Benzoheterocycle-substituted tetrahydroisoquinoline compounds

Abstract

The present invention relates to benzoheterocycle-substituted tetrahydroisoquinoline compounds, particularly to the compound represented by formula (I) and its pharmaceutically acceptable salts, and to the treatment of chronic kidney disease using the same. TIFF2023553732000132.tif57144

Description

[Technical field]

[0001] This application claims priority to: Application number: CN202011508096.4, filing date: December 18, 2020; Application number: CN202110266745.2, filing date: March 11, 2021; Application number: CN202111523273.0, filing date: December 13, 2021.

[0002] The present invention relates to the field of medicinal chemistry, specifically, the present invention relates to benzoheterocycle-substituted tetrahydroisoquinoline compounds and their preparation and use. [Background technology]

[0003] Phosphate is a key mineral that regulates various metabolic processes, including signal transduction, energy production, and mineral metabolism. It is mainly absorbed in the small intestine, filtered by the kidney, and then reabsorbed or excreted through the renal tubules. Therefore, despite differences in daily phosphate intake, serum phosphate concentrations are still maintained within the physiological range. In patients with advanced chronic kidney disease (CKD), the renal phosphorus metabolic function is essentially lost, causing hyperphosphatemia. Studies have shown that hyperphosphatemia is associated with multiple adverse clinical outcomes in CKD patients, including induction of vascular calcification, increased incidence and mortality risk of cardiovascular disease, secondary hyperparathyroidism, metabolic bone disease due to renal osteodystrophy, ectopic calcification, and accelerated progression of renal failure and cardiovascular disease.

[0004] At present, the main treatments for hyperphosphatemia are a low phosphorus diet, hemodialysis treatment, and taking phosphate binder drugs at mealtimes. Clinical experience shows that it is difficult to control phosphate intake through diet, and the efficiency of hemodialysis is limited, so the use of phosphate binder drugs is an important treatment for reducing blood phosphorus at present. At present, there are two types of phosphate binder drugs commonly used in clinical practice: phosphate binders containing metal ions (calcium / magnesium / iron / lanthanum) and ion exchange resin type binders (sevelamer or sevelamer carbonate). For the former phosphate binders containing metal ions, patients need to strengthen the management of metal ions in the drug, and the drug has a weak phosphorus binding effect under the influence of pH, which is prone to causing diarrhea and is intolerable to patients. The latter binds with phosphorus through ion exchange, is not absorbed in the gastrointestinal tract, has reduced accumulation, and has fewer side effects compared with the former. However, both have a large drug usage, high price, and poor patient compliance.

[0005] Currently, it is known that there are two main pathways for phosphate absorption in the intestinal tract: passive paracellular transport and active transport dependent on transporters. Passive paracellular phosphate transport is believed to be the main cause of phosphate absorption in the human body. Paracellular phosphate transport is mainly driven by the concentration gradient of phosphate and is absorbed by tight junction complexes formed between cells, and literature has shown that this tight junction complex is osmotic specific for certain ions through the regulation of signal transduction. Sodium-hydrogen antiporter 3 (NHE3 / SLC9A3) is a gastrointestinal transport protein expressed at the apical end of intestinal epithelial cells and is mainly responsible for maintaining the balance of sodium ions. By inhibiting intestinal NHE3 activity, it affects intestinal sodium absorption, thereby changing the hydrogen ion concentration in intestinal epithelial cells and affecting the change in local pH, reducing the permeability of the tight junction complexes formed between cells to phosphate, and reducing phosphate absorption by the paracellular pathway. In clinical practice, the need for blood phosphorus control in patients with advanced CKD is unmet, and blood phosphorus-lowering drugs with different mechanisms need to be further developed.

[0006] Among the drugs sold in China, the diagnostic methods for hyperphosphatemia in CKD patients are relatively single, so there is a need to further develop more effective and safe drugs to reduce serum phosphorus levels. Summary of the Invention

[0007] In one aspect, the present invention provides a compound represented by formula (I), its optical isomers, and pharma- ceutically acceptable salts thereof. [ka] however, R1 is H, C 1-6 Alkyl, C 3-6 cycloalkyl and 4- to 6-membered heterocycloalkyl; 1-6 Alkyl, C 3-6cycloalkyl or 4-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; R2, R3, R4, R5, and R6 are each independently H, halogen, OH, NH2, CN, or C 1-6 Alkyl and C 1-6 heteroalkyl, 1-6 Alkyl or C 1-6 heteroalkyl is optionally substituted by 1, 2 or 3 R; R7, R8 are each independently selected from H; or R7 and R1 are linked together to form a 5- to 6-membered ring; or R8 and R1 are linked together to form a 5- to 6-membered ring; T is selected from N and CH; Ring A is selected from 5- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkenyl, and 5- to 6-membered heteroaryl, wherein said 5- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkenyl, or 5- to 6-membered heteroaryl is optionally substituted by 1, 2, or 3 R; n is selected from 2 and 3; L1 is [ka] and [ka] is optionally substituted by 1, 2 or 3 R; L2 is [ka] and [ka] is optionally substituted by 1, 2 or 3 R; L3 is a single bond, [ka] and [ka] is optionally substituted by 1, 2 or 3 R; L4 is [ka] and [ka] is optionally substituted by 1, 2 or 3 R; X is a single bond, O, N, NH, or C 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl, C 1-6 Alkyl, C 5-10 Spirocyclyl, 5-10 membered spiroheterocyclyl, C 5-10 Fused cyclyl, 5-10 membered fused heterocyclyl, C 5-10 aryl, 5- to 12-membered heteroaryl, 3-8 Cycloalkyl, 5-10 membered heterocycloalkyl, C 1-6 Alkyl, C 5-10 Spirocyclyl, 5-10 membered spiroheterocyclyl, C 5-10 Fused cyclyl, 5-10 membered fused heterocyclyl, C 5-10 The aryl or 5-12 membered heteroaryl is optionally substituted by 1, 2 or 3 Rx; R X are independently OH, NH2, and C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, 5-6 membered heterocycloalkyl, -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NHC 1-6 Alkyl and -NHC(=O)C 1-6 Alkyl-OC 1-6 alkyl, 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6Alkylamino, 5-6 membered heterocycloalkyl, -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NHC 1-6 Alkyl or -NHC(=O)C 1-6 Alkyl-OC 1-3 alkyl is optionally substituted by 1, 2, 3, 4 or 5 R; R is independently H, halogen, OH, NH2, CN, [ka] , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamino and 5- to 6-membered heterocycloalkyl; 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamino or 5-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R'; R' is selected from F, Cl, Br, I, OH, NH2, CH3 and COOH; The 4- to 6-membered heterocycloalkyl, C 1-6 Heteroalkyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkenyl, 5- to 6-membered heteroaryl, 6- to 12-membered heteroaryl, 5- to 10-membered spiroheterocyclyl, and 5- to 10-membered fused heterocyclyl contain 1, 2, or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, C(=O), C(=O)O, S(=O), S(=O)2, and N.

[0008] In some embodiments of the invention, R is H, F, Cl, Br, I, OH, NH2, COOH, [ka] , Me, CF3, [ka] and the remaining variables are as defined herein.

[0009] In some embodiments of the present invention, R1 is H, CH3, [ka] , piperidinyl and tetrahydropyrrolyl, [ka] , piperidinyl or tetrahydropyrrolyl is optionally substituted by 1, 2 or 3 R, and the remaining variables are as defined herein.

[0010] In some embodiments of the present invention, R1 is H, CH3, [ka] and the remaining variables are as defined herein.

[0011] In some embodiments of the present invention, R2, R3, R4, R5, and R6 are each independently H, F, Cl, Br, OH, NH2, CN, CH3, [ka] and the remaining variables are as defined herein.

[0012] In some embodiments of the present invention, the ring A is selected from pyrrolidin-2-one, isothiazolidine-1,1-dioxide, 1,2-thiazine-1,1-dioxide, piperidin-2-one, 3,4-dihydropyridin-2(1H)-one, 5,6-dihydro-2H-1,2-thiazine-1,1-dioxide, pyridinyl, and pyrazolyl, wherein said pyrrolidin-2-one, isothiazolidine-1,1-dioxide, 1,2-thiazine-1,1-dioxide, piperidin-2-one, 3,4-dihydropyridin-2(1H)-one, 5,6-dihydro-2H-1,2-thiazine-1,1-dioxide, pyridinyl, or pyrazolyl is optionally substituted by one, two, or three R, and the remaining variables are as defined herein.

[0013] In some embodiments of the present invention, the structural unit [ka] and the remaining variables are as defined herein.

[0014] In some embodiments of the present invention, L1 is [ka] and the remaining variables are as defined herein.

[0015] In some embodiments of the present invention, L2 is [ka] and the remaining variables are as defined herein.

[0016] In some embodiments of the present invention, L3 is a single bond. [ka] and the remaining variables are as defined herein.

[0017] In some embodiments of the present invention, L4 is [ka] and [ka] is optionally replaced by 1, 2 or 3 R, and the remaining variables are as defined herein.

[0018] In some embodiments of the present invention, L4 is [ka] and the remaining variables are as defined herein.

[0019] In some embodiments of the present invention, the structural unit [ka] and the remaining variables are as defined herein.

[0020] In some embodiments of the present invention, X is a single bond, N, NH, O, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spirocyclyl, 5-8 membered spiroheterocyclyl, C 5-8 fused cyclyl, 5- to 8-membered fused heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, 1-6 Alkyl, C 3-6 Cycloalkyl, C 5-8 Spirocyclyl, 5-8 membered spiroheterocyclyl, C 5-10 Fused cyclyl, 5- to 8-membered fused heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are each independently selected from 1, 2, or 3 R X and the remaining variables are as defined herein.

[0021] In some embodiments of the present invention, X is a single bond, N, NH, O, C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 5-8 Spirocyclyl, 5-8 membered spiroheterocyclyl, C 5-8 Bridged heterocyclyl, 5-8 membered bridged heterocyclyl, C 5-8 fused cyclyl, 5- to 8-membered fused heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, 1-6 Alkyl, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, C 5-8 Spirocyclyl, 5-8 membered spiroheterocyclyl, C 5-8 Bridged heterocyclyl, 5-8 membered bridged heterocyclyl, C 5-8 Fused cyclyl, 5- to 8-membered fused heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are each independently selected from 1, 2, or 3 R X and the remaining variables are as defined herein.

[0022] In some embodiments of the present invention, X is a single bond, N, NH, O, C 1-6 Alkyl, C 3-8 cycloalkyl, 5- to 8-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, 1-6 Alkyl, C 3-8 Cycloalkyl, 5- to 8-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl are each independently selected from 1, 2, or 3 R X and the remaining variables are as defined herein.

[0023] In some embodiments of the present invention, the R X is OH, NH2, [ka] and the remaining variables are as defined herein.

[0024] In some embodiments of the present invention, X is a single bond, N, [ka] and the remaining variables are as defined herein.

[0025] In a further aspect of the present invention, the present invention further provides compounds of the following formula selected from the following formulae, their optical isomers and pharma- ceutically acceptable salts:

[0026] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0027] In a further aspect of the invention, the present invention further provides the use of the aforementioned compounds, their optical isomers and pharma- ceutically acceptable salts thereof in the manufacture of a medicament for inhibiting NHE-mediated sodium or hydrogen ion reverse transport.

[0028] In a further aspect of the present invention, the present invention further provides the use of the aforementioned compounds, their optical isomers and pharma- ceutically acceptable salts thereof in the manufacture of a medicament for treating irritable bowel syndrome, heart failure, chronic kidney disease, end stage renal disease or liver disease.

[0029] Definitions and Explanations Unless otherwise stated, the following terms and phrases used herein shall have the following meanings: Certain terms or phrases, unless specifically defined, should not be considered indefinite or unclear, but should be understood according to their ordinary meaning. When trade names are mentioned herein, it is intended to refer to the corresponding trade name or its active ingredients.

[0030] As used herein, the term "pharmacologically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals and are commensurate with a reasonable benefit / risk ratio without undue toxicity, irritation, allergic response or other problem or complication.

[0031] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention prepared from a compound having certain substituents found in the present invention and a relatively non-toxic acid or base. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of a base in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a solution or in a suitable inert solvent. Illustrative examples of pharma- ceutically acceptable acid addition salts include inorganic and organic acid salts, as well as salts of amino acids (such as arginine) and organic acids such as glucuronic acid, such as inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like, and organic acids including, for example, acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Certain compounds of the present invention contain both basic and acidic functionalities and thus can be converted into either base or acid addition salts.

[0032] The pharma- ceutically acceptable salts of the present invention can be synthesized from the parent compound that contains an acid or base group by conventional methods. Generally, such salts are prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both.

[0033] The compounds of the present invention can exist in specific geometric or stereoisomeric forms. All such compounds contemplated by the present invention include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and mixtures thereof are included within the scope of the present invention.

[0034] The compounds of the present invention may exist specifically. Unless otherwise stated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can be rapidly interconverted. If tautomers are possible (e.g., in solution), chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via the transfer of protons, such as keto-enol isomerization and imine-enol isomerization. Valence tautomers include interconversions via recombination of some bond electrons. Among them, a specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0035] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I), C-14( 14The compound of the present invention may be labeled with a radioisotope such as 1,2-dihydrogen (1,3,4-trimethylphenyl)-1,2-dihydro-1,2-trimethylphenyl ...

[0036] The term "substituted by" means that any one or more hydrogen atoms at a particular atom are replaced by a substituent, as long as the particular valence state is normal and the substituted compound is stable, and can include variants of deuterium and hydrogen. The term "optionally substituted by" means that it may or may not be substituted, and unless otherwise stated, the type and number of substituents are arbitrary as long as it is chemically feasible.

[0037] When any variable (e.g., R) occurs more than one time in a composition or structure of a compound, its definition is independent at every occurrence. Thus, for example, if a group is substituted with 0-2 R, then said group may be optionally substituted with up to 2 R, and each occurrence of R is independently optional. Also, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds. For example, [ka] You can choose from, etc.

[0038] A dash ("-") that is not between two letters or symbols indicates the site of attachment of a substituent. For example, C 1-6Alkylcarbonyl- refers to a C bonded to the rest of the molecule through a carbonyl. 1-6 However, when the binding site of the substituent is clear to one skilled in the art, for example in the case of a halogen substituent, the "-" may be omitted.

[0039] Unless otherwise stated, the valence bonds of groups are indicated with a dashed line. If you have JPEG0007641383000039.jpg11155, for example, [ka] " in which the dotted line represents the point at which the group is attached to the remainder of the molecule.

[0040] When one of the variables is a single bond, it means that the two groups it connects to are directly bonded, e.g. [ka] When L1 in the formula represents a single bond, the structure is actually [ka] This means that.

[0041] If a recited substituent does not indicate through which atom it is attached to the substituted group, then such substituent may be attached through any atom thereof; for example, pyridinyl as a substituent may be attached to the substituted group through any carbon atom of the pyridine ring.

[0042] When the listed linking group does not indicate the direction of the link, the direction of the link is arbitrary, for example: [ka] The linking group L in [ka] At this time [ka] is a phenyl and cyclopentyl bond in the same order as reading from left to right. [ka] It is also possible to construct the following by linking the phenyl and cyclopentyl in the reverse order of reading from left to right: [ka] Combinations of the above linking groups, substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0043] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of ring members, e.g., a "4- to 6-membered ring" refers to a "ring" having 4 to 6 atoms arranged around it.

[0044] Unless otherwise stated, "C 1-6 The term "alkyl" is used to represent a straight or branched chain saturated hydrocarbon group of 1 to 6 carbon atoms. 1-6 Alkyl has C 1-5 , C 1-4 , C 2-6 alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene) or polyvalent (e.g., methine). 1-5 Illustrative examples of alkyl include, but are not limited to, methyl ("Me"), ethyl ("Et"), propyl, such as n-propyl ("n-Pr") or isopropyl ("i-Pr"), butyl, such as n-butyl ("n-Bu"), isobutyl ("i-Bu"), sec-butyl ("s-Bu") or tert-butyl ("t-Bu"), pentyl, hexyl, and the like.

[0045] Unless otherwise stated, "C 1-3 The term "alkyl" is used to represent a straight or branched chain saturated hydrocarbon group of 1 to 3 carbon atoms. 1-3Alkyl has C 1-2 and C 2-3 alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene) or polyvalent (e.g., methine). 1-3 Illustrative examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0046] Unless otherwise stated, "C 2-6 The term "alkenyl" is used to represent a straight or branched chain hydrocarbon group of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position in the group. 2-6 Alkenyl includes C 2-4 , C 2-3 , C4, C3 and C2 alkenyl, which may be monovalent, divalent or polyvalent. 2-6 Illustrative examples of alkenyl include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, and the like.

[0047] Unless otherwise stated, "C 2-3 The term "alkenyl" is used to represent a straight or branched chain hydrocarbon group of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position in the group. 2-3 Alkenyl includes C3 and C2 alkenyl, 2-3 Alkenyl may be monovalent, divalent or polyvalent. 2-3 Examples of alkenyl include, but are not limited to, ethenyl, propenyl, and the like.

[0048] The term "heteroalkyl", by itself or in combination with other terms, refers to a stable linear or branched alkyl radical or combinations thereof consisting of a number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatoms are selected from B, O, N, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In some other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. In some embodiments, the heteroalkyl is C 1-6 heteroalkyl, and in some other embodiments, the heteroalkyl is C 1-3 Heteroalkyl. The heteroatom or heteroatom group can be placed at any interior position of the heteroalkyl, including the position at which the alkyl is attached to the remainder of the molecule, although the term "alkoxy" is a convention and refers to an alkyl attached to the remainder of the molecule via an oxygen atom. Illustrative examples of heteroalkyl include, but are not limited to, -OCH, -OCHCH, -OCHCHCH, -OCH(CH), -CH-CH-O-CH, -NHCH, -N(CH), -NHCHCH, -N(CH)(CHCH), -CH-CH-NH-CH, -CH-CH-N(CH)-CH, -SCH, -SCHCH, -SCHCHCH, -SCH(CH), -CH-S-CH-CH, -CH-CH, -S(=O)-CH, -CH-CH-S(=O)-CH, and up to two heteroatoms may be consecutive, for example, -CH-NH-OCH.

[0049] Unless otherwise stated, "C 1-6 The term "alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms attached to the remainder of the molecule through an oxygen atom. 1-6 Alkoxy is C 1-4, C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6 Illustrative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, and the like.

[0050] Unless otherwise stated, "C 1-4 The term "alkoxy" refers to an alkyl group containing 1 to 4 carbon atoms attached to the remainder of the molecule through an oxygen atom. 1-4 Alkoxy is C 1-3 , C 1-2 , C 2-4 , C4 and C3 alkoxy, etc. 1-6 Illustrative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, and the like.

[0051] Unless otherwise stated, "C 1-3 The term "alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom. 1-3 Alkoxy includes C 1-2 , C 2-3 , C3 and C2 alkoxy, etc. 1-3 Illustrative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0052] Unless otherwise stated, "C 1-6The term "alkylamino" refers to an alkyl group containing 1 to 6 carbon atoms attached to the remainder of the molecule through an amino group. 1-6 Alkylamino is C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4, C3 and C2 alkylamino, etc. 1-6 Examples of alkylamino include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0053] Unless otherwise stated, "C 1-4 The term "alkylamino" refers to an alkyl group containing 1 to 4 carbon atoms attached to the remainder of the molecule through an amino group. 1-4 Alkylamino is C 1-3 , C 1-2 , C 2-4 , C4, C3 and C2 alkylamino, etc. 1-4 Examples of alkylamino include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0054] Unless otherwise stated, "C 1-3 The term "alkylamino" refers to an alkyl group containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group. 1-3 Alkylamino includes C 1-2 , C3 and C2 alkylamino, etc. 1-3 Examples of alkylamino include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, and the like.

[0055] Unless otherwise stated, "C 1-6 The term "alkylthio" refers to an alkyl group containing 1 to 6 carbon atoms attached to the remainder of the molecule through a sulfur atom. 1-6 Alkylthio includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4, C3 and C2 alkylthio. 1-6 Examples of alkylthio include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0056] Unless otherwise stated, "C 1-4 The term "alkylthio" refers to an alkyl group containing 1 to 4 carbon atoms attached to the remainder of the molecule through a sulfur atom. 1-4 Alkylthio includes C 1-3 , C 1-2 , C 2-4 , C4, C3 and C2 alkylthio. 1-4 Examples of alkylthio include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0057] Unless otherwise stated, "C 1-3 The term "alkylthio" refers to an alkyl group containing 1 to 3 carbon atoms attached to the remainder of the molecule through a sulfur atom. 1-3 Alkylthio includes C 1-3 , C 1-2 and C3 alkylthio. 1-3 Examples of alkylthio include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0058] Unless otherwise stated, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (which may be at a specific point or any two-point interval, e.g., 3, 4, 5, 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms, etc.), more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 (e.g., 3, 4, 5, or 6) carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cycloalkyl, and polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0059] Unless otherwise stated, "C 3-9 "Cycloalkyl" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon radical having 3 to 9 ring carbon atoms, for example, 3 to 8 ring carbon atoms, for example, 3 to 6 ring carbon atoms, for example, 3 to 4 ring carbon atoms. 3-9 "Cycloalkyl" means a cycloalkyl having 3 to 9 ring carbon atoms. 3-8 "Cycloalkyl" means a cycloalkyl having 3 to 8 ring carbon atoms, 3-6 "Cycloalkyl" means a cycloalkyl having 3 to 6 ring carbon atoms, 3-4 "Cycloalkyl" means a cycloalkyl having 3 to 4 ring carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0060] Unless otherwise stated, "C 4-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group of 4 to 6 carbon atoms, which includes monocyclic and bicyclic ring systems, and 4-6 Cycloalkyl has C4-5 , C 5-6 , C4, C5 and C6 cycloalkyl, which may be monovalent, divalent or polyvalent. 4-6 Examples of cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0061] Unless otherwise stated, "C 5-10 The term "spirocyclyl" refers to a polycyclic group sharing one carbon atom (called a spiro atom) between 5- to 10-membered monocyclic rings, which may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. It is preferably 7- to 10-membered. According to the number of spiro atoms shared between the rings, spirocycloalkyls are divided into monospirocycloalkyls, bisspirocycloalkyls or polyspirocycloalkyls, preferably monospirocycloalkyls and bisspirocycloalkyls. More preferably, it is 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospirocycloalkyls. Non-limiting examples of spirocycloalkyls include: [ka] etc.

[0062] Unless otherwise stated, "C 5-10 The term "fused cyclyl" refers to a 5-10 membered all-carbon polycyclic group having any two rings sharing two carbon atoms that are not directly bonded, and may contain one or more double bonds, but neither ring has a completely conjugated π-electron system. It is preferably 7-10 membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic, more preferably a bicyclic or tricyclic. "C 5-10 Non-limiting examples of "fused rings" include: [ka] etc.

[0063] Unless otherwise stated, the term "bridged cycloalkyl" refers to a 5-10 membered all-carbon polycyclic group having any two rings sharing two carbon atoms that are not directly bonded, and may contain one or more double bonds, but neither ring has a completely conjugated π-electron system. It is preferably 6-10 membered, more preferably 7-10 membered. Depending on the number of constituent rings, it is classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic, more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include: [ka] etc.

[0064] Unless otherwise stated, the term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), but not including the -OO-, -OS-, or -SS- ring moieties, the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms (which may be at a specific point or any two-point interval, e.g., 3, 4, 5, 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms, etc.), of which 1 to 4 are heteroatoms, preferably 3 to 8 ring atoms, of which 1 to 3 are heteroatoms, and more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, pyrrolidinyl. Polycyclic heterocyclyls include spirocyclic, fused ring and bridged ring heterocyclyls.

[0065] Unless otherwise stated, the term "3- to 6-membered heterocycloalkyl", by itself or in combination with other terms, means a saturated cyclic group consisting of 3 to 6 ring atoms, respectively, in which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, in which the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)). p、 p is 1 or 2). It includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spiro rings, fused rings, and bridged rings. Also, for the "3- to 6-membered heterocycloalkyl", a heteroatom can occupy the position at which the heterocycloalkyl is attached to the remainder of the molecule. The 3- to 6-membered heterocycloalkyl includes 5- to 6-membered, 4-membered, 5-membered, and 6-membered heterocycloalkyl, etc. Illustrative examples of 4-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperidinyl, etc.

[0066] Unless otherwise stated, the term "5- to 10-membered spiroheterocyclyl" refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5- to 10-membered monocyclic rings, one or more of which ring atoms are nitrogen, oxygen, or S(O) m(where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. It is preferably 7-10 members. According to the number of spiro atoms shared between the rings, spiroheterocyclyl is divided into monospiroheterocyclyl, bisspiroheterocyclyl or polyspiroheterocyclyl, preferably monospiroheterocyclyl and bisspiroheterocyclyl. More preferably, it is 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include: [ka] etc.

[0067] Unless otherwise described, the term "5- to 10-membered fused heterocyclyl" refers to a 5- to 10-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with another ring in the system, one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and one or more of the ring atoms is not nitrogen, oxygen, or S(O) m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 10-membered, more preferably 7 to 10-membered. Depending on the number of constituent rings, it is classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, and is preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyls include: [ka] etc.

[0068] Unless otherwise stated, the term "bridged heterocyclyl" refers to a 5- to 10-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but in which neither ring has a completely conjugated pi-electron system, and in which one or more of the ring atoms is nitrogen, oxygen, or S(O) m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 10-membered, more preferably 7 to 10-membered. Depending on the number of constituent rings, it is classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, preferably a bicyclic, tricyclic or tetracyclic, more preferably a bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyls include: [ka] etc.

[0069] Unless otherwise stated, the term "cycloalkenyl" in the present invention refers to a cyclic alkenyl. 3-7 Cycloalkenyl" includes C, C, C, C, and C cycloalkenyl. Examples of cycloalkenyl include, but are not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl.

[0070] Unless otherwise stated, the term "heterocycloalkenyl" in the present invention refers to a cyclic alkenyl containing several heteroatoms. "5- to 6-membered heterocycloalkenyl", by itself or in combination with other terms, means an unsaturated cyclic group consisting of 5 to 6 ring atoms, each of which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, in which the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)). p、 and p is 1 or 2. Illustrative examples of heterocycloalkenyl are: [ka] These include, but are not limited to:

[0071] Unless otherwise stated, C n-n+m Or C n -C n+m includes any one specific embodiment of n to n+m carbons, for example, C 1-12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 Including any one of the ranges of n to n+m, for example, C 1-12 is C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 Similarly, n-membered to n+m-membered rings indicate that the number of atoms in the ring is n to n+m, and for example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any one of the ranges of n to n+m, and for example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring, etc.

[0072] Unless otherwise stated, the term "heteroaryl" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-20 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5-10 membered with 1-3 heteroatoms, more preferably 5- or 6-membered with 1-3 heteroatoms, non-limiting examples of which include pyrazolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include: [ka] etc.

[0073] Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, which are substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0074] It should be understood by those skilled in the art that some compounds of formula (I) contain one or more chiral centers and therefore exist in two or more stereoisomers. Thus, the compounds of the present invention may exist in the form of single stereoisomers (e.g., enantiomers, diastereomers) and mixtures thereof in any proportion, such as racemates, and, where appropriate, in the form of their tautomers and geometric isomers.

[0075] The term "stereoisomers" as used herein refers to compounds that have identical chemical constitution, but differ with respect to the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers, and the like.

[0076] The term "enantiomers," as used herein, refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0077] As used herein, the term "diastereomer" refers to a stereoisomer with two or more chiral centers and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, or biological activity. Mixtures of diastereomers can be separated by high resolution analytical methods such as electrophoresis or chromatography, such as HPLC.

[0078] For definitions and conventions of stereochemistry, see S.P. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l, or (+) and (-), are used to indicate the sign by which the compound rotates plane-polarized light, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a particular chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that has no optical activity.

[0079] The racemic mixture can be used as is or resolved into the individual isomers. Resolution can provide stereochemically pure compounds or mixtures enriched in one or more isomers. Methods for separating isomers are well known (see Allinger NL and Eliel EL, "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) and include physical methods such as chromatography using chiral adsorbents. The individual isomers in chiral form can be prepared from chiral precursors. Alternatively, diastereomeric salts can be formed with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), chemically separated from the mixture to obtain the individual isomers, stepwise crystallization of the salts, followed by liberation of one or two of the separated bases, and optionally repeating the process to obtain one or two isomers substantially free of the other isomer, i.e., the desired stereoisomer having an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight. Alternatively, the racemate can be covalently bound to a chiral compound (auxiliary) to obtain the diastereomers, as is well known to those skilled in the art.

[0080] The term "tautomer" or "tautomeric form" as used herein refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also called prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence bond tautomers include interconversions via recombination of some of the bonding electrons.

[0081] The compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternative methods known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0082] All technical and scientific terms not specifically defined used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. [Brief description of the drawings]

[0083] [Figure 1] 1 is a standardized correction value, nP, of urinary phosphorus excretion relative to dietary phosphorus intake according to an embodiment of the present invention. [Diagram 2] 1 is a standardized correction value, nNa, of urinary sodium excretion relative to dietary sodium intake according to an embodiment of the present invention. [Diagram 3] 1 is a stool morphology score according to an embodiment of the present invention. [Figure 4] FIG. 2 is an experimental process diagram according to an embodiment of the present invention. [Diagram 5] 1 shows blood phosphorus levels in rats according to an embodiment of the present invention. [Figure 6] 1 is a corrected value nP after standardization of 24-hour urinary phosphorus excretion and dietary phosphorus intake according to an embodiment of the present invention. [Figure 7] 1 is a corrected value nNa after standardization of 24-hour urinary sodium excretion and dietary sodium intake according to an embodiment of the present invention. [Figure 8] 1 is a stool morphology score according to an embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0084] The present invention will be described in detail below with reference to examples, which are not intended to limit the present invention in any way. The present invention has been described in detail herein, and specific embodiments thereof have been disclosed. It is apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0085] [ka]

[0086] Step 1: Preparation of Compound A1-2 Compound A1-1 (6.53 g, 22.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (700 mg, 0.76 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (700 mg, 1.21 mmol), N,N-diisopropylethylamine (3.87 g, 30.0 mmol) were dissolved in 1,4-dioxane (50 mL) solution, and the reaction system was heated to 70° C. under a nitrogen gas atmosphere, and compound benzyl mercaptan (2.48 g, 20.0 mmol) was added dropwise to the reaction system. After the addition was completed, the reaction system was stirred at 70° C. for 3 hours. The reaction solution was cooled to room temperature (25°C), filtered through diatomaceous earth, and the filtrate was concentrated in vacuum to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-6%) to obtain compound A1-2. 1 H NMR (400 MHz, DMSO-d6) δ 7.44 (d, J = 2.0 Hz, 1H), 7.41 - 7.36 (m, 2H), 7.35 - 7.29 (m, 2H), 7.29 - 7.23 (m, 2H), 7.13 (dd, J = 8.0, 0.9 Hz, 1H), 4.27 (s, 2H), 2.18 (s, 3H).

[0087] Step 2: Preparation of compound A1-3 Compound A1-2 (12.9 g, 43.87 mmol) was dissolved in a mixture of acetic acid (120 mL) and water (30 mL), and N-chlorosuccinimide (23.30 g, 175.5 mmol) was added thereto in batches at room temperature (25 ° C). After the addition was completed, the reaction system was stirred at room temperature (25 ° C) for 2 hours. The reaction solution was concentrated under vacuum at low temperature (< 30 ° C) to obtain compound A1-3, which was directly used in the next step reaction without further purification.

[0088] Step 3: Preparation of Compound A1-4 Tert-butylamine (6.3 g, 86 mmol) and triethylamine (13 g, 129 mmol) were dissolved in anhydrous dichloromethane (100 mL), the reaction system was cooled to 0 ° C, and compound A1-3 was added slowly to it. After the addition was completed, the reaction system was warmed to room temperature (25 ° C) and reacted for 2 hours. Water (100 mL) was added to the reaction solution, and then separated. The aqueous phase was extracted with dichloromethane (80 mL × 2). The organic phases were combined and washed with saturated aqueous sodium chloride solution (100 mL), after which the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0 ~ 10%) to obtain compound A1-4. 1 H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J = 2.2 Hz, 1H), 7.55 (dd, J = 8.1, 2.2 Hz, 1H), 7.17 (dd, J = 8.1, 0.8 Hz, 1H), 4.44 (s, 1H), 2.59 (d, J = 0.6 Hz, 3H), 1.24 (s, 9H).

[0089] Step 4: Preparation of Compound A1-5 Compound A1-4 (7 g, 22.8 mmol) was dissolved in carbon tetrachloride (100 mL) and N-bromosuccinimide (4.46 g, 25 mmol) and 2,2'-azobis(2-methylpropionitrile) (370 mg, 2.28 mmol) were added thereto. After the addition was completed, the reaction system was heated to 80°C and stirred for 16 hours. The reaction solution was cooled to room temperature (25°C) and concentrated in vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) to obtain compound A1-5. 1 H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J = 2.1 Hz, 1H), 7.66 (dd, J = 8.2, 2.1 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 4.92 (s, 2H), 1.29 (s, 9H).

[0090] Step 5: Preparation of Compound A1-6 Compound A1-5 (5.65 g, 14.67 mmol), potassium carbonate (4 g, 29.3 mmol), and tetra-n-butylammonium iodide (1 g, 3 mmol) were dissolved in acetonitrile (100 mL). After the addition was completed, the reaction system was heated to 50 ° C and stirred for 16 hours. The reaction solution was cooled to room temperature (25 ° C), water (200 mL) was added thereto, and extracted with ethyl acetate (100 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0 ~ 30%) to obtain compound A1-6. MS (ESI) m / z [(M+H) + -56] = 248.0.

[0091] Step 6: Preparation of Compound A1-8 Compound A1-6 (4.07 g, 13.39 mmol), compound A1-7 (5.54 g, 15.40 mmol), and tetrakis(triphenylphosphine)palladium (775 mg, 0.67 mmol) were dissolved in N,N-dimethylformamide (50 mL). Under a nitrogen gas atmosphere, the reaction system was heated to 100 ° C and reacted for 4 hours. The reaction solution was cooled to room temperature (25 ° C), water (100 mL) was added thereto, and extracted with ethyl acetate (100 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0 ~ 20%) to obtain compound A1-8. MS (ESI) m / z [(M+H) + -56] = 240.0.

[0092] Step 7: Preparation of Compound A1-9 Compound A1-8 (3.54 g, 12 mmol) was dissolved in a mixture of THF (50 ml) and water (20 mL). N-bromosuccinimide (2.13 g, 12 mmol) was added thereto under 0°C conditions, and after the addition was completed, the reaction system was stirred at 0°C for 1 hour. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-30%) to obtain compound A1-9. MS (ESI) m / z [(M+H) + -56] = 291.9.

[0093] Step 8: Preparation of Compound A1-11 Compound A1-9 (3.5 g, 10.1 mmol) and compound A1-10 (1.93 g, 10.1 mmol) were dissolved in 1,4-dioxane (100 mL), and triethylamine (2.05 g, 20.2 mmol) was added thereto. After the addition was completed, the reaction system was stirred at room temperature (25 ° C.) for 2 hours. The reaction solution was filtered, and the filtrate A1-11 was used directly in the next step reaction. MS (ESI) m / z (M+H) + = 455.0.

[0094] Step 9: Preparation of Compound A1-12 Compound A1-11 (the filtrate obtained in step 8) was dissolved in methanol (100 mL), and sodium borohydride (740 mg, 20 mmol) was added thereto in a batch under the condition of 0° C., and the reaction system was warmed to 5° C. and stirred for 2 hours. Acetone (5 mL) was added to the reaction system, and the system was concentrated in vacuum. The residue obtained by concentration was dissolved in dichloromethane (50 mL) and washed with saturated aqueous sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound A1-12, which was used directly in the next step reaction without further purification. MS (ESI) m / z (M+H) + = 457.1.

[0095] Step 10: Preparation of Compound A1-13 Compound A1-12 (4.5 g, 9.82 mmol) was dissolved in anhydrous dichloromethane (20 mL), and concentrated sulfuric acid (20 mL) was added dropwise thereto under the condition of 0°C. After completion of the dropwise addition, the reaction system was heated to 90°C and stirred for 1 hour. The reaction solution was cooled to room temperature (25°C), poured into ice water (200 g), and the pH was adjusted to 9 with 2N aqueous sodium hydroxide solution. Extraction was performed with dichloromethane (100 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified to obtain compound A1-13. 1 H NMR (400 MHz, Methanol-d4) δ 7.55 (d, J = 1.4 Hz, 1H), 7.39 (qd, J = 8.0, 1.2 Hz, 2H), 7.33 - 7.20 (m, 1H), 6.72 (dd, J = 2.1, 0.9 Hz, 1H), 4.51 (s, 1H), 4.34 (s,2H), 3.66 - 3.60 (m, 2H), 2.92 (dd, J = 11.8, 5.4 Hz, 1H), 2.61 (dd, J = 11.7, 7.4 Hz, 1H), 2.38 (s, 3H).

[0096] In a manner similar to the synthesis of intermediate A1-13, the following intermediate A2-13 was synthesized as shown in Table 1 below.

[0097] [Table 1]

[0098] Step 11: Preparation of Compound A1-15 Compound A1-13 (246 mg, 0.642 mmol), A1-14 (290 mg, 0.942 mmol), cesium carbonate (416 mg, 1.280 mmol), and sodium iodide (10 mg, 0.071 mmol) were dissolved in N,N-dimethylformamide (4 mL), and the reaction system was heated to 60 ° C. and stirred for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was purified by C18 reverse phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution (v / v) = 5 ~ 65%) to obtain compound A1-15. MS (ESI) m / z (M+H) + = 614.2.

[0099] Step 12: Preparation of Compound A1-16 Compound A1-15 (240 mg, 0.390 mmol) was dissolved in anhydrous methanol (3 mL), concentrated hydrochloric acid (2 mL) was added thereto, and after the addition was completed, the reaction system was stirred at room temperature (25° C.) for 1 hour. The reaction solution was concentrated in vacuum to obtain a crude product, which was dissolved in dichloromethane (20 mL), water (20 mL) was added thereto, and the pH was adjusted to 9 with saturated aqueous sodium bicarbonate solution, separated, the aqueous phase was extracted with dichloromethane (20 mL×2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound A1-16. MS (ESI) m / z (M+H) + = 514.0.

[0100] Step 13: Preparation of Compound A1 Compound A1-16 (165 mg, 0.320 mmol) was dissolved in N,N-dimethylformamide (2 mL), to which 1,4-diisocyanatobutane (20 mg, 0.128 mmol) was added, and after the addition was completed, the reaction system was stirred at room temperature (25 ° C) for 1 hour. The reaction solution was purified by high-speed preparative liquid chromatography (separation conditions: column: Agilent 10 Prep-C18 250 × 21.2 mm; column temperature: 25 ° C; mobile phase: water (10 mM / L ammonium bicarbonate) - acetonitrile; acetonitrile: 60% ~ 80% 12 min, flow rate: (30 mL / min) to obtain compound A1. 1 H NMR (400 MHz, Methanol-d4) δ 7.58 (d, J = 1.7 Hz, 2H), 7.44 - 7.35 (m, 4H), 7.24 (d, J = 2.0 Hz, 2H), 6.71 (d, J = 2.1 Hz, 2H), 4.45 (s, 4H), 4.32 (t, J = 6.3 Hz, 2H), 3.70 (t, J = 5.2 Hz, 4H), 3.60 (s, 4H), 3.58 - 3.50 (m, 8H), 3.38 (dt, J = 15.5, 5.1 Hz, 8H), 3.15 (t, J = 5.2 Hz, 4H), 3.04 (dd, J = 11.8, 5.3 Hz, 2H), 3.01 - 2.91 (m, 4H), 2.82 - 2.71 (m, 2H), 2.48 (d, J = 3.5 Hz, 6H), 1.40 - 1.27 (m, 4H). MS (ESI) m / z (M+H) + =1169.20. HPLC purity: 100%, retention time: 7.680min.

[0101] Separation conditions: Column: Waters XBridge 4.6×100 mm, 3.5 um; Column temperature: 40°C; Mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; Acetonitrile: 5%-95% 7 min, 95% 8 min; Flow rate: 1.2 mL / min.

[0102] Similar to the synthesis of Example A1, Example A2 was synthesized from A2-13 as shown in Table 2 below.

[0103] [Table 2]

[0104] Synthesis of Example B1 [ka]

[0105] Step 1: Preparation of compound B1-2 Under a nitrogen gas atmosphere, compound B1-1 (8.48 g, 40 mmol), compound A1-7 (17.32 g, 48.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (2.31 g, 2 mmol) were dissolved in N,N-dimethylformamide (80 mL), and the reaction system was heated to 100 ° C. and stirred for 4 hours. After the reaction was cooled to room temperature (25 ° C.), saturated aqueous ammonium chloride solution (200 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed with saturated sodium chloride (200 mL × 2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was dissolved in tetrahydrofuran (60 mL), and aqueous hydrochloric acid solution (2N, 8 mL) was added thereto and stirred for 30 minutes. The reaction was concentrated, slurried with petroleum ether and filtered to give compound B1-2, which was used directly in the next step reaction without further purification. MS (ESI) m / z (M+H) + = 175.8.

[0106] Step 2: Preparation of compound B1-3 Compound B1-2 (200 mg, 1.14 mmol) was dissolved in chloroform (30 mL), and liquid bromine (1.21 g, 7.66 mmol) was added dropwise thereto. After the addition was completed, the reaction system was heated to 70° C. and stirred for 30 minutes. The reaction solution was filtered to obtain compound B1-3, which was directly used in the next step reaction without further purification. MS (ESI) m / z (M+H) + = 256.0.

[0107] Step 3: Preparation of compound B1-4 Compound B1-3 (1.4 g, 5.53 mmol), compound A1-10 (1.25 g, 5.53 mmol) and triethylamine (2.8 g, 27.65 mmol) were dissolved in 1,4-dioxane (20 mL), and the reaction system was reacted at room temperature (25 ° C.) for 3 hours. The reaction solution was concentrated, water (40 mL) was added thereto, and extracted with ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound B1-4, which was directly used in the next step reaction without further purification. MS (ESI) m / z (M+H) + = 363.0.

[0108] Step 4: Preparation of compound B1-5 Compound B1-4 (1.4 g, 3.87 mmol) was dissolved in methanol (20 mL) and sodium borohydride (300 mg, 7.74 mmol) was added thereto in batches at 0° C. After the addition was completed, the reaction system was reacted at 0° C. for 2 hours. Acetone (5 mL) was added to the reaction system to quench the reaction, and the reaction system was concentrated to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 10-1%) to obtain compound B1-5. MS (ESI) m / z (M+H) + = 365.0.

[0109] Step 5: Preparation of Compound B1-6 Compound B1-5 (1.9 g, 5.2 mmol) was dissolved in dichloromethane (5 mL), and concentrated sulfuric acid (3 mL) was added dropwise to it under the condition of 0°C. After the completion of the dropwise addition, the reaction system was warmed to room temperature (25°C) and reacted for 5 hours. The reaction solution was poured into ice water, and the pH was adjusted to 7-8 with 2N aqueous sodium hydroxide solution. Extraction was performed with dichloromethane (80 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified to obtain compound B1-6. 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.54 - 7.40 (m, 4H), 6.86 (d, J = 2.1 Hz, 1H), 4.41 (t, J = 5.4 Hz, 1H), 4.34 (s, 2H), 3.73 (d, J = 16.2 Hz, 1H), 3.47 (d, J = 16.1 Hz, 1H), 2.84 (dd, J = 11.6, 5.1 Hz, 1H), 2.71 - 2.62 (m, 1H), 2.36 (s, 3H). HPLC: 100%, retention time: 5.598min.

[0110] Separation conditions: Column: Waters XBridge 4.6 × 100 mm, 3.5 μm; Column temperature: 40 °C; Mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; Acetonitrile: 5%-95% 7 min; Flow rate: 1.2 mL / min.

[0111] In the same manner as in the synthesis of intermediate B1-6, the following intermediates B2-6 to B5-6 were synthesized as shown in Table 3 below.

[0112] [Table 3-1] [Table 3-2]

[0113] Step 6: Preparation of Compound B1-7 Compound B1-6 (250 mg, 0.72 mmol), compound A1-14 (335 mg, 1.08 mmol), cesium carbonate (585 mg, 1.8 mmol), and 18-crown 6 (19 mg, 0.072 mmol) were added to acetonitrile (25 ml), and the reaction system was heated to 90 ° C. and reacted for 10 hours. The reaction solution was concentrated, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by C18 reverse phase silica gel column chromatography (acetonitrile / water (5% ammonium bicarbonate aqueous solution) (v / v) = 30 ~ 40%) to obtain compound B1-7. MS (ESI) m / z (M+H) + = 578.2.

[0114] Step 7: Preparation of Compound B1-8 Compound B1-7 (134 mg, 0.2 mmol) was dissolved in dichloromethane (2 mL) at room temperature (25 ° C.), hydrogen chloride·1,4-dioxane solution (2 mL) was added thereto, and the reaction mixture was stirred at room temperature (25 ° C.) for 2 h. The reaction mixture was concentrated, and the crude product was dissolved in saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound B1-8. MS (ESI) m / z (M+H) + = 478.0.

[0115] Step 8: Preparation of Compound B1 Compound B1-8 (120 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (1 mL), and 1,4-diisocyanatobutane (14 mg, 0.09 mmol) was added thereto under the condition of 0 ° C., and the reaction system was stirred at room temperature (25 ° C.) for 0.5 hours. The reaction solution was directly purified by high-performance preparative liquid chromatography (separation conditions: column: Welch Xtimate C18 250 × 21.2 mm; column temperature: 25 ° C.; mobile phase: water (10 mM / L ammonium bicarbonate) - acetonitrile; acetonitrile: 50% ~ 70% 12 min, flow rate: (30 mL / min) to obtain compound B1. 1 H NMR (400 MHz, Methanol-d4) δ 7.48 - 7.40 (m, 4H), 7.37 (d, J = 9.4 Hz, 2H), 7.23 (d, J = 1.7 Hz, 2H), 6.76 - 6.64 (m, 2H), 4.51 (s, 4H), 4.35 - 4.28 (m, 2H), 3.75 - 3.61 (m, 10H), 3.54 - 3.50 (m, 6H), 3.48-3.44 (m, 4H), 3.33 (t, J = 5.4 Hz, 4H), 3.09 (t, J = 5.3 Hz, 4H), 3.03 - 2.89 (m, 6H), 2.55 (dd, J = 11.7, 8.1 Hz, 2H), 2.37 (s, 6H), 1.35 (t, J = 4.7 Hz, 4H). MS (ESI) m / z (M+H) + = 1097.4. HPLC purity: 100%, retention time: 6.908min.

[0116] Separation conditions: Column: Waters XBridge 4.6×100 mm, 3.5 um; Column temperature: 40°C; Mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; Acetonitrile: 5%-95% 7 min; Flow rate: 1.2 mL / min.

[0117] Synthesis of Example B3 Step 1: Preparation of compound B3-7 [ka] Compound B3-6 (144 mg, 0.398 mmol) was dissolved in tetrahydrofuran (2 mL), and sodium hydride (29.6 mg, 0.74 mmol) was added under argon gas protection. After the addition was completed, the reaction system was stirred at room temperature (25 ° C) for 0.5 hours. 18-crown 6 (101.6 mg, 0.39 mmol) and compound A1-14 (186 mg, 0.589 mmol) were dissolved in tetrahydrofuran (2 mL), and slowly added to the reaction solution under argon gas protection. After the addition was completed, the reaction system was stirred at room temperature (25 ° C) for 16 hours. The reaction solution was purified by C18 reverse phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution (v / v) = 5 ~ 65%) to obtain compound B3-7. MS (ESI) m / z (M+H) + = 592.40.

[0118] In the same manner as in the synthesis of Example B1, Examples B2 to B6 were synthesized from B2-6 to B3-6 as shown in Table 4 below.

[0119] [Table 4-1] [Table 4-2] [Table 4-3]

[0120] Synthesis of Example C1 [ka]

[0121] Step 1: Preparation of compound C1-2 Compound C1-1 (200.0 mg, 0.548 mmol) was dissolved in a mixed solvent of acetic acid (2.50 mL) and water (0.25 mL), cooled in a 10 ° C water bath, and N-chlorosuccinimide (220.0 mg, 1.64 mmol, 3.0 equiv) was added to it. The reaction was stirred in a 10 ° C water bath for 1.0 h. Saturated saline (5.0 mL) was added to the reaction solution to quench the reaction, followed by extraction with ethyl acetate (10.0 mL x 3 times), combining the organic phases, drying over anhydrous sodium sulfate, and concentrating. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) to obtain compound C1-2. 1 H NMR (400 MHz, Chloroform-d) δ 8.24 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 8.3, 2.1 Hz, 1H), 7.36 (s, 1H), 4.40 (t, J = 6.7 Hz, 2H), 3.44 (t, J = 6.7 Hz, 2H), 2.05 (s, 3H).

[0122] Step 2: Preparation of compound C1-3 tert-Butylamine (44.0 mg, 0.60 mmol, 1.1 equiv) and triethylamine (83.0 mg, 0.82 mmol, 1.5 equiv) were dissolved in dichloromethane (2.50 mL) and cooled in a water bath at 10°C. Compound C1-2 (185.0 mg, 0.54 mmol) was then dissolved in dichloromethane (1.0 mL) and added dropwise to the reaction solution. The reaction system was warmed to room temperature (25°C) and stirred for 2.0 hours. The reaction solution was directly concentrated to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-15%) to obtain compound C1-3. 1H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J = 2.2 Hz, 1H), 7.60 (dd, J = 8.2, 2.2 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 4.33 (t, J = 7.6 Hz, 2H), 3.33 (t, J = 7.6 Hz, 2H), 2.07 (s, 3H), 1.27 (s, 9H).

[0123] Step 3: Preparation of compound C1-4 Compound C1-3 (150.0 mg, 0.398 mmol) was dissolved in a mixed solvent consisting of tetrahydrofuran (0.70 mL), methanol (0.70 mL) and a solution of lithium hydroxide (34.0 mg, 1.4 mmol, 3.5 equiv) in water (0.25 mL) and stirred at room temperature (25 ° C) for 1.0 h. A saturated aqueous solution of ammonium chloride (5.0 mL) was added to the reaction solution to quench the reaction, followed by extraction with ethyl acetate (10.0 mL x 3 times), and the organic phases were combined and washed with saturated saline (10.0 mL x 2 times). The organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain compound C1-4, which was used directly in the next step reaction without further purification. MS (ESI) m / z (M+H) + = 335.8.

[0124] Step 4: Preparation of compound C1-5 Compound C1-4 (1.0g, 3.0mmol) and triphenylphosphine (787.0mg, 3.0mmol, 1.0equiv) were dissolved in dichloromethane (10.0mL) solution, and under the condition of 0°C, a solution of carbon tetrabromide (1.1g, 3.3mmol, 1.1equiv) in dichloromethane (5.0mL) was added thereto, and after the addition was completed, the reaction system was warmed to room temperature (25°C) and stirred for 1.0 hours. The reaction solution was directly concentrated to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) to obtain compound C1-5. 1H NMR (400 MHz, Chloroform-d) δ 8.11 (d, J = 2.1 Hz, 1H), 7.56 (dd, J = 8.2, 2.1 Hz, 1H), 7.20 (s, 1H), 3.65 - 3.55 (m, 2H), 3.44 (t, J = 7.4 Hz) , 2H), 1.20 (d, J = 2.6 Hz, 9H).

[0125] Step 5: Preparation of compound C1-6 Compound C1-5 (8.20 g, 20.65 mmol) and potassium carbonate (5.70 g, 41.3 mmol, 2.0 equiv) were added to a solution of N,N-dimethylformamide (100.0 mL) and stirred overnight at room temperature (25 ° C.). The reaction solution was directly concentrated to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0 ~ 5%) to obtain compound C1-6. 1 H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J = 2.3 Hz, 1H), 7.53 (dt, J = 8.3, 1.8 Hz, 1H), 7.08 (dd, J = 8.4, 1.0 Hz, 1H), 3.98 (ddd, J = 6.8, 5.6, 1.3 Hz, 2H), 2.90 (t, J = 6.2 Hz, 2H), 1.46 (d, J = 1.6 Hz, 9H).

[0126] Step 6: Preparation of compound C1-7 Compound C1-6 (3.17 g, 10.0 mmol), tetrakis(triphenylphosphine)palladium(0) (3.17 g, 10.0 mmol, 0.1 equiv) and tributyl(1-ethoxyvinyl)tin (5.43 g, 15.0 mmol, 1.5 equiv) were added to a solution of N,N-dimethylformamide (30.0 mL), and the reaction system was heated to 100° C. under an argon gas atmosphere and reacted for 16.0 hours. The reaction solution was filtered to remove residues, rinsed with ethyl acetate, and the organic phase was concentrated to give compound C1-7, which was used directly in the next step reaction without further purification. MS (ESI) m / z (M+ H-56) + = 253.8.

[0127] Step 7: Preparation of compound C1-8 Compound C1-7 (309.0 mg, 1.0 mmol) and N-chlorosuccinimide (134.0 mg, 1.0 mmol, 1.0 equiv) were added to a mixture of tetrahydrofuran (3.0 mL) and water (1.0 mL) and stirred for 1.0 hours under ice bath conditions. A saturated aqueous solution of ammonium chloride (10.0 mL) was added to the reaction solution, followed by extraction with ethyl acetate (10.0 mL x 3 times), and the organic phases were combined and washed with saturated saline (10.0 mL x 2 times), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-50%) to obtain compound C1-8. MS (ESI) m / z (M+ H-56) + = 259.8.

[0128] Step 8: Preparation of compound C1-9 Compound C1-8 (3.15 g, 10.0 mmol), compound A1-10 (2.30 g, 12.0 mmol, 1.2 equiv) and potassium carbonate (4.14 g, 30.0 mmol, 3.0 equiv) were added to an acetonitrile (30.0 mL) solution, heated to 80° C. and stirred for 2.0 hours. The reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v)=0-50%) to obtain compound C1-9. MS (ESI) m / z (M+H) + = 469.0.

[0129] Step 9: Preparation of Compound C1-10 Compound C1-9 (2.33 g, 5.0 mmol) was dissolved in methanol (25.0 mL) and cooled to 0°C. Sodium borohydride (380.0 mg, 10.0 mmol, 2.0 equiv) was then added to the reaction solution in small portions and the reaction was continued for 30 minutes. After acetone (2.0 mL) was added to the reaction solution to quench the reaction, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-1%) to obtain compound C1-10. MS (ESI) m / z (M+H) + = 470.8.

[0130] Step 10: Preparation of Compound C1-11 Compound C1-10 (2.0 g, 4.25 mmol) was dissolved in dichloromethane (20.0 mL) solution and cooled to 0 ° C., and then concentrated sulfuric acid (10.0 mL) was gradually added dropwise to the reaction solution in small amounts. After the addition was completed, the reaction system was warmed to room temperature (25 ° C.) and stirred overnight. The reaction solution was added to ice water to quench the reaction, then a saturated aqueous sodium carbonate solution was added to adjust the pH to 8-9, and finally extracted with dichloromethane (100.0 mL x 3 times), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was separated and purified to obtain compound C1-11. 1 H NMR (400 MHz, Chloroform-d) δ 7.72 (d, J = 1.8 Hz, 1H), 7.26 - 7.20 (m, 2H), 7.17 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 4.62 (t, J = 7.9 Hz, 1H), 4.25 (t, J = 6.1 Hz, 1H), 3.80 (q, J = 6.5 Hz, 2H), 3.66 (t, J = 14.3 Hz, 2H), 2.97 (t, J = 6.1 Hz, 3H), 2.63 (dd, J = 11.7, 7.2 Hz, 1H), 2.48 (s, 3H). MS (ESI) m / z (M+H) + = 397.0.

[0131] Similar to the synthesis of Example A1, Example C1 was synthesized from C1-11 as shown in Table 5 below.

[0132] [Table 5]

[0133] Synthesis of Example D1 [ka] Compound D1-1 (1.96 g, 10 mmol) was dissolved in dichloromethane (20 mL), and a solution of potassium hydroxide (1.4 g, 25 mmol) in water (3 mL) was added thereto under the condition of 0° C., followed by the addition of tetrabutylammonium bromide (64 mg, 0.2 mmol) and 2-(chloromethoxy)ethyltrimethylsilane (2.1 mL, 12 mmol), and the reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v)=10%) to obtain compound D1-2. MS (ESI) m / z (M+H) + = 326.8.

[0134] Similar to the synthesis of intermediate B1-6, intermediate D1-7 was synthesized as shown in Table 6 below.

[0135] [Table 6]

[0136] Similar to the synthesis of Example B3, Examples D1-P1 and D1-P2 were synthesized from D1-7 as shown in Table 7 below.

[0137] [Table 7-1] [Table 7-2]

[0138] Similar to the synthesis of Example B3, Example D1-P1-S was synthesized from D1-7-S as shown in Table 8 below.

[0139] [Table 8]

[0140] Example D2 - Synthesis of P1 hydrochloride [ka]

[0141] Step 1: Preparation of compound D2-P1 Example D2-P1 was synthesized from D1-7 in the same manner as in the synthesis of Example B3.

[0142] Step 2: Preparation of compound D2-P1 hydrochloride D2-P1 (113 mg, 0.1 mmol) was dissolved in a mixed solvent of methanol (2 mL) and water (3 mL), and concentrated hydrochloric acid (1 mL) was added thereto at room temperature (25° C.), and the reaction system was sonicated at room temperature for 30 minutes. The reaction system was concentrated and freeze-dried to obtain compound D2-P1 hydrochloride. 1H NMR (400 MHz, DMSO-d6, T=60 ℃) δ 12.13 (s, 2H), 8.38 (d, J = 0.8 Hz, 2H), 7.72 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 2.1 Hz, 4H), 6.78 (s, 4H), 4.93 - 4.76 (m, 2H), 4.59 (t, J = 5.4 Hz, 6H), 4.50 - 4.36 (m, 2H), 3.93 (t, J = 5.4 Hz, 4H), 3.84 - 3.71 (m, 2H), 3.64 (t, J = 11.9 Hz, 2H), 3.54 (dd, J = 5.7, 3.3 Hz, 4H), 3.51 - 3.47 (m, 4H), 3.47 - 3.42 (m, 8H), 3.35 (t, J = 5.9 Hz, 4H), 3.12 (t, J = 5.8 Hz, 4H), 3.03 - 2.90 (m, 10H), 1.37 - 1.30 (m, 4H). MS (ESI) m / z (M+H) + = 1155.60. HPLC retention time: 7.417min.

[0143] Separation conditions: Column: Waters XBridge 4.6×100 mm, 3.5 um; Column temperature: 40°C; Mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; Acetonitrile: 5%-95% 7 min, 95% 8 min; Flow rate: 1.2 mL / min.

[0144] Example D2 - Synthesis of P2 Hydrochloride Example D2-P2 hydrochloride was synthesized from D1-7 in the same manner as in the synthesis of D2-P1 hydrochloride. [ka] 1H NMR (400 MHz, DMSO-d6) δ 12.22 (d, J = 57.8 Hz, 2H), 8.10 (s, 2H), 7.81 - 7.72 (m, 4H), 7.69 - 7.62 (m, 2H), 6.91 (dd, J = 8.3, 1.3 Hz, 2H), 6.75 - 6.61 (m, 2H), 4.97 - 4.76 (m, 2H), 4.75 - 4.51 (m, 6H), 4.51 - 4.33 (m, 2H), 3.97 - 3.60 (m, 8H), 3.51 - 3.42 (m, 4H), 3.42 - 3.34 (m, 12H), 3.31 (t, J = 5.8 Hz, 4H), 3.11 (t, J = 5.8 Hz, 4H), 3.05 - 2.84 (m, 10H), 1.39 - 1.21 (m, 4H). MS (ESI) m / z (M+H) + = 1155.6. HPLC retention time: 7.976min.

[0145] Separation conditions: Column: Waters XBridge 4.6×100 mm, 3.5 um; Column temperature: 40°C; Mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; Acetonitrile: 5%-95% 7 min, 95% 8 min; Flow rate: 1.2 mL / min.

[0146] Synthesis of Example E1 [ka] Step 1: Preparation of compound E1-1 Compound A1-4 (10 g, 32.8 mmol), N-bromosuccinimide (12.85 g, 72.16 mmol), and azobisisobutyronitrile (1.08 g, 6.56 mmol) were dissolved in carbon tetrachloride (80 mL). The reaction system was heated to 80°C and stirred for 18 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, washed with water, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) to obtain compound E1-1. MS (ESI) m / z (M+Na) + = 482.6. 1 H NMR (400 MHz, Chloroform-d) δ 8.08 (d, J = 2.1 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.77 (dd, J = 8.5, 2.1 Hz, 1H), 7.58 (s, 1H), 4.67 (s, 1H), 1.27 (s, 9H).

[0147] Step 2: Preparation of compound E1-2 Compound E1-1 (10 g, 21.7 mmol) was dissolved in a mixed solvent of tetrahydrofuran (75 mL) and water (25 mL), and silver nitrate (11.1 g, 65.1 mmol) was added thereto at room temperature (25 ° C), and the reaction system was heated to 80 ° C and stirred for 2 hours. The reaction solution was cooled to room temperature (25 ° C), filtered through diatomaceous earth, concentrated to 1 / 3 volume, diluted with ethyl acetate (200 mL), washed with water, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0 ~ 10%) to obtain compound E1-2. MS (ESI) m / z (M-55) = 264.

[0148] Step 3: Preparation of compound E1-3 (Methoxymethyl)triphenylphosphonium chloride (8.17 g, 23.9 mmol) was dissolved in tetrahydrofuran (50 mL), and sodium bis(trimethylsilyl)amide (12 mL, 23.9 mmol, 2 M) was added thereto under argon gas atmosphere at 0°C. After the addition was completed, the reaction system was stirred at 0°C for 1 hour. The reaction was cooled to -78°C, and a tetrahydrofuran solution (10 mL) of compound E1-2 of step 2 was added dropwise thereto, and the reaction system was slowly warmed to room temperature (25°C) and stirred for 16 hours. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%) to obtain compound E1-3. 1 H NMR (400 MHz, Chloroform-d) δ 8.16 (d, J = 2.2 Hz, 1H), 7.55 (ddd, J = 8.3, 2.1, 0.6 Hz, 1H), 7.24 (d, J = 0.6 Hz, 1H), 6.96 (d, J = 12.8 Hz, 1H), 6.43 (d, J = 12.8 Hz, 1H), 4.46 (s, 1H), 3.74 (s, 3H), 1.17 (s, 9H).

[0149] Step 4: Preparation of compound E1-4 Compound E1-3 (2.2 g, 6.3 mmol) was dissolved in tetrahydrofuran (30 mL) and 2N HCl (31 mL, 63 mmol) was added thereto at room temperature (25° C.). After the addition was completed, the reaction was heated to 50° C. and stirred for 1 hour. The reaction solution was concentrated to remove tetrahydrofuran, extracted with ethyl acetate (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v)=0-20%) to obtain compound E1-4. 1H NMR (400 MHz, Chloroform-d) δ 8.02 (dt, J = 2.0, 0.5 Hz, 1H), 7.66 (dd, J = 8.4, 2.0 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.29 - 6.24 (m, 1H), 1.62 (s, 9H).

[0150] Step 5: Preparation of Compound E1-8 Compound E1-8 was synthesized in a similar manner to compound B1-5. MS (ESI) m / z (M+H) + = 469.2.

[0151] Step 6: Preparation of Compound E1-9 Compound E1-8 (1.3 g, 2.8 mmol) was dissolved in 1,2-dichloroethane (10 mL), and aluminum trichloride (1.85 g, 14 mmol) was added thereto under nitrogen gas atmosphere, and the reaction was heated to 80° C. and continued to stir for 0.5 hours. The reaction was cooled to room temperature (25° C.), diluted with ethyl acetate (200 mL), adjusted to alkaline pH with saturated aqueous sodium bicarbonate, filtered through diatomaceous earth, washed with water, combined organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated the filtrate to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v)=0-60%) to obtain compound E1-9. MS (ESI) m / z (M+H) + = 395.2. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.46 (dd, J = 8.2, 1.8 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 2.1 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.19 (d, J = 7.6 Hz, 1H), 4.42 (t, J = 5.3 Hz, 1H), 3.75 (d, J = 16.2 Hz, 1H), 3.45 (d, J = 16.2 Hz, 1H), 2.84 (dd, J = 11.6, 5.0 Hz, 1H), 2.74 - 2.68 (m, 1H), 2.37 (s, 3H).

[0152] Similar to the synthesis of Example C1, Example E1 was synthesized from E1-9 as shown in Table 9 below.

[0153] [Table 9]

[0154] Synthesis of Example F1 [ka]

[0155] Step 1: Preparation of compound F1 Compound B1-8 (91 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (2 mL) and ethylenediaminetetraacetic dianhydride (19 mg, 0.07 mmol) and triethylamine (57 mg, 0.57 mmol) were added thereto. After the addition was completed, the reaction system was stirred at room temperature (25 ° C) for 2 hours. The reaction solution was purified by high-performance preparative liquid chromatography (separation conditions: column: Agilent 10 Prep-C18 250 × 21.2 mm; column temperature: 25 ° C; mobile phase: water (10 mM / L ammonium bicarbonate) - acetonitrile; acetonitrile: 60% ~ 80% 12 min, flow rate: (30 mL / min) to obtain compound F1. 1 H NMR (400 MHz, Methanol-d4) δ 7.50 (d, J = 1.5 Hz, 2H), 7.46 (d, J = 7.9 Hz, 2H), 7.36 (dd, J = 7.9, 1.6 Hz, 2H), 7.26 (d, J = 2.3 Hz, 2H), 6.69 (dd, J = 2.2, 1.0 Hz, 2H), 4.51 (s, 4H), 4.45 - 4.39 (m, 2H), 3.92 (d, J = 16.1 Hz, 2H), 3.76 - 3.63 (m, 10H), 3.57 (d, J = 1.5 Hz, 4H), 3.52 - 3.33 (m, 18H), 3.15 (q, J = 5.7 Hz, 6H), 3.03 (s, 4H), 2.77 (dd, J = 11.9, 8.9 Hz, 2H), 2.52 (s, 6H). MS (ESI) m / z (M+H) + =1211.20. HPLC purity: 100%, retention time: 6.180min.

[0156] Separation conditions: Column: Waters XBridge 4.6×100 mm, 3.5 um; Column temperature: 40°C; Mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; Acetonitrile: 5%-95% 7 min, 95% 8 min; Flow rate: 1.2 mL / min.

[0157] Synthesis of Example F2 [ka]

[0158] Step 1: Preparation of compound F2-2 Compound B1-6 (200 mg, 0.58 mmol), F2-1 (410 mg, 1.15 mmol), cesium carbonate (563 mg, 1.73 mmol), and 18-crown 6 (15.2 mg, 0.06 mmol) were dissolved in acetonitrile (1.5 mL), the reaction system was replaced with a nitrogen stream, and the temperature was raised to 90 ° C under nitrogen gas protection and stirred for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was purified by C18 reverse phase silica gel column chromatography (acetonitrile / 0.1% ammonium bicarbonate aqueous solution (v / v) = 5 ~ 75%) to obtain compound F2-2. MS (ESI) m / z (M+H) + = 622.0.

[0159] Step 2: Preparation of compound F2-3 Compound F2-2 (260 mg, 0.42 mmol) was dissolved in anhydrous dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added thereto under ice cooling, the reaction system was warmed to room temperature (25 ° C.) and stirred for 3 hours. The reaction solution was concentrated in vacuum to obtain a crude product, which was dissolved in dichloromethane (20 mL), water (20 mL) was added, the pH was adjusted to 9 with a saturated aqueous solution of sodium bicarbonate, separated, the aqueous phase was extracted with dichloromethane (20 mL × 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound F2-3. MS (ESI) m / z (M+H) + = 522.0.

[0160] Similar to the synthesis of Example F1, Example F2 was synthesized from F2-3 as shown in Table 10 below.

[0161] [Table 10]

[0162] Synthesis of Example G1 [ka] 1,4:3,6-Dianhydro-D-mannitol (15 mg, 0.102 mmol) was dissolved in N,N-dimethylformamide (2 mL) and N,N'-disuccinimidyl carbonate (52.2 mg, 0.204 mmol) was added thereto, and after the addition was complete, the reaction was stirred at room temperature (25°C) for 1 hour. Compound B1-8 (108 mg, 0.226 mmol) and triethylamine (30.9 mg, 0.306 mmol) were added to the reaction solution, and after the addition was completed, the reaction system was reacted at 60 ° C for 16 hours. The reaction solution was purified by high-performance preparative liquid chromatography (separation conditions: column: Agilent 10 Prep-C18 250 × 21.2 mm; column temperature: 25 ° C; mobile phase: water (10 mM / L NH4HCO3) - acetonitrile; acetonitrile: 60% ~ 90% 12 min, flow rate: (30 mL / min) to obtain compound G1. 1 H NMR (400 MHz, Methanol-d4) δ 7.48 - 7.41 (m, 4H), 7.36 (dd, J = 7.9, 1.6 Hz, 2H), 7.22 (d, J = 2.0 Hz, 2H), 6.68 (d, J = 1.9 Hz, 2H), 4.50 (s, 6H), 4.34 - 4.27 (m, 2H), 3.85 - 3.60 (m, 14H), 3.59 - 3.43 (m, 12H), 3.35 (t, J = 5.5 Hz, 4H), 3.08 (t, J = 5.4 Hz, 4H), 2.95 (dd, J = 11.7, 5.6 Hz, 2H), 2.56 (dd, J = 11.7, 8.2 Hz, 2H), 2.37 (s, 6H). MS (ESI) m / z (M+H) + =1155.40. HPLC purity: 100%, retention time: 7.593min.

[0163] Separation conditions: Column: Waters XBridge 4.6×100 mm, 3.5 um; Column temperature: 40°C; Mobile phase: water (10 mM NH4HCO3)-acetonitrile; Acetonitrile: 5%-95% 7 min, 95% 8 min; Flow rate: 1.2 mL / min.

[0164] Synthesis of Example H1 [ka] Compound B1-8 (110 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (2 mL) and N,N'-carbonyldiimidazole (44.8 mg, 0.27 mmol) was added thereto, and after the addition was completed, the reaction system was stirred at room temperature (25°C) for 1 hour. After sampling to monitor the complete conversion to the active intermediate, cis-1,4-cyclohexanediamine (10.5 mg, 0.092 mmol) and triethylamine (81.8 mg, 0.81 mmol) were added to the reaction solution, and after the addition was completed, the reaction system was reacted at 80 °C for 16 h, and the reaction solution was purified by high-performance preparative liquid chromatography (separation conditions: column: Agilent 10 Prep-C18 250 × 21.2 mm; column temperature: 25 °C; mobile phase: water (10 mM / L NH4HCO3)-acetonitrile; acetonitrile: 60%~80% 12 min, flow rate: (30 mL / min) to obtain compound H1. 1 H NMR (400 MHz, Methanol-d4) δ 7.45 - 7.37 (m, 6H), 7.22 (d, J = 2.1 Hz, 2H), 6.69 - 6.65 (d, 2H), 4.48 (s, 4H), 4.32 - 4.27 (t, 2H), 3.71 - 3.62 (m, 10H), 3.54 - 3.42 (m, 12H), 3.30 (t, J = 5.2 Hz, 4H), 3.08 (dd, J = 6.5, 4.8 Hz, 4H), 2.96 - 2.89 (m, 2H), 2.53 (dd, J = 11.7, 8.1 Hz, 2H), 2.36 (s, 6H), 1.56 - 1.36 (m, 8H). MS (ESI) m / z (M+H) + =1123.40. HPLC purity: 100%, retention time: 7.249min.

[0165] Separation conditions: Column: Waters XBridge 4.6×100 mm, 3.5 um; Column temperature: 40°C; Mobile phase: water (10 mM sodium bicarbonate)-acetonitrile; Acetonitrile: 5%-95% 7 min, 95% 8 min; Flow rate: 1.2 mL / min.

[0166] Similar to the synthesis of Example H1, Example H2 was synthesized as shown in Table 11 below.

[0167] [Table 11]

[0168] Synthesis of Example I1 [ka] Step 1: Preparation of Compound I1-2 N,N'-carbonyldiimidazole (487 mg, 3.00 mmol) was dissolved in N,N-dimethylformamide (1.5 ml), and compound I1-1 (146 mg, 1.00 mmol) was added thereto in batches under the condition of 0° C. After the addition was completed, the reaction system was slowly warmed to room temperature (25° C.) and stirred for 2 hours. The reaction system was directly used in the next step reaction without further purification. MS (ESI) m / z (M+H) + = 429.00

[0169] Step 2: Preparation of compound I1 Compound F2-3 (80 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (2 mL), and after the addition was completed, the reaction system was heated to 75 ° C., and the reaction solution of compound I1-2 (0.05 mL, 0.05 mmol) was added dropwise thereto, and after the addition was completed, the reaction system was stirred at 75 ° C. for 17 hours. The reaction solution was purified by high-speed preparative liquid chromatography (separation conditions: column: Welch Xtimate (registered trademark) C18 21.2 × 250 mm; column temperature: 25 ° C.; mobile phase: water (10 mM / L ammonium bicarbonate) - acetonitrile; acetonitrile: 65% ~ 95% 9 min; flow rate 30 mL / min) to obtain compound I1. 1 H NMR (400 MHz, DMSO-d6) δ 7.51-7.44 (m, 12H), 6.84 (d, J = 2.2 Hz, 3H), 5.95 (s, 6H), 4.50 (s, 6H), 4.39 (t, J = 5.3 Hz, 3H), 3.73-3.69 (m, 3H), 3.64-3.59 (m, 12H), 3.52 - 3.46 (m, 15H), 3.46 - 3.44 (m, 6H), 3.43 - 3.40 (m, 6H),3.32- 3.31 (m, 6H), 3.14 - 3.09 (m, 6H), 3.02-3.98 (m, 6H), 2.85-2.82 (m, 3H), 2.68-2.64 (m, 3H), 2.36 (s, 9H). MS (ESI) m / z (M+2H) + / 2=897.0. HPLC purity: 100%, retention time: 3.350min.

[0170] Separation conditions: Column: Waters XSelect CSH C18 4.6×100 mm, 3.5 um; Column temperature: 60°C; Mobile phase: water (0.01% trifluoroacetic acid)-acetonitrile (0.01% trifluoroacetic acid); Acetonitrile: 5%-95% 7 min; Flow rate: 1.2 mL / min.

[0171] Synthesis of Example I2 [ka] Step 1: Preparation of compound I2-3 Compound I2-1 (300mg, 1.29mmol) was dissolved in dichloromethane (3mL), and compound I2-2 (1.26g, 4.5mmol) and triethylamine (911mg, 9.0mmol) were added thereto in sequence under the condition of 0°C. After the addition was completed, the reaction system was slowly warmed to room temperature (25°C) and stirred for 1 hour. The reaction system was the reaction solution of compound I2-3, which was directly used in the next step reaction without further purification. MS (ESI) m / z (M+H) + = 732.00

[0172] Step 2: Preparation of compound I2 Compound F2-3 (80 mg, 0.15 mmol) and triethylamine (31 mg, 0.31 mmol) were dissolved in N,N-dimethylformamide (2 mL), and the reaction solution of compound I2-3 (0.12 mL, 0.05 mmol) was added dropwise thereto under room temperature (25 ° C.) conditions, and after the addition was completed, the reaction system was stirred at room temperature (25 ° C.) for 3 hours. The reaction solution was purified by high-speed preparative liquid chromatography (separation conditions: column: Welch Xtimate (registered trademark) C18 21.2 × 250 mm; column temperature: 25 ° C.; mobile phase: water (10 mM / L ammonium bicarbonate) - acetonitrile; acetonitrile: 65% ~ 95% 9 min; flow rate 30 mL / min) to obtain compound I2. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 3H), 7.50 - 7.45 (m, 12H), 6.84 (d, J = 2.0 Hz, 3H), 4.49 (s, 6H), 4.39 (t, J = 5.5 Hz, 3H), 3.71 (d, J = 16.2 Hz, 3H), 3.66-3.59 (m, 12H), 3.52-3.48 (m, 15H), 3.45 - 3.40 (m, 12H), 3.35-3.43 (m, 6H), 3.17-3.13 (m, 6H), 2.85-2.81 (m, 3H), 2.67-2.58 (m, 9H), 2.35 (s, 9H), 2.18 (s, 6H). MS (ESI) m / z (M+2H) + / 2 = 873.4. HPLC purity: 100%, retention time: 9.618min.

[0173] Separation conditions: Column: Waters XBridge 4.6×100 mm, 3.5 um; Column temperature: 40°C; Mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; Acetonitrile: 5%-95% 7 min, 95% 8 min; Flow rate: 1.2 mL / min.

[0174] Synthesis of Example I3 [ka]

[0175] Step 1: Preparation of compound I3-2 4-(2-Carboxyethyl)-4-[[(9H-fluoren-9-methoxy)carbonyl]amino]heptanedioic acid (94 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (170 mg, 1.32 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (384 mg, 1.0 mmol) were added thereto in sequence. After the addition was completed, the reaction system was stirred at room temperature (25 ° C) for 10 minutes, and compound F2-3 (410 mg, 0.785 mmol) was added thereto, and after the addition was completed, the reaction system was stirred at room temperature (25 ° C) for 18 hours. After filtration, the filtrate was purified by C18 reverse-phase silica gel column chromatography (acetonitrile / 0.1% aqueous ammonium bicarbonate solution (v / v) = 5-95%) to obtain compound I3-2. (ESI) m / z (M / 2+ H) + = 992.0.

[0176] Step 2: Preparation of compound I3 Compound I3-2 (280 mg, 0.141 mmol) was dissolved in N,N-dimethylformamide (3 mL), piperidine (120 mg, 1.41 mmol) was added thereto, and the reaction system was stirred at room temperature (25 ° C) for 1 hour. The reaction solution was purified by high-speed preparative liquid chromatography (separation conditions: column: Agilent 10 Prep-C18 250 × 21.2 mm; column temperature: 25 ° C; mobile phase: water (10 mM / L trifluoroacetic acid) - acetonitrile; acetonitrile: 10% ~ 30% 12 min, flow rate: (30 mL / min) to obtain compound I3. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (t, J = 5.7 Hz, 3H), 7.55 - 7.42 (m, 12H), 6.84 (d, J = 2.0 Hz, 3H), 4.50 (s, 6H), 4.39 (t, J = 5.5 Hz, 3H), 3.71 (d, J = 16.1 Hz, 3H), 3.65 - 3.56 (m, 12H), 3.54 - 3.39 (m, 27H), 3.38 - 3.27 (m, 6H), 3.15 (q, J = 5.8 Hz, 6H), 2.83 (dd, J = 11.6, 5.1 Hz, 3H), 2.73 - 2.61 (m, 3H), 2.35 (s, 9H), 2.12 (t, J = 8.1 Hz, 6H), 1.67 - 1.51 (m, 6H). MS (ESI) m / z (M / 2+ H) + = 881.3. HPLC purity: 98.9%, retention time: 5.747min.

[0177] Separation conditions: Column: ZORBAX Extend-C18 4.6×150mm, 3.5um; Column temperature: 30℃; Mobile phase: water (10mM / L TFA)-acetonitrile; Acetonitrile: 5%-5% 0-8min, 5-95% 8-15min; Flow rate: 1.0mL / min.

[0178] Synthesis of Example I4 [ka]

[0179] Step 1: Preparation of compound I4-2 Intermediate I4-3 was synthesized similarly to the synthesis of compound I3. (ESI) m / z (M / 2+ H) + = 814.5.

[0180] Step 2: Preparation of compound I4-3 Compound I4-2 (90 mg, 0.055 mmol) and triethylamine (33 mg, 0.33 mmol) were dissolved in a mixed solvent of tetrahydrofuran (2 mL) and dichloromethane (2 mL). The reaction system was cooled to 0° C. under a nitrogen gas atmosphere, and then triphosgene (49 mg, 0.165 mmol) was added thereto. The reaction system was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in sequence, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound I4-3, which was used directly in the next step reaction without further purification. (ESI) m / z (M / 2+ H) + = 827.5.

[0181] Step 3: Preparation of compound I4 Compound I4-3 (91 mg, 0.055 mmol) was dissolved in N,N-dimethylformamide (2 mL), and compound I4-4 (32 mg, 0.165 mmol) was added thereto under room temperature (25 ° C) conditions. After the addition was completed, the reaction system was stirred at room temperature (25 ° C) for 1 hour. The reaction solution was purified by high-performance preparative liquid chromatography (separation conditions: column: Agilent 10 Prep-C18 250 × 21.2 mm; column temperature: 25 ° C; mobile phase: water (10 mM / L ammonium bicarbonate) - acetonitrile; acetonitrile: 65% ~ 95% 12 min, flow rate: (30 mL / min) to obtain compound I4. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (t, J = 5.6 Hz, 3H), 7.54 - 7.37 (m, 13H), 6.85 (d, J = 2.1 Hz, 3H), 5.75 (s, 1H), 5.13 (d, J = 4.4 Hz, 1H), 4.55 (dd, J = 14.2, 5.9 Hz, 2H), 4.51 - 4.46 (m, 7H), 4.41 - 4.35 (m, 4H), 3.76 - 3.55 (m, 19H), 3.54 - 3.43 (m, 18H), 3.37 - 3.34 (m, 5H), 3.17 - 3.08 (m, 7H), 2.83 (dd, J = 11.6, 5.1 Hz, 3H), 2.76 (s, 3H), 2.67 - 2.62 (m, 3H), 2.35 (s, 9H), 2.05 - 1.95 (m, 6H), 1.83 - 1.71 (m, 6H). (ESI) m / z (M / 2+ H) + = 924.8. HPLC purity: 100%, retention time: 8.367min.

[0182] Separation conditions: Column: Waters XBridge 4.6×100 mm, 3.5 um; Column temperature: 40°C; Mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; Acetonitrile: 5%-95% 7 min, 95% 8 min; Flow rate: 1.2 mL / min.

[0183] Synthesis of Example J1 [ka]

[0184] Step 1: Preparation of compound J1 Compound F2-3 (90 mg, 0.17 mmol) and compound J1-1 (7.7 mg, 0.06 mmol) were dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (66 mg, 0.17 mmol) and N,N-diisopropylethylamine (45 mg, 0.34 mmol) were added thereto at room temperature (25° C.) in that order. After the addition was completed, the reaction system was stirred at room temperature (25° C.) for 2 hours. The reaction solution was purified by high-performance preparative liquid chromatography (separation conditions: column: Welch Xtimate (registered trademark) C18 21.2 × 250 mm; column temperature: 25 ° C; mobile phase: water (10 mM / L ammonium bicarbonate) - acetonitrile; acetonitrile: 65% to 95% 9 min; flow rate 30 mL / min) to obtain compound J1. 1 H NMR (400 MHz, DMSO-d6) δ 8.04 (t, J = 5.8 Hz, 2H), 7.51 - 7.45 (m, 8H), 6.85 (d, J = 2.0 Hz, 2H), 4.50 (s, 4H), 4.40 (t, J = 5.4 Hz, 2H), 3.92 (s, 4H), 3.72 (d, J = 16.2 Hz, 2H), 3.66-3.59 (m, 8H), 3.53-3.48 (m, 8H), 3.47-3.42 (m, 10H), 3.41-3.38 (m, 4H), 3.27-2.22 (m, 4H), 2.87-2.82 (m, 2H), 2.69 - 2.64 (m, 2H), 2.36 (s, 6H). MS (ESI) m / z (M+H) + =1143.4. HPLC purity: 100%, retention time: 7.582min.

[0185] Separation conditions: Column: Waters XBridge 4.6×100 mm, 3.5 um; Column temperature: 40°C; Mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; Acetonitrile: 5%-95% 7 min, 95% 8 min; Flow rate: 1.2 mL / min.

[0186] In a manner similar to the synthesis of Example J1, Examples J2 to J3 were synthesized as shown in Table 12 below.

[0187] [Table 12]

[0188] Synthesis of Example J4 [ka]

[0189] Step 1: Preparation of compound J4-2 Compound J4-1 (10 g, 47 mmol) was dissolved in methanol (200 mL) and concentrated sulfuric acid (2.5 mL, 47 mmol) was added thereto. After the addition was completed, the reaction system was stirred at 80° C. for 3 days. It was cooled to room temperature and continued to stir for 2 days, and a large amount of solid precipitated. The reaction solution was filtered, the solid was washed with methanol three times, and the solid was dried to obtain compound J4-2, which was directly used in the next step reaction without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 4.92 (d, J = 8.0 Hz, 2H), 4.85 - 4.78 (m, 2H), 4.31 (dd, J = 8.0, 1.1 Hz, 2H), 3.81 - 3.74 (m, 2H), 3.64 (s, 6H).

[0190] Step 2: Preparation of compound J4-3 Compound J4-2 (500 mg, 2.1 mmol) was dissolved in acetone (5 mL) and 2,2-dimethoxypropane (2.6 mL, 47 mmol) and p-toluenesulfonic acid (79 mg, 0.415 mmol) were added thereto, and after the addition was completed, the reaction was stirred at 65° C. for 3 hours. After cooling to room temperature, the reaction solution was spun to dryness to obtain a solid, the solid was added to methanol, the reaction solution was filtered, the solid was washed with methanol three times, and the solid was dried to obtain compound J4-3, which was used directly in the next step reaction without further purification. 1 H NMR (400 MHz, ) δ 4.57 - 4.53 (m, 2H), 4.44 - 4.39 (m, 2H), 3.71 (s, 6H), 1.38 (s, 6H), 1.33 (s, 6H).

[0191] Step 3: Preparation of compound J4-4 Compound J4-3 (500 mg, 1.57 mmol) was dissolved in a mixture of tetrahydrofuran (4 mL) and water (1 mL), and sodium hydroxide (100 mg, 2.5 mmol) was added thereto. After the addition was completed, the reaction system was stirred at room temperature (25° C.) for 16 hours. 3M hydrochloric acid solution was added to the reaction system to adjust the pH to 5, the reaction solution was extracted with ethyl acetate, the organic phase was dried, filtered, and concentrated to obtain a solid, the solid was added to methanol to make a slurry, the reaction solution was filtered, the solid was washed with methanol three times, and the solid was dried to obtain compound J4-4, which was directly used in the next step reaction without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 13.18 (s, 2H), 4.46 - 4.43 (m, 2H), 4.41 - 4.37 (m, 2H), 1.38 (s, 6H), 1.33 (s, 6H).

[0192] Step 4: Preparation of compound J4-5 Compound J4-5 was synthesized in a similar manner to the synthesis of Example J1. MS (ESI) m / z (M+H) + =1211.60

[0193] Step 5: Preparation of compound J4 Compound J4-5 (52 mg, 0.042 mmol) was dissolved in methanol (2 mL), and concentrated hydrochloric acid (0.5 mL) was added thereto. After the addition was completed, the reaction system was stirred at room temperature for 5 hours. The reaction solution was concentrated, and methanol (1 mL) was added to dissolve the compound, and sodium bicarbonate solution was added to adjust the pH to 8. After filtration, the filtrate was purified by high-performance preparative liquid chromatography (separation conditions: column: Agilent 10 Prep-C18 250 × 21.2 mm; column temperature: 25 ° C; mobile phase: water (10 mM / L ammonium bicarbonate) - acetonitrile; acetonitrile: 65% ~ 95% 9 min, flow rate: (30 mL / min) to obtain compound J4. 1 H NMR (400 MHz, DMSO-d6) δ 7.47 (dd, J = 14.8, 7.0 Hz, 4H), 7.40 (q, J = 3.5, 2.9 Hz, 6H), 6.78 (d, J = 2.0 Hz, 2H), 5.20 (d, J = 7.0 Hz, 2H), 4.45 (s, 4H), 4.35 - 4.28 (m, 4H), 4.07 (d, J = 7.0 Hz, 2H), 3.73 (dd, J = 5.8, 2.5 Hz, 2H), 3.68 - 3.54 (m, 10H), 3.47 - 3.32 (m, 14H), 3.22 - 3.18 (m, 2H), 3.12 (dd, J = 13.3, 6.2 Hz, 2H), 2.77 (dd, J = 11.6, 5.1 Hz, 2H), 2.59 (dd, J = 11.6, 5.7 Hz, 2H), 2.29 (s, 6H). MS (ESI) m / z (M+H) + =1131.40 HPLC purity: 100%, retention time: 6.968min.

[0194] Separation conditions: Column: Waters XBridge 4.6×100 mm, 3.5 um; Column temperature: 40°C; Mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile; Acetonitrile: 5%-95% 7 min, 95% 8 min; Flow rate: 1.2 mL / min.

[0195] Experimental Example 1 Cell-based NHE3 activity analysis under transient and sustained conditions Opossum kidney cells (Opossum kindney, OK) were obtained from ATCC and cultured and grown according to their instructions. OK monoclonal stable cell lines expressing rat NHE3 (gene bank accession number: M85300) protein and human NHE3 (gene bank accession number: NM_004174.1) protein were constructed by lentivirus infection.

[0196] The general procedure for cell-based NHE3 activity experiments under transient conditions (transient inhibition) was to measure rat NHE3-mediated Na+-dependent H+ antitransport by an adaptation of the pH-sensitive dye method first reported by Tisen (Proc. Natl. Acad. Sci. USA) (1984) 81(23):7436-7440) and optimization was performed according to the instruction "Measuring Intracellular pH With the FLIPR and FLIPR 384 Fluorometric Imaging Plate Reader Systems" published by Molecular Devices. The specific method is as follows: rat NHE3 OK monoclonal cells or human NHE3 OK monoclonal cells were seeded into 384-well plates and grown overnight. The medium was aspirated from the wells, and the cells were washed twice with FLIPR buffer (Hank's BSS 1X, 20 mM HEPES, 1% BSA) and then incubated with FLIPR buffer (Hank's BSS 1X, 20 mM HEPES, 1% BSA) containing 5 mM BCECF-AM (Invitrogen) for 45 min at room temperature. Next, 5 mL of 200 mM NH4Cl-HEPES buffer (Hank's BSS 1X, 20 mM HEPES, 200 mM NH4Cl) was added and incubated for 15-20 min at room temperature. The cells were washed twice with 20 mM NH4Cl-HEPES buffer (Hank's BSS 1X, 20 mM HEPES, 20 mM NH4Cl). 0.4 mM amiloride (EIPA) and 0-30 mM test compound or Na-HEPES buffer (100 mM NaCl, 50 mM HEPES, 10 mM glucose, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, pH: 7.4) were added, and the intracellular NHE3-mediated pH sensitivity was normalized by monitoring the fluorescence at λem535 nm of BCECF-AM excited at λex440 nm and λex490 nm, respectively. Ratio = fluorescence value (λex490 nm) / fluorescence value (λex440 nm) was set, and the average value of the ratio difference between the end time and the start time between duplicate wells was calculated, and the average value and the concentration value of the compound were plotted, and the IC was calculated using Graphpad Prism software.50 The values ​​were estimated, and the results are shown in Table 13.

[0197] The general procedure for cell-based NHE3 activity experiments under sustained conditions (sustained inhibition) is as follows: Rat NHE3 OK monoclonal cells or human NHE3 OK monoclonal cells were seeded into 384-well plates and grown overnight. The medium was aspirated from the wells and the cells were washed twice with FLIPR buffer (Hank's BSS 1X, 20 mM HEPES, 1% BSA) and then incubated in Na-HEPES buffer (100 mM NaCl, 50 mM HEPES, 10 mM glucose, 5 mM KCl, 2 mM CaCl) containing 0-30 mM test compound. l2 , 1 mM MgCl2, pH: 7.4) was added and incubated at room temperature for 60 min. Compounds were aspirated from the wells and the cells were incubated at room temperature for 45 min in FLIPR buffer (Hank's BSS 1X, 20 mM HEPES, 1% BSA) containing 5 mM BCECF-AM (Invitrogen). Next, 5 mL of 200 mM NH4Cl-HEPES buffer (Hank's BSS 1X, 20 mM HEPES, 200 mM NH4Cl) was added and incubated at room temperature for 15-20 min. Cells were washed twice with 20 mM NH4Cl-HEPES buffer (Hank's BSS 1X, 20 mM HEPES, 20 mM NH4Cl). The intracellular NHE3-mediated pH sensitivity was normalized by adding Na-HEPES buffer (100 mM NaCl, 50 mM HEPES, 10 mM glucose, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, pH: 7.4) containing 0.4 mM amiloride (EIPA, a selective antagonist of NHE3 that does not inhibit NHE-1 activity) and monitoring the fluorescence at λem535 nm of BCECF fluorescence excited at λex440 nm and λex490 nm, respectively. Ratio = fluorescence value (λex490 nm) / fluorescence value (λex440 nm) was set, the average value of the ratio difference between the end time and the start time between duplicate wells was calculated, the average value and the concentration value of the compound were plotted, and the EC was calculated by GraphPad Prism using the dose-response-inhibition (4-parameter) equation. 50The values ​​were calculated, and the results are shown in Tables 13 and 14.

[0198] [Table 13]

[0199] [Table 14]

[0200] Experimental Example 2 Inhibition of phosphate and sodium absorption in the intestinal tract of rats by a single dose Compound D1-P1-S was evaluated by measuring urinary phosphorus concentration, urinary sodium concentration and fecal morphology.

[0201] Six-week-old Sprague-Dawley rats were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Two rats per cage were placed in a SPF-class animal room and allowed to acclimate for approximately 1 week. Animals were allowed free access to food and water throughout the entire study period, and were kept on a 12-h light / 12-h dark light cycle. Animals were divided into groups: vehicle group, n=5; tenapanol 0.3 mg / kg group, n=5; D1-P1-S 0.03 mg / kg group, n=5; D1-P1-S 0.1 mg / kg group, n=5; D1-P1-S 0.3 mg / kg group, n=5; D1-P1-S 1.0 mg / kg group, n=5.

[0202] On the day of the experiment, animals were fasted for 8 hours and then intragastrically administered the test compound or vehicle (0.5% Tween 80 + 99.5% distilled water). The animals were then transferred to metabolic cages for single-cage feeding and food was allowed to return. Urine samples were collected 16 hours after administration, food intake was recorded, and fecal morphology in the collection funnel was evaluated by two independent observations. Fecal morphology score criteria: 1, normal pellet; 2, slightly loose stool (pellets stick to the side walls of the collector due to moisture); 3, loose stool (loses the normal shape of the pellet); 4, loose and amorphous (completely loses shape and has a blotchy pattern); 5, diarrhea (watery stool). The rat fecal morphology score (FFS) was determined by averaging the two independent observation scores of all rats in the same group (n=5). The mean value for the vehicle group was 1.

[0203] Urine was centrifuged at 3220 g for 5 min at 4°C, and urinary phosphorus concentration (phosphomolybdic acid UV end point colorimetric method) and urinary sodium concentration (ion selective electrode method) were measured.

[0204] The results are expressed as mean ± standard error (Means ± SEM). The urinary phosphorus excretion (or urinary sodium excretion) of the rats was standardized and corrected by comparing with the dietary phosphorus (or sodium) intake, and the formula is as follows: standardized corrected value of urinary phosphorus excretion (expressed as nP) = urinary phosphorus excretion / dietary phosphorus intake; standardized corrected value of urinary sodium excretion (expressed as nNa) = urinary sodium excretion / dietary sodium intake; one-way analysis of variance was used; fecal morphology score was verified by non-parametric test. *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001.

[0205] Figures 1-3 show the effects of compound D1-P1-S on urinary phosphorus, urinary sodium excretion and fecal morphology in normal rats after a single dose. These results show that compound D1-P1-S has a dose-effect relationship in reducing urinary phosphorus excretion, and can significantly reduce urinary phosphorus excretion at doses of 0.3 mg / kg and 1.0 mg / kg. The effect of D1-P1-S in reducing urinary phosphorus excretion is superior to tenapanol at the same dose (0.3 mg / kg). Compound D1-P1-S can significantly reduce urinary sodium excretion. The water content of rat feces tends to increase as the dose of compound D1-P1-S increases.

[0206] Experimental Example 3: Effect of multiple administrations on blood phosphorus concentration in rats Compound D1-P1-S was evaluated by measuring serum phosphorus concentration, urinary phosphorus concentration, urinary sodium concentration and fecal morphology in rats.

[0207] Six-week-old Sprague-Dawley rats were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Two rats per cage were placed in a SPF-class animal room and allowed to acclimate for approximately 1 week. Animals were allowed free access to food and water throughout the entire study period, and were kept on a 12-h light / 12-h dark light cycle. Animals were divided into groups: vehicle group, n=5; tenapanol 0.05mg / kg group, n=5; D1-P1-S 0.01mg / kg group, n=5; D1-P1-S 0.05mg / kg group, n=5; D1-P1-S 0.5mg / kg group, n=5; D1-P1-S 1.0mg / kg group, n=5.

[0208] After the start of the experiment, the feeding rhythm of the rats was adjusted to daytime feeding, with a 16-hour overnight fast and an 8-hour daytime feeding resumption. After the start of administration, the test compound or vehicle (0.5% Tween 80 + 99.5% distilled water) was intragastrically administered twice a day at 4-hour intervals for 14 consecutive days during the feeding period. The body weight and food intake of the animals were measured daily, serum phosphorus concentration (including baseline values ​​before administration), 24-hour urinary phosphorus excretion, and 24-hour urinary sodium excretion were measured once or twice a week, and the morphology of the feces in the collection funnel was scored (the morphology of the feces was evaluated by two independent observations). Score criteria for fecal morphology: 1, normal pellets; 2, slightly loose stool (pellets stick to the side walls of the collector due to moisture); 3, loose stool (loses the normal shape of the pellets); 4, loose and amorphous (completely loses shape and has a stained pattern); 5, diarrhea (watery stool). The rat fecal morphology score (FFS) was determined by averaging the scores of two independent observations of all rats in the same group (n=5). The vehicle group had a mean of 1.

[0209] The experimental process is shown in Figure 4 below.

[0210] The blood was left at room temperature for 2 hours and then centrifuged at 4,500 g for 10 minutes at 4°C, and the urine was centrifuged at 3,220 g for 5 minutes at 4°C. Blood phosphorus concentration, urinary phosphorus concentration (phosphomolybdic acid UV endpoint colorimetric method), and urinary sodium concentration (indirect ion electrode method) were measured.

[0211] Results are expressed as mean ± standard error (Means ± SEM), n = 5 rats / group. The urinary phosphorus excretion (or urinary sodium excretion) of rats was standardized and corrected by comparing with the dietary phosphorus (or sodium) intake, using the following formula: standardized corrected value of urinary phosphorus excretion (represented by nP) = urinary phosphorus excretion ÷ dietary phosphorus intake; standardized corrected value of urinary sodium excretion (represented by nNa) = urinary sodium excretion ÷ dietary sodium intake; two-way analysis of variance was used; fecal morphology scores were verified by non-parametric tests. *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001.

[0212] Experimental Results Blood phosphorus level Compared with the blood phosphorus concentration of rats in the solvent control group, compound D1-P1-S significantly reduced the blood phosphorus concentration of rats after 4 days of treatment at a dose of 0.5mg / kg or 1.0mg / kg; after 10 days of treatment at a dose of 0.01mg / kg, 0.05mg / kg, 0.5mg / kg, 1.0mg / kg, significantly reduced the blood phosphorus concentration of rats; except for the highest dose group of 1.0mg / kg, the blood phosphorus of other groups tended to be stable. The blood phosphorus concentration lowering effect of D1-P1-S at a dose of 0.01mg / kg was similar to that of tenapanol at a dose of 0.05mg / kg. Details are shown in Figure 5 below.

[0213] Urinary phosphorus excretion The 24-hour nP of rats in each group was compared with that of rats in the vehicle group, and after one day of treatment with compound D1-P1-S at doses of 0.01 mg / kg, 0.05 mg / kg, 0.5 mg / kg and 1.0 mg / kg, the nP of rats tended to decrease, the higher the dose, the lower the nP, and the nP was significantly decreased at the dose of 1.0 mg / kg. After 10 days of treatment, the nP of rats at doses of 0.01 mg / kg, 0.05 mg / kg, 0.5 mg / kg and 1.0 mg / kg all decreased significantly, and the nP of rats tended to remain stable for the next 15 days, but the nP of rats in the low dose group (0.01 mg / kg) tended to increase. The effect of D1-P1-S at a dose of 0.01 mg / kg to decrease the nP of rats was similar to that of tenapanol at 0.05 mg / kg. For details, see Figure 6 below.

[0214] Urinary sodium excretion The 24-hour nNa of each group of rats was compared with that of the vehicle control group, and after one day of treatment with compound D1-P1-S at doses of 0.01mg / kg, 0.05mg / kg, 0.5mg / kg and 1.0mg / kg, the nNa of the rats was significantly decreased. However, after 10 days of treatment, the nNa of the rats at doses of 0.01mg / kg and 0.05mg / kg tended to increase. Details are shown in Figure 7 below.

[0215] Fecal morphology score Compared with the rats in the vehicle control group, the fecal morphology score of rats was significantly increased after one day of treatment with compound D1-P1-S at doses of 0.05 mg / kg, 0.5 mg / kg, and 1.0 mg / kg. Rats in the high dose groups of 0.5 mg / kg and 1.0 mg / kg had more severe loose stools, but the number of loose stools observed decreased with continued treatment. No rats had loose stools when treated with the low dose of 0.01 mg / kg. Details are shown in Figure 8.

Claims

1. Compounds represented by formula (I), their optical isomers and pharma- ceutically acceptable salts 【Chemistry 1】 (however, R 1 is CH 3 , 【Chemistry 2】 is selected from R ２ , R ３ , R ４ , R ５ , R ６ are each independently H, F, Cl, Br, OH, NH2, CN, CH3, 【Chemistry 3】 is selected from R ７ , R ８ are each independently selected from H; T is selected from N and CH; Ring A is selected from pyrrolidin-2-one, isothiazolidine-1,1-dioxide, 1,2-thiazine-1,1-dioxide, piperidin-2-one, 3,4-dihydropyridin-2(1H)-one, 5,6-dihydro-2H-1,2-thiazine-1,1-dioxide, pyridinyl and pyrazolyl, wherein said pyrrolidin-2-one, isothiazolidine-1,1-dioxide, 1,2-thiazine-1,1-dioxide, piperidin-2-one, 3,4-dihydropyridin-2(1H)-one, 5,6-dihydro-2H-1,2-thiazine-1,1-dioxide, pyridinyl or pyrazolyl is optionally substituted by 1, 2 or 3 R; n is selected from 2 and 3; L １ teeth, 【Chemistry 4】 is selected from L ２ teeth, 【Chemistry 5】 is selected from L ３ is a single bond, 【Chemistry 6】 is selected from L ４ teeth, 【Chemistry 7】 and 【Chemistry 8】 is optionally substituted by 1, 2 or 3 R; X is a single bond, N, NH, O, 【Chemistry 9】 is selected from R is independently H, OH, or NH ２ , 【Chemistry 10】 (selected from ).

2. Structural unit 【Chemistry 11】 teeth, 【Chemistry 12】 The compound according to claim 1, its optical isomers and pharma- ceutically acceptable salts thereof, selected from:

3. L ４ teeth, 【Chemistry 13】 The compound according to claim 1, its optical isomers and pharma- ceutically acceptable salts thereof, selected from:

4. Structural Units 【Chemistry 14】 The compound according to claim 1, its optical isomers and pharma- ceutically acceptable salts thereof, selected from:

5. A compound of the following formula selected from the following formulae, its optical isomers and pharma- ceutically acceptable salts thereof: 【Chemistry 15-1】 【Chemistry 15-2】 【Chemistry 15-3】 【Chemistry 15-4】 【Chemistry 15-5】 【Chemistry 15-6】 【Chemistry 15-7】 【Chemistry 15-8】 【Chemistry 15-9】 【Chemistry 15-10】 【Chemistry 15-11】

6. Use of the compound according to any one of claims 1 to 5, its optical isomers and its pharma- ceutically acceptable salts in the manufacture of a medicament for inhibiting NHE-mediated sodium or proton reverse transport.

7. Use of the compound according to any one of claims 1 to 5, its optical isomer, and its pharma- ceutical acceptable salt in the manufacture of a medicament for treating a disease selected from irritable bowel syndrome, heart failure, chronic kidney disease, end stage renal disease, or liver disease.

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