypertension, autoimmune disease (e.g., type 1 diabetes, ankylosing spondylitis, lupus, alopecia areata, rheumatoid arthritis, polymyalgia rheumatica, fibromyalgia, chronic fatigue syndrome, Sjogren'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 a therapeutic agent; associated with a neuropathic disorder; associated with post-operative constipation (post-operative ileus); associated with a gastrointestinal disorder; associated with idiopathic (functional or slow transit constipation); associated with a neuropathic, metabolic or endocrine disorder (e.g., diabetes, renal failure, hypothyroidism, hyperthyroidism, hypocalcemia, multiple sclerosis, Parkinson's disease, spinal cord lesions, neurofibromatosis, autonomic neuropathy, Chagas' disease, Hirschheimer's disease, or other conditions. Constipation may also be the result of surgery (post-operative ileus) or due to the use of medications such as analgesics (e.g., opioids), antihypertensives, anticonvulsants, antidepressants, antispasmodics and antipsychotics.

[0198] In yet another embodiment, the constipation is caused by a condition such as gastric ulcer, infectious diarrhea, cancer (colorectal), "leaky gut syndrome", cystic fibrosis gastrointestinal disease, multiple organ failure, microscopic colitis, necrotizing enterocolitis, atopy, food allergy, infection (respiratory), acute inflammation (e.g., sepsis, systemic inflammatory response syndrome), chronic inflammation (arthritis), obesity-induced metabolic disease (e.g., nonalcoholic steatohepatitis, type I diabetes, type II diabetes, cardiovascular disease), kidney disease, diabetic kidney disease, cirrhosis, nonalcoholic fatty liver disease, and the like. It is associated with fatty hepatitis, nonalcoholic 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, Sjogren's syndrome, vitiligo, thyroiditis, vasculitis, urticaria (hives), Raynaud's syndrome), schizophrenia, autism spectrum disorder, hepatic encephalopathy, small intestinal bacterial overgrowth, and chronic alcoholism.

[0199] Therefore, it should be noted that the present disclosure also relates to a treatment method comprising the administration of the compound of the present disclosure or a pharmaceutical composition comprising such compound.Such a method may include, for example, a method for increasing gastrointestinal motility in a patient, comprising administering to the patient a substantially non-permeable or substantially non-bioavailable NHE inhibitor compound or a pharmaceutical composition comprising the same.In addition, or alternatively, the method may be for reducing the activity of intestinal NHE transporter in a patient, comprising administering to the patient a substantially non-permeable or substantially non-bioavailable NHE inhibitor compound or a pharmaceutical composition comprising the same. Additionally or alternatively, the method may be for treating gastrointestinal disorders, gastrointestinal motility disorders, irritable bowel syndrome, calcium induced constipation in osteoporosis patients, chronic constipation occurring in cystic fibrosis patients, chronic constipation occurring in chronic kidney disease patients, functional gastrointestinal disorders, gastroesophageal reflux disease, functional heartburn, dyspepsia, functional dyspepsia, non-ulcer dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, colonic pseudo-obstruction, Crohn's disease, ulcerative colitis, inflammatory bowel disease, which method comprises administering orally or by rectal suppository an antagonist of intestinal NHE, and more particularly a substantially non-permeable or substantially bioavailable NHE inhibiting compound, or a pharmaceutical composition comprising same. Additionally or alternatively, the method may be for treating or alleviating pain, including visceral pain, pain associated with gastrointestinal disorders or pain associated with some other disorders, comprising administering to a patient a substantially non-permeable or substantially non-bioavailable NHE-inhibiting compound, or a pharmaceutical composition comprising the same. Additionally or alternatively, the method may be for treating inflammation of the gastrointestinal tract, including inflammation associated with gastrointestinal disorders or infections or some other disorders, comprising administering to a patient a substantially non-permeable or substantially non-bioavailable NHE-inhibiting compound, or a pharmaceutical composition comprising the same.

[0200] 3. Metabolic disorders Pharmaceutical compositions or formulations that can be used in accordance with the present disclosure for the treatment of various metabolic disorders, including the treatment or alleviation of type II diabetes mellitus (T2DM), metabolic syndrome, and / or symptoms associated with such disorders, generally include the substantially impermeable or substantially systemically non-bioavailable NHE inhibitor compounds of the present disclosure, as well as various other optional components (e.g., pharma- ceutical acceptable additives, etc.) as further detailed herein below. Thus, the compounds used in the treatment methods of the present disclosure, as well as pharmaceutical compositions comprising same, 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 detailed elsewhere herein). In another embodiment, the pharmaceutical composition is a therapeutic agent for treating nonalcoholic steatohepatitis, type I and II diabetes, and In addition, it can be used to treat other metabolic diseases such as cardiovascular diseases.

[0201] Obesity is becoming a worldwide epidemic. In the United States, approximately two-thirds of the population is overweight (body mass index [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 the development of diabetes and related complications, including cardiovascular disease and chronic kidney disease (CKD). The prevalence of T2DM in the United States is growing alarmingly. The American Diabetes Association (ADA) estimates that over 23 million adult Americans aged 20 years or older have diabetes, and T2DM accounts for nearly 95% of these cases. The World Health Organization (WHO) estimates that the number of people with diabetes worldwide is approximately 170 million (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 syndrome and, subsequently, CKD. Metabolic syndrome, formerly known as syndrome X, multiple metabolic disorders syndrome, metabolic syndrome, and by other names, consists of a constellation 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, RR 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 syndrome is common in patients with CKD and is an important risk factor for the development and progression of CKD.

[0203] Hemodynamic factors appear to play a crucial role in obesity-induced renal dysfunction. Hypertension, which is closely related to obesity, appears to be the main cause of renal dysfunction in obese patients (Wahba,IMet al“Obesity and obesity-initiated metabolic syndrome:mechanistic 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 be caused by afferent arteriolar dilation as a result of proximal salt reabsorption, coupled with efferent renal arteriolar vasoconstriction as a result of elevated angiotensin II levels. These effects may contribute to hyperfiltration, glomerular hypertrophy, and late focal glomerulosclerosis. Although GFR is elevated in obesity, urinary sodium excretion in response to saline loading is often delayed and individuals exhibit abnormal pressure natriuresis, indicating voracious proximal tubular sodium reabsorption. In addition, increased fat distribution can lead to increased intraperitoneal pressure, leading to renal vein compression and therefore increased renal venous pressure and decreased renal perfusion. Increased fat can lead to increased renal interstitial fluid hydrostatics through various mechanisms, stimulating renal sodium retention and thereby contributing to hypertension (Wahba_2007).

[0204] In view of the above, it is desirable to develop a mechanism that bypasses the kidney or is not dependent on normal renal function. There is a need in the art for agents that can remove sodium and fluid from a subject. Subjects with metabolic diseases, including T2DM, metabolic syndrome, and the like, can be humans, but can also be animals, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.), in need of treatment with the compounds of the present disclosure.

[0205] Thus, the compounds used in the treatment methods of the present disclosure, as well as pharmaceutical compositions containing them, may be administered alone or as part of a combination therapy or regimen that includes the administration or use of other therapeutic compounds related to the treatment of metabolic disorders such as T2DM and metabolic syndrome. In some specific embodiments, the NHE inhibitor compound, including any pharmaceutical composition that contains the compound, is administered with a liquid-absorbing polymer.

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

[0207] B. Combination Therapy 1. Fluid retention and / or salt overload disorders As mentioned above, the compounds described herein can be used alone or in combination with other drugs.For example, the compounds can be administered with diuretics (i.e., high-potency loop diuretics, benzothiadiazido 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 agonist drugs or compounds, or with liquid-absorbing polymers, as described more fully below.The drugs can be covalently bound to the compounds described herein, or they can be separate drugs that are administered together 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, such as the substantially non-permeable or substantially systemically non-bioavailable NHE inhibitor compound described herein and a diuretic, a cardiac glycoside, an ACE inhibitor, an angiotensin-2 receptor antagonist, an aldosterone antagonist, an aldosterone synthase inhibitor, a renin inhibitor, a calcium channel blocker, a beta blocker, an alpha blocker, a central alpha agonist, a vasodilator, an anticoagulant, an antiplatelet drug 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 together with a separate formulation that includes a third drug. In combination therapy, two or more drugs can be administered simultaneously, but need not necessarily be. For example, the administration of a first drug (or combination of drugs) can be minutes, hours, days, or weeks before the administration of a second drug (or combination of drugs). Therefore, two or more drugs may be administered within minutes of each other or within 1, 2, 3, 6 The combination drugs may be administered within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9 weeks or more of each other. In some cases, even longer intervals are possible. In many cases, it is desirable for two or more drugs used in combination therapy to be present in the patient's body at the same time, although this need not be the case.

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

[0210] The compounds described herein can be used in combination therapy with diuretics. Useful diuretics include, for example, strong loop diuretics [furosemide (Lasix), ethacrynic acid (Edecrin), bumetanide (Bumex)], benzothiadiazide diuretics [hydrochlorothiazide (Hydrodiuril), chlorothiazide (Diuril), chlorthalidone (Hygroton), benzthiazide (Aguapres), bendroflumethiazide (Naturetin), methyclothiazide (Aguatensen), polythiazide ( Diuretics include the potassium-sparing diuretics [spironolactone (Aldactone), triamterene (Dyrenium), amiloride (Midamor)], and the osmotic diuretics [mannitol (Osmitrol)]. Various classes of diuretics are known and described in the literature.

[0211] Cardiac glycosides (cardenolides) or other digitalis preparations can be administered with the compounds of the present disclosure in co-therapy. Useful cardiac glycosides include, for example, digitoxin (Crystodigin), digoxin (Lanoxin) or deslanoside (Cedilanid-D). Various classes of cardiac glycosides are described in the literature.

[0212] Angiotensin-converting enzyme inhibitors (ACE inhibitors) can be administered with the compounds of the present disclosure in simultaneous therapy.Useful ACE inhibitors include, for example, captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil).Various classes of ACE inhibitors are described in the literature.

[0213] Angiotensin-2 receptor antagonist (AT 1 -antagonists or angiotensin receptor blockers, or ARBs, can be administered with the compounds of the present disclosure in co-therapy. Useful angiotensin-2 receptor antagonists include, for example, candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), telmisartan (Micardis), valsartan (Diovan). Various classes of angiotensin-2 receptor antagonists are described in the literature.

[0214] Calcium channel blockers, such as amlodipine (Norvasc, Lotrel), bepridil (Vascor), diltiazem (Cardizem, Tiazac), felodipine (Plendil), nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine (Sular), verapamil (Calan, Isoptin, Verelan) as well as those disclosed in, for example, EP 625162 B1, U.S. Pat. No. 5,364,842, U.S. Pat. No. 5,587,454, U.S. Pat. No. 5,824,645, U.S. Pat. No. 5,859,186, U.S. Pat. No. 5,994,305, U.S. Pat. No. 6,087,091, U.S. Pat. No. 6,136,786, WO 93 / 131 28A1, EP 1336409A1, EP 835126A1, EP 835126B1, U.S. Pat. No. 5,795,864, U.S. Pat. No. 5,891,849, U.S. Pat. No. 6,054,429, and related compounds described in WO 97 / 01351 A1, the entire contents of which are incorporated by reference herein for all relevant consistent purposes, can be used with the compounds of the present disclosure.

[0215] Beta blockers can be administered with the compounds of the present disclosure in simultaneous therapy.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), timolol (Blocadren).Various classes of beta blockers are described in the literature.

[0216] PPAR gamma agonists, such as thiazolidinediones (also called glitazones), can be administered with the compounds of the present disclosure in co-therapy. Useful PPAR agonists include, for example, rosiglitazone (Avandia), pioglitazone (Actos), and rivoglitazone.

[0217] Aldosterone antagonists can be administered with the compounds of the present disclosure in co-therapy. Particularly useful aldosterone antagonists include, for example, eplerenone, spironolactone, and canrenone.

[0218] Renin inhibitors can be administered with the compounds of the present disclosure in co-therapy. Particularly useful renin inhibitors include, for example, aliskiren.

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

[0220] Central alpha agonists can be administered with the compounds of the present disclosure in simultaneous therapy.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), methyldopa and hydrochlorothiazide (Aldoril).Various classes of central alpha agonists are described in the literature.

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

[0222] Anticoagulants can be administered with the compounds of the present disclosure in co-therapy. Useful anticoagulants include, for example, warfarin (Coumadin) and heparin. Various classes of anticoagulants are described in the literature.

[0223] Antiplatelet drugs can be administered with the compounds of the present disclosure in simultaneous therapy.Useful antiplatelet drugs include, for example, cyclooxygenase inhibitors (aspirin), adenosine diphosphate (ADP) receptor inhibitors (clopidogrel (Plavix), ticlopidine (Ticlid)), phosphodiesterase inhibitors (cilostazol (Pletal)), glycoprotein IIB / IIIA inhibitors (abciximab (ReoPro), eptifibatide (Integrilin), tirofiban (Aggrastat), defibrotide), adenosine reuptake inhibitors (dipyridamole (Persantine)).Various classes of antiplatelet drugs are described in the literature.

[0224] Lipid-lowering drugs can be administered with the compounds of the present disclosure in co-therapy. 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 sequestrants or bile acid binders) [cholestyramine (Questran, Questran Light, Prevalite, Locholest, Locholest Light), colestipol (Colestid), colesevelam hydrochloride (WelChol)], fibrates (fibric acid derivatives) [gemfibrozil (Lopid), fenofibrate (Antara, Lofibra, Tricor, and Triglide), clofibrate (Atromid-S)], and niacin (nicotinic acid). Various classes of lipid-lowering drugs have been described in the literature.

[0225] The compounds of the present 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 second messengers or cyclic guanosine monophosphate (cGMP) along with increased chloride and bicarbonate secretion into the intestinal lumen and a concomitant increase in fluid secretion. Examples of such peptides include linaclotide (MD-1100 acetate), the endogenous hormones guanylin and uroguanylin, and enterobacterial peptides of the heat-stable enterotoxin family (ST peptides), as well as those described in U.S. Patent Nos. 5,140,102, 5,489,670, 5,969,097, WO2006 / 001931A2, WO2008 / 002971A2, WO2008 / 106429A2, US2008 / 0227685A1 and U.S. Patent No. 7,041,786, the entire contents of which are incorporated herein by reference for all relevant consistent purposes.

[0226] The compounds of the present disclosure can be used in combination with type 2 chloride channel agonists, such as Amitiza (Lubiprostone) and other related compounds described in U.S. Pat. No. 6,414,016, the entire contents of which are incorporated herein by reference for all relevant consistent purposes.

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

[0228] The compounds of the present disclosure can be used in combination with P2Y2 receptor agonists, such as those described in European Patent No. 1196396B1 and U.S. Patent No. 6,624,150, the entire contents of which are incorporated herein by reference for all relevant consistent purposes.

[0229] Other medications include natriuretic peptides such as nesiritide, recombinant brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP). Vasopressin receptor antagonists such as tolvaptan and conivaptan may be co-administered, as well as phosphate binders such as Renagel, Renleva, Phoslo and Fosrenol. Other agents include phosphate transport inhibitors (U.S. Pat. Nos. 4,806,532; 6,355,823; 6,787,528; 7,119,120; 7,109,184; U.S. Patent Application Publication Nos. 2007 / 021509; 2006 / 0280719; 2006 / 0217426; International Patent Application Publication Nos. WO2001 / 005398, WO2001 / 087294, WO2001 / 082924, 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 drugs.For example, the compounds can be administered together with analgesic peptides or compounds.The analgesic peptides or compounds can be covalently bound to the compounds described herein, or they can be another drug that is administered together with the compounds described herein or sequentially in combination therapy.

[0231] Combination therapy can be achieved by administering two or more drugs, for example, the substantially non-permeable or substantially non-bioavailable NHE inhibitor compound and analgesic peptide or compound described herein, which are each formulated and administered separately, 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 with another formulation containing a third drug.Two or more drugs in combination therapy can be administered simultaneously, but they are not required.For example, the administration of a first drug (or combination of drugs) can be minutes, hours, days, or weeks before the administration of a second drug (or combination of drugs). Thus, two or more drugs may be administered 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, 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9 weeks or more of each other.In some cases, even longer intervals are possible.Although it is often desirable that two or more drugs used in combination therapy are present in the patient's body at the same time, this is not necessarily the case.

[0232] Combination therapy may also include more than one administration of one or more of the agents used in the combination. For example, when agent X and agent Y are used in combination, they can be administered one or more times in any combination, sequentially, for example, in the order XYX, XXY, YXY, YYX, XXYY, etc.

[0233] The compounds described herein can be used in combination therapy with an analgesic agent, such as an analgesic compound or an analgesic peptide. Optionally, the analgesic agent can be covalently attached to the compounds described herein. Useful analgesics include, for example, Ca channel blockers, 5HT3 agonists (e.g., MCK-733), 5HT4 agonists (e.g., tegaserod, pullulan, etc.), and the like. These include analgesics such as caropride, and 5HT1 receptor antagonists, opioid receptor agonists (loperamide, fedotozine, and fentanyl), NK1 receptor antagonists, CCK receptor agonists (e.g., loxiglumide), NK1 receptor antagonists, NK3 receptor antagonists, norepinephrine-serotonin reuptake inhibitors (NSR1), vanilloid and canavanoid receptor agonists, and sialorphin. Various classes of analgesics have been described in the literature.

[0234] Opioid receptor antagonists and agonists can be administered with the compounds of the present disclosure in simultaneous therapy or can be linked to the compounds of the present disclosure, for example, by covalent bonding.For example, opioid receptor antagonists such as naloxone, naltrexone, methylnalozone, nalmefene, cypridime, betafunaltrexamine, naloxonazine, naltrindole, and nor-binaltorphimine are considered to be useful in the treatment of opioid-induced constipation (OIC).It may also be useful to formulate this type of opioid antagonist in a delayed or sustained release formulation, such that the initial release of antagonist occurs in the mid to terminal small intestine and / or ascending colon.Such antagonists are described in U.S. Patent No. 6,734,188 (WO01 / 32180 A2), the entire contents of which are incorporated herein by reference for all relevant consistent purposes. Enkephalin pentapeptide (HOE825; Tyr-D-Lys-Gly-Phe-L-homoserine) is an agonist of μ- and γ-opioid receptors and is believed to be useful for increasing intestinal motility (Eur. J. Pharm., 219:445, 1992), and this peptide can be used with the compounds of the present disclosure. Also useful is trimebutine, which is believed to bind to mu / delta / kappa opioid receptors, activate the release of motilin, and regulate the release of gastrin, vasoactive intestinal peptide, gastrin, and glucagon. Kappa opioid receptor agonists, such as fedotozine, ketocyclazocine, and compounds described in US2005 / 0176746 (WO03 / 097051A2), the entire contents of which are incorporated herein by reference for all relevant consistent purposes, can be used with or linked to the compounds of the present disclosure. In addition, morphine, diphenyloxylate, and flavonoids (H-Tyr-D-Ala-Phe(F)-Phe-NH 2 (as disclosed in WO01 / 019849A1, the entire contents of which are incorporated herein by reference for all relevant consistent purposes) and μ-opioid receptor agonists such as loperamide can be used.

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

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

[0237] Peptide analogues of thymulin (U.S. Pat. No. 7,309,690 or French Patent No. 2830451, the entire contents of which are incorporated herein by reference for all relevant consistent purposes) have analgesic activity and can be used with or linked to the compounds of the present disclosure.

[0238] Loxiglumide and dexloxiglumide (the R isomer of loxiglumide) (U.S. Pat. No. 6,313,633, the entire contents of which are incorporated herein by reference for all relevant consistent purposes) CCK (CCKa or CCKb) receptor antagonists, including those described in US Pat. No. 5,130,474 or WO 88 / 05774, have analgesic activity and may be used in conjunction with or linked to the compounds of the present disclosure.

[0239] Other useful analgesics include 5-HT4 agonists such as tegaserod / Zelnorm and lilexapride.Such agonists are described in EP1321142A1, WO03 / 053432A1, EP505322A1, EP505322B1, EP507672A1, EP507672B1, U.S. Patent No. 5,510,353 and U.S. Patent No. 5,273,983, the entire contents of which are incorporated herein by reference for all relevant consistent purposes.

[0240] Calcium channel blockers such as ziconotide and related compounds described in, for example, EP 625162B1, U.S. Pat. No. 5,364,842, U.S. Pat. No. 5,587,454, U.S. Pat. No. 5,824,645, U.S. Pat. No. 5,859,186, U.S. Pat. No. 5,994,305, U.S. Pat. No. 6,087,091, U.S. Pat. No. 6,136,786, WO 93 / 13128 A1, EP 1 336 409 A1, EP 835126 A1, EP 835126 B1, U.S. Pat. No. 5,795,864, U.S. Pat. No. 5,891,849, U.S. Pat. No. 6,054,429, WO 97 / 01351 A1, the entire contents of which are incorporated herein by reference for all relevant consistent purposes, may be used with or linked to the compounds of the present disclosure.

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

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

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

[0244] NK3 receptor antagonists such as osanetant (Sanofi-Synthelabo), talnetant, and related compounds described in, for example, WO02 / 094187 A2, EP876347A1, 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), the entire contents of which are incorporated herein by reference for all relevant consistent purposes, may be used with or linked to the compounds of the present disclosure.

[0245] Norepinephrine-serotonin reuptake inhibitors, such as milnacipran and related compounds described in WO03 / 077897A1, the entire contents of which are incorporated herein by reference for all relevant consistent purposes, may be used in conjunction with or in combination with the compounds of the present disclosure. They can be linked together.

[0246] Vanilloid receptor antagonists, such as arvanil and related compounds described in WO01 / 64212A1, the entire contents of which are incorporated herein by reference for all relevant consistent purposes, may be used with or linked to the compounds of the present disclosure.

[0247] The compounds can be used in combination therapy with phosphodiesterase inhibitors (examples of such inhibitors can be found in U.S. Pat. No. 6,333,354, the entire contents of which are incorporated herein by reference for all relevant consistent purposes).

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

[0249] Alternatively, said compound can be used alone or in combination therapy to treat calcium-induced constipation.Constipation is common in the elderly population, especially in osteoporosis patients who must take calcium supplements.Calcium supplements are beneficial for osteoporosis patients to restore bone density, but due to the associated constipation, they show poor compliance.

[0250] The compounds of the present disclosure can be used in combination with opioids.The use of opioids is mainly aimed at relieving pain, but their prominent side effects are GI disorders, such as constipation.These drugs act by binding to opioid receptors, which are mainly found in the central nervous system and gastrointestinal tract.The receptors in these two organ systems mediate both beneficial effects and undesirable side effects, such as reduced intestinal motility and subsequent constipation. Opioids suitable for use typically belong to one of the following exemplary classes: natural opiates, which are alkaloids found in the resin of the poppy, including morphine, codeine, and thebaine; semi-synthetic opiates 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 propoxyphene; endogenous opioid peptides, which are produced naturally in the body, such as endorphins, enkephalins, dynorphins, and endomorphines.

[0251] The compounds of the present disclosure can be used alone or in combination therapy to alleviate the GI disorders faced by patients with renal failure (stages 3-5). Constipation is the second most commonly reported symptom in that category of patients (Murtagh et.al., 2006; Murtagh et.al., 2007a; Murtagh et.al., 2007b). Without being bound by theory, it is believed that renal failure is accompanied by stimulation of intestinal sodium reabsorption (Hatch and Freel, 2008). Total or partial inhibition of such transport by administration of the compounds of the present disclosure may have therapeutic effects in improving GI transit and relieving abdominal pain. In that regard, the compounds of the present disclosure may be used in combination with angiotensin modulating agents: angiotensin converting enzyme (ACE) inhibitors (e.g., captopril, enalopril, lisinopril, ramipril) and angiotensin II receptor antagonist therapy (AT 1-antagonists or 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 extended-release metoprolol; inotropes: digoxin, dobutamine; phosphodiesterase inhibitors such as milrinone vasodilators: isosorbide dinitrate / hydralazine 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 (Renagel, Renleva, Phoslo, Fosrenol); U.S. Pat. Nos. 4,806,532, 6,355,823, 6,787,528, WO2001 / 005398, WO2001 / 0872, the entire contents of which are incorporated herein by reference for all relevant consistent purposes. 94, WO2001 / 082924, WO2002 / 028353, WO2003 / 048134, WO2003 / 057225, U.S. Patent No. 7119120, European Patent No. 1465638, U.S. Patent Application Publication No. 2007 / 021509, WO2003 / 080630, U.S. Patent No. 7109184, U.S. Patent Application Publication No. 2006 / 0280719, European Patent No. 1485391, WO2004 / 085448, WO2004 / 085382, U.S. Patent Application Publication No. 2006 / 0217426, Japanese Patent No. 2007 / 131532, or phosphate transport inhibitors such as those described in the above, or phosphate transport antagonists (nicotinamide).

[0252] The compounds of the present 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 second messenger, or cyclic guanosine monophosphate (cGMP), along with increased chloride and bicarbonate secretion into the intestinal lumen and concomitant fluid secretion. Examples of such peptides are linaclotide (MD-1100 acetate), the endogenous hormones guanylin and uroguanylin and enterobacterial peptides of the heat-stable enterotoxin family (ST peptides) and those described in U.S. Pat. Nos. 5,140,102, 5,489,670, 5,969,097, WO2006 / 001931A2, WO2008 / 002971A2, WO2008 / 106429A2, U.S. Patent Application Publication No. 2008 / 0227685A1 and U.S. Pat. No. 7,041,786, the entire contents of which are incorporated herein by reference for all relevant consistent purposes.

[0253] The compounds of the present disclosure may be used in combination with type 2 chloride channel agonists, such as Amitiza (lubiprostone) and other related compounds described in U.S. Pat. No. 6,414,016, the entire contents of which are incorporated herein by reference for all relevant consistent purposes.

[0254] The compounds of the present disclosure can be used in combination with P2Y2 receptor agonists, such as those described in European Patent No. 1196396B1 and U.S. Patent No. 6,624,150, the entire contents of which are incorporated herein by reference for all relevant consistent purposes.

[0255] The compounds of the present disclosure can be used in combination with laxatives such as bulk laxatives, for example, stool softeners / surfactants such as psyllium husk (Metamucil), methylcellulose (Citrucel), polycarbophil, dietary fiber, apple, docusate (Colace, Diocto), etc.; hydrating agents (isotonic agents) such as dibasic sodium phosphate, magnesium citrate, magnesium hydroxide (milk of magnesia), magnesium sulfate (Epsom salt), monobasic sodium phosphate, sodium biphosphate, etc.; hyperosmolar agents: glycerin suppositories, sorbitol, lactulose, and polyethylene glycol (PEG). The compounds of the present disclosure can also be used in combination with agents that stimulate intestinal peristalsis, such as bisacodyl tablets (Dulcolax), casanthranol, aloin from senna and Aloe Vera.

[0256] In one embodiment, the compounds of the present disclosure are capable of administering the active ingredient(s) to the body without substantially affecting gastric residence time. That is, they facilitate gastrointestinal transit, and more specifically, colonic transit, without a significant effect on gastric emptying time. Even more specifically, the compounds of the present invention restore colonic transit without the 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 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 thereof with a fluid-absorbing polymer ("FAP"). Intestinal fluid-absorbing polymers useful for administration according to embodiments of the present disclosure can be orally administered in combination with non-absorbable NHE inhibitors (e.g., NHE-3 inhibitors) to absorb intestinal fluids resulting from the action of sodium transport inhibitors. Such polymers expand in the colon and bind fluids, providing the stool with a consistency acceptable to the patient. The fluid-absorbing polymers described herein can be selected from polymers with laxative properties, also called bulking agents (i.e., polymers that retain some intestinal fluids in the stool, providing a higher degree of hydration in the stool and facilitating its passage). Optionally, the fluid-absorbing polymers can also be selected from pharmaceutical polymers with anti-diarrheal functions, i.e., agents that maintain some consistency to the stool to avoid watery stool and potential incontinence.

[0258] The ability of a polymer to maintain a particular consistency in feces with high liquid content can be characterized by its "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 were narrowly correlated with fecal water retention capacity. Water retention capacity is determined as the water content of a given fecal material that achieves a particular level of consistency after centrifuging the reconstituted fecal material at a particular g-number (corresponding to the consistency of "formed feces"). Without being bound to any particular theory, it has been found that fecal water retention capacity is increased by ingestion of a particular polymer with a given liquid absorption profile. More specifically, the water retention capacity of the polymer has been found to correlate with its absorbency of liquid under load (AUL); even more specifically, the AUL of the polymer is greater than 15 g of isotonic fluid per gram of polymer under a static pressure of 5 kPa, or under a static pressure of 10 kPa.

[0259] The FAPs used in the treatment methods of the present disclosure may also have an AUL of at least about 10 g, about 15 g, about 20 g, about 25 g, or more of isotonic liquid per gram of polymer at a static pressure of about 5 kPa, or about 10 kPa, and a liquid absorbency of about 20 g, about 25 g, or more, as determined using means commonly known in the art. Additionally or alternatively, the FAPs may have minimal consistency in fecal material and, in some embodiments, when the water insoluble solid fraction of the feces is 10%-20% and the polymer concentration is 1%-5% by weight of the feces. The polymer may be uncharged or have a low charge density (e.g., 1-2 meq / gr). Alternatively, or in addition, the polymer may be delivered directly to the colon using known delivery methods to avoid premature distension in the esophagus.

[0260] In one embodiment of the present disclosure, the FAP is a "superabsorbent" polymer (i.e., a lightly crosslinked, partially neutralized polyelectrolyte hydrogel similar to those used in baby diapers, feminine hygiene products, agricultural additives, etc.). Superabsorbent polymers can be made from lightly crosslinked polyacrylic acid hydrogels. Polymer swelling is essentially driven by two effects: (i) the entropy of hydration and mixing of the polymer backbone and (ii) the osmotic pressure resulting from counter ions (e.g., Na ions) in the gel. The swelling ratio of the gel at equilibrium is controlled by the elastic resistance inherent to the polymer network and by the chemical potential of the bathing solution; i.e., the gel will deswell at higher salt concentrations because the background electrolyte reduces the apparent charge density on the polymer, reducing the free ion concentration difference inside and outside the gel that drives the osmotic pressure. The swelling ratio SR (synonymous with "liquid absorbency" and grams of liquid per gram of dry polymer) can vary from 1000 in pure water to 30 in 0.9% NaCl solution, which substitutes for saline (i.e., isotonic). SR can increase with the degree of neutralization and decrease with crosslink density. SR generally decreases with applied load, with the degree of reduction depending on the strength of the gel, i.e., crosslink density. The salt concentration within the gel may be lower compared to the external solution as a result of the Donnan effect due to the internal potential.

[0261] Fluid-absorbing polymers may include cross-linked polyacrylic acids that are fluid-absorbent, such as those prepared from α,β-ethylenically unsaturated monomers, such as monocarboxylic acids, polycarboxylic acids, acrylamides and their derivatives. These polymers may have repeat units of acrylic acid, methacrylic acid, metal salts of acrylic acid, acrylamide, and acrylamide derivatives (e.g., 2-acrylamido-2-methylpropanesulfonic acid), as well as various combinations of such repeat units as copolymers. Such derivatives include acrylic acid polymers with hydrophilic grafts of polymers such as polyvinyl alcohol. Examples of suitable polymers and processes, including gel polymerization processes, for preparing such polymers are described in U.S. Pat. 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 4,512,711, which are incorporated by reference herein for all relevant consistent purposes. ,459,396; 4,708,997; 4,076,663; 4,190,562; 4,286,082; 4,857,610; 4,985,518; 5,145,906; 5,629,377 and 6,908,609 (see also Buchholz, FL and Graham, AT, "Modern Superabsorbent Polymer Technology," John Wiley & Sons (1998), which is also incorporated herein by reference for all relevant consistent purposes). A preferred class of polymers for treatment in combination with NHE inhibitors are polyelectrolytes.

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

[0263] In some embodiments, the FAP used in the treatment is calcium carbophil (registry number: 9003-97-8, also known as Carbopol EX-83) and Carbopol 934P.

[0264] In some embodiments, the liquid-absorbing polymer is prepared by the High Internal Phase Emulsion ("HIPE") process. The HIPE process induces polymer cellular slabs with a very large porosity fraction (about 100 μm) of interconnected large voids (i.e., open cell structure). This technique produces flexible and collapsible cellular materials with exceptional suction pressure and liquid absorption (see U.S. Pat. Nos. 5,650,222; 5,763,499 and 6,107,356, which are incorporated herein by reference for all relevant consistent purposes). The polymer is hydrophobic, and therefore its surface should be modified to be wetted by aqueous liquids. This is achieved by post-treating the cellular material with a surfactant to reduce the interfacial tension. It is claimed that these materials are less compliant with loads, i.e., less de-expanded under static pressure.

[0265] In some embodiments, liquid-absorbing gels are prepared by aqueous free radical polymerization of acrylamide or its derivatives, a crosslinker (e.g., methylene-bis-acrylamide) and a free radical redox initiation system in water. The material is obtained as a slab. Typically, the swelling ratio of crosslinked polyacrylamide at low crosslink density (e.g., 2%-4% when expressed as weight percent of methylene-bis-acrylamide) is 25-40 (F. Horkay, Macromolecules, 22, pp. 2007-09 (1989)). The swelling properties of these polymers have been extensively studied and are essentially the same as those of crosslinked polyacrylic acid at high salt concentrations. Under these conditions, the osmotic pressure is zero due to the presence of counterions, and swelling is controlled by the free energy of mixing and the elastic energy of the network. Stated another way, a cross-linked polyacrylamide gel of the same cross-link density as neutralized polyacrylic acid will exhibit the same swelling ratio (i.e., liquid absorption properties) and will deswell under pressure to the same extent as a cross-linked polyelectrolyte of high salt content (e.g., 1M). The properties (e.g., swelling) of the neutral hydrogel will not be sensitive to the salt environment as long as the polymer remains in good solvent conditions. Without being bound to any particular theory, it is believed that the liquid contained within the gel has the same salt composition as the surrounding liquid (i.e., there is no partitioning of salt due to the Donnan effect).

[0266] Another subclass of liquid-absorbing polymers that can be used are hydrogel materials that include N-alkylacrylamide polymers, such as N-isopropylacrylamide (NIPAM). The corresponding aqueous polyNIPAM hydrogels exhibit a temperature transition at about 35° C. Above this temperature, the hydrogel may collapse. The mechanism is generally reversible, and the gel re-expands to its original swelling ratio when the temperature returns to room temperature. This allows for the production of nanoparticles by emulsion polymerization (R. Pelton, Advances in Colloid and Interface Science, 85, pp. 1-33, (2000)). The swelling properties of polyNIPAM nanoparticles below the transition temperature have been reported to be similar to those reported for bulk gels of polyNIPAM and comparable 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, the FAP used in the treatment in combination with the NHE inhibitor is administered intragastrically to treat obesity (J. Chen, Journal of Controlled Release, 65, pp. 73-82 (2000) or to deliver proteins. A polyacrylic acid-based SAP with a macroporous structure may also be used. Macroporous SAP and superporous gel differ in that the porous structure remains almost intact in the dry state for superporous gels, whereas it disappears upon drying for macroporous SAP. Although the methods of preparation are different, both methods involve the use of blowing agents (e.g., CO during polymerization). 2 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 in which polymer phase separation is induced by a non-solvent. The polymer can be poly-NIPAM, and the non-solvent used can be glucose (see, for example, Z. Zhang, J. Org. Chem., 69, 23 (2004)) or NaCl (see, for example, 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, SR, of the material is maintained in a salt isotonic solution and if the gel does not collapse under load. The "service" temperature should be shifted below body temperature, for example, by diluting NIPAM in a polymer with a monomer that lacks the transition temperature phenomenon.

[0269] In some embodiments, the liquid-absorbing polymer can be selected from certain natural polymers, such as those containing carbohydrate moieties. In a preferred embodiment, such carbohydrate-containing hydrogels are non-digestible and have 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, guar, wellan, hemicellulose, alkyl-cellulose, hydro-alkyl-cellulose, carboxy-alkyl-cellulose, carrageenan, dextran, hyaluronic acid, and agarose. In a preferred embodiment, the gel-forming polymer is psyllium. Psyllium (or "ispaghula") is the common name used for some members of the plant genus Plantago, the seeds of which are used commercially in the manufacture of rubber paste. The liquid absorbing polymers are found in the gel forming fraction of psyllium, i.e., neutral saccharide copolymers of arabinose (25%) and xylose (75%) as characterized in (J. Marlett, Proceedings of the Nutrition Society, 62, pp. 2-7-209 (2003); and M. Fischer, Carbohydrate Research, 339, 2009-2012 (2004)) and described in U.S. Pat. Nos. 6,287,609; 7,026,303; 5,126,150; 5,445,831; 7,014,862; 4,766,004; and 4,999,200, each of which is further incorporated by reference herein for all relevant consistent purposes, and the neutral saccharide copolymers sold under the trade name Metamucil (The Procter and Gamble Company, Inc., New York, NY). Psyllium-containing dosage forms are also suitable for chewing, in that the chewing action disintegrates the tablet into smaller discrete particles before swallowing, yet undergo minimal gelling in the mouth and have an acceptable texture and good aesthetics as perceived by patients.

[0270] Psyllium-containing dosage forms comprise physically discrete units suitable as unitary dosage forms for human subjects and other mammals, each containing a predetermined amount of active material (e.g., gel-forming polysaccharides) calculated to produce a desired therapeutic effect. Solid oral dosage forms suitable for the present compositions include tablets, pills, capsules, lozenges, chewable tablets, troches, cachets, pellets, wafers, and the like.

[0271] In some embodiments, the FAP is a polysaccharide particle, the polysaccharide component of which comprises xylose and arabinose. The ratio of xylose to arabinose may be at least about 3:1 by weight, as described in U.S. Patent Nos. 6,287,609; 7,026,303 and 7,014,862, each of which is incorporated herein by reference for all relevant consistent purposes.

[0272] The fluid-absorbing polymer described herein can be used in combination with an NHE inhibitor compound or a pharmaceutical composition comprising the same.The NHE inhibitor and FAP can be administered with other drugs, including those described under the heading of "combination therapy", without departing from the scope of the present disclosure.As described above, the NHE inhibitor compound can be administered alone without the use of a fluid-absorbing polymer to resolve symptoms without eliciting significant diarrhea or fluid secretion in feces, which may require the simultaneous administration of a fluid-absorbing polymer.

[0273] The fluid-absorbing polymers described herein can be selected so as not to induce any substantial interaction with the NHE inhibitor compound ...

Claims

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

Images