An inositol derivative and its uses

Abstract

This relates to an inositol derivative and its uses. Specifically, a compound is provided comprising two or more portions of formula (D) connected by a common central linker L2, as shown below.

Description

Technical Field

[0001] This disclosure belongs to the field of pharmaceutical technology, specifically relating to inositol derivatives and their uses. Background Technology

[0002] Currently, the incidence of chronic kidney disease (CKD) in my country is as high as 10.8%, and it is showing an increasing trend year by year. It is estimated that there will be nearly 3 million patients with end-stage renal disease (ESRD) in 2018. Among ESRD patients undergoing hemodialysis, the mortality rate from cardiovascular events is 5 to 30 times higher than that of general patients. Clinically, it has been found that at least 80% of hemodialysis patients develop cardiovascular calcification (CVC). CVC is a secondary lesion, mainly related to calcium and phosphorus metabolism disorders. The formation and growth of calcium crystals are the key mechanisms of CVC. Currently, the main treatments used clinically include vitamin D, phosphate conjugates, and calcimimetic agents.

[0003] Large vessel calcium deposition leading to coronary atherosclerosis, arteriosclerosis, left ventricular hypertrophy, and myocardial ischemia is a major cause of increased morbidity and mortality in patients with chronic kidney disease. Calcification defense is a severe form of CVC, characterized by vascular calcification and blockage of small blood vessels in the subcutaneous adipose tissue layer and dermis. It is a rare but life-threatening disease that can cause severe pain and ischemic skin necrosis (Nigwekar SU et al, N Engl J Med. 2018, 378(18), 1704-1714.). Once calcification defense is diagnosed, the patient's prognosis is poor. Calcification defense mainly affects patients with end-stage renal disease (ESRD) and has not received sufficient clinical attention. A high proportion of ESRD patients have extraosseous calcification. Although most of these extraosseous calcifications are not calcification defense, calcification defense cannot be simply regarded as ordinary vascular calcification in ESRD patients. Infections and other wound-related complications caused by calcification defense are the main causes of morbidity and hospitalization. Patients usually only receive painkillers and wound treatment, and there is still no approved treatment to address the root cause.

[0004] SNF472 is an intravenous formulation of IP6 sodium salt developed by Sanifit. It inhibits the continued growth of hydroxyapatite (HAP) crystals (the main component of calcium deposits) at calcification sites, thus preventing vascular occlusion (Perelló J et al. Br J Clin Pharmacol. 2018, 84(12), 2867-2876.). In 2012, SNF472 received orphan drug designation from the FDA and EMA for the treatment of calcification defense. Summary of the Invention

[0005] This disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotational isomer, or tautomer thereof.

[0006]

[0007] It consists of two or more parts represented by equation (D) connected by a common connector L. 2 The connected equation (D) is shown below:

[0008] in, for o and q are each independently selected from 0 to 2, and the value of o+q is 0, 1, or 2, L 1 It represents -O-, -NH-, -C(=O)-, -OC(=O)-, -NHC(=O)-, -S-, or a single bond;

[0009] At least one X is independently selected from R. 1 The R 1 Selected from or containing formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown or of formula R 4 -O-(CH2-CHOR 5 -CH2O) g The polyglycerol shown is given, and the remaining X's are each independently selected from hydrogen, -OH, OPO3. 2- OPSO2 2- OSO3 - or CO2 - And each formula (D) may be the same or different, wherein the polyethylene glycol or polyglycerol may optionally be selected from one or more groups selected from hydroxyl, deuterium, halogen, nitrile, nitro, amino, C 1-6 Alkyl, C 1-6 Alkyl groups, -OC(O)R 4 C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds;

[0010] L 2 For the common central connector connected to equation (D), C is included. 2-20 Straight-chain or branched alkylene, C 2-20 Straight-chain or branched alkeneoxy groups, C 2-20 Straight-chain or branched alkylamino groups, C 2-20 Straight-chain or branched alkylene mercapto, C 2-20 Straight-chain or branched sub-alkenyl groups, C 2-20 Straight-chain or branched alkenyloxy groups, C2-20 Cycloalkylene, -(OCH2CH2) e O-, -(OCH2CH2) e -or-O-(CH2-CHOR) 2 -CH2O) e - and optionally includes part A, wherein part A is selected from oxygen atom, nitrogen atom, sulfur atom, C 1-6 Alkyl, C 3-7 Cycloalkyl, five- or six-membered heterocyclic, aromatic, or heteroaromatic groups, wherein the alkylene group, alkoxide group, alkylamino group, alkoxidethiol group, alkenyl group, alkenoxy group, cycloalkylene group, or -(OCH2CH2) is used. e O-, -(OCH2CH2) e -or-O-(CH2-CHOR) 2 -CH2O) e Optionally selected by one or more groups selected from hydroxyl, halogen, deuterium, amino, nitrile, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl or C 3-7 Cycloalkylene-substituted, the C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 The cycloalkyl group may be optionally replaced by halogen, hydroxyl, deuterium, amino, nitrile or nitro groups;

[0011] When part A is selected from C 1-6 When A is an alkyl or nitrogen atom, it may be optionally replaced by R. 3 Replaced by, R 3 The group is selected from hydrogen, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, SR', NR'(R”), COOR' or CONR'(R”), wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally replaced by one or more groups selected from alkyl, alkoxy, cycloalkyl, heterocyclic, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclic, haloaryl, haloheteroaryl;

[0012] When part A is selected from sulfur atoms, A can be arbitrarily replaced by oxygen;

[0013] R 4 Selected from hydrogen, C 1-6 Alkyl or C 3-7 cycloalkyl, the C 1-6 Alkyl or C 3-7 The cycloalkyl group may optionally be substituted by one or more groups selected from deuterium, nitrile, nitro, amino, hydroxyl, or halogen; further, R 4 Preferably, it is hydrogen, methyl, ethyl, trifluoromethyl, or cyclopropyl;

[0014] R 2 Or R 5 Each is independently selected from hydrogen and C 1-6 Alkyl or glycerol chain, preferably hydrogen, methyl or ethyl;

[0015] R' or R" is independently selected from hydrogen, hydroxyl, alkyl, alkoxy, alkenyl, acyl, aryl, or heteroaryl, wherein the alkyl, alkoxy, aryl, or heteroaryl group is optionally selected by one or more groups selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxyl, nitro, nitrile, or -R. a Replaced; R a Selected from aryl or heteroaryl, wherein the aryl or heteroaryl group is optionally substituted by one or more groups selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxyl, aryl, heteroaryl, nitro, nitrile, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclic, haloaryl or haloheteroaryl.

[0016] g = 1 - 200;

[0017] n is selected from 2 to 8, for example, 2, 3, 4, 6, 7 and 8;

[0018] e = an integer between 1 and 20 (including but not limited to 1, 2, 3, 4, 6, 7, 12, 13, 14, 16 or 17).

[0019] In this disclosure, "-OC(=O)-" or "-NHC(=O)-" does not specifically indicate whether the functional group it is connected to is on the left or right end. For example, "-OC(=O)-" and "-C(=O)O-" have the same definition. "-NHC(=O)-" and "-C(=O)NH-" have the same definition.

[0020] In some implementations, L 1 This represents "-OC(=O)-" or "-C(=O)O-". In some implementations, L 1 This represents "-NHC(=O)-" and "-C(=O)NH-". In some implementations, L 1 Indicated as -O-. In some implementations, L 1 This represents -C (=O)-. In some implementations, L 1 Indicates -S- or a single key.

[0021] In some embodiments, the compounds disclosed herein Selected from CHL 1 -、CH(L 1 -)CHX、CHXCH(L 1 -), CHXCH(L 1 -)CHX、CHX-CHXCH(L1 -)CHX、CH(L 1 -)CHX-CHX、CHXCH(L 1 -)CHX-CHX or CHX-CHXCH(L) 1 -)CHX-CHX, where "-" represents a bond.

[0022] In some embodiments, the compounds disclosed herein comprise five to seven-membered rings, wherein at least four ring members can be represented by the formula CH-X, and one ring member can be represented by the formula -CH-L. 1 .

[0023] In some embodiments, the compounds disclosed herein comprise a five-membered ring, wherein four ring members may be represented by the formula CH-X, and one ring member may be represented by the formula -CH-L. 1 -

[0024] In some embodiments, the compounds disclosed herein comprise a six-membered ring, wherein five ring members may be represented by the formula CH-X, and one ring member may be represented by the formula -CH-L. 1 -

[0025] In some embodiments, the compounds disclosed herein comprise a seven-membered ring, wherein six ring members may be represented by the formula CH-X, and one ring member may be represented by the formula -CH-L. 1 -

[0026] In some embodiments, the compounds disclosed herein comprise a six-membered ring, wherein five ring members may be represented by the formula CH-X, and one ring member may be represented by the formula -CH-L. 1 -

[0027] In some embodiments, the compound of formula (I) is:

[0028]

[0029] In some embodiments, the compounds disclosed herein comprise the portion represented by formula (D) as shown in formula (Da) or (Db):

[0030]

[0031] Among them, L 1 X is as defined in the compound of formula (I) above.

[0032] Polyglycerol, such as formula R 4 -O-(CH2-CHOH-CH2O) g - As shown, where R 4 Selected from hydrogen, methyl, or ethyl, g = 1-200, branched or hyperbranched polyglycerol as shown in formula R 4 -O-(CH2-CHOR5 -CH2O) g - As shown, where R 5 Selected from hydrogen, C 1-6 Alkyl or glycerol chain, and R 4 Selected from hydrogen, methyl, or ethyl.

[0033] Glycerol chain, as shown in formula R 4 -O-(CH2-CHOR 2 -CH2O) g -, where R 2 It is hydrogen.

[0034] Polyethylene glycol, as shown in formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - As shown, where R 4 Selected from hydrogen, methyl or ethyl, g = 1-200.

[0035] In this disclosure, the molar mass of polyethylene glycol or polyglycerol is selected from 100 g / mol to 3000 g / mol, particularly 100 g / mol to 2500 g / mol, even more particularly 100 g / mol to 2000 g / mol, or 200 g / mol to 3000 g / mol, particularly 300 g / mol to 2500 g / mol, even more particularly 400 g / mol to 2000 g / mol.

[0036] In some embodiments, at least one X of the compound is selected from R. 1 The R 1 Selected from or containing formula R 4 -O-(CH2-CHOH-CH2O) g - The polyglycerol shown, where R 4 Selected from hydrogen, methyl, or ethyl, g = 1-200. In other embodiments, g = 3-20. In other embodiments, g = 10-20. In other embodiments, g = 9-45. Other embodiments provide compounds of Formula I in which g is 2 to 100, 2 to 50, 2 to 20, or 2 to 10.

[0037] In some embodiments, at least one X in the compound is selected from R. 1 The R 1 Selected from or containing R 4 -O-(CH2-CHOR 5 -CH2O) g - The branched or hyperbranched polyglycerol shown, wherein R 5 Selected from hydrogen or glycerol chains, and R 4The X is selected from hydrogen, methyl, or ethyl. In other embodiments, one, two, three, four, or five X's in the compound are selected from R. 1 The R 1 Selected from or containing formula R 4 -O-(CH2-CHOH-CH2O) g - As shown in the polyglycerol or R 4 -O-(CH2-CHOR 5 -CH2O) g - The branched or hyperbranched polyglycerol shown, wherein R 5 Selected from hydrogen or glycerol chains, and R 4 Selected from hydrogen, methyl, or ethyl, g = 1-200. In some embodiments, X in the compound is selected from R. 1 The R 1 Selected from or containing formula R 4 -O-(CH2-CHOH-CH2O) g - As shown in the polyglycerol or R 4 -O-(CH2-CHOR 5 -CH2O) g - The branched or hyperbranched polyglycerol shown, with a molar mass of 100 g / mol to 3000 g / mol, particularly 100 g / mol to 2500 g / mol, more particularly about 100 g / mol to 2000 g / mol, or 200 g / mol to 3000 g / mol, particularly 300 g / mol to 2500 g / mol, more particularly about 400 g / mol to 2000 g / mol.

[0038] In some embodiments, at least one X in the compound is selected from R. 1 The R 1 Selected from or containing formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown, where R 4 Selected from hydrogen, methyl, or ethyl, g = 1-200, the polyethylene glycol is optionally coated with one or more elements selected from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 The alkylene oxide is substituted. In some embodiments, g = 3-20. In some embodiments, g = 10-20. In some embodiments, g = 9-45.

[0039] In some embodiments, at least one X in the compound is selected from R. 1 The R 1 Selected from or containing formula R4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol or R shown 4 O(CH2-CHOH-CH2O) g - As shown in the polyglycerol or R 4 -O-(CH2-CHOR 5 -CH2O) g - The branched or hyperbranched polyglycerol shown, wherein g = 2-100, the polyethylene glycol is optionally composed of one or more elements selected from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 The compound is substituted with a cycloalkylene group. In some embodiments, g = 7-50; in others, g = 7-15; in still others, g = 40-50. Other embodiments provide compounds of Formula I in which g is 2 to 100, 2 to 50, 2 to 20, or 2 to 10. In some embodiments, three of the X's in the compound are selected from R. 1 The R 1 Selected from or containing formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown, and in the same formula (D) portion, the polyethylene glycol is optionally composed of one or more elements selected from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0040] In other embodiments, the 1, 2, 3, 4, or 5 X's in the compound are selected from R. 1 The R 1 Selected from or containing formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown, where R 4 Selected from hydrogen, methyl, or ethyl, g = 1-200, the polyethylene glycol is optionally coated with one or more elements selected from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0041] In some embodiments, X in the compound is selected from R 1 The R 1 Selected from or containing formula R4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown, wherein the polyethylene glycol is optionally composed of one or more elements selected from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 The alkylene oxide is substituted, and the molar mass is from 100 g / mol to 3000 g / mol, particularly from 100 g / mol to 2500 g / mol, even more particularly from 100 g / mol to 2000 g / mol, or from 200 g / mol to 3000 g / mol, particularly from 300 g / mol to 2500 g / mol, even more particularly from 400 g / mol to 2000 g / mol.

[0042] In some embodiments, at least two or three of the X atoms in the aforementioned compound are selected from R. 1 The R 1 Selected from or containing formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown, wherein the polyethylene glycol is optionally composed of one or more elements selected from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 The alkylene group is substituted, and the remaining X groups are all OPO3. 2- Or they are all OPSO2 2 -or both are OSO3 - In other embodiments, at least two of the X atoms in the aforementioned compound are selected from R. 1 The R 1 Selected from or containing formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown, wherein the polyethylene glycol is optionally composed of one or more elements selected from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 The alkylene groups are substituted, and in the same formula (D) part, all the remaining X are OPO3. 2- Or they are all OPSO2 2 -or both are OSO3 - .

[0043] In some embodiments, at least one X in formula (D) of the aforementioned compound is selected from R. 1 The R1 Selected from or containing formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown or derived from formula R 4 -O-(CH2-CHOH-CH2O) g - The polyglycerol shown, where R 4 Selected from hydrogen, methyl, or ethyl, g = 1-200, the polyethylene glycol or polyglycerol is optionally mixed with one or more elements selected from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0044] In some embodiments, at least two or three X's on formula (D) of the aforementioned compound are selected from R. 1 The R 1 Selected from or containing formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown, where R 4 Selected from hydrogen, methyl, or ethyl, g = 1-200, the polyethylene glycol is optionally coated with one or more elements selected from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 The polyethylene glycol is substituted with cycloalkylene compounds. Further, the molar mass of the polyethylene glycol is from 100 g / mol to 3000 g / mol, particularly from 100 g / mol to 2500 g / mol, even more particularly from 100 g / mol to 2000 g / mol, or from 200 g / mol to 3000 g / mol, particularly from 300 g / mol to 2500 g / mol, even more particularly from 400 g / mol to 2000 g / mol.

[0045] In some embodiments, at least two or three X's on formula (D) of the aforementioned compound are selected from R. 1 The R 1 Selected from or containing formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown, where R 4 Selected from hydrogen, methyl, or ethyl, g = 1-200, the polyethylene glycol is optionally coated with one or more elements selected from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C3-7 Substituted with cycloalkylene compounds; the remaining X's are all OPO3. 2- Or they are all OPSO2 2 -or both are OSO3 - Furthermore, the molar mass of polyethylene glycol is from 100 g / mol to 3000 g / mol, particularly from 100 g / mol to 2500 g / mol, even more particularly from 100 g / mol to 2000 g / mol, or from 200 g / mol to 3000 g / mol, particularly from 300 g / mol to 2500 g / mol, even more particularly from 400 g / mol to 2000 g / mol.

[0046] In some embodiments, at least two or three X's on formula (D) of the aforementioned compound are selected from R. 1 The R 1 Selected from or containing formula R 4 -O-(CH2-CHOH-CH2O) g - The polyglycerol shown, where R 4 Selected from hydrogen, methyl, or ethyl, g = 1-200, the polyglycerol is optionally coated with one or more elements selected from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 The polyethylene glycol is substituted with cycloalkylene compounds. Further, the molar mass of the polyethylene glycol is from 100 g / mol to 3000 g / mol, particularly from 100 g / mol to 2500 g / mol, even more particularly from 100 g / mol to 2000 g / mol, or from 200 g / mol to 3000 g / mol, particularly from 300 g / mol to 2500 g / mol, even more particularly from 400 g / mol to 2000 g / mol.

[0047] In some embodiments, at least two or three X's on formula (D) of the aforementioned compound are selected from R. 1 The R 1 Selected from or containing formula R 4 -O-(CH2-CHOH-CH2O) g - The polyglycerol shown, wherein the polyglycerol is optionally composed of one or more elements selected from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 The alkylene group is substituted, and the remaining X groups are all OPO3. 2- Or they are all OPSO2 2 -or both are OSO3 - , where R 4Selected from hydrogen, methyl, or ethyl, g = 1-200. Further, the molar mass of polyethylene glycol is from 100 g / mol to 3000 g / mol, particularly from 100 g / mol to 2500 g / mol, even more particularly from 100 g / mol to 2000 g / mol, or from 200 g / mol to 3000 g / mol, particularly from 300 g / mol to 2500 g / mol, even more particularly from 400 g / mol to 2000 g / mol.

[0048] In some embodiments, the disclosed compound or its pharmaceutically acceptable salt, or their stereoisomers, rotational isomers, or tautomers are:

[0049]

[0050] Furthermore, the compounds disclosed herein exist in different spatial configurations. In the embodiments, the different spatial configurations do not affect the compound activity or inhibit calcium ion crystallization efficiency. In optional embodiments, the compound of formula (III) can be selected from:

[0051]

[0052] In some embodiments, the aforementioned compound is L as in formula (III) 2 Selected from C 3-10 Straight-chain or branched alkylene, C 3-10 Straight-chain or branched alkene groups, wherein the alkylene group or alkene group is optionally surrounded by one or more groups selected from hydroxyl, halogen, deuterium, amino, nitrile, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds. In some embodiments, L 2 Selected from C 3-5 Straight-chain or branched alkylene, C 3-5 Straight-chain or branched alkeneoxy groups. In some embodiments, L 2 Selected from C 4-8 Straight-chain or branched alkylene, C 4-8 Straight-chain or branched alkeneoxy groups. In some embodiments, L 2 Selected from C 3-4 Straight-chain or branched alkylene, C 3-4 Straight-chain or branched alkeneoxy groups.

[0053] In some embodiments, L2 in the aforementioned compound as in formula (III) is selected from... Where r and s are selected from integers between 1 and 6, for example, 1, 2, or 3. The radical is optionally selected from one or more groups selected from hydroxyl, halogen, deuterium, amino, nitrile, nitro, C 1-6Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl or C 3-7 Substituted with a cycloalkylene group; A is as defined in the aforementioned compound of formula (I), and when A is partially selected from nitrogen atoms, A may optionally be replaced by C. 1-6 Alkyl substitution, such as methyl; L 1 As defined in compound (I).

[0054] In some embodiments, L2 in the aforementioned compound as in formula (III) is selected from... The The radical is optionally selected from one or more groups selected from hydroxyl, halogen, deuterium, amino, nitrile, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl or C 3-7 Substituted with cyclohexane, L 1 Selected from -O-, -NH-, -C(=O)-, -OC(=O)- or -S-, where A is selected from oxygen atom, nitrogen atom, or sulfur atom.

[0055] In some embodiments, in the aforementioned compound such as formula (III), A is selected from oxygen atom, nitrogen atom, sulfur atom or C. 1-6 Alkyl group, and when A is selected from carbon or nitrogen atoms, A is optionally divided by C. 1-6 Alkyl groups, including but not limited to methyl, ethyl, propyl, or butyl.

[0056] In some embodiments, L2 in the aforementioned compound as in formula (III) is selected from... Where r and s are 2 or 3 respectively, the... The radical is optionally selected from one or more groups selected from hydroxyl, halogen, deuterium, amino, nitrile, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds; L 1 Selected from -O-, -OC(=O)-; A is selected from oxygen atom, nitrogen atom, sulfur atom or C. 1-6 Alkyl group, and when A is selected from carbon or nitrogen atoms, A is optionally divided by C. 1-6 Alkyl groups, including but not limited to methyl, ethyl, propyl, or butyl.

[0057] In other embodiments, the aforementioned compound is L as in formula (III). 2 Selected from -(OCH2CH2) e O-, -(OCH2CH2) e -or-O-(CH2-CHOR) 2 -CH2O) e-, e = an integer between 1 and 20, such as 2, 3, 4, 5, 6, 7, 8, where -(OCH2CH2) e O-, -(OCH2CH2) e -or-O-(CH2-CHOR) 2 -CH2O) e -Optionally selected by one or more groups selected from hydroxyl, halogen, deuterium, amino, nitrile, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0058] In other embodiments, the aforementioned compound is L as in formula (III). 1 It has a single bond, and the molar mass of polydiethanol is less than 2000 g / mol.

[0059] In some implementations, L in formula (III) 2 -(OCH2CH2) e CH2O-, e = 1-20, L 1 It is a single key.

[0060] In other implementations, L in equation (III) 2 It is -O-(CH2-CHOH-CH2O) e -, e = 1-20, L 1 It is a single key.

[0061] In the alternative embodiments, the compound of formula (III) or its pharmaceutically acceptable salt, or its stereoisomers, rotational isomers, or tautomers are:

[0062] X as defined in claim 1, further wherein R 1 Preferred from or containing R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - represents polyethylene glycol, and R 4 Preferably, the polyethylene glycol is selected from hydrogen, methyl, ethyl, trifluoromethyl, or cyclopropyl, and is optionally substituted with one or more radicals selected from hydroxyl, deuterium, halogen, C. 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0063] In some embodiments, at least two of the aforementioned compounds of formula (III) have X selected from R. 1 The R 1 Selected from or containing formula R4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown, and on the same formula (D), wherein the polyethylene glycol is optionally mixed with one or more elements selected from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 The alkyl group is substituted with a cycloalkyl group, and the remaining X groups are each independently selected from hydrogen, -OH, OPO3. 2- OPSO2 2- OSO3 - or CO2 - .

[0064] In some embodiments, three of the aforementioned compounds, such as formula (III), have X selected from R. 1 The R 1 Selected from or containing formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown, and on the same formula (D), wherein the polyethylene glycol is optionally mixed with one or more elements selected from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 The alkyl group is substituted with a cycloalkyl group, and the remaining X groups are each independently selected from hydrogen, -OH, OPO3. 2- OPSO2 2- OSO3 - or CO2 - .

[0065] In some embodiments, the aforementioned compound is L as in formula (III) 2 Selected from:

[0066] -(OCH2CH2) h OA-(OCH2CH2) j O-, -(OCH2-CH2) h CH2O-A-(OCH2-CH2) j CH2O- or -(OCH2CH(OH)CH2) h OA-(OCH2CH(OH)CH2) j O-, the A portion is selected from C 1-6 Alkyl, C 3-7 Cycloalkyl (including cyclopropyl, n-butyl, cyclopentyl, or cyclohexyl), five- or six-membered heterocyclic or aromatic or heteroaromatic (including tetrahydrofuranyl, pyrroleyl, pyridyl, or phenyl), wherein -(OCH2CH2)h OA-(OCH2CH2) j O-, -(OCH2-CH2) h -A-(OCH2-CH2) j -or-(OCH2CH(OR) 2 CH2) h OA-(OCH2CH(OR 2 CH2) j O- optionally contains one or more elements selected from hydroxyl, halogen, deuterium, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds; h or j is an integer between 1 and 10, for example, 1, 2, 3, or 4. Further, L 1 Single bonds are preferred.

[0067] On the other hand, in some embodiments, the compound represented by Formula I or a pharmaceutically acceptable salt thereof, or their stereoisomers, rotational isomers, or tautomers, are...

[0068] Among them, X 1 To X 5 At least one of them is independently selected from R 1 The R 1 Selected from formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown or of formula R 4 -O-(CH2-CHOR 5 -CH2O) g The polyglycerol shown is selected from hydrogen, -OH, and OPO3, with the remainder independently selected. 2- OPSO2 2- OSO3 - or CO2 - ;X 6 To X 10 Each is independently selected from hydrogen, -OH, and OPO3. 2- OPSO2 2- OSO3 - CO2 - Or R 1 The R 1 Selected from formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown or of formula R 4 -O-(CH2-CHOR5 -CH2O) g - As shown in the polyglycerol, R 4 L 1 To L 3 As defined in Formula I, the polyethylene glycol or polyglycerol may optionally be selected from one or more elements chosen from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0069] In some implementations, X in Formula III-1 1 To X 5 At least one of them is independently selected from R 1 The R 1 Selected from formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown or of formula R 4 -O-(CH2-CHOR 5 -CH2O) g The polyglycerol shown is selected from hydrogen, -OH, and OPO3, with the remainder independently selected. 2- OPSO2 2- OSO3 - or CO2 - X 6 To X 10 Each is independently selected from hydrogen, -OH, and OPO3. 2- OPSO2 2- OSO3 - CO2 - The polyethylene glycol or polyglycerol may optionally be selected from one or more elements chosen from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0070] In some implementations, X in Formula III-1 1 To X 5 At least two of them are independently selected from R 1 The R 1 Selected from formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown or of formula R 4 -O-(CH2-CHOR 5 -CH2O) gThe polyglycerol shown is selected from hydrogen, -OH, and OPO3, with the remainder independently selected. 2- OPSO2 2- OSO3 - or CO2 - X 6 To X 10 Each is independently selected from hydrogen, -OH, and OPO3. 2- OPSO2 2- OSO3 - CO2 - The polyethylene glycol or polyglycerol may optionally be selected from one or more elements chosen from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0071] In some implementations, X in Formula III-1 1 To X 5 At least two of them are independently selected from R 1 The R 1 Selected from formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown or of formula R 4 -O-(CH2-CHOR 5 -CH2O) g - The polyglycerol shown, the rest are independently selected from OPO3 2- OPSO2 2- OSO3 - or CO2 - X 6 To X 10 Each is independently selected from hydrogen, -OH, and OPO3. 2- OPSO2 2- OSO3 - CO2 - The polyethylene glycol or polyglycerol may optionally be selected from one or more elements chosen from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0072] In some implementations, X in Formula III-1 1 To X 5 At least two of them are independently selected from R 1 The R 1 Selected from formula R 4 -(OCH2CH2) g O- or R4 -(OCH2CH2) g - The polyethylene glycol shown or of formula R 4 -O-(CH2-CHOR 5 -CH2O) g - The polyglycerol shown, the rest are independently selected from OPO3 2- or CO2 - X 6 To X 10 Each is independently selected from hydrogen, -OH, and OPO3. 2- OPSO2 2- OSO3 - CO2 - The polyethylene glycol or polyglycerol may optionally be selected from one or more elements chosen from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0073] In some implementations, X in Formula III-1 1 To X 5 At least two of them are independently selected from R 1 The R 1 Selected from formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown is selected independently from OPO3. 2- or CO2 - X 6 To X 10 Each is independently selected from hydrogen, -OH, and OPO3. 2- OPSO2 2- OSO3 - CO2 - The polyethylene glycol or polyglycerol may optionally be selected from one or more elements chosen from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0074] In some implementations, X in Formula III-1 6 To X 10 At least one of them is independently selected from R 1 The R 1 Selected from formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown or of formula R4 -O-(CH2-CHOR 5 -CH2O) g - The polyglycerol shown, the rest are independently selected from OPO3 2- or CO2 - The polyethylene glycol or polyglycerol may optionally be selected from one or more elements chosen from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0075] In some implementations, X in Formula III-1 6 To X 10 At least one of them is independently selected from R 1 The R 1 Selected from formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown is selected independently from OPO3. 2- or CO2 - The polyethylene glycol or polyglycerol may optionally be selected from one or more elements chosen from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0076] In some implementations, X in Formula III-1 6 To X 10 At least two of them are independently selected from R 1 The R 1 Selected from formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown or of formula R 4 -O-(CH2-CHOR 5 -CH2O) g - The polyglycerol shown, the rest are independently selected from OPO3 2- or CO2 - The polyethylene glycol or polyglycerol may optionally be selected from one or more elements chosen from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0077] In some implementations, X in Formula III-1 6 To X 10 At least two of them are independently selected from R1 The R 1 Selected from formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown is selected independently from OPO3. 2- or CO2 - The polyethylene glycol or polyglycerol may optionally be selected from one or more elements chosen from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0078] In some implementations, X in Formula III-1 1 To X 5 One of them is independently selected from R 1 The R 1 Selected from formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown is selected independently from OPO3. 2- or CO2 - X 6 To X 10 One of them is independently selected from R 1 The R 1 Selected from formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown is selected independently from OPO3. 2- or CO2 - The polyethylene glycol or polyglycerol may optionally be selected from one or more elements chosen from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0079] In some implementations, X in Formula III-1 1 To X 5 Two of them are independently selected from R 1 The R 1 Selected from formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown is selected independently from OPO3.2- or CO2 - X 6 To X 10 Two of them are independently selected from R 1 The R 1 Selected from formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown is selected independently from OPO3. 2- or CO2 - The polyethylene glycol or polyglycerol may optionally be selected from one or more elements chosen from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0080] Furthermore, Formula III-1 can have different spatial configurations. In the embodiments, different spatial configurations do not affect the compound's activity or inhibit calcium ion crystallization efficiency. In optional embodiments, the compound of Formula (III) can be selected from:

[0081]

[0082] In some implementations, X in Formula III-1 1 To X 5 At least two of them are independently selected from R 1 The R 1 Selected from or containing formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown or of formula R 4 -O-(CH2-CHOR 5 -CH2O) g - The polyglycerol shown, and X 6 To X 10 Each is independently selected from hydrogen, -OH, and OPO3. 2- OPSO2 2- OSO3 - or CO2 - R 4 L 1 To L 3 As defined in Formula I, the polyethylene glycol or polyglycerol may optionally be selected from one or more elements chosen from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0083] In some implementations, X in Formula III-1 1 To X 5 At least three of them are independently selected from R 1 The R 1 Selected from or containing formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown or of formula R 4 -O-(CH2-CHOR 5 -CH2O) g - The polyglycerol shown, and X 6 To X 10 Each is independently selected from hydrogen, -OH, and OPO3. 2- OPSO2 2- OSO3 - or CO2 - R 4 L 1 To L 3 As defined in Formula I, the polyethylene glycol or polyglycerol may optionally be selected from one or more elements chosen from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0084] In other embodiments, X in Formula III-1 1 X 4 Selected from R 1 The R 1 Selected from or containing formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown or of formula R 4 -O-(CH2-CHOR 5 -CH2O) g - The polyglycerol shown, and X 2 X 4 X 5 X 6 To X 10 Each is independently selected from hydrogen, -OH, and OPO3. 2- OPSO2 2- OSO3 - or CO2 - R 4 L 1 To L 3As defined in Formula I, the polyethylene glycol or polyglycerol may optionally be selected from one or more elements chosen from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0085] In other embodiments, X in Formula III-1 2 X 4 Selected from R 1 The R 1 Selected from or containing formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown or of formula R 4 -O-(CH2-CHOR 5 -CH2O) g - The polyglycerol shown, wherein the polyethylene glycol or polyglycerol is optionally selected from one or more elements selected from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds, and X 1 X 4 X 5 X 6 To X 10 Each is independently selected from hydrogen, -OH, and OPO3. 2- OPSO2 2- OSO3 - or CO2 - R 4 L 1 To L 3 As defined in Equation I.

[0086] In some implementation schemes, X in Equation III-1 6 To X 10 Selected from OPO3 2- OSO3 - or CO2 - In some implementations, X in Formula III-1 6 To X 10 Selected from OPO3 2- or OSO3 - In some implementations, X in Formula III-1 6 To X 10 Selected from OPO3 2- .

[0087] Furthermore, in some embodiments, the polyethylene glycol in Formula III-1 is optionally mixed with one or more elements selected from hydroxyl, halogen, deuterium, C1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 The alkylene oxide is substituted. In some embodiments, the polyethylene glycol in formula III-1 is replaced by one or more alkylene oxides selected from deuterium, C64, and C46. 1-6 Alkyl groups are substituted. In some embodiments, the polyethylene glycol in formula III-1 is substituted with one or more groups selected from deuterium, methyl, ethyl, or propyl.

[0088] In other embodiments, the compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or its stereoisomers, rotational isomers, or tautomers are...

[0089] Where X 1 To X 10 As defined in Equation III-1.

[0090] In some implementations, L in Formula I 2 For the common central connector connected to equation (D), C is included. 2-20 Straight-chain or branched alkylene, C 2-20 Straight-chain or branched alkeneoxy groups, -(OCH2CH2) e O- or -(OCH2CH2) e -, the alkylene group, alkene group, -(OCH2CH2) e O- or -(OCH2CH2) e -Optionally selected from one or more of hydroxyl, deuterium, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0091] In other implementations, L in Formula I 2 For the common central connector connected to equation (D), C is included. 2-10 Straight-chain or branched alkylene groups, -(OCH2CH2) e O- or -(OCH2CH2) e -, the alkylene group, -(OCH2CH2) e O- or -(OCH2CH2) e -Optionally selected from one or more of hydroxyl, deuterium, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds; L 1 This represents -O- or a single bond. In other embodiments, e in Formula I is 2 to 15, 2 to 10, 2 to 8, or 2 to 4.

[0092] On the other hand, the compounds disclosed herein are:

[0093]

[0094] The A portion is selected from nitrogen atoms, C 1-6 Alkyl, C 3-7 Cycloalkyl, five- or six-membered heterocyclic, aromatic, or heteroaromatic groups, wherein the C 1-6 Alkyl, C 3-7 Cycloalkyl, five- or six-membered heterocyclic or aromatic or heteroaromatic rings may be optionally replaced by halogen, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, SR', NR'(R”), COOR' or CONR'(R”);

[0095] e = 3 to 8, for example, 3, 4, 5, 6;

[0096] R', R”, L 2 As defined in the compound of formula (I) above.

[0097] Some embodiments provide compounds or pharmaceutically acceptable salts thereof, or their stereoisomers, rotational isomers, or tautomers, as follows:

[0098]

[0099] In some embodiments, the compounds disclosed herein, such as those of formula (V), contain L. 2 Selected from:

[0100] Where r, s, and t are each independently selected from integers between 1 and 6, for example, 1, 2, or 3; A, R 3 As defined in the compound of formula (I) above; L 1 It represents -O-, -NH-, -C(=O)-, -OC(=O)-, -NHC(=O)-, -S-, or a single bond.

[0101] In some embodiments, the compounds disclosed herein, such as those of formula (V), contain L. 2 Selected from:

[0102] Where r, s, and t are each independently selected from integers between 1 and 6, for example, 1, 2, or 3; A, R 3 As defined in the compound of formula (I) above; L 1 It represents -O-, -NH-, -C(=O)-, -OC(=O)-, or a single bond.

[0103] In some embodiments, the compounds disclosed herein, such as those of formula (V), contain L. 2 Selected from:

[0104] Where r, s, and t are each independently selected from integers between 1 and 6, for example, 1, 2, or 3; A, R 3 As defined in the compound of formula (I) above; L 1 Represents -O-, -OC(=O)-; A is selected from nitrogen atom, C 1-6 Alkyl groups (including but not limited to methyl, ethyl, propyl, or butyl). Further, R 3 Selected from hydrogen, hydroxyl, C 1-6 Alkyl groups (including but not limited to methyl, ethyl, propyl, or butyl), C 1-6 Alkoxy groups (including but not limited to methoxy, ethoxy, propoxy, or butoxy), C 3-7 Cycloalkyl groups (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl).

[0105] In some embodiments, the compounds disclosed herein, such as those of formula (V), contain L. 2 Selected from:

[0106] The A portion is selected from nitrogen atoms, C 1-6 Alkyl, C 3-7 Cycloalkyl, five- or six-membered heterocyclic, aromatic, or heteroaromatic groups, wherein the carbon atom, nitrogen atom, C 3-7 Cycloalkyl, five- or six-membered heterocyclic, aromatic, or heteroaryl rings may be optionally substituted with halogens, hydroxyl groups, alkyl groups, alkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, SR', NR'(R”), COOR', or CONR'(R”), preferably carbon atoms, nitrogen atoms, or phenyl groups, and j, k, l are each independently selected from integers between 1 and 6, for example, 1, 2, or 3. Further, wherein L 1 Selected from -C(=O)-, -OC(=O)-, -NHC(=O)-, or single bonds; R 3 As defined in the compound of formula (I) above.

[0107] In some embodiments, the aforementioned compound is as shown in formula (V) where R 3 Selected from hydrogen, C 1-6 Alkyl (including but not limited to methyl, ethyl, propyl or pentyl), C 1-6 Alkoxy groups (including, but not limited to, methoxy, ethoxy, propoxy, or pentoxy), C 3-7 Cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, cyclopentyl), five- or six-membered heterocyclic groups (including but not limited to furanyl), five- or six-membered aryl (including but not limited to phenyl) or five- or six-membered heteroaryl (including but not limited to pyridyl).

[0108] In some embodiments, at least two of the X atoms in the aforementioned compound of formula (V) are selected from R. 1The R 1 Selected from or containing formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown, and on the same formula (D), wherein the polyethylene glycol is optionally mixed with one or more elements selected from hydroxyl, halogen, deuterium, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 The alkyl group is substituted with a cycloalkyl group, and the remaining X groups are each independently selected from hydrogen, -OH, OPO3. 2- OPSO2 2- OSO3 - or CO2 - .

[0109] In other embodiments, the disclosed compound or its pharmaceutically acceptable salt, or its stereoisomers, rotational isomers, or tautomers are:

[0110] Where j, k, l are each independently selected from integers between 1 and 6, such as 1, 2, or 3; X is as defined in equation (I).

[0111] In other embodiments, the disclosed compound or its pharmaceutically acceptable salt, or its stereoisomers, rotational isomers, or tautomers are...

[0112]

[0113] Where X is selected from R 1 The R 1 Selected from or containing R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - represents polyethylene glycol, wherein the polyethylene glycol is optionally oxidized by one or more elements selected from hydroxyl, halogen, deuterium, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds, and R 4 It is selected from hydrogen, methyl, ethyl, trifluoromethyl or cyclopropyl.

[0114] In some embodiments, the aforementioned compound as shown in formula (Va) contains R 3 It is selected from hydrogen, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl.

[0115] In some embodiments, the aforementioned compound as shown in formula (Va) contains R 3 Selected from C 1-6Alkyl groups, such as methyl, ethyl, and propyl. In some embodiments, the aforementioned compound is represented by R in formula (Va). 3 Selected from C 1-6 Alkyl groups, such as methoxy or ethoxy groups.

[0116] In some embodiments, the aforementioned compound as shown in formula (Va) contains R 3 Selected from C 3-7 Cycloalkyl groups, such as methoxy or ethoxy groups.

[0117] On the other hand, the disclosed compounds or their pharmaceutically acceptable salts, or their stereoisomers, rotational isomers, or tautomers, are:

[0118] Among them, X and L 1 L 2 As defined in the aforementioned compound (I)

[0119] In some embodiments, the aforementioned compound is L as in formula (VI). 1 Selected from -C(=O)-, -OC(=O)-, -NHC(=O)- or single bonds.

[0120] In some embodiments, L in the aforementioned compound such as compound (VI) 2 Selected from:

[0121] The A portion therein is selected from C. 1-6 Alkyl, C 3-7 Cycloalkyl, five- or six-membered heterocyclic, aromatic, or heteroaromatic groups, wherein the carbon atom, nitrogen atom, C 3-7 Cycloalkyl, five- or six-membered heterocyclic or aromatic or heteroaromatic rings may be optionally replaced by halogen, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, SR', NR'(R”), COOR' or CONR'(R”), preferably nitrogen atom, C1-6 alkyl or phenyl; r, s, t, v, j, k, l are each independently selected from integers between 1 and 6, for example 1, 2 or 3.

[0122] In some embodiments, at least two of the X molecules in the aforementioned compound (VI) are selected from R. 1 The R 1 Selected from or containing formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown, and on the same formula (D), wherein the polyethylene glycol is optionally mixed with one or more elements selected from hydroxyl, halogen, deuterium, C 1-6 Alkyl, C 3-7 cycloalkyl or C3-7 The alkyl group is substituted with a cycloalkyl group, and the remaining X groups are each independently selected from hydrogen, -OH, OPO3. 2- OPSO2 2- OSO3 - or CO2 - .

[0123] In some embodiments, A in the aforementioned compound of formula (VI) is selected from C. 1-6 Alkyl groups (such as methyl, ethyl, propyl), C 3-7 Cycloalkyl groups (such as n-butyl, cyclopentyl, or cyclohexyl) and hexacyclic aromatic groups (such as phenyl).

[0124] In some embodiments, part A of the compound is Where X is independently selected from hydroxyl group, OPO3, etc. 2- OPSO2 2 -、OSO3 - .

[0125] In some embodiments, part A of the compound is Where X is OPO3. 2- Or they are all OPSO2 2 - All are OSO3 - .

[0126] In some embodiments, L in the aforementioned compound (VI) 2 Selected from:

[0127]

[0128] In some embodiments, R in the aforementioned compound (VI) 1 Includes R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - represents polyethylene glycol, wherein the polyethylene glycol is optionally oxidized by one or more elements selected from hydroxyl, halogen, deuterium, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds, and R 4 It is selected from hydrogen, methyl, ethyl, trifluoromethyl or cyclopropyl.

[0129] On the other hand, in the compounds disclosed herein, n = 5 or 6. In some embodiments, where L 2 Includes C 2-20 Straight-chain or branched alkylene groups, -(OCH2CH2) e O-, -(OCH2CH2) e -or-O-(CH2-CHOR)2 -CH2O) e - and includes part A, wherein part A is selected from C. 1-6 Alkyl, C 3-7 Cycloalkyl, five- or six-membered heterocyclic, aromatic, or heteroaromatic groups, wherein the alkylene group, -(OCH2CH2) e O-, -(OCH2CH2) e -or-O-(CH2-CHOR) 2 -CH2O) e -Optionally selected from one or more elements chosen from hydroxyl, halogen, deuterium, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0130] In some embodiments, part A of the compound is Where X is independently selected from hydroxyl group, OPO3, etc. 2- OPSO2 2 -、OSO3 - .

[0131] In some embodiments, part A of the compound is

[0132] In some embodiments, n = 5 in the compound disclosed herein, wherein L 2 Selected from:

[0133]

[0134] In some embodiments, L in the compound of this disclosure (I) 2 Includes C 2-10 Straight-chain or branched alkylene, C 2-10 Straight-chain or branched alkeneoxy groups, C 2-10 Straight-chain or branched alkylamino groups, C 2-10 Straight-chain or branched alkylene mercapto, C 2-10 Straight-chain or branched sub-alkenyl groups, C 2-10 Straight-chain or branched alkenyloxy or C 2-10 Cycloalkylene-(OCH2CH2) e O-, -(OCH2CH2) e -or-O-(CH2-CHOR) 2 -CH2O) e -, the L 2 Further optionally, it is selected from one or more elements chosen from hydroxyl, halogen, deuterium, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0135] In some embodiments, the R described in the compound of this disclosure (I) 3 Selected from hydrogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, five- or six-membered heterocyclic, aromatic, or heteroaromatic.

[0136] In some embodiments, L in the compound of this disclosure (I) 1 It represents -O-, -C(=O)-, -OC(=O)-, or a single bond.

[0137] In some implementations, R 2 Or R 5 Selected from hydrogen, methyl, or ethyl.

[0138] In some embodiments, at least three X's in the compound of disclosure (I) are each independently selected from R. 1 The R 1 Selected from or including R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown, where R 4 Selected from hydrogen, methyl, or ethyl, g = 1-200, the polyethylene glycol is optionally coated with one or more elements selected from hydroxyl, halogen, deuterium, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds; the remaining X's are all OPO3. 2- Or they are all OPSO2 2 - All are OSO3 - .

[0139] In some embodiments, the compound of disclosure (I) has three X's, each independently selected from R. 1 The R 1 Selected from or including R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - The polyethylene glycol shown, and X is in the same formula (D), where R 4 Selected from hydrogen, methyl, or ethyl, g = 1-200, the polyethylene glycol is optionally coated with one or more elements selected from hydroxyl, halogen, deuterium, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds; the remaining X's are all OPO3. 2- Or they are all OPSO2 2 - All are OSO3- .

[0140] In some embodiments, the molar mass of polyglycerol or polyethylene glycol in the compound of formula (I) is selected from 100 g / mol to 3000 g / mol, preferably from 100 g / mol to 2500 g / mol, and more preferably from 100 g / mol to 2000 g / mol.

[0141] On the other hand, L in the disclosed compound 2 Selected from:

[0142] -(OCH2CH2)2O-, -(OCH2CH2)3O-, -(OCH2CH2)4O-, -(OCH2CH2)5O-, The L 2 Further optionally, it is selected from one or more groups selected from hydroxyl, halogen, deuterium, amino, nitrile, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 cycloalkyl or C 3-7 Substituted with cycloalkylene compounds.

[0143] Typical compounds disclosed herein, or pharmaceutically acceptable salts thereof, or their stereoisomers, rotational isomers, or tautomers, including but not limited to:

[0144]

[0145]

[0146]

[0147] On the other hand, the typical compounds disclosed herein, or their pharmaceutically acceptable salts, or their stereoisomers, rotational isomers, or tautomers, including but not limited to:

[0148]

[0149]

[0150] On the other hand, this disclosure also provides the following compounds or pharmaceutically acceptable salts thereof, or their stereoisomers, rotational isomers, or tautomers:

[0151]

[0152]

[0153] On the other hand, this disclosure also provides a pharmaceutical composition comprising at least one therapeutically effective amount of a compound of the aforementioned formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer, rotational isomer or tautomer thereof, and a pharmaceutical excipient optionally selected from at least one of pharmaceutically acceptable excipients.

[0154] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0155] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.01%-99.99% of pharmaceutically acceptable excipients, based on the total weight of the composition.

[0156] On the other hand, this disclosure provides the use of the compounds described in the above-mentioned schemes or their pharmaceutically acceptable salts or their stereoisomers, rotational isomers or tautomers, or the aforementioned pharmaceutical compositions in the preparation of medicaments for the treatment or prevention of calcium disorder-related diseases selected from kidney stones, cardiovascular calcification, cardiovascular disease, osteoporosis, bone cancer, gout in the foot, calcific tendinitis, cutaneous calcification, rheumatoid arthritis, bone mineral disorders, osteomalacia, degenerative osteopathy, calcium allergy, and cardiovascular disease.

[0157] The compounds disclosed herein may be present in any form commonly used in pharmaceutical technology. Specific embodiments include, but are not limited to, sodium, magnesium, potassium salts, or mixtures thereof. Other pharmaceutically acceptable salts are known to those skilled in the art and are available, in particular, from Haynes et al., J. Pharmaceutical Sci. 94, 2005, 2111-2120. In some embodiments, the aforementioned compounds, such as those of formula (I), are present as their sodium, potassium, or magnesium salts.

[0158] On the other hand, hydrogen in the functional groups of the compounds disclosed herein can be deuterated to obtain corresponding deuterated compounds, which retain selectivity and potential comparable to hydrogen analogs; the deuterated bonds are more stable, resulting in different "ADME" (adverse drug kinetics), thereby providing clinically beneficial effects.

[0159] Pharmacokinetics refers to the processes by which the body absorbs, distributes, metabolizes, and excretes exogenous chemicals.

[0160] Terminology Explanation:

[0161] "Pharmaceutical excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0162] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0163] The compounds disclosed herein may contain one or more asymmetric centers, thus producing enantiomers, diastereomers, and other stereoisomers that can be defined by absolute stereochemistry as (R)- or (S)- or (D)- or (L)- for amino acids. This disclosure includes all possible isomers as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or using conventional methods such as chromatography and fractional crystallization. Conventional methods for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution using, for example, chiral high-performance liquid chromatography (HPLC) of racemates (or racemates of salts or derivatives). When the compounds described herein contain an alkene double bond or other geometrically asymmetric centers, unless otherwise stated, it means that the compounds include E and Z geometric isomers. Furthermore, all tautomeric forms are also included.

[0164] This disclosure also includes compounds identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I,125 I and 36 Cl, etc.

[0165] The compounds disclosed herein may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 Deuterated drugs can be formed by replacing hydrogen with deuterium (H). The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure.

[0166] In addition, heavier isotopes (such as deuterium) are used. 2 H)) substitution can provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in certain situations, where deuterium substitution can be partial or complete, with partial deuterium substitution referring to at least one hydrogen being replaced by at least one deuterium.

[0167] Unless otherwise stated, when a position is specifically designated as deuterium (D), that position shall be understood to be deuterium having an abundance of at least 3,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium incorporation).

[0168] "Stereoisomers" refer to compounds composed of identical atoms bonded by the same bonds but having different three-dimensional structures, and are not interchangeable. Various stereoisomers and mixtures thereof are contemplated in this disclosure, and include "enantiomers," which refer to two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0169] "Tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. This disclosure includes tautomers of any of the said compounds.

[0170] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be or Or simultaneously include and Two configurations. Although all the above structural formulas are shown in certain isomer forms for simplicity, the present invention can include all isomers, such as tautomers, rotational isomers, geometric isomers, diastereomers, racemates, and enantiomers. A “monovalent group” refers to a compound having one monovalent atom or group removed “in form.” A “subunit” refers to a compound having two monovalent or one divalent atom or group removed “in form.” Example: “alkyl” refers to the portion remaining after removing one hydrogen atom from an alkane molecule, including straight-chain and branched monovalent groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and their various branched isomers. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any usable connection point, preferably one or more of the following groups, independently selected from aryl, heteroaryl, and halogen-substituted groups.

[0171] "alkylene (-CH2-)" refers to the portion remaining after removing two hydrogen atoms from an alkane molecule, including straight-chain and branched subgroups with 1 to 20 carbon atoms. Alkylenes containing 1 to 6 carbon atoms, in non-limiting examples, include methylene (-CH2-), ethylene (e.g., -CH2CH2- or -CH(CH3)-), propylene (e.g., -CH2CH2CH2- or -CH(CH2CH3)-), and butylene (e.g., -CH2CH2CH2CH2-). Alkylenes can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable linker, preferably one or more of the following groups, independently selected from aryl, heteroaryl, and halogen-substituted groups.

[0172] Similarly, the definitions of "alkoxide", "alkaneamino", "alkanethiol", "alkenyl", "alkeneoxy", "cycloalkylene", and "polyethylene glycol alkyl" are the same as "alkaneamino". For example, alkoxide includes straight-chain or branched alkoxides with 2 to 20 carbon atoms, non-limiting examples: -(CH2OCH2OCH2OCH2O)-, -(OCH2OCH2OCH2)-, -(CH2O)-. Alkanethiol includes straight-chain or branched alkanethiols with 2 to 20 carbon atoms, non-limiting examples: -(CH2SCH2SCH2SCH2S)-, -(SCH2SCH2SCH2)-, -(SCH2)-. "Alkaneamino" includes straight-chain or branched alkaneaminos with 2 to 20 carbon atoms, non-limiting examples: -(CH2NCH2NCH2NCH2N)-, -(NCH2)-, -(NCH2NCH2NCH2)-.

[0173] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain alkyl groups with 2 to 20 carbon atoms or branched alkyl groups with 2 to 20 carbon atoms. Non-limiting examples include n-butyl, n-pentyl, n-hexyl, or n-heptyl, and their various branched isomers. Alkyl groups can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any usable link, preferably one or more of the following groups, independently selected from hydroxyl, halogen, alkyl, nitrile, nitro, aryl, heteroaryl, or alkenyl.

[0174] "Alkenyl" includes branched and straight-chain alkenes having 2 to 20 carbon atoms or alkenes containing aliphatic hydrocarbon groups. For example, "C 2-6 "Alkenyl" refers to an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl, and 4-hexenyl.

[0175] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 2 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0176] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0177] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 2 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). wThe heteroatom (where w is an integer from 0 to 2) excluding the ring portion of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0178] The heterocyclic ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0179] wait.

[0180] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0181] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0182]

[0183] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group, preferably phenyl.

[0184] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 6 to 12-membered, more preferably 5-membered or 6-membered. For example, non-limiting examples include: imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrroleyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, and pyrazine. etc.

[0185] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0186] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester group.

[0187] The term "halogenated alkyl" refers to an alkyl group that has been substituted with a halogen, wherein the alkyl group is as defined above.

[0188] The term "halogenated aryl" refers to an aryl group that has been substituted with a halogen, where the aryl group is as defined above.

[0189] The term "halogenated heteroaryl" refers to a heteroaryl group that has been substituted with a halogen, wherein the heteroaryl group is as defined above.

[0190] The term "halogenated heterocyclic group" refers to a heterocyclic group that has been substituted with a halogen, wherein the heterocyclic group is as defined above.

[0191] The term "halogenated cycloalkyl" refers to a cycloalkane that has been substituted with a halogen, wherein the cycloalkyl group is as defined above.

[0192] The term "hydroxyl group" refers to the -OH group.

[0193] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0194] The term "amino" refers to -NH2.

[0195] The term "cyano" refers to -CN.

[0196] The term "nitro" refers to -NO2.

[0197] The term "oxo" refers to the =O substituent.

[0198] The term "thio" refers to the =S substituent.

[0199] "Optional" or "optionally" means that the event or circumstance described below may, but does not have to, occur. This description includes situations in which the event or circumstance may or may not occur. For example, "optionally alkyl-substituted heterocyclic group" means that an alkyl group may, but does not have to, be present. This description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0200] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, that are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (through experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene). On the other hand, when the substituent is a "divalent group," such as a cycloalkylene group, two hydrogen atoms in the group are simultaneously substituted by the cycloalkylene group to form a cycloalkyl group.

[0201] The values ​​in this disclosure are instrument measurements and are subject to a certain degree of error. Generally, ±10% is within the reasonable error range. Of course, the context in which the value is used must be considered. For example, for the molar mass of polyethylene glycol, where the error variation after measurement does not exceed ±10%, the error can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0202] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard. The spatial configurations of the optical isomers (isomers) of the compounds were further confirmed by measuring single-crystal parameters.

[0203] HPLC determinations were performed using a Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200LC high performance liquid chromatograph (ACQUITY UPLC BEH C18 1.7UM 2.1X50MM column, Ultimate XB-C18 3.0*150mm column, or Ultimate C18 2.1*30mm column).

[0204] MS measurements were performed using a Waters SQD2 mass spectrometer in positive / negative ion mode, with a mass scan range of 100–1200.

[0205] Chiral HPLC analysis was performed using the following columns: Chiralpak IC-3 100×4.6mm ID, 3µm; Chiralpak AD-3 150×4.6mm ID, 3µm; Chiralpak AD-3 50×4.6mm ID, 3µm; Chiralpak AS-3 150×4.6mm ID, 3µm; Chiralpak AS-3 100×4.6mm ID, 3µm; ChiralCel OD-3 150×4.6mm I.D., 3µm; Chiralcel OD-3 100×4.6mm ID, 3µm; ChiralCel OJ-H 150×4.6mm ID, 5µm; and Chiralcel OJ-3 150×4.6mm ID, 3µm.

[0206] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0207] Rapid column purification systems use either the Combiflash Rf150 (TELEDYNE ISCO) or Isolara One (Biotage).

[0208] Normal column chromatography generally uses Yantai Huanghai silica gel of 100-200 mesh, 200-300 mesh or 300-400 mesh as the carrier, or Changzhou Santai pre-filled ultrapure normal phase silica gel column (40-63μm, 60, 12g, 25g, 40g, 80g or other specifications).

[0209] Reversed-phase column chromatography typically uses Changzhou Sante pre-packed ultrapure C18 silica gel columns (20-45μm). 40g, 80g, 120g, 220g or other sizes).

[0210] The high-pressure column purification system uses Waters AutoP, in conjunction with the Waters XBridge BEH C18 OBDPrep Column. 5μm, 19mm x 150mm or Atlantis T3 OBD Prep Column, 5μm, 19mm x 150mm.

[0211] Chiral preparation columns used were DAICL CHIRALPAK IC (250 mm * 30 mm, 10 μm) or Phenomenex-Amylose-1 (250 mm * 30 mm, 5 μm).

[0212] The known starting materials used in this disclosure can be synthesized using or according to methods known in the art, or can be purchased from companies such as Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0213] Unless otherwise specified in the examples, the reactions can be carried out under an argon or nitrogen atmosphere.

[0214] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0215] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0216] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0217] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0218] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0219] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0220] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.

[0221] The reaction process in the examples was monitored using thin-layer chromatography (TLC). Detailed Implementation

[0222] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0223] Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0224] Example 1

[0225]

[0226] In a 250 mL single-necked flask, compound 1-1 (3.04 g, 10 mmol, synthesized according to method CN108367080A) and DMF (30 mL) were added. The mixture was cooled in an ice bath, and 0.96 g of NaH (24 mmol) was added. 6.03 g of compound 1-2 (synthesized according to method US6645951) was dissolved in 30 mL of DMF and added dropwise to the previous reaction system. The reaction was stirred at room temperature until the reaction was almost complete. The mixture was extracted with MTBE, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 2.15 g of compound 1-3.

[0227] Ms(ESI): m / z 509[M+H] + .

[0228] 1 H-NMR (400MHz, CDCl3): δ5.51(s,1H),4.43(s,1H),4.25-4.20(m,3H),4.1 2-4.11(m,2H),3.75-3.50(m,16H),3.37(s,6H),0.93(s,9H),0.13(s,6H).

[0229]

[0230] Compound 1-3 (1.52 g, 2.99 mmol) and THF (15 mL) were added to a 100 mL plastic bottle. The mixture was cooled in an ice bath, and then pyridine hydrogen fluoride (15 mL, containing 65–70% HF) was added. The reaction mixture was reacted at room temperature for 12 h. The reaction solution was quenched in a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 1.1 g of compound 1-4, Ms(ESI): m / z 395 [M+H]. + .

[0231]

[0232] In a 100 mL single-necked flask, compound 1-4 (1.379 g, 3.5 mmol) and DMF (14 mL) were added. The flask was cooled in an ice bath, and 120 mg of NaH was added. After the addition was complete, 1.75 g of compound 1-5 (synthesized according to US4001279) was dissolved in 20 mL of DMF and then added dropwise to the reaction solution. The reaction was allowed to proceed until almost complete. The reaction solution was diluted with water (70 mL), extracted with MTBE (35 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was column chromatography to give 1.43 g of compound 1-6.

[0233] Ms(ESI): m / z 637[M+H] + .

[0234] 1 H-NMR (400MHz, CDCl3): δ7.810-7.791(d,2H),7.356-7.337(d,2H),5.48(s,1H),4.47-4.16(m,6H),3.82-3.53(m,24H),3.37(s,6H),2.45(s,3H).

[0235]

[0236] In a 50 mL single-necked flask, compound 1-4 (0.788 g, 2 mmol) and DMF (8 mL) were added. The mixture was cooled in an ice bath, and 120 mg of NaH was added. After the addition was complete, 1.271 g of compound 1-6 was dissolved in 12 mL of DMF and then added dropwise to the reaction solution. The reaction was heated to 40 °C until the reaction was almost complete. The reaction solution was diluted with water (40 mL), extracted with methyl tert-butyl ether, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was passed through a silica gel column to give 1.08 g of compound 1-7.

[0237] Ms(ESI): m / z 859[M+H] + .

[0238] 1 H-NMR (400MHz, CDCl3): 5.50(s,2H),4.50-4.45(m,2H),4.40-4.32(m,4H),4.30-4.25(m,4H),3.83-3.54(m,42H),3.38(s,12H).

[0239] In a 100 mL single-necked flask, compounds 1-7 (1.08 g, 1.26 mmol), MeOH (29 mL), and 0.1 N HCl (29 mL) were added, and the mixture was heated to slight reflux. The solution was directly concentrated to give 1.06 g of crude product, Ms(ESI): m / z 839 [M+H]. + .

[0240]

[0241] In a 50 mL single-necked flask, the product from the previous step (600 mg, 0.7161 mmol) and tetrazolium (451 mg, 6.444 mmol) were added, dissolved in dichloromethane / acetonitrile (5 mL / 18 mL). 2.223 g of compounds 1-8 were added dropwise, and the reaction was stirred at room temperature for 18 h after the addition was complete. The reaction was cooled to -50 °C, and 1.312 g of m-chloroperoxybenzoic acid was added. The mixture was then brought back to room temperature and stirred until the reaction was nearly complete. The reaction was quenched with 50 mL of water, extracted with methyl tert-butyl ether, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purification by silica gel column chromatography yielded 453 mg of compounds 1-9 (HPLC purity >98%).

[0242] 1 H-NMR (400MHz, CDCl3): δ7.30-7.26(m,60H),5.05-5.00(m,24H),4.27(s,2H) ),4.15-3.90(m,6H),3.81-3.74(m,16H),3.54-3.28(m,28H),3.16(s,12H).

[0243]

[0244] In a 25 mL single-necked flask, compounds 1-9 (162 mg, 0.06 mmol), Pd(OH)₂ / C (50 mg, wet), EtOH / H₂O (5 mL / 5 mL), and 34 mg of sodium bicarbonate were added. The reaction was carried out under a hydrogen atmosphere for 8 h. The mixture was filtered, and the filtrate was concentrated to remove most of the organic solvent. The filtrate was then lyophilized to give the target product 1a (87 mg, yield: 100%).

[0245] 1 H-NMR (400MHz, D2O): δ4.21 (s, 2H), 3.99-3.69 (m, 50H), 3.34 (s, 12H).

[0246] Example 2

[0247]

[0248] In a 250 mL single-necked flask, compound 1-4 (1.8 g, 4.57 mmol) and DMF (20 mL) were added. The mixture was cooled in an ice bath, and 220 mg of NaH was added. The reaction was carried out at room temperature for half an hour. 3.35 g of compound 2-1 was dissolved in 40 mL of DMF and added dropwise to the reaction solution. The mixture was heated to 40 °C and stirred for 18 h. The reaction solution was diluted and quenched with water (120 mL), extracted with methyl tert-butyl ether (60 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain 3 g of compound 2-2, Ms(ESI): m / z 835 [M+H]. +.

[0249]

[0250] In a 250 mL hydrogenation flask, compound 2-2 (2.8 g, 3.36 mmol), Pd(OH)₂ / C (1.4 g, wet), and THF (56 mL) were added. The mixture was heated to 40 °C for 12 h under a hydrogen atmosphere (1 atm). The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound 2-3 (1.675 g), Ms: 655 [M+H]. + .

[0251] 1 H-NMR (400MHz, CDCl3): δ5.50(s,2H),4.54(s,3H),4.47-4.24(m,10H),3.93-3.53(m,25H),3.38(s,6H).

[0252] The target product 2a was then prepared by referring to the steps in Example 1.

[0253] 1 H-NMR (400MHz, D2O): δ4.43-3.63(m,36H),3.37(s,6H).

[0254] Example 3

[0255]

[0256] In a 250 mL single-necked flask, compound 3-1 (synthesized according to the method in Organic and Biomolecular Chemistry, 2014, 13, 866-875, 4.44 g, 12 mmol) and DMF (50 mL) were added. The mixture was cooled in an ice bath, and 0.624 g of NaH was added. Then, 5.98 g of compound 3-2 was dissolved in 60 mL of DMF and added dropwise to the reaction solution. The reaction was stirred at room temperature until it was almost complete. The reaction solution was diluted and quenched with water (240 mL), extracted with methyl tert-butyl ether (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was passed through a silica gel column to give 3.36 g of compound 3-2.

[0257] Ms(ESI):m / z 811[M+H] + .

[0258] 1H-NMR (400MHz, CDCl3): δ7.32-7.26(m,20H),5.50(s,2H),4.70-4.55(m,8H),4.43( s,2H),4.35-4.32(m,7H),4.13-4.11(m,1H),4.00-3.88(m,2H),3.69-3.62(m,8H).

[0259]

[0260] In a 250 mL hydrogenation flask, compound 3-2 (2.6 g, 3.21 mmol), Pd / C (1.3 g, wet), and THF (52 mL) were added. The mixture was heated to 40 °C for 3 h under a hydrogen atmosphere (1 atm). The mixture was filtered, the filtrate was concentrated, and purified by silica gel column chromatography to obtain compound 3-3 (1.4 g, yield 96.9%).

[0261] Ms(ESI): m / z 451[M+H] + .

[0262] 1 H-NMR (400MHz, D2O): δ5.50(s,2H),4.50-4.44(m,4H),4.40-4.30(m,4H),4 .25-4.24(m,2H),4.00-3.90(m,2H),3.82-3.80(m,4H),3.73-3.71(m,4H).

[0263]

[0264] In a 250 mL single-necked flask, compound 3-3 (1.4 g, 3.11 mmol), MeOH (30 mL), and 0.5 N HCl (30 mL) were added. The mixture was heated to 65 °C and reacted for 5 h. The reaction solution was then directly concentrated to obtain 1.14 g of compound 3-4. Ms(ESI): m / z 431 [M+H] + .

[0265] The target product 3a was then prepared by referring to the steps in Example 1.

[0266] 1 H-NMR (400MHz, D2O): δ4.50-4.40(m,4H), 4.20-3.95(m,12H), 3.62-3.60(m,4H).

[0267] Example 4

[0268]

[0269] In a 50 mL single-necked flask, compound 3-1 (740 mg, 2 mmol, synthesized according to the method in Organic and Biomolecular Chemistry, 2014, 13, 866-875), compound 4-1 (1.377 g, 4 mmol, synthesized according to the method in Tetrahedron Asymmetry, 1995, 5, 1097-1104), and DMSO (15 mL) were added. The mixture was cooled in an ice bath, and 560 mg of KOH was added. The reaction mixture was stirred at 70 °C for 5 h. The reaction solution was diluted and quenched with water (30 mL), extracted with methyl tert-butyl ether (40 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to give 1.02 g of compound 4-2.

[0270] Ms(ESI): m / z 429[M+H] + .

[0271]

[0272] In a 100 mL single-necked flask, compound 1-4 (1.64 g, 4.19 mmol) and DMF (5 mL) were added. The mixture was cooled in an ice bath, and 252 mg of NaH was added. The reaction was carried out at room temperature for half an hour. 1.93 g of compound 4-3 (synthesized according to the method in Chemistry-A European Journal, 2009, 31, 7534-7538) was dissolved in 17 mL of DMF and added dropwise to the reaction solution. The mixture was heated to 45 °C and stirred for 5 h. The reaction solution was diluted and quenched with water (44 mL), extracted with methyl tert-butyl ether (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to give 2.08 g of compound 4-4.

[0273] Ms(ESI):m / z 529[M+H]+.

[0274]

[0275] In a 100 mL hydrogenation flask, compound 4-4 (2.08 g, 3.94 mmol), Pd(OH)2 / C (1 g, wet), and THF (42 mL) were added. The mixture was heated to 45 °C for 5 h under a hydrogen atmosphere (1 atm). After filtration, the filtrate was concentrated to give compound 4-5 (1.632 g).

[0276] Ms(ESI): 439[M+H] + .

[0277]

[0278] In a 100 mL single-necked flask, compound 4-5 (1.632 g, 3.73 mmol), triethylamine (756 mg, 7.46 mmol), and 32 mL of dichloromethane were added. The mixture was cooled in an ice bath and reacted at room temperature for half an hour. Subsequently, TsCl (851 mg, 4.48 mmol) and 48 mg of DMAP were added, and the reaction was carried out at room temperature for 18 hours. The reaction solution was directly concentrated and purified by silica gel column chromatography to obtain 2.08 g of compound 4-6.

[0279] Ms(ESI):m / z 593[M+H]+.

[0280]

[0281] In a 50 mL single-necked flask, compound 4-2 (0.685 g, 1.74 mmol) and DMF (10 mL) were added. The mixture was cooled in an ice bath, and 139 mg of NaH was added. The reaction was carried out at room temperature for half an hour. 1.922 g of compound 4-6 was dissolved in 10 mL of DMF and added dropwise to the reaction solution. The mixture was heated to 40 °C and stirred for 18 h. The reaction solution was diluted and quenched with water (40 mL), extracted with methyl tert-butyl ether (40 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to give 1.627 g of compound 4-7.

[0282] Ms(ESI): m / z 849[M+H] + .

[0283] 1 H-NMR (400MHz, CDCl3) δ7.29-7.26(m,10H),5.49(s,2H),4.68-4.24(m,10H),3.93-3.51(m,25H),3.38(s,6H),1.18(d,J=6.4Hz,6H).

[0284]

[0285] In a 100 mL hydrogenation flask, compound 4-7 (1.627 g, 1.92 mmol), Pd(OH)₂ / C (0.82 g, wet), and THF (33 mL) were added. The mixture was heated to 45 °C for 5 h under a hydrogen atmosphere (1 atm). The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 4-8 (740 mg).

[0286] Ms(ESI): m / z 669[M+H] + .

[0287] 1H-NMR (400MHz, CDCl3) δ5.50 (s, 2H), 4.55-4.24 (m, 11H), 3.88-3.53 (m, 26H), 3.38 (s, 6H), 1.18 (d, J = 6.4Hz, 6H).

[0288]

[0289] In a 50 mL single-necked flask, compound 4-8 (740 mg, 1.11 mmol), MeOH (15 mL), and 0.5 N HCl (15 mL) were added, and the mixture was heated to reflux and reacted for 2 h. The crude compound 4-9 was then directly concentrated to obtain 750 mg.

[0290] Ms(ESI):m / z 649[M+H]+.

[0291]

[0292] In a 100 mL single-necked flask, compound 4-9 (350 mg, 0.54 mmol) and tetrazolium (910 mg, 12.96 mmol) were added, dissolved in dichloromethane / acetonitrile (35 mL / 15 mL). After reacting for 20 min, 2.24 g of compound 1-8 was added dropwise. After the addition was complete, the reaction was stirred at room temperature for 1 h. The reaction was cooled to approximately -50 °C, and 1.98 g of m-chloroperoxybenzoic acid was added. The mixture was then heated to room temperature and stirred for 2 h. The reaction was quenched with 50 mL of water, extracted with methyl tert-butyl ether, and the organic phases were combined. After drying with anhydrous sodium sulfate and filtering, the crude product was directly concentrated. The crude product was purified by silica gel column chromatography to obtain 700 mg of compound 4-10 (HPLC purity >98%).

[0293] 1 H-NMR(400MHz, CDCl3)δ7.40-7.12(m,80H),5.04-4.92(m,34H),4.52(s,1H), 4.40-4.02(m,7H),3.81-3.72(m,9H),3.53-3.15(m,22H),1.07(d,J=6Hz,3H).

[0294]

[0295] In a 50 mL single-necked flask, compound 4-10 (537 mg, 0.197 mmol), 20% Pd(OH)₂ / C (179 mg, wet), EtOH / H₂O (16 mL / 16 mL), and 132 mg of sodium bicarbonate were added. The reaction was carried out under a hydrogen atmosphere for 3 h. The mixture was filtered, and the filtrate was concentrated to remove most of the organic solvent. The filtrate was then lyophilized to obtain the target compound 4a (285 mg, yield: 100%).

[0296] 1 H-NMR(400MHz,D2O)δ4.54-4.49(m,2H),4.25-3.63(m,42H),3.42(s,6H),1.35-1.31(m,3H).

[0297] Example 5

[0298]

[0299] In a 100 mL single-necked flask, compound 3-1 (0.9 g, 2.43 mmol) and DMAc (3.6 mL) were added. The mixture was cooled in an ice bath, and t-BuONa (0.47 g, 2.0 eq) was added. After the addition was complete, 10 g of compound 3-2 (synthesis referenced in Organic and Biomolecular Chemistry, 2006, 4, 2082–2087) was dissolved in 27 mL of DMAc and then added dropwise to the reaction solution. The reaction was allowed to proceed until almost complete. The reaction solution was diluted with water, filtered, and the filter cake was washed with MTBE. The organic phases were combined, concentrated, and crystallized. The filter cake was removed by filtration, and the filtrate was concentrated. The crude product was column chromatography to give 1.1 g of compound 2-1, with a yield of 73.9%.

[0300] Ms(ESI): m / z 613[M+H] + .

[0301] 1 H-NMR (400MHz, CDCl3): δ7.79-7.77(d,J=8Hz,2H),7.32-7.26(m,12H),5.51(s,1H),4.70-4.67(d,J=12Hz,2H),4.58-4.55(d,J=12Hz,2H),4.45(s, 1H),4.36-4.32(m,4H),4.13-4.11(m,2H),3.94(s,1H),3.69-3.62(m,6H),2.42(s,3H).

[0302]

[0303] In a 250 mL reaction flask, compound 5-1 (0.50 g, 1.18 mmol) and compound 2-1 (1.09 g, 1.78 mmol) along with DMSO (4 mL) were added and dissolved. At room temperature, 0.17 g of sodium tert-butoxide was added, and the reaction was allowed to proceed for 3 h. Then, methanol (0.2 mL) was added, and the mixture was stirred at room temperature for 0.5 h. The reaction solution was then added to a 20% ammonium chloride solution and methyl tert-butyl ether. The mixture was separated, and the aqueous phase was extracted with methyl tert-butyl ether. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was passed through a silica gel column to give 0.72 g of compound 5-2, yield: 70.5%.

[0304] Ms(ESI): m / z 863[M+H] + .

[0305] 1 H-NMR (400MHz, CDCl3) δ7.29 (s, 10H), 5.50 (d, J = 2.2Hz, 2H), 4.68 (d, J = 11.6Hz, 2H), 4.58 (d, J = 11.6Hz, 2H), 4.49–4.42 (m, 2H), 4.35-4.34(m,6H),4.30-4.28(m,2H),3.97(s,1H),3.82(s,1H),3.76–3.60(m,18H),3.41–3.27(m,10H),1.14(d,J=6.3Hz,6H).

[0306] The target product 5a was then prepared following the steps in Example 4. M+HM+H 1 H-NMR(400MHz,D2O)δ4.42(d,J=9.4Hz,2H),4.17-4.10(m,5H),4.00-3.74(m,23H),3.47–3.38(m,4H),3.31(s,6H),1.11(d,J=6.4Hz,6H).

[0307]

[0308] In a 3L three-necked flask, compound a1 (1.01 g, 11.3 mmol) and THF (10 mL) were added. The mixture was cooled in an ice bath, and NaHMDS (6.19 mL, 1.1 eq) was added dropwise. The reaction was continued in an ice bath for 2 hours. Then, 1.53 g of compound a2 was added in portions to the reaction mixture in an ice bath, and the reaction was continued at room temperature for 2 hours until the reaction was essentially complete. Sulfuric acid and water were added at room temperature, and the mixture was stirred for 16 hours. The mixture was filtered, and the filtrate was concentrated. The crude product was then distilled to give 0.94 g of compound a3, yield: 62.3%.

[0309] Ms(ESI): m / z 135[M+H] + .

[0310] 1 H-NMR (400MHz, CDCl3): δ3.72-3.64(m,4H),3.59-3.52(m,1H),3.40-3.32(m,5H),2.68(s,1H),1.13(d,3H,J=6.4Hz).

[0311]

[0312] In a 1L three-necked flask, compound a4 (0.72g, 5.39mmol), Et3N (0.654g, 6.46mmol), DMAP (0.066g), and DCM (3.6mL) were added. The flask was cooled in an ice bath. 1.13g of compound TsCl was dissolved in 3.6mL of DCM and then added dropwise to the reaction solution. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, water was added, and the mixture was separated. The organic layer was washed successively with dilute hydrochloric acid and brine, dried, filtered, and the filtrate was concentrated to give 1.55g of compound a5, yield: 99.8%.

[0313] Ms(ESI): m / z 289[M+H] + .

[0314] 1 H-NMR (400MHz, CDCl3): δ7.80 (d, 2H, J = 8.4Hz), 7.33 (d, 2H, J = 8.0Hz), 4.14 (t, 2H, J = 2.4Hz), 3 .71(t,2H,J=2.6Hz),3.60-3.56(m,1H),3.35-3.25(m,5H),2.44(s,3H),1.08(d,3H,J=6.4Hz).

[0315]

[0316] In a 1L three-necked flask, compound 1-1 (0.30 g, 0.986 mmol), compound 1-2 (0.71 g, 2.46 mmol), and THF (4.5 mL) were added. A NaHMDS THF solution (1.7 mL, 3.45 mmol) was added dropwise. The reaction was allowed to proceed until it was nearly complete. The reaction solution was then transferred to a 1L PTFE flask, cooled in an ice bath, and 65-70% pyridine hydrofluoric acid solution (1.2 mL) was added. The reaction was allowed to proceed at room temperature. The reaction solution was washed with saturated sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined. The mixture was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 0.165 g of compound 5-1, with a yield of 40%.

[0317] Ms:(ESI):m / z 423[M+H] + .

[0318] 1 H-NMR (400MHz, CDCl3): δ5.46(s,1H),4.47-4.45(m,1H),4.30-4.23(m,4H),4.08(s ,1H),3.76-3.71(m,2H),3.67-3.60(m,8H),3.41-3.31(m,11H),1.16-1.15(m,6H).

[0319] Example 6

[0320]

[0321]

[0322] Compound 6-1 (0.85 g, 2.3 mmol) was dissolved in DMAc (3.5 mL), cooled to 0 °C, and t-BuONa (0.44 g, 4.6 mmol) was added. Then, a DMAc solution of compound 6-2 (7.7 g, 18.4 mmol, synthesized according to patent WO200923233A1) (26 mL) was added dropwise, and the reaction proceeded until nearly complete. The reaction solution was diluted with water (75 mL), filtered, and the filter cake was washed with MTBE (80 mL x 2). The organic phases were combined, concentrated, filtered, and purified by column chromatography to obtain 1 g of 6-3, with a yield of 70%.

[0323] MS-ESI: m / z 617.2 [M+H] + .

[0324] 1 H NMR (400MHz, CDCl3) δ7.78(d,J=8.3Hz,2H),7.35-7.24(m,12H),5.49(s,1H),4.68(d,J=11.6Hz,2H),4.57(d,J =11.6Hz,2H),4.47-4.42(m,1H),4.38-4.23(m,4H),3.94(d,J=1.3Hz,1H),3.63(d,J=24.6Hz,4H),2.42(s,3H).

[0325]

[0326] Compounds 6-3 (1 g, 1.62 mmol) and 5-1 (0.57 g, 1.35 mmol) were dissolved in DMSO (6 mL), and sodium tert-butoxide (0.19 g, 2.0 mmol) was added. The reaction mixture was reacted at room temperature for 3 hours. Methanol (0.2 mL) was added, and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was then added to 20% ammonium chloride solution (100 mL) and methyl tert-butyl ether (100 mL). The mixture was separated, and the aqueous phase was extracted with methyl tert-butyl ether (50 mL). The organic phases were combined, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 1.05 g of 6-4, in 90% yield.

[0327] MS-ESI: m / z 867.4 [M+H] + .

[0328] 1 H NMR (400MHz, CDCl3) δ7.29(s,10H),5.50(d,J=2.6Hz,2H),4.68(d,J=11.7Hz,2H),4.58(d,J=11.7Hz,2H),4.48-4.42(m,2H ),4.41-4.25(m,8H),3.96(s,1H),3.81(s,1H),3.76-3.54(m,14H),3.41-3.28(m,9H),3.22(s,1H),1.14(d,J=6.2Hz,6H).

[0329] The target product 6a was then prepared by referring to the steps in Example 4.

[0330] 1 H NMR (400MHz, D2O) δ4.38(dd,J=19.1,9.6Hz,2H),4.19-3.59(m,24H),3.50-3.38(m,4H),3.31(s,6H),1.11(d,J=6.4Hz,6H).

[0331] Example 7

[0332]

[0333] The target product 7a was prepared according to the steps in Example 4.

[0334] 1 H NMR (400MHz, D2O) δ4.35 (dd, J = 19.0, 9.5Hz, 2H), 4.10-3.67 (m, 28H), 3.44-3.36 (m, 4H), 3.29 (s, 6H), 1.09 (d, J = 4.0Hz, 6H).

[0335] Example 8

[0336]

[0337] Compound b1 (10.0 g, 11.1 mmol) was dissolved in THF (100 mL), cooled to 0 °C, and NaHMDS (61 mL, 122.0 mmol) was added dropwise. The reaction was carried out at 0 °C for 2 hours. Compound a2 (15.2 g, 122.0 mmol) was added in portions, and the reaction was carried out at room temperature for 2 hours. Sulfuric acid (61 mL) and water (61 mL) were added at room temperature, and the mixture was stirred for 16 hours. The pH was adjusted to neutral by adding NaOH, and the residue was filtered and concentrated. The residue was dissolved in dichloromethane (70 mL), and TEA (14.0 g) and DMAP (1.4 g) were added sequentially at room temperature. A solution of TsCl (24.2 g) in dichloromethane (70 mL) was added under ice bath conditions, and the reaction was carried out at room temperature for 2 hours. The mixture was washed sequentially with water and dilute hydrochloric acid, and the organic phase was concentrated and purified by column chromatography to give 23 g of compound b3, with a two-step yield of 70%.

[0338] MS-ESI: m / z 289.1 [M+H] + .

[0339] 1 H-NMR (400MHz, CDCl3) δ7.79 (d, 2H, J = 8.4Hz), 7.32 (d, 2H, J = 8.4Hz), 4.13 (t, 2H, J = 5.2Hz), 3. 70(t,2H,J=5.2Hz),3.61-3.54(m,1H),3.32-3.24(m,5H),2.43(s,3H),1.07(d,3H,J=6.4Hz).

[0340]

[0341] Compound 8-1 (4.0 g, 11.6 mmol, synthesized according to the literature Carbohydrate Research, 2002, 337, 2399–2410) and b3 (7.0 g, 24.4 mmol) were dissolved in DMSO (40 mL), and sodium tert-butoxide (2.8 g) was added at room temperature. The reaction was carried out for 16 hours. Water and EA were added for extraction and separation. The organic phase was concentrated and purified by column chromatography to give 3.8 g of compound 8-2, with a yield of 56%.

[0342] MS-ESI: m / z 577.2 [M+H] + .

[0343] 1H-NMR (400MHz, CDCl3) δ7.86(d,J=8.4Hz,2H),7.35(d,J=8.4Hz,2H),5.46(d,J=0.8Hz,1H),5.04(d,J=1.2Hz,1H ),4.45-4.43(m,1H),4.27-4.21(m,4H),3.68-3.58(m,10H),3.41-3.30(m,10H),2.44(s,3H),1.15-1.13(m,6H).

[0344]

[0345] Compound 8-3 (2.0 g, 3.47 mmol) was dissolved in methanol (20 mL), and a 30% sodium methoxide methanol solution (10 mL) was added. The mixture was heated to 70 °C and reacted for 3 hours. The methanol was removed by rotary evaporation, and the residue was dissolved in water, extracted with dichloromethane, and concentrated to give 1.3 g of compound 8-4, with a yield of 88%.

[0346] MS-ESI: m / z 423.2 [M+H] + .

[0347] The target product 8a was obtained by following the steps in Example 4.

[0348] 1 H NMR (400MHz, D2O) δ4.38 (dd, J=19.0, 9.5Hz, 2H), 4.21-3.55 (m, 28H), 3.47-3.35 (m, 4H), 3.30 (s, 6H), 1.09 (d, J=6.4Hz, 6H).

[0349] Test Example 1

[0350] The inhibitory effect of the test compound on the formation of hydroxyapatite (HAP) in human plasma was determined using a spectrophotometric pharmacodynamics (PD) assay.

[0351] Experimental methods

[0352] 1.1 Reagent Preparation

[0353] 1) Human plasma anticoagulated with EDTA-K2.

[0354] 2) Mixed solution: 5mM disodium hydrogen phosphate, 41.67mM calcium chloride, adjust the pH to 7.4 and filter using a 0.22um filter.

[0355] 3) Sodium chloride solution: 0.15M, pH adjusted to 7.4 and filtered using a 0.22µm filter.

[0356] 2.1 Test Procedure

[0357] 1) Prepare the test compound using 0.15M sodium chloride solution.

[0358] 2) Reprocessing of human plasma samples. Take a sufficient amount of plasma and centrifuge at 10000g for 30 minutes at room temperature for later use.

[0359] 3) Add plasma to a 96-well plate, 75 μL / well.

[0360] 4) Add 5 μL of the candidate drug per well.

[0361] 5) Add 120 μL / well of a mixture of disodium hydrogen phosphate and calcium chloride, with expected final concentrations of 1.5 mM and 12.5 mM, respectively.

[0362] 6) Place the well plate on a shaker (750 rpm) and incubate at room temperature (25°C). Measure the absorbance at 550 nm every 3 minutes.

[0363] 7) The final readout value is set as the slope of the absorbance change between 6 and 24 minutes.

[0364] 3 Calculation Formula

[0365]

[0366] 4 Experimental Results

[0367] sample IC50 (Mean±SD, nM) INS 3001 1864±142 1a (Example 1) 306±104 2a (Example 2) 230±163 3a (Example 3) 343±154

[0368] Note: INS 3001 was prepared according to the method described in CN108367080.

[0369] Test Example 2

[0370] 1. Experimental Objective

[0371] In a Na₂HPO₄ and NaCl buffer system, the crystallization process of hydroxyapatite (HAP) was initiated by adding a high concentration of CaCl₂. HAP crystals exhibited a maximum absorption peak at 550 nm, and the intensity of this peak was positively correlated with the HAP content in the system. The compounds possess the ability to bind to and inhibit the formation and growth of HAP crystals. Therefore, the inhibitory activity of different series of compounds on HAP crystallization was evaluated by measuring the OD value at 550 nm in the inorganic salt solution system.

[0372] 2 Experimental Procedure

[0373] 1) Prepare the inorganic salt system: 25mM CaCl2 solution; 55mM Na2HPO4·12H2O solution; 1.5M NaCl solution;

[0374] 2) Mixed solution: Add 55mM Na2HPO4·12H2O, 1.5M NaCl, and ddH2O in a volume ratio of 1:1:6, and adjust the pH to 7.4;

[0375] 3) Add 160 μL of mixed solution to a 96-well plate, and then add 20 μL of compound solutions of different concentrations (concentrations: 100, 30, 10, 3, 1, 0.3, 0.1, 0.01 μM);

[0376] 4) Add 20 μL of 25 mM CaCl2 solution to each well;

[0377] 5) Place the orifice plate on the shaker (300 rpm) and mix for 30 seconds;

[0378] 6) Measure the absorbance at 550nm wavelength every 3 minutes at room temperature (place the well plate on a shaker (300 rpm) and mix for 30 seconds before measurement). The measurement time is 60 minutes.

[0379] 3 Experimental Results

[0380] HAP crystal formation was measured in a 96-well plate by monitoring absorbance. Absorbance was read every 3 minutes at 550 nm, and the plate was oscillated continuously for 1 hour. For each well, two linear equations were derived based on the OD values ​​during the reading period: the first line represented the baseline absorbance with a slope close to 0, and the second line represented the maximum slope of the increase in baseline absorbance. The induction time for HAP formation for each sample was calculated; the intersection of the two lines (baseline absorbance and maximum slope increase) represented the time required for HAP crystal formation. The induction time for different concentrations of each compound was measured and compared with the control induction time. The IC50 was obtained by nonlinear fitting of the time-concentration curves using GraphPad software.

[0381] Table 1

[0382] compound IC50 (μM) 1a 1.04±0.54 2a 4.04±2.55 3a 5.19±0.31 5a 1.13±0.26 7a 1.35±0.14 8a 1.73±0.57

[0383] References: Mechanism of action of SNF472, a novel calcificationinhibitor to treat vascular calcification and calciphylaxis[J]. British Journal of Pharmacology, 2020, 177(19).

Claims

1. A compound represented by formula (III) or a pharmaceutically acceptable salt thereof or a stereoisomer, a rotamer thereof ###0001### (III) g = 2 to 10; e is selected from 2, 3, 4, 5, 6, 7, 8. comprising wherein, L 1 represents a single bond; two X are each independently selected from R 1 , said R 1 is selected from or comprises a polyethylene glycol of the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g -; the remaining X are each independently selected from OPO3 2- , said polyethylene glycol is substituted by one or more R 1-6 alkyl groups; L 2 selected from -(OCH2CH2) e O- or -(OCH2CH2) e -; R 4 selected from C 1-6 alkyl; 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer, a rotamer thereof, which is ###0003### 4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof or a stereoisomer, a rotamer thereof, which is ###0004### 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof or their stereoisomers, rotamers, wherein R 4 is selected from methyl or ethyl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof or a stereoisomer, a rotamer thereof, which is ###0005### wherein, two X are each independently selected from R 1 , said R 1 is selected or comprises R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - represents a polyethylene glycol, and R 4 is selected from methyl or ethyl, said polyethylene glycol is substituted by one or more R 1-6 alkyl, e is selected from 2, 3, 4, 5, 6, 7, 8.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or a stereoisomer, a rotamer thereof and optionally at least one pharmaceutical adjuvant selected from pharmaceutically acceptable excipients. wherein X 1 to X 5 are independently selected from R 1 , said R 1 is selected from or comprises a polyethylene glycol of the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g -; R 4 is selected from methyl or ethyl, said polyethylene glycol is substituted by one or more alkyl groups selected from C 1-6 alkyl groups, the remainder being selected from OPO3 2- , g, e are as defined in claim 1 ; X 6 to X 10 are selected from OPO3 2- .

7. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or a stereoisomer, a rotamer thereof or of a pharmaceutical composition according to claim 6 for the manufacture of a medicament for the treatment or prevention of a disease associated with a calcium disorder selected from the group consisting of kidney stones, osteoporosis, bone cancer, podagra, calcific tendinitis, calcinosis cutis, rheumatoid arthritis, bone mineral disease, osteomalacia, adynamic bone disease, calciphylaxis and cardiovascular disease.

8. The use according to claim 7, wherein the cardiovascular disease is selected from cardiovascular calcification. ​ ​

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