NHE3-binding compound and method for inhibiting phosphate transport

Abstract

This invention provides a method for inhibiting phosphate uptake in the gastrointestinal tract. [Solution] A method for inhibiting phosphate uptake in the gastrointestinal tract of a patient requiring phosphate reduction, comprising administering to the patient, via enteral administration, a compound that is substantially active in binding to NHE3 and inhibiting the transport of phosphate ions (Pi) within it in the gastrointestinal tract, and is substantially not systemically bioavailable.

Description

[Technical Field]

[0001] Related applications This application claims priority under Section 119(e) of the United States Patent Act to U.S. Provisional Patent Application No. 61 / 888,879, filed on 9 October 2013, and U.S. Provisional Patent Application No. 81 / 811,613, filed on 12 April 2013. The full texts of the aforementioned applications are expressly incorporated herein by reference.

[0002] Technical field The present invention relates to NHE3 binding and / or NHE3 modulators having activity as phosphate transport inhibitors, including inhibitors of phosphate transport in the gastrointestinal tract and kidneys, and to methods of use as therapeutic or prophylactic agents. [Background technology]

[0003] Patients with renal failure, hypoparathyroidism, or certain other medical conditions (such as hereditary hyperphosphatemia, Albright hereditary osteodystrophy, amyloidosis, etc.) often have hyperphosphatemia or elevated serum phosphate levels (e.g., levels above approximately 6 mg / dL). In particular, if present over a long period, hyperphosphatemia can lead to severe abnormalities in calcium and phosphorus metabolism, often resulting in secondary hyperparathyroidism, bone disease, and ectopic calcification in the circulatory system, joints, lungs, eyes, and other soft tissues. Higher serum phosphate levels are strongly associated with progression of renal failure, circulatory calcification, and mortality in patients with end-stage renal disease (ESRD). High to normal serum phosphate levels were associated with cardiovascular events and mortality between individuals with chronic kidney disease (CKD) and those with normal renal function (see, e.g., Joy et al., J. Manag. Care Pharm., 13(5):397-41 1 (2007)). The progression of kidney disease can be delayed by reducing phosphate retention. Therefore, treatment to reduce phosphate retention is beneficial for patients with renal failure who have hyperphosphatemia and patients with chronic kidney disease who have normal or only slightly elevated serum phosphate levels.

[0004] For patients experiencing hyperphosphatemia, calcium salts have been widely used to bind to intestinal phosphates and prevent their absorption. Various types of calcium salts, including calcium salts of carbonate, acetate, citrate, arginine, and keto acids, have been used for phosphate binding. However, these treatments often cause hypercalcemia, a condition resulting from the absorption of large amounts of ingested calcium. Hypercalcemia can lead to serious side effects, including arrhythmias, renal failure, and calcification of the skin and blood vessels. Frequent monitoring of serum calcium levels is necessary during treatment with calcium-based phosphate binders. Other phosphate binders that do not contain calcium or aluminum, such as the cross-linked polyamine polymer sevelamer, have drawbacks, including the need for dosages and frequencies necessary to be therapeutically active. In vivo, the relatively moderate phosphate-binding capacity of these drugs forces patients to escalate their doses (up to 7 grams or more per day). Such doses have been shown to cause gastrointestinal discomfort, including gastrointestinal disorders, abdominal pain, and, in extreme cases, intestinal perforation.

[0005] Another approach to preventing phosphate absorption from the intestines of patients with elevated serum phosphate levels is through inhibition of the intestinal transport system that mediates phosphate uptake in the intestines. Phosphate absorption in the upper intestines is mediated, at least partially, by carrier-mediated mechanisms that couple phosphate absorption with sodium absorption. Inhibition of intestinal phosphate transport will reduce the body's phosphate overload. In patients with progressive renal disease (e.g., stages 4 and 5), body's phosphate overload manifests as serum phosphate concentrations above normal levels, i.e., hyperphosphatemia. Hyperphosphatemia is directly associated with mortality and morbidity. Inhibition of intestinal phosphate transport will lower serum phosphate concentrations and therefore improve outcomes for those patients. In patients with chronic renal disease in stages 2 or 3, body's phosphate overload does not necessarily lead to hyperphosphatemia; i.e., some patients remain at normal phosphate levels. However, even in their early stages, it is necessary to reduce or prevent body's phosphate overload to avoid associated bone and vascular damage and ultimately improve mortality. Similarly, inhibition of intestinal phosphate transport should be particularly beneficial in patients with treatable diseases by inhibiting phosphate uptake from the intestines. Inhibition of phosphate absorption from glomerular filtrate in the kidneys should also be beneficial for the treatment of chronic renal failure. Furthermore, inhibition of phosphate transport may slow the progression of renal failure and reduce the risk of cardiovascular events. [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] Despite advances in this field, the need for further improvements in phosphate transport inhibitors remains in the art. This invention fulfills this need and provides further relevant advantages. [Means for solving the problem]

[0007] The present invention generally relates to NHE3 binding and / or NHE modulating compounds (including their stereoisomers, pharmaceutically acceptable salts and prodrugs) that are active as phosphate transport inhibitors, including, for example, inhibitors of phosphate transport in the gastrointestinal tract and kidneys, and to the use of such compounds for treating several different medical conditions or diseases by inhibiting phosphate uptake, thereby obtaining a therapeutic effect by regulating phosphate uptake.

[0008] Embodiments of the present invention include a method for inhibiting phosphate uptake in the gastrointestinal tract or kidney of a patient requiring phosphate reduction, comprising administering to the patient a compound that, when administered to the patient, is substantially active in binding to NHE3 and inhibiting the transport of phosphate ions (Pi) within it in the gastrointestinal tract or kidney.

[0009] Certain embodiments include a method for inhibiting phosphate uptake in the gastrointestinal tract of a patient requiring phosphate reduction, comprising administering to the patient, by enteral administration, a substantially non-systemic bioavailable compound that, when administered to the patient, is substantially active in binding to NHE3 and inhibiting the transport of phosphate ions (Pi) within the gastrointestinal tract. In some embodiments, the method includes: (a) a method for treating hyperphosphatemia, which may be postprandial hyperphosphatemia; (b) a method for treating renal disease, which may be chronic kidney disease (CKD) or end-stage renal disease (ESRD); (c) a method for reducing serum creatinine levels; (d) a method for treating proteinuria; (e) a method for delaying the timing of renal transplantation therapy (RRT), which may be dialysis; (f) a method for reducing FGF23 levels; (g) a method for reducing the effects of active vitamin D on hyperphosphatemia; (h) a method for attenuating hyperparathyroidism, which may be secondary hyperparathyroidism; (i) serum parathyroid (j) Methods to reduce phosphate hormone (PTH); (k) Methods to reduce interdialysis weight gain (IDWG); (l) Methods to improve endothelial cell dysfunction, which may also be induced by postprandial serum phosphate; (m) Methods to reduce vascular calcification, which may also be induced by intimal localized vascular calcification; (n) Methods to reduce urinary phosphite; (g) Methods to normalize serum phosphate levels; (o) Methods to reduce phosphate load in elderly patients; (p) Methods to reduce dietary phosphate intake; (q) Methods to reduce nephrohypertrophy; (r) Methods to reduce cardiac hypertrophy; and (s) Methods to treat obstructive sleep apnea, one or more of these methods are selected.

[0010] In some embodiments, the compound is substantially active in inhibiting the transport of Pi within the apical side of the epithelium of the gastrointestinal tract. In certain embodiments, the compound is substantially impermeable to the epithelium of the gastrointestinal tract.

[0011] In certain embodiments, when the compound is administered to a patient who requires it, the compound reaches a Pi transport inhibitory concentration IC50. 50 Lower, C max This indicates the maximum concentration detectable in serum, as defined by this definition.

[0012] In some embodiments, systemic exposure to the compound is achieved using fecal collection of approximately 80%, approximately 90%, or approximately 95%, with a pIC of less than 10% at the PD dose. 50 In certain embodiments, the compound is substantially active in inhibiting the transport of Pi within the small intestine.

[0013] In certain embodiments, administration to a patient in need of it (a) reduces serum phosphate concentration or value to about 150% or less of normal serum phosphate levels, and / or (b) reduces dietary phosphite intake by at least about 10% compared to an untreated state. In some embodiments, administration to a patient in need of it reduces urinary phosphate concentration or value by at least about 10% compared to an untreated state. In certain embodiments, administration to a patient in need of it increases fecal phosphate levels by at least about 10% compared to an untreated state.

[0014] In some embodiments, the compound is a sustained inhibitor of NHE3-mediated antiportation of sodium and hydrogen ions. In certain embodiments, the compound is substantially active in inhibiting NHE3-mediated antiportation of sodium and hydrogen ions in the gastrointestinal tract when administered to a patient in need. In some embodiments, the compound is substantially active in inhibiting NHE3-mediated antiportation of sodium and hydrogen ions on the apical side of the epithelium in the gastrointestinal tract. In certain embodiments, the compound is substantially active in inhibiting NHE3-mediated antiportation of sodium and hydrogen ions in the large intestine when administered to a patient in need.

[0015] In certain embodiments, sustained inhibition is characterized by the time-dependent inhibitory activity of the compound in in vitro inhibition assays of NHE3-mediated antiports of sodium and hydrogen ions, and pIC under enhanced conditions. 50 (pIC 50promp ) is the pIC of the compound under sustained conditions. 50 (pIC 50pers) is substantially comparable. In some embodiments, the sustained inhibition is characterized by the time-dependent inhibitory activity of the compound in an in vitro inhibitory assay of the NHE3-mediated antiport of sodium ions and hydrogen ions, and the pIC 50promp ) and pIC 50pers ) of the compound under promoting conditions (pIC 50 ) is approximately about 7.0 or greater. In some embodiments, the compound has an EC 50 P f =(r)EC 50 Na (where r is from about 0.7 to about 1.3) for the increase in fecal excretion of phosphate ions, the EC 50 (EC 50 P f ) and the EC 50 (EC 50 Na) of the inhibition of the NHE3-mediated antiport of sodium ions and hydrogen ions. In some embodiments, the compound has an EC 50 P u =(r)EC 50 Na (where r is from about 0.7 to about 1.3) for the decrease in urine volume of phosphate ions, the EC 50 (EC 50 P u ) and the EC 50 (EC 50 Na) of the inhibition of the NHE3-mediated antiport of sodium ions and hydrogen ions. In certain embodiments, the compound has an EC 50 P=(r)EC 50 Na (where r is from about 0.7 to about 1.3) for the EC 50 (EC 50 P) of the inhibition of phosphate ion transport and the EC 50 (EC 50 Na) of the inhibition of the NHE3-mediated antiport of sodium ions and hydrogen ions.

[0016] In some embodiments, administration to a patient in need increases the patient's daily fecal excretion of sodium and / or body fluids. In certain embodiments, when administered in doses resulting in an increase of at least about 10% in fecal water content, the compound is an IC of NHE3. 50 Less than approximately 10x IC 50 Less than 100xIC 50 C is less than max It holds.

[0017] In certain embodiments, the patient requiring it has ESRD, and administration to the patient (a) reduces serum phosphate concentration or value to about 150% or less of normal serum phosphate levels, and (b) reduces interdialysis weight gain (IDWG) by at least about 10% compared to the untreated state.

[0018] In some embodiments, the patient requiring it has CKD, and administration to the patient (a) reduces FGF23 levels and serum untreated parathyroid hormone (iPTH) by at least about 10% compared to an untreated state, and (b) reduces blood pressure and proteinuria by at least about 10% compared to an untreated state.

[0019] In some embodiments, the compound is a non-sustaining ligand for NHE3. In certain embodiments, the compound has maximum inhibition of NHE3-mediated antiportation of sodium and hydrogen ions at less than about 50%, less than about 20%, or less than about 10%, and the maximum inhibition is characterized by the inhibitory activity of the compound in in vitro inhibition assays of NHE3-mediated antiportation of sodium and hydrogen ions, and is associated with sodium-free conditions. In some embodiments, the compound is substantially inactive in the gastrointestinal tract to inhibit NHE3-mediated antiportation of sodium and hydrogen ions therein when administered to the patient in need. In certain embodiments, the compound is substantially inactive in the large intestine to inhibit NHE3-mediated antiportation of sodium and hydrogen ions therein.

[0020] In certain embodiments, non-sustained activity is characterized by the time-dependent inhibitory activity of the compound in in vitro inhibition assays of NHE3-mediated antiports of sodium and hydrogen ions, and pIC under enhanced conditions. 50 (pIC 50promp ) is the pIC of the compound under sustained conditions. 50 (pIC 50pers ) is (substantially) greater. In some embodiments, non-sustaining activity is characterized by the time-dependent inhibitory activity of the compound in in vitro inhibition assays of NHE3-mediated antiports of sodium and hydrogen ions, and pIC under enhanced conditions. 50 (pIC 50promp ) is approximately 7.0 or greater, and the pIC of the compound under sustained conditions. 50 (pIC 50pers ) is approximately 6.0 or less. In certain embodiments, the compound is of formula EC 50 P f =(r)EC 50 The EC2 of increased fecal excretion of phosphate ions is defined as Na (where r is approximately 0.1 to 0.5). 50 (EC 50 P f ) and inhibition of NHE3-mediated antiport of sodium ions and hydrogen ions in EC 50 (EC 50 It has Na. In some embodiments, the compound is of formula EC 50 P u =(r)EC 50 The EC2 of phosphate ions, defined as Na (where r is approximately 0.1 to 0.5), reduces urine volume. 50 (EC 50 P u ) and inhibition of NHE3-mediated antiport of sodium ions and hydrogen ions in EC 50 (EC 50 It has Na. In some embodiments, the compound is of formula EC 50 P=(r)EC 50 The EC2 of phosphate ion transport inhibition is defined as Na (where r is approximately 0.1 to 0.5) 50 (EC 50P) and EC inhibition of NHE-mediated antiport of sodium ions and hydrogen ions 50 (EC 50 It has Na.

[0021] In certain embodiments, administration to patients requiring it increases the phosphate / sodium ratio in fecal excretion by at least about 10% compared to the untreated state. In some embodiments, administration to patients requiring it increases the daily fecal excretion of phosphate without substantially altering the shape of the stool or the water content of the stool. In certain embodiments, administration to rodents increases the small intestine (Na) by at least about 10% compared to the untreated state. SI ) / Cumula (Na c Increase the sodium ratio of ).

[0022] The method comprises administering to a patient, by a route other than enteral administration, (a) a compound that is substantially systemically bioavailable, or (b) a compound that is substantially not systemically bioavailable; the method also includes a method of increasing phosphateuria in a patient requiring phosphate reduction, wherein the compound, when administered to the patient requiring it, is substantially active in inhibiting the transport of phosphate ions (Pi) in the kidneys. In some embodiments, the method includes: (a) a method for treating hyperphosphatemia, which may be postprandial hyperphosphatemia; (b) a method for treating renal disease, which may be chronic kidney disease (CKD) or end-stage renal disease (ESRD); (c) a method for reducing serum creatinine levels; (d) a method for treating proteinuria; (e) a method for delaying the timing of kidney transplant treatment (RRT), which may be dialysis; (f) a method for reducing FGF23 levels; (g) a method for reducing the effect of active vitamin D on hyperphosphatemia; (h) a method for attenuating hyperparathyroidism, which may be secondary hyperparathyroidism; (i) serum parathyroid (j) Methods to reduce phosphate hormone (PTH); (k) Methods to reduce interdialysis weight gain (IDWG); (l) Methods to improve endothelial cell dysfunction, which may also be induced by postprandial serum phosphate; (m) Methods to reduce vascular calcification, which may also be induced by intimal localized vascular calcification; (n) Methods to reduce urinary phosphite; (g) Methods to normalize serum phosphate levels; (o) Methods to reduce phosphate load in elderly patients; (p) Methods to reduce dietary phosphate intake; (q) Methods to reduce nephrohypertrophy; (r) Methods to reduce cardiac hypertrophy; and (s) Methods to treat obstructive sleep apnea, one or more of these methods are selected.

[0023] In some embodiments, the compound is substantially permeable to the epithelium of the gastrointestinal tract. In certain embodiments, administration to the patient requiring it reduces serum phosphate concentration or value to about 150% or less of normal serum phosphate levels. In some embodiments, administration to the patient requiring it increases urinary phosphate concentration or value by at least about 10% compared to the untreated state.

[0024] In certain embodiments, the compound is (i) in an unsalted form, with a concentration of at least about 200 Å. 2 (ii) a tPSA and a molecular weight of at least about 710 daltons, or (ii) at least about 270 Å 2It has tPSA. In certain embodiments, the compound has at least about 250 Å 2 tPSA of at least approximately 270 Å 2 tPSA of at least approximately 300 Å 2 tPSA of at least approximately 350 Å 2 tPSA, at least about 400 Å 2 tPSA of at least approximately 500 Å 2 It has tPSA. In certain embodiments, the compound has a molecular weight of at least about 500 Da, or at least about 1000 Da, or at least about 2500 Da, or at least about 5000 Da.

[0025] In some embodiments, the compound has (i) a total number of NH and / or OH and / or other possible hydrogen bond donor moieties greater than about 5; (ii) a total number of O atoms and / or N atoms and / or other possible hydrogen bond acceptors greater than about 10; and / or (iii) about 10 5 It has a Moriguchi partition coefficient that is greater than or less than about 10. In certain embodiments, the compound has a partition coefficient of about 100 x 10 -6 Less than cm / s, or approximately 10x10 -6 Less than cm / s, or approximately 1 x 10⁻⁶ -6 Less than cm / s, or approximately 0.1 x 10⁻⁶ -6 Transmission coefficient P less than cm / s app It holds.

[0026] In some embodiments, the compound is of formula (I) or (X): [ka] (wherein NHE is an NHE-binding small molecule comprising (i) a heteroatom containing a moiety, and (ii) a cyclic or heterocyclic skeleton or support moiety directly or indirectly bonded thereto, wherein the heteroatom-containing moiety is selected from a substituted guanidinyl moiety and a substituted heterocyclic moiety which may condense with the skeleton or support moiety to form a condensed bicyclic structure; and Z is a moiety having at least one site for binding to an NHE-binding small molecule, and having overall physicochemical properties that make the resulting NHE-Z molecule substantially impermeable or substantially not bioavailable systemically; and E is an integer with a value of 1 or greater.) It has the structure of [the object].

[0027] In some embodiments, the compound is an oligomer, dendrimer, or polymer, and further, Z is a core portion having two or more sites that bind directly or indirectly to a plurality of NHE-binding small molecules by a linking portion L, and the compound is of formula (X): [ka] (In the formula, L is a bond or linker connecting the core and the NHE-binding small molecule, n is an integer of 2 or more, and each NHE-binding small molecule may be the same as or different from one another, or may be a pharmaceutically acceptable salt.) It has the structure of [the object].

[0028] In certain embodiments, the total number of freely rotatable bonds in the NHE-Z molecule is at least about 10. In certain embodiments, the total number of hydrogen bond donors in the NHE-Z molecule is at least about 5. In some embodiments, the total number of hydrogen bond acceptors in the NHE-Z molecule is at least about 10. In certain embodiments, the total number of hydrogen bond donors and hydrogen bond acceptors in the NHE-Z molecule is at least about 10. In some embodiments, the LogP of the NHE-Z bond compound is at least about 5. In certain embodiments, the LogP of the NHE-Z bond compound is less than about 1 or less than about 0. In certain embodiments, the skeleton is a 5-membered or 6-membered ring or heterocyclic moiety. In certain embodiments, the skeleton is aromatic.

[0029] In some embodiments, the skeleton of the NHE-binding small molecule is bonded to the portion Z, and the compound is of formula (II): [ka] (wherein Z is a core having one or more sites for binding to one or more NHE-binding small molecules, and having overall physicochemical properties that make the resulting NHE-Z molecule substantially impermeable or substantially not bioavailable systemically; B is a heteroatom-containing portion of the NHE-binding small molecule, selected from a substituted guanidinyl portion and a substituted heterocyclic portion which may condense with the skeleton to form a condensed bicyclic structure; the skeleton is a cyclic or heterocyclic skeleton or support portion of the NHE-binding small molecule which is directly or indirectly bound to the heteroatom-containing portion B and which may be additionally substituted by one or more hydrocarbyl or heterohydrocarbyl portions; X is a substituted or unsubstituted hydrocarbyl or heterohydrocarbyl portion which binds or binds B and the skeleton, and in particular, a substituted or unsubstituted C) 1~7 Hydrocarbyl or heterohydrocarbyl, and substituted or unsubstituted, saturated or unsaturated C 1~7A spacer portion selected from the group consisting of hydrocarbyl or heterohydrocarbyl and substituted or unsubstituted, saturated or unsaturated, cyclic or heterocyclic parts; and D and E are integers, each independently having a value of 1 or greater. It has the structure of [the object].

[0030] In some embodiments, the NHE-binding small molecule is of formula (IV): [ka] or stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof (In the formula: Each R1, R2, R3, R5 and R9 is independently selected from H, halogen, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8; R7 and R8 are independently selected from H or a bond connecting the NHE-bonded small molecule to L, provided that at least one of them is a bond connecting the NHE-bonded small molecule to L; R4 is selected from H, C1-C7 alkyl, or a bond connecting the NHE-bonded small molecule to L; R6 is absent or selected from H and C1-C7 alkyl; and Ar1 and Ar2 are independently aromatic rings or heterocyclic aromatic rings.) It has the structure of [the object].

[0031] In a particular embodiment, the NHE-binding small molecule has the following structure: [ka] or stereoisomers, prodrugs, or pharmaceutically acceptable salts thereof (wherein each R1, R2 and R3 is independently selected from H, halogen, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, and R7 and R8 are independently selected from H or a bond connecting the NHE-binding small molecule and L, provided that at least one is a bond connecting the NHE-binding small molecule and L) has

[0032] In some embodiments, the NHE-binding small molecule has the following structure: [Chemical formula] or has one of its stereoisomers, prodrugs or pharmaceutically acceptable salts. In certain embodiments, L is a polyalkylene glycol linker. In certain embodiments, L is a polyethylene glycol linker. In some embodiments, n is 2.

[0033] In certain embodiments, the core has the following structure: [Chemical formula] (wherein: X is selected from the group consisting of a bond, -O-, -NH-, -S-, C 1~6 alkylene, -NHC(=O)-, -C(=O)NH-, -NHC(=O)NH-, -SO2NH-, and -NHSO2-; Y is selected from the group consisting of a bond, optionally substituted C 1~8 alkylene, optionally substituted aryl, optionally substituted heteroaryl, polyethylene glycol linker, -(CH2) 1~6 O(CH2) 1~6 -, and -(CH2) 1~6 NY1(CH2) 1~6 -, and Y1 is hydrogen, optionally substituted C 1~8(Selected from the group consisting of alkyl, optionally substituted aryl, or optionally substituted heteroaryl, or a pharmaceutically acceptable salt thereof) It holds.

[0034] In some embodiments, the core is: [ka] Selected from the group consisting of

[0035] In some embodiments, the compound has the following structural formula (IH): [ka] or its stereoisomer, prodrug or pharmaceutically acceptable salt (wherein: (a) n is an integer of 2 or more; (b) core is a core portion having two or more sites that bind to two or more NHE-binding small molecule portions; (c) L is a bond or linker that connects the core portion to two or more NHE-binding small molecules; and (d) NHE is the following structural formula (XI-H): [ka] (In the formula: B is selected from the group consisting of aryl and heterocyclyl; each R5 is independently hydrogen, halogen, or C which may be substituted) 1~4 Alkyl, possibly substituted C 1~4 Alkoxy, C may be substituted. 1~4 Thioalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxyl, oxo, cyano, nitro, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, -NR7C(=O)NR8R9, -NR7SO2R8, -NR7S(O)2NR8R9, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -S(O) 1~2 Selected from the group consisting of R7 and -SO2NR7R8, R7, R8, and R9 are independently hydrogen, C1~4 Selected from the group consisting of an alkyl or a bond connecting the NHE-binding small molecule moiety and L, provided that at least one is a bond connecting the NHE-binding small molecule and L; R3 and R4 are each independently hydrogen, optionally substituted C 1~4 alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl and optionally substituted heteroaryl; or R3 and R4 together with the nitrogen to which they are attached form an optionally substituted 4- to 8-membered heterocyclyl; and each R1 is independently hydrogen, halogen, optionally substituted C 1~6 alkyl and optionally substituted C 1~6 selected from the group consisting of alkoxy)). In some embodiments, n is 2. In certain embodiments, L is a polyalkylene glycol linker. In certain embodiments, L is a polyethylene glycol linker.

[0036] In certain embodiments, the core has the following structure:

Chemical formula

[0037] In some embodiments, the core is [ka] Selected from the group consisting of

[0038] In a particular embodiment, the NHE-binding small molecule portion has the following structural formula (XII-H): [ka] (In the formula: Each R3 and R4 is independently hydrogen and / or substituted C) 1~4 R3 and R4, selected from the group consisting of alkyl groups or together with the nitrogen to which they are bound, form a substituted 4- to 8-membered heterocycline; each R1 independently consists of hydrogen, halogen, and C 1~6 Alkyl, and C 1~6 R5 is selected from the group consisting of haloalkyls; and R5 is selected from the group consisting of -SO2-NR7- and -NHC(=O)NH-, and R7 is hydrogen or C 1~4 (It is alkyl.) It holds.

[0039] In some embodiments, R3 and R4, together with the nitrogen to which they are bound, form an optionally substituted 5 or 6-membered heterocycline. In certain embodiments, the optionally substituted 5 or 6-membered heterocycline is pyrrolidinyl or piperidinyl. In certain embodiments, the optionally substituted 5 or 6-membered heterocycline is pyrrolidinyl or piperidinyl, each substituted with at least one amino or hydroxyl molecule. In some embodiments, R3 and R4 are independently C 1~4It is alkyl. In certain embodiments, R3 and R4 are methyl. In some embodiments, each R1 is independently selected from the group consisting of hydrogen or halogen. In certain embodiments, each R1 is independently selected from the group consisting of hydrogen, F and Cl.

[0040] In a particular embodiment, the compound has the following structural formula (II): [ka] or stereoisomers, prodrugs or their pharmaceutically acceptable salts (wherein (a)NHE is the following structural formula (AI): [ka] (In the formula: Each R1, R2, R3, R5 and R9 is independently selected from H, halogen, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, and R7 and R8 are independently selected from H, C 1~6 Alkyl, C 1~6 R4 is selected from the group consisting of alkyl-OH or a bond connecting the NHE-bonded small molecule and L, provided that at least one of them is a bond connecting the NHE-bonded small molecule and L; R6 is absent or selected from H and C1-C7 alkyl; and Ar1 and Ar2 are independently aromatic rings or heterocyclic aromatic rings. (b) The core has the following structural formula (BI): [ka] (In the formula: X is C(X1), N and N(C 1~6 Selected from alkyl; X1 is hydrogen, may be substituted alkyl, -NX a X b -NO2, -NX c-C(=O)-NX c -X a -C(=O)NX c -X a , -NX c -C(=O)-X a -NX c -SO2-X a -C(=O)-X a and -OX a Selected from, each X a and X b Y is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl; Y is C 1~6 It is alkylene; Z is -NZ when X is CX1. a -C(=O)-NZ a -, -C(=O)NZ a -, -NZ a -C(=O)- and heteroaryls are selected; Z is N or N(C) 1~6 When it is alkyl, -NZ a -C(=O)-NZ a -, -NZ a Selected from -C(=O)- and heteroaryls; and each X c and Z a These are, independently, hydrogen and C 1~6 (c)L is a core portion having (selected from alkyl) and (c)L is a bond or linker connecting the core portion and the NHE-bonded small molecule portion. It is a core part having;

[0041] In some embodiments, the NHE-binding small molecule portion has the following structure: [ka] (In the formula: Each R1, R2 and R3 is independently selected from H, halogen, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, and R7 and R8 are independently selected from H, C 1~6 Alkyl, -C 1~6 (Selected from alkyl-OH or a bond connecting the NHE-bonded small molecule and L, provided that at least one of them is a bond connecting the NHE-bonded small molecule and L.) It holds.

[0042] In some embodiments, the NHE-binding small molecule portion has the following structure: [ka] It holds.

[0043] In some embodiments, L is a polyalkylene glycol linker. In certain embodiments, L is a polyethylene glycol linker. In some embodiments, X is C(X1). In some embodiments, each X c is hydrogen. In certain embodiments, X is N. In certain embodiments, each Z a It is hydrogen.

[0044] In some embodiments, the compound is of formula (II-I): [ka] or its stereoisomer, prodrug, or pharmaceutically acceptable salt (wherein (a)NHE is the following structural formula (AI): [ka] (In the formula: Each R1, R2, R3, R5 and R9 is independently selected from H, halogen, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, and R7 and R8 are independently selected from H, C 1~6 Alkyl, C 1~6 (b) The core is an NHE-bonded small molecule moiety having the following structure (CI): [ka] (wherein W is selected from alkylene, polyalkylene glycol, -C(=O)-NH-(alkylene)-NH-C(=O)-, -C(=O)-NH-(polyalkylene glycol)-NH-C(=O)-, -C(=O)-(alkylene)-C(=O)-, -C(=O)-(polyalkylene glycol)-C(=O)- and cycloalkyl; X is N; Y is C 1~6 It is alkylene; Z is -NZ a -C(=O)-NZ a -, -C(=O)NZ a -, -NZ a Selected from -C(=O)- and heteroaryls; each Z a These are, independently, hydrogen and C 1~6 (c)L is a core portion having (selected from alkyl) and (c)L is a bond or linker connecting the core portion and the NHE-bonded small molecule. It has the structure of [the object].

[0045] In a particular embodiment, the NHE-binding small molecule portion has the following structure: [Chemical formula] (Where each R1, R2, and R3 is independently selected from H, halogen, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, and R7 and R8 are independently selected from H, C 1~6 alkyl, -C 1~6 alkyl-OH or a bond that connects the NHE-binding small molecule and L, provided that at least one is a bond that connects the NHE-binding small molecule and L) has

[0046] In certain embodiments, the NHE-binding small molecule moiety has the following structure: [Chemical formula] has one of the following:

[0047] In specific embodiments, the compound is selected from the compounds of Table E3 or Table E4, or a pharmaceutically acceptable salt thereof. [[ID= 29]]

[0048] In certain embodiments, the compound is: [Chemical formula] or a pharmaceutically acceptable salt thereof. ]

[0049] In certain embodiments, the compound is: [Chemical formula] is.

[0050] Certain methods further include administering one or more additional bioactive agents. In certain embodiments, the compound and the one or more additional bioactive agents are administered as part of a single pharmaceutical composition. In some embodiments, the compound and the one or more additional bioactive agents are administered as separate pharmaceutical compositions. In some embodiments, the separate pharmaceutical compositions are administered sequentially. In some embodiments, the separate pharmaceutical compositions are administered simultaneously.

[0051] In certain embodiments, the additional bioactive agent is selected from vitamin D2 (ergocalciferol), vitamin D3 (cholecalciferol), active vitamin D (calcitriol), and active vitamin D analogs (e.g., doxelcalciferol, paricalcitol).

[0052] In some embodiments, the additional bioactive agent is a phosphorus adsorbent. In certain embodiments, the phosphorus adsorbent is selected from the group consisting of sevelamer (e.g., Renvela® (sevelamer carbonate), Renagel® (sevelamer hydrochloride)), lanthanum carbonate (e.g., Fosrenol®), calcium carbonate (e.g., Calcichew®, Titralac®), calcium acetate (e.g., PhosLo®, Phosex®), calcium acetate / magnesium carbonate (e.g., Renepho®, OsvaRen®), MCI-196, ferric citrate (e.g., Zerenex®), iron magnesium hydroxycarbonate (e.g., Fermagate®), aluminum hydroxide (e.g., Alucaps®, Basaljel®), APS1585, SBR-759, and PA-21.

[0053] In some embodiments, the additional bioactive agent is a NaPi2b inhibitor. In certain embodiments, the additional bioactive agent is niacin or nicotinamide.

[0054] In some embodiments, the compound or composition is administered orally. In certain embodiments, the compound or composition is administered orally once daily.

[0055] These and other aspects of the present invention will become apparent with reference to the following embodiments for carrying out the invention. [Brief explanation of the drawing]

[0056] [Figure 1] Figures 1A and 1B show the effects of the test compounds on reducing phosphate intake in normally functioning rats (see Example 3). Figure 1A shows that compound 004, a non-sustained-release NHE3 inhibitor, was as effective in reducing Pi intake as sustained-release inhibitors such as compound 003. Figures 1B and 1C show that compound 003 significantly reduced Pi intake in the presence of glucose / Ca(1B) and Ca(1C). [Figure 2] Figure 2 shows the test design for testing the compound's activity in a rat model of uremic-associated vascular calcification. [Figure 3] Figures 3A–F show baseline body weight (3A) and serum parameters (serum phosphorus (3B); serum calcium (3C); serum creatinine (3D); serum urea nitrogen (3E–F)) in a rat model of uremic-associated vascular calcification. [Figure 4] Figures 4A–F show the effects of the test compound on serum parameters (plasma creatinine (4A); blood urea nitrogen (4B); plasma albumin (4C); plasma phosphorus (4D); plasma calcium (4E); and plasma FGF23 (4F)) in a rat model of uremic-associated vascular calcification. These results indicate that the test compound significantly reduced plasma creatinine, plasma phosphorus, and plasma FGF23. The test compound also significantly increased plasma albumin and slightly increased plasma calcium. [Figure 5] Figure 5 shows the effect of the test compound on the endpoint cardiac and renal remnant weight in a rat model of uremic-associated vascular calcification. Administration of the test compound significantly reduced organ weight / body weight values ​​for both the heart and kidneys. [Figure 6] Figures 6A - B show the effects of the test compound on endpoint creatinine clearance (CCr) and plasma aldosterone levels in a rat model of uremia - related vascular calcification. Administration of the test compound maintained creatinine clearance and significantly increased plasma aldosterone compared to vehicle alone. [Figure 7] Figures 7A - B show the effects of the test compound on endpoint vascular and soft - tissue calcification in a rat model of uremia - related vascular calcification. Administration of the test compound significantly decreased the mineral content of the stomach and aorta for phosphorus and calcium. [Figure 8] Figure 8A shows the test design for testing the activity of the compound in an adenine - induced uremia rat model. Figures 8B - C show that it significantly decreased serum phosphorus and serum creatinine at an early time point in this model of acute kidney injury. [Figure 9] Figures 9A - B show the organ weight collection data from week 3 of an adenine - induced uremia rat model. Administration of the test compound showed a tendency to decrease cardiac and renal remodeling. [Figure 10] Figures 10A - B show the tissue calcification data from week 3 of an adenine - induced uremia rat model. Administration of the test compound decreased calcification of the heart and kidney at high dose (5 mpk). [Figure 11] Figure 11A shows the test design for testing the activity of the compound in a salt - induced partial nephrectomy model of chronic kidney disease (CKD). Figure 11B shows the effect of the test compound on urinary excretion of phosphorus. [Figure 12] Figure 12 shows the test protocol for testing the activity of the test compound on urinary excretion of phosphate and calcium in rats. [Figure 13] Figures 13A - D show that administration of the test compound decreased both urinary phosphorus mass and urinary calcium mass compared to vehicle - only controls. Increasing the dosage of the test compound significantly decreased urinary phosphorus mass compared to Renvela® at 48 mg / kg. [Figure 14]Figures 14A-B show the average daily fecal excretion of Na (14A; + / -SE) and phosphorus (14B; + / -). Excretion data were averaged over a 7-day treatment period (days 1-7) and reported as mEq / day (see Example 8). Statistical analysis was performed using one-way ANOVA; (*); p<0.05, (**); p<0.01, (***); p<0.001. [Figure 15] Figures 15A-C show the mean daily fecal excretion of phosphorus (15A; + / -SE), the mean daily urinary excretion of sodium (15B; + / -SE), and phosphorus (15C; + / -) (see Example 9). Statistical analysis was performed using one-way ANOVA; (*); p<0.05, (**); p<0.01, (***); p<0.001. [Figure 16] Figures 16A-B show the mean daily fecal excretion of sodium (16A; + / -SE) and phosphorus (16B; + / -SE) (see Example 10). Statistical analysis was performed by one-way ANOVA, followed by a Turkey multiple comparison study; (*); p<0.05, (**); p<0.01, (***); p<0.001. vs. predose. [Modes for carrying out the invention]

[0057] The following description will specify certain details to allow for a full understanding of the various embodiments of the present invention. However, those skilled in the art will understand that the present invention can be carried out even without these details.

[0058] Unless the context requires otherwise, the term “comprise” and its variations such as “comprises” and “comprising” throughout this specification and the claims should be interpreted in an open, comprehensive sense, that is, “including, but not limited to.”

[0059] Throughout this specification, any reference to “one embodiment” or “an embodiment” means that certain features, structures, or characteristics associated with that embodiment are included in at least one embodiment of the present invention. Therefore, occurrences of the phrase “in one embodiment” or “in an embodiment” in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, such particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0060] Certain embodiments relate to the unexpected discovery that phosphate absorption from the intestines of subjects with elevated serum phosphate levels can be substantially inhibited by the use of NHE3 conjugates and / or NHE3 modifiers, to a limited extent, and preferably, by inhibiting the intestinal transport system that mediates phosphate uptake in the intestines. It was also unexpectedly discovered that such NHE3 conjugates and / or NHE3 modifiers can inhibit the renal transport system that mediates phosphate uptake in the kidneys.

[0061] In some embodiments, inhibition of phosphate uptake in the gastrointestinal tract may be achieved by administration of certain compounds and / or pharmaceutical compositions containing them, and such compounds may be advantageously designed to be absorbed into the bloodstream little or substantially no (i.e., designed to be non-systemic or substantially non-systemic). In this regard, such compounds are characterized by being little or substantially ineffective in enteral administration, including oral administration. In other words, such compounds are not absorbed into the bloodstream at a significant level and therefore have no activity there, but instead have substantially their activity localized in the gastrointestinal tract.

[0062] Accordingly, in the specific exemplary embodiments described herein, the compounds of the present invention generally require a combination of structural and / or functional features related to or contributing to their activity in the gastrointestinal tract, and / or their substantial non-advanced bioavailability. Such features include, for example, one or more (i) specific tPSA and / or MW values ​​(e.g., at least about 190 Å each). 2 (i) a specific level of fecal recovery of the compound and / or at least about 736 daltons after administration (e.g., greater than 50% in 72 hours); (iii) a specific number of NH and / or OH and / or potential hydrogen bond donor moieties (e.g., greater than about 5); (iv) a specific number of rotatable bonds (e.g., greater than about 5); (iv) specific permeability properties (e.g., about 100 x 10⁻¹⁶ daltons); (ii) specific levels of fecal recovery of the compound and / or its metabolites after administration (e.g., greater than 50% in 72 hours); (iii) a specific number of NH and / or OH and / or potential hydrogen bond donor moieties (e.g., greater than about 5); (iv) a specific number of rotatable bonds (e.g., greater than about 5); (iv) specific permeability properties (e.g., about 100 x 10⁻¹⁶ daltons); -6 P less than cm / s app ); and / or any of the many other features and characteristics described in the specification.

[0063] The substantially non-systemic compounds described herein offer numerous benefits in the treatment of gastrointestinal and other disorders. For example, these compounds are active against phosphate transporters located at the apex of the intestine and, virtually, not against other phosphate transporters expressed in other tissues and organs. Since NHE3 is expressed on cells, many systemic tissues or organs, the use of NHE3 conjugates or modulators may raise concerns about whether they are on-target or off-target in terms of systemic effects. These particular compounds do not raise such concerns due to limitations in their systemic efficacy.

[0064] As described above, certain embodiments relate to the discovery that phosphate absorption from glomerular filtrate in the kidneys of patients with elevated serum phosphate levels can be limited, and preferably substantially inhibited, by inhibiting the renal tubular transport system that mediates phosphate uptake in the kidneys. In some embodiments, inhibition of phosphate uptake in the kidneys can be achieved by administration of other substantially non-systemic bioavailable compounds described herein by routes other than enteral or intestinal administration, i.e., routes other than administration through the gastrointestinal tract. Examples, not limited to those described herein and known in the art, include parenteral administration, such as intravenous, intra-arterial, intramuscular, and subcutaneous administration.

[0065] In some embodiments, inhibition of phosphate uptake in the kidneys may be achieved by administration of specific compounds and / or pharmaceutical compositions containing them, the majority of which can be advantageously designed to be absorbed into the bloodstream (i.e., designed to be systemic or substantially systemic). In this regard, the compounds have characteristics that result in systemic efficacy, including oral availability. In other words, the compounds have almost, if not all, of their systemic activity in organs such as the kidneys, compared to having their activity absorbed into the bloodstream at a significant level and therefore substantially present in the gastrointestinal tract. Accordingly, in certain embodiments, particularly for targeting systemic tissues by enteral administration, or by other means, the compounds described herein may have a combination of structural and / or functional characteristics that relate to or contribute to their substantially systemic bioavailability. Regarding functional characteristics, for example, the compounds may be substantially permeable to the epithelium of the gastrointestinal tract, including the mouth, esophagus, stomach, upper intestine, lower intestine, and others.

[0066] As further detailed below, phosphate absorption in the upper intestine is mediated, at least partially, by carrier-mediated mechanisms that couple phosphate and sodium absorption. Renal phosphate transport is mediated, at least partially, by the activity of sodium-dependent phosphate transporters, Npt2a, Npt2c, and PiT-2, located within the apical brush margin membrane of the proximal tubule. Therefore, inhibition of intestinal or renal phosphate transport would reduce physical phosphate overload.

[0067] In patients with progressive kidney disease (e.g., stages 4 and 5), physical phosphate overload is manifested by serum phosphate concentrations above normal levels, i.e., hyperphosphatemia. Hyperphosphatemia is directly associated with mortality and morbidity. Inhibition of intestinal or renal phosphate transport will reduce serum phosphate concentrations and therefore improve outcomes for those patients. In patients with chronic kidney disease in stages 2 and 3, physical phosphate overload does not necessarily lead to hyperphosphatemia; i.e., the patient remains at normal phosphate levels. However, even in those early stages, physical phosphate overload needs to be reduced to avoid associated bone and vascular damage and ultimately improve mortality.

[0068] Inhibition of intestinal phosphate transport would be particularly beneficial in patients with diseases treatable by inhibiting phosphate uptake from the intestines. Similarly, inhibition of phosphate absorption from glomerular filtrate in the kidneys should also be beneficial for the treatment or prevention of chronic renal failure and other hemorrhoidal conditions. Furthermore, inhibition of phosphate transport may slow the progression of renal failure and reduce the risk of cardiovascular events in other diseases or conditions associated with the need for phosphate reduction.

[0069] I. Compounds that inhibit phosphate transport Embodiments of the present invention generally relate to the discovery that NHE3-binding and / or NHE3-modulating compounds inhibit the transport or uptake of phosphate ions (Pi) in tissues such as the gastrointestinal tract and / or kidneys. The Pi transport inhibitory activity of a compound in a given tissue will generally depend, for example, on the systemic bioavailability or non-systemic bioavailability of the compound, the route of administration, or a combination thereof.

[0070] Accordingly, embodiments of the present invention include compounds that bind to and / or modulate NHE3 (e.g., NHE inhibitors) that have substantially activity to inhibit the transport or uptake of Pi in human subjects, animal models, and / or cell lines or biochemical assays.

[0071] In some embodiments, the compound binds to NHE3. In these and related embodiments, if the compound reacts with the protein at a detectable level, it is said that the compound "bounds" or "specifically binds" to the NHE3 protein, and does not need to react with unrelated proteins under similar conditions in a statistically significant manner. In certain exemplary embodiments, the compound has a binding "affinity" (e.g., dissociation constant, or K) to NHE3 proteins with a density of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 nM or less. d (Measured by) may have

[0072] In some embodiments, when administered to a subject requiring it, either alone or in combination with one or more additional pharmaceutically active compounds or agents, or when measured in animal models or cell line assays, one or more of the compounds described herein inhibit Pi transport or uptake at approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 nM or less IC50. 50 In certain embodiments, when administered alone or in combination with one or more additional pharmaceutically active compounds or agents to a subject requiring it, or when measured in an animal model or cell line assay, one or more of the compounds described herein may have concentrations of approximately 6.0, 6.05, 6.1, 6.15, 6.2, 6.25, 6.3, 6.35, 6.4, 6.45, 6.5, 6.55, 6.6, 6.65, 6.7, 6.75, 6.8, 6.85, 6.9, 6.95, 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, 7.4, 7.45, 7.5, 7.55, 7.6, 7.65. pIC of inhibition of Pi transport or intake of 7.7, 7.75, 7.8, 7.85, 7.9, 7.95, 8.0, 8.05, 8.1, 8.15, 8.2, 8.25, 8.3, 8.35, 8.4, 8.45, 8.5, 8.55, 8.6, 8.65, 8.7, 8.75, 8.8, 8.85, 8.9, 8.95, or 9.0 or higher 50 It may have.

[0073] When used herein, IC 50 pIC is defined as a quantitative measure that indicates the compound concentration at which 50% of its maximum inhibitory effect is observed, for example, in human subjects, animal models, and / or cell lines or biochemical assays. 50 IC 50 The inverse logarithm of (or pIC) 50 =-log(IC 50(See Selvaraj et al., Current Trends in Biotechnology and Pharmacy. 5: 1 104-1 109, 2011). Activity assays for inhibitors of phosphate transport or uptake are described in the accompanying examples.

[0074] For the treatment of associated conditions in subjects requiring inhibition of Pi transport or uptake within the gastrointestinal tract and phosphate reduction, embodiments of the present invention will generally use compounds that are substantially not systemically bioavailable. Such compounds are preferably formulated or suitable for enteral administration, including oral administration. Examples of substantially not systemically bioavailable compounds and their associated characteristics are provided elsewhere herein. In these and related embodiments, administration of the compound to subjects requiring it reduces one or more serum phosphate concentrations or values, dietary phosphorus, and / or urinary phosphate concentrations or values. In some embodiments, the serum phosphate concentration or value in hyperphosphatemic subjects is reduced to approximately 150%, 145%, 140%, 135%, 130%, 125%, 120%, 115%, 110%, 105%, or 100% or less (normalized) of normal serum phosphate levels (for healthy subjects, e.g., adults, 2.5–4.5 mg / dL or 0.81–1.45 mmol / L). In some embodiments, dietary phosphorus intake is reduced by at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% or more compared to the untreated state. In some embodiments, urinary phosphate concentrations or values ​​decrease by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, preferably about 20%, 30%, 40%, 50%, or 60% compared to the untreated state. In some embodiments, administration of the compound to subjects requiring it increases fecal phosphate levels by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or 200%, compared to the untreated state.

[0075] For the treatment of associated conditions in subjects requiring inhibition of Pi transport or uptake within the kidney and phosphate reduction, embodiments of the present invention will generally use substantially systemically bioavailable compounds by any route of administration as appropriate, or substantially non-systemically bioavailable compounds described herein by any route of administration except enteral administration. In these and related embodiments, administration of the compounds will reduce the serum phosphate concentration or value in hyperphosphatemic subjects to normal serum phosphate levels (2.5–4.5 mg / dL or 0.81–1.45 mmol / L for healthy subjects, e.g., adults) to about 150%, 145%, 140%, 135%, 130%, 125%, 120%, 115%, 110%, 105%, or less than 100% (normalized). In some embodiments, administration of the compound to a subject requiring it increases urinary phosphate concentration or value by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or more compared to an untreated state.

[0076] In certain embodiments, the NHE3-binding compounds of the present invention are further characterized by their activity against NHE3-mediated antiports of sodium and hydrogen ions. For example, certain embodiments are substantially active in inhibiting the NHE3-mediated antiports of sodium and hydrogen ions. Thus, such “dual-activity” compounds can be used to inhibit both phosphate and sodium transport or uptake in the gastrointestinal tract and / or kidneys. In other embodiments, the compounds are substantially inactive in inhibiting the NHE3-mediated antiports of sodium and hydrogen ions. Such “single-activity” compounds can be used to inhibit phosphate uptake in the gastrointestinal tract and / or kidneys without significantly modulating sodium transport or uptake in them or other tissues.

[0077] While we do not wish to be bound to any single theory, “sustained” NHE3 inhibitor compounds (e.g., compounds that bind to NHE3 and inhibit the NHE3-mediated antiportation of sodium and hydrogen ions under both “promoted” and “sustained” conditions) are effectively active in tissues, inhibiting both Pi transport and the NHE3-mediated antiportation of sodium and hydrogen ions. In contrast, non-sustained NHE3 ligands (e.g., compounds that bind to or otherwise interact with NHE3 and can inhibit the NHE3-mediated antiportation of sodium and hydrogen ions under “promoted” conditions, but not under “sustained” conditions) are active in tissues, inhibiting Pi transport, but substantially inactive in inhibiting the NHE3-mediated antiportation of sodium and hydrogen ions. The specific properties of these compounds are described below.

[0078] A. Dual active compounds Specific embodiments relate to NHE3-binding and / or NHE3-modulating compounds that inhibit both the transport of phosphate ions (Pi) and the NHE3-mediated antiportation of sodium and hydrogen ions. These and related embodiments include, for example, compounds that are substantially active in inhibiting Pi transport and the NHE3-mediated antiportation of sodium and hydrogen ions in Pi when administered to subjects requiring it, in the gastrointestinal tract and / or kidney. In specific embodiments, the compounds are substantially active in inhibiting the NHE3-mediated antiportation of sodium and hydrogen ions on the apical side of the gastrointestinal tract (e.g., when administered enterally). Compounds that are substantially active in inhibiting the NHE3-mediated antiportation of sodium and hydrogen ions in the large intestine (e.g., cecum, ascending colon, descending colon, sigmoid colon) when administered to subjects requiring it.

[0079] In some embodiments, the dual-active compounds are characterized by their “sustained” binding to NHE3 and inhibition of NHE3-mediated antiports of sodium and hydrogen ions, i.e., their “sustained inhibition” of NHE3-mediated antiports of sodium and hydrogen ions. In certain embodiments, sustained inhibition is characterized by the time-dependent inhibitory activity of the compound when measured under “sustained” conditions, which may be compared to “enhanced” conditions, in an in vitro inhibition assay of NHE3-mediated antiports of sodium and hydrogen ions (see PNAS USA. (1984) 81(23): 7436-7440; and Examples 1-2).

[0080] For sustained conditions, for example, when pre-incubating the test compound with cells, the intracellular pH is lowered for approximately 10, 20, 30, 40, 50, 60, 80, 100, or 120 minutes or longer, and then washed out before testing for NHE3-mediated recovery of neutral intracellular pH. Post-incubation washing can be performed for approximately 10, 20, 30, 40, 50, 60, 80, 100, or 120 minutes or longer to lower the intercellular pH and before testing for NHE3-mediated recovery of neutral intracellular pH. In some sustained conditions, the test compound is pre-incubated with cells for the desired time, then washed out of the cell medium, and a buffer is added to lower the intracellular pH (e.g., incubating for approximately 10, 20, 30, 40, 50, or 60 minutes or longer), and NHE3-mediated recovery of neutral intracellular pH is initiated with the addition of an appropriate buffer, without any test compound.

[0081] Facilitating conditions include, for example, incubating the test compound with cells during testing for NHE3-mediated recovery of neutral intracellular pH, i.e., not washing out the compound before or during the initiation of intracellular pH recovery. Under specific facilitating conditions, the NHE3-mediated recovery of neutral intracellular pH is initiated by adding a buffer containing the test compound to a lower intracellular pH (e.g., after incubation for approximately 10, 20, 30, 40, 50, or 60 minutes or longer). In one example cell line assay, intracellular pH recovery can be measured, for example, by monitoring the pH-sensitive change in the fluorescence of a marker normalized to the pH-insensitive fluorescence of the marker. An example of a marker is bis(acetoxymethyl)3,3'-(3',6'-bis(acetoxymethoxy)-5-((acetoxymethoxy)carbonyl)-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-2',7'-diyl)dipropanoate (BCECF).

[0082] In certain embodiments, the dual-active compound is characterized by its time-dependent inhibitory activity in in vitro inhibition assays of NHE3-mediated antiports of sodium and hydrogen ions, and the pIC of the compound under enhanced conditions. 50 (pIC 50promp ) is the pIC of the compound under sustained conditions. 50 (pIC 50pers ) is substantially comparable. For example, the pIC 50promp Value and pIC 50pers Examples include cases where the value is within approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%. In certain embodiments, the pIC 50promp and pIC 50pers7.0 is approximately or at least approximately 7.0, and approximately or at least approximately 6.5, 6.55, 6.6, 6.65, 6.7, 6.75, 6.8, 6.85, 6.9, 6.95, 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, 7.4, 7.45, 7.5, 7.55, 7.6, Includes 7.65, 7.7, 7.75, 7.8, 7.85, 7.9, 7.95, 8.0, 8.05, 8.1, 8.15, 8.2, 8.25, 8.3, 8.35, 8.4, 8.45, 8.5, 8.55, 8.6, 8.65, 8.7, 8.75, 8.8, 8.85, 8.9, 8.95, or 9.0. In some embodiments, the pIC of the compound under accelerated conditions. 50 (pIC 50promp ) is the pIC of the compound under sustained conditions. 50 (pIC 50pers ) is substantially comparable. For example, the pIC 50promp Value and pIC 50pers Examples include cases where the value is within approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%. In certain embodiments, the pIC 50promp and pIC 50pers These are approximately 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, or less than 0.001 μM, or approximately 0.001~0.3, 0.001~0.2, 0.001~0.1, 0.001~0.05. The range is 0.001 to 0.01, 0.001 to 0.005 μM, or approximately 0.005 to 0.3, 0.005 to 0.2, 0.005 to 0.1, 0.005 to 0.05, 0.005 to 0.01, or approximately 0.01 to 0.3, 0.01 to 0.2, 0.01 to 0.1, or 0.01 to 0.05 μM, or approximately 0.1 to 0.3 or 0.1 to 0.2 μM.

[0083] In some embodiments, the dual-active compounds are characterized by their relative activity in inhibiting phosphate transport and inhibiting NHE3-mediated antiportation of sodium and hydrogen ions. For example, when administered enterally to subjects requiring phosphate reduction, certain compounds are formulated with formula EC 50 P f =(r)EC 50 Na (wherein r is about 0.6 to about 1.5, preferably about 0.7 to about 1.3, or about 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5, including the entire intermediate range) is defined as the EC of increased fecal excretion of phosphate ions. 50 (EC 50 P f ) and inhibition of NHE3-mediated antiport of sodium ions and hydrogen ions in EC 50 (EC 50 It may contain Na). In some embodiments, for example, when administered enterally to subjects requiring phosphate reduction, certain compounds may have the formula EC. 50 P u =(r)EC 50 Na (wherein r is about 0.6 to about 1.5, preferably about 0.7 to about 1.3, or about 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5, including the entire intermediate range) is defined as the decrease in urinary excretion of phosphate ions in the EC 50 (EC 50 P u ) and inhibition of NHE3-mediated antiport of sodium ions and hydrogen ions in EC 50 (EC 50 It may have Na). In some embodiments, for example, when administered to achieve systemic availability (e.g., to bring about activity in the kidneys), certain compounds may have formula EC 50 P u =(r)EC 50Na (wherein r is approximately 0.6 to approximately 1.5, preferably approximately 0.7 to approximately 1.3, or approximately 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5, including the entire intermediate range) is defined as the EC of increased urinary excretion of phosphate ions. 50 (EC 50 P u ) and inhibition of NHE3-mediated antiport of sodium ions and hydrogen ions in EC 50 (EC 50 It may contain Na). In certain embodiments, for example, when administered enterally to subjects requiring phosphate reduction or in cell line assays, certain compounds may have formula EC 50 P=(r)EC 50 Na (wherein r is approximately 0.6 to approximately 1.5, preferably approximately 0.7 to approximately 1.3, or approximately 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5, including the entire intermediate range) is defined as EC2, which inhibits phosphate ion transport. 50 (EC 50 P) and EC of NHE3-mediated antiport inhibition of sodium ions and hydrogen ions 50 (EC 50 It may contain Na.

[0084] In some embodiments, and in addition to its effect on Pi values, administration (e.g., by enteral administration) of a dual-active compound (or in a dosage that enables dual activity) to a subject requiring it increases the daily fecal excretion of sodium and / or body fluids in that subject. In some cases, the fecal excretion of sodium is increased by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 1100%, 1200%, 1300%, 1400%, 1500%, 1600%, 1700%, 1800%, 1900%, or 2000% or more compared to an untreated state. In some cases, the excretion of such bodily fluids or the water content in the feces increases by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 1100%, 1200%, 1300%, 1400%, 1500%, 1600%, 1700%, 1800%, 1900%, or 2000% or more compared to the untreated state.

[0085] B. Single active compound Certain embodiments relate to NHE3-binding compounds that inhibit the transport of phosphate ions (Pi) but do not substantially inhibit the NHE3-mediated antiportation of sodium and hydrogen ions in a given drug administration. These and related embodiments include, for example, non-sustained ligands of NHE3 that are substantially active in inhibiting Pi transport when administered to a target requiring it, but are substantially inactive in inhibiting the NHE3-mediated antiportation of sodium and hydrogen ions in the gastrointestinal tract and / or kidney. In some embodiments, the non-sustained ligand of NHE3 is substantially inactive in inhibiting the NHE3-mediated antiportation of sodium and hydrogen ions in the large intestine (e.g., when administered enterally).

[0086] In some embodiments, non-sustaining NHE3 ligands are characterized by their maximal inhibitory activity against NHE3-mediated antiports of sodium and hydrogen ions, for example, in cell line assays or other in vitro assays. In one example, a non-sustaining NHE3 ligand has maximal inhibition of NHE3-mediated antiports of sodium and hydrogen ions at about 50%, 40%, 30%, 35%, 20%, 15%, 10%, or less than 5%, where the maximal inhibition is characterized by the inhibitory activity of the compound in an in vitro inhibition assay of NHE3-mediated antiports of sodium and hydrogen ions, and is associated with sodium-free conditions. In these and related embodiments, sodium-free conditions essentially represent zero activity against NHE3-mediated antiports of sodium and hydrogen ions and can therefore be used to set a value of 100% or maximal inhibition.

[0087] In some embodiments, the non-sustaining NHE3 ligands are characterized by their "non-sustaining" nature to binding to NHE3 and inhibition of NHE3-mediated antiportation of sodium and hydrogen ions, i.e., their relative absence or reduction in "sustaining inhibition" of NHE3-mediated antiportation of sodium and hydrogen ions. In certain embodiments, sustained inhibition may be compared, for example, to "enhanced" conditions, and is characterized by the time-dependent inhibitory activity of the compound in in vitro inhibition assays of NHE3-mediated antiportation of sodium and hydrogen ions when measured under "sustained" conditions (see, e.g., PNAS USA. (1984) 81(23): 7436-7440; and Examples 1-2). Examples of sustained and enhanced conditions are described above.

[0088] In certain embodiments, the non-sustaining NHE3 ligand is characterized by its time-dependent inhibitory activity in in vitro inhibition assays of NHE3-mediated antiports of sodium and hydrogen ions, and the pIC of the compound under enhanced conditions. 50 (pIC 50promp ) is the pIC of the compound under sustained conditions. 50 (pIC 50persLarger than or substantially larger than pIC. Substantially larger means, for example, pIC 50promp However, at least approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200% or more, pIC 50pers A case where it is larger is one example. In certain embodiments, pIC 50promp 7.0 is approximately or at least approximately 7.0, and approximately or at least approximately 6.5, 6.55, 6.6, 6.65, 6.7, 6.75, 6.8, 6.85, 6.9, 6.95, 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, 7.4, 7.45, 7.5, 7.55, 7.6, 7 Includes 0.65, 7.7, 7.75, 7.8, 7.85, 7.9, 7.95, 8.0, 8.05, 8.1, 8.15, 8.2, 8.25, 8.3, 8.35, 8.4, 8.45, 8.5, 8.55, 8.6, 8.65, 8.7, 8.75, 8.8, 8.85, 8.9, 8.95, or 9.0, and pIC 50pers It is approximately or at least approximately 6.0, and approximately 6.4, 6.35, 6.3, 6.25, 6.2, 6.15, 6.1, 6.05, 6.0, 5.95, 5.9, 5.85, 5.7, 5.75, 5.6, 5.65, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5. Includes 0, 4.95, 4.9, 4.85, 4.8, 4.75, 4.7, 4.65, 4.6, 4.55, 4.5, 4.45, 4.4, 4.35, 4.3, 4.25, 4.2, 4.15, 4.1, 4.05, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, or less than or equal to 3.0.

[0089] In some embodiments, the pIC of the non-sustaining NHE3 ligand under enhanced conditions 50 (pIC 50promp ) is the pIC of the compound under sustained conditions. 50 (pIC 50pers It is substantially smaller than pIC. "Substantially smaller" means, for example, pIC 50promp However, approximately or at least approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, or 1000%, pIC50pers A smaller case is also possible. For example, in some embodiments, pIC 50promp These are approximately 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, or less than 0.001 μM, or approximately 0.001~0.3, 0.001~0.2, 0.001~0.1, 0.001~0.05, 0. The pIC is in the range of 0.01~0.01, 0.001~0.005 μM, or approximately in the range of 0.005~0.3, 0.005~0.2, 0.005~0.1, 0.005~0.05, 0.005~0.01, or approximately in the range of 0.01~0.3, 0.01~0.2, 0.01~0.1, or 0.01~0.05 μM, or approximately in the range of 0.1~0.3 or 0.1~0.2 μM. 50pers This refers to a range of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or greater than 1000 μM, or in the range of approximately 1-10, 1-20, 1-30, 1-40, 1-50, 1-100, 1-500, 1-1000 μM, or in the range of approximately 2-10, 2-20, 2-30, 2-40, 2-50, 2-100, 2-500, 2-1000 μM, or greater than 1000 μM. The ranges are approximately 5-10, 5-20, 5-30, 5-40, 5-50, 5-100, 5-500, 5-1000 μM, or approximately 10-20, 10-30, 10-40, 10-50, 10-100, 10-500, 10-1000 μM, or approximately 20-30, 20-40, 20-50, 20-100, 20-500, 20-1000 μM, or approximately 50-100, 50-500, 50-1000 μM, or approximately 100-500 or 100-1000 μM.

[0090] In some embodiments, the non-sustaining NHE3 ligands are characterized by their relative activity in inhibiting phosphate transport and inhibiting NHE3-mediated antiportation of sodium and hydrogen ions. For example, when administered enterally to subjects requiring phosphate reduction, certain compounds are formulated with formula EC 50 P f =(r)EC 50 Na (wherein r is approximately 0.1 to approximately 0.5, or approximately 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, or 0.55, including the entire intermediate range) is defined as the EC of increased fecal excretion of phosphate ions. 50 (EC 50 P f ) and inhibition of NHE3-mediated antiport of sodium ions and hydrogen ions in EC 50 (EC 50 It may contain Na) in some embodiments when administered enterally to subjects requiring phosphate reduction. 50 P u =(r)EC 50 Na (wherein r is approximately 0.1 to approximately 0.5, or approximately 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, or 0.55, including the entire intermediate range) is defined as the decrease in urinary excretion of phosphate ions in the EC 50 (EC 50 P u ) and inhibition of NHE3-mediated antiport of sodium ions and hydrogen ions in EC 50 (EC 50 It may contain Na). In certain embodiments, for example, when administered enterally to subjects requiring phosphate reduction or in cell line assays, certain compounds may have formula EC 50 P=(r)EC 50 Na (wherein r is approximately 0.05 or 0.1 to approximately 0.5 or 0.55, or approximately 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, or 0.55, including the entire intermediate range) is defined as the EC2 of phosphate ion transport inhibition. 50 (EC 50P) and EC of NHE3-mediated antiport inhibition of sodium ions and hydrogen ions 50 (EC 50 It may have Na). In some embodiments, for example, when administered to achieve systemic availability (e.g., to yield significant activity in the kidneys), certain non-sustaining NHE3 ligand compounds have formula EC 50 P u =(r)EC 50 Na (wherein r is approximately 0.1 to approximately 0.5, or approximately 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, or 0.55, including the entire intermediate range) is defined as the EC of increased urinary excretion of phosphate ions. 50 (EC 50 P u ) and inhibition of NHE3-mediated antiport of sodium ions and hydrogen ions in EC 50 (EC 50 It may contain Na.

[0091] In certain embodiments, administration of a non-sustained NHE3 ligand to subjects requiring it (e.g., by enteral administration) increases the phosphate / sodium ratio of fecal excretion by approximately or at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or 200% or more compared to the untreated state. In some embodiments, administration to subjects requiring it (e.g., by enteral administration) increases the daily fecal excretion of phosphate without substantially altering the stool consistency or water content in the stool. For example, in these and related embodiments, the stool consistency may be approximately or within approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, or 20% compared to the untreated state. In some embodiments, the stool consistency on the Bristol Stool Scale (types 1, 2, 3, 4, 5, 6, and 7; type 1 is hard, type 7 is watery) may be the same as or within about 1-2 units compared to the untreated state (see, e.g., Rao et al., Neurogastroenterol Motil. 23:8-23, 2011; and Lewis and Heaton, Scand. J. Gastroenterol. 32:920-4, 1997). In specific embodiments, the stool consistency on the Bristol Stool Scale is type 3 or type 4. In some embodiments, administration to rodents (e.g., rats, mice) results in at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200% or more of small intestine (Na) compared to the untreated state. SI ) / Cumula (Na C Increase the sodium ratio within the parentheses.

[0092] II. Compounds that are substantially not systemically bioavailable A. Physical and performance characteristics of compounds that can be localized in the gastrointestinal tract Certain compounds described herein are designed to be substantially active or localized in the gastrointestinal lumen of human or animal subjects. The term “gastrointestinal lumen” is used herein interchangeably with the term “lumen” to refer to the space or cavity within the gastrointestinal tract (also known as the gastrointestinal tract (GI) or gut) separated by the apical membrane of the gastrointestinal epithelial cells of the subject. In some embodiments, the compounds are not absorbed through the layer of epithelial cells of the gastrointestinal tract (also known as the gastrointestinal epithelium (GI)). “Gastrointestinal mucosa” refers to the layer of cells separating the gastrointestinal lumen from other parts of the body, including the mucosa of the stomach and intestines, such as the mucosa of the small intestine. As used herein, “gastrointestinal epithelial cells” or “gut epithelial cells” refers to any epithelial cells on the surface of the gastrointestinal mucosa facing the lumen of the gastrointestinal tract, including, for example, gastric epithelial cells, intestinal epithelial cells, and colonic epithelial cells.

[0093] When used herein, “substantially systemic bioavailable” and / or “substantially impermeable” (as used herein, not just in its variations) generally describe a situation in a statistically significant amount, where, in some embodiments, essentially all of the compound remains in the gastrointestinal lumen. For example, according to one or more embodiments of this disclosure, preferably at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, 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 represents a reduction in the net motility of the compound across the gastrointestinal lamina of epithelial cells, not only by active and / or passive transport, but also via both transcellular and paracellular transport. In such embodiments, the compound is prevented from net permeability to the gastrointestinal epithelial cell lamina of transcellular transport, for example, through the apical membrane of the epithelial cells of the small intestine. In these embodiments, the compound also inhibits net permeability through "tight junctions" of paracellular transport between gastrointestinal epithelial cells lining the lumen.

[0094] In this regard, in one particular embodiment, the compound is not absorbed in any way by the gastrointestinal tract or gastrointestinal lumen. As used herein, the terms “substantially impermeable” or “substantially not systemically bioavailable” include embodiments in which no detectable amount of absorption, permeability, or systemic exposure of the compound is detected by means of means generally known in the art.

[0095] However, in this regard, in another embodiment, “substantially impermeable” or “substantially not systemically bioavailable” may mean that “substantially impermeable” or “substantially not systemically bioavailable” results in or allows some limited absorption into the gastrointestinal tract, more particularly into the intestinal epithelium (e.g., absorption of some detectable amounts, such as at least about 0.1%, 0.5%, 1% or more and about 30%, 20%, 10%, 5%, etc., the absorption range is, for example, about 1% and 30%, or 5% and 20%, etc.); that is, “substantially impermeable” or “substantially not systemically bioavailable” may mean that less than about 20% of the administered compound shows some detectable permeability to the epithelial layer of cells in the gastrointestinal tract (e.g., about 15%, about 10%, or even about 5%, 4%, 3%, or 2%, and for example, greater than about 0.5% or 1%) and then the compound is cleaned by the liver (i.e., hepatic extract) and / or kidney (i.e., renal extract).

[0096] In this regard, in certain embodiments, the substantial impermeability and / or lack of practical systemic bioavailability of the compounds of the present invention, approximately 50%, 60%, 70%, 80%, 90%, or 95% or more, is such that the compounds can be recovered from feces over a period of, for example, 24, 36, 48, 60, 72, 84, or 96 hours after administration to a subject requiring it. In this embodiment, the recovered compounds may include the parent compound and the sum of metabolites derived from the parent compound by means of, for example, hydrolysis, conjugation, reduction, oxidation, N-alkylation, glucuronidation, acetylation, methylation, sulfation, phosphorylation, or any other modification by adding or removing atoms from the parent compound, the metabolites being generated by any enzymatic action or exposure to any physiological environment, including pH, temperature, pressure, or interaction with food when present in a digestive environment.

[0097] The fecal recovery of compounds and metabolites can be measured using standard methods. For example, the compound may be administered orally at an appropriate dose (e.g., 10 mg / kg), and feces are then collected at predetermined times after administration (e.g., 24, 36, 48, 60, 72, 96 hours). The parent compound and metabolites can be extracted with an organic solvent and quantitatively analyzed by mass spectrometry. A mass balance analysis of the parent compound and metabolites (including parent = M, metabolite 1 [M+16], and metabolite 2 [M+32]) may be used to determine the recovery percentage in feces.

[0098] (i) Transparency In this regard, in various embodiments, the performance of a compound that is substantially not systemically bioavailable depends on the amount of compound introduced, its size, and / or other physicochemical parameters (e.g., polar surface area, the number of its hydrogen bond donors and / or acceptors, the number of freely rotatable bonds, etc.). More specifically, the absorption characteristics of a compound can be selected by applying the principles of pharmacokinetics, for example, by applying Lipinski's Law, also known as the "Rule of Five." Rather than a law, it is a set of guidelines, but Lipinski has shown that small molecule drugs having (i) molecular weight, (ii) number of hydrogen bond donors, (iii) number of hydrogen bond acceptors, and / or (iv) a water / octanol partition coefficient (MoriguchiLogP) greater than a certain threshold generally do not show significant systemic concentrations (i.e., are generally not absorbed to any significant degree). (See, for example, Lipinski et al, Advanced Drug Delivery Reviews, 46:3-26, 2001 (as incorporated herein by reference).) Thus, compounds that are substantially not systemically bioavailable can be designed to have one or more molecular structures that exceed the Lipinski threshold (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 the Causes of Poor Solubility and Poor Permeability, J. Pharm. & Toxicol. Methods, 44:235-249 (2000) (as incorporated herein by reference)).

[0099] In some embodiments, for example, a substantially impermeable or substantially non-systemic bioavailable compound of the present disclosure may be interpreted as having one or more of the following properties: (i) about 500 Da, about 600 Da, about 700 Da, about 800 Da, about 900 Da, about 1000 Da, about 1200 Da, about 1300 Da, about 1400 Da, about 1500 Da, about 1600 Da, about 1800 Da, about 2000 Da, about 2500 Da, about 3000 Da, about 4000 Da, about 5000 Da, (ii) a total number of NH and / or OH and / or other potential hydrogen bond donors greater than approximately 7500 Da and approximately 10,000 Da (in the non-salt form of the compound); (ii) a total number of NH and / or OH and / or other potential hydrogen bond donors greater than approximately 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 20 or more; (iii) a total number of O atoms and / or N atoms and / or other potential hydrogen bond acceptors greater than approximately 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 20 or more; (iv) approximately 10 5 (v) a LogP greater than or equal to about 5, about 6, about 7, about 8, about 9, about 10, or greater than or equal to about 10 (i.e., a LogP less than 1, or even 0); (v) a total number of rotatable bonds greater than about 5, about 10, or about 15. In certain embodiments, the compound has a LogP less than 14, for example, a LogP in the range of about 6-7, 6-8, 6-9, 6-10, 6-11, 6-12, 6-13, 7-8, 7-9, 7-10, 7-11, 7-12, 7-13, 8-9, 8-10, 8-11, 8-12, 8-13, 9-10, 9-11, 9-12, 9-13, 10-11, 10-12, 10-13, 11-12, 11-13, or 12-13.

[0100] In addition to the parameters mentioned above, molecular polar surface area (i.e., "PSA"), which can be characterized as a surface belonging to a polar atom, is a descriptor that has been shown to correlate well with membrane-based passive transport and thus enable the prediction of drug transport properties. It has been successfully applied to the prediction of intestinal absorption and Caco2 cell monolayer permeability. Details of an example Caco2 cell monolayer permeability test (e.g., see the description of the Caco2 model provided in U.S. Patent No. 6,737,423 (as incorporated herein by reference), in particular the text describing the Caco2 model that may be applied to the evaluation or testing of the compound of the present invention). PSA is Å 2 Expressed in square angstroms, it is computer-calculated from a 3D molecular representation. Faster calculation methods are also available using desktop computers and commercially available chemical graphic tool packages such as ChemDraw (see, for example, Ertl et al, Journal of Medicinal Chemistry, 2000, 43,3714-3717 (the full text of which is incorporated herein by reference for all purposes of relevance and consistency)). The term "topological PSA" (tPSA) was coined for this faster calculation method. tPSA correlates well with human absorption data for common drugs (see Table 1, from Ertl et al, J. Med. Chem., 2000, 43:3714-3717): [Table 1]

[0101] Accordingly, in some embodiments, the compounds of the Disclosure are substantially impermeable (e.g., cellular impermeable) or substantially not systemically bioavailable (as otherwise defined herein) at about 100 Å. 2 , about 116Å 2 Approximately 120 Å 2 Approximately 130 Å 2 , or approximately 140 Å 2 , and in some cases, approximately 150 Å 2 , about 160Å2 , about 170Å 2 , about 180Å 2 Approximately 190 Å 2 , about 200Å 2 , about 225Å 2 , about 250Å 2 , about 270Å 2 , about 300Å 2 , about 350Å 2 Approximately 400 Å 2 Approximately 450 Å 2 , about 500Å 2 , approximately 750 Å 2 , or even about 1000 Å 2 Larger, or approximately 100-120 Å 2 , 100~130 Å 2 , 100~140 Å 2 , 100~150 Å 2 , 100~160 Å 2 , 100~170 Å 2 , 100~170 Å 2 , 100~190 Å 2 , 100~200 Å 2 , 100~225Å 2 , 100~250Å 2 , 100~300Å 2 , 100~400Å 2 , 100~500 Å 2 , 100~750 Å 2 , 100~1000 Å 2 , 116~120 Å 2 , 116~130 Å 2 , 116~140 Å 2 , 116~150 Å 2 , 116~160 Å 2 , 116~170 Å 2 , 116~170 Å 2 , 116~190 Å 2 , 116~200Å 2 , 116~225Å 2 , 116~250Å 2 , 116~300Å 2 , 116~400Å 2 , 116~500Å 2 , 116~750 Å 2 , 116~1000 Å 2、120~130Å 2 、120~140Å 2 、120~150Å 2 、120~160Å 2 、120~170Å 2 、120~170Å 2 、120~190Å 2 、120~200Å 2 、120~225Å 2 、120~250Å 2 、120~300Å 2 、120~400Å 2 、120~500Å 2 、120~750Å 2 、120~1000Å 2 、130~140Å 2 、130~150Å 2 、130~160Å 2 、130~170Å 2 、130~170Å 2 、130~190Å 2 、130~200Å 2 、130~225Å 2 、130~250Å 2 、130~300Å 2 、130~400Å 2 、130~500Å 2 、130~750Å 2 、130~1000Å 2 、140~150Å 2 、140~160Å 2 、140~170Å 2 、140~170Å 2 、140~190Å 2 、140~200Å 2 、140~225Å 2 、140~250Å 2 、140~300Å 2 、140~400Å 2 、140~500Å 2 、140~750Å 2 、140~1000Å 2 、150~160Å 2 、150~170Å 2 、150~170Å 2, 150~190 Å 2 , 150~200 Ų, 150~225 Å 2 , or 150-250 Å 2 , 150~300Å 2 , 150~400Å 2 , 150~500 Å 2 , 150~750Å 2 , 150~1000 Å 2 , 200~250 Å 2 , 200~300Å 2 , 200~400Å 2 , 200~500Å 2 , 200~750Å 2 , 200~1000Å 2 , 250~250Å 2 This can be interpreted as indicating a tPSA value within that range.

[0102] Because of Lipinski's law, or exceptions to the tPSA model, the permeability properties of the compounds of this disclosure can be experimentally screened. Permeability coefficients can be determined by methods known to those skilled in the art, including those of the Caco2 cell permeability assay and / or the example using an artificial membrane as a model of gastrointestinal epithelial cells. For example, to mimic the net permeability properties of the gastrointestinal mucosa, a synthetic membrane impregnated with lectin and / or dodecane can be used as a gastrointestinal mucosal model. The membrane can be used to separate a compartment containing the compounds of this disclosure from a compartment for monitoring permeability. A balanced artificial membrane permeability assay (PAMPA) can also be performed. Such in vitro measurements can reasonably indicate the actual permeability within the body (see Wohnsland et al, J. Med. Chem. 44:923-930, 2001; Schmidt et al, Millipore Corp. Application Note, 2002, n AN 1725EN00, and n AN 1728EN00 (as incorporated herein by reference)).

[0103] Accordingly, in some embodiments, the compounds used in the methods of this disclosure have a transmittance coefficient of approximately 100 x 10 when measured by means known in the art.-6 Less than cm / s, or approximately 10x10 -6 Less than cm / s, or approximately 1 x 10⁻⁶ -6 Less than cm / s, or approximately 0.1 x 10⁻⁶ -6 P less than cm / s app It may have (for example, the permeability experiment described in Wohnsland et al, 2001 above).

[0104] As described above, according to the present disclosure, compounds can be modified to prevent their net absorption through the intestinal epithelial cell layer, making them substantially systemically bioavailable. In some embodiments, the compounds of the present disclosure include compounds that link, conjugate, or bind to an unabsorbable moiety, which may be an oligomeric moiety, a polymeric moiety, a hydrophobic moiety, a hydrophilic moiety, and / or a charged moiety, making the entire molecule substantially impermeable or substantially systemically bioavailable. In some preferred embodiments, the compound is conjugated to a part or part of a polymer or polymer such that the resulting molecule is substantially impermeable or substantially systemically bioavailable. Some or all of the polymer may have molecular weights greater than about 500 daltons (Da), about 1000 Da, about 2500 Da, about 5000 Da, or about 10,000 Da, and in particular may have molecular weights in the range of about 1000 daltons (Da) to about 500,000 Da, preferably in the range of about 5000 to about 200,000 Da, and more preferably have molecular weights high enough to essentially inhibit any net absorption of the compound through the intestinal epithelial cell layer. In these or other specific embodiments, the compound is modified to substantially inhibit its net absorption through the intestinal epithelial cell layer.

[0105] (ii)C max and IC 50 or EC 50 In some embodiments, when a substantially non-systemic bioavailable compound detailed herein is administered (e.g., enterally) to a subject requiring it, either alone or in combination with one or more additional pharmaceutically active compounds or agents, the phosphate ion (Pi) transport or uptake inhibitory concentration of the compound occurs. 50 C max This indicates the maximum concentration detectable in serum defined as C. max IC is an inhibitor of Pi transport or uptake. 50 Lower by approximately or at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. In some embodiments, the C max IC is an inhibitor of Pi transport or uptake. 50 X is approximately 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 (0.9 times).

[0106] In certain embodiments, when one or more substantially systemically non-bioavailable compounds detailed herein are administered (e.g., enterally) to a subject requiring them, C max :I C 50 It may have a ratio (for inhibition of Pi transport or uptake), C max and IC 50 These are approximately 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or less than or equal to 1.0, or approximately 0.01 to 1.0, 0.01 to 0.9, 0.01 to 0.8, 0.01 to 0.7, 0.01 to 0.6, 0. It is expressed in the same units within the range of 0.1 to 0.5, 0.01 to 0.4, 0.01 to 0.3, 0.01 to 0.2, or between 0.01 and 0.1, or within the range of approximately 0.1 to 1.0, 0.1 to 0.9, 0.1 to 0.8, 0.1 to 0.7, 0.1 to 0.6, 0.1 to 0.5, 0.1 to 0.4, 0.1 to 0.3, or between 0.1 and 0.2.

[0107] In some embodiments, the substantially non-systemic bioavailable compounds detailed herein, when administered (e.g., enterally) to a subject requiring them, either alone or in combination with one or more additional pharmaceutically active compounds or agents, increase fecal excretion by approximately or at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% in the EC of the compound for increasing fecal excretion of phosphates. 50 C max This indicates the maximum concentration detectable in serum defined as C. max This is due to increased phosphate excretion in feces. 50 It is approximately or at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% smaller than C. In some embodiments, the C max The EC of the increase in fecal excretion of phosphate is approximately 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 x (0.9 times) phosphate. 50 That is the case.

[0108] In some embodiments, when one or more substantially systemically non-bioavailable compounds detailed herein are administered (e.g., enterally) to a subject requiring it, or when measured in an animal model or cell line assay, they increase the IC of fecal excretion of phosphates of approximately or at least approximately 10 μM, 9 μM, 8 μM, 7 μM, 7.5 μM, 6 μM, 5 μM, 4 μM, 3 μM, 2.5 μM, 2 μM, 1 μM, 0.5 μM, 0.1 μM, 0.05 μM, or 0.01 μM or less. 50 It may have, for example, 50This range is approximately 0.01 μM to 10 μM, or approximately 0.01 μM to 7.5 μM, or approximately 0.01 μM to 5 μM, or approximately 0.01 μM to 2.5 μM, or approximately 0.01 μM to 1.0 μM, or approximately 0.1 μM to 10 μM, or approximately 0.1 μM to 7.5 μM, or approximately 0.1 μM to 5 μM, or approximately 0.1 μM to 2.5 μM, or approximately 0.1 μM to 1.0 μM, or approximately 0.5 μM to 10 μM, or approximately 0.5 μM to 0.5 μM, or approximately 0.5 μM to 7.5 μM, or approximately 0.5 μM to 5 μM, or approximately 0.5 μM to 2.5 μM, or approximately 0.5 μM to 1.0 μM.

[0109] In certain embodiments, a substantially systemically non-bioavailable compound detailed herein, when administered (e.g., enterally) to a subject requiring it, either alone or in combination with one or more additional pharmaceutically active compounds or agents, reduces urinary excretion by approximately or at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% in the EC of the compound for reducing urinary excretion of phosphates. 50 C is approximately the same as or smaller than C max This indicates the maximum concentration detectable in serum defined as C. max This is due to a decrease in urinary excretion of phosphates in the EC. 50 Smaller by approximately or at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. In some embodiments, the C max This represents a decrease in urinary phosphate excretion of approximately 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 x (0.9 times) EC 50 That is the case.

[0110] In some embodiments, when one or more substantially systemically non-bioavailable compounds detailed herein are administered (e.g., enterally) to a subject requiring it, either alone or in combination with one or more additional pharmacoactive compounds or agents, or when measured in animal models or cell line assays, an increase in urinary excretion of phosphates of approximately or at least approximately 10 μM, 9 μM, 8 μM, 7 μM, 7.5 μM, 6 μM, 5 μM, 4 μM, 3 μM, 2.5 μM, 2 μM, 1 μM, 0.5 μM, 0.1 μM, 0.05 μM, or 0.01 μM is observed in the EC of an animal model or cell line assay. 50 It may have, for example, 50 This range is approximately 0.01 μM to 10 μM, or approximately 0.01 μM to 7.5 μM, or approximately 0.01 μM to 5 μM, or approximately 0.01 μM to 2.5 μM, or approximately 0.01 μM to 1.0 μM, or approximately 0.1 μM to 10 μM, or approximately 0.1 μM to 7.5 μM, or approximately 0.1 μM to 5 μM, or approximately 0.1 μM to 2.5 μM, or approximately 0.1 μM to 1.0 μM, or approximately 0.5 μM to 10 μM, or approximately 0.5 μM to 0.5 μM, or approximately 0.5 μM to 7.5 μM, or approximately 0.5 μM to 5 μM, or approximately 0.5 μM to 2.5 μM, or approximately 0.5 μM to 1.0 μM.

[0111] In certain embodiments, when one or more substantially systemically non-bioavailable compounds detailed herein are administered (e.g., enterally) to a subject requiring them, C max :EC 50 The ratio may be such that (for example, increased fecal excretion of phosphate, decreased urinary excretion of phosphate), C max and EC 50These are approximately 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or less than or equal to 1.0, or approximately 0.01 to 1.0, 0.01 to 0.9, 0.01 to 0.8, 0.01 to 0.7, 0.01 to 0.6. It is expressed in the range of 0.01-0.5, 0.01-0.4, 0.01-0.3, 0.01-0.2, or 0.01-0.1, or in the same units within the range of approximately 0.1-1.0, 0.1-0.9, 0.1-0.8, 0.1-0.7, 0.1-0.6, 0.1-0.5, 0.1-0.4, 0.1-0.3, or 0.1-0.2.

[0112] In addition, or / or, when one or more substantially systemically non-systemic bioavailable compounds detailed herein are administered (e.g., enterally) to a subject requiring them, either alone or in combination with one or more additional pharmaceutically active compounds or agents, the C content should be approximately 10 ng / ml, approximately 7.5 ng / ml, approximately 5 ng / ml, approximately 2.5 ng / ml, approximately 1 ng / ml, or approximately 0.5 ng / ml or less. max It may have the C max For example, this ranges from approximately 1 ng / ml to approximately 10 ng / ml, or from approximately 2.5 ng / ml to approximately 7.5 ng / ml.

[0113] B. Examples of Structures Generally speaking, the disclosure includes any small molecule, which may be monovalent or polyvalent, that conjugates and / or modulates with NHE3 to have activity as a phosphate transport inhibitor, and includes small molecules that are substantially impermeable in the gastrointestinal tract or substantially not systemically bioavailable, and includes known NHE-conjugating compounds that may be modified or functionalized in accordance with the disclosure to alter their physicochemical properties in order to make the entire compound substantially active in the gastrointestinal tract.

[0114] Therefore, the compounds of this disclosure are generally defined by formula (I): [ka] It can be represented by: In the formula: (i) NHE is an NHE-binding small molecule, and (ii) Z is a moiety having at least one site for binding to the NHE-binding small molecule, wherein the resulting NHE-Z molecule has overall physicochemical properties that make it substantially impermeable or substantially not bioavailable systemically. The NHE-binding small molecule generally comprises a heteroatom-containing moiety and a cyclic or heterocyclic skeleton or a support moiety directly or indirectly bound thereto. In particular, structural studies of small molecules reported to date as NHE binders or inhibitors, as further illustrated below herein, mostly comprise a cyclic or heterocyclic support or skeleton directly or indirectly bound (e.g., by a hydrocarbyl or heterohydrocarbyl moiety, such as an acyl moiety or alkyl, alkenyl, heteroalkyl, or heteroalkenyl moiety) to a heteroatom-containing moiety capable of acting as a sodium atom or sodium ion mimic, typically selected from substituted guanidinyl moieties and substituted heterocyclic moieties (e.g., nitrogen-containing heterocyclic moieties). Optionally, the heteroatom-containing portion may condense with the skeleton or supporting portion to form a condensed bicyclic structure and / or may be capable of forming a positive charge at physiological pH.

[0115] In this regard, while a sodium atom or heteroatom-containing portion capable of acting as an ionic mimic may generate a positive charge, this should not be understood or interpreted as requiring the entire compound to have a net positive charge or only a single positively charged portion within it. Rather, in various embodiments, the compound may not have a charged portion, or it may have a multivalently charged portion (it may have a positive charge, a load charge, or a combination thereof; for example, the compound may be a zwitterion). In addition, it should be understood that the entire compound may have a net neutral charge, a net positive charge (e.g., +1, +2, +3, etc.), or a net load charge (e.g., -1, -2, -3, etc.).

[0116] The Z moiety may be bound at essentially any position on or within the NHE small molecule, in particular: (i) bound to the skeleton or support portion, (ii) bound at a position on or within the heteroatom-containing portion, and / or (iii) bound at a position on or within the spacer portion that connects the skeleton to the heteroatom-containing portion, provided that the introduction of the Z moiety does not significantly adversely affect the NHE binding activity. In one particular embodiment, Z may be in the form of an oligomer, dendrimer, or polymer (e.g., bonded to the backbone or spacer portion) conjugated with an NHE small molecule, or Z may be in the form of a linker that acts to increase all of the following as defined herein: (i) the total molecular weight and / or polar surface area of ​​the NHE-Z molecule; and / or (ii) the number of freely rotatable bonds of the NHE-Z molecule; and / or (iii) the number of hydrogen bond donors and / or acceptors of the NHE-Z molecule; and / or (iv) the LogP value of the NHE-Z molecule, which is at least about 5 (or less than 1, or even about 0), so that the entire NHE-conjugated compound (i.e., the NHE-Z compound) is substantially impermeable or substantially not bioavailable systemically.

[0117] More specifically, this disclosure relates to a substantially impermeable or substantially systemically non-bioavailable NHE-conjugated compound, or a salt thereof, having the structure of formula (II): [ka] In the formula: (i) Z is a portion bound to or incorporated with the NHE-binding small molecule such that the resulting NHE-Z has overall physicochemical properties that make it substantially impermeable or substantially not bioavailable systemically; (ii) B is a heteroatom-containing portion of the NHE-binding small molecule, selected from a substituted guanidinyl portion and a substituted heterocyclic portion, which in one particular embodiment may condense with the skeletal portion to form a condensed bicyclic structure; (iii) The skeleton is a cyclic or heterocyclic portion to which the heteroatom-containing portion (e.g., the substituted guanidinyl portion or the substituted heterocyclic portion) is directly or indirectly bound, and this is 1 (iv) X is a spacer portion selected from the group consisting of bonds or substituted or unsubstituted hydrocarbyl or heterohydrocarbyl portions, in particular a substituted or unsubstituted C1-C7 hydrocarbyl or heterohydrocarbyl (e.g., C1-C7 alkyl, alkenyl, heteroalkyl or heteroalkenyl) and a substituted or unsubstituted, saturated or unsaturated, cyclic or heterocyclic portion (e.g., C4-C7 cyclic or heterocyclic portion) linking B and the skeleton; and (v) D and E are integers, each independently having a value of 1 or 2 or more.

[0118] In one or more specific embodiments, B may be selected from a guanidinyl moiety or a guanidinyl bioisoster moiety selected from the group consisting of substituted cyclobutendione, substituted imidazole, substituted thiazole, substituted oxadiazole, substituted pyrazole, or substituted amine, as further illustrated herein. More specifically, B may be selected from guanidine bioisosters such as guanidinyl, acylguanidinyl, sulfonylguanidinyl, or cyclobutendione, substituted or unsubstituted imidazole, aminoimidazole, alkylimidazole, thiazole, oxadiazole, pyrazole, alkylthioimidazole, or other functionalities such as amines (e.g., tertiary amines), alkylamines, etc., which may be positively charged at physiological pH or which may function as a sodium mimetic. In one particularly preferred embodiment, B is a substituted guanidinyl moiety or a substituted heterocyclic moiety which may be positively charged at physiological pH and function as a sodium mimetic. In one illustrative embodiment, a compound of the present disclosure (or more specifically, a pharmaceutically acceptable HCl salt thereof, illustrated) may have the structure of formula (III): [ka] In the formula, Z may be bonded to any one of a number of sites on the NHE bonded small molecule, and furthermore, the R1, R2, and R3 substituents of the aromatic ring are as described herein and / or in detail in U.S. Patent No. 6,399,824 (the entire contents of which are incorporated herein by reference for all relevant and consistent purposes).

[0119] However, in this regard, the substantially impermeable or substantially systemically non-bioavailable NHE-binding compounds of the Disclosure may have structures other than those illustrated above without departing from the scope of the Disclosure. For example, in various other embodiments, one or both of the terminal nitrogen atoms of the guanidine moiety may be substituted by one or more substituents and / or modified or functionalized moieties, and Z may generally be bound to the NHE-binding compound by means of (i) the skeleton, (ii) the spacer X, or (iii) the heteroatom-containing moiety, B, as further illustrated in the structures shown below: [ka]

[0120] Furthermore, in this regard, as used herein, “bioisoster” generally refers to a portion having physical and chemical properties similar to the guanidine portion, and in this case, the biological properties are again attributed to that given portion similar to the guanidine portion. (See, for example, Ahmad, S. et al., Aminoimidazoles as Bioisosteres of Acylguanidines: Novel, Potent, Selective and Orally Bioavailable Inhibitors of the Sodium Hydrogen Exchanger Isoform-1, Boorganic & Med. Chem. Lett., pp. 177-180 (2004) (Its entire contents are incorporated herein by reference for all relevant and consistent purposes)).

[0121] As will be further detailed below, known NHE-binding small molecules or chemical types that can serve as suitable starting materials (for modification or functionalization to make them substantially impermeable or substantially systemically bioavailable, and / or for use in pharmaceutical formulations) are generally, for example: [ka] They can be grouped into numerous subsets, such as: In the formula: the terminal ring (or, in the case of non-acylguanidines, "R") is the skeleton or supporting portion; the guanidine moiety (or substituted heterocycle, and more specifically, the piperidine ring in the case of non-guanidine inhibitors) is B; and X is the acyl moiety, or the -AB-acyl- moiety (or, in the case of non-acylguanidines and non-guanidine inhibitors, the bond) (e.g., Lang, HJ, "Chemistry of NHE Inhibitors" in The Sodium-Hydrogen Exchanger, Harmazyn, M., Avkiran, M. and Fliegel, L., Eds., Kluwer Academic Publishers 2003. See also B. Masereel et al., An Overview of Inhibitors of Na+ / H+ Exchanger, European J. of Med. Chem., 38, pp. 547-554). (2003) (The entire contents thereof are incorporated herein by reference for all relevant and consistent purposes) (see reference). Without being bound by any particular theory, at physiological pH, a guanidine group, or an acylguanidine group, or a charged guanidine or acylguanidine group (or, in the case of non-guanidine inhibitors, a heterocyclic or other functional group that can reproduce the molecular interactions of guanidinyl functionality, including a protonated nitrogen atom of a piperidine ring) can mimic a sodium ion at the binding site of the exchanger or antiport (see, for example, Vigne et al., J. Biol. Chem. 1982, 257, 9394).

[0122] While heteroatom-containing portions may be capable of generating a positive charge, this should not be understood or interpreted as the entire compound having a net positive charge, or containing only portions that are charged with a single positive charge, or that the heteroatom-containing portion is capable of generating a positive charge in all cases. Rather, in various other embodiments, the compound may not have any charged portions, or it may have multivalent charged portions (which may have positive charges, negative charges, or a combination thereof). In addition, the entire compound should be understood to have a net neutral charge, a net positive charge, or a net negative charge.

[0123] In this regard, the U.S. patents and publications cited above or elsewhere in this specification are incorporated herein by reference in their entirety for all relevant and consistent purposes.

[0124] In addition to the structures illustrated above and elsewhere in this specification, bioequivalent substitutions for guanidine or acylguanidine may also be used. Potentially, viable bioequivalents identified to date, "guanidine substitutions," have a five-membered or six-membered heterocyclic ring with a similar donor / receptor and pKa pattern to guanidine or acylguanidine (see, for example, Ahmad, S. et al., Aminoimidazoles as Bioisosteres of Acylguanidines: Novel, Potent, Selective and Orally Bioavailable Inhibitors of the Sodium Hydrogen Exchanger Isoform-1, Boorganic & Med. Chem. Lett., pp. 177-180 (2004) (its entire contents are incorporated herein by reference for all relevant and consistent purposes)), and include those illustrated below: [ka]

[0125] The above-described embodiment of biological equivalence (i.e., the basis of the above structure) corresponds to "B" in the structure of formula (II), and the interrupted bond therein is bonded to "X" (for example, the acyl moiety or the bond linking the bioisoster to the skeleton) which has a bond with Z in formula (III) not shown herein.

[0126] It should be noted that in many of the structures illustrated herein, not all various linkages or connections will be shown in all cases. For example, in one or more of the illustrated structures, the linkage or connection between the NHE-binding small molecule and the modified or functionalized moiety Z is not always shown. However, this should not be seen in a limited sense. Rather, the NHE-binding small molecule should be understood to be bound or connected to Z in some way (e.g., by linkage or some kind of linker) so that the resulting NHE-Z molecule is suitable for use (i.e., substantially impermeable in the gastrointestinal tract or substantially not systemically bioavailable). Alternatively, Z may be incorporated into the NHE-binding small molecule, for example, by being located between the guanidine moiety and the skeleton.

[0127] Furthermore, numerous structures are provided herein for NHE-binding compounds that are substantially impermeable or substantially systemically bioavailable, and / or NHE-binding small molecules suitable for modification or functionalization in accordance with this disclosure to make them substantially impermeable or substantially systemically bioavailable. For the majority of these structures, various identifiers (e.g., atomic identifiers of chains or rings, identifiers of substituents on rings or chains, etc.) may be used more than once. Thus, an identifier for one structure should not be considered to have the same meaning in various structures unless specifically mentioned (e.g., "R1" in one structure may or may not be the same as "R1" in another structure). In addition, for one or more structures further illustrated herein, specific details of the structure, including one or more of these identifiers, may be provided in the references, and their contents are specifically incorporated herein by reference for all relevant and consistent purposes.

[0128] C. Exemplary Small Molecule Embodiments The substantially impermeable or substantially systemically non-bioavailable NHE3-binding compounds of this disclosure can generally be derived or synthesized from essentially any small molecule capable of binding to and / or modulating NHE3, including small molecules that have already been reported or confirmed to bind to and / or modulate NHE3 activity but lack impermeability (i.e., substantially impermeable). In one particularly preferred embodiment, the compound utilized in various ways of this disclosure is derived or synthesized from a small molecule that binds to the NHE3, -2, and / or -8 isoforms. While this disclosure generally relates to NHE3-binding compounds, compounds exhibiting NHE2 and / or -8 binding or inhibition are also covered. However, a suitable starting point may be known NHE3, -2, and / or -8-binding or inhibitory small molecules, but small molecules confirmed to bind to or inhibit other NHE subtypes, including NHE1, are also covered and can be optimized for selectivity and binding to the NHE3 subtype antiporter.

[0129] Examples of small molecules suitable for use (i.e., suitable for use as substantially bioavailable compounds, and suitable for modification or functionalization to produce compounds that are substantially not systemically bioavailable) are given below. Note that, in this regard, the binding or linking with Z (i.e., the modification or functionalization that makes the small molecule substantially impermeable or substantially not systemically bioavailable) is not specifically shown. As stated, the Z moiety may bind to or be contained within the small molecule at essentially any site or position that does not impair the ability of the resulting compound to effectively bind to the target NHE antiport (e.g., steric interference). More specifically, Z may bind to essentially any site on the NHE-binding small molecule, for example, by substituting all or part of the original or intrinsically present substituents thereon, as illustrated below, provided that the site of introduction of the Z moiety does not substantially adversely affect its NHE-binding activity. However, in one particular embodiment, the bond or linkage extends from Z to a site on a small molecule that effectively positions the bond point far from the atoms present in the resulting compound that act effectively as an atom or a sodium ion mimic (e.g., the atom or an atom capable of generating a positive ion under physiological pH conditions) (e.g., based on the intervening atom or number of bonds). In a preferred embodiment, the bond or linkage extends from Z to a ring, preferably a site within an aromatic ring in a small molecule that acts as the backbone.

[0130] In view of the foregoing, in one particular embodiment, the following small molecules disclosed in U.S. Patent Application No. 2005 / 0054705 (the entire content therein, and in particular the text on pages 1-2 therein, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference. In one particularly preferred embodiment, R6 and R7 are halogens (e.g., Cl), R5 is a lower alkyl (e.g., CH3), and R1-R4 are H, and the compound is, for example, structure; [ka] It holds.

[0131] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which (and in particular pages 1-2 therein) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0132] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entire content therein (and in particular, page 49 therein) is incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0133] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entire contents thereof, and in particular pages 118-120 and 175-177 thereof, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0134] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which (and in particular pages 129-131 therein) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference. (In this regard, substituent Z in the illustrated structure should not be confused with the sub-Z that binds to the NHE-binding small molecule in accordance with this disclosure to make the resulting "NHE-Z" molecule substantially impermeable.)

[0135] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which (and in particular pages 127-129 therein) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference. (In this regard, substituent Z in the illustrated structure should not be confused with the sub-Z that binds to the NHE-binding small molecule in accordance with this disclosure to make the resulting "NHE-Z" molecule substantially impermeable.)

[0136] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which (and in particular pages 134-137 therein) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0137] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entire contents thereof, and in particular pages 31-32 and 137-139 thereof, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0138] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which (and in particular pages 37-45 therein) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference. (In this regard, substituent Z in the illustrated structure should not be confused with the sub-Z that binds to the NHE-binding small molecule in accordance with this disclosure to make the resulting "NHE-Z" molecule substantially impermeable.)

[0139] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which (and in particular pages 100-102 therein) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference (in particular, the wavy lines indicate variable length or variable number of atoms).

[0140] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which (and in particular pages 90-91 therein) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0141] In yet another specific embodiment, the following small molecules disclosed in U.S. Patent No. 5,900,436 (or EP0822182B1) (the entire contents of which, in particular, paragraphs 10-55 of the first paragraph, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0142] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which (and in particular pages 35-47 therein) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0143] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which (and in particular pages 154-155 therein) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0144] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which (and in particular pages 132-133 therein) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0145] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entire contents thereof, and in particular pages 58-65 and 141-148 thereof, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference. (In this regard, substituent Z in the illustrated structure should not be confused with the sub-Z that binds to the NHE-binding small molecule in accordance with this disclosure to make the resulting "NHE-Z" molecule substantially impermeable.)

[0146] In yet another specific embodiment, the following small molecules disclosed in U.S. Patent Nos. 6,911,453 and 6,703,405 (the entire contents thereof (and in particular paragraphs 1-7 and 46 of No. 6,911,453 and paragraphs 14-15 of No. 6,703,405) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference. Particularly preferred small molecules included in the above structure are further exemplified below (for example, Example 1 of Patent No. 6,911,453, the entire contents of which are specifically incorporated herein by reference): [ka]

[0147] In yet another specific embodiment, the following small molecules disclosed in U.S. Patent Publications 2004 / 0039001, 2004 / 0224965, 2005 / 0113396 and 2005 / 0020612 (their entire contents incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure are defined above and / or in one or more of the cited patent applications, and their details are incorporated herein by reference and / or as illustrated above (interrupted bonds indicate the bond points of the Y portion with the fused heterocyclic ring). In particular, in various embodiments, the combinations of X and Y may be: [ka]

[0148] In a particularly preferred embodiment of the above structure, the small molecule has a general structure: [ka] It holds. In the formula, R1, R2, and R3 may be the same or different, but preferably different, and independently H, NR'R'' (wherein R' and R'' are independently H and a hydrocarbyl such as a lower alkyl, as defined elsewhere herein) and the structure: [ka] Selected from.

[0149] In a more particularly preferred embodiment of the above structure, the small molecules included in the above structure are further illustrated below (see, for example, compound I1 on page 5 of Japanese Patent Application No. 2005 / 0020612, the entire contents of which are specifically incorporated herein by reference): [ka]

[0150] In yet another specific embodiment, the following small molecules disclosed in U.S. Patent No. 6,399,824 (the entire contents of which, and in particular the text of Example 1, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] In the structure, R can preferably be selected from H and (CH3)2NCH2CH2-, with H being particularly preferred in various embodiments.

[0151] In yet another specific embodiment, the following small molecules disclosed in U.S. Patent No. 6,005,010 (and in particular its first to third paragraphs) and / or U.S. Patent No. 6,166,002 (and in particular its first to third paragraphs) (the entirety of which (and in particular the text of Example 1) is incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variable ("R") in the structure is defined in the cited patent application, and its details are incorporated herein by reference.

[0152] In yet another specific embodiment, the following small molecules disclosed in U.S. Patent Application No. 2008 / 0194621 (the entire contents thereof, and in particular the text of Example 1 thereof, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka] The variables in the structure ("R1", "R2", and "R3") are as defined above and are defined in the cited patent application, the details of which are incorporated herein by reference.

[0153] In yet another specific embodiment, the following small molecules disclosed in U.S. Patent Application No. 2007 / 0225323 (the entire contents of which, and in particular the text of Example 36, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka]

[0154] In yet another specific embodiment, the following small molecules disclosed in U.S. Patent No. 6,911,453 (the entire contents of which, and in particular the text of Example 35, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use or modification in accordance with this disclosure (for example, modified to bind to or include Z such that the resulting NHE-Z molecule is substantially impermeable or substantially not systemically bioavailable). [ka]

[0155] In one particularly preferred embodiment of this disclosure, the small molecule is: [ka] A selection can be made from the group consisting of the following:

[0156] In these structures, bonds or links (not shown) may extend between, for example, the core and the amine-substituted aromatic ring (first structure), the heterocyclic ring or the aromatic ring to which it is bonded, or the chloro-substituted aromatic ring (second structure), or the difluoro-substituted aromatic ring or the sulfonamide-substituted aromatic ring (third structure).

[0157] D. Examples of small molecule selectivity Examples of various NHE-binding small molecules and their selectivity across NHE1, -2, and -3 isoforms are shown below. (See, for example, B. Masereel et al., An Overview of Inhibitors of Na+ / H+ Exchanger, European J. of Med. Chem., 38, pp. 547-554 (2003) (which is incorporated herein by reference for all relevant and consistent purposes)). Most of these small molecules are optimized as NHE1 inhibitors, which is reflected in their selectivity with respect to that (the IC50 of subtype 1 is significantly potent (numerically lower) than that of subtype 3). However, the data in Table 2 show that NHE3 binding activity can be designed in the series of compounds initially optimized for different isoforms. For example, amiloride is insufficient as an NHE3 binding agent / inhibitor and was inactive against this antiport at the highest concentration tested (IC50 > 100 μM); however, analogs of this compound, such as DMA and EIPA, have NHE3 IC50s of 14 and 2.4 μM, respectively. Cinnamoylguanidine S-2120 is more than 500 times more active against NHE1 than against NHE3; however, this selectivity is reversed in the positional isomer S-3226. Thus, it is possible to design NHE3 binding selectivity into a chemical series optimized for the strength of action against other antiport isoforms; that is, the inhibitor classification exemplified in this art may not only be modified to be substantially impermeable or substantially systemically bioavailable, but the activity and selectivity for NHE3 (or NHE2 and / or NHE8) may also be appropriately modified. [ka] [Table 2]

[0158] As described above, the NHE-binding small molecules disclosed herein, including those described above, can be advantageously modified to make them substantially impermeable or substantially systemically bioavailable. Thus, the compounds described herein are effectively localized in the gastrointestinal tract or lumen, in one particular embodiment, in the colon. Since various NHE isoforms can be found in many different internal organs (e.g., brain, heart, liver, etc.), localization of the NHE-binding compound into the intestinal lumen is desirable to minimize or eliminate systemic effects (i.e., prevent or significantly limit exposure of such organs to these compounds). Accordingly, this disclosure provides NHE-binding compounds, in particular NHE3,-2 and / or-8 inhibitors, that are substantially systemically bioavailable in the gastrointestinal tract, and more specifically, substantially systemically impermeable to the intestinal epithelium, as further described herein.

[0159] E. Exemplary Embodiments In one or more particularly preferred embodiments of the present disclosure, the “NHE-Z” molecule is monovalent; that is, the molecule comprises one moiety that effectively binds to and / or modulates NHE3, and also inhibits phosphate transport in the gastrointestinal tract or kidney. In such embodiments, the NHE-Z molecule may be selected from, for example, one of the following structures of formula (IV), (V), (VI), or (VII): [ka] In the formula, each R1, R2, R3, R5 and R9 is independently selected from H, halogen (e.g., Cl), -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, and R7 and R8 are independently selected from H or Z, where Z is substituted or unsubstituted, hydrocarbyl, heterohydrocarbyl, polyal, whose substituent is selected from hydroxyls, amines, amidines, carboxylates, phosphonates, sulfonates, and guanidines. R4 is selected from chloromethyl glycols and polyols; R4 is selected from H, C1-C7 alkyl or Z, where Z is substituted or unsubstituted, hydrocarbyl, heterohydrocarbyl, polyalkylene glycol and polyol, with substituents selected from hydroxyls, amines, amidines, carboxylates, phosphonates, sulfonates and guanidines; R6 is absent or selected from H and C1-C7 alkyl; and Ar1 and Ar2 are independently aromatic rings, or heteroaromatic rings in which one or more carbon atoms are substituted with N, O or S atoms; [ka] In the formula, each R1, R2, R3, and R5 is independently selected from H, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, R7 and R8 are independently selected from H or Z, where Z is substituted or unsubstituted, selected from hydroxyls, amines, amidines, carboxylates, phosphonates, sulfonates, and guanidines, hydrocarbyl, heterohydrocarbyl, polyalkylene glycol, and polyol, and may be linked to ring Ar1 by a heterocyclic linker; R4 and R 12 R7 is independently selected from H and R7, where R7 is as defined above; R 10 and R11 If present, is independently selected from H and C1-C7 alkyl groups; and Ar1 and Ar2 are independently an aromatic ring, or a heteroaromatic ring in which one or more carbon atoms are substituted with N, O, or S atoms; [ka] In the formula, each X is a halogen which may be the same or different; R1 is selected from -SO2-NR7R8, -NR7(CO)R8, -(CO)NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, and R7 and R8 are independently selected from H or Z, where Z is selected from substituted or unsubstituted, hydrocarbyl, heterohydrocarbyl, polyalkylene glycol and polyol, whose substituents are selected from hydroxyls, amines, amidines, carboxylates, phosphonates, sulfonates and guanidines; R3 is selected from H or R7, where R7 is as defined above; R 13 R2 and R 12 R is independently selected from H or R7, where R7 is as defined above; R 10 and R 11 If present, Ar1 is independently selected from H and C1-C7 alkyl groups; Ar1 ​​is an aromatic ring or a heteroaromatic ring in which one or more carbon atoms are substituted with N, O, or S atoms; and Ar2 is an aromatic ring or a heteroaromatic ring in which one or more carbon atoms are substituted with N, O, or S atoms.

[0160] Regarding the structure of equation (V), in one particular embodiment, one of R1, R2, and R3 is structure: [ka] (In the formula, R is R1, R2, R3, or R5 attached to it.) The ring Ar2 is connected by a heterocyclic linker having the following characteristics:

[0161] In another specific embodiment, the NHE-Z molecule of this disclosure may have the structure of formula (IV): [ka] In the formula: Each R1, R2, R3, R5 and R9 is independently selected from H, halogen, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, R7 and R8 are independently selected from H or Z, and Z is a substituted hydrocarbyl, heterohydrocarbyl, or polyoxide whose substituent is selected from phosphinates, phosphonates, phosphoamides, phosphates, phosphothioates, and phosphodithioates. R4 is selected from hydroxyls and / or substituted or unsubstituted polyalkylene glycols; R4 is selected from H or Z, where Z is substituted or unsubstituted, hydrocarbyl, heterohydrocarbyl, polyalkylene glycol, and polyol, with substituents selected from hydroxyls, amines, amidines, carboxylates, phosphonates, sulfonates, and guanidines; R6 is selected from -H and C1-C7 alkyls; and Ar1 and Ar2 are independently aromatic rings, or heteroaromatic rings in which one or more carbon atoms are substituted with N, O, or S atoms.

[0162] In addition, or in one or more embodiments of the compounds described above, the compound is at least about 100 Å. 2 , approximately 150 Å 2 , about 200Å 2 , about 250Å 2 , about 270Å 2 The tPSA may have the above values ​​and / or a molecular weight of at least about 710 Da.

[0163] F. Polyvalent Structures: Macromolecules and Oligomers (i).General structure As described above, specific embodiments relate to structurally modified or functionalized NHE-binding small molecules to alter their physicochemical properties (by bonding or inclusion with part Z), more specifically, to alter the physicochemical properties of the NHE-Z molecule, thereby making it substantially impermeable or substantially not systemically bioavailable. In one particular embodiment, and as further detailed elsewhere herein, the NHE-Z compound may be polyvalent (i.e., oligomer, dendrimer, or polymer part), where Z may generally be referred to in this embodiment as the “core” part, and the NHE-binding small molecule may be bonded thereto directly or indirectly (by means of the linking part), and the polyvalent compound may have, for example, one of the following general structural formulas: (VIII), (IX), and (X): [ka] In the formula: core (or Z) and NHE are as defined above; L is a bond or linker as further defined elsewhere herein; and E and n are both integers greater than or equal to 2. In various other embodiments, however, the NHE-binding small molecule may be made substantially impermeable or substantially systemically bioavailable by a polymer structure consisting of multiple NHE-binding small molecules linked or bonded by a series of linkers, L, which may also be the same or different, and the compound may have the structure of formula (XI), for example: [ka] In the formulas: core (or Z) and NHE are as defined above; L is a bond or linker as further defined elsewhere herein; and m is an integer of 0 or greater. In these embodiments, the physicochemical properties, in particular the molecular weight or polar surface area of ​​the NHE-bonded small molecules, are modified (e.g., increased) by having a series of NHE-bonded small molecules linked together to make them substantially impermeable or substantially not bioavailable systemically. In these or any further additional embodiments, the polyvalent compound may be in the form of a dimer, oligomer or polymer, for example, Z or the core being a skeleton on which a plurality of NHE-bonded small molecules are linked (e.g., by means of a linker). Such a compound may have, for example, the structure of formula (XIIA) or (XIIB): [ka] In the formula, L is the linking portion; NHE is the NHE-bound small molecule, as described above and further below; and n is a non-zero integer (i.e., an integer greater than or equal to 1).

[0164] The core portion has one or more binding sites to which the NHE-binding small molecule is bound, preferably covalently by a bond or linker. The core portion can generally be anything (e.g., an atom, a small molecule, etc.) that makes the compound substantially impermeable or substantially not bioavailable systemically, but one or more preferred embodiments are oligomers, dendrimers, or polymer portions in each case having two or more binding sites of L. The combination of the core and the NHE-binding small molecule (i.e., the "NHE-Z" molecule) may have physicochemical properties that make the entire compound substantially impermeable or substantially not bioavailable systemically.

[0165] In this regard, the repeating units of formulas (XIIA) and (XIIB) generally encompass repeating units of various polymer embodiments, which may be manufactured by the methods referenced herein. In each polymer, or more generally, in polyvalent embodiments, each repeating unit may be the same or different, and may or may not be linked to the NHE-binding small molecule by, if present, the same or different linkers. In this regard, as used herein, "polyvalent" refers to a molecule having multiple (e.g., 2, 4, 6, 8, 10 or more) NHE-binding moieties.

[0166] The embodiments described above are further illustrated in this specification. For example, the following example oligomeric compounds, in which various parts of the compound corresponding to the structure of formula (X) have been identified, are shown below for the purpose of providing a broad perspective of the disclosure provided herein. Note that each "NHE" part (i.e., the NHE small molecule) in the following structure is the same, but each may be independently selected and may be the same or different, within the scope of this disclosure. In the figure below, the linker part is a polyethylene glycol (PEG) motif. PEG derivatives are advantageous, partly due to their water solubility, which can help avoid hydrophobic breakdown (intramolecular interactions of hydrophobic motifs that can occur when hydrophobic molecules are exposed to an aqueous environment) (see, e.g., Wiley, RA; Rich, DH Medical Research Reviews 1993, 13(3), 327-384). The core part in the figure below also allows for an increase in the distance between the NHE-binding compounds while minimizing the rotational degrees of freedom. n It is advantageous because it provides some rigidity to the molecule. [ka]

[0167] In another embodiment (for example, in equation (XI) where m=0, the structure is, for example: [ka] It is possible.

[0168] In the polyvalent compounds used for treatment according to this disclosure, n and m (when m is not 0) can be independently selected from the range of about 1 to about 10, more preferably about 1 to about 5, and even more preferably about 1 to about 2. However, in other embodiments, n and m can be independently selected from the range of about 1 to about 500, preferably about 1 to about 300, more preferably about 1 to about 100, and most preferably about 1 to about 50. In these or other specific embodiments, both n and m may be in the range of about 1 to about 50, or about 1 to about 20.

[0169] The structure provided above is a diagram of one embodiment of a compound used for administration, in which absorption is limited by means of increasing the molecular weight of the NHE-binding small molecule (i.e., the compound is made substantially impermeable or substantially not systemically bioavailable). In another approach, as described elsewhere herein, the NHE-binding small molecule may be made substantially impermeable or substantially not systemically bioavailable by means of altering, more specifically increasing, the topological polar surface area, as further illustrated by the following structure in which a substituted aromatic ring is bonded to the “backbone” of the NHE-binding small molecule. The selection of ionizable groups, such as phosphonates, sulfonates, guanidines and similar groups, may be particularly advantageous in preventing paracellular permeability. Hydrocarbons are also advantageous, significantly increasing tPSA while minimizing the increase in molecular weight due to their uncharged nature. [ka]

[0170] In addition, among the various embodiments illustrated herein, NHE-binding small molecules suitable for use (i.e., suitable for use as substantially bioavailable compounds suitable for modification or functionalization to make them substantially impermeable or substantially not systemically bioavailable) are, in particular, independently, benzoylguanidines, heteroaloylguanidines, and "spacers," as described above and in further detail below. —Extended —One or more small molecules described as aroylguanidines, nonacylguanidines and acylguanidine isosters, and / or, for example: US5866610; US6399824; US6911453; US6703405; US6005010; US6887870; US6737423; US7326705; US55824691 (WO94 / 026709); US6399824 (WO02 / 024637); US2 004 / 0339001(WO02 / 020496);US2005 / 0020612(WO03 / 055490);WO01 / 072742;CA2387529(WO01021582);CA02241531(WO US2005 / 0020612;US2005 / 0054705;US2008 / 0194621;US2007 / 0225323;U Small molecules may be selected from those detailed in S2004 / 0039001;US2004 / 0224965;US2005 / 0113396;US2007 / 0135383;US2007 / 0135385;US2005 / 0244367;US2007 / 0270414; and CA2177007 (EP0744397) (the entire contents thereof are incorporated herein by reference for all relevant and consistent purposes). Again, when the NHE-binding small molecules are referred to as being selected independently, it is intended that, for example, the oligomer structures represented by formulas (X) and (XI) above may contain NHE-binding small molecules of different structures within the same oligomer or polymer. In other words, each "NHE" in a given multivalent embodiment may independently be the same as or different from other "NHE" portions in the same multivalent embodiment.

[0171] In the design and manufacture of substantially impermeable or substantially systemically bioavailable NHE-binding compounds that may be used in the therapies detailed in this disclosure, it may be advantageous to first determine possible binding sites with the small molecule NHE-binding compounds to which the core or linker may be introduced or bound before manufacturing a series of candidate multivalent or polyvalent compounds. This may be done by known methods by systematically introducing functional groups, or functional groups indicating fragments of the desired core or linker, at various positions on the NHE-binding small molecule, and then testing these adducts to determine whether the modified compound still retains the desired physiological properties (e.g., NHE3 binding and / or regulation, phosphate transport inhibition). Understanding the SAR of the compound also enables the design of cores and / or linkers that positively contribute to the activity of the resulting compound. For example, the SAR of an NHE-bonded compound system may indicate that an N-alkylated piperazine actively contributes to biochemical activity (increased potency) or pharmaceutical properties (increased solubility); the piperazine moiety can then be used as a bonding site for the desired core or linker via N-alkylation. Thus, the resulting compound retains the desirable biochemical or pharmaceutical properties of the parent molecule. In another example, the SAR of an NHE-bonded compound system may indicate that a hydrogen bond donor is important for activity or selectivity. The core or linker moiety can then be designed to ensure that this H bond donor is retained. These cores and / or linkers may be further designed to attenuate or enhance the pKa of the H bond donor, allowing for powerful improvements in potency and selectivity. In another scenario, an aromatic ring in the compound may be a key pharmacophore interacting with a biological target via π-stacking effects or π-cation interactions. The linker and core motif can similarly be isosters, or otherwise designed to cooperate with the aromatic characteristics of the small molecule. Thus, once the structure-activity relationships within the molecular system are understood, the molecule in question can be classified into major pharmacophores that act as essential molecular recognition elements.When considering the introduction of core or linker motifs, these motifs may be designed to leverage this SAR, and may be introduced to be isoparticulate and isoelectronic, resulting in compounds that retain biological activity but significantly reduce permeability.

[0172] Another way in which SARs in a compound system can be utilized for the introduction of core or linker groups is to understand that regions of the molecule are less responsive to structural changes. For example, the X-ray eutectic structure of a protein-bound compound is solvent exposure and can reveal these parts of the compound that are not involved in productive interactions with the target. Such regions can also be experimentally confirmed when chemical modification of these regions results in a "flat SAR" (i.e., the modification appears to have a minimal contribution to biochemical activity). Those skilled in the art have often utilized such regions to design compounds with pharmaceutically acceptable properties, for example, by introducing motifs that can improve solubility or enhance ADME properties. In the same manner, such regions are expected to be advantageous sites for introducing core or linker groups to create the compounds described in this disclosure. These regions are also expected to be sites for adding highly polar functionalities, such as carboxylic acids, phosphosulfonic acids, and similar compounds, for example, to significantly increase tPSA.

[0173] Another aspect considered in the design of cores and linkers exhibiting NHE-binding activity is the limitation or prevention of hydrophobic breakdown. Compounds with extended hydrocarbon functionality can undergo intramolecular breakdown, resulting in an increased enthalpy barrier for interaction with a desired biological target. Therefore, when designing cores and linkers, they are preferably designed to exhibit resistance to hydrophobic breakdown. For example, structural constraints such as rigid monocyclic, bicyclic, or polycyclic rings can be introduced into the core or linker to increase the rigidity of the structure. Unsaturated bonds, such as alkenes and alkynes, can also be introduced, or alternatively. Such modifications can ensure that the NHE-binding compound is available for productive binding with its target. Furthermore, the hydrophilicity of the linker can be improved by the addition of hydrogen bond donor or acceptor motifs, or ionic motifs, such as amines that are protonated in the gastrointestinal tract or acids that are deprotonated. Such modifications will help increase the hydrophilicity of the core or linker and prevent hydrophobic breakdown. Furthermore, such modifications will likely contribute to the impermeability of the resulting compound due to the increase in tPSA.

[0174] Specific examples of modified NHE-bonded small molecules consistent with the principles detailed above are illustrated below. These parts indicate functional groups that facilitate their adducts to {Z} (e.g., core group, core, or linking group L). These functional groups may include electrophiles that can react with nucleophilic cores or linkers, and nucleophiles that can react with electrophilic cores or linkers. Small molecule NHE-bonded compounds can similarly be derived, for example, from there using boronic acids that can react with suitable cores or linkers by palladium-mediated cross-coupling reactions. The NHE-bonded compounds may then include olefins that can react with suitable cores or linkers by olefin metathesis chemistry, or alkynes or azides that can react with suitable cores or linkers by [2+3] cycloaddition reactions. Those skilled in the art can conceive of a variety of functional groups that would enable easy and specific bonding of the NHE-bonded small molecule to a desired core or linker. Examples of derivatives having functional groups that exemplify NHE include, but are not limited to, the following: Scheme 1 Cinnamoylguanidine NHE bond having a functional group exhibiting electrophilic or nucleophilic activity that promotes reaction with the core and linker. [ka] In the formula, the variables in the above structure (e.g., R, etc.) are defined as in U.S. Patent No. 6,399,824 (the entire contents of which are incorporated herein by reference for all relevant and consistent purposes). Scheme 2 The cytetrahydroisoquinoline NHE bond has a functional group that exhibits electrophilic or nucleophilic activity, promoting the reaction with the core and linker. [ka] In the formula, the variables in the above structure (for example, R 7~9 These terms (and others) are defined in U.S. Patent No. 6,911,453 (the entire contents of which (and in particular the first to fourth paragraphs) are incorporated herein by reference for all relevant and consistent purposes). See also Linz et al., Hypertension. 60: 1560-7, 2012. Scheme 3 The quinazoline NHE bond has a functional group that exhibits electrophilic or nucleophilic activity, promoting the reaction with the core and linker. [ka] In the formula, the variables in the above structure (for example, R 7~9 These terms (and others) are defined in U.S. Patent Application No. 2005 / 0020612 and U.S. Patent No. 6,911,453 (the entirety of which (and in particular, paragraphs 1-4) is incorporated herein by reference for all relevant and consistent purposes).

[0175] Those skilled in the art may encounter numerous core or linker moieties that can be functionalized with appropriate electrophiles or nucleophiles. A series of such compounds, selected based on several design considerations including solubility, steric effects, and the ability to provide or maintain a desirable structure-activity relationship, are shown below. However, in this regard, the structures provided below and above are for illustrative purposes only and should not be considered limiting.

[0176] Examples of electrophilic and nucleophilic linker regions include, but are not limited to, the linker regions shown below: Nucleophilic linker (for use with electrophilic NHE inhibitory derivatives) [ka] Electrophilic linker (for use with nucleophilic NHE inhibitory derivatives) [ka]

[0177] In each of the embodiments described (including embodiments in which the NHE-bonded small molecule is linked to a core such as atoms, another small molecule, a polymer moiety, an oligomer moiety, or a non-repeating moiety), the linking moiety, L, may be a chemical linker, such as a bond or other moiety, which may be hydrophilic and / or hydrophobic, and may contain, for example, about 1 to about 200 atoms, or about 1 to about 100 atoms, or about 1 to about 50 atoms. In one embodiment, the linking moiety may be a polymer moiety grafted onto a polymer backbone, for example, using a living free radical polymerization technique known in the art. Preferred L structures or moies may also be selected from, for example, oligoethylene glycol, oligopeptide, oligoethyleneimine, oligotetramethylene glycol, and oligocaprolactone.

[0178] As stated, the core portion may be an atom, small molecule, oligomer, dendrimer, or polymer portion in each case having one or more binding sites to L. For example, the core portion may be a non-repeating portion (considered as a whole including the linkage with the compound) selected from the group consisting of any of the aforementioned, substituted with, for example, alkyl, phenyl, aryl, alkenyl, alkynyl, heterocyclic, amine, ether, sulfide, disulfide, hydrazine, and oxygen, sulfur, sulfonyl, phosphonyl, hydroxyl, alkoxyl, amine, thiol, ether, carbonyl, carboxyl, ester, amide, alkyl, alkenyl, alkynyl, aryl, heterocyclic, and combinations thereof (in each permutation). The non-repeating portion may include separate repeating units (e.g., methylene) that constitute the portion as a whole (e.g., in the sense of a polymer or oligomer).

[0179] Examples of core components include, but are not limited to, the core component and ether portion, ester portion, sulfide portion, disulfide portion, amine portion, aryl portion, alkoxyl portion, and others as illustrated in the examples: [ka] In the JPEG2026053537000083.jpg221129 formula, the fusion is interrupted (i.e., through them, a wave-like fusion is performed). [ka] The linking point (having) is a linking point to either an MHE-bonded compound or an NHE-bonded compound linker moiety, the linking point may be created using chemicals and functional groups known in the field of medicinal chemistry, and each p, q, r and s is independently an integer selected from about 0 to about 48, preferably about 0 to about 36, or about 0 to about 24, or about 0 to about 16. In some cases, each p, q, r and s may be an integer independently selected from about 0 to about 12. In addition, R can generally be selected from moieties including halides, hydroxyls, amines, thiols, ethers, carbonyls, carboxyls, esters, amides, carbocyclics, heterocyclics, and combinations thereof.

[0180] Alternatively, the core portion is defined as a dendrimer, which is a repeatedly branched molecule (see, for example, JMJ Frechet, DA Tomalia, Dendrimers and Other Dendritic Polymers, John Wiley & Sons, Ltd. NY, NY, 2001), as shown in Figure 17.

[0181] In this method, the NHE-binding small molecule is bound through L to one, some, or all of the terminals located around the dendrimer. In another method, a block called a dendron is constructed, and the dendrimer shown above is used as a core, with the NHE-binding group bound to one, some, or all of the terminals located around the dendrimer. As used herein, the generation number is typically between about 0 and about 6, preferably between about 0 and about 3. (Generations are defined, for example, in JMJ Frechet, DA Tomalia, Dendrimers and Other Dendritic Polymers, John Wiley & Sons, Ltd. NY, NY.) Dendrimer and / or dendron structures are well known in the art and are shown or illustrated, for example, in (i) JMJ Frechet, DA Tomalia, 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.

[0182] In yet another method, the core portion may be a polymer portion or an oligomer portion. In either case, the polymer or oligomer independently comprises repeating units selected from any of the aforementioned, which may also be substituted with alkyl (e.g., -CH2-), substituted alkyl (e.g., -CHR- (wherein R is hydroxyl)), alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, aryl, heterocyclic, amine, ether, sulfide, disulfide, hydrazine, and oxygen, sulfur, sulfonyl, phosphonyl, hydroxyl, alkoxyl, amine, thiol, ether, carbonyl, carboxyl, ester, amide, alkyl, alkenyl, alkynyl, aryl, heterocyclic, or combinations thereof. In yet another method, the core portion comprises repeating units obtained from the polymerization of ethylenic monomers (e.g., ethylenic monomers listed elsewhere in this specification below).

[0183] Preferred polymers for polymer moieties useful for constructing polyvalent, substantially impermeable, or substantially systemically bioavailable NHE-binding compounds for use in therapies of the various therapeutic methods disclosed herein may be synthesized by any suitable technique, such as free radical polymerization, condensation polymerization, addition polymerization, ring-opening polymerization, and / or derived from natural polymers, such as saccharide polymers. Furthermore, in some embodiments, any of these polymer moieties may be functionalized.

[0184] Examples of polysaccharides useful for the synthesis of such compounds include, but are not limited to, substances from plant or animal sources, including cellulose materials, hemicellulose, alkylcellulose, hydroxyalkylcellulose, carboxymethylcellulose, sulfoethylcellulose, starch, xylan, amylopectin, chondroitin, hyaluronic acid, heparin, gaua, xanthan gum, mannan, galactomannan, chitin, and / or chitosan. Polymeric moieties that do not decompose or are not significantly decomposed under physiological conditions of the gastrointestinal tract (e.g., carboxymethylcellulose, chitosan, and sulfoethylcellulose) are more preferred, at least in some cases.

[0185] When free radical polymerization is used, the polymer moiety can be synthesized from a variety of monomers, including, for example, acrylics, methacrylics, styrenes, vinyls, and dienes, typical examples of which are shown below: styrene, substituted styrenes, alkyl acrylates, substituted alkyl acrylates, alkyl methacrylates, substituted alkyl methacrylates, acrylonitriles, methacrylonitriles, acrylamides, methacrylamides, N-alkylacrylamides, N-alkylmethacrylamides, N,N-dialkylacrylamides, N,N-dialkylmethacrylamides, isoprene, butadienes, ethylenes, vinyl acetates, and combinations thereof. Functionalized versions of these monomers may also be used, and any of these monomers may be used as comonomers in combination with other monomers.For example, specific monomers or comonomers that may be used in this disclosure include methyl methacrylate, ethyl methacrylate, propyl methacrylate (all isomers), butyl methacrylate (all isomers), 2-ethylhexyl methacrylate, isobornyl 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, isobornyl acrylate, and acrylic acid. Benzyl acrylate, 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) (Vitamins), N,N-dimethylaminoethyl acrylate, N,N-diethylaminoethyl acrylate, triethylene glycol acrylate, methacrylamide, N-methylacrylamide, N,N-dimethylacrylamide, N-tert-butylmethacrylamide, Nn-butylmethacrylamide, N-methylolmethacrylamide, N-ethylolmethacrylamide, N-tert-butylacrylamide, Nn-butylmethacrylamide, N-methylolacrylamide, N-ethylolacrylamide, 4-acryloylmorpholine, vinyl benzoate (Total isomers), diethylaminostyrene (total isomers), methylvinyl α-benzoate (total isomers), diethylamino α-methylstyrene (total isomers), p-vinylbenzene sulfonate, sodium p-vinylbenzene sulfonate, alkoxy and alkylsilane functional monomers, maleic anhydride, N-phenylmaleimide, N-butylmaleimide, butadiene, isoprene, chloroprene, ethylene, vinyl acetate, vinyl formate, allylamine, vinylpyridines (total isomers), fluorinated acrylates, methacrylates, and combinations thereof.The main chain heteroatom polymer moieties may also be used, including polyethyleneimines and polyethers such as polyethylene oxide and polypropylene oxide, as well as their comonomers.

[0186] In one particular embodiment, the NHE-bound small molecule, the polymer to which the NHE is bound or otherwise part thereof, is a polyol (e.g., a polymer having repeating hydroxyl-substituted alkyl units such as -CH(OH)-). With or without their reducible or reducible end groups, polyols, such as mono- and disaccharides, can be good candidates for introducing additional functionalities that can make the compound substantially impermeable.

[0187] In one particular embodiment, the NHE-binding small molecule, NHE, binds to one or both ends of the polymer chain. More specifically, in yet another alternative approach to the multivalent embodiments of this disclosure, a macromolecule (e.g., a polymer or oligomer) having one of the following exemplary structures may be designed and constructed as described herein: [ka] JPEG2026053537000086.jpg228104JPEG2026053537000087.jpg214113JPEG2026053537000088.jpg6886

[0188] Furthermore, the repeating portion of formula (XIIA) or (XIIB) generally includes repeating units of polymers and copolymers produced by the methods referenced herein.

[0189] Furthermore, the various properties of the oligomers and polymers forming the core components disclosed herein can be optimized for a given use or application using experimental means and principles generally known in the art. For example, the total molecular weight of the compounds or structures presented herein can be selected to achieve non-absorbency, sustained inhibition, and / or potency.

[0190] In addition, embodiments of these polymers include or contain compounds generally represented by the structure of formula (I) herein, and / or these compounds or structures have pendant chains hanging from the polymer backbone or chain, as cited herein, in many patents and patent applications (e.g., US5866610; US6399824; US6911453; US6703405; US6005010; US6887870) ;US6737423;US7326705;US55824691(WO94 / 026709);US6399824(WO02 / 024637);US2004 / 0339001(WO02 / 020496) ;US2005 / 0020612(WO03 / 055490);WO01 / 072742;CA2387529(WO01021582);CA02241531(WO97 / 024113);US2005 / 0 113396(WO03 / 051866);US2005 / 0020612;US2005 / 0054705;US2008 / 0194621;US2007 / 0225323;US2004 / 0039001;US2004 / 0224965;US2005 / 0113396;US2007 / 0135383;US2007 / 0135385;US2005 / 0244367;US2007 / 0270414;and CA With respect to those disclosed in the examples in 2177007 (EP0744397) (the entire contents thereof are incorporated herein by reference for all relevant and consistent purposes), the composition of the polymer backbone, as well as the overall size or molecular weight of the polymer and / or the number of pendant molecules present therein, may be selected in accordance with various principles known in the art from the viewpoint of the intended application or use.

[0191] Regarding the polymer composition of the NHE-binding compound, a number of polymers can be used, for example, including synthetic and / or natural aliphatic, alicyclic, and / or aromatic polymers. In preferred embodiments, the polymer portion is stable under the physiological conditions of the gastrointestinal tract. "Stability" means that the polymer portion does not decompose, not significantly decompose, or not essentially decompose under the physiological conditions of the gastrointestinal tract. For example, at least about 90%, preferably at least about 95%, more preferably about 98%, and even more preferably about 99% of the polymer portion remains undegraded or unchanged after residence in the gastrointestinal tract for at least about 5 hours, at least about 12 hours, at least about 18 hours, at least about 24 hours, or at least about 48 hours. Stability in the gastrointestinal tract can be evaluated using gastrointestinal mimicry, for example, a small intestine gastric or intestinal mimicry that substantially models the physiological conditions at one or more locations therein.

[0192] The polymer portions detailed herein for use as the core portion may be hydrophilic, hydrophobic, amphiphilic, uncharged or nonionic, negatively charged or positively charged, or a combination thereof. In addition, the polymer structure of the polymer portion may be linear, grafted, comb-shaped, block-shaped, star-shaped, and / or dendritic, preferably selected to obtain the desired solubility and / or stability properties described above.

[0193] In addition, or otherwise, the modification is carried out to create an NHE-binding small molecule that increases tPSA, and thus can contribute to the impermeability of the resulting compound. Such modifications preferably include the addition of dianions such as phosphonates, malonates, sulfonates and similar compounds, and polyols such as hydrocarbons and similar compounds. Examples of derivatives that result in increased tPSA from NHE include, but are not limited to, the following: [ka]

[0194] (ii) Practical Embodiments In one or more particularly preferred embodiments of the present disclosure, the “NHE-Z” molecule is polyvalent; that is, the molecule comprises two or more moieties that effectively bind to and / or modulate NHE3, and also inhibit phosphate transport in the gastrointestinal tract or kidney. In such embodiments, the NHE-Z molecule may be selected, for example, from one of the following formulas: (IV), (V), (VI), or (VII): [ka] In the formula: Each R1, R2, R3, R5 and R9 is independently selected from H, halogen (e.g., Cl), -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, and R7 and R8 are independently selected from H or Z, where Z is substituted or unsubstituted, hydrocarbyl, heterohydrocarbyl, polyal, whose substituent is selected from hydroxyls, amines, amidines, carboxylates, phosphonates, sulfonates, and guanidines. R4 is selected from chloromethyl glycols and polyols; R4 is selected from H, C1-C7 alkyl or Z, where Z is substituted or unsubstituted, hydrocarbyl, heterohydrocarbyl, polyalkylene glycol and polyol, with substituents selected from hydroxyls, amines, amidines, carboxylates, phosphonates, sulfonates and guanidines; R6 is absent or selected from H and C1-C7 alkyl; and Ar1 and Ar2 are independently aromatic rings, or heteroaromatic rings in which one or more carbon atoms are substituted with N, O or S atoms; [ka] In the formula: Each R1, R2, R3, and R5 is independently selected from H, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8; R7 and R8 are independently selected from H or Z, where Z is substituted or unsubstituted, selected from hydroxyls, amines, amidines, carboxylates, phosphonates, sulfonates, and guanidines, hydrocarbyl, heterohydrocarbyl, polyalkylene glycol, and polyol, and may be linked to ring Ar1 by a heterocyclic linker; R4 and R 12 R7 is independently selected from H and R7, where R7 is as defined above; R 10 and R 11 If present, is independently selected from H and C1-C7 alkyl groups; and Ar1 and Ar2 are independently an aromatic ring, or a heteroaromatic ring in which one or more carbon atoms are substituted with N, O, or S atoms; [ka] In the formula, each X is a halogen which may be the same or different; R1 is selected from -SO2-NR7R8, -NR7(CO)R8, -(CO)NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, and R7 and R8 are independently selected from H or Z, where Z is selected from substituted or unsubstituted, hydrocarbyl, heterohydrocarbyl, polyalkylene glycol and polyol, whose substituents are selected from hydroxyls, amines, amidines, carboxylates, phosphonates, sulfonates and guanidines; R3 is selected from H or R7, where R7 is as defined above; R 13 R2 and R 12 R is independently selected from H or R7, where R7 is as defined above; R 10 and R11 If present, Ar1 is independently selected from H and C1-C7 alkyl groups; Ar1 ​​is an aromatic ring or a heteroaromatic ring in which one or more carbon atoms are substituted with N, O, or S atoms; and Ar2 is an aromatic ring or a heteroaromatic ring in which one or more carbon atoms are substituted with N, O, or S atoms.

[0195] Regarding the structure of formula (V), in one particular embodiment, R1, R2 and R3 are connected to the ring Ar1, and / or R5 is part of the structure: [ka] (In the formula, R is R1, R2, R3, or R5 attached to it.) It is connected to Ar2 by a heterocyclic linker having [a specific component].

[0196] In one particular embodiment, the NHE-binding small molecule has the structure of formula (IV): [ka] or its stereoisomers, prodrugs, or pharmaceutically acceptable salts (wherein each R1, R2, R3, R5, and R9 is independently selected from H, halogen, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, and R7 and R8 are independently H R4 is selected from the bonds connecting the NHE-bonded small molecule and L, provided that at least one of them is a bond connecting the NHE-bonded small molecule and L; R4 is selected from H, C1-C7 alkyl, or a bond connecting the NHE-bonded small molecule and L; R6 is absent or selected from H and C1-C7 alkyl; and Ar1 and Ar2 are independently aromatic rings or heterocyclic aromatic rings).

[0197] In a more specific embodiment of the above embodiment, the NHE-binding small molecule has the following structure: [ka] or its stereoisomer, prodrug, or pharmaceutically acceptable salt (wherein R1, R2, and R3 are independently selected from H, halogen, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, and R7 and R8 are independently selected from H or a bond linking the NHE-binding small molecule to L, provided that at least one of them is a bond linking the NHE-binding small molecule to L). It holds.

[0198] In one embodiment, the compound has the structure of formula (X): [ka]

[0199] In a more specific embodiment of the above embodiment, the NHE-binding small molecule has the following structure: [ka] It has one of these, or a stereoisomer thereof, a prodrug, or a pharmaceutically acceptable salt thereof.

[0200] In a more specific embodiment of the above embodiment, L is a polyalkylene glycol linker, such as a polyethylene glycol linker.

[0201] In a more specific embodiment of the above embodiment, n is 2.

[0202] In a more specific embodiment of the above embodiment, the core has the following structure: [ka] (In the formula: X is a bond, -O-, -NH-, -S-, C) 1~6Selected from the group consisting of alkylene, -NHC(=O)-, -C(=O)NH-, -NHC(=O)NH-, -SO2NH-, and -NHSO2-; Y may be bonded to or substituted with C 1~8 Alkylene, optionally substituted aryl, optionally substituted heteroaryl, polyethylene glycol linker, -(CH2) 1~6 O(CH2) 1~6 -and-(CH2) 1~6 NY1(CH2) 1~6 - is selected from the group consisting of; and Y1 is hydrogen, or C which may be substituted. 1~8 (Selected from the group consisting of alkyl, optionally substituted aryl, or optionally substituted heteroaryl) It holds.

[0203] In a more specific embodiment of the above embodiment, the core is: [ka] Selected from the group consisting of

[0204] H. General structure of additional example compounds In one embodiment, the compounds of the present disclosure are generally represented by formula (IH): [ka] or its stereoisomers, prodrugs, or pharmaceutically acceptable salts (wherein: (i) NHE is the NHE-binding and / or regulatory small molecule described below, (ii) n is an integer of 2 or more, (iii) core is a core portion having two or more sites for binding to two or more NHE-binding small molecule portions, and (iv) L is a linker that binds or connects the core to two or more NHE-binding small molecule portions, and the resulting NHE-binding compound (i.e., the compound of formula (I)) has overall physicochemical properties that make it substantially impermeable or substantially not systemically bioavailable. The core portion may bind to essentially any position on or within the NHE-binding small molecule portions, provided that its introduction does not significantly adversely affect the NHE-binding activity.

[0205] It should be noted that not all various linkages or connections will be observed in all of the structures illustrated herein. For example, in one or more of the illustrated structures, a linkage or connection between the NHE-binding small molecule portion and the core portion is not necessarily observed. However, this should not be taken as limiting. Rather, the NHE-binding small molecule portion is linked or connected to the core portion in some way (e.g., by some bond or linker) so that the resulting NHE-binding compound is suitable for use (i.e., substantially impermeable in the gastrointestinal tract or substantially not systemically bioavailable).

[0206] A small NHE-binding molecule suitable for use in the synthesis of substantially impermeable or substantially non-systemically bioavailable NHE-binding compounds of this disclosure (i.e., suitable for modification or functionalization in accordance with this disclosure) is disclosed in WO2010 / 025856 (the entire contents thereof are incorporated herein by reference for all relevant and consistent purposes) and has the following structure of formula (XH): [ka] The variables in the structure are defined in WO2010 / 025856, and their details are incorporated herein by reference.

[0207] In a more specific embodiment, the NHE-binding small molecule portion has the following structure: [ka] In the formula: B is selected from the group consisting of aryl and heterocyclyl compounds; each R5 is independently hydrogen, or C which may be substituted. 1~4 Alkyl, possibly substituted C 1~4 Alkoxy, C may be substituted. 1~4 Thioalkyl, may be substituted C 1~4 Heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxyl, oxo, cyano, nitro, -NR7R8, -NR7C(=O)R8, -NR7C(=O)OR8, -NR7C(=O)NR8R9, -NR7SO2R8, -NR7S(O)2NR8R9, -C(=O)OR7, -C(=O)R7, -C(=O)NR7R8, -S(O) 1~2 Selected from the group consisting of R7 and -SO2NR7R8, R7, R8, and R9 are independently hydrogen, C 1~4 R3 and R4 are selected from the group consisting of alkyl groups or bonds that connect the NHE bonded small molecule portion to L, wherein at least one of them is a bond that connects the NHE bonded small molecule portion to L; R3 and R4 are independently hydrogen, or optionally substituted C 1~4 R1 is selected from the group consisting of alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; or R3 and R4, together with the nitrogen to which they are bound, form optionally substituted 4-8 membered heterocyclyl; and each R1 is independently hydrogen, halogen, or optionally substituted C 1~6Alkyl and optionally substituted C 1~6 Selected from the group consisting of alkoxys.

[0208] In a more specific embodiment, the NHE-binding small molecule portion has the following structure: [ka] In the formula: Each R3 and R4 is independently hydrogen and / or substituted C. 1~4 R3 and R4, selected from the group consisting of alkyls or together with the nitrogen to which they are bound, may form a substituted 4- to 8-membered heterocycline; each R1 independently consists of hydrogen, halogen, and C 1~4 Alkyl, and C 1~4 Selected from the group consisting of haloalkyls; and R5 is where R7 is hydrogen or C 1~4 The alkyl group is selected from the group consisting of -SO2-NR7- and -NHC(=O)NH-.

[0209] In various other embodiments, the NHE-binding small molecule moiety may be made substantially impermeable or substantially systemically bioavailable by forming a polymer structure from multiple NHE-binding small molecule moieties linked or bonded to a series of linkers L, which may also be the same or different, and the compound may have the structure of formula (II-H), for example: [ka] In the formula, NHE is as defined above; L is a bond or linker as further defined elsewhere herein; and m is an integer of 0 or greater. In this embodiment, the physicochemical properties of the NHE-bound small molecule portion, and in particular its molecular weight or polar surface area, are modified (e.g., increased) by linking a series of NHE-bound small molecule portions together in a chain.

[0210] In yet another additional embodiment, the polyvalent NHE-binding compound may be in oligomeric or polymeric form, with a backbone bonded to multiple NHE-binding small molecule moieties (e.g., by linker means). Such a compound may have, for example, a structure of formula (IIIA-H) or (IIIB-H): [ka] In the formulas: NHE is as defined above; L is a bond or linker as further defined herein; and n is a non-zero integer (i.e., an integer greater than or equal to 1). The repeating units of formulas (IIIA-H) or (IIIB-H) generally encompass repeating units of various polymer embodiments, including linear, branched, and dendritic structures which may be produced by methods referenced herein. In each polymer, or more generally in polyvalent embodiments, each repeating unit may or may not be linked to its NHE-binding small molecule moiety by linkers, which may be the same or different, and, if present, may be the same or different in sequence. In this regard, as used herein, “polyvalent” refers to a molecule having multiple (e.g., 2, 4, 6, 8, 10 or more) NHE-binding small molecule moieties.

[0211] In the aforementioned polyvalent embodiment, L may be a polyalkylene glycol linker such as a polyethylene glycol linker; and / or the core may have the following structure: [ka] (In the formula: X is a bond, -O-, -NH-, -S-, C) 1~6 Selected from the group consisting of alkylene, -NHC(=O)-, -C(=O)NH-, -NHC(=O)NH-, -SO2NH-, and -NHSO2-; Y may be bonded to or substituted with C 1~8 Alkylene, optionally substituted aryl, optionally substituted heteroaryl, polyethylene glycol linker, -(CH2) 1~6 O(CH2) 1~6 -and-(CH2) 1~6NY1(CH2) 1~6 - is selected from the group consisting of; and Y1 is hydrogen, or C which may be substituted. 1~8 (Selected from the group consisting of alkyl, optionally substituted aryl, or optionally substituted heteroaryl) It may have: For example, in a more specific embodiment, the core may have: [ka] A selection can be made from the group consisting of the following:

[0212] In other, more specific embodiments, the core may be, for example: [ka] The image can be selected from the group consisting of JPEG2026053537000109.jpg43127.

[0213] The embodiments described above are further illustrated below in this specification. For example, the first representation below of an example oligomeric compound in which various parts of the compound have been identified is intended to provide a broad perspective for the disclosures provided herein. Although each NHE-binding small molecule portion in the following structures is the same, each may be independently selected and may be the same or different, which is within the scope of this disclosure. In the figure below, the linker portion is a polyethylene glycol (PEG) motif. PEG derivatives are also advantageous due to their water solubility, which can help avoid hydrophobic breakdown (intramolecular interactions of hydrophobic motifs that can occur when hydrophobic molecules are exposed to an aqueous environment (see, e.g., Wiley, RA; Rich, DH Medical Research Reviews 1993, 13(3), 327-384)). The core portion in the figure below is also advantageous because it is somewhat rigid to the molecule, allowing for an increase in the distance between the NHE-binding small molecule portions while minimizing the increase in rotational degrees of freedom. [ka]

[0214] In another embodiment, when m=0 in the formula, the structure is, for example: [ka] It is possible.

[0215] In the polyvalent compounds used in the treatments according to this disclosure, n and m (when m is non-zero) can be independently selected from the range of about 1 to about 10, more preferably about 1 to about 5, and even more preferably about 1 to about 2. However, in other embodiments, n and m can be independently selected from the range of about 1 to about 500, more preferably about 1 to about 300, even more preferably about 1 to about 100, and most preferably about 1 to about 50. In these or other specific embodiments, E, n, and m may be in the range of about 1 to about 50, or about 1 to about 20.

[0216] When designing and manufacturing substantially impermeable or substantially systemically bioavailable NHE-binding compounds that may be used in the therapies detailed in this disclosure, it may be advantageous for the core or linker to first determine the likely binding sites of the NHE-binding small molecule moieties that can be introduced or bound to a series of candidate multivalent or polyvalent compounds. This can be carried out by known methods by systematically introducing functional groups or functional groups representing the desired core or linker fragment to various positions on the NHE-binding small molecule moiety, and then testing these adducts to determine whether the modified compounds still retain the desired biological properties (e.g., NHE-binding activity). Understanding the SAR of the compound also enables the design of cores and / or linkers that positively contribute to the activity of the resulting compound.

[0217] Another aspect considered in the design of cores and linkers is the limitation or prevention of hydrophobic breakdown. Compounds with extended hydrocarbon functionality can break down intramolecularly, contributing to an increased enthalpy barrier against interaction with desired biological targets. Therefore, when designing cores and linkers, they are preferably designed to be resistant to hydrophobic breakdown. Structural constraints, such as rigid monocyclic, bicyclic, or polycyclic rings, can be introduced into the core or linker to increase the rigidity of the structure. Unsaturated bonds, such as those of alkenes and alkynes, can also be introduced, or alternatively. Such modifications can ensure that the NHE-bonded compound can reach productive bonding with its target. Furthermore, the hydrophilicity of the linker can be improved by the addition of hydrogen bond donor or acceptor motifs, or ionic motifs such as amines that are protonated in the gastrointestinal tract or acids that are deprotonated. Such modifications will increase the hydrophilicity of the core or linker, helping to prevent hydrophobic breakdown. Furthermore, such modifications will likely contribute to the impermeability of the resulting compound due to the increase in tPSA.

[0218] Those skilled in the art can conceive of various functional groups that would enable easy and specific bonding between a core or linker and an NHE-bonded small molecule moiety. These functional groups may include electrophiles that can react with a nucleophilic core or linker, and nucleophiles that can react with an electrophilic core or linker. The NHE-bonded small molecule moiety can similarly be derived, for example, by a palladium-mediated cross-coupling reaction, using a suitable core or linker and a boronic acid group that can react therewith. The NHE-bonded small molecule moiety may then include olefins that can react with a suitable core or linker by olefin metathesis chemistry, or alkynes or azides that can react with a suitable core or linker by a [2+3] cycloaddition reaction.

[0219] Those skilled in the art can conceive of numerous core or linker moieties that can be functionalized with suitable electrophiles or nucleophiles. A series of such compounds selected based on several design considerations, including their solubility, steric effects, and their ability to provide or match a desirable structure-activity relationship, are shown below. However, it should be noted that, in this regard, the structures below and above are provided for illustrative purposes only and should not be considered limiting.

[0220] Examples of electrophilic and nucleophilic linker regions include, but are not limited to, the linker regions shown below: Nucleophilic linker (for use with electrophilic NHE) [ka]

[0221] Electrophilic linker (for use with nucleophilic NHE) [ka]

[0222] Each linking portion L of the described embodiments (including embodiments in which the NHE-bonded small molecule portion is linked to a core such as atoms, another small molecule, a polymer portion, an oligomer portion, or a non-repeating portion) may be a chemical linker such as a bond or other portion that may be hydrophilic and / or hydrophobic, for example, comprising about 1 to about 200 atoms, or about 1 to about 100 atoms, or about 1 to about 50 atoms. In one embodiment, the linking portion may be a polymer portion grafted onto a polymer backbone, for example, using living free radical polymerization techniques known in the art. Preferred L structures or portions may also be selected from, for example, oligoethylene glycol, oligopeptide, oligoethyleneimine, oligotetramethylene glycol, and oligocaprolactone.

[0223] As described above, the core portion may, in each case, be an atom, small molecule, oligomer, dendrimer, or polymer portion having one or more bonding sites with L. For example, the core portion may be a non-repeating portion (considered as a whole including the linkage points with the NHE-bonded small molecule portion) selected from the group consisting of any of the aforementioned, substituted with, for example, alkyl, phenyl, aryl, alkenyl, alkynyl, heterocyclic, amine, ether, sulfide, disulfide, hydrazine, and oxygen, sulfur, sulfonyl, phosphonyl, hydroxyl, alkoxyl, amine, thiol, ether, carbonyl, carboxyl, ester, amide, alkyl, alkenyl, alkynyl, aryl, heterocyclic, and combinations thereof (in each permutation). The non-repeating portion may not have separate repeating units constituting the portion as a whole (for example, in the sense of a polymer or oligomer), but may contain repeating units (e.g., methylene) in part or within a segment (e.g., within an alkyl segment).

[0224] Examples of core components include, but are not limited to, the core components illustrated in the examples, as well as ether portions, ester portions, sulfide portions, disulfide portions, amine portions, aryl portions, alkoxyl portions, and others, such as the following: [ka] In the JPEG2026053537000115.jpg225155 formula, the fusion is interrupted (i.e., through them, a wave-like fusion is performed). [ka] The linker moiety (having) is a linking point to either an MHE-bonded small molecule moiety or an NHE-bonded small molecule moiety, and the linking point may be created using chemicals and functional groups known in the field of medicinal chemistry; furthermore, each p, q, r and s is an integer independently selected from the range of about 0 to about 48, preferably about 0 to about 36, or about 0 to about 24, or about 0 to about 16. In some cases, each p, q, r and s may be an integer independently selected from the range of about 0 to 12. In addition, R may generally be selected from moieties including halides, hydroxyls, amines, thiols, ethers, carbonyls, carboxyls, esters, amides, carbocyclics, heterocyclics, and combinations thereof.

[0225] Alternatively, the core portion can be a dendrimer, defined as a repeatedly branched molecule (see, for example, JMJ Frechet, DA Tomalia, Dendrimers and Other Dendritic Polymers, John Wiley & Sons, Ltd. NY, NY, 2001), schematically shown in Figure 17.

[0226] In this method, the NHE-binding small molecule portion is bonded by L to one, some, or all of the ends located around the dendrimer. In another method, a block called a dendron is constructed, and the dendrimer shown above is used as a core, to which the NHE-binding small molecule portion is bonded to one, some, or all of the ends located around the dendrimer. As used herein, the number of generations is typically between about 0 and about 6, preferably between about 0 and about 3. (Generations are defined, for example, in JMJ Frechet, DA Tomalia, Dendrimers and Other Dendritic Polymers, John Wiley & Sons, Ltd. NY, NY.) Dendrimer and / or dendron structures are well known in the art and are shown or illustrated, for example, in (i) JMJ Frechet, DA Tomalia, 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.

[0227] In yet another method, the core portion may be a polymer portion or an oligomer portion. In either case, the polymer or oligomer independently comprises repeating units selected from any of the aforementioned, which may also be substituted with alkyl (e.g., -CH2-), substituted alkyl (e.g., -CHR- (wherein R is hydroxyl)), alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, aryl, heterocyclic, amine, ether, sulfide, disulfide, hydrazine, and oxygen, sulfur, sulfonyl, phosphonyl, hydroxyl, alkoxyl, amine, thiol, ether, carbonyl, carboxyl, ester, amide, alkyl, alkenyl, alkynyl, aryl, heterocyclic, or combinations thereof. In yet another method, the core portion comprises repeating units obtained from the polymerization of ethylenic monomers (e.g., ethylenic monomers listed elsewhere in this specification below).

[0228] Preferred polymers for polymer moieties useful for constructing polyvalent, substantially impermeable, or substantially systemically bioavailable NHE-binding compounds for use in therapies of the various therapeutic methods disclosed herein may be synthesized by any suitable technique, such as free radical polymerization, condensation polymerization, addition polymerization, ring-opening polymerization, and / or derived from natural polymers, such as saccharide polymers. Furthermore, in some embodiments, any of these polymer moieties may be functionalized.

[0229] Examples of polysaccharides useful for the synthesis of such compounds include, but are not limited to, substances from plant or animal sources, including cellulose materials, hemicellulose, alkylcellulose, hydroxyalkylcellulose, carboxymethylcellulose, sulfoethylcellulose, starch, xylan, amylopectin, chondroitin, hyaluronic acid, heparin, gaua, xanthan gum, mannan, galactomannan, chitin, and / or chitosan. Polymeric moieties that do not decompose or are not significantly decomposed under physiological conditions of the gastrointestinal tract (e.g., carboxymethylcellulose, chitosan, and sulfoethylcellulose) are more preferred, at least in some cases.

[0230] When free radical polymerization is used, the polymer moiety can be synthesized from a variety of monomers, including, for example, acrylics, methacrylics, styrenes, vinyls, and dienes, typical examples of which are shown below: styrene, substituted styrenes, alkyl acrylates, substituted alkyl acrylates, alkyl methacrylates, substituted alkyl methacrylates, acrylonitriles, methacrylonitriles, acrylamides, methacrylamides, N-alkylacrylamides, N-alkylmethacrylamides, N,N-dialkylacrylamides, N,N-dialkylmethacrylamides, isoprene, butadienes, ethylenes, vinyl acetates, and combinations thereof. Functionalized versions of these monomers may also be used, and any of these monomers may be used as comonomers in combination with other monomers.For example, specific monomers or comonomers that may be used in this disclosure include methyl methacrylate, ethyl methacrylate, propyl methacrylate (all isomers), butyl methacrylate (all isomers), 2-ethylhexyl methacrylate, isobornyl 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, isobornyl acrylate, and acrylic acid. Benzyl acrylate, 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) (Vitamins), N,N-dimethylaminoethyl acrylate, N,N-diethylaminoethyl acrylate, triethylene glycol acrylate, methacrylamide, N-methylacrylamide, N,N-dimethylacrylamide, N-tert-butylmethacrylamide, Nn-butylmethacrylamide, N-methylolmethacrylamide, N-ethylolmethacrylamide, N-tert-butylacrylamide, Nn-butylmethacrylamide, N-methylolacrylamide, N-ethylolacrylamide, 4-acryloylmorpholine, vinyl benzoate (Total isomers), diethylaminostyrene (total isomers), methylvinyl α-benzoate (total isomers), diethylamino α-methylstyrene (total isomers), p-vinylbenzene sulfonate, sodium p-vinylbenzene sulfonate, alkoxy and alkylsilane functional monomers, maleic anhydride, N-phenylmaleimide, N-butylmaleimide, butadiene, isoprene, chloroprene, ethylene, vinyl acetate, vinyl formate, allylamine, vinylpyridines (total isomers), fluorinated acrylates, methacrylates, and combinations thereof.The main chain heteroatom polymer moieties may also be used, including polyethyleneimines and polyethers such as polyethylene oxide and polypropylene oxide, as well as their comonomers.

[0231] In one particular embodiment, the NHE-bonded small molecule portion, or the polymer to which it is bonded, or otherwise part thereof, is a polyol (e.g., a polymer having repeating hydroxyl-substituted alkyl units, such as -CH(OH)-). With or without their reducible or reducible end groups, polyols, such as mono- and disaccharides, can be good candidates for introducing additional functionalities that can make the compound substantially impermeable.

[0232] In one particular embodiment, the NHE-binding small molecule portion is bound to one or both ends of the polymer chain. More specifically, in yet another alternative approach to the multivalent embodiments of this disclosure, a macromolecule (e.g., a polymer or oligomer) having one of the following exemplary structures may be designed and constructed as described herein: [ka] JPEG2026053537000118.jpg100146

[0233] I. General Structure of Additional Example Compounds In one embodiment, the compound is provided having the structure of formula (II): [ka] or its stereoisomer, prodrug or pharmaceutically acceptable salt, where (a)NHE is an NHE-binding small molecule having the following structure of formula (AI): [ka] In the formula: Each R1, R2, R3, R5 and R9 is independently selected from H, halogen, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, and R7 and R8 are independently selected from H, C 1~6 Alkyl, -C 1~6 (b) The core is selected from the group consisting of alkyl-OH or a bond connecting the NHE-bonded small molecule to L, provided that at least one of them is a bond connecting the NHE-bonded small molecule to L; R4 is selected from the group consisting of H, C1-C7 alkyl, or a bond connecting the NHE-bonded small molecule to L; R6 is absent or selected from H and C1-C7 alkyl; and Ar1 and Ar2 are independently an aromatic ring or a heterocyclic aromatic ring; (b) The core is a core portion having the following structure of formula (BI): [ka] In the formula, X is C(X1), N and N(C 1~6 Selected from alkyl; X1 is hydrogen, may be substituted alkyl, -NX a X b -NO2, -NX c -C(=O)-NX c -X a -C(=O)NX c -X a -NX c -C(=O)-X a -NX c -SO2-X a -C(=O)-X a and -OX a Selected from, each X a and X bY is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl; Y is C 1~6 It is alkylene; Z is -NZ when X is CX1. a -C(=O)-NZ a -, -C(=O)NZ a -, -NZ a -C(=O)- and heteroaryls are selected; Z is N or N(C) 1~6 When it is alkyl, -NZ a -C(=O)-NZ a -, -NZ a Selected from -C(=O)- and heteroaryls; and each X c and Z a These are, independently, hydrogen and C 1~6 (c)L is selected from alkyl groups; and (c)L is a bond or linker connecting the core portion and the NHE-binding small molecule portion, and the resulting NHE-binding compound (i.e., the compound of formula (I)) has overall physicochemical properties such that it is substantially impermeable or substantially not systemically bioavailable. The core portion may be bound to any position or inside the NHE-binding small molecule portion, provided that its introduction does not significantly adversely affect the activity.

[0234] In another embodiment, the compound is provided having the structure of formula (II-I): [ka] or its stereoisomer, prodrug or pharmaceutically acceptable salt, where (a)NHE is an NHE-binding small molecule having the following structure of formula (AI): [ka] In the formula: Each R1, R2, R3, R5 and R9 is independently selected from H, halogen, -NR7(CO)R8, -(CO)NR7R8, -SO2-NR7R8, -NR7SO2R8, -NR7R8, -OR7, -SR7, -O(CO)NR7R8, -NR7(CO)OR8, and -NR7SO2NR8, and R7 and R8 are independently selected from H, C 1~6 Alkyl, -C 1~6 (b) The core is selected from the group consisting of alkyl-OH or a bond connecting the NHE-bonded small molecule to L, provided that at least one of them is a bond connecting the NHE-bonded small molecule to L; R4 is selected from the group consisting of H, C1-C7 alkyl, or a bond connecting the NHE-bonded small molecule to L; R6 is absent or selected from H and C1-C7 alkyl; and Ar1 and Ar2 are independently an aromatic ring or a heterocyclic aromatic ring; (b) The core is a core portion having the following structure of formula (CI): [ka] In the formula, W is selected from alkylene, polyalkylene glycol, -C(=O)-NH-(alkylene)-NH-C(=O)-, -C(=O)-NH-(polyalkylene glycol)-NH-C(=O)-, -C(=O)-(alkylene)-C(=O)-, -C(=O)-(polyalkylene glycol)-C(=O)-, and cycloalkyl; X is N; Y is C 1~6 It is alkylene; Z is -NZ a -C(=O)-NZ a -, -C(=O)NZ a -, -NZ a Selected from -C(=O)- and heteroaryls; each Z a These are, independently, hydrogen and C 1~6(c)L is selected from alkyl groups; and (c)L is a linker that binds or connects the core portion to the NHE-binding small molecule, and the resulting NHE-binding compound (i.e., the compound of formula (I)) has overall physicochemical properties that make it substantially impermeable or substantially not systemically bioavailable. The core portion may bind to essentially any position or inside the NHE-binding small molecule portion, provided that its introduction does not significantly adversely affect the activity.

[0235] It should be noted that not all of the various linkages or connections shown in the structures illustrated herein will necessarily be shown in all cases. For example, in one or more of the illustrated structures, the linkage or connection between the NHE-binding small molecule portion and the core portion is not always shown. However, this should not be taken in a restrictive sense. Rather, the NHE-binding small molecule portion should be understood to be bound or connected to the core portion in some way (e.g., by linkage or some kind of linker) so that the resulting NHE-binding compound is suitable for use (i.e., substantially impermeable in the gastrointestinal tract or substantially not systemically bioavailable).

[0236] The embodiments described above are further illustrated below in this specification. For example, the first representation below of an example oligomeric compound in which various parts of the compound have been identified is intended to provide a broad perspective for the disclosures provided herein. Although each NHE-binding small molecule portion in the following structures is the same, each may be independently selected and may be the same or different, which is within the scope of this disclosure. In the figure below, the linker portion is a polyethylene glycol (PEG) motif. PEG derivatives are also advantageous due to their water solubility, which can help avoid hydrophobic breakdown (intramolecular interactions of hydrophobic motifs that can occur when hydrophobic molecules are exposed to an aqueous environment (see, e.g., Wiley, RA; Rich, DH Medical Research Reviews 1993, 13(3), 327-384)). The core portion in the figure below is also advantageous because it is somewhat rigid to the molecule, allowing for an increase in the distance between the NHE-binding small molecule portions while minimizing the increase in rotational degrees of freedom. [ka]

[0237] When designing and manufacturing substantially impermeable or substantially systemically bioavailable NHE-binding compounds that may be used for the therapies detailed in this disclosure, it may be advantageous for the core or linker to first determine possible binding sites of the NHE-binding small molecule moieties that can be introduced or bound to a series of candidate multivalent or polyvalent compounds. This can be carried out by known methods by systematically introducing functional groups or functional groups representing the desired core or linker fragment to various positions on the NHE-binding small molecule moiety, and then testing these adducts to determine whether the modified compounds still retain the desired biological properties (e.g., inhibition of phosphate transport). Understanding the SAR of the compound also enables the design of cores and / or linkers that positively contribute to the activity of the resulting compound.

[0238] Another aspect considered in the design of cores and linkers is the limitation or prevention of hydrophobic breakdown. Compounds with extended hydrocarbon functionality can break down intramolecularly, contributing to an increased enthalpy barrier against interaction with desired biological targets. Therefore, when designing cores and linkers, they are preferably designed to be resistant to hydrophobic breakdown. Structural constraints, such as rigid monocyclic, bicyclic, or polycyclic rings, can be introduced into the core or linker to increase the rigidity of the structure. Unsaturated bonds, such as those of alkenes and alkynes, can also be introduced, or alternatively. Such modifications can ensure that the NHE-bonded compound can reach productive bonding with its target. Furthermore, the hydrophilicity of the linker can be improved by the addition of hydrogen bond donor or acceptor motifs, or ionic motifs such as amines that are protonated in the gastrointestinal tract or acids that are deprotonated. Such modifications will increase the hydrophilicity of the core or linker, helping to prevent hydrophobic breakdown. Furthermore, such modifications will likely contribute to the impermeability of the resulting compound due to the increase in tPSA.

[0239] Any embodiment of the compounds of the present invention described above, and any specific substituent of such compounds described herein, may be independently combined with other embodiments and / or substituents of such compounds to form embodiments of the present invention not specifically described above. In addition, where a substituent list is enumerated for any specific substituent in a particular embodiment and / or claim, each individual substituent may be removed from that particular embodiment and / or claim, and the remaining substituent list will be considered to be within the scope of the present invention. Furthermore, it is understood herein that substituent combinations and / or variables in the depicted formulas are acceptable only if such contributions result in a stable compound.

[0240] III. Compounds that are substantially bioavailable throughout the body A. Physical and performance properties of the compound The specific compounds described herein are designed to be substantially active in systemic tissues, including renal tissue, when administered by any route, including enteral administration. For enteral administration, including oral delivery, certain compounds are substantially permeable to the epithelium of the gastrointestinal tract, including the epithelium of the oral cavity, esophagus, stomach, small intestine, and / or large intestine. The term “gastrointestinal lumen” is used herein interchangeably with the term “lumen” and refers to the space or cavity within the gastrointestinal tract (GI tract, may also be called the gut) demarcated by the apical membrane of the gastrointestinal epithelial cells of the subject. In some embodiments, the compounds are substantially absorbed via the epithelial cell layer of the gastrointestinal tract (also known as GI epithelium). “Gastrointestinal mucosa” refers to the cell layer that separates the gastrointestinal lumen from the rest of the body and includes the mucosa of the stomach and intestines, such as the mucosa of the small intestine. As used herein, “gastrointestinal epithelial cells” or “luminal epithelial cells” refers to any epithelial cells on the surface of the gastrointestinal mucosa facing the lumen of the gastrointestinal tract, including, for example, gastric epithelial cells, intestinal epithelial cells, and colonic epithelial cells.

[0241] When used herein, “substantially systemic bioavailable” and / or “substantially permeable” (and variations thereof) generally include a state in which, statistically significant amounts, and in some embodiments, essentially all of the compounds of this disclosure enter the bloodstream or systemic tissues via the gastrointestinal lumen. For example, according to one or more embodiments of this disclosure, preferably at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or even about 99.5% of the compound enters the bloodstream or systemic tissues via the gastrointestinal lumen. In such cases, localization to the bloodstream or systemic tissues represents an increase in the net motility of the compound across the gastrointestinal lamina of epithelial cells, not only by active and / or active transport, but also by both transcellular and paracellular transport. In these embodiments, the compound permeates the gastrointestinal epithelial cell layer by transcellular transport, for example, via the apical membrane of the epithelial cells of the small intestine. In these embodiments, the compound may also permeate by transcellular transport between gastrointestinal epithelial cells lining the lumen, via "tight junctions".

[0242] However, in this regard, in another embodiment, “substantially permeable” or “substantially systemic bioavailable” provides or enables some limited retention within the gastrointestinal tract to occur (e.g., some detectable absorption amounts such as about 0.1%, 0.5%, less than 1%, or about 30%, 20%, 10%, less than 5%, etc., e.g., a range of retention between about 1% and 30%, or 5% and 20%, etc.).

[0243] In this regard, in certain embodiments, due to the substantial permeability and / or substantial systemic bioavailability of the compound of the present invention, about 50%, 60%, 70%, 80%, 90%, or 95% or less of the compound of the present invention can be recovered from the feces over a period of 24, 36, 48, 60, 72, 84, or 96 hours after administration (e.g., enterally) to a subject requiring it. In some embodiments, about 40%, 30%, less than 20%, or less than about 10%, or less than 5% of the administered amount of the compound is present in the feces of the subject and recoverable. In this regard, the recovered compound may include the parent compound and the totality of its metabolites derived from the parent compound by any other modification, such as hydrolysis, conjugation, reduction, oxidation, N-alkylation, glucuronidation, acetylation, methylation, sulfation, phosphorylation, or adding or removing atoms from the parent compound, the metabolites being produced when they are present in an early summer environment by any enzymatic action or exposure to any physiological environment, including interaction with pH, ​​temperature, pressure, or food.

[0244] The fecal recovery of compounds and metabolites can be measured using standard methods. For example, the compound may be administered enterally (e.g., orally) at an appropriate dose (e.g., 10 mg / kg), and feces are then collected at predetermined times after administration (e.g., 24, 36, 48, 60, 72, 96 hours). The parent compound and metabolites are extracted with an organic solvent and quantitatively analyzed by mass spectrometry. A mass balance analysis of the parent compound and metabolites (including parent = M, metabolite 1 [M+16], and metabolite 2 [M+32]) may be used to determine the recovery percentage in the feces.

[0245] (I C max and IC 50 In some embodiments, the substantially systemic bioavailable compounds detailed herein, when administered alone or in combination with one or more additional pharmaceutically active compounds or agents to a subject requiring them, inhibit the phosphate ion (Pi) transport or uptake concentration of the compounds. 50 C is approximately the same as or larger than C max This indicates the maximum concentration detected in serum, which is defined as C. max This involves the inhibition of Pi transport or uptake in IC. 50 Larger by approximately or at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500% or more. In some embodiments, the C max This involves the inhibition of Pi transport or uptake in IC. 50 It is approximately 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100X (100 times).

[0246] In addition, or in some of the various embodiments of this disclosure, one or more of the compounds detailed herein, when administered to a subject requiring them, C max :I C 50 (Inhibition of Pi transport or uptake) may have a ratio, C max and IC 50These are expressed in the same units, approximately or at least approximately 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100, or in the range of approximately 1 to 100, or 1 to 10.

[0247] In addition, or in some of the various embodiments of this disclosure, when administered (e.g., enterally) to a subject requiring it, either alone or in combination with one or more additional pharmaceutically active compounds or agents, the C200 ng / ml is approximately or greater than approximately 10 ng / ml, approximately 12.5 ng / ml, approximately 15 ng / ml, approximately 17.5 ng / ml, approximately 20 ng / ml, approximately 30 ng / ml, approximately 40 ng / ml, approximately 50 ng / ml, approximately 60 ng / ml, approximately 70 ng / ml, approximately 80 ng / ml, approximately 90 ng / ml, approximately 100 ng / ml, or approximately 200 ng / ml. max It may have the C max For example, this ranges from approximately 10 ng / ml to approximately 200 ng / ml, 10 ng / ml to approximately 100 ng / ml, or approximately 10 ng / ml to approximately 50 ng / ml.

[0248] B. Examples of substantially systemic bioavailable compounds In general, this disclosure includes small molecules that are essentially monovalent or polyvalent and have activity as phosphate transport inhibitors, which bind to, interact with, and / or modulate NHE3, and which are substantially permeable or substantially systemically bioavailable when administered via the gastrointestinal tract or other routes, and which include known NHE-binding and NHE-inhibiting compounds. Accordingly, specific embodiments include compounds represented by the “NHE” portion as otherwise described herein (e.g., above), in which NHE is an NHE-binding small molecule.

[0249] Examples of small molecules suitable for use (i.e., suitable for use as substantially bioavailable compounds) are shown below.

[0250] In view of the foregoing, in one particular embodiment, the following small molecule disclosed in U.S. Patent Application No. 2005 / 0054705 (which is incorporated herein by reference in its entirety (and in particular, the text on pages 1-2 therein) for all purposes of relevance and consistency) may be suitable for use as a substantially systemically bioavailable NHE-binding compound. [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference. In one particularly preferred embodiment, R6 and R7 are halogens (e.g., Cl), R5 is a lower alkyl (e.g., CH3), and R1-R4 are H, and the compound is, for example, structure; [ka] It holds.

[0251] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which, and in particular, pages 1-2 therein, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0252] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which (and in particular, page 49 of which) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0253] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which (and in particular pages 118-120 and 175-177 therein) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0254] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which (and in particular pages 129-131 therein) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference. (In this regard, substituent Z in the illustrated structure should not be confused with the sub-Z that may bind to the NHE-binding small molecule in order to make the resulting "NHE-Z" molecule substantially impermeable according to this disclosure.)

[0255] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which (and in particular pages 127-129 therein) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference. (In this regard, substituent Z in the illustrated structure should not be confused with the sub-Z that may bind to the NHE-binding small molecule in order to make the resulting "NHE-Z" molecule substantially impermeable according to this disclosure.)

[0256] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which, and in particular, pages 134-137 thereof, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0257] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entire contents thereof, and in particular pages 31-32 and 137-139 thereof, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0258] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which (and in particular pages 37-45 therein) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference. (In this regard, substituent Z in the illustrated structure should not be confused with the sub-Z that may bind to the NHE-binding small molecule in order to make the resulting "NHE-Z" molecule substantially impermeable according to this disclosure.)

[0259] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which (and in particular pages 100-102 therein) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference (in particular, the wavy lines indicate variable length or variable number of atoms).

[0260] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which, and in particular, pages 90-91 thereof, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0261] In yet another specific embodiment, the following small molecules disclosed in U.S. Patent No. 5,900,436 (or EP0822182B1) (the entire contents thereof, and in particular lines 10-55 of the first paragraph thereof, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0262] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entire contents thereof, and in particular pages 35-47 thereof, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0263] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which (and in particular pages 154-155 therein) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0264] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entirety of which (and in particular pages 132-133 therein) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference.

[0265] In yet another specific embodiment, the following small molecules disclosed in Canadian Patent Application No. 2,241,531 (or International Patent Publication No. WO97 / 24113) (the entire contents thereof, and in particular pages 58-65 and 141-148 thereof, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference. (In this regard, substituent Z in the illustrated structure should not be confused with the sub-Z that may bind to the NHE-binding small molecule in order to make the resulting "NHE-Z" molecule substantially impermeable according to this disclosure.)

[0266] In yet another specific embodiment, the following small molecules disclosed in U.S. Patent Nos. 6,911,453 and 6,703,405 (the entire contents thereof (and in particular paragraphs 1-7 and 46 of No. 6,911,453 and paragraphs 14-15 of No. 6,703,405) are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variables in the structure are defined in the cited patent application, and their details are incorporated herein by reference. Particularly preferred small molecules included in the above structure are further exemplified below (for example, Example 1 of Patent No. 6,911,453, the entire contents of which are specifically incorporated herein by reference): [ka]

[0267] In yet another specific embodiment, the following small molecules disclosed in U.S. Patent Publications 2004 / 0039001, 2004 / 0224965, 2005 / 0113396 and 2005 / 0020612 (their entire contents incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variables in the structure are defined above and / or in one or more of the cited patent applications, and their details are incorporated herein by reference and / or as illustrated above (interrupted bonds indicate the bond points of the Y portion with the fused heterocyclic ring). In particular, in various embodiments, the combinations of X and Y may be: [ka]

[0268] In a particularly preferred embodiment of the above structure, the small molecule has a general structure: [ka] It holds. In the formula, R1, R2, and R3 may be the same or different, but preferably different, and independently H, NR'R'' (wherein R' and R'' are independently H and a hydrocarbyl such as a lower alkyl, as defined elsewhere herein) and the structure: [ka] Selected from.

[0269] In a more particularly preferred embodiment of the above structure, the small molecules included in the above structure are further illustrated below (see, for example, compound I1 on page 5 of Japanese Patent Application No. 2005 / 0020612, the entire contents of which are specifically incorporated herein by reference): [ka]

[0270] In another particular embodiment, the following small molecules disclosed in U.S. Patent No. 6,399,824 (the entire contents thereof, and in particular the text of Example 1 thereof, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] In the structure, R can preferably be selected from H and (CH3)2NCH2CH2-, with H being particularly preferred in various embodiments.

[0271] In yet another specific embodiment, the following small molecules disclosed in U.S. Patent No. 6,005,010 (and in particular its first to third paragraphs) and / or U.S. Patent No. 6,166,002 (and in particular its first to third paragraphs) (the entire contents thereof are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variable ("R") in the structure is defined in the cited patent application, and its details are incorporated herein by reference.

[0272] In another embodiment, the NHE-binding small molecule suitable for use as a substantially systemically bioavailable compound is disclosed in WO2010 / 025856 (the entire contents thereof are incorporated herein by reference for all relevant and consistent purposes) and has the following structure: [ka] The variables in the structure are defined in WO2010 / 025856 (the details thereof are incorporated herein by reference).

[0273] In yet another particularly preferred embodiment, the following small molecules disclosed in U.S. Patent Application No. 2008 / 0194621 (the entire contents thereof, and in particular the text of Example 1 thereof, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka] The variables in the structure ("R1", "R2", and "R3") are as defined above and are defined in the cited patent application, the details of which are incorporated herein by reference.

[0274] In yet another particularly preferred embodiment, the following small molecules disclosed in U.S. Patent Application No. 2007 / 0225323 (the entire contents thereof, and in particular the text of Example 36 thereof, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka]

[0275] In yet another particularly preferred embodiment, the following small molecules disclosed in U.S. Patent No. 6,911,453 (the entire contents thereof, and in particular the text of Example 35 thereof, are incorporated herein by reference for all relevant and consistent purposes) may be suitable for use as substantially systemically bioavailable NHE-binding compounds. [ka]

[0276] In one particularly preferred embodiment of this disclosure, the small molecule is: [ka] A selection can be made from the group consisting of the following:

[0277] In some embodiments, the substantially systemically bioavailable NHE-binding and / or regulatory compounds are selected from one or more of the following: [ka]

[0278] IV. Pharmaceutical compositions and therapeutic methods For the purpose of administration, the compounds of the present invention may be formulated as chemical active ingredients for administration to a patient or subject, or as pharmaceutical compositions. Pharmaceutical compositions of the present invention generally comprise the compounds of the present invention and pharmaceutically acceptable carriers, diluents, or excipients. The compounds are present in the composition in an amount effective for treating specific diseases or conditions of the subjects described herein. The activity of the compounds can be determined by those skilled in the art, for example, as described in the following examples. Appropriate concentrations and doses can be readily determined by those skilled in the art.

[0279] The compounds or compositions of the present invention may be used in a manner to essentially treat any disease or other condition in a subject who would benefit from inhibition of phosphate uptake in the gastrointestinal tract and / or kidneys.

[0280] For example, but not limited to, renal impairment reduces the production and activity of 1α-hydroxylase in the kidneys, leading to a decrease in 1,25-dihydroxyvitamin D. This decrease in vitamin D limits gastrointestinal calcium absorption, causing a decrease in serum calcium levels. The combination of low 1,25-dihydroxyvitamin D and low serum calcium levels synergistically stimulates parathyroid tissue, which produces and secretes PTH. Nephron deficiency also impairs Pi excretion, but serum P levels are actively defended by the action of PTH and FGF-23, and by elevated serum P levels, which significantly increase urinary PO4 excretion. However, the tubular action of PTH and FGF-23 cannot maintain serum P levels against continuous nephron deficiency. Once renal failure progresses to a decrease of approximately 40-50% of renal function, the reduction in the amount of functional renal tissue prevents the excretion of the total amount of ingested phosphate required to maintain homeostasis. As a result, hyperphosphatemia develops. In addition, elevated serum phosphorus levels interfere with renal 1α-hydroxylase activity, further suppressing activated vitamin D levels and stimulating PTH, leading to secondary hyperparathyroidism (sHPTH).

[0281] However, phosphorus imbalance is not necessarily the same as hyperphosphatemia. Rather, the majority of CKD patients who are not yet on dialysis have normal phosphate levels, but their phosphorus balance is positive for excess phosphorus accumulating in vascular structures in the form of ectopic calcification, such as intimal localized vascular calcification. Clinically, patients with CKD have elevated FGF-23 levels, which are significantly associated with decreased renal function and decreased calcitriol levels, and it is hypothesized that FGF-23 synthesis is induced by the presence of excess phosphorus in the body in persistent renal failure.

[0282] Furthermore, an unrecognized effect on cardiovascular disease is postprandial phosphatemia, i.e., serum phosphorus range of motion secondary to food intake. In addition, the acute effects of phosphorus on endothelial function, both in vitro and in vivo, have been studied. Exposure of bovine aortic endothelial cells to phosphorus load increased the production of reactive oxygen species and decreased nitric oxide, a known vasodilator. In the aforementioned acute phosphorus load test in healthy volunteers, flow-dependent dilation was found to be inversely correlated with postprandial serum phosphorus (Shuto et al., 2009b, J.Am.Soc.Nephrol, v. 20, no. 7, p. 1504-1512).

[0283] Accordingly, in certain embodiments, the compounds or compositions of the present invention may be used in a manner selected from one or more of the following: a method for treating hyperphosphatemia, which may also be postprandial hyperphosphatemia; a method for treating renal disease (e.g., chronic kidney disease (CKD), end-stage renal disease (ESRD)); a method for lowering serum creatinine levels; a method for treating proteinuria; a method for delaying the timing of kidney transplant treatment (RRT), such as dialysis; a method for lowering FGF23 levels; a method for reducing the effect of active vitamin D on hyperphosphatemia; a method for attenuating hyperparathyroidism, such as secondary hyperparathyroidism; a method for reducing serum parathyroid hormone (PTH or iPTH); a method for reducing interdialysis weight gain (IDWG). Methods for improving endothelial cell dysfunction, which may also be induced by postprandial serum phosphate; methods for reducing vascular calcification or intimal localized vascular calcification; methods for reducing urinary phosphorus (e.g., enteral administration of a gastrointestinal compound that is substantially not systemically bioavailable); methods for increasing urinary phosphorus (e.g., administration of a substantially systemically bioavailable compound, or administration of a substantially not systemically bioavailable compound via a route other than enteral administration); methods for normalizing serum phosphate levels; methods for reducing phosphate load in elderly patients; methods for reducing dietary phosphate intake; methods for reducing postprandial calcium absorption; methods for reducing renal hypertrophy; methods for reducing cardiac hypertrophy; and methods for treating obstructive sleep apnea.

[0284] In some embodiments, the present invention provides treatment for hyperphosphatemia, including postprandial hyperphosphatemia; treatment for renal diseases (e.g., chronic kidney disease (CKD), end-stage renal disease (ESRD)); reduction of serum creatinine levels; treatment of proteinuria; delay of the timing of kidney transplantation therapy (RRT), such as dialysis; reduction of FGF23 levels; reduction of the effects of active vitamin D on hyperphosphatemia; attenuation of hyperparathyroidism, such as secondary hyperparathyroidism; reduction of serum parathyroid hormone (PTH or iPTH); reduction of interdialysis weight gain (IDWG); and improvement of endothelial cell dysfunction, which may also be induced by postprandial serum phosphate. The present invention provides: reduction of vascular calcification or intimal localized vascular calcification; reduction of urinary phosphorus (e.g., enteral administration of a gastrointestinal compound that is substantially systemically bioavailable); increase of urinary phosphorus (e.g., administration of a substantially systemically bioavailable compound, administration of a substantially systemically bioavailable compound via a route other than enteral administration); normalization of serum phosphate levels; reduction of phosphate load in elderly patients; reduction of dietary phosphate intake; reduction of postprandial calcium absorption; reduction of renal hypertrophy; reduction of cardiac hypertrophy; and use of the compound or composition for the treatment of obstructive sleep apnea.

[0285] In some embodiments, the present invention may include: treatment of hyperphosphatemia, including postprandial hyperphosphatemia; treatment of renal diseases (e.g., chronic kidney disease (CKD), end-stage renal disease (ESRD)); reduction of serum creatinine levels; treatment of proteinuria; delay of the timing of kidney transplantation therapy (RRT), such as dialysis; reduction of FGF23 levels; reduction of the effect of active vitamin D on hyperphosphatemia; attenuation of hyperparathyroidism, such as secondary hyperparathyroidism; reduction of serum parathyroid hormone (PTH or iPTH); reduction of interdialysis weight gain (IDWG); improvement of endothelial cell dysfunction, which may also be induced by postprandial serum phosphate; blood The invention provides for the following benefits: reduction of tubular calcification or intimal localized vascular calcification; reduction of urinary phosphorus (e.g., enteral administration of a gastrointestinal compound that is substantially systemically bioavailable); increase of urinary phosphorus (e.g., administration of a substantially systemically bioavailable compound, administration of a substantially systemically bioavailable compound via a route other than enteral administration); normalization of serum phosphate levels; reduction of phosphate load in elderly patients; reduction of dietary phosphate intake; reduction of postprandial calcium absorption; reduction of renal hypertrophy; reduction of cardiac hypertrophy; and use of the compound or composition in pharmaceutical manufacturing for the treatment of obstructive sleep apnea.

[0286] In some embodiments, the present invention may include: treatment of hyperphosphatemia, including postprandial hyperphosphatemia; treatment of renal diseases (e.g., chronic kidney disease (CKD), end-stage renal disease (ESRD)); reduction of serum creatinine levels; treatment of proteinuria; delay of the timing of kidney transplantation therapy (RRT), such as dialysis; reduction of FGF23 levels; reduction of the effects of active vitamin D on hyperphosphatemia; attenuation of hyperparathyroidism, such as secondary hyperparathyroidism; reduction of serum parathyroid hormone (PTH or iPTH); reduction of interdialysis weight gain (IDWG); and improvement of endothelial cell dysfunction, which may also be induced by postprandial serum phosphate. The present invention provides a pharmaceutical composition comprising a compound or composition for the treatment of obstructive sleep apnea, comprising: reduction of vascular calcification or intimal localized vascular calcification; reduction of urinary phosphorus (e.g., enteral administration of a gastrointestinal compound that is substantially systemically bioavailable); increase of urinary phosphorus (e.g., administration of a substantially systemically bioavailable compound, administration of a substantially systemically bioavailable compound via a route other than enteral administration); normalization of serum phosphate levels; reduction of phosphate load in elderly patients; reduction of dietary phosphate intake; reduction of postprandial calcium absorption; reduction of renal hypertrophy; reduction of cardiac hypertrophy; and obstructive sleep apnea.

[0287] Hyperphosphatemia is a condition characterized by elevated levels of phosphate in the blood. The average serum phosphorus level in human adults is typically in the range of approximately 2.5–4.5 mg / dL (approximately 0.81–1.45 mmol / L). Due to the influence of growth hormone, values ​​are often about 50% higher in infants and about 30% higher in children. Therefore, specific methods include the treatment of adult human patients with hyperphosphatemia, who have a serum phosphorus level of approximately or at least approximately 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5 mg / dL. In some embodiments, the treatment reduces the serum phosphate concentration or value of a patient with hyperphosphatemia to approximately 150%, 145%, 140%, 135%, 130%, 125%, 120%, 115%, 110%, 105%, or 100% (normal) of a normal serum phosphate value (e.g., 2.5–4.5 mg / dL or 0.81–1.45 mmol / L in adults). In some embodiments, the treatment regimen results in and / or includes monitoring phosphate levels so that they remain within the range of approximately 2.5–4.5 mg / dL (approximately 0.81–1.45 mmol / L). Methods for treating child or adolescent human patients having a serum phosphorus mass of approximately or at least approximately 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0 mg / dL. As described herein, in these and related embodiments, administration of the compounds or compositions described herein may reduce the serum phosphorus mass of the subject by approximately or at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120% or more.

[0288] A particular embodiment relates to a method for treating chronic kidney disease (CKD), a condition characterized by progressive loss of renal function. Common causes of CKD include diabetes mellitus, hypertension, and glomerulonephritis. Therefore, the particular method includes the treatment of a subject suffering from CKD, who may also have one or more of the aforementioned conditions.

[0289] In some aspects, if the subjects are 60 mL / min / 1.73 m³ over approximately 3 months, 2 If the glomerular filtration rate (GFR) is less than 10, the classification depends on whether renal impairment is also present. Therefore, specific methods include approximately or at least approximately 60, 55, 50, 45, 40, 30, 35, 20, 25, 20, 15, or 10 mL / min / 1.73 m³. 2 This includes the treatment of subjects having a GFR of around 50%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200% or more.

[0290] CKD is most often characterized according to the stage of the disease: Stage 1, Stage 2, Stage 3, Stage 4, and Stage 5. Stage 1 CKD is characterized by renal impairment and normal or approximately 90 mL / min / 1.73 m³ 2 This includes subjects with relatively high GFR. Stage 2 CKD is defined as renal impairment and approximately 60-89 mL / min / 1.73m². 2 This includes subjects with a GFR of [specified value]. Stage 3 CKD is characterized by renal impairment and approximately 30-59 mL / min / 1.73m². 2 This includes subjects with GFR. Stage 4 CKD is characterized by renal impairment and approximately 15-29 mL / min / 1.73m 2 This includes subjects with a GFR of [value missing]. Stage 5 CKD is defined as having impaired renal failure and approximately 15 mL / min / 1.73 m 2 This includes subjects with a GFR of less than 5. Stage 5 CKD also represents end-stage renal disease (ESRD). Thus, in certain ways, subjects have stage 1, 2, 3, 4, or 5 CKD and one or more of its associated clinical features (e.g., defined GFR, renal impairment). In some embodiments, the subjects have ESRD and one or more of its associated clinical features described herein and known in the art.

[0291] CKD can be characterized according to the affected area of ​​the kidney. For example, in certain embodiments, CKD may include vascular-related CKDs, such as macrovascular diseases including bilateral renal artery stenosis, and small vessel diseases including ischemic nephropathy, hemolytic uremic syndrome, and vasculitis. In certain embodiments, CKD may include glomerular-related CKDs, such as primary glomerular diseases including focal segmental glomerulosclerosis and IgA nephritis, and secondary glomerular diseases including diabetic nephropathy and lupus nephritis. Ureteral-interstitial-related CKDs may also be included, such as polycystic kidney disease, drug and toxin-induced chronic tubulointerstitial nephritis, and reflux nephropathy. Thus, a particular patient being treated for CKD may have one or more of the aforementioned CKD-related features.

[0292] Specific aspects relate to methods for treating subjects with renal impairment or one or more symptoms / clinical signs of renal impairment. Examples of renal impairment (e.g., CKD-related renal impairment) and its associated symptoms include pathological abnormalities and markers of impairment, including abnormalities confirmed by blood tests (e.g., elevated blood or serum creatinine levels, creatinine clearance), urinalysis (e.g., proteinuria), and / or imaging studies.

[0293] Creatinine is a breakdown product of creatine phosphate in muscles and provides a useful, easily measurable indicator of renal health. The normal human reference range for blood or serum creatinine is approximately 0.5–1.0 mg / dL (approximately 45–90 μmol / l) for women and approximately 0.7–1.2 mg / dL (approximately 60–110 μmol / l) for men. Therefore, certain subjects of treatment according to the methods described herein (e.g., pre-treatment, initial) may have blood or serum creatine levels of approximately 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 mg / dL or higher. In these and related embodiments, administration of the compounds or compositions described herein may reduce the overall blood or serum creatinine level of the subject by about or at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or 200% or more.

[0294] Creatinine clearance rate (C Cr Creatinine clearance (or CrCl) represents the amount of plasma excreted of creatinine per unit time; it is measured by comparing blood creatinine levels to urinary creatinine levels over a period of time (e.g., 24 hours). Creatinine clearance is often measured as milliliters / minute (ml / min) or as a function of body weight (ml / min / kg). Depending on the test performed, normal values ​​range from approximately 97–137 ml / min for men and approximately 88–128 ml / min for women. Decreased creatinine clearance provides a useful sign of renal impairment. Therefore, for a particular male subject to treatment according to the method described herein (e.g., pre-treatment, initial), the C values ​​are approximately or approximately 97, 96, 95, 94, 93, 92, 91, 90, 89, 88, 87, 86, 85, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50 or less. Cr . A specific female subject of treatment according to the method described herein (e.g., pre-treatment, initial) may have a C of approximately or approximately 88, 87, 86, 85, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 47, 46, 45, 44, 43, 42, 41, 40 or less Cr It may have the following properties. In some embodiments, the administration of the compound or composition described herein may affect the target C Cr It may be maintained or increased by approximately or at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or 200% or more.

[0295] Proteinuria is a condition characterized by an excess of protein in the urine. It is associated with a variety of diseases, including kidney damage. Proteinuria is often characterized by a urinary protein / creatinine ratio greater than approximately 45 mg / mmol, or, in specific tests, an albumin / creatine ratio greater than approximately 30 mg / mmol. Certain subjects of treatment according to the methods provided herein (e.g., pre-treatment) include subjects having proteinuria alone or in conjunction with CKD or other renal impairments, and having a urinary protein / creatinine ratio of approximately 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or 120 mg / mmol or higher and / or a urinary albumin / creatinine ratio of approximately 30, 35, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or 120 mg / mmol or higher. In these and related embodiments, administration of the compounds or compositions described herein may treat proteinuria by reducing the urinary protein / creatinine ratio and / or urinary albumin / creatinine ratio by, for example, about or at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or 200% or more.

[0296] CKD is associated with a variety of clinical symptoms. Examples include hypertension, urea accumulation, hyperkalemia, anemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, and atherosclerosis. Therefore, in certain ways, subjects with CKD may also have or be at risk of having one or more of the aforementioned clinical symptoms. In certain embodiments, subjects with CKD may have or be at risk of having hyperphosphatemia, as described herein.

[0297] Kidney transplant therapy (RRT) relates to a variety of life-sustaining treatments for renal failure, including those initiated in the later stages of chronic kidney disease (CKD) and endovascular disease (ESRD). Examples of RRT include dialysis, hemodialysis, hemofiltration, and kidney transplantation. In certain embodiments, subjects receiving treatment according to the methods provided herein are about to experience, are experiencing, or have experienced one or more types of RRT. In some embodiments, the subject has not yet experienced RRT, and administration of the compounds described herein delays the timing of initiating RRT by about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks, or about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, or about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 years or more (e.g., compared to untreated cases).

[0298] Fibroblast growth factor 23 (FGF23) regulates phosphorus and vitamin D metabolism. It promotes hyperphosphatemia and also reduces calcitriol production. Elevated FGF23 levels are associated with mortality, left ventricular hypertrophy (or left ventricular myocardial mass index), cardiomyopathy, endothelial cell dysfunction, and progression of chronic kidney disease (CKD). In fact, FGF23 levels progressively increase in early CKD, perhaps as a physiological adaptation, to maintain normal phosphate levels or a normal phosphorus balance. FGF23 levels should also directly contribute to tissue damage of the heart, blood vessels, and kidneys. Therefore, certain embodiments concern the treatment of subjects with elevated blood or serum FGF23 levels, including subjects with CKD and those undergoing dialysis / hemodialysis (see, e.g., Kirkpantur et al., Nephrol Dial Transplant. 26: 1346-54, 2011). In some embodiments, administration of the compounds or compositions described herein reduces the logarithm of blood or serum FGF23 levels by about or at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or 200% or more.

[0299] Vitamin D, in particular, stimulates the absorption of phosphate ions in the small intestine. Therefore, an excess or activity of vitamin D can cause elevated phosphate levels and hyperphosphatemia. Accordingly, certain embodiments relate to methods for reducing the hyperphosphatemic effects of active vitamin D in subjects with elevated vitamin D levels or activity. In some embodiments, the subject has vitamin D toxicity due to excessive intake of vitamin D.

[0300] Hyperparathyroidism is a disorder in which the parathyroid glands produce too much parathyroid hormone (PTH). Secondary hyperparathyroidism is characterized by excessive secretion of PTH in response to hypocalcemia and associated parathyroid enlargement. Chronic kidney disease (CKD) is the most common cause of secondary hyperparathyroidism, as the kidneys generally fail to convert sufficient vitamin D into its active form and excrete sufficient phosphate. Insoluble calcium phosphate is produced in the body and thus removes calcium from the circulation, leading to hypocalcemia. The parathyroid glands then further increase PTH secretion in an attempt to increase serum calcium levels. Therefore, certain subjects of treatment according to the methods provided herein may have concomitant CKD, hyperphosphatemia, hypocalcemia, or other conditions or symptoms described herein, and may develop hyperparathyroidism and / or elevated PTH levels (e.g., before treatment, in the early stages). In some embodiments, administration of the compounds or compositions described herein may reduce hyperparathyroidism, including secondary hyperparathyroidism, in subjects requiring its use. In some embodiments, administration of the compounds or compositions described herein may reduce PTH levels by about or at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or 200% or more, for example, by reducing serum phosphate levels and associated production of insoluble calcium phosphate, increasing available calcium, and thereby reducing hypocalcemia-induced production of PTH.

[0301] In certain embodiments, administration of the compounds described herein, for example, dual-active compounds that inhibit both Pi transport and NHE3-mediated antiportation of sodium and hydrogen ions, may provide multiple therapeutic effects to subjects suffering from CKD. In some cases, administration of the dual-active compounds may reduce the logarithm of FGF23 levels and serum parathyroid hormone (PTH) by approximately or at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or 200% compared to an untreated state, reduce blood pressure, and reduce proteinuria by at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or 200% compared to an untreated state.

[0302] In certain embodiments, administration of the compounds described herein, for example, dual-active compounds that inhibit both Pi transport and NHE3-mediated antiportation of sodium and hydrogen ions, may provide multiple therapeutic effects to subjects suffering from ESRD (or stage 5 CKD). In specific cases, administration of the dual-active compounds reduces serum phosphate concentration or value by approximately or at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or 200% or more compared to an untreated state, and reduces interdialysis weight gain (IDWG) by approximately or at least approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or 200% or more compared to an untreated state. IDWG is an easily measurable parameter that is routinely evaluated before, during, or after dialysis (see Sarkar et al., Semin Dial. 19:429-33, 2006).

[0303] Hyperphosphatemia can lead to endothelial cell dysfunction in both healthy subjects and those with renal disease, independently of vascular calcification (see, e.g., Di Marco et al., Kidney International. 83:213-222, 2013). Dietary phosphate restriction or management of serum phosphate levels with phosphate binders may prevent such subjects from developing cardiovascular disease. Studies have also shown that dietary phosphate restriction may improve aortic endothelial cell dysfunction (e.g., in CKD complicated with hyperphosphatemia) by increasing the active phosphorylation of endothelial nitric oxide synthase and Akt (see, e.g., Van et al., J Clin Biochem Nutr. 51:27-32, 2012). Certain subjects of treatment according to the methods provided herein may have hyperphosphatemia, renal disease, or any other condition described herein, and may have or be at risk of having endothelial cell dysfunction. By reducing postprandial or dietary phosphate intake, either alone or in combination with dietary phosphate restriction, administration of the compounds or compositions described herein may reduce the risk of developing endothelial cell dysfunction or improve existing endothelial cell dysfunction, including postprandial serum phosphate-induced endothelial cell dysfunction.

[0304] Hyperphosphatemia is a major inducer of vascular calcification (see Giachelli, Kidney Int. 75:890-897, 2009). Calcium phosphate deposition, mostly in the form of apatite, is characteristic of vascular calcification and can occur in blood vessels, myocardium, and heart valves. Along with the passive deposition of calcium phosphate in extraosseous tissues, inorganic phosphates can also directly induce arterial calcification through "osteogenesis" of the media in vascular structures. Furthermore, vascular smooth muscle cells respond to elevated phosphate levels by undergoing osteochondrogenic phenotypic changes and by calcifying their extracellular matrix through mechanisms involving sodium-dependent phosphate cotransporters.

[0305] Intimal calcification is typically found within atherosclerotic lesions. Medial calcification is usually observed in age-related atherosclerosis and diabetes mellitus, and is the primary form of calcification observed in ESRD. Indeed, extensive calcification of arterial walls and soft tissues is a frequent feature in patients with chronic kidney disease (CKD), including those with ESRD. In the valves, calcification is a defining feature of aortic stenosis and occurs predominantly at sites of inflammation and mechanical load, in both lobular and annular structures. These mechanical changes are associated with increased arterial pulse velocity and pulse pressure, leading to impaired arterial distensibility and increased afterload that causes left ventricular hypertrophy, impairing coronary perfusion (see Guerin et al., Circulation. 103:987-992, 2001). Therefore, both intimal and medial calcification can contribute to morbidity and mortality associated with cardiovascular disease and tend to be major contributors to the significant increase in cardiovascular mortality risk observed in patients with CKD and ESRD. Accordingly, controlling serum phosphate can reduce the production of calcium / phosphate products and thereby reduce vascular calcification. Accordingly, certain subjects of treatment according to the methods provided herein may have any of the following conditions: hyperphosphatemia, CKD, and ESRD, and may have or be at risk of having vascular calcification, including intimal and / or medial calcification. In some embodiments, administration of the compounds or compositions described herein reduces the risk of having vascular calcification or reduces its production or level in subjects requiring it. In certain embodiments, administration of the compounds or compositions described herein may reduce vascular calcification by, for example, about or at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or 200% or more compared to an untreated state.

[0306] Elderly patients are particularly susceptible to elevated phosphate levels. For example, dietary and genetic engineering studies provide in vivo evidence that phosphate toxins accelerate the aging process and suggest a novel role of phosphate in mammalian aging (see, e.g., Ohnishi and Razzaque, FASEB J. 24:3562-71, 2010). These studies link excessive phosphate to many signs of premature aging, including kyphosis, noncoordinated movement, hypogonadism, infertility, skeletal muscle loss, emphysema and osteopenia, as well as systemic atrophy of the skin, intestines, thymus, and spleen. Accordingly, certain embodiments relate to reducing the phosphate load in elderly patients, for example, to reduce one or more signs of premature aging, by administering the compounds described herein to such elderly patients. In some cases, elderly patients are approximately or at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 years of age or older.

[0307] Hypertrophy refers to an increase in the volume of an organ or tissue due to the enlargement of its constituent cells. Hyperphosphatemia is associated with myocardial hypertrophy, including left ventricular hypertrophy (see Neves et al., Kidney Int. 66:2237-44, 2004; and Achinger and Ayus, Am Soc Nephrol. 17(12 Suppl 3):S255-61, 2006) and compensatory renal hypertrophy, including glomerular hypertrophy, the latter of which is often observed in CKD. Specific subjects of treatment according to the methods provided herein may have myocardial hypertrophy, renal hypertrophy, or both, either alone or in conjunction with CKD or renal impairment (e.g., pre-treatment, early stage). In some embodiments, administration of the compounds described herein may reduce myocardial hypertrophy and / or renal hypertrophy by about or at least about 5%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or 200% or more compared to an untreated state.

[0308] Sleep apnea is a sleep disorder characterized by abnormal pauses in breathing during sleep, either apnea or abnormally low breathing. Pauses in breathing are called apneas, and low breathing events are called hypopneas. These events can last from seconds to minutes and can occur multiple times within an hour (e.g., >30 times per hour). The apnea-hypopnea index (AHI) is calculated by dividing the total number of apneas or hypopneas by the number of sleep hours. Mild, moderate, and severe sleep apnea are defined as AHI 5–14, 15–29, and ≥30 events / hour, respectively. Obstructive sleep apnea (OSA) is the most common type of sleep apnea. In OSA, breathing is obstructed when the soft tissue walls in the airway collapse, and the body's muscle tone is normally relaxed during sleep. Chronic severe OSA can lead to hypoxemia (low blood oxygen levels), sleep deprivation, and other complications, including cardiovascular complications. Furthermore, CKD has a high incidence in patients with severe OSA, including those without hypertension or diabetes. A significant positive correlation is also observed between the severity of OSA and renal impairment (see Chou et al., Nephrol. Dial. Transplant. 0: 1-6, 2011). In addition, acute hypoxia is associated with signs of proteinuria, kidney impairment, or kidney dysfunction (see Luks et al., J Am Soc Nephrol. 19:2262-2271, 2008). Therefore, OSA and hypoxia are associated with renal impairment, and OSA is considered an independent risk factor for CKD (Chou et al., above). Accordingly, certain subjects of treatment according to the methods provided herein may have OSA alone or in combination with other symptoms of CKD or renal impairment. Administration of the compounds or compositions described herein to subjects having OSA may reduce the AHI by about or at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or more.

[0309] Administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, in their pure form or in suitable pharmaceutical compositions, may be carried out by any acceptable method of administration of the drug for the same utility. Pharmaceutical compositions of the present invention may be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable carriers, diluents, or excipients, and may be formulated for pharmaceutical use in solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Conventional routes for administering such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, oral cavity, rectal, vaginal, and nasal. As used herein, the term parenteral includes, but is not limited to, subcutaneous injection, intravenous, intramuscular, intrasternal injection, or infusion techniques. Pharmaceutical compositions of the present invention are formulated so that the active ingredients contained herein are bioavailable when the compound is administered to a patient. The composition to be administered to the subject or patient will take the form of one or more dosing units; for example, a tablet may be a single dosing unit, and a container of the aerosolized compound of the present invention may contain multiple dosing units. Practical methods for pharmacopoeia such dosing forms are known or will be apparent to those skilled in the art; e.g., Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The administered composition will in any case contain a pharmaceutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, for the treatment of the disease or condition of the subject, in accordance with the teachings of the present invention.

[0310] The pharmaceutical composition of the present invention may be in solid or liquid form. In one embodiment, the carrier is fine particles, such that the composition is, for example, in the form of tablets or powders. The carrier may be, for example, an oral syrup, an injectable liquid, or a liquid formulation containing the composition, such as an aerosol useful for inhalation administration.

[0311] When intended for oral administration, the pharmaceutical composition is preferably either a solid or a liquid, and semi-solid, semi-liquid, suspension, and gel forms are included in the forms considered herein, either as a solid or a liquid.

[0312] As a solid composition for oral administration, the pharmaceutical composition may be formulated in the form of a powder, granules, compressed tablets, pills, capsules, chewing gum, wafers, or similar forms. Such a solid composition will typically contain one or more inert diluents or food carriers. In addition, one or more of the following may be present: fillers such as carboxymethylcellulose, ethylcellulose, crystalline cellulose, tragacanth gum, or gelatin; excipients such as starch, lactose, or dextrin; disintegrants such as arginine, sodium arginate, Primogel, corn starch, and similar; lubricants such as magnesium stearate or Sterotex; flow enhancers such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; flavorings such as peppermint, methyl salicylate, or orange flavor; and colorants.

[0313] When the pharmaceutical composition is in the form of a capsule, for example, a gelatin capsule, it may contain a liquid carrier such as polyethylene glycol or oil in addition to the above-mentioned substance.

[0314] The pharmaceutical composition may be in the form of a liquid, such as an elixir, syrup, emulsion, or suspension. The liquid may, as two examples, be for oral administration or for delivery by injection. When intended for oral administration, a preferred composition includes, in addition to the compound, one or more sweeteners, preservatives, colorants, and flavorings. Compositions intended for administration by injection may include one or more surfactants, preservatives, wetting agents, dispersants, suspensions, buffers, stabilizers, and isotonic agents.

[0315] The liquid pharmaceutical compositions of the present invention, whether in liquid, suspension or other similar forms, may contain one or more adjuvants: sterile diluents such as water for injection, saline, preferably physiological saline, Ringer's solution, or isotonic saline; fixing oils such as synthetic mono or diglycerides that can serve as solvents or suspension media; polyethylene glycols, glycerin, propylene glycol, or other solvents; antimicrobial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffering agents such as acetates, citrates, or phosphates; and tonic modifiers such as sodium chloride or dextrose. Parenteral formulations may be enclosed in ampoules, disposable syringes, or glass or plastic multi-dose vials. Physiological saline is a preferred adjuvant. The injectable pharmaceutical compositions are preferably sterile.

[0316] Liquid pharmaceutical compositions of the present invention intended for either parenteral or oral administration should contain an amount of the compound of the present invention such that an appropriate dosage can be obtained.

[0317] The pharmaceutical compositions of the present invention may be intended for topical administration, in which case the carrier may appropriately comprise a liquid, emulsion, ointment, or gel base. The base may comprise, for example, one or more of the following: diluents such as petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, water, and alcohol, as well as emulsions and stabilizers. Thickeners may be present in the topical pharmaceutical composition. If intended for transdermal administration, the composition may comprise a transdermal patch or an ion electrophoresis apparatus.

[0318] The pharmaceutical compositions of the present invention may be intended for rectal administration, for example, in the form of suppositories that dissolve in the rectum to release the drug. The rectal compositions may include an oily base as a suitable non-irritating excipient. Examples of such bases include, but are not limited to, lanolin, cocoa butter, and polyethylene glycol.

[0319] The pharmaceutical compositions of the present invention may contain various substances that modify the physical form of a solid or liquid drug delivery unit. For example, the composition may contain a substance that forms a coating shell around the active ingredient. The substance forming the coating shell is usually inert and can be selected from, for example, sugars, shellac, and other enteric coating agents. Alternatively, the active ingredient may be encapsulated in a gelatin capsule.

[0320] The pharmaceutical compositions of the present invention, whether solid or liquid, may contain agents that bind to the compounds of the present invention, thereby assisting in the delivery of said compounds. Suitable agents capable of acting in this capacity include monoclonal or polyclonal antibodies, proteins, or liposomes.

[0321] The pharmaceutical compositions of the present invention may consist of dosing units that can be administered as aerosols. The term aerosol is used to refer to a variety of systems ranging from colloidal to systems consisting of pressurized packaging. Delivery may be by liquefaction or compressed gas or by a suitable pump system for dispensing the active ingredient. The aerosols of the compounds of the present invention may be delivered in a single-phase, two-phase, or three-phase system for delivering the active ingredient. The delivery of the aerosols may include the necessary containers, activators, valves, sub-containers, and the like, which together may form a kit. Those skilled in the art can determine a preferred aerosol without excessive experimentation.

[0322] The pharmaceutical compositions of the present invention can be formulated by methods well known in the pharmaceutical field. For example, a pharmaceutical composition intended to be administered by injection can be formulated by mixing the compound of the present invention with sterile distilled water to produce a liquid formulation. Surfactants may be added to promote the formation of a homogeneous liquid or suspension. The surfactant is a compound that interacts non-covalently with the compound of the present invention in the aqueous delivery system to promote the dissolution or homogeneous suspension of the compound.

[0323] The compounds of the present invention, or their pharmaceutically acceptable salts, are administered in a therapeutic effect dose that will vary depending on various factors, including the activity of the specific compound used; the metabolic stability and duration of action of the compound; the patient's age, weight, general health status, sex, and diet; the method and frequency of administration; the rate of excretion; concomitant use of other drugs; the severity of a particular disorder or condition; and the patient's medical history.

[0324] In certain embodiments, the usual dosage of the substantially impermeable or substantially non-systemic bioavailable compound may be between about 0.2 mg / day and about 2 g / day, or between about 1 mg / day and about 1 g / day, or between about 5 mg and about 500 mg, or between about 10 mg and about 250 mg / day, and is administered to subjects requiring treatment.

[0325] The administration frequency of the compounds and compositions described herein may vary from once daily (QD) to twice daily (BID) or three times daily (TID), and the exact frequency of administration may vary depending on, for example, the patient's condition, the dosage, and other factors.

[0326] The compounds of the present invention, or their pharmaceutically acceptable derivatives, may be administered concurrently with, before, or after, the administration of one or more other therapeutic or bioactive agents, nutritional supplements, or any combination thereof. Such combination therapies include the administration of a single-dose formulation containing the compounds of the present invention and one or more additional activators, as well as the administration of the compounds of the present invention and each activator in its own individual-dose formulation. For example, the compounds of the present invention and other activators may be administered together to the patient in a single-dose composition, such as in tablets or capsules, or each drug administered in separate oral-dose formulations. When separate-dose formulations are used, the compounds of the present invention and one or more additional activators may be administered at essentially the same time, i.e., simultaneously, or at separately staggered time, i.e., successively; combination therapy is considered to encompass all of these regimens.

[0327] For example, in certain embodiments, the additional bioactive agent included in the pharmaceutical composition (or method) of the present invention is selected from, for example, vitamin D2 (ergocalciferol), vitamin D3 (cholecalciferol), active vitamin D (calcitriol), and active vitamin D analogs (e.g., doxelcalciferol, paricalcitol).

[0328] In other specific embodiments, the additional bioactive agents included in the pharmaceutical composition (or method) of the present invention are phosphate binders such as sevelamer (e.g., Renvela® (sevelamer carbonate), Renagel® (sevelamer hydrochloride), lanthanum carbonate (e.g., Fosrenol®), calcium carbonate (e.g., Calcichew®, Titralac®), calcium acetate (e.g., PhosLo®, Phosex®), calcium acetate / magnesium carbonate (e.g., Renepho®, OsvaRen®), MCI-196, ferric citrate (e.g., Zerenex®), iron magnesium hydroxycarbonate (e.g., Fermagate®), aluminum hydroxide (e.g., Alucaps®, Basaljel®), APS1585, SBR-759, and PA-21 and similar.

[0329] In some embodiments, the compound may act synergistically with phosphate binders, achieving a higher efficacy than the sum of the efficacy of the transport inhibitor and the efficacy of the phosphate binder administered alone. While we do not wish to be bound by theory, this synergy appears to arise from the different mechanisms of action of phosphate transport inhibitors and phosphate binders. More specifically, phosphate binders sequester free phosphate ions in the intestinal lumen, while phosphate transport inhibitors block intraepithelial transport of phosphates.

[0330] The effectiveness of phosphate binders, when measured by their biobinding capacity (the number of moles of bound phosphate ions per gram of binder), is essentially expressed by: i) the density of binding sites (i.e., the amine groups of polymeric amine substances such as Renvela® (sevelamer); or polyvalent cations such as calcium or lanthanum of Phoslo® (calcium acetate) or Phosrenol (lanthanum carbonate)); and ii) the affinity of the binding sites for phosphate ions. In particular, only the fraction of binding sites is available to other anions, such as bile acids and fatty acids, that bind to phosphates in vivo, competing for the binding sites, and therefore having lower effectiveness. Bound phosphate ions are in equilibrium with free phosphates in the intestinal lumen and are themselves subjected to vigorous pumping by phosphate transport proteins that line the epithelium. Experiments have shown that the effectiveness of intestinal phosphate absorption is remarkably high, exceeding 95% of the phosphate presented to the epithelium. Active phosphate transport is thought to reduce the concentration of free phosphate in the lumen, thus contributing to a lower binding equilibrium for phosphate binders. It is also thought that reducing enteral phosphate transport using phosphate transport inhibitors restores a higher biobinding capacity for phosphate sequesters. This synergistic effect appears even more pronounced when the contribution of active phosphate transport increases, for example, as a result of drugs that promote NaPi2b expression or vitamin D therapy.

[0331] In some embodiments, the additional bioactive agent is an inhibitor of the enteric sodium-dependent phosphate transporter (NaPi2b inhibitor). Examples of NaPi2b inhibitors can be found, for example, in International Patent Applications PCT / US2011 / 043267; PCT / US2011 / 043261; PCT / US2011 / 043232; PCT / US2011 / 043266; and PCT / US2011 / 043263; and U.S. Patent No. 8,134,015 (each of which shall be incorporated by reference to its entirety).

[0332] In certain embodiments, the additional bioactive agent is niacin or nicotinamide.

[0333] In this specification, the substituents and / or variable combinations in the illustrated formulas are permissible only if such contributions result in a stable or reasonably stable compound.

[0334] It will be understood by those skilled in the art that, in the methods described herein, the functional groups of the intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxy, amino, mercapto, and carboxylic acids. Suitable protecting groups for hydroxyl groups include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, and benzyl. Suitable protecting groups for amino, amidino, and guanidino groups include t-butoxycarbonyl and benzyloxycarbonyl. Suitable protecting groups for mercapto groups include -C(O)-R''' (wherein R'' is alkyl, aryl, or arylalkyl), p-methoxybenzyl, and trityl. Suitable protecting groups for carboxylic acids include alkyl, aryl, or arylalkyl esters. Protecting groups may be added or removed according to the standard techniques known to those skilled in the art and described herein. The use of protecting groups is described in detail in Green, TW and PGM Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As those skilled in the art will understand, the protecting group may also be a polymer, such as Wang resin, Rink resin, or 2-chlorotrityl chloride resin.

[0335] Such protective derivatives of the compounds of the present invention may not themselves possess pharmaceutically active properties, but it will be understood by those skilled in the art that they may be administered to mammals and subsequently metabolized in the body to produce the pharmaceutically active compounds of the present invention. Therefore, such derivatives may be described as "prodrugs." All prodrugs of the present invention are included within the scope of the present invention.

[0336] Furthermore, all compounds of the present invention, existing in the form of free bases or acids, can be converted to their pharmaceutically acceptable salts by treatment with appropriate inorganic or organic bases or acids, using methods known to those skilled in the art. Salts of the compounds of the present invention can be converted back to their free base or acid form by standard techniques. Definitions and Terms

[0337] "Amino" represents the -NH2 radical.

[0338] "Aminocarbonyl" represents the -C(=O)NH2 radical.

[0339] "Carboxylate" represents the -CO2H radical. "Carboxylate" represents its salt or ester.

[0340] "Cyano" represents the -CN radical.

[0341] "Hydroxy" or "hydroxyl" represents the -OH radical.

[0342] "Imino" represents the NH radical.

[0343] "Nitro" represents -NO2.

[0344] "Oxo" or "carbonyl" represents an =O radical.

[0345] "Thioxo" represents the =S radical.

[0346] "Guanidinyl" (or "guanidine") represents the -NHC (=NH)NH2 radical.

[0347] "Amidinyl" (or "amidine") represents the -C(=NH)NH2 radical.

[0348] "Phosphate" represents the -OP(=O)(OH)2 radical.

[0349] "Phosphonate" represents the -P(=O)(OH)2 radical.

[0350] "Phosphinate" represents the -PH(=O)OH radical, R a This is independently an alkyl group as defined herein.

[0351] "Sulfate" represents the -OS(=O)2OH radical.

[0352] "Sulfonate" or "hydroxysulfonyl" represents the -S(=O)2OH radical.

[0353] "Sulfinate" represents the -S(=O)OH radical.

[0354] "Sulfonyl" refers to the part containing the -SO2- group. For example, "alkylsulfonyl" or "alkylsulfone" is -SO2-R a group (in the formula, R a (where represents an alkyl group as defined herein.)

[0355] "Alkyl" refers to a group of 1 to 12 carbon atoms (C 1~12 Alkyl), preferably 1 to 8 carbon atoms (C 1~8 Alkyl) or 1 to 6 carbon atoms (C 1~6 Alkyl compounds (S) may be substituted unless otherwise specified in the specification. They may be saturated or unsaturated (i.e., containing one or more double and / or triple bonds) and bonded to the remainder of the molecule by single bonds, representing simply linear or branched hydrocarbon chain radicals consisting of carbon and hydrogen atoms (e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl, propa-1-enyl, buta-1-enyl, penta-1-enyl, penta-1,4-dienyl, ethinyl, propynyl, butynyl, pentynyl, hexynyl, etc.). Unless otherwise specified in the specification, alkyl groups may be substituted.

[0356] "Alkylene" or "alkylene chain" refers to a linear or branched divalent hydrocarbon chain consisting of carbon and hydrogen, having 1 to 12 carbon atoms, and being saturated or unsaturated (i.e., containing one or more double and / or triple bonds), linking a radical group to the molecular residue (e.g., methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, etc.). The alkylene chain is bonded to the molecular residue by single or double bonds and to the radical group by single or double bonds. The bonding sites between the alkylene chain and the molecular residue and the radical group may be via one carbon or any two carbons in the chain. Unless otherwise specified in the specification, alkylene chains may be substituted.

[0357] "alkoxy" is the formula -OR a (In the formula, R a (wherein is an alkyl radical as defined above, containing 1 to 12 carbon atoms) represents a radical. Unless otherwise specified in the specification, the alkoxy group may be substituted.

[0358] "Alkylamino" is formula -NHR a or -NR a R a (In the formula, R a This independently represents a radical of an alkyl radical (which is defined above and contains 1 to 12 carbon atoms). Unless otherwise specified in the specification, the alkylamino group may be substituted.

[0359] "Thioalkyl" is represented by formula -SR a (In the formula, R a is a radical of the alkyl radical defined above, which contains 1 to 12 carbon atoms. Unless otherwise specified in the specification, the thioalkyl group may be substituted.

[0360] "Aryl" represents a carbocyclic radical comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For the purposes of the present invention, the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring structure, which may include condensed or crosslinked ring structures. Examples of aryl radicals include, but are not limited to, aryl radicals derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluorantene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In particular, unless otherwise specified, the term "aryl" or the prefix "ar-" (as in "aralkyl") shall include aryl radicals, which may be substituted.

[0361] "Aralkill" is formula -R b -R c (In the formula, R b R is the alkylene chain defined above, c represents a radical of one or more aryl radicals as defined above (e.g., benzyl, diphenylmethyl, etc.). Unless otherwise specified in the specification, the aralkyl group may be substituted.

[0362] "Cycloalkyl" or "monocyclic ring" simply refers to a stable, non-aromatic monocyclic or polycyclic hydrocarbon radical that consists of carbon and hydrogen, has 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, may include a condensed or crosslinked ring structure, is saturated or unsaturated, and is bonded to the molecular residue by a single bond. Examples of monocyclic radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic radicals include adamantyl, norbornyl, dekalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise specified in the specification, cycloalkyl groups may be substituted.

[0363] "Cycloalkylalkyl" is defined by formula -R b -R d (In the formula, R d R is the alkylene chain defined above, g (wherein is the cycloalkyl radical defined above) represents the radical. Unless otherwise specified in the specification, the cycloalkylalkyl group may be substituted.

[0364] "Condensation" refers to any of the ring structures described herein that are condensed into the current ring structure of the compound of the present invention. When the condensed ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the current ring structure that becomes part of the condensed heterocyclyl ring or the condensed heteroaryl ring may be substituted with a nitrogen atom.

[0365] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodine.

[0366] "Haloalkyl" represents an alkyl radical defined above that is substituted with one or more halo radicals defined above (e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.). Unless otherwise specified in the specification, haloalkyls may be substituted.

[0367] "Heterocyclyl" or "heterocyclic" represents a stable 3- to 18-membered non-aromatic ring radical consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In this specification, unless otherwise specified, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring structure which may include condensed or bridging ring structures; and the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical may be oxidized; the nitrogen atom may be quaternized; and the heterocyclyl radical may be partially or completely saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanil, thienyl[1,3]dithianil, decahydroisoquinolyl, imidazolinil, imidazolidinil, isothiazolidinil, morpholinil, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, oxazolidinil, piperidinil, piperazinil, 4-piperidonyl, pyrrolidinil, pyrazolidinil, quinuclidinil, thiazolidinil, tetrahydrofuryl, trithianil, tetrahydropyranil, thiomorpholinil, thiamorpholinil, 1-oxo-thiomorpholinil, and 1,1-dioxo-thiomorpholinil. Unless otherwise specified in the specification, heterocyclyl groups may be substituted.

[0368] "N-heterocyclyl" represents the heterocyclyl radical defined above, which contains at least one nitrogen atom, and the bond between the heterocyclyl radical and the rest of the molecule is due to the nitrogen atom in the heterocyclyl radical. Unless otherwise specified in the specification, the N-heterocyclyl group may be substituted.

[0369] "Heterocyclylalkyl" is a compound of formulas -R b -R e (In the formula, R b R is the alkylene chain defined above, e(where is the heterocyclyl radical as defined above), and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may bond with the alkyl radical at the nitrogen atom. Unless otherwise specified in the specification, the heterocyclylalkyl group may be substituted.

[0370] "Heteroaryl" represents a 5- to 14-membered ring structure radical comprising a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. For the purposes of the present invention, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring structure which may include a condensed or bridging ring structure; and the nitrogen, carbon, or sulfur atom in the heteroaryl radical may be oxidized; and the nitrogen atom may be quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6 ]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranil, dibenzothiophenyl, furanil, furanonil, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolyl, indolidinyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranil, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyridinyl, 1-oxidepyridazinyl, 1 Examples include, but are not limited to, phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified in the specification, heteroaryl groups may be substituted.

[0371] "N-heteroaryl" represents the heteroaryl radical defined above, which contains at least one nitrogen atom, and the bond between the heteroaryl radical and the molecular residue is due to the nitrogen atom in the heteroaryl radical. Unless otherwise specified in the specification, the N-heteroaryl group may be substituted.

[0372] "Heteroarylalkyl" is a compound of the formula -R b -R f (In the formula, R b R is the alkylene chain defined above, f (wherein is the heteroaryl radical defined above) represents a radical. In this specification, unless otherwise specified, heteroarylalkyl groups may be substituted.

[0373] As used herein, the term “substituting” means that at least one hydrogen atom is replaced, but is not limited to: halogen atoms such as F, Cl, Br, and I; oxygen at...

Claims

1. A method for inhibiting phosphate uptake in the gastrointestinal tract of a patient requiring phosphate reduction, comprising administering to the patient, via enteral, a compound that, when administered to the patient, is substantially active in binding to NHE3 and inhibiting the transport of phosphate ions (Pi) within it in the gastrointestinal tract, and is substantially not systemically bioavailable.

2. The aforementioned compound has the structure of formula (X): 【Chemistry 1】 (In the formula, NHE is, 【Chemistry 2】 And; L is a polyalkylene glycol linker; n is 2; and The core is, 【Transformation 3】 (Selected from) The method according to claim 1, wherein the material is a compound having, or a pharmaceutically acceptable salt thereof.

3. The method according to claim 2, wherein the polyalkylene glycol linker is polyethylene glycol.

4. The aforementioned compound, 【Chemistry 4】 The method according to any one of claims 1 to 3, wherein the salt is pharmaceutically acceptable or a pharmaceutically acceptable salt thereof.

5. The aforementioned pharmaceutically acceptable salt is 【Transformation 5】 The method according to claim 4.

6. The method according to claim 1, wherein the compound is a compound from Table E3 or Table E4, or a pharmaceutically acceptable salt thereof.

7. The method according to any one of claims 1 to 6, wherein the compound is a persistent inhibitor of NHE3-mediated antiports of sodium ions and hydrogen ions.

8. Sustained inhibition is characterized by the time-dependent inhibitory activity of the compound in an in vitro inhibition assay of NHE3-mediated antiports of sodium and hydrogen ions, and under favorable conditions (pIC). ５０ｐｒｏｍｐ ) pIC of the compound below ５０ However, the persistence conditions (pIC ５０ｐｅｒｓ ) pIC of the compound below ５０ The method according to claim 7 is substantially equivalent to the method described above.

9. The following compounds 【Transformation 6】 A method for treating hyperphosphatemia in a subject requiring such treatment, comprising administering to the subject an effective amount of a pharmaceutically acceptable salt thereof.

10. The aforementioned pharmaceutically acceptable salt is 【Transformation 7】 The method according to claim 9.

11. The method according to any one of claims 1 to 10, wherein the method is selected from: a method for treating hyperphosphatemia, which may be postprandial hyperphosphatemia; a method for treating renal disease, which may be chronic kidney disease (CKD) or end-stage renal disease (ESRD); a method for lowering serum creatinine levels; a method for treating proteinuria; a method for delaying the timing of renal transplantation therapy (RRT), which may be dialysis; a method for lowering FGF23 levels; a method for reducing the effect of active vitamin D on hyperphosphatemia; a method for attenuating hyperparathyroidism, which may be secondary hyperparathyroidism; a method for reducing serum parathyroid hormone (PTH); a method for reducing interdialysis weight gain (IDWG); a method for improving endothelial cell dysfunction, which may be induced by postprandial serum phosphate; a method for reducing vascular calcification, which may be intimal localized vascular calcification; a method for reducing urinary phosphite; a method for normalizing serum phosphate levels; a method for reducing phosphate load in elderly patients; a method for reducing dietary phosphate intake; a method for reducing renal hypertrophy; a method for reducing cardiac hypertrophy; and a method for treating obstructive sleep apnea.

12. The compound is of formula (I) or (IX): 【Transformation 8】 (In the formula, NHE is an NHE-bonded small molecule comprising (i) a heteroatom-containing moiety, and (ii) a cyclic or heterocyclic skeleton or support moiety directly or indirectly bonded thereto, wherein the heteroatom-containing moiety is selected from a substituted guanidinyl moiety and a substituted heterocyclic moiety that may condense with the skeleton or support moiety to form a condensed bicyclic structure; and Z is a portion having at least one site for binding to an NHE-binding small molecule, and the resulting NHE-Z molecule has overall physicochemical properties that make it substantially impermeable or substantially non-systemic bioavailable; and E is an integer with a value of 1 or greater. The method according to any one of claims 1, 7, 8, or 11, having the structure of [the specified structure].

13. The compound is an oligomer, dendrimer, or polymer, and further, Z is a core portion having two or more sites that are directly or indirectly bound to a plurality of NHE-binding small molecules by a linking portion L, and the compound is of formula (X): 【Chemistry 9】 (In the formula, L is a bond or linker that connects the core and the NHE-binding small molecule, n is an integer of 2 or more, and each NHE-binding small molecule may be the same or different from one another.) The method according to claim 12, having the structure.

14. The aforementioned NHE-bound small molecule is given by formula (IV): 【Chemistry 10】 or its stereoisomers, prodrugs, or pharmaceutically acceptable salts. (In the formula: Each R １ 、R ２ 、R ３ 、R ５ and R ９ are, independently, H, halogen, -NR ７ (CO)R ８ 、-(CO)NR ７ R ８ 、-SO ２ -NR ７ R ８ 、-NR ７ SO ２ R ８ 、-NR ７ R ８ 、-OR ７ 、-SR ７ 、-O(CO)NR ７ R ８ 、-NR ７ (CO)OR ８ 、and -NR ７ SO ２ NR ８ selected from, R ７ and R ８ are, independently, H or a bond that connects the NHE-binding small molecule and L, provided that at least one is a bond that connects the NHE-binding small molecule and L; R ４ H, C １ ~C ７ Selected from alkyl, or a bond linking the NHE-bonded small molecule and L; R ６ It does not exist, or H and C １ ~C ７ Selected from alkyl groups; and Ar1 and Ar2 are independently aromatic rings or heterocyclic aromatic rings. The method according to claim 13, having the structure.

15. The aforementioned compound has the following structural formula (I-H): 【Chemistry 11】 or its stereoisomer, prodrug, or pharmaceutically acceptable salt. (In the formula: (a) n is an integer greater than or equal to 2; (b) The core is a core portion having two or more sites that bind to two or more NHE-binding small molecule portions; (c) L is a bond or linker connecting the core portion and two or more NHE-bonded small molecule portions; and (d) NHE has the following structural formula (XI-H): 【Chemistry 12】 (In the formula: B is selected from the group consisting of aryls and heterocyclines; Each R ５ These are, independently, hydrogen, halogen, and possibly substituted C １～４ Alkyl, optionally substituted C １～４ Alkoxy, possibly substituted C １～４ Thioalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxyl, oxo, cyano, nitro, -NR ７ R ８ , -NR ７ C(=O)R ８ , -NR ７ C (=O) OR ８ , -NR ７ C(=O)NR ８ R ９ , -NR ７ SO ２ R ８ , -NR ７ S(O) ２ NR ８ R ９ , -C (=O) OR ７ , -C(=O)R ７ , -C(=O)NR ７ R ８ , -S(O) １～２ R ７ , and -SO ２ NR ７ R ８ Selected from the group consisting of R ７ , R ８ , and R ９ These are, independently, hydrogen, C １～４ Selected from the group consisting of alkyl groups or bonds connecting the NHE-bonded small molecule portion and L, wherein at least one of them is a bond connecting the NHE-bonded small molecule portion and L; R ３ and R ４ These are, independently, hydrogen, and C which may be substituted. １～４ Selected from the group consisting of alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; or R ３ and R ４ They, together with the nitrogen to which they bind, form a substituted 4- to 8-membered heterocycline; and Each R １ These are, independently, hydrogen, halogen, and possibly substituted C １～６ Alkyl and optionally substituted C １～６ (Selected from the group consisting of alkoxys) (This is an NHE-binding small molecule portion.) The method according to any one of claims 1, 7, 8, or 11, comprising

16. The NHE-binding small molecule portion has the following structural formula (XII-H): 【Chemistry 13】 (In the formula: Each R ３ and R ４ These are, independently, hydrogen and possibly substituted C １～４ R selected from the group consisting of alkyl groups, or together with the nitrogen to which they are bonded. ３ and R ４ However, it may form a substituted 4- to 8-membered heterocycline; Each R １ These are, independently, hydrogen, halogen, and C １～６ Alkyl and C １～６ Selected from the group consisting of haloalkyls; and R ５ is selected from the group consisting of -SO ２ -NR ７ - and -NHC(=O)NH-, and R ７ is hydrogen or C １～４ alkyl) The method according to claim 15, comprising:

17. The above compound has the following structural formula (I-I): 【Chemistry 14】 or its stereoisomer, prodrug, or pharmaceutically acceptable salt. (In the formula: (a) NHE has the following structural formula (A-I): 【Chemistry 15】 (In the formula: Each R １ 、R ２ 、R ３ 、R ５ and R ９ is independently selected from H, halogen, -NR ７ (CO)R ８ 、-(CO)NR ７ R ８ 、-SO ２ -NR ７ R ８ 、-NR ７ SO ２ R ８ 、-NR ７ R ８ 、-OR ７ 、-SR ７ 、-O(CO)NR ７ R ８ 、-NR ７ (CO)OR ８ 、and -NR ７ SO ２ NR ８ and is selected from R ７ and R ８ is independently selected from H, C １～６ alkyl, C １～６ alkyl-OH or a bond that connects the NHE-binding small molecule and L, provided that at least one is a bond that connects the NHE-binding small molecule and L; R ４ H, C １ ~C ７ Selected from the group consisting of alkyl or a bond connecting the NHE bonded small molecule and L; R ６ It does not exist, or H and C １ ~C ７ Selected from alkyl groups; and Ar1 and Ar2 are independently aromatic rings or heterocyclic aromatic rings. It is an NHE-binding small molecule portion having; (b) The core has the following structural formula (B-I): 【Chemistry 16】 (In the formula: X is C(X １ ), N and N(C １～６ Selected from alkyl; X １ is hydrogen, optionally substituted alkyl, -NX ａ X ｂ , -NO ２ , -NX ｃ -C(=O)-NX ｃ -X ａ -C(=O)NX ｃ -X ａ , -NX ｃ -C(=O)-X ａ , -NX ｃ -SO ２ -X ａ -C(=O)-X ａ and -OX ａ Selected from, Each X ａ and X ｂ independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; Y is C １～６ It is alkylene; Z is X is CX １ When that is the case, -NZ ａ -C(=O)-NZ ａ -, -C(=O)NZ ａ -, -NZ ａ Selected from -C(=O)- and heteroaryls; Z is when X is N or N(C) １～６ When it is alkyl, -NZ ａ -C(=O)-NZ ａ -, -NZ ａ Selected from -C(=O)- and heteroaryls; and Each X ｃ and Z ａ These are, independently, hydrogen and C １～６ (Selected from alkyl groups) It is a core part having; and (c) L is a bond or linker that connects the core portion and the NHE-bonded small molecule portion. The method according to any one of claims 1, 7, 8, or 11, comprising

18. The above compound has the following structural formula (II): 【Chemistry 17】 or its stereoisomer, prodrug, or pharmaceutically acceptable salt. (In the formula: (a) NHE has the following structural formula (A-I): [Chemistry 18] (In the formula: Each R １ , R ２ , R ３ , R ５ and R ９ These are independently H, halogen, and -NR ７ (CO)R ８ ,-(CO)NR ７ R ８ , -SO ２ -NR ７ R ８ , -NR ７ SO ２ R ８ , -NR ７ R ８ , -OR ７ ,-SR ７ , -O(CO)NR ７ R ８ , -NR ７ (CO)OR ８ , and -NR ７ SO ２ NR ８ Selected from, R ７ and R ８ H and C are independent of each other. １～６ Alkyl, C １～６ A bond is selected from the group consisting of an alkyl-OH or a bond connecting the NHE-bonded small molecule and L, wherein at least one of the bonds is a bond connecting the NHE-bonded small molecule and L; R ４ H, C １ ~C ７ Selected from the group consisting of alkyl or a bond connecting the NHE bonded small molecule and L; R ６ It does not exist, or H and C １ ~C ７ Selected from alkyl groups; and Ar1 and Ar2 are independently aromatic rings or heterocyclic aromatic rings. It is an NHE-binding small molecule portion having; (b) The core has the following structural formula (C-I): 【Chemistry 19】 (In the formula: W is selected from alkylene, polyalkylene glycol, -C(=O)-NH-(alkylene)-NH-C(=O)-, -C(=O)-NH-(polyalkylene glycol)-NH-C(=O)-, -C(=O)-(alkylene)-C(=O)-, -C(=O)-(polyalkylene glycol)-C(=O)-, and cycloalkyl. X is N; Y is C １～６ It is alkylene; Z is -NZ ａ -C(=O)-NZ ａ -, -C(=O)NZ ａ -, -NZ ａ Selected from -C(=O)- and heteroaryls; Each Z ａ These are, independently, hydrogen and C １～６ (Selected from alkyl groups) It is a core part having; and (c) L is a bond or linker that connects the core portion and the NHE-binding small molecule. The method according to any one of claims 1, 7, 8, or 11, comprising

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