Inositol derivatives and uses thereof

Abstract

The present disclosure relates to inositol derivatives and uses thereof. Specifically, the present disclosure relates to inositol derivatives and uses thereof. 2 The present invention provides a compound comprising two or more moieties of formula (D) connected by: TIFF2023523630000113.tif44150

Description

[Technical Field]

[0001] The present disclosure is in the field of pharmaceutical technology, and specifically relates to inositol derivatives and uses thereof. [Background technology]

[0002] Currently, the prevalence of chronic kidney disease in China is as high as 10.8% and is increasing year by year, with the number of end-stage renal disease (ESRD) patients expected to reach nearly 3 million by 2018. ESKD patients undergoing hemodialysis have a 5-30 times higher risk of cardiovascular mortality than non-hemodialysis patients. Clinically, at least 80% of hemodialysis patients develop cardiovascular calcification (CVC). CVC is a secondary lesion primarily associated with impaired calcium and phosphorus metabolism, with calcium crystal formation and growth being the key mechanism behind CVC. Currently, clinical treatment primarily involves the use of vitamin D, phosphate complexes, and calcimimetics.

[0003] Coronary atherosclerosis, arterial vascular stiffness, left ventricular hypertrophy, and myocardial ischemia due to calcium deposition in large blood vessels contribute to increased morbidity and mortality in patients with chronic kidney disease. Calciphylaxis, a severe form of CVC, is a rare but life-threatening condition characterized by calcified occlusion of small blood vessels in the subcutaneous adipose tissue and dermis, which can cause severe pain and ischemic skin necrosis (Nigwekar SU et al., N Engl J Med. 2018, 378(18), 1704-1714). Once a diagnosis of calciphylaxis is established, patients have a poor prognosis. Calciphylaxis primarily affects patients with end-stage renal disease (ESRD) and has received insufficient clinical attention. Although ESRD patients have a high rate of extraskeletal calcifications, and most of these extraskeletal calcifications are not calciphylaxis, calciphylaxis should not be considered simply a common vascular calcification in ESRD patients. Infections and other wound-related complications due to calciphylaxis are contributing factors to morbidity and hospitalization. Patients typically receive only pain medication and wound care, and no "curative" treatments have yet been approved.

[0004] SNF472 is an intravenous formulation of IP6 sodium salt developed by Sanifit. By binding to hydroxyapatite (HAP) crystals (the main component of calcium deposits) at calcified sites, it inhibits their continued growth and prevents vascular occlusion (Perello 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 calciphylaxis. Summary of the Invention

[0005] The disclosure provides compounds of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer, rotamer or tautomer thereof: [ka] A linker L having two or more moieties represented by formula (D) in common 2 and equation (D) is as follows: [ka] Among them, [ka] teeth, [ka] where o and q are each independently selected from 0 to 2, and the value of o+q is 0, 1, or 2; L 1 represents -O-, -NH-, -C(=O)-, -OC(=O)-, -NHC(=O)-, -S- or a single bond, At least one X is independently R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R4 -(OCH2CH2) g - or polyethylene glycol represented by the formula R 4 -O-(CH2-CHOR 5 -CH2O) g -, wherein the remaining Xs are each independently hydrogen, -OH, OPO3 2- , OPSO2 2- , OSO3 - or CO2 - and each formula (D) is the same or different, and the polyethylene glycol or polyglycerol may optionally contain a hydroxy group, a deuterium, a halogen, a nitrile group, a nitro group, an amino group, C 1-6 Alkyl group, C 1-6 Alkoxy group, -OC(O)R 4 , C 3-7 Cycloalkyl group or C 3-7 cycloalkylene groups, L 2 is a common central linker connected to formula (D), and C 2-20 A straight or branched chain alkylene group, C 2-20 A straight or branched chain alkyleneoxy group, C 2-20 Straight or branched chain alkyleneamino group, C 2-20 Linear or branched alkylene mercapto group, C 2-20 A straight or branched chain alkenylene group, C 2-20 Linear or branched alkenyleneoxy group, C 2-20 Cycloalkylene group, -(OCH2CH2) e O-, -(OCH2CH2) e - or -O-(CH2-CHOR 2 -CH2O) e and optionally comprising an A moiety, wherein the A moiety is selected from the group consisting of an oxygen atom, a nitrogen atom, a sulfur atom, C 1-6 Alkyl group, C 3-7A cycloalkyl group, a 5- or 6-membered heterocyclyl group, an aromatic ring group, or a heteroaromatic ring group, among which the above alkylene group, alkyleneoxy group, alkyleneamino group, alkylenemercapto group, alkenylene group, alkenyleneoxy group, cycloalkylene group, -(OCH2CH2) e O-, -(OCH2CH2) e - or -O-(CH2-CHOR 2 -CH2O) e is optionally a hydroxy group, a halogen, a deuterium, an amino group, a nitrile group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-7 Cycloalkyl group or C 3-7 cycloalkylene groups, and 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 the cycloalkylene group is optionally substituted with halogen, hydroxy, deuterium, amino, nitrile, or nitro groups; A part is C 1-6 When selected from an alkyl group or a nitrogen atom, A is optionally R 3 can be substituted with R 3 is selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, SR', NR'(R"), COOR', or CONR'(R"), wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted with one or more selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxy, halogen, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl, and haloheteroaryl groups; When the A moiety is selected from a sulfur atom, A can be optionally substituted with oxygen; R 4 is hydrogen, C 1-6 Alkyl group or C 3-7cycloalkyl groups, and 1-6 Alkyl group or C 3-7 The cycloalkyl group is optionally substituted with one or more selected from deuterium, nitrile, nitro, amino, hydroxy, or halogen, and further includes R 4 is preferably a hydrogen atom, a methyl group, an ethyl group, a trifluoromethyl group, or a cyclopropyl group, R 2 or R 5 are each independently hydrogen, C 1-6 selected from alkyl groups or glycerol chains, preferably hydrogen, methyl or ethyl groups; R' or R'' are independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl, acyl, aryl, or heteroaryl groups, and the alkyl, alkoxy, aryl, or heteroaryl groups are optionally selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, nitro, nitrile, or -R a and R a is selected from an aryl group or a heteroaryl group, and the aryl group or heteroaryl group is optionally substituted with one or more selected from a halogen, an alkyl group, a cycloalkyl group, an alkoxy group, an alkenyl group, an alkynyl group, an oxy group, a hydroxy group, an aryl group, a heteroaryl group, a nitro group, a nitrile group, a haloalkyl group, a haloalkoxy group, a halocycloalkyl group, a haloheterocyclyl group, a haloaryl group, or a haloheteroaryl group; g=1-200, n is selected from 2 to 8, for example, 2, 3, 4, 6, 7, and 8; e=an integer between 1 and 20 (including but not limited to 1, 2, 3, 4, 6, 7, 12, 13, 14, 16, or 17).

[0006] In the present disclosure, "-OC(=O)-" or "-NHC(=O)-" does not specify whether the functional group attached thereto is at the left end or the right end, and for example, "-OC(=O)-" and "-C(=O)O-" have the same definition. "-NHC(=O)-" and "-C(=O)NH-" have the same definition.

[0007] In some embodiments, L 1 represents "-OC(=O)-" or "-C(=O)O-". In some embodiments, L 1 represents "-NHC(=O)-" and "-C(=O)NH-". In some embodiments, L 1 represents -O-. In some embodiments, L 1 represents -C(=O)-. In some embodiments, L 1 represents -S- or a single bond.

[0008] In some embodiments, in the compounds of the present disclosure, [ka] is CHL 1 -, CH(L 1 -)CHX, CHXCH(L 1 -), CHXCH(L 1 -)CHX, CHX-CHXCH(L 1 -)CHX, CH(L 1 -)CHX-CHX, CHXCH(L 1 -)CHX-CHX or CHX-CHXCH(L 1 -)CHX-CHX, where "-" represents a bond.

[0009] In some embodiments, compounds of the present disclosure include a 5- to 7-membered ring, of which at least four ring members can be represented by CH—X and one ring member can be represented by the formula —CH—L 1 It can be expressed as:

[0010] In some embodiments, compounds of the present disclosure include a five-membered ring, of which four ring members can be represented by CH—X and one ring member can be represented by the formula —CH—L 1 It can be expressed as:

[0011] In some embodiments, compounds of the present disclosure include a six-membered ring, of which five ring members can be represented by CH—X and one ring member can be represented by the formula —CH—L 1 It can be expressed as:

[0012] In some embodiments, compounds of the present disclosure include a seven-membered ring, of which six ring members can be represented by CH—X and one ring member can be represented by the formula —CH—L 1 It can be expressed as:

[0013] In some embodiments, compounds of the present disclosure include a six-membered ring, of which five ring members can be represented by CH—X and one ring member can be represented by the formula —CH—L 1 It can be expressed as:

[0014] In some embodiments, the compound of formula (I) is [ka] is.

[0015] In some embodiments, compounds of the present disclosure include a moiety of formula (D), as shown in formula (Da) or (Db): [ka] Among them, L 1 , X is as defined above for compounds of formula (I).

[0016] Polyglycerols have the formula R 4 -O-(CH2-CHOH-CH2O) g -, where R 4is selected from hydrogen, a methyl group or an ethyl group, g=1 to 200, and the branched or hyperbranched polyglycerol is represented by the formula R 4 -O-(CH2-CHOR 5 -CH2O) g -, where R 5 is hydrogen, C 1-6 alkyl group or glycerol chain, and R 4 is selected from hydrogen, a methyl group, or an ethyl group.

[0017] The glycerol chain has the formula R 4 -O-(CH2-CHOR 2 -CH2O) g -, where R 2 is hydrogen.

[0018] Polyethylene glycol has the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g -, where R 4 is selected from hydrogen, a methyl group, or an ethyl group, and g=1 to 200.

[0019] The molar mass of the polyethylene glycol or polyglycerol according to the present disclosure is selected from 100 g / mol to 3000 g / mol, in particular from 100 g / mol to 2500 g / mol, more in particular from 100 g / mol to 2000 g / mol, or from 200 g / mol to 3000 g / mol, in particular from 300 g / mol to 2500 g / mol, more in particular from 400 g / mol to 2000 g / mol.

[0020] In some embodiments, at least one X in the compound is R 1 and R 1 is the formula R 4 -O-(CH2-CHOH-CH2O) g -, wherein R 4is selected from hydrogen, a methyl group, or an ethyl group, and g is 1 to 200. In some other embodiments, g is 3 to 20. In some other embodiments, g is 10 to 20. In some other embodiments, g is 9 to 45. In the compound of Formula I according to some other embodiments, g is 2 to 100, 2 to 50, 2 to 20, or 2 to 10.

[0021] In some embodiments, at least one X in the compound is R 1 and R 1 is R 4 -O-(CH2-CHOR 5 -CH2O) g -branched or hyperbranched polyglycerols, 5 is selected from hydrogen or a glycerol chain, and R 4 is selected from hydrogen, a methyl group, or an ethyl group. In some other embodiments, the compound has 1, 2, 3, 4, or 5 X's that are R 1 and R 1 is the formula R 4 -O-(CH2-CHOH-CH2O) g - or polyglycerol represented by R 4 -O-(CH2-CHOR 5 -CH2O) g -branched or hyperbranched polyglycerols, 5 is selected from hydrogen or a glycerol chain, and R 4 is selected from hydrogen, a methyl group, or an ethyl group, and g=1 to 200. In some embodiments, X in the compound is R 1 and R 1 is the formula R 4 -O-(CH2-CHOH-CH2O) g - or polyglycerol represented by R 4 -O-(CH2-CHOR 5 -CH2O) g- and having a molar mass of 100 g / mol to 3000 g / mol, in particular 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, in particular 300 g / mol to 2500 g / mol, more particularly about 400 g / mol to 2000 g / mol.

[0022] In some embodiments, at least one X in the compound is R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g -, wherein R4 is selected from hydrogen, a methyl group, or an ethyl group, and g=1 to 200; and the polyethylene glycol may optionally contain a hydroxyl group, a deuterium group, a halogen, or a C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 In some other embodiments, g is 3 to 20. In some other embodiments, g is 10 to 20. In some other embodiments, g is 9 to 45.

[0023] In some embodiments, at least one X in the compound is R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - or polyethylene glycol represented by R 4 O(CH2-CHOH-CHO) g - or polyglycerol represented by R 4 -O-(CH2-CHOR 5 -CH2O) g-, wherein g=2 to 100, and the polyethylene glycol is optionally substituted with a hydroxy group, a deuterium atom, a halogen atom, a C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 In some embodiments, g is 7 to 50. In some embodiments, g is 7 to 15. In some embodiments, g is 40 to 50. In some embodiments, the compound represented by Formula I is provided, wherein g is 2 to 100, 2 to 50, 2 to 20, or 2 to 10. In some embodiments, three Xs in the compound are R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - and in the same formula (D) moiety, the polyethylene glycol may optionally contain a hydroxy group, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0024] In some other embodiments, one, two, three, four, or five X in the compound are R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - or containing polyethylene glycols represented by the formula: 4 is selected from hydrogen, a methyl group, or an ethyl group, and g=1 to 200; the polyethylene glycol may optionally contain a hydroxy group, a deuterium group, a halogen, or C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0025] In some embodiments, X in the compound is R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g -, wherein the polyethylene glycol is optionally substituted with a hydroxy group, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 and the molar mass is 100 g / mol to 3000 g / mol, particularly 100 g / mol to 2500 g / mol, 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, more particularly 400 g / mol to 2000 g / mol.

[0026] In some embodiments, at least two or three X in the compound are R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g -, wherein the polyethylene glycol is optionally substituted with a hydroxy group, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The remaining Xs are all OPO3 2- Or all OPSO2 2 - or all OSO3 - In some embodiments, at least two X in the compound are R 1 and R 1is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g -, wherein the polyethylene glycol is optionally substituted with a hydroxy group, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 In the same formula (D) portion, the remaining Xs are all OPO3 2- Or all OPSO2 2 - or all OSO3 - is.

[0027] In some embodiments, at least one X in the formula (D) moiety in the compound is R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - or polyethylene glycol represented by the formula R 4 -O-(CH2-CHOH-CH2O) g -, wherein R 4 is selected from hydrogen, a methyl group, or an ethyl group, and g=1 to 200; and the polyethylene glycol or polyglycerol may optionally contain a hydroxy group, a deuterium group, a halogen, or a C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0028] In some embodiments, at least two or three X in the formula (D) moiety in the compound are R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g- or containing polyethylene glycols represented by the formula: 4 is selected from hydrogen, a methyl group, or an ethyl group, and g=1 to 200; the polyethylene glycol may optionally contain a hydroxy group, a deuterium group, a halogen, or C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The polyethylene glycol may have a molar mass of 100 g / mol to 3000 g / mol, particularly 100 g / mol to 2500 g / mol, 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, more particularly 400 g / mol to 2000 g / mol.

[0029] In some embodiments, at least two or three X in the formula (D) moiety in the compound are R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - or containing polyethylene glycols represented by the formula: 4 is selected from hydrogen, a methyl group, or an ethyl group, and g=1 to 200; the polyethylene glycol may optionally contain a hydroxy group, a deuterium group, a halogen, or C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The remaining Xs are all OPO3 2- Or all OPSO2 2 - or all OSO3 -Furthermore, the molar mass of the polyethylene glycol is 100 g / mol to 3000 g / mol, in particular 100 g / mol to 2500 g / mol, more particularly 100 g / mol to 2000 g / mol, or 200 g / mol to 3000 g / mol, in particular 300 g / mol to 2500 g / mol, more particularly 400 g / mol to 2000 g / mol.

[0030] In some embodiments, at least two or three X in the formula (D) moiety in the compound are R 1 and R 1 is the formula R 4 -O-(CH2-CHOH-CH2O) g -, wherein R 4 is selected from hydrogen, a methyl group, or an ethyl group, and g=1 to 200; and the polyglycerol may optionally contain a hydroxyl group, a deuterium group, a halogen, or a C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The polyethylene glycol may have a molar mass of 100 g / mol to 3000 g / mol, particularly 100 g / mol to 2500 g / mol, 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, more particularly 400 g / mol to 2000 g / mol.

[0031] In some embodiments, at least two or three X in the formula (D) moiety in the compound are R 1 and R 1 is the formula R 4 -O-(CH2-CHOH-CH2O) g -, wherein the polyglycerol is selected from or comprises a polyglycerol represented by the formula: 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7The remaining Xs are all OPO3 2- Or all OPSO2 2 - or all OSO3 - Among them, R 4 is selected from hydrogen, a methyl group, or an ethyl group, and g = 1 to 200. Furthermore, the molar mass of the polyethylene glycol is 100 g / mol to 3000 g / mol, particularly 100 g / mol to 2500 g / mol, 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, more particularly 400 g / mol to 2000 g / mol.

[0032] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer thereof, is [ka] is.

[0033] Additionally, compounds of the present disclosure have different configurations, and in embodiments, the differences in configuration do not affect the activity of the compounds or inhibit the efficiency of calcium ion crystallization. In alternative embodiments, the compound of formula (III) is: [ka] may be selected from

[0034] In some embodiments, the compound of formula (III) includes L 2 is C 3-10 A straight or branched chain alkylene group, C 3-10 A straight or branched chain alkyleneoxy group, wherein the alkylene or alkyleneoxy group is optionally selected from the group consisting of hydroxyl, halogen, deuterium, amino, nitrile, nitro, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-7 Cycloalkyl group or C 3-7In some embodiments, L is substituted with one or more groups selected from the group consisting of cycloalkylene groups. 2 is C 3-5 A straight or branched chain alkylene group, C 3-5 In some embodiments, L is selected from linear or branched alkyleneoxy groups. 2 is C 4-8 A straight or branched chain alkylene group, C 4-8 In some embodiments, L is selected from linear or branched alkyleneoxy groups. 2 is C 3-4 A straight or branched chain alkylene group, C 3-4 It is selected from linear or branched alkyleneoxy groups.

[0035] In some embodiments, the compound of formula (III) includes L 2 teeth [ka] wherein r and s are each selected from integers between 1 and 6, for example, 1, 2, or 3; [ka] is optionally a hydroxy group, a halogen, a deuterium, an amino group, a nitrile group, a nitro group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-7 Cycloalkyl group or C 3-7 cycloalkylene groups, where A is as defined above in the compounds of formula (I), and when the A moiety is selected from a nitrogen atom, A is optionally substituted with one or more selected from C 1-6 It can be substituted with an alkyl group, for example, a methyl group, and L 1 is as defined for compounds of formula (I).

[0036] In some embodiments, the compound of formula (III) includes L 2 teeth [ka] Selected from the above [ka] is optionally a hydroxy group, a halogen, a deuterium, an amino group, a nitrile group, a nitro group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-7 Cycloalkyl group or C 3-7 cycloalkylene groups; 1 is selected from -O-, -NH-, -C(=O)-, -OC(=O)- or -S-, and A is selected from an oxygen atom, a nitrogen atom and a sulfur atom.

[0037] In some embodiments, in the compound of formula (III), A is an oxygen atom, a nitrogen atom, a sulfur atom, or C 1-6 When the A moiety is selected from alkyl groups and a carbon atom or a nitrogen atom, A is optionally selected from C 1-6 substituted with an alkyl group, 1-6 Alkyl groups include, but are not limited to, methyl, ethyl, propyl, or butyl groups.

[0038] In some embodiments, the compound of formula (III) includes L 2 teeth [ka] wherein r and s are each 2 or 3; [ka] is optionally a hydroxy group, a halogen, a deuterium, an amino group, a nitrile group, a nitro group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-7 Cycloalkyl group or C 3-7 cycloalkylene groups; 1 is selected from -O- and -OC(=O)-, and A is an oxygen atom, a nitrogen atom, a sulfur atom or C 1-6When the A moiety is selected from alkyl groups and a carbon atom or a nitrogen atom, A is optionally selected from C 1-6 substituted with an alkyl group, 1-6 Alkyl groups include, but are not limited to, methyl, ethyl, propyl, or butyl groups.

[0039] In some other embodiments, the compound of formula (III) includes L 2 Ha-(OCH2CH2) e O-, -(OCH2CH2) e - or -O-(CH2-CHOR 2 -CH2O) e -, where e=an integer between 1 and 20, for example, 2, 3, 4, 5, 6, 7, or 8, and the above -(OCH2CH2) e O-, -(OCH2CH2) e - or -O-(CH2-CHOR 2 -CH2O) e - optionally represents a hydroxy group, a halogen, a deuterium, an amino group, a nitrile group, a nitro group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0040] In some other embodiments, the compound of formula (III) includes L 1 is a single bond and the molar mass of polydiethanol is less than 2000 g / mol.

[0041] In some embodiments, Formula (III) includes L 2 Ha-(OCH2CH2) e CHO-, e=1 to 20, L 1 is a single bond.

[0042] In some embodiments, Formula (III) includes L 2 is -O-(CH2-CHOH-CH2O) e -, e=1 to 20, L 1is a single bond.

[0043] In the alternative above, the compound of formula (III) or a pharmaceutically acceptable salt thereof or a stereoisomer, rotamer or tautomer thereof is [ka] and X is as defined in claim 1, and further wherein R 1 is R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - or includes polyethylene glycols represented by the formula: 4 is preferably selected from hydrogen, methyl, ethyl, trifluoromethyl or cyclopropyl groups, and the polyethylene glycol may optionally contain hydroxyl, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0044] In some embodiments, the compound of formula (III) includes at least two X's that are R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g -, and in the same formula (D), the polyethylene glycol may optionally contain a hydroxy group, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 cycloalkylene groups, and the remaining Xs are each independently hydrogen, —OH, OPO3 2- , OPSO2 2- , OSO3 - or CO2 - Selected from.

[0045] In some embodiments, in the compound of formula (III), three Xs are R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g -, and in the same formula (D), the polyethylene glycol may optionally contain a hydroxy group, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 cycloalkylene groups, and the remaining Xs are each independently hydrogen, —OH, OPO3 2- , OPSO2 2- , OSO3 - or CO2 - Selected from.

[0046] In some embodiments, the compound of formula (III) includes L 2 teeth, [ka] and the A portion is selected from C 1-6 Alkyl group, C 3-7 selected from cycloalkyl groups (including cyclopropyl, n-butyl, cyclopentyl, and cyclohexyl groups), 5- or 6-membered heterocyclyl groups, aromatic ring groups, and heteroaromatic ring groups (including tetrahydrofuranyl, pyrrolyl, pyridyl, and phenyl groups); [ka] optionally containing hydroxy groups, halogens, deuterium, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 cycloalkylene groups, and h or j is an integer between 1 and 10, for example, 1, 2, 3, or 4.1 is preferably a single bond.

[0047] In another aspect, in some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer thereof, is [ka] Among them, X 1 ~X 5 At least one in 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - or polyethylene glycol represented by the formula R 4 -O-(CH2-CHOR 5 -CH2O) g -, the remainder being independently hydrogen, -OH, OPO3 2- , OPSO2 2- , OSO3 - or CO2 - Selected from X 6 ~X 10 are independently hydrogen, -OH, OPO3 2- , OPSO2 2- , OSO3 - , CO2 - or R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - or polyethylene glycol represented by the formula R 4 -O-(CH2-CHOR 5 -CH2O) g -, and R 4 , L 1 ~L 3is as defined in formula I, and the polyethylene glycol or polyglycerol optionally contains hydroxy groups, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0048] In some embodiments, Formula III-1 includes X 1 ~X 5 At least one of the 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - or polyethylene glycol represented by the formula R 4 -O-(CH2-CHOR 5 -CH2O) g -, the remainder being independently hydrogen, -OH, OPO3 2- , OPSO2 2- , OSO3 - or CO2 - Selected from X 6 ~X 10 are independently hydrogen, -OH, OPO3 2- , OPSO2 2- , OSO3 - , CO2 - The polyethylene glycol or polyglycerol may optionally contain a hydroxy group, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0049] In some embodiments, Formula III-1 includes X 1 ~X 5 At least two of the 1 and R 1 is the formula R 4 -(OCH2CH2)g O- or R 4 -(OCH2CH2) g - or polyethylene glycol represented by the formula R 4 -O-(CH2-CHOR 5 -CH2O) g -, the remainder being independently hydrogen, -OH, OPO3 2- , OPSO2 2- , OSO3 - or CO2 - Selected from X 6 ~X 10 are independently hydrogen, -OH, OPO3 2- , OPSO2 2- , OSO3 - , CO2 - The polyethylene glycol or polyglycerol may optionally contain a hydroxy group, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0050] In some embodiments, Formula III-1 includes X 1 ~X 5 At least two of the 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - or polyethylene glycol represented by the formula R 4 -O-(CH2-CHOR 5 -CH2O) g -, the remainder being independently selected from or including polyglycerols represented by OPO3 2- , OPSO2 2- , OSO3 - or CO2 - Selected from X 6 ~X 10 are independently hydrogen, -OH, OPO3 2- , OPSO22- , OSO3 - , CO2 - The polyethylene glycol or polyglycerol may optionally contain a hydroxy group, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0051] In some embodiments, Formula III-1 includes X 1 ~X 5 At least two of the 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - or polyethylene glycol represented by the formula R 4 -O-(CH2-CHOR 5 -CH2O) g -, the remainder being independently selected from or including polyglycerols represented by OPO3 2- or CO2 - Selected from X 6 ~X 10 are independently hydrogen, -OH, OPO3 2- , OPSO2 2- , OSO3 - , CO2 - The polyethylene glycol or polyglycerol may optionally contain a hydroxy group, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0052] In some embodiments, Formula III-1 includes X 1 ~X 5 At least two of the 1 and R 1 is the formula R 4 -(OCH2CH2) gO- or R 4 -(OCH2CH2) g -, the remainder being independently selected from or including polyethylene glycols represented by OPO3 2- or CO2 - Selected from X 6 ~X 10 are independently hydrogen, -OH, OPO3 2- , OPSO2 2- , OSO3 - , CO2 - The polyethylene glycol or polyglycerol may optionally contain a hydroxy group, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0053] In some embodiments, Formula III-1 includes X 6 ~X 10 At least one of the 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - or polyethylene glycol represented by the formula R 4 -O-(CH2-CHOR 5 -CH2O) g -, the remainder being independently selected from or including polyglycerols represented by OPO3 2- or CO2 - The polyethylene glycol or polyglycerol may optionally contain a hydroxy group, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0054] In some embodiments, Formula III-1 includes X 6 ~X 10 At least one of the1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g -, the remainder being independently selected from or including polyethylene glycols represented by OPO3 2- or CO2 - The polyethylene glycol or polyglycerol may optionally contain a hydroxy group, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0055] In some embodiments, Formula III-1 includes X 6 ~X 10 At least two of the 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - or polyethylene glycol represented by the formula R 4 -O-(CH2-CHOR 5 -CH2O) g -, the remainder being independently selected from or including polyglycerols represented by OPO3 2- or CO2 - The polyethylene glycol or polyglycerol may optionally contain a hydroxy group, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0056] In some embodiments, Formula III-1 includes X 6 ~X 10 At least two of the 1 and R 1 is the formula R 4-(OCH2CH2) g O- or R 4 -(OCH2CH2) g -, the remainder being independently selected from or including polyethylene glycols represented by OPO3 2- or CO2 - The polyethylene glycol or polyglycerol may optionally contain a hydroxy group, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0057] In some embodiments, Formula III-1 includes X 1 ~X 5 One in R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g -, the remainder being independently selected from or including polyethylene glycols represented by OPO3 2- or CO2 - Selected from X 6 ~X 10 One in R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g -, the remainder being independently selected from or including polyethylene glycols represented by OPO3 2- or CO2 - The polyethylene glycol or polyglycerol may optionally contain a hydroxy group, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0058] In some embodiments, Formula III-1 includes X 1 ~X 5 The two in are independently R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g -, the remainder being independently selected from or including polyethylene glycols represented by OPO3 2- or CO2 - Selected from X 6 ~X 10 The two in are independently R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g -, the remainder being independently selected from or including polyethylene glycols represented by OPO3 2- or CO2 - The polyethylene glycol or polyglycerol may optionally contain a hydroxy group, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0059] Additionally, formula III-1 has different configurations, and in embodiments, the different configurations do not affect the activity of the compound or inhibit the efficiency of calcium ion crystallization. In alternative embodiments, the compound of formula (III) is [ka] may be selected from

[0060] In some embodiments, Formula III-1 includes X 1 ~X 5 At least two of the 1 and R 1is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - or polyethylene glycol represented by the formula R 4 -O-(CH2-CHOR 5 -CH2O) g - or containing polyglycerols represented by the formula: 6 ~X 10 are independently hydrogen, -OH, OPO3 2- , OPSO2 2- , OSO3 - or CO2 - Selected from R 4 , L 1 ~L 3 is as defined in formula I, and the polyethylene glycol or polyglycerol optionally contains hydroxy groups, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0061] In some embodiments, Formula III-1 includes X 1 ~X 5 At least three of the 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - or polyethylene glycol represented by the formula R 4 -O-(CH2-CHOR 5 -CH2O) g - or containing polyglycerols represented by the formula: 6 ~X 10 are independently hydrogen, -OH, OPO3 2- , OPSO2 2- , OSO3 - or CO2 - Selected from R 4 , L 1 ~L3 is as defined in formula I, and the polyethylene glycol or polyglycerol optionally contains hydroxy groups, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0062] In some other embodiments, Formula III-1 includes X 1 , X 4 is R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - or polyethylene glycol represented by the formula R 4 -O-(CH2-CHOR 5 -CH2O) g - or containing polyglycerols represented by the formula: 2 , X 4 , X 5 , X 6 ~X 10 are independently hydrogen, -OH, OPO3 2- , OPSO2 2- , OSO3 - or CO2 - Selected from R 4 , L 1 ~L 3 is as defined in formula I, and the polyethylene glycol or polyglycerol optionally contains hydroxy groups, deuterium, halogen, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0063] In some other embodiments, Formula III-1 includes X 2 , X 4 is R 1 and R 1 is the formula R 4 -(OCH2CH2)g O- or R 4 -(OCH2CH2) g - or polyethylene glycol represented by the formula R 4 -O-(CH2-CHOR 5 -CH2O) g -, wherein the polyethylene glycol or polyglycerol is optionally selected from the group consisting of hydroxy groups, deuterium, halogens, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 cycloalkylene groups, and X 1 , X 4 , X 5 , X 6 ~X 10 are independently hydrogen, -OH, OPO3 2- , OPSO2 2- , OSO3 - or CO2 - Selected from R 4 , L 1 ~L 3 is as defined in Formula I.

[0064] In certain embodiments, Formula III-1 includes X 6 ~X 10 is OPO3 2- , OSO3 - or CO2 - In some embodiments, Formula III-1 includes X 6 ~X 10 is OPO3 2- or OSO3 - In some embodiments, Formula III-1 includes X 6 ~X 10 is OPO3 2- Selected from.

[0065] Further, in some embodiments, in formula III-1, the polyethylene glycol optionally contains a hydroxy group, a halogen, a deuterium, a C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C3-7 In certain embodiments, the polyethylene glycol in formula III-1 is substituted with one or more selected from the group consisting of deuterium, C 1-6 In some embodiments, in Formula III-1, the polyethylene glycol is substituted with one or more selected from deuterium, methyl, ethyl, or propyl groups.

[0066] In some other embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer thereof, is: [ka] Among them, X 1 ~X 10 is as defined in formula III-1.

[0067] In some embodiments, Formula I includes L 2 is a common central linker connected to formula (D), and C 2-20 A straight or branched chain alkylene group, C 2-20 A straight or branched chain alkyleneoxy group, -(OCH2CH2) e O- or -(OCH2CH2) e -, and the above alkylene group, alkyleneoxy group, -(OCH2CH2) e O- or -(OCH2CH2) e - optionally represents a hydroxy group, a deuterium group, an amino group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0068] In some other embodiments, Formula I includes L 2 is a common central linker connected to formula (D), and C 2-10 A straight or branched chain alkylene group, -(OCH2CH2) e O- or -(OCH2CH2)e -, the alkylene group, -(OCH2CH2) e O- or -(OCH2CH2) e - optionally represents a hydroxy group, a deuterium group, an amino group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-7 Cycloalkyl group or C 3-7 cycloalkylene groups; 1 represents -O- or a single bond. In some other embodiments, in Formula I, e is 2 to 15, 2 to 10, 2 to 8, or 2 to 4.

[0069] In another aspect, the compounds of the present disclosure are [ka] and Among them, the above A part is a nitrogen atom, C 1-6 Alkyl group, C 3-7 a cycloalkyl group, a 5- or 6-membered heterocyclyl group, an aromatic ring group, or a heteroaromatic ring group, 1-6 Alkyl group, C 3-7 the cycloalkyl group, the 5- or 6-membered heterocycle or the aromatic or heteroaromatic ring is optionally substituted with halogen, hydroxy group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, SR', NR'(R"), COOR', or CONR'(R"); e=3 to 8, for example, 3, 4, 5, 6, R', R'', L 2 is as defined above for compounds of formula (I).

[0070] Some embodiments provide a compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer thereof, wherein: [ka] is.

[0071] In some embodiments, compounds of the present disclosure having formula (V) include L 2 teeth, [ka] wherein r, s, and t are each independently selected from integers between 1 and 6, e.g., 1, 2, or 3; A, R 3 is as defined above for compounds of formula (I), and L 1 represents -O-, -NH-, -C(=O)-, -OC(=O)-, -NHC(=O)-, -S- or a single bond.

[0072] In some embodiments, compounds of the present disclosure having formula (V) include L 2 teeth, [ka] wherein r, s, and t are each independently selected from integers between 1 and 6, e.g., 1, 2, or 3; A, R 3 is as defined above for compounds of formula (I), and L 1 represents -O-, -NH-, -C(=O)-, -OC(=O)- or a single bond.

[0073] In some embodiments, compounds of the present disclosure having formula (V) include L 2 teeth, [ka] wherein r, s, and t are each independently selected from integers between 1 and 6, e.g., 1, 2, or 3; A, R 3 is as defined above for compounds of formula (I), and L 1 represents -O-, -OC(=O)-, A represents a nitrogen atom, C 1-6 alkyl groups (including, but not limited to, methyl, ethyl, propyl, or butyl groups). 3 is hydrogen, hydroxyl group, C 1-6alkyl groups (including, but not limited to, methyl, ethyl, propyl, or butyl groups), C 1-6 Alkoxy groups (including, but not limited to, methoxy, ethoxy, propoxy, or butoxy groups), C 3-7 It is selected from cycloalkyl groups (including, but not limited to, cyclopropyl, cyclobutyl, and cyclopentyl groups).

[0074] In some embodiments, compounds of the present disclosure having formula (V) include L 2 teeth, [ka] wherein the A moiety is selected from the group consisting of a nitrogen atom, C 1-6 Alkyl group, C 3-7 a cycloalkyl group, a 5- or 6-membered heterocyclyl group, an aromatic ring group, or a heteroaromatic ring group, and 3-7 The cycloalkyl group, 5- or 6-membered heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally substituted with halogen, hydroxy group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, SR', NR'(R"), COOR', or CONR'(R"), and is preferably a carbon atom, a nitrogen atom, or a phenyl group, and j, k, and l are each independently selected from integers between 1 and 6, for example, 1, 2, or 3. Furthermore, where L 1 is selected from -C(=O)-, -OC(=O)-, -NHC(=O)- or a single bond, and R 3 is as defined above for compounds of formula (I).

[0075] In some embodiments, the compound of formula (V) includes R 3 is hydrogen, C 1-6 alkyl groups (including, but not limited to, methyl, ethyl, propyl, or pentyl groups), C 1-6 Alkoxy groups (including, but not limited to, methoxy, ethoxy, propoxy, and pentoxy groups), C 3-7It is selected from a cycloalkyl group (including, but not limited to, a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group), a 5- or 6-membered heterocyclyl group (including, but not limited to, a furyl group), a 5- or 6-membered aryl group (including, but not limited to, a phenyl group), or a 5- or 6-membered heteroaryl group (including, but not limited to, a pyridyl group).

[0076] In some embodiments, the compound of formula (V) includes at least two X's that are R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g -, and in the same formula (D), the polyethylene glycol may optionally contain a hydroxy group, a halogen, a deuterium, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 cycloalkylene groups, and the remaining Xs are each independently hydrogen, —OH, OPO3 2- , OPSO2 2- , OSO3 - or CO2 - Selected from.

[0077] In some other embodiments, the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer thereof is: [ka] wherein j, k, and l are each independently selected from integers between 1 and 6, for example, 1, 2, or 3, and X is as defined in formula (I).

[0078] In some other embodiments, the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer thereof is: [ka] where X is R 1 and R 1 is R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g -, wherein the polyethylene glycol is optionally substituted with a hydroxy group, a halogen, a deuterium, a C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 cycloalkylene groups, and R 4 is selected from hydrogen, a methyl group, an ethyl group, a trifluoromethyl group, and a cyclopropyl group.

[0079] In some embodiments, the compound of Formula (Va) includes R 3 is selected from hydrogen, a hydroxy group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group.

[0080] In some embodiments, the compound of Formula (Va) includes R 3 is C 1-6 In some embodiments, the compound of formula (Va) may include an alkyl group, such as a methyl group, an ethyl group, or a propyl group. 3 is C 1-6 It is selected from alkoxy groups, such as methoxy or ethoxy groups.

[0081] In some embodiments, the compound of Formula (Va) includes R 3 is C 3-7 It is selected from cycloalkyl groups, for example methoxy or ethoxy groups.

[0082] In another aspect, a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer thereof, is [ka] Among them, X and L 1 , L 2 is as defined above for compound (I).

[0083] In some embodiments, the compound of formula (VI) includes L 1 is selected from -C(=O)-, -OC(=O)-, -NHC(=O)- or a single bond.

[0084] In some embodiments, the compound of formula (VI) includes L 2 teeth, [ka] Among these, the A portion is selected from C 1-6 Alkyl group, C 3-7 a cycloalkyl group, a 5- or 6-membered heterocyclyl group, an aromatic ring group, or a heteroaromatic ring group, and 3-7 The cycloalkyl group, the 5- or 6-membered heterocycle or the aromatic or heteroaromatic ring is optionally substituted with a halogen, a hydroxy group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, SR', NR'(R"), COOR' or CONR'(R"), and preferably a nitrogen atom, C 1-6 It is an alkyl group or a phenyl group, and r, s, t, v, j, k, and l are each independently selected from integers of 1 to 6, for example, 1, 2, or 3.

[0085] In some embodiments, the compound of formula (VI) includes at least two Xs that are R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g-, and in the same formula (D), the polyethylene glycol may optionally contain a hydroxy group, a halogen, a deuterium, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 cycloalkylene groups, and the remaining Xs are each independently hydrogen, —OH, OPO3 2- , OPSO2 2- , OSO3 - or CO2 - Selected from.

[0086] In some embodiments, in the compound of formula (VI), A is C 1-6 Alkyl groups (e.g., methyl, ethyl, and propyl groups), C 3-7 It is selected from a cycloalkyl group (for example, an n-butyl group, a cyclopentyl group, or a cyclohexyl group), and a six-membered aromatic ring group (for example, a phenyl group).

[0087] In some embodiments, the A moiety in the compound is [ka] wherein X is independently a hydroxy group, OPO3 2- , OPSO2 2- , OSO3 - Selected from.

[0088] In some embodiments, the A moiety in the compound is [ka] Of these, X is OPO3 2- Or all OPSO2 2- All OSO3 - is.

[0089] In some embodiments, the compound of formula (VI) includes L 2 teeth, [ka] Selected from.

[0090] In some embodiments, the compound of formula (VI) above includes R 1 is R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g -, wherein the polyethylene glycol optionally contains a hydroxy group, a halogen, a deuterium, a C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 cycloalkylene groups, and R 4 is selected from hydrogen, a methyl group, an ethyl group, a trifluoromethyl group, and a cyclopropyl group.

[0091] In another aspect, compounds of the present disclosure have n=5 or 6. In some embodiments, L 2 is C 2-20 A straight or branched chain alkylene group, -(OCH2CH2) e O-, -(OCH2CH2) e - or -O-(CH2-CHOR 2 -CH2O) e and comprises a moiety A, wherein said moiety A is C 1-6 Alkyl group, C 3-7 a cycloalkyl group, a 5- or 6-membered heterocyclyl group, an aromatic ring group, or a heteroaromatic ring group, and the alkylene group, -(OCH2CH2) e O-, -(OCH2CH2) e - or -O-(CH2-CHOR 2 -CH2O) e - is optionally a hydroxy group, a halogen, deuterium, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0092] In some embodiments, the A moiety in the compound is [ka] wherein X is independently a hydroxy group, OPO3 2- , OPSO2 2- , OSO3 - Selected from.

[0093] In some embodiments, the A moiety in the compound is [ka] is.

[0094] In some embodiments, the compounds of the present disclosure include those in which n=5 and L 2 teeth, [ka] Selected from.

[0095] In some embodiments, the compounds of formula (I) of the present disclosure include L 2 is C 2-10 A straight or branched chain alkylene group, C 2-10 A straight or branched chain alkyleneoxy group, C 2-10 Straight or branched chain alkyleneamino group, C 2-10 Linear or branched alkylene mercapto group, C 2-10 A straight or branched chain alkenylene group, C 2-10 A straight or branched chain alkenyleneoxy group or C 2-10 Cycloalkylene group, -(OCH2CH2) e O-, -(OCH2CH2) e - or -O-(CH2-CHOR 2 -CH2O) e - including the above L 2 may further optionally contain a hydroxy group, a halogen, deuterium, C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0096] In some embodiments, the compounds of formula (I) of the present disclosure include the R 3 is hydrogen, hydroxyl group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-7 It is selected from a cycloalkyl group, a 5- or 6-membered heterocyclyl group, an aromatic ring group, or a heteroaromatic ring group.

[0097] In some embodiments, the compounds of formula (I) of the present disclosure include L 1 represents -O-, -C(=O)-, -OC(=O)- or a single bond.

[0098] In some embodiments, R 2 or R 5 is selected from hydrogen, a methyl group, or an ethyl group.

[0099] In some embodiments, in compounds of Formula (I) of the present disclosure, at least three X are each independently selected from R 1 and R 1 is the formula R 4 -(OCH2CH2) g O- or R 4 -(OCH2CH2) g - or containing polyethylene glycols represented by the formula: 4 is selected from hydrogen, a methyl group, or an ethyl group, and g=1 to 200. The polyethylene glycol may optionally contain a hydroxyl group, a halogen, a deuterium, or a C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The remaining Xs are all OPO3 2- Or all OPSO2 2 -All OSO3 - is.

[0100] In some embodiments, in compounds of Formula (I) of the present disclosure, three X's are each independently selected from R 1 and R 1 is the formula R 4-(OCH2CH2) g O- or R 4 -(OCH2CH2) g - and X is of the same formula (D), in which R 4 is selected from hydrogen, a methyl group, or an ethyl group, and g=1 to 200. The polyethylene glycol may optionally contain a hydroxyl group, a halogen, a deuterium, or a C 1-6 Alkyl group, C 3-7 Cycloalkyl group or C 3-7 The remaining Xs are all OPO3 2- Or all OPSO2 2 -All OSO3 - is.

[0101] In some embodiments, in the compounds of Formula (I) of the present disclosure, the molar mass of the polyglycerol or polyethylene glycol is selected from 100 g / mol to 3000 g / mol, preferably 100 g / mol to 2500 g / mol, more preferably 100 g / mol to 2000 g / mol.

[0102] In another aspect, the compounds of the present disclosure include L 2 teeth, -(OCH2CH2)2O-, -(OCH2CH2)3O-, -(OCH2CH2)4O-, -(OCH2CH2)5O-, [ka] Selected from the above L 2 may further optionally contain a hydroxy group, a halogen, a deuterium, an amino group, a nitrile group, a nitro group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-7 Cycloalkyl group or C 3-7 The cycloalkylene group is substituted with one or more groups selected from the group consisting of cycloalkylene groups.

[0103] Exemplary compounds of the present disclosure or pharmaceutically acceptable salts thereof, or stereoisomers, rotamers or tautomers thereof are: [ka] [ka] [ka] Including, but not limited to:

[0104] In another aspect, exemplary compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or stereoisomers, rotamers, or tautomers thereof, are [ka] Including, but not limited to:

[0105] In another aspect, the present disclosure further provides the following compound or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer thereof: [ka]

[0106] In another aspect, the present disclosure further provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I) above or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer thereof, and optionally at least one pharmaceutical additive selected from a pharmaceutically acceptable excipient.

[0107] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0108] In certain embodiments, the pharmaceutical composition contains 0.01% to 99.99% of the compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition.

[0109] In another aspect, the disclosure provides the use of the compound or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer thereof, in any of the above forms, or the pharmaceutical composition, in the preparation of a medicament for treating or preventing a disease associated with calcium disorders, wherein the disease associated with calcium disorders is selected from kidney stones, cardiovascular calcification, cardiovascular disease, osteoporosis, bone cancer, foot gout, calcific tendonitis, calcinosis cutis, rheumatoid arthritis, bone mineral disorders, osteomalacia, adynamic bone disease, calciphylaxis, and cardiovascular disease.

[0110] The compounds disclosed herein can be present in any form commonly used in the pharmaceutical arts. Specific embodiments include, but are not limited to, sodium salts, magnesium salts, potassium salts, or mixtures of the above forms. Other pharmaceutically acceptable salts are well known to those skilled in the art and can be obtained, inter alia, from Haynes et al., J. Pharmaceutical Sci. 94, 2005, 2111-2120. In some embodiments, the compounds of Formula (I) are present in the form of their sodium, potassium, or magnesium salts.

[0111] In another embodiment, hydrogens in the functional groups of the compounds described herein can be deuterated to obtain the corresponding deuterated compounds, which retain the same selectivity and potency as the hydrogen analogs, while the deuterium bonds are more stable, resulting in different "ADME" or "toxicokinetics" and providing clinically beneficial effects.

[0112] Toxicokinetics is the process of absorption, distribution, metabolism, and excretion of exogenous chemicals by the body.

[0113] Explanation of terms: A "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, filler, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicity agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or domestic animals.

[0114] A "pharmaceutical composition" is intended to include a mixture of one or more compounds described herein or physiologically pharmaceutically acceptable salts or prodrugs thereof with other chemical components, and other components, such as physiologically pharmaceutically acceptable carriers and excipients, to facilitate administration to a living body and contribute to the absorption of the active ingredients, thereby further exerting biological activity.

[0115] The compounds of the present disclosure may contain one or more asymmetric centers and thus can form enantiomers, diastereomers, and can be defined by absolute stereochemistry as (R)- or (S)- or, as with amino acids, (D)- or (L)-, other stereoisomeric forms. The present disclosure includes all possible isomers and 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 by conventional methods, such as chromatography and fractional crystallization. Conventional methods for preparing / separating individual enantiomers include chiral synthesis from appropriate optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) by, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other center of geometric asymmetry, unless otherwise specified, it is intended that the compounds include both the E and Z geometric isomers. All tautomers are also meant to be included.

[0116] The present disclosure further includes certain isotopically labeled compounds of the present disclosure that are the same as those described herein, except that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Illustrative isotopes that can be attached to compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example, 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.

[0117] The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, tritium ( 3 Compounds may be labeled with radioactive isotopes, such as H, and deuterium may be substituted for hydrogen to form deuterated drugs, where the bond between deuterium and carbon is stronger than the normal hydrogen-carbon bond, and deuterated drugs have the advantages of reduced toxicity and side effects, increased drug stability, improved therapeutic efficacy, and a longer biological half-life compared to non-deuterated drugs. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.

[0118] Note that relatively heavy isotopes (e.g., deuterium (i.e. 2 H)) substitution may be preferable in some cases because it can provide several therapeutic advantages arising from higher metabolic stability (e.g., increased in vivo half-life or reduced required dosage), whereby deuterium substitution may be partial or complete, with partial deuterium substitution meaning that at least one hydrogen is replaced with at least one deuterium.

[0119] Unless otherwise specified, when a position is specifically designated as deuterium (D), it is to be understood that the position is deuterium having an abundance at least 3000 times greater than the natural abundance of deuterium (0.015%) (i.e., at least 45% deuterium is incorporated).

[0120] "Stereoisomer" refers to a compound composed of the same atoms joined by the same bonds but with different, incompatible three-dimensional structures. Various stereoisomers and mixtures thereof are contemplated in this disclosure and include "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0121] "Tautomer" refers to a form in which a proton has moved from one atom of a molecule to another atom of the same molecule. The present disclosure includes any tautomers of the compounds.

[0122] In the chemical structures of the compounds described in this disclosure, [ka] represents an unspecified configuration, i.e., if chiral isomers exist in a chemical structure, the bond [ka] teeth [ka] or [ka] For convenience, all of the above structural formulas are depicted as certain isomeric forms, but the present invention also encompasses all isomers, such as tautomers, rotamers, geometric isomers, diastereomers, racemates, and enantiomers. A "monovalent group" is an atom or group resulting from the "formal" removal of one monovalent atom from a compound. A "subunit" is an atom or group of atoms resulting from the "formal" removal of two monovalent atoms or one divalent atom from a compound. For example, an "alkyl group" refers to the moiety remaining after removing one hydrogen atom from an alkane molecule, and includes straight- and branched-chain monovalent groups of 1 to 20 carbon atoms. Non-limiting examples of alkyl groups containing 1 to 6 carbon atoms 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 various branched chain isomers thereof. Alkyl groups can be substituted or unsubstituted, and when substituted, the substituents can be at any available point of attachment and are preferably substituted with one or more groups independently selected from aryl groups, heteroaryl groups, and halogens.

[0123] An "alkylene group (-CH-)" refers to the moiety remaining after removing two hydrogen atoms from an alkane molecule and includes straight- and branched-chain groups of 1 to 20 carbon atoms. Non-limiting examples of alkylene groups containing 1 to 6 carbon atoms include methylene (-CH-), ethylidene (e.g., -CHCH- or -CH(CH)-), propylidene (e.g., -CHCHCH- or -CH(CHCH)-), and butylidene (e.g., -CHCHCHCH-). Alkylene groups can be substituted or unsubstituted, and when substituted, the substituents can be at any available point of attachment and are preferably substituted with one or more groups independently selected from aryl groups, heteroaryl groups, and halogens.

[0124] Similarly, the definitions of "alkyleneoxy group," "alkyleneamino group," "alkylenemercapto group," "alkenylene group," "alkenyleneoxy group," "cycloalkylene group," and "polyethylene glycol group" are the same as those of "alkylene group." For example, alkyleneoxy groups include linear or branched alkyleneoxy groups of 2 to 20 carbon atoms, non-limiting examples of which are -(CHOCHOCHOCHOCHO)-, -(OCHOCHOCH)-, and -(CHO)-. Alkylenemercapto groups include linear or branched alkylenemercapto groups of 2 to 20 carbon atoms, non-limiting examples of which are -(CHSCHSCHSCHS)-, -(SCHSCHSCH)-, and -(SCH)-. An "alkyleneamino group" includes straight or branched chain alkyleneamino groups of 2 to 20 carbon atoms, non-limiting examples being -(CH2NCH2NCH2NCH2N)-, -(NCH2)-, and -(NCH2NCH2NCH2)-.

[0125] "Alkyl group" refers to a saturated aliphatic hydrocarbon group, including straight-chain alkyl groups of 2 to 20 carbon atoms and branched-chain alkyl groups of 2 to 20 carbon atoms. Non-limiting examples include n-butyl, n-pentyl, n-hexyl, or n-heptyl groups, and various branched-chain isomers thereof. Alkyl groups can be substituted or unsubstituted, and when substituted, the substituents can be at any available point of attachment and are preferably one or more groups independently selected from hydroxy, halogen, alkyl, nitrile, nitro, aryl, heteroaryl, or alkenyl groups.

[0126] The term "alkenyl group" includes branched and straight chain olefins having 2 to 20 carbon atoms or olefins having an aliphatic hydrocarbon group. 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.

[0127] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where 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, cycloheptatrienyl, cyclooctyl, and the like, and polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups.

[0128] The cycloalkyl ring may be fused to an aryl group, a heteroaryl group, or a heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy, or carboxylic acid ester groups.

[0129] The term "heterocyanine group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 2 to 20 ring atoms, one or more of which may be nitrogen, oxygen, or S(O). w (wherein w is an integer of 0 to 2), but does not include the ring moiety -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, and more preferably 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyl groups include spirocyclic, fused-ring, and bridged-ring heterocyclyl groups.

[0130] The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl group, non-limiting examples of which are: [ka] Includes:

[0131] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxy groups, and carboxylic acid ester groups.

[0132] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl groups. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, of which the ring connected to the parent structure is an aryl ring, non-limiting examples of which are: [ka] Includes.

[0133] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxy groups, and carboxylic acid ester groups, and a phenyl group is preferred.

[0134] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 6 to 12-membered, more preferably 5 or 6-membered. Non-limiting examples include imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, and the like. [ka] Includes:

[0135] Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, sulfhydryl groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxy groups, or carboxylic acid ester groups.

[0136] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl is defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy. An alkoxy group may be optionally substituted or unsubstituted; if substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy, or carboxylic acid ester.

[0137] The term "haloalkyl group" refers to an alkyl group substituted with a halogen, wherein alkyl group is defined above.

[0138] The term "haloaryl" refers to an aryl group substituted with a halogen, wherein aryl is defined above.

[0139] The term "haloheteroaryl" refers to a heteroaryl group substituted with a halogen, wherein heteroaryl is defined above.

[0140] The term "haloheterocyclyl group" refers to a heterocyclyl group substituted with a halogen, wherein the heterocyclyl group is defined above.

[0141] The term "halocycloalkyl group" refers to a cycloalkyl group substituted with a halogen, wherein cycloalkyl group is defined above.

[0142] The term "hydroxy group" refers to an --OH group.

[0143] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0144] The term "amino group" refers to -NH2.

[0145] The term "cyano" refers to -CN.

[0146] The term "nitro group" refers to -NO2.

[0147] The term "oxo" refers to a ═O substituent.

[0148] The term "thio" refers to the ═S substituent.

[0149] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and the phrase includes cases where the event or circumstance occurs and cases where it does not. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the phrase includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0150] "Substituted" means that one or more hydrogen atoms, preferably 5 or less, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Of course, substituents are located only at chemically feasible positions, and those skilled in the art can identify possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino or hydroxy group having a free hydrogen atom may be unstable when bonded to a carbon atom having an unsaturated (e.g., olefinic) bond. In another embodiment, when the substituent is a "divalent group" such as a cycloalkylene group, two hydrogen atoms in the group are simultaneously substituted with a cycloalkylene group to form a cycloalkyl group.

[0151] The values ​​described in this disclosure are measured by an instrument and have a certain degree of error, and generally, ±10% is within a reasonable error range. Of course, the context in which the value is used must be taken into consideration. For example, in the case of the molar mass of polyethylene glycol, the value may have an error change of no more than ±10% after measurement, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, with ±5% being preferred.

[0152] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are 10 -6 The NMR spectrum is expressed in ppm (ppm). A Bruker AVANCE-400 nuclear magnetic resonance spectrometer is used for NMR measurements, and the solvents used are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard. The configuration of the optical isomers (isomers) of a compound is further confirmed by measuring single crystal parameters.

[0153] For HPLC measurements, Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200 LC high-pressure liquid chromatograph (ACQUITY UPLC BEH C18 1.7UM 2.1 mm*50 mm column, Ultimate XB-C18 3.0 mm*150 mm column, or Xtimate C18 2.1 mm*30 mm column) is used.

[0154] For MS measurements, a mass spectrometer Waters SQD2 was used, scanning in positive / negative ion mode with a mass scan range of 100-1200.

[0155] For measurements of chiral HPLC analysis, Chiralpak IC-3 100×4.6 mm ID, 3 μm, Chiralpak AD-3 150×4.6 mm ID, 3 μm, Chiralpak AD-3 50×4.6 mm ID, 3 μm, Chiralpak AS-3 150×4.6 mm ID, 3 μm, Chiralpak AS-3 100×4.6 mm ID, 3 μm, ChiralCel OD-3 150×4.6 mm ID, 3 μm, Chiralcel OD-3 100×4.6 mm ID, 3 μm, ChiralCel OJ-H 150×4.6 mm ID, 5 μm, Chiralcel OJ-3 150×4.6 mm ID, 3 μm columns are used.

[0156] Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography. The silica gel plate specifications for thin-layer chromatography (TLC) are 0.15 mm to 0.2 mm, and those for separating and purifying products by thin-layer chromatography are 0.4 mm to 0.5 mm.

[0157] The flash column purification system used is Combiflash Rf150 (Teledyne ISCO) or Isolara one (Biotage).

[0158] For normal-phase column chromatography, Yantai Yellow Sea silica gel with a mesh size of 100 to 200, 200 to 300, or 300 to 400 is generally used as the carrier, or Changzhou Santai Yo packed ultra-high purity normal-phase silica gel columns (40 μm to 63 μm, 60, 12 g, 25 g, 40 g, 80 g, or other specifications) are used.

[0159] Reverse-phase column chromatography is typically performed using Changzhou Santai pre-packed ultra-high purity C18 silica gel columns (20 μm to 45 μm, 100 Å, 40 g, 80 g, 120 g, 220 g, or other specifications).

[0160] The high-pressure column purification system used was a Waters AutoP, equipped with a Waters XBridge BEH C18 OBD Prep Column (130 Å, 5 μm, 19 mm*150 mm) or an Atlantis T3 OBD Prep Column (100 Å, 5 μm, 19 mm*150 mm).

[0161] The chiral preparative column used is DAICEL CHIRALPAK IC (250 mm*30 mm, 10 μm) or Phenomenex-Amylose-1 (250 mm*30 mm, 5 μm).

[0162] Known starting materials in this disclosure may be synthesized by or according to methods known in the art, or may be purchased from companies such as Shanghai Taitan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.), and Darui Chemicals.

[0163] In the examples, unless otherwise stated, all reactions can be carried out in an argon or nitrogen atmosphere.

[0164] An argon or nitrogen atmosphere refers to an argon or nitrogen balloon with a volume of approximately 1 L connected to the reaction flask.

[0165] A hydrogen atmosphere refers to a hydrogen balloon with a volume of approximately 1 L attached to the reaction flask.

[0166] For the pressurized hydrogenation reaction, a Parr 3916EKX hydrogenator and a Seiran QL-500 hydrogen generator or an HC2-SS hydrogenator are used.

[0167] The hydrogenation reaction usually involves repeating the process of evacuating and refilling with hydrogen three times.

[0168] For microwave reactions, a CEM Discover-S 908860 microwave reactor is used.

[0169] In the examples, unless otherwise stated, solutions refer to aqueous solutions.

[0170] In the examples, unless otherwise specified, the reaction temperature is room temperature, 20°C to 30°C.

[0171] Thin layer chromatography (TLC) is employed to monitor the reaction process in the examples. DETAILED DESCRIPTION OF THE INVENTION

[0172] The present disclosure will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present disclosure.

[0173] In this disclosure, experimental methods for which specific conditions are not specified in the examples generally follow conventional conditions or conditions recommended by raw material or product manufacturers. Reagents for which specific sources are not specified are conventional commercially available reagents. [Example]

[0174] Example 1 [ka] In a 250 mL single-neck flask, compound 1-1 (obtained by synthesis according to the method of CN108367080A, 3.04 g, 10 mmol) and DMF (30 mL) were added, and the mixture was cooled in an ice bath. 0.96 g of NaH (24 mmol) was added, and 6.03 g of compound 1-2 (obtained by synthesis according to the method of 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 essentially complete, and the mixture was extracted with MTBE. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified through a silica gel column to obtain 2.15 g of compound 1-3. MS (ESI): m / z 509 [M+H] + . 1 H-NMR (400 MHz, CDCl3): δ 5.51 (s, 1H), 4.43 (s, 1H), 4.25-4.20 (m, 3H), 4.12-4.11 (m, 2H), 3.75-3.50 (m, 16H), 3.37 (s, 6H), 0.93 (s, 9H), 0.13 (s, 6H).

[0175] [ka] Compound 1-3 (1.52 g, 2.99 mmol) and THF (15 mL) were added to a 100 mL plastic bottle and cooled in an ice bath. Hydrogen fluoride pyridine (15 mL, containing 65% to 70% HF) was added and the reaction was allowed to proceed at room temperature for 12 h. The reaction mixture was quenched by addition to saturated aqueous sodium bicarbonate, 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] + .

[0176] [ka] Compound 1-4 (1.379 g, 3.5 mmol) and DMF (14 mL) were added to a 100 mL single-neck flask and cooled in an ice bath. 120 mg of NaH was added. Upon completion of the addition, 1.75 g of compound 1-5 (synthesized according to the method described in US4001279) was dissolved in 20 mL of DMF and added dropwise to the reaction mixture. The reaction mixture was diluted with water (70 mL) and 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-cooled to give 1.43 g of compound 1-6. MS (ESI): m / z 637 [M+H] + . 1 H-NMR (400 MHz, CDCl3): δ 7.810-7.791 (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).

[0177] [ka] Compound 1-4 (0.788 g, 2 mmol) and DMF (8 mL) were added to a 50 mL single-neck flask and cooled in an ice bath. 120 mg of NaH was added. Upon completion of the addition, 1.271 g of compound 1-6 was dissolved in 12 mL of DMF and added dropwise to the reaction mixture. The temperature was raised to 40 °C and the reaction was continued until essentially complete. The reaction mixture was diluted with water (40 mL) and extracted with methyl tert-butyl ether. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was loaded onto a silica gel column to yield 1.08 g of compound 1-7. MS (ESI): m / z 859 [M+H] + . 1H-NMR (400 MHz, 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).

[0178] Compound 1-7 (1.08 g, 1.26 mmol), MeOH (29 mL), and 0.1 N HCl (29 mL) were added to a 100 mL single-neck flask and heated to slight reflux. Direct concentration gave 1.06 g of crude product. Ms (ESI): m / z 839 [M+H] + .

[0179] [ka] To a 50 mL single-neck flask, the product from the previous step (600 mg, 0.7161 mmol) and tetrazolium tetrazolium (451 mg, 6.444 mmol) were dissolved in dichloromethane / acetonitrile (5 mL / 18 mL). 2.223 g of compound 1-8 was added dropwise. After the addition was complete, the reaction was stirred at room temperature for 18 h. The reaction was cooled to -50 °C, 1.312 g of metachloroperbenzoic acid was added, and the temperature was raised to room temperature and stirred until the reaction was essentially complete. The reaction was quenched by adding 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 give the crude product, which was purified on a silica gel column to give 453 mg of compound 1-9 (HPLC purity >98%). 1 H-NMR (400 MHz, CDCl3): δ 7.30-7.26 (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).

[0180] [ka] Compound 1-9 (162 mg, 0.06 mmol), Pd(OH) / C (50 mg, wet), EtOH / HO (5 mL / 5 mL), and 34 mg of sodium bicarbonate were added to a 25 mL single-neck flask. The mixture was reacted under hydrogen atmosphere for 8 h, filtered, and the filtrate was concentrated to remove most of the organic solvent and lyophilized to give the target product 1a (87 mg, 100% yield). 1 H-NMR (400 MHz, D2O): δ 4.21 (s, 2H), 3.99-3.69 (m, 50H), 3.34 (s, 12H).

[0181] Example 2 [ka] Compound 1-4 (1.8 g, 4.57 mmol) and DMF (20 mL) were added to a 250 mL single-neck flask and cooled in an ice bath. 220 mg of NaH was added and the mixture was allowed to react at room temperature for 0.5 h. 3.35 g of compound 2-1 was dissolved in 40 mL of DMF and added dropwise to the reaction mixture. The mixture was heated to 40 °C and stirred for 18 h. The reaction mixture was quenched by diluting with water (120 mL) and extracted with methyl tert-butyl ether (60 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 3 g of compound 2-2. MS (ESI): m / z 835 [M+H] + .

[0182] [ka] Compound 2-2 (2.8 g, 3.36 mmol), Pd(OH) / C (1.4 g, wet), and THF (56 mL) were added to a 250 mL hydrogenation flask and heated to 40 °C under a hydrogen atmosphere (1 atm) for 12 h. The reaction 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] + . 1 H-NMR (400 MHz, CDCl3): δ 5.50 (s, 2H), 4.54 (s, 3H), 4.47-4.24 (m, 10H), 3.93-3.53 (m, 25H), 3.38 (s, 6H).

[0183] Further preparation was carried out with reference to the steps in Example 1 to obtain the target product 2a. 1 H-NMR (400 MHz, D2O): δ 4.43-3.63 (m, 36H), 3.37 (s, 6H).

[0184] Example 3 [ka] Compound 3-1 (4.44 g, 12 mmol, synthesized according to the method described in Organic and Biomolecular Chemistry, 2014, 13, 866-875) and DMF (50 mL) were added to a 250 mL single-neck flask and cooled in an ice bath. 0.624 g of NaH was added, and then 5.98 g of compound 3-2 was dissolved in 60 mL of DMF and added dropwise to the reaction mixture. The reaction was stirred at room temperature until essentially complete. The reaction mixture was then quenched by diluting with water (240 mL) and extracting with methyl tert-butyl ether (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was loaded onto a silica gel column to yield 3.36 g of compound 3-2. MS (ESI): m / z 811[M+H] + . 1 H-NMR (400 MHz, CDCl3): δ 7.32-7.26 (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).

[0185] [ka] Compound 3-2 (2.6 g, 3.21 mmol), Pd / C (1.3 g, wet), and THF (52 mL) were added to a 250 mL hydrogenation flask, heated to 40 °C under a hydrogen atmosphere (1 atm), and reacted for 3 h. The mixture was then filtered, and the filtrate was concentrated and purified by silica gel column chromatography to give compound 3-3 (1.4 g, 96.9% yield). MS (ESI): m / z 451[M+H] + . 1 H-NMR (400 MHz, D2O): δ 5.50 (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).

[0186] [ka] Compound 3-3 (1.4 g, 3.11 mmol), MeOH (30 mL), and 0.5 N HCl (30 mL) were added to a 250 mL single-neck flask, and the mixture was heated to 65 °C and reacted for 5 h. The reaction mixture was then directly concentrated to give 1.14 g of compound 3-4. MS (ESI): m / z 431 [M+H] + .

[0187] Further preparation was carried out with reference to the steps in Example 1 to obtain the target product 3a. 1 H-NMR (400 MHz, D2O): δ 4.50-4.40 (m, 4H), 4.20-3.95 (m, 12H), 3.62 -3.60 (m, 4H).

[0188] Example 4 [ka] Compound 3-1 (740 mg, 2 mmol, synthesized according to the method of Organic and Biomolecular Chemistry, 2014, 13, 866-875), compound 4-1 (1.377 g, 4 mmol, synthesized according to the method of Tetrahedron Asymmetry, 1995, 5, 1097-1104), and DMSO (15 mL) were added to a 50 mL single-neck flask, cooled in an ice bath, and 560 mg of KOH was added. The mixture was stirred at 70 °C for 5 h. The reaction mixture was quenched by diluting with water (30 mL) and extracted with methyl tert-butyl ether (40 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 1.02 g of compound 4-2. MS (ESI): m / z 429[M+H] + .

[0189] [ka] Compound 1-4 (1.64 g, 4.19 mmol) and DMF (5 mL) were added to a 100 mL single-neck flask and cooled in an ice bath. 252 mg of NaH was added and the mixture was allowed to react at room temperature for 0.5 h. 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 mixture. The mixture was heated to 45 °C and stirred for 5 h. The reaction mixture was quenched by diluting with water (44 mL) and extracted with methyl tert-butyl ether (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 2.08 g of compound 4-4. Ms (ESI): m / z 529[M+H]+.

[0190] [ka] Compound 4-4 (2.08 g, 3.94 mmol), Pd(OH) / C (1 g, wet), and THF (42 mL) were added to a 100 mL hydrogenation flask and heated to 45 °C under a hydrogen atmosphere (1 atm) for 5 h. The mixture was filtered and the filtrate was concentrated to give compound 4-5 (1.632 g). Ms (ESI): 439[M+H] + .

[0191] [ka] Compound 4-5 (1.632 g, 3.73 mmol), triethylamine (756 mg, 7.46 mmol), and 32 mL of dichloromethane were added to a 100 mL single-neck flask, cooled in an ice bath, and reacted at room temperature for 0.5 h. TsCl (851 mg, 4.48 mmol) and 48 mg of DMAP were then added, and the reaction mixture was reacted at room temperature for 18 h. The reaction mixture was directly concentrated and purified by silica gel column chromatography to give 2.08 g of compound 4-6. Ms (ESI): m / z 593[M+H]+.

[0192] [ka] Compound 4-2 (0.685 g, 1.74 mmol) and DMF (10 mL) were added to a 50 mL single-neck flask and cooled in an ice bath. 139 mg of NaH was added and the mixture was allowed to react at room temperature for 0.5 h. 1.922 g of compound 4-6 was dissolved in 10 mL of DMF and added dropwise to the reaction mixture. The mixture was heated to 40 °C and stirred for 18 h. The reaction mixture was quenched by diluting with water (40 mL) and extracted with methyl tert-butyl ether (40 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 1.627 g of compound 4-7. MS (ESI): m / z 849[M+H] + . 1H-NMR (400 MHz, CDCl3) δ 7.29-7.26 (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).

[0193] [ka] Compound 4-7 (1.627 g, 1.92 mmol), Pd(OH) / C (0.82 g, wet), and THF (33 mL) were added to a 100 mL hydrogenation flask and heated to 45 °C under a hydrogen atmosphere (1 atm) for 5 h. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to give compound 4-8 (740 mg). MS (ESI): m / z 669[M+H] + . 1 H-NMR (400 MHz, CDCl3) δ 5.50 (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).

[0194] [ka] Compound 4-8 (740 mg, 1.11 mmol), MeOH (15 mL), and 0.5 N HCl (15 mL) were added to a 50 mL single-neck flask, heated to reflux, and reacted for 2 h. Direct concentration gave 750 mg of crude product, compound 4-9. Ms (ESI): m / z 649[M+H]+.

[0195] [ka] Compound 4-9 (350 mg, 0.54 mmol) and tetrazolium nitrate (910 mg, 12.96 mmol) were added to a 100 mL single-neck flask and dissolved in dichloromethane / acetonitrile (35 mL / 15 mL). After 20 min of reaction, 2.24 g of compound 1-8 was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 h. The reaction was cooled to approximately -50 °C, and 1.98 g of metachloroperbenzoic acid was added. The mixture was then warmed to room temperature and stirred for 2 h. The reaction was quenched by the addition of 50 mL of water, extracted with methyl tert-butyl ether, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and directly concentrated to give the crude product, which was purified on a silica gel column to give 700 mg of compound 4-10 (HPLC purity >98%). 1 H-NMR (400 MHz, CDCl3) δ 7.40-7.12 (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=6 Hz, 3H).

[0196] [ka] Compound 4-10 (537 mg, 0.197 mmol), 20% Pd(OH) / C (179 mg, wet), EtOH / HO (16 mL / 16 mL), and 132 mg of sodium bicarbonate were added to a 50 mL single-neck flask. The mixture was reacted under hydrogen atmosphere for 3 h, filtered, and the filtrate was concentrated to remove most of the organic solvent and lyophilized to give the target compound 4a (285 mg, 100% yield). 1 H-NMR (400 MHz, D2O) δ 4.54-4.49 (m, 2H), 4.25-3.63 (m, 42H), 3.42 (s, 6H), 1.35-1.31 (m, 3H).

[0197] Example 5 [ka] Compound 3-1 (0.9 g, 2.43 mmol) and DMAc (3.6 mL) were added to a 100 mL single-neck flask, cooled in an ice bath, and t-BuONa (0.47 g, 2.0 eq) was added. Upon completion of the addition, 10 g of compound 3-2 (synthesized with reference to Organic and Biomolecular Chemistry, 2006, 4, 2082-2087) was dissolved in 27 mL of DMAc and added dropwise to the reaction mixture, allowing the reaction to proceed essentially completely. The reaction mixture was diluted with water, filtered, and the filter cake was slurried and washed with MTBE. The organic phases were combined and concentrated to precipitate crystals. The filter cake was removed by filtration, and the filtrate was concentrated. The crude product was column-cooled to give 1.1 g of compound 2-1 in 73.9% yield. MS (ESI): m / z 613 [M+H] + . 1 H-NMR (400 MHz, CDCl3): δ 7.79-7.77 (d, J= 8 Hz,2H), 7.32-7.26 (m, 12H), 5.51 (s, 1H), 4.70-4.67 (d, J= 12 Hz,2H), 4.58-4.55 (d, J= 12 Hz, 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).

[0198] [ka] Compound 5-1 (0.50 g, 1.18 mmol), compound 2-1 (1.09 g, 1.78 mmol), and DMSO (4 mL) were added to a 250 mL reaction flask and dissolved. 0.17 g of sodium tert-butoxide was added at room temperature. After the addition was complete, the reaction mixture was allowed to react for 3 h. Methanol (0.2 mL) was added and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was then poured into 20% ammonium chloride solution and methyl tert-butyl ether (MTBE). The mixture was separated, the aqueous phase was extracted with MTBE, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was loaded onto a silica gel column to give 0.72 g of compound 5-2 (70.5% yield). MS (ESI): m / z 863 [M+H] + . 1 H-NMR (400 MHz, CDCl3) δ 7.29 (s, 10H), 5.50 (d, J = 2.2 Hz, 2H), 4.68 (d, J = 11.6 Hz, 2H), 4.58 (d, J = 11.6 Hz, 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).

[0199] Further preparation was carried out with reference to the steps in Example 4 to obtain the target product 5a. 1 H-NMR (400 MHz, D2O) δ 4.42 (d, J = 9.4 Hz, 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 = 6.4 Hz, 6H).

[0200] [ka] Compound a1 (1.01 g, 11.3 mmol) and THF (10 mL) were added to a 3 L three-neck flask and cooled in an ice bath. NaHMDS (6.19 mL, 1.1 eq) was added dropwise and the mixture was allowed to react in the ice bath for 2 h. 1.53 g of compound a2 was added in portions in the ice bath and the mixture was allowed to react at room temperature for 2 h, at which point the reaction was essentially complete. Sulfuric acid and water were added at room temperature and the mixture was stirred for 16 h. The mixture was filtered, the filtrate was concentrated, and the crude product was distilled to give 0.94 g of compound a3 in a 62.3% yield. MS (ESI): m / z 135[M+H] + . 1 H-NMR (400 MHz, CDCl3):δ 3.72-3.64(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).

[0201] [ka] Compound a4 (0.72 g, 5.39 mmol), EtN (0.654 g, 6.46 mmol), DMAP (0.066 g), and DCM (3.6 mL) were added to a 1 L three-neck flask and cooled in an ice bath. 1.13 g of compound TsCl was dissolved in 3.6 mL of DCM and added dropwise to the reaction mixture. The mixture was allowed to react at room temperature for 1 hour. Upon completion of the reaction, water was added, the mixture was separated, and the organic layer was washed with dilute hydrochloric acid and brine, dried, filtered, and the filtrate was concentrated to obtain 1.55 g of compound a5. The yield was 99.8%. MS (ESI): m / z 289[M+H] + . 1 H-NMR (400 MHz, CDCl3): δ 7.80(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).

[0202] [ka] 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 to a 1 L three-neck reaction flask, and a solution of NaHMDS in THF (1.7 mL, 3.45 mmol) was added dropwise. The reaction was allowed to proceed until essentially complete. The reaction mixture was then transferred to a 1 L tetrafluoroethylene flask, cooled in an ice bath, and a 65%-70% solution of hydrofluoric acid in pyridine (1.2 mL) was added. The reaction mixture was allowed to proceed at room temperature. The reaction mixture was washed with saturated sodium bicarbonate and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography to give 0.165 g of compound 5-1 in a 40% yield. MS: (ESI): m / z 423[M+H] + . 1 H-NMR (400 MHz, CDCl3): δ 5.46 (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).

[0203] Example 6 [ka] Compound 6-1 (0.85 g, 2.3 mmol) was dissolved in DMAc (3.5 mL) and cooled to 0 °C. t-BuONa (0.44 g, 4.6 mmol) was added, followed by the dropwise addition of a solution of compound 6-2 (7.7 g, 18.4 mmol, synthesized according to patent WO200923233A1) in DMAc (26 mL). The reaction mixture was then allowed to react essentially completely. The reaction mixture was diluted with water (75 mL), filtered, and the filter cake was washed with MTBE (80 mL x 2) by pulping. The organic phases were combined, concentrated, filtered, and purified by column chromatography to give 1 g of 6-3 in 70% yield. MS-ESI: m / z 617.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.3 Hz, 2H), 7.35-7.24 (m, 12H), 5.49 (s, 1H), 4.68 (d, J = 11.6 Hz, 2H), 4.57 (d, J = 11.6 Hz, 2H), 4.47-4.42 (m, 1H), 4.38-4.23 (m, 4H), 3.94 (d, J = 1.3 Hz, 1H), 3.63 (d, J = 24.6 Hz, 4H), 2.42 (s, 3H).

[0204] [ka] Compounds 6-3 (1 g, 1.62 mmol) and 5-1 (0.57 g, 1.35 mmol) were dissolved in DMSO (6 mL), sodium tert-butoxide (0.19 g, 2.0 mmol) was added, and the mixture was allowed to react at room temperature for 3 h. Methanol (0.2 mL) was added and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was then poured into 20% ammonium chloride solution (100 mL) and methyl tert-butyl ether (100 mL). The aqueous phase was extracted with methyl tert-butyl ether (50 mL). The combined organic phases were 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. MS-ESI: m / z 867.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.29 (s, 10H), 5.50 (d, J = 2.6 Hz, 2H), 4.68 (d, J = 11.7 Hz, 2H), 4.58 (d, J = 11.7 Hz, 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).

[0205] Further preparation was carried out with reference to the steps in Example 4 to obtain the target product 6a. 1 H NMR (400 MHz, D2O) δ 4.38 (dd, J = 19.1, 9.6 Hz, 2H), 4.19-3.59 (m, 24H), 3.50-3.38 (m, 4H), 3.31 (s, 6H), 1.11 (d, J = 6.4 Hz, 6H).

[0206] Example 7 [ka] The target product 7a was prepared by following the steps in Example 4. 1 H NMR (400 MHz, D2O) δ 4.35 (dd, J = 19.0, 9.5 Hz, 2H), 4.10-3.67 (m, 28H), 3.44-3.36 (m, 4H), 3.29 (s, 6H), 1.09 (d, J = 4.0 Hz, 6H).

[0207] Example 8 [ka] 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 mixture was then incubated at 0 °C for 2 h. Compound a2 (15.2 g, 122.0 mmol) was added in several portions and the mixture was incubated at room temperature for 2 h. Sulfuric acid (61 mL) and water (61 mL) were added at room temperature and the mixture was stirred for 16 h. The pH was adjusted to neutral with NaOH, 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 in an ice bath and the mixture was incubated at room temperature for 2 h. The mixture was washed with water and then dilute hydrochloric acid. The organic phase was concentrated and purified by column chromatography to give 23 g of compound b3, with a two-step yield of 70%. MS-ESI: m / z 289.1[M+H] + . 1 H-NMR (400 MHz, CDCl3) δ 7.79 (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=6.4 Hz).

[0208] [ka] 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 mixture was allowed to react for 16 h. The mixture was extracted with water and EA, and the layers were separated. The organic phase was concentrated and purified by column chromatography to give 3.8 g of compound 8-2 in a 56% yield. MS-ESI: m / z 577.2 [M+H] + . 1 H-NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 5.46 (d, J = 0.8 Hz, 1H), 5.04 (d, J = 1.2 Hz, 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).

[0209] [ka] Compound 8-3 (2.0 g, 3.47 mmol) was dissolved in methanol (20 mL), and a 30% solution of sodium methoxide in methanol (10 mL) was added. The mixture was heated to 70 °C and reacted for 3 h. The methanol was removed by rotary evaporation, and the residue was cleared with water. The mixture was extracted with dichloromethane and concentrated to give 1.3 g of compound 8-4 in 88% yield. MS-ESI: m / z 423.2 [M+H] + .

[0210] Further preparation was carried out with reference to the steps in Example 4 to obtain the target product 8a. 1H NMR (400 MHz, D2O) δ 4.38 (dd, J = 19.0, 9.5 Hz, 2H), 4.21-3.55 (m, 28H), 3.47-3.35 (m, 4H), 3.30 (s, 6H), 1.09 (d, J = 6.4 Hz, 6H).

[0211] Test Example 1 The inhibitory effect of test compounds on the formation of human plasma hydroxyapatite (HAP) was measured by spectrophotometric pharmacodynamics (PD) assay.

[0212] Experimental Method 1.1 Preparation of reagents 1) Human plasma anticoagulated with EDTA-K2. 2) Mixed solution: 5 mM disodium hydrogen phosphate, 41.67 mM calcium chloride, adjusted to pH 7.4, and filtered through a 0.22 μm filter. 3) Sodium chloride solution: 0.15 M, adjusted to pH 7.4, and filtered through a 0.22 μm filter.

[0213] 2.1 Test Procedure 1) Test compounds were prepared using 0.15 M sodium chloride solution. 2) Human plasma samples were reprocessed: sufficient plasma was collected and centrifuged at 10,000 g for 30 min at room temperature for use. 3) Plasma was added to a 96-well plate at 75 μL / well. 4) Candidate drugs were added at 5 μL / well. 5) A mixture of disodium hydrogen phosphate and calcium chloride was added at 120 μL / well to give final concentrations of 1.5 mM and 12.5 mM, respectively. 6) The well plate was placed on a shaker (750 rpm) and incubated at room temperature (25°C), and the absorbance at a wavelength of 550 nm was measured every 3 minutes. 7) The final reading was set as the slope of the absorbance change from 6 min to 24 min.

[0214] 3 Calculation formula

number

[0215] 4. Experimental results [Table 1]

[0216] Test Example 2 1. Experimental Objectives The crystallization process of hydroxyapatite (HAP) was initiated in a NaHPO, NaCl buffer solution by adding a high concentration of CaCl. HAP crystals have a maximum absorption peak at a wavelength of 550 nm, and the intensity of this absorption peak is positively correlated with the HAP content in the system. Because compounds bind to and inhibit the formation and growth of HAP crystals, the inhibitory activity of different series of compounds against the formation of HAP crystals was evaluated by measuring the OD value at 550 nm in the inorganic salt solution system.

[0217] 2. Experimental Procedure 1) Preparation of inorganic salt system: 25 mM CaCl2 solution, 55 mM Na2HPO4·12H2O solution, 1.5 M NaCl solution. 2) Mixing of solutions: 55 mM Na2HPO4·12H2O, 1.5 M NaCl, and ddH2O were added in a volume ratio of 1:1:6, and the pH was adjusted to 7.4. 3) 160 μL of the mixed solution was added to a 96-well plate, and 20 μL of compound solutions of different concentrations (concentrations: 100 μM, 30 μM, 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.01 μM) were added, respectively. 4) 20 μL / well of 25 mM CaCl2 solution was added to each well. 5) The well plate was placed on a shaker (300 rpm) and mixed uniformly for 30 seconds. 6) The absorbance at a wavelength of 550 nm was measured every 3 minutes at room temperature (before measurement, the well plate was placed on a shaker (300 rpm) and mixed uniformly for 30 seconds). The measurement time was 60 minutes.

[0218] 3. Experimental results The formation of HAP crystals was measured in 96-well plates by monitoring absorbance. Absorbance was read every 3 minutes at a wavelength of 550 nm, and the plates were continuously shaken for 1 hour. Two linear equations were obtained for the OD values ​​of each experimental well during the reading period: the first represented a line with a slope close to zero at the basal absorbance, and the second represented the maximum slope of the increase in baseline absorbance. The induction time for HAP formation by each sample was calculated. The intersection point between the two lines (basal absorbance and maximum slope of the increase) represented the time required for HAP crystal formation. The induction time for each compound at different concentrations was measured and compared with the control induction time. The time-concentration curves were nonlinearly fitted using GraphPad software to obtain IC50 values. [Table 2] Reference: Mechanism of action of SNF472, a novel calcification inhibitor to treat vascular calcification and calciphylaxis[J]. British Journal of Pharmacology, 2020, 177(19). Furthermore, the present invention includes the following aspects. [Aspect 1] A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer or tautomer thereof, [ka] A linker L having two or more moieties represented by formula (D) in common 2 and equation (D) is as follows: [ka] Among them,

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Claims

1. Formula (III): 【Chemistry 1】 （ 【Chemistry 2】 (including [In the formula, L １ represents —O— or a single bond, At least two Xs are each independently R １ and R １ is the formula R ４ -(OCH ２ CH ２ ) ｇ O- or R ４ -(OCH ２ CH ２ ) ｇ - or polyethylene glycol represented by formula R ４ -O-(CH ２ -CHOR ５ -CH ２ O) ｇ -, and the remaining Xs are each independently selected from OPO ３ ２－ and the polyethylene glycol or polyglycerol is a hydroxy group, a deuterium, a halogen, a nitrile group, a nitro group, an amino group, a C １－６ Alkyl group, C １－６ Alkoxy group, —OC(O)R ４ , C ３－７ Cycloalkyl group and C ３－７ substituted with one or more groups selected from cycloalkylene groups; L ２ is -(OCH ２ CH ２ ) ｅ O- or -(OCH ２ CH ２ ) ｅ - including R ４ is C １－６ is an alkyl group, R ５ are each independently hydrogen; g=1-200; e=an integer of 2, 3, 4, 5, 6, 7, or 8. or a pharmaceutically acceptable salt thereof. 【Request Item 2】 【Chemistry 3】 [wherein at least two Xs are each independently R １ and R １ is R ４ -(OCH ２ CH ２ ) ｇ O- or R ４ -(OCH ２ CH ２ ) ｇ and R ４ is selected from a methyl group and an ethyl group, and the polyethylene glycol is selected from a hydroxy group, a deuterium group, a halogen, a C １－６ Alkyl group, C ３－７ Cycloalkyl group and C ３－７ cycloalkylene groups] 2. The compound of claim 1, wherein:

3. At least three Xs are each independently R １ and R １ is the formula R ４ -(OCH ２ CH ２ ) ｇ O- or R ４ -(OCH ２ CH ２ ) ｇ -, wherein R ４ is selected from a methyl group and an ethyl group, g=1 to 200, and the polyethylene glycol is １－６ Alkyl group, C ３－７ Cycloalkyl group and C ３－７ cycloalkylene groups, and the remaining Xs are all OPO ３ ２－ That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

4. g=2 to 100; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein g is 7 to 50.

6. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein g is 7 to 15 or 40 to 50. 【Request Item 7】 【Chemistry 4】 [In the formula, X １ ~X ５ At least one in １ and R １ is the formula R ４ -(OCH ２ CH ２ ) ｇ O- or R ４ -(OCH ２ CH ２ ) ｇ -, and the remainder are each independently selected from or include polyethylene glycols represented by OPO ３ ２－ and X ６ ~X １０ are each independently OPO ３ ２－ and R １ wherein R １ is the formula R ４ -(OCH ２ CH ２ ) ｇ O- or R ４ -(OCH ２ CH ２ ) ｇ -, and the polyethylene glycol is selected from or includes a polyethylene glycol represented by the formula: １－６ Alkyl group, C ３－７ Cycloalkyl group and C ３－７ cycloalkylene groups, and R ４ , L １ and L ２ is as defined in claim 1] That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. 【Request Item 8】 【Chemistry 5】 [In the formula, X １ ~X １０ is as defined in claim 7] 8. The compound of claim 7, wherein:

9. X １ ~X ５ At least two of the １ and R １ is the formula R ４ -(OCH ２ CH ２ ) ｇ O- or R ４ -(OCH ２ CH ２ ) ｇ -, and R ４ is selected from a methyl group and an ethyl group, and the polyethylene glycol is selected from a hydroxy group, a deuterium group, a halogen, a C １－６ Alkyl group, C ３－７ Cycloalkyl group and C ３－７ cycloalkylene groups, and the remainder is OPO ３ ２－ and g is as defined in claim 1.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof.

10. X ６ ~X １０ is OPO ３ ２－ That is, 10. The compound of claim 9 or a pharmaceutically acceptable salt thereof. 【Request Item 11】 【Chemistry 6】 That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

12. A compound represented by the formula: or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and optionally at least one medicinal additive selected from pharmaceutically acceptable excipients.

14. 14. The pharmaceutical composition according to claim 13, for treating or preventing a disease associated with calcium disorders, wherein the disease associated with calcium disorders is selected from kidney stones, cardiovascular calcification, osteoporosis, bone cancer, foot gout, calcific tendonitis, calcinosis cutis, rheumatoid arthritis, bone mineral disorders, osteomalacia, adynamic bone disease, calciphylaxis and cardiovascular diseases.

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