CN112679427A - Tetrahydroisoquinoline derivatives, preparation method and medical application thereof - Google Patents

Abstract

The disclosure relates to tetrahydroisoquinoline derivatives, a preparation method thereof and application thereof in medicine. Specifically, the disclosure relates to tetrahydroisoquinoline derivatives shown in a general formula (I) and pharmaceutically acceptable salts thereof, a preparation method thereof and application thereof as NHE3 inhibitors, in particular to application thereof as therapeutic agents of diseases related to fluid retention or salt overload or gastrointestinal tract diseases, wherein the definition of each substituent in the general formula (I) is the same as that in the specification.

Description

Tetrahydroisoquinoline derivatives, preparation method and medical application thereof

Technical Field

The disclosure belongs to the field of medicines, and relates to a tetrahydroisoquinoline derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application of the derivative as an NHE3 inhibitor, in particular to a therapeutic agent for diseases related to fluid retention or salt overload or gastrointestinal tract diseases.

Background

When cardiac insufficiency prevents proper perfusion of the surrounding tissues, a clinical syndrome of chf (systemic heart failure) occurs. In CHF patients, neurohumoral compensation mechanisms are activated in an attempt to maintain normal circulation. As the blood volume in the heart increases, the cardiac output increases proportionally to the extent that the heart cannot relax further. In a failing heart, contractility is reduced, allowing the heart to operate at higher volumes and higher filling pressures to maintain output. The filling pressure eventually increases to a level that allows body fluids to leak into the lungs and cause congestive symptoms (e.g., edema, breathlessness). All of these symptoms are associated with fluid and salt retention, and this long-term fluid and salt overload further contributes to the progression of the disease.

Patients with end stage renal disease ("ESRD"; i.e., stage 5 chronic renal failure) must undergo hemodialysis treatment three times a week. Dialysis can be used to remove uremic toxins and also to adjust the dynamic balance of salts and body fluids. However, when a patient is over dialyzed, symptomatic intradialytic hypotension occurs. About 15% to 25% of the ESRD population exhibit this hypotension. As in the case of hypertensive and CHF patients, ESRD patients recommend dietary restrictions specifically for salt and body fluids, but this restriction is not well followed due to dietary habits.

The cause of essential hypertension is not clear at present, but several observations suggest that the kidney is a major contributing factor. Essential hypertension is a typical example of a complex multifactorial and polygenic trait. All of these monogenic hypertensive syndromes are in fact limited to mutations in genes involved in increased function of the various components of the renin-angiotensin-aldosterone system, leading to excessive sodium retention in the kidneys. Broadly, these syndromes are characterized by an increase in sodium reabsorption in the kidney caused by a primary defect in the sodium transport system or stimulation of mineralocorticoid receptor activity.

Irritable Bowel Syndrome (IBS) is a common gastrointestinal disorder associated with altered motility, secretion and visceral sensation. A variety of clinical symptoms may characterize the condition, including the number and shape of bowel movements, abdominal pain, and abdominal distension. The pathophysiology of IBS is not fully understood, visceral hypersensitivity is generally considered to be an important cause, and it has been suggested that even biomarkers can be used to distinguish IBS from other causes of abdominal pain. Other treatment options currently prescribed or used in clinical studies for treating related gastrointestinal disorders (including OIC) such as IBS, chronic constipation, and the like include (but are not limited to): serotonin receptor ligands, chloride channel activators, opioid receptor antagonists, guanylate cyclase receptor agonists, and nucleotide P2Y (2) receptor agonists. These treatments are either less than ideal or ineffective in some patients; or may cause long-term side effects; or may generate a dependency.

There are two main mechanisms of sodium absorption, charge neutrality and rawAnd (4) electrotransport. Electrotransport is performed by the epithelial sodium channel ("EnaC"). The charge-neutral transport is essentially achieved by Sodium hydrogen exchanger (NHE). Cells rely primarily on NHE on the plasma membrane to regulate the homeostasis of intracellular pH, affecting transmembrane transport of intracellular and extracellular ions, cellular volume, osmolarity, etc. To date, 9 subtypes of NHE (NHE 1-NHE 9) are known, which together form the membrane-exchange protein family. Human NHE3, encoded by the SLC9A3 gene, is the third discovered subtype of NEP, is predominantly present in the basement membrane of epithelial cells, has high expression in kidney and gastrointestinal tissues, and is primarily responsible for Na uptake by these two organ systems. NHE3 is also present in ovaries, thymus, prostate, etc. NHE3 consists of 831 amino acid residues, roughly divided into two domains: the N terminal consists of 12 transmembrane regions consisting of 1-454 amino acid residues and contains H⁺The receptive region, which mediates ion exchange, is also the most fixed sequence of NHE; the C end consists of 455-831 amino acid residues, is an intracellular activity regulating region, and realizes the regulation of the activity of NHE3 by connecting a cytoskeleton and a regulating factor. Under normal physiological conditions, NHE3 was expressed at an equimolecular ratio to extracellular Na⁺And intracellular H⁺And performing electric neutral transmembrane exchange to adjust the dynamic balance of the pH value in the cell. The ion passage through NHE3 is mainly composed of Na⁺Concentration gradient driven, while Na⁺Gradient is formed by Na⁺-K⁺-ATPase provides energy maintenance. When the chemical gradient is reversed, NHE3 may behave in the reverse direction (i.e., intracellular Na)⁺Exchange of extracellular H⁺). Thus, according to extracellular Na⁺The kinetics of ion transport for NHE3 exist for different concentration gradients with a simple michaelis equation: i.e. a simple mie constant. When extracellular Na⁺When the Hill coefficient of concentration is 1,1 Na is out of the cell⁺The binding site is exposed. Despite the high extracellular concentration of Li⁺And H⁺Can be combined with Na⁺Compete for the binding site, but NHE3 selectively preferentially binds Na⁺. And H in the cell⁺The transport is complicated when intracellular H⁺H when the Hill coefficient of concentration is 2⁺Synergistic activation of two H's in NHE3 cells⁺Binding site: one is H⁺The metastatic site and the other, an allosteric modification binding site, called the "set point", play a role in acute regulation of NHE 3. Downregulation of the above NHE3 binding site corrects for excessive cellular alkalization.

Patent applications for NHE3 inhibitors that have been disclosed so far include WO2003053434, WO2009006066, WO2010025856, WO2010078449, WO2018129557 and the like.

NHE3 plays an important role in salt reabsorption and maintenance of body fluid levels. However, there has been very little research to date on NHE inhibitors that are not absorbed (i.e. not systemic) and target the gastrointestinal tract. These inhibitors are useful for treating disorders associated with fluid retention and salt overload or gastrointestinal disorders. Despite advances in this field, there remains a need in the art for novel compounds that can be used in disorders associated with fluid retention and salt overload or gastrointestinal disorders.

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R¹、R²、R³or R⁴The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, cyano, nitro, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy;

provided that R is¹、R²、R³Or R⁴At least one is an alkyl group;

R⁵selected from the group consisting of hydrogen atoms, alkyl groups and cycloalkyl groups;

R⁶the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, cyano, nitro, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and cycloalkyl;

l is an alkylene group;

d is selected from

m is 1,2,3,4 or 5; and is

n is 0,1, 2,3 or 4.

In a preferred embodiment of the present disclosure, the compound of formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II) or (III), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein: D. l, m, n, R¹～R⁶As defined in formula (I); and provided that R is¹、R²、R³Or R⁴At least one of which is an alkyl group.

In another preferred embodiment of the present disclosure, the compound of formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (IV) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein: D. l, m, n, R²、R⁴～R⁶As defined in formula (I); and provided that R is²Or R⁴At least one of which is an alkyl group.

In another preferred embodiment of the present disclosure, the compound of formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (V) or (VI), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein: D. l, m, n, R²、R⁴～R⁶As defined in formula (I); and provided that R is²Or R⁴At least one of which is an alkyl group.

In another preferred embodiment of the present disclosure, a compound of formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is-CH₂-CH₂-。

In another preferred embodiment of the present disclosure, the compound of formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein m is 3.

In another preferred embodiment of the present disclosure, a compound of formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein D is selected from the group consisting of:

preferably, it is

In another preferred embodiment of the present disclosure, a compound of formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is¹And R³Is a hydrogen atom.

In another preferred embodiment of the present disclosure, a compound of formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is²And R⁴Each independently selected from halogen or alkyl; and provided that R is²And R⁴At least one of which is an alkyl group.

In another preferred embodiment of the present disclosure, a compound of formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is²Is alkyl or halogen, and R⁴Is an alkyl group; or R²Is alkyl, and R⁴Is halogen.

In another preferred embodiment of the present disclosure, a compound of formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is²Is alkyl, and R⁴Is halogen; preferably R²Is methyl, and R⁴Is chlorine.

In another preferred embodiment of the present disclosure, a compound of formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁵Is an alkyl group, preferably a methyl group.

In another preferred embodiment of the present disclosure, the compound of formula (I) according to the present disclosure or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereofOr a pharmaceutically acceptable salt thereof, wherein R⁶Is a hydrogen atom.

Typical compounds of the present disclosure include, but are not limited to:

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

Another aspect of the present disclosure relates to a compound of formula (I-a) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, useful as an intermediate in the preparation of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R¹、R²、R³or R⁴The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, cyano, nitro, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy;

provided that R is¹、R²、R³Or R⁴At least one is an alkyl group;

R⁵selected from the group consisting of hydrogen atoms, alkyl groups and cycloalkyl groups;

R⁶the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, cyano, nitro, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and cycloalkyl;

l is an alkylene group;

m is 1,2,3,4 or 5; and is

n is 0,1, 2,3 or 4.

In a preferred embodiment, the compound of formula (I-a) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II-a) or formula (III-a), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein: l, m, n, R¹～R⁶As defined in formula (I-A); and provided that R is¹、R²、R³Or R⁴At least one of which is an alkyl group.

In another preferred embodiment of the present disclosure, the compound represented by the general formula (I-a) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IV-a), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein: l, m, n, R²、R⁴～R⁶As defined in formula (I-A); and provided that R is²Or R⁴At least one of which is an alkyl group.

In another preferred embodiment of the present disclosure, the compound represented by the general formula (I-a) according to the present disclosure or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (V-a) or general formula (VI-a) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein: l, m, n, R²、R⁴～R⁶As defined in formula (I-A); and provided that R is²Or R⁴At least one of which is an alkyl group.

Typical compounds of the general formula (I-A) of the present disclosure include, but are not limited to:

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

a compound of formula (I-A) or a pharmaceutically acceptable salt thereof with R^aO-D-OR^aReacting to obtain a compound of a general formula (I);

wherein: the pharmaceutically acceptable salt of the compound of formula (I-A) is preferably the hydrochloride salt; r^aIs a hydrogen atom or an alkyl group, preferably a hydrogen atom; D. l, m, n, R¹～R⁶As defined in formula (I); and provided that R is¹、R²、R³Or R⁴At least one of which is an alkyl group.

Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (II) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

a compound of the general formula (II-A) or a pharmaceutically acceptable salt thereof with R^aO-D-OR^aReacting to obtain a compound of a general formula (II);

wherein: the pharmaceutically acceptable salt of the compound of formula (II-A) is preferably the hydrochloride salt; r^aIs a hydrogen atom or an alkyl group, preferably a hydrogen atom; D. l, m, n, R¹～R⁶As defined in formula (II); and provided that R is¹、R²、R³Or R⁴At least one of which is an alkyl group.

Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (III) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

a compound of the general formula (III-A) or a pharmaceutically acceptable salt thereof with R^aO-D-OR^aReacting to obtain a compound of a general formula (III);

wherein: the pharmaceutically acceptable salt of the compound of formula (III-A) is preferably the hydrochloride; r^aIs a hydrogen atom or an alkyl group, preferably a hydrogen atom; D. l, m, n, R¹～R⁶As defined in formula (III); and provided that R is¹、R²、R³Or R⁴At least one of which is an alkyl group.

Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (IV) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

a compound of the general formula (IV-A) or a pharmaceutically acceptable salt thereof with R^aO-D-OR^aReacting to obtain a compound of a general formula (IV);

wherein: the pharmaceutically acceptable salt of the compound of formula (IV-A) is preferably the hydrochloride salt; r^aIs a hydrogen atom or an alkyl group, preferably a hydrogen atom; D. l, m, n, R²、R⁴～R⁶As defined in formula (IV); and provided that R is²Or R⁴At least one of which is an alkyl group.

Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (V) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

a compound of the formula (V-A) or a pharmaceutically acceptable salt thereof with R^aO-D-OR^aReacting to obtain a compound of a general formula (V);

wherein: the pharmaceutically acceptable salt of the compound of formula (V-A) is preferably the hydrochloride salt; r^aIs a hydrogen atom or an alkyl group, preferably a hydrogen atom; D. l, m, n, R²、R⁴～R⁶As defined in formula (V); and provided that R is²Or R⁴At least one of which is an alkyl group.

Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (VI) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

a compound of the general formula (VI-A) or a pharmaceutically acceptable salt thereof with R^aO-D-OR^aObtaining the compound of the general formula (VI) after reaction;

wherein: the pharmaceutically acceptable salt of the compound of formula (VI-A) is preferably the hydrochloride salt; r^aIs a hydrogen atom or an alkyl group, preferably a hydrogen atom; D. l, m, n, R²、R⁴～R⁶As defined in formula (VI); and provided that R is²Or R⁴At least one of which is an alkyl group.

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The present disclosure further relates to the use of a compound of general formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for inhibiting NHE 3-mediated sodium/hydrogen ion exchange.

The present disclosure further relates to the use of a compound of general formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment of a disorder associated with fluid retention or salt overload.

The present disclosure further relates to the use of a compound of formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment of heart failure (e.g., congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention, hypertension, edema, hyperphosphatemia, hypernatremia, gastrointestinal disorders or pain associated with gastrointestinal disorders, wherein the gastrointestinal disorders are selected from irritable bowel syndrome, gastrointestinal dyskinesia, constipation, functional gastrointestinal disorders, chronic intestinal pseudo-obstruction, pseudocolon pseudoobstruction, crohn's disease, ulcerative colitis, or inflammatory bowel disease, or the like, wherein the irritable bowel syndrome is selected from constipation-predominant irritable bowel syndrome (C-IBS), diarrhea-predominant irritable bowel syndrome (D-IBS), and the like, wherein the constipation is selected from chronic constipation, chronic constipation in cystic fibrosis patients, chronic constipation in chronic kidney disease patients, idiopathic constipation (e.g., functional constipation or slow transit constipation), post-operative constipation (e.g., post-operative ileus), constipation associated with neurological, metabolic, or endocrine disorders (e.g., diabetes, kidney failure, hypothyroidism, hyperthyroidism, hypocalcemia, multiple sclerosis, Parkinson's disease, spinal cord injury, neurofibromatosis, autonomic neuropathy, Chagas ' disease, Hirschsprung's disease, cystic fibrosis, and the like), constipation associated with the use of a therapeutic agent (e.g., by the use of an analgesic agent (e.g., an opioid drug), Constipation caused by drugs such as calcium tonics, antihypertensives, anticonvulsants, antidepressants, antispasmodics, antipsychotics, etc.), and the like. Preferably in the manufacture of a medicament for the treatment of heart failure, chronic kidney disease, end stage renal disease, irritable bowel syndrome or constipation.

The present disclosure also relates to a method of inhibiting NHE 3-mediated sodium/hydrogen ion exchange comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) according to the present disclosure or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method of treating a disorder associated with fluid retention or salt overload comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) according to the present disclosure or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

In other words, the present disclosure relates to a method of treating heart failure (e.g., congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention, hypertension, edema, hyperphosphatemia, hypernatremia, gastrointestinal disorders, or pain associated with gastrointestinal disorders, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the gastrointestinal disorder is selected from irritable bowel syndrome, gastrointestinal dyskinesia, constipation, functional gastrointestinal disorder, chronic intestinal pseudo-obstruction, crohn's disease, irritable bowel syndrome, chronic kidney disease, liver disease, peroxisome proliferator-induced fluid retention, hypertension, edema, hyperphosphatemia, hyper, Ulcerative colitis, inflammatory bowel disease, or the like, wherein the irritable bowel syndrome is selected from constipation-predominant irritable bowel syndrome (C-IBS), diarrhea-predominant irritable bowel syndrome (D-IBS), or the like, wherein the constipation is selected from chronic constipation, chronic constipation experienced by cystic fibrosis patients, chronic constipation experienced by chronic kidney disease patients, idiopathic constipation (e.g., functional constipation or slow transit constipation), post-operative constipation (e.g., post-operative ileus), constipation associated with neurological, metabolic, or endocrine disorders (e.g., diabetes, kidney failure, hypothyroidism, hyperthyroidism, hypocalcemia, multiple sclerosis, Parkinson's disease, spinal cord injury, neurofibromatosis, autonomic neuropathy, Chagas ' disease, Hirschsprung's disease, or cystic fibrosis), constipation associated with the use of a therapeutic agent (e.g., by the use of an analgesic (e.g., an opioid drug), Constipation caused by drugs such as calcium tonics, antihypertensives, anticonvulsants, antidepressants, antispasmodics, antipsychotics, etc.), and the like.

The present disclosure also relates to a compound represented by general formula (I) according to the present disclosure, or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, as a medicament for inhibiting NHE 3-mediated sodium/hydrogen ion exchange.

The disclosure also relates to compounds of general formula (I) according to the present disclosure or tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, as medicaments for the treatment of disorders associated with fluid retention or salt overload.

The present disclosure also relates to a compound represented by the general formula (I) according to the present disclosure or its tautomer, meso-isomer, racemic body, enantiomer, diastereomer or mixture thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, as a medicament for treating heart failure (e.g., congestive heart failure), chronic kidney disease, end-stage kidney disease, liver disease, peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention, hypertension, edema, hyperphosphatemia, hypernatremia, gastrointestinal disorders or pain associated with gastrointestinal disorders, wherein the gastrointestinal disorders are selected from irritable bowel syndrome, gastrointestinal dyskinesia, constipation, functional gastrointestinal disorders, chronic intestinal pseudo-obstruction, colonic pseudo-obstruction, crohn's disease, ulcerative colitis, inflammatory bowel disease, or the like, wherein the irritable bowel syndrome is selected from constipation-type irritable bowel syndrome (C-IBS) or diarrhea-type intestinal bowel disease Irritable syndrome (D-IBS), and the like, wherein the constipation is selected from chronic constipation, chronic constipation occurring in patients with cystic fibrosis, chronic constipation occurring in patients with chronic kidney disease, idiopathic constipation (e.g., functional constipation or slow transit constipation), postoperative constipation (e.g., postoperative ileus), constipation associated with neurological, metabolic, or endocrine disorders (e.g., diabetes, kidney failure, hypothyroidism, hyperthyroidism, hypocalcemia, multiple sclerosis, parkinson's disease, spinal cord injury, neurofibromatosis, autonomic neuropathy, chagas ' disease, herschiprostrate's disease, cystic fibrosis, or the like), constipation associated with the use of therapeutic agents (e.g., constipation resulting from the use of drugs such as analgesics (e.g., opioids), calcium supplements, antihypertensives, anticonvulsants, antidepressants, antispasmodics, or antipsychotics), or the like).

The active compound may be formulated so as to be suitable for administration by any suitable route, preferably in unit dose form, or in such a way that the patient may self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid.

The dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound. However, as a general guide, a suitable unit dose may be 0.1 to 1000 mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl paraben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are illustrative of the examples given above. Other excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated to form a microemulsion by adding to a mixture of water and glycerol. The injection solution or microemulsion may be injected into the bloodstream of a patient by local bulk injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

The pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health condition of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, and the like; in addition, the optimal treatment regimen, such as the mode of treatment, the daily amount of compound (I) of the formula or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Detailed description of the invention

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms (e.g., 1,2,3,4, 5, 6, 7, 8, 9, 10, 11, and 12), more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently optionally substituted with one or more substituents selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkylene group"refers to a saturated straight or branched chain aliphatic hydrocarbon group having 2 residues derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkylene group containing 1 to 12 carbon atoms (e.g., 1,2,3,4, 5, 6, 7, 8, 9, 10, 11, and 12), more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH)₂-), 1-ethylidene (-CH (CH)₃) -), 1, 2-ethylene (-CH)₂CH₂-), 1-propylene (-CH (CH)₂CH₃) -), 1, 2-propylene (-CH)₂CH(CH₃) -), 1, 3-propylene (-CH)₂CH₂CH₂-) 1, 4-butylene (-CH₂CH₂CH₂CH₂-) and the like. The alkylene group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently optionally substituted with one or more substituents selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent group is preferably one or more groups substituted with one or more substituents independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (e.g., 3,4,5, 6, 7, 8, 9, 10, 11, and 12), preferably 3 to 8 carbon atoms, more preferably 4 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered mono spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes a cycloalkyl ring (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring as described above, wherein the rings attached to the parent structure are cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like; preferably phenyl and cyclopentyl, tetrahydronaphthyl.

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably independently optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O)₂But does not include the ring moiety of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms (e.g., 3,4,5, 6, 7, 8, 9, 10, 11 and 12), of which 1 to 4 are heteroatoms (e.g., 1,2,3 and 4); more preferably 3 to 8 ring atoms, wherein 1-3 is a heteroatom; more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1, 2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to 5-to 20-membered polycyclic heterocyclic groups in which one atom (referred to as the spiro atom) is shared between monocyclic rings, one of which isOr a plurality of ring atoms are selected from nitrogen, oxygen, sulfur, S (O) or S (O)₂The remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, and one or more of the rings may contain one or more double bonds in which one or more of the ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O)₂The remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-to 5-membered, 5-to 6-membered or 6-to 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms which are not directly attached, which may contain one or more double bonds in which one or more ring atoms is selected from nitrogen, oxygen, sulfur, S (O) or S (O)₂The remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8, 9 or 10). Can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclicA ring or a tricyclic ring. Non-limiting examples of bridged heterocyclic groups include:

the heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring as described above, wherein the ring to which the parent structure is attached is a heterocyclyl, non-limiting examples of which include:

and the like.

The heterocyclyl group may be substituted or unsubstituted and when substituted, the substituents may be substituted at any available point of attachment, preferably independently optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably independently optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g. 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, e.g. furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably independently optionally substituted with one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

The term "hydroxy" refers to an-OH group.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "amino" refers to the group-NH₂。

The term "cyano" refers to — CN.

The term "nitro" means-NO₂。

The disclosure also includes various deuterated forms of the compounds of formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds of the formula (I) with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane tetrahydrofuran solutions, deuterated lithium aluminum hydrides, deuterated iodoethanes, deuterated iodomethanes, and the like.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the disclosed compounds which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.

In the disclosure, different terms such as "X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C", etc. all express the same meaning, that is, X may be any one or more of A, B, C.

To achieve better therapeutic efficacy and better meet market needs, we hope to develop a new generation of NHE3 inhibitors that are highly potent and low toxic, are not absorbed (i.e. not systemic) and target the gastrointestinal tract.

WO2010078449 discloses example 241 (structure shown below) in which the benzene ring of the tetrahydroisoquinoline of the compound is substituted with two chlorine atoms.

We have now found that when in the compounds of formula (I) D is

Preferably D is

When alkyl is introduced to the benzene ring of tetrahydroisoquinoline at the same time, such compounds exhibit excellent effects and actions, preferably when R is R in the compound represented by the general formula (I)²Is alkyl, and R⁴When the compound is halogen, the compound has better NHE3 inhibition effect and stronger and effective Na promotion effect⁺The effect of excretion from the intestinal tract.

Synthesis of the Compounds of the disclosure

For the purpose of synthesis of the present disclosure, the present disclosure adopts the following synthesis scheme:

scheme one

The preparation method of the compound shown in the general formula (I) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof, or the pharmaceutically acceptable salt thereof comprises the following steps: :

the tetrahydroisoquinoline azido compound (I-a) and a reducing agent (such as triphenylphosphine) are subjected to reduction reaction in a solvent to obtain the tetrahydroisoquinoline amino compound (I-A) or a pharmaceutically acceptable salt thereof, and the compound (I-A) or the pharmaceutically acceptable salt thereof and R^aO-D-OR^aCarrying out amidation reaction under alkaline condition and optionally under the action of catalyst (such as 1H-benzotriazole-1-yl-oxy-tripyrrolidinyl hexafluorophosphate) to obtain a compound shown in a general formula (I);

wherein: the pharmaceutically acceptable salt of the compound of formula (I-A) is preferably the hydrochloride salt; r^aIs a hydrogen atom or an alkyl group, preferably a hydrogen atom; D. l, m, n, R¹～R⁶As defined in formula (I); and provided that R is¹、R²、R³Or R⁴At least one of which is an alkyl group.

Scheme two

The preparation method of the compound shown in the general formula (II) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof, or the pharmaceutically acceptable salt thereof comprises the following steps:

the tetrahydroisoquinoline azido compound (II-a) and a reducing agent (such as triphenylphosphine) are subjected to reduction reaction in a solvent to obtain a tetrahydroisoquinoline amino compound (II-A) or a pharmaceutically acceptable salt thereof, and the compound (II-A) or the pharmaceutically acceptable salt thereof and R^aO-D-OR^aCarrying out amidation reaction under alkaline condition and optionally under the action of catalyst (such as 1H-benzotriazole-1-yl-oxy-tripyrrolidinyl hexafluorophosphate) to obtain a compound shown in a general formula (II);

wherein: the pharmaceutically acceptable salt of the compound of formula (II-A) is preferably the hydrochloride salt; r^aIs a hydrogen atom or an alkyl groupPreferably a hydrogen atom; D. l, m, n, R¹～R⁶As defined in formula (II); and provided that R is¹、R²、R³Or R⁴At least one of which is an alkyl group.

Scheme three

The preparation method of the compound shown in the general formula (III) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof, or the pharmaceutically acceptable salt thereof comprises the following steps:

the tetrahydroisoquinoline azido compound (III-a) and a reducing agent (such as triphenylphosphine) are subjected to reduction reaction in a solvent to obtain the tetrahydroisoquinoline amino compound (III-A) or a pharmaceutically acceptable salt thereof, and the compound (III-A) or the pharmaceutically acceptable salt thereof and R^aO-D-OR^aCarrying out amidation reaction under alkaline condition and optionally under the action of catalyst (such as 1H-benzotriazole-1-yl-oxy-tripyrrolidinyl hexafluorophosphate) to obtain a compound shown in a general formula (III);

wherein: the pharmaceutically acceptable salt of the compound of formula (III-A) is preferably the hydrochloride; r^aIs a hydrogen atom or an alkyl group, preferably a hydrogen atom; D. l, m, n, R¹～R⁶As defined in formula (III); and provided that R is¹、R²、R³Or R⁴At least one of which is an alkyl group.

Scheme four

The preparation method of the compound shown in the general formula (IV) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof, or the pharmaceutically acceptable salt thereof comprises the following steps:

halogenated compound (IV-a) reacts with benzylamine compound (IV-b) in a solvent under the alkaline condition to obtainA compound (IV-c), the compound (IV-c) reacts with a reducing agent (such as sodium borohydride) in a solvent to obtain a hydroxyl compound (IV-d), the hydroxyl compound (IV-d) reacts with benzyl mercaptan in the solvent under the acidic (such as concentrated sulfuric acid) condition to obtain a compound (IV-e), the compound (IV-e) reacts with benzyl mercaptan under the alkaline condition and the action of a catalyst to obtain a compound (IV-f), the compound (IV-f) reacts with an oxidizing chlorination reagent (such as N-chlorosuccinimide) under the acidic (such as hydrochloric acid) condition to obtain a sulfonyl chloride compound (IV-g), the compound (IV-g) reacts with the compound (IV-h) in the solvent under the alkaline condition to obtain an azide compound (IV-i), the azide compound (IV-i) and a reducing agent (such as triphenylphosphine) are subjected to reduction reaction in a solvent to obtain a tetrahydroisoquinoline amino compound (IV-A) or a pharmaceutically acceptable salt thereof, and the compound (IV-A) or the pharmaceutically acceptable salt thereof and R^aO-D-OR^aCarrying out amidation reaction under alkaline condition and optionally under the action of catalyst (such as 1H-benzotriazole-1-yl-oxy-tripyrrolidinyl hexafluorophosphate) to obtain a compound shown in a general formula (IV);

wherein: the pharmaceutically acceptable salt of the compound of formula (IV-A) is preferably the hydrochloride salt; x¹Or X²Each independently is halogen, preferably bromine; r^aIs a hydrogen atom or an alkyl group, preferably a hydrogen atom; D. l, m, n, R²、R⁴～R⁶As defined in formula (IV); and provided that R is²Or R⁴At least one of which is an alkyl group.

Scheme five

The preparation method of the compound shown in the general formula (V) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof, or the pharmaceutically acceptable salt thereof comprises the following steps:

chiral HPLC resolution of the compound (IV-f) is carried out to obtain a compound (V-a), and the compound (V-a) is subjected to acidic (such as hydrochloric acid) condition and in the presence of an oxidative chlorination reagent (such as N-chlorosuccinimide) to obtain a sulfonyl chloride compound (V-b)The compound (V-b) and the compound (IV-h) carry out substitution reaction in a solvent under the alkaline condition to obtain an azide compound (V-c), the azide compound (V-c) and a reducing agent (such as triphenylphosphine) carry out reduction reaction in the solvent to obtain a tetrahydroisoquinoline amino compound (V-A) or a pharmaceutically acceptable salt thereof, and the compound (V-A) or the pharmaceutically acceptable salt thereof and R^aO-D-OR^aCarrying out amidation reaction under alkaline condition and optionally under the action of catalyst (such as 1H-benzotriazole-1-yl-oxy-tripyrrolidinyl hexafluorophosphate) to obtain a compound shown in a general formula (V);

wherein: the pharmaceutically acceptable salt of the compound of formula (V-A) is preferably the hydrochloride salt; r^aIs a hydrogen atom or an alkyl group, preferably a hydrogen atom; D. l, m, n, R²、R⁴～R⁶As defined in formula (V); and provided that R is²Or R⁴At least one of which is an alkyl group.

Scheme six

The preparation method of the compound shown in the general formula (VI) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture thereof, or the pharmaceutically acceptable salt thereof comprises the following steps: :

chiral HPLC resolution is carried out on the compound (IV-f) to obtain a compound (VI-a), the compound (VI-a) is subjected to an acidic (such as hydrochloric acid) condition and an oxidative chlorination reagent (such as N-chlorosuccinimide) to obtain a sulfonyl chloride compound (VI-b), the compound (VI-b) is subjected to a substitution reaction with the compound (IV-h) in a solvent under an alkaline condition to obtain an azide compound (VI-c), the azide compound (VI-c) is subjected to a reduction reaction with a reducing agent (such as triphenylphosphine) in the solvent to obtain a tetrahydroisoquinoline amino compound (VI-A) or a pharmaceutically acceptable salt thereof, and the compound (VI-A) or the pharmaceutically acceptable salt thereof and R^aO-D-OR^aAmidation under basic conditions, optionally in the presence of a catalyst (e.g. 1H-benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate), to give compounds of the general formula (VI);

wherein:the pharmaceutically acceptable salt of the compound of formula (VI-A) is preferably the hydrochloride salt; r^aIs a hydrogen atom or an alkyl group, preferably a hydrogen atom; D. l, m, n, R²、R⁴～R⁶As defined in formula (VI); and provided that R is²Or R⁴At least one of which is an alkyl group.

In the above schemes one to six, the reagent providing basic conditions comprises an organic base including, but not limited to, triethylamine, N-diisopropylethylamine, pyridine, 2, 6-dimethylpyridine, N-butyllithium, potassium tert-butoxide or tetrabutylammonium bromide, and an inorganic base including, but not limited to, cesium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide or sodium hydride.

In the above schemes four through six, the conditions that provide acidity include, but are not limited to, hydrochloric acid, sulfuric acid, formic acid, acetic acid, methanesulfonic acid, or trifluoroacetic acid.

In the first to sixth schemes, the reducing agent includes, but is not limited to, triphenylphosphine, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride, or hydrogen.

In the first to sixth schemes above, the catalyst includes, but is not limited to, 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene, tris (dibenzylidene-BASE acetone) dipalladium (0), 1H-benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, bis (triphenylphosphine) palladium dichloride, triphenylphosphine, palladium dichloride, palladium acetate, cuprous iodide, palladium/carbon or raney nickel.

In the above schemes one to six, the solvents used include, but are not limited to: n, N-dimethylformamide, xylene, toluene, water, acetonitrile, tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, methanol, ethanol, methyl tert-butyl ether, 1, 4-dioxane, dimethyl sulfoxide and mixtures thereof.

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Experimental procedures, in which specific conditions are not noted in the examples of the present disclosure, are generally performed under conventional conditions, or under conditions recommended by manufacturers of raw materials or commercial products. Reagents of specific sources are not indicated, and conventional reagents are purchased in the market.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10^-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Internal standard is Tetramethylsilane (TMS).

MS was determined using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, Acros Organics, Aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a developing solvent system of: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound.

The eluent system for column chromatography and the developing agent system for thin-layer chromatography used for purifying compounds comprise: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can also be added for adjustment.

Example 1

N¹,N⁴-bis (2- (2- (2- (2- (3- (8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) phenylsulfonylamino) ethoxy) ethyl) -2, 3-dihydroxysuccinamide 1

First step of

1- (3-bromophenyl) -2- ((2-chloro-4-methylbenzyl) methylamino) ethanone 1b

2-bromo-1- (3-bromophenyl) ethanone 1a (8.22g, 29.59mmol) was dissolved in 50mL of dichloromethane, cooled to 0 deg.C, triethylamine (5.98g, 59.18mmol) and 1- (2-chloro-4-methylphenyl) -N-methylmethanamine (5g, 29.59mmol) were added, and the reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 1B (7g), yield: 64.8 percent.

MS m/z(ESI):368.1[M+1]

Second step of

1- (3-bromophenyl) -2- ((2-chloro-4-methylbenzyl) methylamino) ethanol 1c

Compound 1b (1.25g, 3.41mmol) was dissolved in 10mL of methanol, cooled to 0 deg.C, and sodium borohydride (0.26g, 6.82mmol) was added and reacted with stirring for 1.5 hours. 15mL of acetone was added, the reaction solution was concentrated under reduced pressure, 30mL of water and 30mL of ethyl acetate were added, the aqueous phase was extracted with ethyl acetate (50 mL. times.3), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 1c (1.35g), which was directly subjected to the next reaction without purification.

MS m/z(ESI):370.1[M+1]

The third step

4- (3-bromophenyl) -8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinoline 1d

Crude 1c (1.21g, 3.28mmol) was dissolved in 10mL of dichloromethane, cooled to 0 deg.C, concentrated sulfuric acid (9g, 91.91mmol) was added, warmed to room temperature, and stirred for 12 hours. The reaction was poured into 30mL of ice water, 4M potassium hydroxide solution was added dropwise to a reaction pH of 9-10, extracted with dichloromethane (50mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 1d (1g), yield: 87.0 percent.

MS m/z(ESI):352.2[M+1]

The fourth step

4- (3- (benzylthio) phenyl) -8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinoline 1e

Compound 1d (950mg, 2.71mmol), tris (dibenzylidene-BASE acetone) dipalladium (0) (199mg, 0.22mmol) and 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (188mg, 0.33mmol) were dissolved in 10mL of xylene, warmed to 40 deg.C, stirred for 40 minutes, cooled to room temperature, benzylmercaptan (505mg, 4.06mmol) and potassium carbonate (186mg, 1.35mmol) were added, warmed to 140 deg.C, stirred for 2 hours, and stirred at 120 deg.C for 16 hours. Filtration and concentration of the filtrate under reduced pressure and purification of the resulting residue by silica gel column chromatography with eluent system B gave the title product 1e (270g), yield: 25.5 percent.

MS m/z(ESI):394.3[M+1]

The fifth step

3- (8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) benzene-1-sulfonyl chloride 1f

Compound 1e (200mg, 0.51mmol) was dissolved in 3mL of 2M mixed solvent of hydrochloric acid and acetonitrile (V/V ═ 1:5), cooled to 0 ℃, N-chlorosuccinimide (271mg, 2.03mmol) was added, and the reaction was stirred for 1.5 hours. 10mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (15 mL. times.3), the organic phases combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude title product 1f (210mg) which was directly subjected to the next reaction without purification.

MS m/z(ESI):372.2[M+1]

The sixth step

2,2'- (2,2' -oxabis (ethane-2, 1-diyl) bis (oxa)) bis (ethane-2, 1-diyl) bis (4-methylbenzenesulfonate) for 1h

2,2'- (2,2' -oxabis (ethane-2, 1-diyl) bis (oxa)) diethanol (1g, 3.08g, 20mmol) was dissolved in 100mL of dichloromethane, triethylamine (8.10g, 80mmol) and 50mL of p-toluenesulfonyl chloride (9.50g, 50mmol) were added, and the reaction was stirred for 12 hours. 50mL of water was added, extracted with ethyl acetate (50 mL. times.3), the organic phases combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude title product 1h (8.47g), which was directly subjected to the next reaction without purification.

MS m/z(ESI):520.4[M+18]

Seventh step

1-azido-2- (2- (2- (2-azidoethoxy) ethoxy) ethane 1j

Dissolve the crude product for 1h (19g, 54.12mmol) in 50mL water, add sodium bicarbonate (3.19g, 37.90mmol) and sodium azide (7.74g, 119mmol), heat to 100 deg.C, stir for 1h, cool to 90 deg.C, stir for 12 h. Cooled to room temperature, extracted with ethyl acetate (30mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 1j (11.76g), which was directly subjected to the next reaction without purification.

MS m/z(ESI):262.3[M+18]

Eighth step

2- (2- (2- (2-azidoethoxy) ethoxy) ethylamine 1k

Crude 1j (2.44g, 10mmol) was dissolved in 15mL of 5% hydrochloric acid, 10mL of a toluene solution of triphenylphosphine (2.36g, 9mmol) was added dropwise over 1 hour, and the reaction was stirred for 12 hours. 30mL of water was added, extracted with dichloromethane (20 mL. times.2), 2M sodium hydroxide solution was added dropwise to the aqueous phase until the pH was 12, extracted with dichloromethane (50 mL. times.2), washed with water (30mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 1k (2.09g), which was directly subjected to the next reaction without purification.

MS m/z(ESI):219.3[M+1]

The ninth step

N¹,N⁴Bis (2- (2- (2- (2-azidoethoxy) ethoxy) ethyl) -2, 3-dihydroxysuccinamide 1m

Crude 1k (370mg, 1.70mmol) was dissolved in 10mL of dichloromethane, tartaric acid (85mg, 0.56mmol), 1-hydroxybenzotriazole (189mg, 1.40mmol) and N, N-diisopropylethylamine (433mg, 3.36mmol) were added, and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 1m (133mg), yield: 43.2 percent.

MS m/z(ESI):551.5[M+1]

The tenth step

N¹,N⁴Bis (2- (2- (2- (2-aminoethoxy) ethoxy) ethyl) -2, 3-dihydroxysuccinamide 1n

Compound 1m (330mg, 0.60mmol) was dissolved in 20mL of methanol, palladium on carbon (33mg, 10%) was added, hydrogen gas was substituted three times, and the reaction was stirred for 2 hours. Filtration and concentration of the filtrate under reduced pressure gave the crude title product 1n (248mg), which was directly used in the next reaction without purification.

MS m/z(ESI):499.5[M+1]

The eleventh step

N¹,N⁴-bis (2- (2- (2- (2- (3- (8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) phenylsulfonylamino) ethoxy) ethyl) -2, 3-dihydroxysuccinamide 1

Crude 1f (188mg, 0.51mmol) was dissolved in 5mL of dichloromethane, cooled to 0 deg.C, compound 1N (101mg, 0.20mmol) and N, N-diisopropylethylamine (199mg, 1.55mmol) were added, warmed to room temperature, and the reaction was stirred for 12 hours. The reaction was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developer system a to give the title product 1(4mg), yield: 1.7 percent.

MS m/z(ESI):1163.7[M-1]

¹H NMR(400MHz,CD₃OD)δ7.75(d,2H),7.68(s,2H),7.52-7.45(m,4H),7.11(s,2H),6.60(s,2H),4.47(s,2H),4.38(t,2H),3.81(d,2H),3.63-3.41(m,30H),3.06-3.01(m,6H),2.65-2.60(m,2H),2.48(s,6H),2.16(s,6H)

Example 2

N¹,N⁴-bis (2- (2- (2- (2- (3- (6-chloro-2, 8-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) phenylsulfonylamino) ethoxy) ethyl) -2, 3-dihydroxysuccinamide 2

First step of

1- (3-bromophenyl) -2- ((4-chloro-2-methylbenzyl) methylamino) ethanone 2a

2-bromo-1- (3-bromophenyl) ethanone 1a (1.84g, 6.61mmol) was dissolved in 20mL of dichloromethane, cooled to 0 deg.C, triethylamine (1.34g, 13.22mmol) and 1- (4-chloro-2-methylphenyl) -N-methylmethanamine (1.20g, 6.95mmol) were added, and the reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure to give the crude title product 2a (2.42g), which was directly used in the next reaction without purification.

MS m/z(ESI):366.1[M-1]

Second step of

1- (3-bromophenyl) -2- ((4-chloro-2-methylbenzyl) methylamino) ethanol 2b

Crude 2a (2.40g, 6.61mmol) was dissolved in 15mL of methanol, cooled to 0 deg.C, sodium borohydride (503mg, 13.22mmol) was added and the reaction stirred for 2 hours. 10mL of acetone was added, the reaction solution was concentrated under reduced pressure, 30mL of water and 30mL of ethyl acetate were added, the aqueous phase was extracted with ethyl acetate (50 mL. times.3), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 2b (2.15g), which was directly subjected to the next reaction without purification.

MS m/z(ESI):370.1[M+1]

The third step

4- (3-bromophenyl) -6-chloro-2, 8-dimethyl-1, 2,3, 4-tetrahydroisoquinoline 2c

Crude 2b (2.15g, 5.83mmol) was dissolved in 20mL of dichloromethane, cooled to 0 deg.C, concentrated sulfuric acid (16g, 163.30mmol) was added, warmed to room temperature, and stirred for 12 hours. The reaction was poured into 30mL of ice water, 3M potassium hydroxide solution was added dropwise to a reaction pH of 9 to 10, extracted with dichloromethane (50mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 2c (1.40g), yield: 68.6 percent.

MS m/z(ESI):352.1[M+1]

The fourth step

4- (3- (benzylthio) phenyl) -6-chloro-2, 8-dimethyl-1, 2,3, 4-tetrahydroisoquinoline 2d

Compound 2c (1.36g, 3.88mmol), tris (dibenzylidene-BASE acetone) dipalladium (0) (284mg, 6.31mmol) and 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (270mg, 0.47mmol) were dissolved in 20mL of xylene, warmed to 40 deg.C, stirred for 40 minutes, cooled to room temperature, benzylmercaptan (722mg, 5.82mmol) and potassium carbonate (268mg, 1.94mmol) were added, warmed to 140 deg.C, stirred for 2 hours, and stirred at 120 deg.C for 12 hours. Filtration and concentration of the filtrate under reduced pressure and purification of the resulting residue by silica gel column chromatography with eluent system B gave the title product 2d (630g), yield: 41.4 percent.

MS m/z(ESI):392.3[M-1]

The fifth step

3- (6-chloro-2, 8-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) benzene-1-sulfonyl chloride 2e

Compound 2d (600mg, 1.52mmol) was dissolved in 11mL of a mixed solvent of 2M hydrochloric acid and acetonitrile (V/V ═ 1:5), cooled to 0 ℃, and N-chlorosuccinimide (814mg, 6.09mmol) was added and the reaction was stirred for 3 hours. 10mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (15 mL. times.3), the organic phases combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude title product 2e (600mg) which was directly subjected to the next reaction without purification.

The sixth step

N- (2- (2- (2- (2-azidoethoxy) ethoxy) ethyl) -3- (6-chloro-2, 8-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) benzenesulfonamide 2f

Compound 2e (563mg, 1.52mmol) was dissolved in 15mL of dichloromethane, cooled to 0 deg.C, N-diisopropylethylamine (590mg, 4.56mmol) and 2- (2- (2- (2-azidoethoxy) ethoxy) ethylamine 1k (432mg, 1.98mmol) were added, warmed to room temperature, and the reaction was stirred for 12 hours. The reaction was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 2f (350g), yield: 41.7 percent.

MS m/z(ESI):550.3[M-1]

Seventh step

N- (2- (2- (2- (2-aminoethoxy) ethoxy) ethyl) -3- (6-chloro-2, 8-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) benzenesulfonamide hydrochloride 2g

Compound 2f (420mg, 0.76mmol) was dissolved in 11mL of a mixture of tetrahydrofuran and water (V/V ═ 10:1), triphenylphosphine (600mg, 2.28mmol) was added, the temperature was raised to 25 ℃, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, 4mL of 2M hydrochloric acid and 8mL of ethyl acetate were added, and the aqueous phase was washed with ethyl acetate (10 mL. times.2) and concentrated under reduced pressure to give 2g (335mg) of the crude title product, which was used in the next reaction without purification.

MS m/z(ESI):524.4[M-1]

Eighth step

N¹,N⁴-bis (2- (2- (2- (2- (3- (6-chloro-2, 8-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) phenylsulfonylamino) ethoxy) ethyl) -2, 3-dihydroxysuccinamide 2

2g (340mg, 0.57mmol) of the crude product was dissolved in 3.5mL of dimethylformamide, N-diisopropylethylamine (367mg, 2.84mmol) and tartaric acid (43mg, 0.28mmol) were added, and the mixture was stirred for reaction for 5 minutes, and 1H-benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (355mg, 0.68mmol) was further added, and the mixture was heated to 25 ℃ and stirred for reaction for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developer system a to give the title product 2(89mg), yield: 27.0 percent.

MS m/z(ESI):1165.9[M+1]

¹H NMR(400MHz,CD₃OD)δ7.75(d,2H),7.68(s,2H),7.52(t,2H),7.46(d,2H),7.06(s,2H),6.62(s,2H),4.47(s,2H),4.38(t,2H),3.72(d,2H),3.62-3.54(m,18H),3.50-3.48(m,5H),3.44-3.42(m,7H),3.07-3.02(m,6H),2.64-2.59(m,2H),2.47(s,6H),2.27(s,6H).

Example 3

N¹,N⁴-bis (2- (2- (2- (2- (3- (2,6, 8-trimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) phenylsulfonylamino) ethoxy) ethyl) -2, 3-dihydroxysuccinamide 3

First step of

1- (3-bromophenyl) -2- ((2, 4-dimethylbenzyl) methylamino) ethanone 3a

2-bromo-1- (3-bromophenyl) ethanone 1a (2.60g, 9.35mmol) was dissolved in 20mL of dichloromethane, cooled to 0 ℃ and triethylamine (1.90g, 18.70mmol) and 1- (2, 4-xylyl) -N-methylmethanamine (1.46g, 9.82mmol) were added and the reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure to give the crude title product 3a (4.50g), which was directly used in the next reaction without purification.

MS m/z(ESI):348.1[M+1]

Second step of

1- (3-bromophenyl) -2- ((2, 4-dimethylbenzyl) methylamino) ethanol 3b

Crude 3a (3.24g, 9.35mmol) was dissolved in 15mL of methanol, cooled to 0 deg.C, sodium borohydride (711mg, 18.70mmol) was added, and the reaction was stirred for 2 hours. 10mL of acetone was added, the reaction solution was concentrated under reduced pressure, 30mL of water and 30mL of ethyl acetate were added, the aqueous phase was extracted with ethyl acetate (50 mL. times.3), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 3b (3g), which was directly subjected to the next reaction without purification.

MS m/z(ESI):348.1[M+1]

The third step

4- (3-bromophenyl) -2,6, 8-trimethyl-1, 2,3, 4-tetrahydroisoquinoline 3c

Crude 3b (3g, 8.61mmol) was dissolved in 20mL of dichloromethane, cooled to 0 deg.C, concentrated sulfuric acid (23.60g, 241mmol) was added, the reaction was stirred for 1.5 hours, warmed to room temperature, and stirred for 3 hours. The reaction was poured into 30mL of ice water, 3M potassium hydroxide solution was added dropwise to a reaction pH of 9-10, extracted with dichloromethane (50mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 3c (2.20g), yield: 77.5 percent.

MS m/z(ESI):331.1[M+1]

The fourth step

4- (3- (benzylthio) phenyl) -2,6, 8-trimethyl-1, 2,3, 4-tetrahydroisoquinoline 3d

Compound 3c (2.20g, 6.66mmol), tris (dibenzylidene-BASE acetone) dipalladium (0) (488mg, 0.53mmol) and 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (463mg, 0.80mmol) were dissolved in 25mL of xylene, warmed to 40 deg.C, stirred for 40 minutes, cooled to room temperature, benzylmercaptan (1.24g, 10mmol) and potassium carbonate (460mg, 3.33mmol) were added, warmed to 140 deg.C, stirred for 2 hours, stirred at 120 deg.C for 12 hours. Filtration and concentration of the filtrate under reduced pressure and purification of the resulting residue by silica gel column chromatography with eluent system B gave the title product 3d (1.50g), yield: 60.5 percent.

MS m/z(ESI):374.2[M+1]

The fifth step

3- (2,6, 8-trimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) benzene-1-sulfonyl chloride 3e

Compound 3d (600mg, 1.60mmol) was dissolved in 12mL of a mixed solvent of 2M hydrochloric acid and acetonitrile (V/V ═ 1:5), cooled to 0 ℃, and N-chlorosuccinimide (858mg, 6.40mmol) was added and the reaction was stirred for 3 hours. 10mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (15 mL. times.3), the organic phases combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude title product 3e (560mg) which was directly subjected to the next reaction without purification.

The sixth step

N- (2- (2- (2- (2-azidoethoxy) ethoxy) ethyl) -3- (2,6, 8-trimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) benzenesulfonamide 3f

Crude 3e (560mg, 1.60mmol) was dissolved in 20mL of dichloromethane, cooled to 0 deg.C, N-diisopropylethylamine (1g, 8mmol) and 2- (2- (2- (2-azidoethoxy) ethoxy) ethylamine 1k (520mg, 2.40mmol) were added, warmed to room temperature, and the reaction was stirred for 12 hours. The reaction was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 3f (400g, white oil), yield: 47.1 percent.

MS m/z(ESI):532.3[M+1]

Seventh step

N- (2- (2- (2- (2-aminoethoxy) ethoxy) ethyl) -3- (2,6, 8-trimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) benzenesulfonamide hydrochloride 3g

Compound 3f (400mg, 0.75mmol) was dissolved in 13.2mL of a mixture of tetrahydrofuran and water (V/V ═ 10:1), triphenylphosphine (592mg, 2.25mmol) was added, the temperature was raised to 25 ℃, and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, 2mL of water and 2mL of ethyl acetate were added, 6mL of 2M hydrochloric acid was added, the aqueous phase was washed with ethyl acetate (10 mL. times.2), and concentrated under reduced pressure to give 3g (410M) of the crude title product, which was subjected to the next reaction without purification.

MS m/z(ESI):506.3[M+1]

Eighth step

N¹,N⁴-bis (2- (2- (2- (2- (3- (2,6, 8-trimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) phenylsulfonylamino) ethoxy) ethyl) -2, 3-dihydroxysuccinamide 3

In an ice bath, 3g (405mg, 0.56mmol) of the crude product was dissolved in 3mL of dimethylformamide, N-diisopropylethylamine (363mg, 2.80mmol) and tartaric acid (43mg, 0.28mmol) were added, and the mixture was stirred for 5 minutes, 1H-benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (351mg, 0.67mmol) was further added, and the mixture was warmed to room temperature and stirred for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developer system a to give the title product 3(160mg), yield: 50.6 percent.

MS m/z(ESI):1122.9[M-1]

¹H NMR(400MHz,DMSO-d₆)δ7.67-7.61(m,8H),7.50-7.47(m,4H),6.84(s,2H),6.46(s,2H),5.60(d,2H),4.27-4.22(m,4H),3.59(d,2H),3.48-3.35(m,25H),3.29-3.19(m,5H),2.89-2.79(m,6H),2.62-2.58(m,2H),2.34(s,6H),2.18(s,6H),2.10(s,6H).

Example 4

(2R,3R)-N¹,N⁴-bis (2- (2- (2- (2- (3- ((S) -8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) phenylsulfonylamino) ethoxy) ethyl) -2, 3-dihydroxysuccinamide 4

First step of

(S) -3- (8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) benzene-1-sulfonyl chloride 4a

4- (3- (benzylthio) phenyl) -8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinoline 1e (5g, 12.70mmol) was subjected to chiral HPLC resolution (separation condition: chiral column CHIRAL PAK AD-H, mobile phase: isopropanol: n-hexane: 1: 19, flow rate: 0.5 mL/min), the corresponding fractions were collected (chiral HPLC analysis: retention time 6.104 min, chiral purity 99.6%, chromatographic column: CHIRALPAK IA, 0.46cm I.C.. times.15 cm L, fluidity: methanol, flow rate: 1.0mL/min), solvent was removed by rotary evaporation to obtain (S) -4- (3- (benzylthio) phenyl) -8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinoline (1.73g, 4.39 mmol). (S) -4- (3- (benzylthio) phenyl) -8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinoline (600mg, 1.52mmol) was dissolved in 12mL of a mixed solvent of 2M hydrochloric acid and acetonitrile (V/V ═ 1:5), cooled to 0 ℃, N-chlorosuccinimide (812mg, 6.08mmol) was added, and the reaction was stirred for 2.5 hours. The reaction was concentrated under reduced pressure to give the crude title product 4a (564mg), which was carried on to the next reaction without purification.

The second step is (S) -N- (2- (2- (2- (2-azidoethoxy) ethoxy) ethyl) -3- (8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) benzenesulfonamide 4b

Compound 4a (542mg, 1.52mmol) was dissolved in 15mL of dichloromethane, cooled to 0 deg.C, N-diisopropylethylamine (982mg, 7.60mmol) and 2- (2- (2- (2-azidoethoxy) ethoxy) ethylamine 1k (498mg, 2.28mmol) were added, warmed to room temperature, and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 4b (800mg), yield: 95.4 percent.

MS m/z(ESI):552.1[M+1]

The third step is (S) -N- (2- (2- (2- (2-aminoethoxy) ethoxy) ethyl) -3- (8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) benzenesulfonamide hydrochloride 4c

Compound 4b (780mg, 1.41mmol) was dissolved in 22mL of a mixture of tetrahydrofuran and water (V/V ═ 10:1), and triphenylphosphine (1.10g, 4.23mmol) was added to the solution, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, 5mL of 2M hydrochloric acid and 10mL of ethyl acetate were added, the aqueous phase was washed with ethyl acetate (10 mL. times.2), and concentrated under reduced pressure to give the crude title product 4c (710mg), which was used in the next reaction without purification.

MS m/z(ESI):524.1[M-1]

Fourth step (2R,3R) -N¹,N⁴-bis (2- (2- (2- (2- (3- ((S) -8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) phenylsulfonylamino) ethoxy) ethyl) -2, 3-dihydroxysuccinamide 4

Crude 4c (690mg, 1.15mmol) was dissolved in 3mL of dimethylformamide, and N, N-diisopropylethylamine (748mg, 5.75mmol) and L (+) -tartaric acid (86mg, 0.58mmol) were added and the reaction was stirred for 5 minutes, and 1H-benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (719mg, 1.38mmol) was added and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developer system a to give the title product 4(280mg), yield: 41.8 percent.

MS m/z(ESI):584.3[M/2+1]

¹HNMR(400MHz,CD₃OD)δ7.75(d,2H),7.68(s,2H),7.53-7.45(m,4H),7.11(s,2H),6.60(s,2H),4.46(s,2H),4.38(t,2H),3.81(d,2H),3.61-3.55(m,18H),3.51-3.47(m,4H),3.45-3.41(m,8H),3.05-3.01(m,6H),2.65-2.60(m,2H),2.47(s,6H),2.16(s,6H).

Example 5

(2R,3R)-N¹,N⁴-bis (2- (2- (2- (2- (3- ((R) -8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) phenylsulfonylamino) ethoxy) ethyl) -2, 3-dihydroxysuccinamide 5

First step of

(R) -3- (8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) benzene-1-sulfonyl chloride 5a

Compound 1e (5g, 12.70mmol) was subjected to chiral HPLC resolution (separation conditions: chiral column CHIRAL PAK AD-H, mobile phase: isopropanol: n-hexane: 1: 19, flow rate: 0.5 mL/min), and the corresponding fractions were collected (chiral HPLC analysis: retention time 5.682 min, chiral purity 99.6%, column: CHIRALPAK IA, 0.46cm I.C.. times.15 cm L, flow rate: methanol, flow rate: 1.0mL/min), and solvent was removed by rotary evaporation to give (R) -4- (3- (benzylthio) phenyl) -8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinoline (1.60g, 4.06 mmol). (R) -4- (3- (benzylthio) phenyl) -8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinoline (600mg, 1.52mmol) was dissolved in 12mL of a mixed solvent of 2M hydrochloric acid and acetonitrile (V/V ═ 1:5), cooled to 0 ℃, N-chlorosuccinimide (812mg, 6.08mmol) was added, and the reaction was stirred for 2.5 hours. The reaction was concentrated under reduced pressure to give the crude title product 5a (564mg), which was carried on to the next reaction without purification.

The second step (R) -N- (2- (2- (2- (2-azidoethoxy) ethoxy) ethyl) -3- (8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) benzenesulfonamide 5b

Compound 5a (564mg, 1.52mmol) was dissolved in 15mL of dichloromethane, cooled to 0 deg.C, N-diisopropylethylamine (982mg, 7.60mmol) and 2- (2- (2- (2-azidoethoxy) ethoxy) ethylamine 1k (498mg, 2.28mmol) were added, warmed to room temperature, and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 5b (464mg), yield: and (5) 55.3%.

The third step

(R) -N- (2- (2- (2- (2-aminoethoxy) ethoxy) ethyl) -3- (8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) benzenesulfonamide hydrochloride 5c

Compound 5b (464mg, 0.84mmol) was dissolved in 11mL of a mixture of tetrahydrofuran and water (V/V ═ 10:1), triphenylphosphine (660mg, 2.52mmol) was added, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, 1mL of 2M hydrochloric acid was added, the reaction mixture was concentrated under reduced pressure, 3mL of water was added, the aqueous phase was washed with ethyl acetate (10 mL. times.2), and concentrated under reduced pressure to give the crude title product 5c (500mg), which was subjected to the next reaction without purification.

MS m/z(ESI):523.9[M-1]

The fourth step

(2R,3R)-N¹,N⁴Bis (2- (2- (2- (2-), (3- ((R) -8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) phenylsulfonylamino) ethoxy) ethyl) -2, 3-dihydroxysuccinamide 5

Crude 5c (300mg, 0.51mmol) was dissolved in 5mL of dimethylformamide, N-diisopropylethylamine (197mg, 1.53mmol) and L (+) -tartaric acid (38mg, 0.26mmol) were added, and the mixture was stirred for reaction for 5 minutes, and 1H-benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (292mg, 0.56mmol) was added and the mixture was stirred for reaction for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developer system a to give the title product 5(100mg), yield: 33.0 percent.

MS m/z(ESI):584.0[M/2+1]

¹H NMR(400MHz,CDCl₃)δ7.76(d,2H),7.69(S,2H),7.54-7.48(m,4H),7.12(s,2H),6.61(S,2H),4.47(s,2H),4.41-4.37(m,2H),3.82(d,2H),3.62-3.56(m,17H),3.51-3.49(m,4H),3.46-3.42(m,7H),3.07-3.01(m,6H),2.66-2.61(m,2H),2.48(s,6H),2.17(s,6H).

Example 6

(2S,3S)-N¹,N⁴-bis (2- (2- (2- (2- (3- ((S) -8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) phenylsulfonylamino) ethoxy) ethyl) -2, 3-dihydroxysuccinamide 6

Crude 4c (660mg, 1.10mmol) was dissolved in 3mL of dimethylformamide, N-diisopropylethylamine (715mg, 5.50mmol) and D (-) -tartaric acid (83mg, 0.55mmol) were added and the reaction stirred for 5 minutes, 1H-benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (687mg, 1.32mmol) was added and the reaction stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developer system a to give the title product 6(190mg), yield: 29.6 percent.

MS m/z(ESI):585.0[M/2+1]

¹HNMR(400MHz,CD₃OD)δ7.76(d,2H),7.69(s,2H),7.53-7.45(m,4H),7.12(s,2H),6.61(s,2H),4.47(s,2H),4.39(t,2H),3.82(d,2H),3.61-3.56(m,18H),3.51-3.49(m,4H),3.46-3.41(m,8H),3.06-3.01(m,6H),2.65-2.60(m,2H),2.47(s,6H),2.17(s,6H).

Example 7

(2R,3S,4R,5S)-N¹,N⁶-bis (2- (2- (2- (2- (3- ((S) -8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) phenylsulfonylamino) ethoxy) ethyl) -2,3,4, 5-tetrahydroxyadipamide 7

First step of

(2R,3S,4R,5S) -2,3,4, 5-Tetrahydroxyadipic acid dimethyl ester 7b

(2R,3S,4R,5S) -2,3,4, 5-tetrahydroxyadipic acid 7a (3g, 14.27mmol) was dissolved in 30mL of methanol, 0.3mL of concentrated sulfuric acid was added thereto, the temperature was raised to 85 ℃ and the reaction was stirred for 7 hours. Cooling, filtering, dissolving a filter cake in 50.8mL of mixed solvent of methanol and triethylamine (V: V is 50:0.8), heating and refluxing for 30 minutes, cooling, filtering, drying the filter cake to obtain crude product 7b (2.80g), and directly carrying out the next reaction without purification on the product. MS M/z (ESI) 256.1[ M +18]

Second step of

(2R,3S,4R,5S)-N¹,N⁶-bis (2- (2- (2- (2- (3- ((S) -8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) phenylsulfonylamino) ethoxy) ethyl) -2,3,4, 5-tetrahydroxyadipamide 7

Crude 7b (29mg, 0.12mmol) and triethylamine (73mg, 0.72mmol) were dissolved in 3mL of methanol, warmed to 85 ℃ and 1mL of a solution of crude 4c (180mg, 0.30mmol) in methanol was added and the reaction stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developer system a to give the title product 7(60mg), yield: 40.8 percent.

MS m/z(ESI):614.1[M/2+1]

¹H NMR(400MHz,CD₃OD)δ7.75(d,2H),7.68(s,2H),7.53-7.45(m,4H),7.11(s,2H),6.60(s,2H),4.40-4.36(m,4H),3.98(s,2H),3.81(d,2H),3.64-3.44(m,30H),3.06-3.01(m,6H),2.65-2.60(m,2H),2.47(s,6H),2.16(s,6H).

Example 8

(2R,3S,4R,5S)-N¹,N⁶-bis (2- (2- (2- (2- (3- ((S) -8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) phenylsulfonylamino) ethoxy) ethyl) -2,3,4, 5-tetrahydroxyadipamide 8

First step of

Dimethyl sulfonic acid ((1, 2-ethylenebis (oxy)) bis (2, 1-ethylene)) ester 8b

Triethylene glycol 8a (10g, 66.67mmol) was dissolved in 50mL tetrahydrofuran, cooled to 0 ℃, triethylamine (14.80g, 146.67mmol) and methanesulfonyl chloride (16.80g, 146.67mmol) were added, the mixture was warmed to room temperature, and the reaction was stirred for 3 hours. The reaction was quenched by the addition of 20mL of saturated sodium bicarbonate solution, the reaction was concentrated under reduced pressure, 20mL of water was added, extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, washed sequentially with 1% citric acid (20 mL. times.1) and saturated sodium chloride solution (20 mL. times.1), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 8b (20.40g) which was directly subjected to the next reaction without purification.

Second step of

1, 2-bis (2-azidoethoxy) ethane 8c

Crude 8b (20.40g, 66.67mmol) was dissolved in 40mL of water, sodium bicarbonate (3.92g, 46.67mmol) and sodium azide (9.97g, 153.34mmol) were added, the temperature was raised to 100 deg.C, the reaction was stirred for 1 hour, the temperature was lowered to 90 deg.C, and the reaction was stirred for 12 hours. Cooled to room temperature, extracted with ethyl acetate (30mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 8c (10g), which was directly subjected to the next reaction without purification.

The third step

2- (2- (2-azidoethoxy) ethoxy) ethylamine 8d

Crude 8c (10g, 0.05mol) was dissolved in 50mL of methyl tert-butyl ether, 70mL of 2M hydrochloric acid was added, the temperature was reduced to 0 deg.C, 5mL of a solution of triphenylphosphine (12.05g, 46mmol) in methyl tert-butyl ether was added, the mixture was warmed to room temperature, and the reaction was stirred for 12 hours. Extraction with ethyl acetate (20 mL. times.2), combining the organic phases, washing with 0.5M hydrochloric acid (10 mL. times.2), dropwise addition of 4M sodium hydroxide solution to the aqueous phase pH 10-11, extraction with dichloromethane (50 mL. times.2), washing with water (30mL), drying over anhydrous magnesium sulfate, filtration, and concentration of the filtrate under reduced pressure gave the crude title product 8d (7.30g, pale yellow oil) which was directly reacted to the next step without purification.

MS m/z(ESI):175.5[M+1]

The fourth step (S) -N- (2- (2- (2-azidoethoxy) ethoxy) ethyl) -3- (8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) benzenesulfonamide 8e

Compound 4a (752mg, 2.03mmol) was dissolved in 20mL of dichloromethane, cooled to 0 deg.C, N-diisopropylethylamine (1.31g, 10.15mmol) and crude 8d (460mg, 2.64mmol) were added, the mixture was warmed to room temperature, and the reaction was stirred for 12 hours. 20mL of water was added, extraction was performed with dichloromethane (30 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent System A to give the title product 8e (500mg), yield: 48.5 percent. MS M/z (ESI) 508.2[ M +1]

The fifth step

(S) -N- (2- (2- (2- (2-aminoethoxy) ethoxy) ethyl) -3- (8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) benzenesulfonamide hydrochloride salt 8f

Compound 8e (500mg, 0.98mmol) was dissolved in 11mL of a mixture of tetrahydrofuran and water (V/V ═ 10:1), and triphenylphosphine (775mg, 2.95mmol) was added to the solution, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, 5mL of 2M hydrochloric acid and 10mL of ethyl acetate were added, the aqueous phase was washed with ethyl acetate (10 mL. times.2), and concentrated under reduced pressure to give the crude title product 8f (480mg), which was used in the next reaction without purification.

MS m/z(ESI):480.3[M-1]

The sixth step

(2R,3S,4R,5S)-N¹,N⁶-bis (2- (2- (2- (2- (3- ((S) -8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) phenylsulfonylamino) ethoxy) ethyl) -2,3,4, 5-tetrahydroxyadipamide 8

Crude 7b (28mg, 0.12mmol) and triethylamine (70mg, 0.69mmol) were dissolved in 3mL of methanol, warmed to 85 ℃ and 1mL of a solution of crude 8f (160mg, 0.29mmol) in methanol was added and the reaction stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developer system a to give the title product 8(50mg), yield: 38.2 percent.

MS m/z(ESI):570.2[M/2+1]

¹H NMR(400MHz,CD₃OD)δ7.77(d,2H),7.69(s,2H),7.52(t,2H),7.46(d,2H),7.12(s,2H),6.61(s,2H),4.41-4.37(m,4H),4.00(s,2H),3.82(d,2H),3.62-3.42(m,22H),3.07-3.02(m,6H),2.65-2.60(m,2H),2.47(s,6H),2.17(s,6H).

Example 9

(S) -N, N' - (10, 17-dioxo-3, 6,21, 24-tetraoxa-9, 11,16, 18-tetraazahexacosane-1, 26-diyl) bis (3- ((S) -8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) phenylsulfonamide) 9

First step of

1, 4-Diisocyanic acid n-butyl ester 9b

1, 4-butanediamine 9a (176mg, 2mmol) was dissolved in 10mL of tetrahydrofuran, triethylamine (808mg, 8mmol) was added, the temperature was lowered to 0 ℃ and bis (trichloromethyl) carbonate (414mg, 1.40mmol) was added, the mixture was warmed to room temperature and stirred for reaction for 1.5 hours. 30mL of ethyl acetate was added, filtered and the filtrate was concentrated under reduced pressure to give the crude title product 9b (100mg) which was directly used in the next reaction without purification.

Second step of

(S) -N, N' - (10, 17-dioxo-3, 6,21, 24-tetraoxa-9, 11,16, 18-tetraazahexacosane-1, 26-diyl) bis (3- ((S) -8-chloro-2, 6-dimethyl-1, 2,3, 4-tetrahydroisoquinolin-4-yl) phenylsulfonamide) 9

Crude 8f (80mg, 0.14mmol) was dissolved in 5mL of dichloromethane, triethylamine (30mg, 0.29mmol) and 0.3mL of a solution of 1, 4-diisocyanato-n-butyl ester 9b (10mg, 0.07mmol) in dichloromethane were added, and the reaction was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with developer system a to give the title product 9(25mg), yield: 31.4 percent.

MS m/z(ESI):553.1[M/2+1]

¹H NMR(400MHz,CD₃OD)δ7.75(d,2H),7.67(s,2H),7.53-7.46(m,4H),7.11(s,2H),6.60(s,2H),4.38(t,2H),3.81(d,2H),3.62-3.43(m,18H),3.29-3.26(m,4H),3.10-3.00(m,10H),2.66-2.61(m,2H),2.47(s,6H),2.16(s,6H),1.47(s,4H).

Test example:

biological evaluation

Test example 1 measurement of inhibitory Activity of the disclosed Compound on NHE3

The method is used for determining the inhibition effect of the compound disclosed by the invention on the activity of the human NHE3 protein expressed in hNHE3/OK stable transgenic cells.

First, experimental material and instrument

1. BCECF-AM (B262-10, Dojindo chemistry);

2. NaCl-HEPES buffer (100mM NaCl,50mM HEPES,10mM glucose, 5mM KCl,2mM CaCl)₂,1mM MgCl₂,pH 7.4)；

3、NH₄Cl buffer (20mM NH)₄Cl,80mM NaCl,50mM HEPES,5mM KCl,2mM CaCl₂,1mM MgCl₂,5μM BCECF-AM,pH7.4)；

4. Contains no ammonium and no Na⁺HEPES buffer (100mM choline, 50mM HEPES,10mM glucose, 5mM KCl,2mM CaCl)₂,1mM MgCl₂,pH7.4)；

5. FlexStation3 microplate reader.

Second, the experimental procedure

Using mammalian expression vector containing hNHE3 gene

LTX with Plus^TMTransferring the reagent into OK cells; antibiotic selection was started every other day and monoclonal cell lines were selected. hNHE3/OK stable transformants were plated one day in 96-well plates at 10000 cells/well. Removing the culture medium, and washing twice with NaCl-HEPES buffer solution; then using NH₄BCECF-AM dye was diluted in Cl buffer, added to the plate at 100. mu.L/well, and incubated at 37 ℃ for 70 minutes. Removing the dye-containing buffer, and adding Na without ammonium⁺Washed once with HEPES buffer, and then added 100. mu.L/well of ammonium-free and Na-free buffer⁺And various concentrations of compound were added and incubated at room temperature for 15 minutes. BCECF fluorescence (em505, em439) was measured immediately for each well on a FlexStation3 microplate reader by adding 100. mu.L/well NaCl-HEPES buffer. IC of the Compound₅₀Values were obtained by varying the fluorescence ratio of BCECF (ex505/ex439) at different concentrations.

NHE3 inhibitory Activity of Compounds of the present disclosure IC was determined by the above assay₅₀The values are shown in Table 1.

TABLE 1 IC inhibition of hNHE3 protein Activity by this disclosed compound₅₀

Example numbering	IC50(nM)
		1	2
2	13
		3	34
4	0.23
		6	0.14
7	105
		8	643
9	60

And (4) conclusion: the compound shown in the general formula (I) has obvious inhibition effect on the activity of hNHE3 protein, and the inhibition effect is obviously higher than that of D

The compound (example 7 to 9).

Test example 2 determination of inhibitory Activity of Compounds of the present disclosure on NHE3

The method is used for determining the inhibition effect of the compound disclosed by the disclosure on the activity of mouse-derived NHE3 protein expressed in rat NHE3/OK stable transgenic cells.

First, experimental material and instrument

1. BCECF-AM (B262-10, Dojindo chemistry);

2. NaCl-HEPES buffer (100mM NaCl,50mM HEPES,10mM glucose, 5mM KCl,2mM CaCl)₂,1mM MgCl₂,pH 7.4)；

3、NH₄Cl buffer (20mM NH)₄Cl,80mM NaCl,50mM HEPES,5mM KCl,2mM CaCl₂,1mM MgCl₂,5μM BCECF-AM,pH7.4)；

4. Contains no ammonium and no Na⁺HEPES buffer (100mM choline, 50mM HEPES,10mM grape)Sugar, 5mM KCl,2mM CaCl₂,1mM MgCl₂,pH7.4)；

5. FlexStation3 microplate reader.

Second, the experimental procedure

Mammalian expression vector containing rat NHE3 gene is used

LTX with Plus^TMTransferring the reagent into OK cells; antibiotic selection was started every other day and monoclonal cell lines were selected. Rat NHE3/OK stable transformants were plated in 96-well plates at 10000 cells/well one day in advance. Removing the culture medium, and washing twice with NaCl-HEPES buffer solution; then using NH₄BCECF-AM dye was diluted in Cl buffer, added to the plate at 100. mu.L/well, and incubated at 37 ℃ for 70 minutes. Removing the dye-containing buffer, and adding Na without ammonium⁺Washed once with HEPES buffer, and then added 100. mu.L/well of ammonium-free and Na-free buffer⁺And various concentrations of compound were added and incubated at room temperature for 15 minutes. BCECF fluorescence (em505, em439) was measured immediately for each well on a FlexStation3 microplate reader by adding 100. mu.L/well NaCl-HEPES buffer. IC of the Compound₅₀Values were calculated from the change in the fluorescence ratio of BCECF (ex505/ex439) at different concentrations.

The inhibitory activity of the compounds of the present disclosure on rat NHE3 was determined by the above assay, comparing it with the positive compound (example 241 in WO 2010078449), the IC measured₅₀The values are shown in Table 1 below,

TABLE 1 IC of inhibition of rat NHE3 protein Activity by Compounds of the present disclosure₅₀

And (4) conclusion: the compound disclosed by the disclosure has an obvious inhibition effect on the activity of rat NHE3 protein, and the inhibition effect is obviously higher than that of a positive compound.

Evaluation of pharmacodynamics

Test example 3, example 4 of the present disclosure, pharmacodynamic testing of the Compound of example 6

1. Abstract

This experiment utilizes normal Wistar rats given a certain salt intake to evaluate the compounds of this disclosure for Na⁺Metabolism (feces Na)⁺And urine Na⁺) The influence of (c).

2. Test protocol

2.1 test drugs: example 4, example 6 compound, positive compound (example 241 in WO 2010078449).

2.2 test animals

Male Wistar rats (batch: 2008001627877, sipel-bikeka) 20 had an age of 13 weeks and a body weight of about 230 g.

2.3 pharmaceutical formulation

A proper amount of sample is weighed and prepared into 1mg/3mL suspension by using edible olive oil (food production license number QS320502011305, Shanghai Jiage food Co., Ltd.) and the suspension is prepared at present.

2.4 administration

20 Wistar male rats, 4-6 per group, were divided into 4 groups (compound group, positive compound group and solvent control group of example 4, example 6), fasted overnight and then gavaged with the compound, positive compound or olive oil of each example, at a dose of 1.0mg/kg and a volume of 3 mL/kg.

3. Operation of

After one hour of single gavage administration of each example compound, positive compound or olive oil, 300mg/kg/3mL sodium chloride solution was gavage administered to each animal, after which the rats were placed in metabolic cages, fed freely with water, and total urine and feces were collected and metered for 0-24 hours. Adding 10-20 mL of double-distilled water into the excrement, mashing and uniformly mixing to obtain Na⁺Fully dissolved in water, centrifuged at 4000rpm multiplied by 8 minutes with urine respectively, absorbed supernatant and then Na is measured by a sodium detection kit (specification: 30T, batch number: 20130108, product number: C002, Nanjing institute of bioengineering) and a full-wavelength microplate reader⁺The content of Na in the feces or urine is calculated after 24 hours⁺Amount of the compound (A).

4. Pharmacodynamic parameter results

The pharmacodynamic parameters of the compounds of the present disclosure are as follows:

and (4) conclusion: if the positive compound group (example 241 in WO 2010078449) is compared with the solvent group, the feces Na is⁺The rate of increase was 100%, examples 4 and 6 were made of rat feces Na⁺The rate of rise was 222.91% and 167.60%, respectively. The disclosed compound can obviously promote Na⁺Is excreted through gastrointestinal tract, and has stronger effect than positive compound.

Claims (20)

1. A compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R¹、R²、R³or R⁴The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, cyano, nitro, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy;

provided that R is¹、R²、R³Or R⁴At least one is an alkyl group;

R⁵selected from the group consisting of hydrogen atoms, alkyl groups and cycloalkyl groups;

R⁶the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, cyano, nitro, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and cycloalkyl;

l is an alkylene group;

d is selected from

m is 1,2,3,4 or 5; and is

n is 0,1, 2,3 or 4.

2. The compound of formula (I) according to claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (II) or (III), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein: D. l, m, n, R¹～R⁶As defined in claim 1; and provided that R is¹、R²、R³Or R⁴At least one of which is an alkyl group.

3. The compound of formula (I) according to claim 1 or 2, or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (IV) or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein: D. l, m, n, R²、R⁴～R⁶As defined in claim 1; and provided that R is²Or R⁴At least one of which is an alkyl group.

4. A compound of formula (I) according to any one of claims 1 to 3, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of formula (V) or (VI), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein: D. l, m, n, R²、R⁴～R⁶As defined in claim 1; and provided that R is²Or R⁴At least one of which is an alkyl group.

5. The compound of formula (I) according to any one of claims 1 to 4, wherein L is-CH, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof₂-CH₂-。

6. The compound of formula (I) according to any one of claims 1 to 5, wherein m is 3, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

7. A compound of formula (I) according to any one of claims 1 to 6, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein D is selected from:

preferably, it is

8. A compound of formula (I) according to any one of claims 1 to 7, wherein R is R or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof²And R⁴Each independently selected from halogen or alkyl; and provided that R is²And R⁴At least one of which is an alkyl group.

9. A compound of formula (I) according to any one of claims 1 to 8, wherein R is R or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof²Is alkyl, and R⁴Is halogen.

10. The compound of formula (I) according to any one of claims 1 to 9, wherein R is a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof⁵Is an alkyl group.

11. A compound of formula (I) according to any one of claims 1 to 10, wherein R is R or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof⁶Is a hydrogen atom.

12. A compound of formula (I) according to any one of claims 1 to 11, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

13. a compound of formula (I-A) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R¹、R²、R³or R⁴The same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, cyano, nitro, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and haloalkoxy;

provided that R is¹、R²、R³Or R⁴At least one is an alkyl group;

R⁵selected from the group consisting of hydrogen atoms, alkyl groups and cycloalkyl groups;

R⁶the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, cyano, nitro, amino, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, and cycloalkyl;

l is an alkylene group;

m is 1,2,3,4 or 5; and is

n is 0,1, 2,3 or 4.

14. The compound of the general formula (I-a) according to claim 13, wherein the compound is selected from the group consisting of:

15. a process for the preparation of a compound of formula (I) according to claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

a compound of formula (I-A) or a pharmaceutically acceptable salt thereof with R^aO-D-OR^aReacting to obtain a compound of a general formula (I);

wherein: r^aIs a hydrogen atom or an alkyl group; D. l, m, n, R¹～R⁶As defined in claim 1; and provided that R is¹、R²、R³Or R⁴At least one of which is an alkyl group.

16. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 12, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

17. Use of a compound of general formula (I) according to any one of claims 1 to 12, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for the preparation of a medicament for inhibiting NHE 3-mediated sodium/hydrogen ion exchange.

18. Use of a compound of general formula (I) according to any one of claims 1 to 12 or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for the preparation of a medicament for the treatment of disorders associated with fluid retention or salt overload.

19. Use of a compound of formula (I) according to any one of claims 1 to 12, or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for the manufacture of a medicament for the treatment of heart failure, chronic kidney disease, end-stage renal disease, liver disease, peroxisome proliferator-activated receptor (PPAR) γ agonist-induced fluid retention, hypertension, edema, hyperphosphatemia, hypernatremia, gastrointestinal disorders or pain associated with gastrointestinal disorders.

20. The use according to claim 19, wherein the gastrointestinal disorder is selected from irritable bowel syndrome, gastrointestinal motility disorder, constipation, functional gastrointestinal disorder, chronic intestinal pseudo-obstruction, crohn's disease, ulcerative colitis, or inflammatory bowel disease; wherein the irritable bowel syndrome is constipation-type irritable bowel syndrome.