WO2021219135A1 - 一种肌醇衍生物及其用途 - Google Patents

一种肌醇衍生物及其用途 Download PDF

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WO2021219135A1
WO2021219135A1 PCT/CN2021/091548 CN2021091548W WO2021219135A1 WO 2021219135 A1 WO2021219135 A1 WO 2021219135A1 CN 2021091548 W CN2021091548 W CN 2021091548W WO 2021219135 A1 WO2021219135 A1 WO 2021219135A1
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och
alkyl
group
cycloalkyl
formula
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PCT/CN2021/091548
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English (en)
French (fr)
Inventor
张连山
黄建
祝令建
唐应刚
黄琪
孟佳
Original Assignee
上海森辉医药有限公司
上海盛迪医药有限公司
江苏恒瑞医药股份有限公司
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Priority to US17/920,736 priority Critical patent/US20230167140A1/en
Priority to EP21796822.1A priority patent/EP4144742A4/en
Priority to JP2022566043A priority patent/JP2023523630A/ja
Priority to CN202180021967.6A priority patent/CN115427418A/zh
Publication of WO2021219135A1 publication Critical patent/WO2021219135A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/117—Esters of phosphoric acids with cycloaliphatic alcohols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/093—Polyol derivatives esterified at least twice by phosphoric acid groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present disclosure belongs to the field of medical technology, and specifically relates to inositol derivatives and uses thereof.
  • CVC cardiovascular calcification
  • Calcification defense is a serious form of CVC. It is a rare but life-threatening disease that is clinically characterized by calcification and blockage of small blood vessels in the subcutaneous fat tissue layer and dermal layer. It can cause severe pain and ischemic skin necrosis. Change (Nigwekar SU et al, N Engl J Med. 2018, 378(18), 1704-1714.). Once the diagnosis of calcification defense is established, the patient's prognosis is poor.
  • Calcification defense mainly affects patients with end-stage renal disease (ESRD) and has not received sufficient clinical attention.
  • ESRD patients have a high proportion of extraosseous calcification problems. Although most of these extraosseous calcifications are not calcification defenses, calcification defenses cannot be Simply regarded as common vascular calcification in ESRD patients. Infections and other wound-related complications caused by calcification defenses are the main causes of morbidity and hospitalization. Patients usually only receive painkillers and wound treatment, and no “root-care” therapy has been approved for marketing.
  • SNF472 is an intravenous preparation of IP6 sodium salt developed by Sanifit. It can be combined with hydroxyapatite (HAP) crystals (the main component of calcium deposits) in the calcification site to inhibit the continued growth of the crystals and prevent blood vessel blockage (Perelló J et al. Br J Clin Pharmacol. 2018, 84 (12) , 2867-2876.). In 2012, SNF472 obtained the FDA and EMA orphan drug designation for the treatment of calcification defense.
  • HAP hydroxyapatite
  • the disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof or their stereoisomers, rotamers or tautomers
  • At least one X is each independently selected from R 1 , and the R 1 is selected from or comprises a polyethylene represented by the formula R 4 -(OCH 2 CH 2 ) g O- or R 4 -(OCH 2 CH 2 ) g- Diol or polyglycerol represented by the formula R 4 -O-(CH 2 -CHOR 5 -CH 2 O) g -, and the remaining Xs are each independently selected from hydrogen, -OH, OPO 3 2- , OPSO 2 2- , OSO 3 - or CO 2 - , and each formula (D) is the same or different, the polyethylene glycol or polyglycerol is optionally selected from hydroxyl, deuterium, halogen, nitrile, nitro, amino , C 1-6 alkyl, C 1-6 alkoxy, -OC(O)R 4 , C 3-7 cycloalkyl or C 3-7 cycloalkylene substituted;
  • L 2 is a common central linker connected to formula (D), including C 2-20 linear or branched alkylene, C 2-20 linear or branched alkyleneoxy, C 2-20 linear Or branched alkyleneamino, C 2-20 linear or branched alkylene sulfhydryl, C 2-20 linear or branched alkenylene, C 2-20 linear or branched alkenyleneoxy, C 2- 20 Cycloalkylene, -(OCH 2 CH 2 ) e O-, -(OCH 2 CH 2 ) e -or -O-(CH 2 -CHOR 2 -CH 2 O) e -, and optionally include A part , The A part is selected from oxygen atom, nitrogen atom, sulfur atom, C 1-6 alkyl, C 3-7 cycloalkyl, five-membered or six-membered heterocyclic group or aromatic ring group or heteroaromatic ring group, wherein The alkylene, alkyleneoxy, alkyleneamino
  • A may be optionally substituted by R 3 , and R 3 is selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Group, heteroaryl, SR', NR'(R”), COOR' or CONR'(R”), the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is any One or more selected from alkyl, alkoxy, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, nitro, nitrile, hydroxyl, halogen, halogenated alkyl, halogenated alkyl Oxy, halogenated cycloalkyl, halogenated heterocyclic group, halogenated aryl group, halogenated heteroaryl group;
  • moiety A When moiety A is selected from sulfur atoms, A may be optionally substituted by oxygen;
  • R 4 is selected from hydrogen, C 1-6 alkyl or C 3-7 cycloalkyl, and the C 1-6 alkyl or C 3-7 cycloalkyl is optionally selected by one or more selected from deuterium and nitrile. , Nitro, amino, hydroxy or halogen, further, R 4 is preferably hydrogen, methyl, ethyl, trifluoromethyl or cyclopropyl;
  • R 2 or R 5 are each independently selected from hydrogen, C 1-6 alkyl or glycerol chain, preferably hydrogen, methyl or ethyl;
  • R'or R" is independently selected from hydrogen, hydroxy, alkyl, alkoxy, alkenyl, acyl, aryl or heteroaryl, the alkyl, alkoxy, aryl or heteroaryl group is optionally one or more substituents selected from halo, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, alkoxy, hydroxy, nitro, nitrile, or substituted with -R a;
  • R a is selected from aryl or heteroaryl Aryl, the aryl or heteroaryl is optionally selected by one or more selected from halogen, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, oxy, hydroxy, aryl, heteroaryl , Nitro, nitrile, haloalkyl, haloalkoxy, halocycloalkyl, haloheterocyclyl, haloaryl or haloheter
  • n is selected from 2 to 8, such as 2, 3, 4, 6, 7 and 8;
  • e an integer between 1-20 (including but not limited to 1, 2, 3, 4, 6, 7, 12, 13, 14, 16 or 17).
  • the compounds of the present disclosure Selected from 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.
  • the compounds of the present disclosure comprise a five- to seven-membered ring, wherein at least four ring members can be represented by the formula CH-X, and one ring member can be represented by the formula -CH-L 1 .
  • the compound of the present disclosure contains a five-membered ring, where four ring members can be represented by the formula CH-X, and one ring member can be represented by the formula -CH-L 1 -.
  • the compound of the present disclosure contains a six-membered ring, where five ring members can be represented by the formula CH-X, and one ring member can be represented by the formula -CH-L 1 -.
  • the compounds of the present disclosure comprise a seven-membered ring, where six ring members can be represented by the formula CH-X, and one ring member can be represented by the formula -CH-L 1 -.
  • the compound of the present disclosure contains a six-membered ring, where five ring members can be represented by the formula CH-X, and one ring member can be represented by the formula -CH-L 1 -.
  • the compound of formula (I) is:
  • the compound of the present disclosure includes the moiety represented by formula (D) as represented by formula (Da) or (Db):
  • L 1 and X are as defined in the aforementioned compound of formula (I).
  • Glycerin chain such as the formula R 4 -O-(CH 2 -CHOR 2 -CH 2 O) g -, where R 2 is hydrogen.
  • the molar mass of polyethylene glycol or polyglycerol in the present disclosure is selected from 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, especially 300 g/mol to 2500 g/mol, more especially 400 g/mol to 2000 g/mol.
  • At least one X in the compound is selected from R 1 , and the R 1 is selected from or comprises a branched chain or super chain represented by R 4 -O-(CH 2 -CHOR 5 -CH 2 O) g- Branched polyglycerol, wherein R 5 is selected from hydrogen or glycerol chain, and R 4 is selected from hydrogen, methyl or ethyl.
  • R 1 is selected from or comprises the formula R 4 -O-(CH 2 -CHOH-CH 2 O )
  • the polyglycerol represented by g -or the branched or hyperbranched polyglycerol represented by R 4 -O-(CH 2 -CHOR 5 -CH 2 O) g -, wherein R 5 is selected from hydrogen or glycerol chain, and R 4 is selected from hydrogen, methyl or ethyl, and g 1 to 200.
  • X in the compound is selected from R 1
  • R 1 is selected from or comprises polyglycerol represented by the formula R 4 -O-(CH 2 -CHOH-CH 2 O) g -or R 4- O-(CH 2 -CHOR 5 -CH 2 O) g -shown as branched or hyperbranched polyglycerol with a molar mass of 100g/mol to 3000g/mol, especially 100g/mol to 2500g/mol, more Especially about 100 g/mol to 2000 g/mol, or 200 g/mol to 3000 g/mol, especially 300 g/mol to 2500 g/mol, more especially about 400 g/mol to 2000 g/mol.
  • Other embodiments provide that g in the compound represented by formula I is 2-100, 2-50, 2-20, or 2-10.
  • three Xs in the compound are selected from R 1 , and the R 1 is selected from or comprises the formula R 4 -(OCH 2 CH 2 ) g O- or R 4 -(OCH 2 CH 2 ) g -Shown in the polyethylene glycol, and in the same formula (D) part, the polyethylene glycol is optionally selected from hydroxyl, deuterium, halogen, C 1-6 alkyl, C 3- 7 cycloalkyl or C 3-7 cycloalkylene substituted.
  • X in the compound is selected from R 1 , and R 1 is selected from or comprises the formula R 4 -(OCH 2 CH 2 ) g O- or R 4 -(OCH 2 CH 2 ) g-
  • the polyethylene glycol is optionally selected by one or more selected from hydroxyl, deuterium, halogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkylene Substituted, and the molar mass is 100g/mol to 3000g/mol, especially 100g/mol to 2500g/mol, more particularly 100g/mol to 2000g/mol, or 200g/mol to 3000g/mol, especially 300g/mol To 2500 g/mol, more particularly 400 g/mol to 2000 g/mol.
  • At least 2 or 3 Xs in the aforementioned compound are selected from R 1 , and the R 1 is selected from or comprises the formula R 4 -(OCH 2 CH 2 ) g O- or R 4 -(OCH 2 CH 2 )
  • the polyethylene glycol shown in g - the polyethylene glycol is optionally selected from hydroxyl, deuterium, halogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 3 -7 substituted cycloalkylene
  • X is OPO 3 2- rest or are OPSO 2 2 - or are OSO 3 -.
  • At least two Xs in the aforementioned compound are selected from R 1 , and the R 1 is selected from or comprises the formula R 4 -(OCH 2 CH 2 ) g O- or R 4 -(OCH 2 CH 2 )
  • the polyethylene glycol shown in g - the polyethylene glycol is optionally selected from hydroxyl, deuterium, halogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 3- 7 cycloalkylene substituted, and in the same formula (D) portion, are the remaining X is OPO 3 2- or OPSO 2 2 - or are OSO 3 -.
  • the molar mass of polyethylene glycol is 100g/mol to 3000g/mol, especially 100g/mol to 2500g/mol, more particularly 100g/mol to 2000g/mol, or 200g/mol to 3000g/mol, especially 300 g/mol to 2500 g/mol, more particularly 400 g/mol to 2000 g/mol.
  • the molar mass of polyethylene glycol is 100g/mol to 3000g/mol, especially 100g/mol to 2500g/mol, more particularly 100g/mol to 2000g/mol, or 200g/mol to 3000g/mol, especially 300 g/mol to 2500 g/mol, more particularly 400 g/mol to 2000 g/mol.
  • the molar mass of polyethylene glycol is 100g/mol to 3000g/mol, especially 100g/mol to 2500g/mol, more particularly 100g/mol to 2000g/mol, or 200g/mol to 3000g/mol, especially 300 g/mol to 2500 g/mol, more particularly 400 g/mol to 2000 g/mol.
  • the molar mass of polyethylene glycol is 100g/mol to 3000g/mol, especially 100g/mol to 2500g/mol, more particularly 100g/mol to 2000g/mol, or 200g/mol to 3000g/mol, especially 300 g/mol to 2500 g/mol, more particularly 400 g/mol to 2000 g/mol.
  • the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer thereof is:
  • the compounds of the present disclosure have different spatial configurations.
  • the different spatial configurations do not affect the activity of the compound or inhibit the efficiency of calcium ion crystallization.
  • the compound of formula (III) may be selected from:
  • L 2 is selected from a C 3-10 linear or branched alkylene group, a C 3-10 linear or branched alkyleneoxy group, the alkylene group Or alkyleneoxy is optionally selected by one or more selected from hydroxyl, halogen, deuterium, amino, nitrile, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl Or substituted by C 3-7 cycloalkylene.
  • L 2 is selected from C 3-5 linear or branched alkylene, C 3-5 linear or branched alkyleneoxy.
  • L 2 is selected from C 4-8 linear or branched alkylene, C 4-8 linear or branched alkyleneoxy. In some embodiments, L 2 is selected from C 3-4 linear or branched alkylene, C 3-4 linear or branched alkyleneoxy.
  • the aforementioned compound is selected from the group consisting of L2 in formula (III) Wherein r and s are respectively selected from integers between 1 and 6, such as 1, 2 or 3, the Optionally by one or more selected from hydroxyl, halogen, deuterium, amino, nitrile, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl or C 3-7 Cycloalkylene substituted; A is as defined in the aforementioned compound of formula (I), and when the part A is selected from a nitrogen atom, A may be optionally substituted with a C 1-6 alkyl group, such as methyl; L 1 is as in formula (I) As defined in the compound.
  • A is selected from an oxygen atom, a nitrogen atom, a sulfur atom or a C 1-6 alkyl group in the aforementioned compound as in formula (III), and when the moiety A is selected from a carbon atom or a nitrogen atom, A is optionally C 1-6 alkyl includes but is not limited to methyl, ethyl, propyl or butyl.
  • the aforementioned compound, as in formula (III), L 1 is a single bond, and the molar mass of the polydiethanol is less than 2000 g/mol.
  • R 1 is preferably selected from or comprises polyethylene glycol represented by R 4 -(OCH 2 CH 2 ) g O- or R 4 -(OCH 2 CH 2 ) g -
  • R 4 is preferably selected from hydrogen, methyl, ethyl, trifluoromethyl or cyclopropyl
  • the polyethylene glycol is optionally selected from hydroxyl, deuterium, halogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkylene substituted.
  • At least two of the aforementioned compounds of formula (III) have X selected from R 1 , and said R 1 is selected from or comprises formula R 4 -(OCH 2 CH 2 ) g O- or R 4 -(OCH 2 CH 2 ) g -represented by polyethylene glycol, and in the same formula (D), the polyethylene glycol is optionally selected from hydroxyl, deuterium, halogen, C 1- 6 Alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkylene substituted, and the remaining X is each independently selected from hydrogen, -OH, OPO 3 2- , OPSO 2 2- , OSO 3 - or CO 2 -.
  • three of the aforementioned compounds in formula (III) have X selected from R 1 , and said R 1 is selected from or comprises formula R 4 -(OCH 2 CH 2 ) g O- or R 4- (OCH 2 CH 2 ) g -represented by polyethylene glycol, and in the same formula (D), the polyethylene glycol is optionally selected from hydroxyl, deuterium, halogen, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkylene substituted, and the remaining Xs are each independently selected from hydrogen, -OH, OPO 3 2- , OPSO 2 2- , OSO 3 - or CO 2 - .
  • L 2 is selected from:
  • the A part is selected from C 1-6 alkyl, C 3-7 cycloalkyl (including, cyclopropyl , N-butyl, cyclopentyl or cyclohexyl), five-membered or six-membered heterocyclic group or aromatic ring group or heteroaromatic ring group (including tetrahydrofuranyl, pyrrolyl, pyridyl or phenyl), the -( OCH 2 CH 2 ) h OA-(OCH 2 CH 2 ) j O-, -(OCH 2 -CH 2 ) h
  • the compound represented by Formula I or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer thereof is
  • X 1 to X 5 is independently selected from R 1 , and the R 1 is selected from formula R 4 -(OCH 2 CH 2 ) g O- or R 4 -(OCH 2 CH 2 ) g-
  • X 6 to X 10 are each independently selected from hydrogen, -OH, OPO 3 2-, OPSO 2 2-, OSO 3 -, CO 2 - or R 1, of R 1 It is selected from polyethylene glycol represented by formula R 4 -(OCH 2 CH 2 ) g O- or R 4 -(OCH 2 CH 2 ) g -or formula R 4 -O-(CH 2 -CHOR 5- CH 2 O) g -represented by poly
  • At least one of X 1 to X 5 in formula III-1 is independently selected from R 1 , and the R 1 is selected from the group consisting of R 4 -(OCH 2 CH 2 ) g O- or R 4 -(OCH 2 CH 2 ) g -represented by polyethylene glycol or formula R 4 -O-(CH 2 -CHOR 5 -CH 2 O) g -represented by polyglycerol, the rest are independently selected from hydrogen,- OH, OPO 3 2-, OPSO 2 2-, OSO 3 - or CO 2 -, X 6 to X 10 are each independently selected from hydrogen, -OH, OPO 3 2-, OPSO 2 2-, OSO 3 -, CO 2 - ,
  • the polyethylene glycol or polyglycerol is optionally substituted by one or more selected from hydroxyl, deuterium, halogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkylene replace.
  • At least two of X 1 to X 5 in formula III-1 are independently selected from R 1 , and the R 1 is selected from the group consisting of R 4 -(OCH 2 CH 2 ) g O- or R Polyethylene glycol represented by 4 -(OCH 2 CH 2 ) g -or polyglycerol represented by formula R 4 -O-(CH 2 -CHOR 5 -CH 2 O) g -, the rest are independently selected from hydrogen, -OH, OPO 3 2-, OPSO 2 2-, OSO 3 - or CO 2 -, X 6 to X 10 are each independently selected from hydrogen, -OH, OPO 3 2-, OPSO 2 2-, OSO 3 -, CO 2 -, the polyethylene glycol or polyglycerol optionally substituted with one or more substituents selected from hydroxy, deuterium, halo, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkylene Replaced.
  • At least two of X 1 to X 5 in formula III-1 are independently selected from R 1 , and the R 1 is selected from the group consisting of R 4 -(OCH 2 CH 2 ) g O- or R Polyethylene glycol represented by 4 -(OCH 2 CH 2 ) g -or polyglycerol represented by formula R 4 -O-(CH 2 -CHOR 5 -CH 2 O) g -, the rest are independently selected from OPO 3 2-, OPSO 2 2-, OSO 3 - or CO 2 -, X 6 to X 10 are each independently selected from hydrogen, -OH, OPO 3 2-, OPSO 2 2-, OSO 3 -, CO 2 -, the Polyethylene glycol or polyglycerol is optionally substituted with one or more selected from hydroxyl, deuterium, halogen, C 1-6 alkyl, C 3-7 cycloalkyl, or C 3-7 cycloalkylene.
  • At least two of X 1 to X 5 in formula III-1 are independently selected from R 1 , and the R 1 is selected from the group consisting of R 4 -(OCH 2 CH 2 ) g O- or R Polyethylene glycol represented by 4 -(OCH 2 CH 2 ) g -or polyglycerol represented by formula R 4 -O-(CH 2 -CHOR 5 -CH 2 O) g -, the rest are independently selected from OPO 3 2- or CO 2 -, X 6 to X 10 are each independently selected from hydrogen, -OH, OPO 3 2-, OPSO 2 2-, OSO 3 -, CO 2 -, the polyethylene glycol or polyglycerol optionally It is substituted by one or more selected from hydroxyl, deuterium, halogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkylene.
  • At least two of X 1 to X 5 in formula III-1 are independently selected from R 1 , and the R 1 is selected from the group consisting of R 4 -(OCH 2 CH 2 ) g O- or R 4 - (OCH 2 CH 2) g - polyethylene glycol shown, the rest are independently selected OPO 3 2- or CO 2 -, X 6 to X 10 are each independently selected from hydrogen, -OH, OPO 3 2- , OPSO 2 2-, OSO 3 - , CO 2 -, the polyethylene glycol or polyglycerol optionally substituted with one or more substituents selected from hydroxy, deuterium, halo, C 1-6 alkyl, C 3-7 cycloalkyl Alkyl or C 3-7 cycloalkylene substituted.
  • At least one of X 6 to X 10 in formula III-1 is independently selected from R 1 , and the R 1 is selected from the group consisting of R 4 -(OCH 2 CH 2 ) g O- or R 4 -(OCH 2 CH 2 ) g -represented by polyethylene glycol or formula R 4 -O-(CH 2 -CHOR 5 -CH 2 O) g -represented by polyglycerol, the rest are independently selected from OPO 3 2 - or CO 2 -, the polyethylene glycol or polyglycerol optionally substituted with one or more substituents selected from hydroxy, deuterium, halo, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 alkylene Cycloalkyl substituted.
  • At least one of X 6 to X 10 in formula III-1 is independently selected from R 1 , and the R 1 is selected from the group consisting of R 4 -(OCH 2 CH 2 ) g O- or R 4 - (OCH 2 CH 2) g - polyethylene glycol represented by the remainder are independently selected OPO 3 2- or CO 2 -, the polyethylene glycol or polyglycerol optionally substituted with one or more groups selected from hydroxy , Deuterium, halogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkylene substituted.
  • At least two of X 6 to X 10 in formula III-1 are independently selected from R 1 , and the R 1 is selected from the group consisting of R 4 -(OCH 2 CH 2 ) g O- or R Polyethylene glycol represented by 4 -(OCH 2 CH 2 ) g -or polyglycerol represented by formula R 4 -O-(CH 2 -CHOR 5 -CH 2 O) g -, the rest are independently selected from OPO 3 2- or CO 2 - , the polyethylene glycol or polyglycerol is optionally selected from one or more of hydroxyl, deuterium, halogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 Cycloalkylene substituted.
  • At least two of X 6 to X 10 in formula III-1 are independently selected from R 1 , and the R 1 is selected from the group consisting of R 4 -(OCH 2 CH 2 ) g O- or R 4 - (OCH 2 CH 2) g - polyethylene glycol shown, the rest are independently selected OPO 3 2- or CO 2 -, the polyethylene glycol or polyglycerol optionally substituted with one or more substituents selected from Hydroxy, deuterium, halogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkylene substituted.
  • one of X 1 to X 5 in formula III-1 is independently selected from R 1 , and the R 1 is selected from the group consisting of R 4 -(OCH 2 CH 2 ) g O- or R 4 - (OCH 2 CH 2) g - polyethylene glycol shown, the rest are independently selected OPO 3 2- or CO 2 -, X 6 to X 10 are independently selected from a R 1, of R 1 selected from the group comprising the formula R 4 - (OCH 2 CH 2 ) g O- or R 4 - (OCH 2 CH 2 ) g - polyethylene glycol shown, the rest are independently selected OPO 3 2- or CO 2 - ,
  • the polyethylene glycol or polyglycerol is optionally substituted by one or more selected from hydroxyl, deuterium, halogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkylene .
  • two of X 1 to X 5 in formula III-1 are independently selected from R 1 , and the R 1 is selected from the group consisting of R 4 -(OCH 2 CH 2 ) g O- or R 4 - (OCH 2 CH 2) g - polyethylene glycol shown, the rest are independently selected OPO 3 2- or CO 2 -, X 6 to X 10 has two independently selected R 1, the R 1 is selected from including polyethylene glycol represented by the formula R 4 -(OCH 2 CH 2 ) g O- or R 4 -(OCH 2 CH 2 ) g -, and the rest are independently selected from OPO 3 2- or CO 2 -, the polyethylene glycol or polyglycerol optionally substituted with one or more substituents selected from hydroxy, deuterium, halo, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkylene Replaced.
  • the formula III-1 has different spatial configurations.
  • the different spatial configurations do not affect the activity of the compound or inhibit the efficiency of calcium ion crystallization.
  • the compound of formula (III) may be selected from:
  • At least two of X 1 to X 5 in formula III-1 are independently selected from R 1 , and said R 1 is selected from or comprises the formula R 4 -(OCH 2 CH 2 ) g O- or Polyethylene glycol represented by R 4 -(OCH 2 CH 2 ) g -or polyglycerol represented by formula R 4 -O-(CH 2 -CHOR 5 -CH 2 O) g -, and X 6 to X 10 are each independently selected from hydrogen, -OH, OPO 3 2-, OPSO 2 2-, OSO 3 - or CO 2 -, R 4, L 1 to L 3 are defined as in formula I, the polyethylene glycol or The polyglycerol is optionally substituted with one or more selected from hydroxyl, deuterium, halogen, C 1-6 alkyl, C 3-7 cycloalkyl, or C 3-7 cycloalkylene.
  • At least three of X 1 to X 5 in formula III-1 are independently selected from R 1 , and said R 1 is selected from or comprises the formula R 4 -(OCH 2 CH 2 ) g O- or Polyethylene glycol represented by R 4 -(OCH 2 CH 2 ) g -or polyglycerol represented by formula R 4 -O-(CH 2 -CHOR 5 -CH 2 O) g -, and X 6 to X 10 are each independently selected from hydrogen, -OH, OPO 3 2-, OPSO 2 2-, OSO 3 - or CO 2 -, R 4, L 1 to L 3 are defined as in formula I, the polyethylene glycol or The polyglycerol is optionally substituted with one or more selected from hydroxyl, deuterium, halogen, C 1-6 alkyl, C 3-7 cycloalkyl, or C 3-7 cycloalkylene.
  • X 1 and X 4 in formula III-1 are selected from R 1 , and said R 1 is selected from or comprises the formula R 4 -(OCH 2 CH 2 ) g O- or R 4 -(OCH 2 CH 2 ) g -represented by polyethylene glycol or formula R 4 -O-(CH 2 -CHOR 5 -CH 2 O) g -represented by polyglycerol, and X 2 , X 4 , X 5 , X 6 to X 10 are each independently selected from hydrogen, -OH, OPO 3 2-, OPSO 2 2-, OSO 3 - or CO 2 -, R 4, L 1 to L 3 are defined as in formula I, the poly Ethylene glycol or polyglycerol is optionally substituted with one or more selected from hydroxyl, deuterium, halogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkylene.
  • X 2 and X 4 in formula III-1 are selected from R 1 , and R 1 is selected from or comprises the formula R 4 -(OCH 2 CH 2 ) g O- or R 4 -(OCH 2 CH 2 ) g -represented by polyethylene glycol or formula R 4 -O-(CH 2 -CHOR 5 -CH 2 O) g -represented by polyglycerol, the polyethylene glycol or polyglycerol is optional Is substituted by one or more selected from hydroxyl, deuterium, halogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkylene, and X 1 , X 4 , X 5 , X 6 to X 10 are each independently selected from hydrogen, -OH, OPO 3 2-, OPSO 2 2-, OSO 3 - or CO 2 -, R 4, L 1 to L 3 in formula I as defined above.
  • X 6 to X 10 is selected from OPO 3 2-, OSO 3 - or CO 2 -. In some embodiments, the Formula III-1 X 6 to X 10 is selected from OPO 3 2- or OSO 3 -. In some embodiments, X 6 to X 10 in Formula III-1 are selected from OPO 3 2- .
  • the polyethylene glycol in formula III-1 is optionally substituted with one or more selected from hydroxyl, halogen, deuterium, C 1-6 alkyl, C 3-7 cycloalkyl or C 3 -7 substituted by cycloalkylene. In certain embodiments, the polyethylene glycol in formula III-1 is substituted with one or more selected from deuterium and C 1-6 alkyl. In some embodiments, the polyethylene glycol in Formula III-1 is substituted with one or more selected from deuterium, methyl, ethyl, or propyl.
  • the compound represented by Formula I or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer thereof is
  • X 1 to X 10 are as defined in formula III-1.
  • L 2 in formula I is a common central linker connected to formula (D), comprising C 2-20 linear or branched alkylene, C 2-20 linear or branched alkylene Alkoxy, -(OCH 2 CH 2 ) e O- or -(OCH 2 CH 2 ) e -, the alkylene, alkyleneoxy, -(OCH 2 CH 2 ) e O- or -(OCH 2 CH 2 ) e -optionally selected by one or more selected from hydroxyl, deuterium, amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl or C 3-7 subring Alkyl substituted.
  • formula (D) comprising C 2-20 linear or branched alkylene, C 2-20 linear or branched alkylene Alkoxy, -(OCH 2 CH 2 ) e O- or -(OCH 2 CH 2 ) e -, the alkylene, alkyleneoxy, -(OCH 2 CH 2
  • L 2 in formula I is a common central linker connected to formula (D), including C 2-10 linear or branched alkylene, -(OCH 2 CH 2 ) e O -Or-(OCH 2 CH 2 ) e -, the alkylene group, -(OCH 2 CH 2 ) e O- or -(OCH 2 CH 2 ) e -is optionally selected by one or more selected from hydroxyl, deuterium , Amino, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl or C 3-7 cycloalkylene substituted; L 1 represents -O- or a single bond.
  • e in Formula I is 2-15, 2-10, 2-8, or 2-4.
  • the A part is selected from nitrogen atom, C 1-6 alkyl, C 3-7 cycloalkyl, five-membered or six-membered heterocyclic group or aromatic ring group or heteroaromatic ring group, the C 1-6 alkane Group, C 3-7 cycloalkyl, five-membered or six-membered heterocyclic ring or aromatic ring or heteroaromatic ring is optionally halogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Substituted by aryl, SR', NR'(R”), COOR' or CONR'(R”);
  • e 3 to 8, such as 3, 4, 5, 6;
  • R', R", and L 2 are as defined in the aforementioned compound of formula (I).
  • L 2 in the compound of the present disclosure such as the compound of formula (V) is selected from:
  • r, s, and t are each independently selected from an integer between 1 and 6, such as 1, 2 or 3;
  • a and R 3 are as defined in the aforementioned compound of formula (I);
  • L 2 in the compound of the present disclosure such as the compound of formula (V) is selected from:
  • r, s, and t are each independently selected from an integer between 1 and 6, such as 1, 2 or 3;
  • a and R 3 are as defined in the aforementioned compound of formula (I);
  • L 2 in the compound of the present disclosure such as the compound of formula (V) is selected from:
  • r, s, t are each independently selected from an integer between 1 and 6, such as 1, 2 or 3;
  • a and R 3 are as defined in the aforementioned compound of formula (I);
  • A is selected from nitrogen atom, C 1-6 alkyl (including but not limited to methyl, ethyl, propyl or butyl).
  • R 3 is selected from hydrogen, hydroxyl, C 1-6 alkyl (including but not limited to methyl, ethyl, propyl or butyl), C 1-6 alkoxy (including but not limited to methoxy , Ethoxy, propoxy or butoxy), C 3-7 cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, cyclopentyl).
  • L 2 in the compound of the present disclosure such as the compound of formula (V) is selected from:
  • the A part is selected from nitrogen atom, C 1-6 alkyl, C 3-7 cycloalkyl, five-membered or six-membered heterocyclic group or aromatic ring group or heteroaromatic ring group
  • the carbon atom, nitrogen atom , C 3-7 cycloalkyl, five-membered or six-membered heterocyclic ring or aromatic ring or heteroaromatic ring is optionally halogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl Group, SR', NR'(R"), COOR' or CONR'(R"), preferably a carbon atom, a nitrogen atom or a phenyl group, j, k, and l are each independently selected from an integer between 1 and 6, For example, 1, 2 or 3.
  • R 3 in the aforementioned compound of formula (V) is selected from hydrogen, C 1-6 alkyl (including but limited to methyl, ethyl, propyl or pentyl), C 1-6 alkoxy Group (including but limited to methoxy, ethoxy, propoxy or pentyloxy), C 3-7 cycloalkyl (including but not limited to, cyclopropyl, cyclobutyl, cyclopentyl), five A five-membered or six-membered heterocyclic group (including but not limited to furyl), a five-membered or six-membered aryl group (including but not limited to phenyl), or a five-membered or six-membered heteroaryl group (including but not limited to pyridyl).
  • At least two Xs of the aforementioned compound as in formula (V) are selected from R 1 , and the R 1 is selected from or comprises the formula R 4 -(OCH 2 CH 2 ) g O- or R 4- (OCH 2 CH 2 ) g -represented by polyethylene glycol, and in the same formula (D), the polyethylene glycol is optionally selected from hydroxyl, halogen, deuterium, C 1-6 Alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkylene substituted, and the remaining Xs are each independently selected from hydrogen, -OH, OPO 3 2- , OPSO 2 2- , OSO 3 - or CO 2 - .
  • the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer thereof is:
  • j, k, and l are each independently selected from an integer between 1 and 6, such as 1, 2 or 3;
  • X is as defined in formula (I).
  • the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer, or tautomer thereof is
  • R 1 is selected from or comprises polyethylene glycol represented by R 4 -(OCH 2 CH 2 ) g O- or R 4 -(OCH 2 CH 2 ) g -, said polyethylene
  • the diol is optionally substituted by one or more selected from hydroxyl, halogen, deuterium, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkylene, and R 4 is selected from hydrogen, Methyl, ethyl, trifluoromethyl or cyclopropyl.
  • R 3 in the aforementioned compound as in formula (Va) is selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • R 3 in the aforementioned compound as in formula (Va) is selected from C 1-6 alkyl groups, such as methyl, ethyl, and propyl. In some embodiments, R 3 in the aforementioned compound as in formula (Va) is selected from C 1-6 alkoxy, such as methoxy or ethoxy.
  • R 3 in the aforementioned compound as in formula (Va) is selected from C 3-7 cycloalkyl, such as methoxy or ethoxy.
  • the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or their stereoisomers, rotamers or tautomers are:
  • L 2 in the aforementioned compound such as the compound of formula (VI) is selected from:
  • the A part is selected from C 1-6 alkyl, C 3-7 cycloalkyl, five-membered or six-membered heterocyclic group or aromatic ring group or heteroaromatic ring group, the carbon atom, nitrogen atom, C 3 -7 Cycloalkyl, five-membered or six-membered heterocyclic ring or aromatic ring or heteroaromatic ring is optionally halogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, SR ', NR'(R”), COOR' or CONR'(R”), preferably nitrogen, C1-6 alkyl or phenyl; r, s, t, v, j, k, l are each independently selected An integer from 1 to 6, such as 1, 2 or 3.
  • At least two Xs in the aforementioned compound such as (VI) are selected from R 1 , and the R 1 is selected from or comprises the formula R 4 -(OCH 2 CH 2 ) g O- or R 4 -( OCH 2 CH 2 ) g -represented by polyethylene glycol, and in the same formula (D), the polyethylene glycol is optionally selected from hydroxyl, halogen, deuterium, C 1-6 alkane group, C 3-7 cycloalkyl or C 3-7 cycloalkyl substituted alkylene, the remaining X are each independently selected from hydrogen, -OH, OPO 3 2-, OPSO 2 2-, OSO 3 - or CO 2 - .
  • a in the aforementioned compound of formula (VI) is selected from C 1-6 alkyl (such as methyl, ethyl, propyl), C 3-7 cycloalkyl (such as n-butyl, cyclopentyl) Or cyclohexyl), six-membered aromatic ring group (such as phenyl).
  • the A part of the compound is Wherein X is independently selected from hydroxy, OPO 3 2-, OPSO 2 2 -, OSO 3 -.
  • the A part of the compound is Wherein X is OPO 3 2- or are OPSO 2 2 - is OSO 3 -.
  • L 2 in the aforementioned compound of formula (VI) is selected from:
  • R 1 in the aforementioned compound of formula (VI) comprises polyethylene glycol represented by R 4 -(OCH 2 CH 2 ) g O- or R 4 -(OCH 2 CH 2 ) g -, and the poly Ethylene glycol is optionally substituted with one or more selected from hydroxyl, halogen, deuterium, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkylene, and R 4 is selected from hydrogen , Methyl, ethyl, trifluoromethyl or cyclopropyl.
  • L 2 comprises C 2-20 linear or branched alkylene, -(OCH 2 CH 2 ) e O-, -(OCH 2 CH 2 ) e -or -O-(CH 2 -CHOR 2 -CH 2 O) e -, and includes a moiety A selected from the group consisting of C 1-6 alkyl, C 3-7 cycloalkyl, five- or six-membered heterocyclic group or aromatic ring group or Heteroaryl ring group, the alkylene group, -(OCH 2 CH 2 ) e O-, -(OCH 2 CH 2 ) e -or -O-(CH 2 -CHOR 2 -CH 2 O) e -optional It is substituted by one or more selected from hydroxyl, halogen, deuterium, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycl
  • the A part of the compound is Wherein X is independently selected from hydroxy, OPO 3 2-, OPSO 2 2 -, OSO 3 -.
  • the A part of the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • n 5 in the compound of the present disclosure, and L 2 is selected from:
  • L 2 in the compound of formula (I) of the present disclosure comprises C 2-10 linear or branched alkylene, C 2-10 linear or branched alkyleneoxy, C 2-10 linear Or branched alkyleneamino, C 2-10 linear or branched alkylene mercapto, C 2-10 linear or branched alkenylene, C 2-10 linear or branched alkenyleneoxy or C 2- 10 Cycloalkylene -(OCH 2 CH 2 ) e O-, -(OCH 2 CH 2 ) e -or -O-(CH 2 -CHOR 2 -CH 2 O) e -, the L 2 is further optional It is substituted by one or more selected from hydroxyl, halogen, deuterium, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkylene.
  • the R 3 in the compound of formula (I) of the present disclosure is selected from hydrogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, five-membered or Six-membered heterocyclic group or aromatic ring group or heteroaromatic ring group.
  • R 2 or R 5 is selected from hydrogen, methyl, or ethyl.
  • At least three Xs of the compound of formula (I) of the present disclosure are each independently selected from R 1 , and the R 1 is selected from or includes the formula R 4 -(OCH 2 CH 2 ) g O- or R 4- (OCH 2 CH 2 )
  • the polyethylene glycol represented by g -, wherein R 4 is selected from hydrogen, methyl or ethyl, g 1-200, and the polyethylene glycol is optionally selected from one or more Hydroxyl, halogen, deuterium, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkylene substituted; the rest of X are all OPO 3 2- or all OPSO 2 2 -all OSO 3 -.
  • the molar mass of polyglycerol or polyethylene glycol in the compound of formula (I) of the present disclosure 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. mol.
  • L 2 in the compound of the present disclosure is selected from:
  • the L 2 is further optionally selected by one or more selected from hydroxyl, halogen, deuterium, amino, nitrile, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl Or substituted by C 3-7 cycloalkylene.
  • Typical compounds of the present disclosure or their pharmaceutically acceptable salts or their stereoisomers, rotamers or tautomers including but not limited to:
  • typical compounds of the present disclosure or their pharmaceutically acceptable salts or their stereoisomers, rotamers or tautomers include but are not limited to:
  • the present disclosure also provides the following compounds or their pharmaceutically acceptable salts or their stereoisomers, rotamers or tautomers:
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one therapeutically effective amount of the aforementioned compound of formula (I) or a pharmaceutically acceptable salt thereof, or their stereoisomers, rotamers or mutual Tautomers, and pharmaceutical excipients optionally selected from at least one of pharmaceutically acceptable excipients.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition based on the total weight of the composition, contains 0.01-99.99% of the aforementioned compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of pharmaceutically acceptable excipients based on the total weight of the composition.
  • the present disclosure provides the compound or pharmaceutically acceptable salt or stereoisomer, rotamer or tautomer of the above-mentioned scheme, or the foregoing pharmaceutical composition is prepared for treatment or Use in medicines for preventing diseases related to calcium disorders, which are selected from the group consisting of kidney stones, cardiovascular calcification, cardiovascular disease, osteoporosis, bone cancer, foot gout, calcified tendinitis, skin calcinosis Disease, rheumatoid arthritis, bone mineral disease, osteomalacia, hypodynamic bone disease, calcium allergy and cardiovascular disease.
  • diseases related to calcium disorders which are selected from the group consisting of kidney stones, cardiovascular calcification, cardiovascular disease, osteoporosis, bone cancer, foot gout, calcified tendinitis, skin calcinosis Disease, rheumatoid arthritis, bone mineral disease, osteomalacia, hypodynamic bone disease, calcium allergy and cardiovascular disease.
  • the compounds disclosed herein can exist in any form commonly used in pharmaceutical technology. Specific embodiments include, but are not limited to, sodium salt, magnesium salt, potassium salt, or a mixture of the foregoing forms. Other pharmaceutically acceptable salts are known to those skilled in the art, and are especially available from Haynes et al., J. Pharmaceutical Sci. 94, 2005, 21111-2120. In some embodiments, the aforementioned compounds are of formula (I) The compound exists in the form of its sodium, potassium or magnesium salt.
  • the hydrogen in the functional group of the compound described in the present disclosure can be deuterated to obtain the corresponding deuterated compound.
  • the deuterated compound retains the selectivity and potential comparable to the hydrogen analog; the deuterium bond is more stable, making “ADME” namely The "toxic pharmacokinetics” are different, thereby providing clinically beneficial effects.
  • Toxic pharmacokinetics refers to the absorption, distribution, metabolism and excretion of foreign chemicals by the body.
  • “Pharmaceutically acceptable excipients” include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents that have been approved by the U.S. Food and Drug Administration for use in humans or livestock animals. Agents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. Shape agent. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
  • the compounds in the present disclosure can contain one or more asymmetric centers, so they can produce enantiomers, diastereomers, and can be defined as (R)- or (S)- or used in absolute stereochemistry according to absolute stereochemistry. (D)- or (L)- other stereoisomeric forms of amino acids.
  • 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 conventional methods can be used For example, chromatography and fractional crystallization preparation.
  • the present disclosure also includes some compounds of the present disclosure that are the same as those described herein, but have one or more atoms replaced with an isotope-labeled atom having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature.
  • isotopes that can be bound to the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • the compounds of the present disclosure may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • radioactive isotopes can be used to label compounds, such as tritium ( 3 H), and heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
  • the bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon.
  • Deuterated drugs have the advantages of reducing toxic and side effects, increasing drug stability, enhancing efficacy, and prolonging the biological half-life of drugs. All changes in the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included in the scope of the present disclosure.
  • substitution with heavier isotopes can provide certain therapeutic advantages resulting from higher metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and therefore in certain situations
  • deuterium substitution can be partial or complete, and partial deuterium substitution refers to the substitution of at least one hydrogen by at least one deuterium.
  • deuterium when a position is specifically designated as deuterium (D), the position should be understood as having an abundance of deuterium (ie, at least 45 % Deuterium incorporation).
  • Stereoisomers refer to compounds of the same atomic composition that are bonded by the same bond but have different three-dimensional structures, and they are not interchangeable.
  • Various stereoisomers and mixtures thereof are contemplated in the present disclosure, and include “enantiomers”, which refers to two stereoisomers whose molecules are non-superimposable mirror images of each other.
  • Tautomer refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule.
  • the present disclosure includes tautomers of any of the compounds.
  • the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or Or both with Two configurations.
  • the present invention may include all isomers, such as tautomers, rotamers, geometric isomers, and diastereomers. Isomers, racemates and enantiomers.
  • a "monovalent group” refers to a compound that "formally” eliminates a monovalent atom or group.
  • “Subunit” refers to a compound “formally” eliminates two monovalent or one divalent atoms or groups of atoms.
  • alkyl refers to the remaining part after removing 1 hydrogen atom from an alkane molecule, and includes linear and branched monovalent groups of 1 to 20 carbon atoms.
  • An alkyl group containing 1 to 6 carbon atoms non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl , 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched isomers.
  • the alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from aryl, heteroaryl, Replaced by halogen.
  • Alkylene (-CH 2 -) refers to the remaining part of the alkane molecule after removing 2 hydrogen atoms, including linear and branched subgroups of 1 to 20 carbon atoms.
  • An alkylene group containing 1 to 6 carbon atoms include methylene (-CH 2 -), ethylene (such as -CH 2 CH 2 -or -CH(CH 3 )-), Propyl (such as -CH 2 CH 2 CH 2 -or -CH(CH 2 CH 3 )-), butylene (such as -CH 2 CH 2 CH 2 CH 2 -).
  • the alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point, preferably one or more of the following groups, independently selected from aryl and heteroaryl , Substituted by halogen.
  • alkyleneoxy including a straight or branched chain alkyleneoxy group of 2 to 20 carbon atoms, non-limiting examples: -(CH 2 OCH 2 OCH 2 OCH 2 O)-, -(OCH 2 OCH 2 OCH 2 )-, -(CH 2 O)-.
  • Alkylene sulfhydryl groups including linear or branched alkylene sulfhydryl groups of 2 to 20 carbon atoms, non-limiting examples: -(CH 2 SCH 2 SCH 2 S)-, -(SCH 2 SCH 2 SCH 2 )- , -(SCH 2 )-.
  • Alkyleneamino includes straight or branched chain alkyleneamino of 2 to 20 carbon atoms, non-limiting examples: -(CH 2 NCH 2 NCH 2 N)-, -(NCH 2 )-,- (NCH 2 NCH 2 NCH 2 )-.
  • Alkyl refers to a saturated aliphatic hydrocarbon group, including a straight chain alkyl group of 2 to 20 carbon atoms or a branched chain alkyl group of 2 to 20 carbon atoms. Non-limiting examples include n-butyl, n-pentyl, n-hexyl, or n-heptyl, and various branched isomers thereof, and the like.
  • the alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from hydroxyl, halogen, alkyl , Nitrile, nitro, aryl, heteroaryl or alkenyl.
  • alkenyl includes branched and straight chain olefins having 2 to 20 carbon atoms or olefins containing aliphatic hydrocarbon groups.
  • C 2-6 alkenyl means an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms.
  • 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.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 2 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 7 Carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptanyl, etc. Cycloalkyl groups may be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 2 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) w (where w is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 12-membered, such as benzene Base and naphthyl.
  • the aryl ring may be fused on a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
  • the aryl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group, carboxyl group or carboxylate group, preferably phenyl group.
  • heteroaryl 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 membered or 6 membered.
  • Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine, and many more.
  • Heteroaryl groups may be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where the definition of alkyl is as described above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • groups are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxy
  • haloalkyl refers to an alkyl substituted by halogen, where alkyl is as defined above.
  • haloaryl refers to an aryl group substituted by halogen, wherein the aryl group is as defined above.
  • haloheteroaryl refers to a heteroaryl group substituted by halogen, wherein the heteroaryl group is as defined above.
  • halogenated heterocyclic group refers to a heterocyclic group substituted by halogen, wherein the heterocyclic group is as defined above.
  • halocycloalkyl refers to a cyclic group substituted by halogen, wherein cycloalkyl is as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but does not have to be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • the substituent is a "divalent group" such as a cycloalkylene group
  • two hydrogen atoms in the group are simultaneously substituted by a cycloalkylene group to form a cycloalkyl group.
  • the numerical values in this disclosure are measured by instruments, and there is a certain degree of error. Generally speaking, plus or minus 10% are within a reasonable error range. Of course, you need to consider the context where the value is used, for example, the molar mass of polyethylene glycol. The value is that the error after measurement does not exceed plus or minus 10%, and it can be plus or minus 9%, plus or minus 8%, plus or minus 7%. , Plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methylsilane
  • the spatial configuration of optical isomers (isomers) of compounds can be further confirmed by measuring single crystal parameters.
  • HPLC determination uses Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent 1200LC high pressure liquid chromatograph (ACQUITY UPLC BEH C18 1.7UM 2.1X50MM column, Ultimate XB-C18 3.0*150mm Chromatographic column or Xtimate C18 2.1*30mm chromatographic column).
  • the MS is measured with Waters SQD2 mass spectrometer, scanning in positive/negative ion mode, and the mass scanning range is 100 ⁇ 1200.
  • Chiralpak IC-3 100 ⁇ 4.6mm ID, 3um, Chiralpak AD-3 150 ⁇ 4.6mm ID, 3um, Chiralpak AD-3 50 ⁇ 4.6mm ID, 3um, Chiralpak AS-3 150 ⁇ 4.6mm ID, 3um, Chiralpak AS-3 100 ⁇ 4.6mm ID, 3 ⁇ m, ChiralCel OD-3 150 ⁇ 4.6mm ID, 3um, Chiralcel OD-3 100 ⁇ 4.6mm ID, 3 ⁇ m, ChiralCel OJ-H 150 ⁇ 4.6mm ID, 5um, Chiralcel OJ-3 150 ⁇ 4.6mm ID, 3um chromatographic column;
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the thin layer chromatography separation and purification product is 0.4mm. ⁇ 0.5mm.
  • the fast column purification system uses Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).
  • Forward column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as the carrier, or Changzhou Santai pre-filled and pre-filled ultra-pure normal phase silica gel column (40-63 ⁇ m, 60, 12g) ,, 25g, 40g, 80g or other specifications).
  • RP column chromatography generally uses Changzhou Santai pre-packed ultra-pure C18 silica gel column (20-45 ⁇ m, 40g, 80g, 120g, 220g or other specifications).
  • the high-pressure column purification system uses Waters AutoP, together with Waters XBridge BEH C18 OBD Prep Column, 5 ⁇ m, 19mm X 150mm or Atlantis T3 OBD Prep Column, 5 ⁇ m, 19mm X 150mm.
  • the chiral preparation column uses DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).
  • the known starting materials in this disclosure can be synthesized by or according to methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc), Darui Chemicals and other companies.
  • reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction uses the CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20 OC to 30 OC.
  • TLC thin layer chromatography
  • the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the raw material or commodity manufacturers.
  • the reagents without specific sources are the conventional reagents purchased on the market.
  • compound 1-4 (1.8 g, 4.57 mmol) and DMF (20 mL) were added, cooled in an ice bath, 220 mg NaH was added, and reacted at room temperature for half an hour. 3.35 g of compound 2-1 was dissolved in 40 mL of DMF, dropped into the reaction solution, and heated to 40° C. and stirred for 18 hours.
  • reaction solution was diluted and quenched with water (120mL), extracted with methyl tert-butyl ether (60mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column to obtain 3g of compound 2-2, Ms (ESI): m/z 835[M+H] + .
  • reaction solution was diluted and quenched with water (30 mL), extracted with methyl tert-butyl ether (40 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column to obtain 1.02 g of compound 4-2.
  • reaction solution was diluted and quenched with water (44 mL), extracted with methyl tert-butyl ether (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column to obtain 2.08 g of compound 4-4.
  • reaction temperature was cooled to about -50°C, 1.98g m-chloroperoxybenzoic acid was added, warmed to room temperature and stirred for 2h, 50mL water was added to quench the reaction, extracted with methyl tert-butyl ether, the organic phases were combined, dried over anhydrous sodium sulfate and filtered Then, it was directly concentrated to obtain the crude product, which was purified by silica gel column to obtain 700 mg of compound 4-10 (HPLC purity>98%).
  • reaction solution was diluted with water, filtered, the filter cake was added to MTBE to be beaten and washed, the organic phases were combined, concentrated and crystallized, filtered to remove the filter cake, the filtrate was concentrated, and the crude product was passed through the column to obtain 1.1 g of compound 2-1 with a yield of 73.9%.
  • PD spectrophotometric pharmacodynamics
  • the final readout value is set as the slope of the absorbance change between 6-24 min.
  • INS 3001 is prepared by referring to the method in CN108367080
  • HAP hydroxyapatite
  • the HAP crystal has a maximum absorption peak at a wavelength of 550 nm, and its absorption peak intensity is consistent with the HAP content in the system Become positively correlated.
  • the compound has the effect of binding and inhibiting the formation and growth of HAP crystals. Therefore, by measuring the OD value of the inorganic salt solution system at 550nm, the inhibitory activity of different series of compounds on the formation of HAP crystals can be evaluated.
  • HAP crystals The formation of HAP crystals was measured in a 96-well plate by monitoring the absorbance, and the absorbance was read at a wavelength of 550 nm every 3 minutes, and the plate was continuously shaken for 1 hour.
  • Two linear equations were obtained for the OD value during the reading of each experimental well: the first line represents the basic absorbance with a slope close to 0, and the second line represents the maximum slope of the baseline absorbance increase.
  • Calculate the induction time of HAP formation for each sample that is, the intersection between the two lines (basic absorbance and maximum increase slope) represents the time required for the formation of HAP crystals.
  • the induction time at different concentrations of each compound was measured and compared with the control induction time.
  • Use GraphPad software to perform nonlinear fitting on the time-concentration curve to obtain IC50.

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Abstract

涉及一种肌醇衍生物及其用途。具体而言，提供了一种化合物，其包含由共同中心连接子L2连接的两个或多个式(D)所示的部分，式(D)如下所示。

Description

一种肌醇衍生物及其用途 技术领域
本公开属于医药技术领域，具体涉及肌醇衍生物及其用途。
背景技术
目前，我国慢性肾病发病率高达10.8％，且呈逐年上升的趋势，预计2018年终末期肾病(ESRD)患者近300万。在接受血液透析的ESKD患者中，由心血管事件造成的死亡率比一般患者要高出5～30倍。临床上发现，至少80％的血透患者会发生心血管钙化(CVC)。CVC是一种继发性病变，主要与钙磷代谢紊乱有关，钙结晶的生成和生长是CVC的关键机制。目前临床上主要使用维生素D、磷酸盐结合物和拟钙剂等进行治疗。
大血管钙沉积导致的冠状动脉粥样硬化、动脉血管变硬、左心室肥大、心肌缺血等是慢性肾病患者发病率和死亡率升高的重要原因。钙化防御是CVC的一种严重形式，是以皮下脂肪组织层及真皮层小血管的血管钙化堵塞为临床特点的一类少见但是却可以威胁生命的疾病，可以导致剧烈疼痛及缺血性皮肤坏死改变(Nigwekar SU et al,N Engl J Med.2018,378(18),1704-1714.)。一旦钙化防御诊断成立，病人的预后较差。钙化防御主要影响终末期肾脏病(ESRD)患者，且一直未得到临床足够重视，ESRD患者存在很高比例的骨外钙化问题，虽然这些骨外钙化大部分都不是钙化防御，但是钙化防御不能被简单的看作是ESRD患者普通的血管钙化。钙化防御导致的感染和其它伤口相关的并发症是发病和住院的主要原因，患者通常只接受止痛药和伤口处理，仍无“治本”的疗法获批上市。
SNF472是由Sanifit公司开发的IP6钠盐静脉制剂。可通过与钙化部位的羟基磷灰石(HAP)晶体(钙沉积物的主要成分)结合，从而抑制晶体继续生长，防止血管阻塞(Perelló J et al.Br J Clin Pharmacol.2018,84(12),2867-2876.)。2012年SNF472获FDA和EMA孤儿药资格，用于治疗钙化防御。
发明内容
本公开(the disclosure)提供了一种式(I)所示化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体
Figure PCTCN2021091548-appb-000001
其为两个或多个式(D)所示的部分由共用的连接子L 2连接的，式(D)如下所示：
Figure PCTCN2021091548-appb-000002
其中，
Figure PCTCN2021091548-appb-000003
为
Figure PCTCN2021091548-appb-000004
o和q各自独立地选自0至2，且o+q的值为0、1或2，L 1表示-O-、-NH-、-C(＝O)-、-OC(＝O)-、-NHC(＝O)-、-S-或单键；
至少一个X各自独立地选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或式R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的聚甘油，其余X各自独立地选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -或CO 2 -，且每个式(D)相同或不同，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、腈基、硝基、氨基、C 1-6烷基、C 1-6烷氧基、-OC(O)R 4、C 3-7环烷基或C 3-7亚环烷基所取代；
L 2为连接于式(D)上的共用中心连接子，包含C 2-20直链或支链亚烷基、C 2-20直链或支链亚烷氧基、C 2-20直链或支链亚烷氨基、C 2-20直链或支链亚烷巯基、C 2-20直链或支链亚烯基、C 2-20直链或支链亚烯氧基、C 2-20亚环烷基、-(OCH 2CH 2) eO-、-(OCH 2CH 2) e-或-O-(CH 2-CHOR 2-CH 2O) e-，且任选包含A部分，所述A部分选自氧原子、氮原子、硫原子、C 1-6烷基、C 3-7环烷基、五元或六元杂环基或芳环基或杂芳环基，其中所述亚烷基、亚烷氧基、亚烷氨基、亚烷巯基、亚烯基、亚烯氧基、亚环烷基、-(OCH 2CH 2) eO-、-(OCH 2CH 2) e-或-O-(CH 2-CHOR 2-CH 2O) e任选被一个或多个选自羟基、卤素、氘、氨基、腈基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基或C 3-7亚环烷基所取代，所述C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基任选被卤素、羟基、氘、氨基、腈基或硝基所取代；
当A部分选自C 1-6烷基或氮原子时，A可任选被R 3所取代，R 3选自氢、羟基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、SR'、NR'(R”)、COOR'或CONR'(R”)，所述烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自烷基、烷氧基、环烷基、杂环基、烯基、炔基、芳基、杂芳基、硝基、腈基、羟基、卤素、卤代烷基、卤代烷氧基、卤代环烷基、卤代杂环基、卤代芳基、卤代杂芳基所取代；
当A部分选自硫原子时，A可任选被氧取代；
R 4选自氢、C 1-6烷基或C 3-7环烷基，所述C 1-6烷基或C 3-7环烷基任选被一个或多个选自氘、腈基、硝基、氨基、羟基或卤素所取代，进一步地，R 4优选氢、甲基、乙基、三氟甲基或环丙基；
R 2或R 5各自独立选自氢、C 1-6烷基或甘油链，优选氢、甲基或乙基；
R'或R”独立地选自氢、羟基、烷基、烷氧基、烯基、酰基、芳基或杂芳基，所述烷基、烷氧基、芳基或杂芳基任选被一个或多个选自卤素、烷基、环烷基、烷氧基、烯基、炔基、氧基、羟基、硝基、腈基或-R a所取代；R a选自芳基或杂芳基，所述芳基或杂芳基任选被一个或多个选自卤素、烷基、环烷基、烷氧基、烯基、炔基、氧基、羟基、芳基、杂芳基、硝基、腈基、卤代烷基、卤代烷氧基、卤代环烷基、卤代杂环基、卤代芳基或卤代杂芳基所取代；
g＝1-200；
n选自2至8，例如2、3、4、6、7和8；
e＝1-20之间整数(包括但不限于1、2、3、4、6、7、12、13、14、16或17)。
本公开中“-OC(＝O)-”或“-NHC(＝O)-”并未特指与其连接的官能团处于左端或右端，例如“-OC(＝O)-”与“-C(＝O)O-”具有相同的定义。“-NHC(＝O)-”与“-C(＝O)NH-”具有相同的定义。
在一些实施方案中，L 1表示“-OC(＝O)-”或“-C(＝O)O-”。在一些实施方案中，L 1表示“-NHC(＝O)-”与“-C(＝O)NH-”。在一些实施方案中，L 1表示-O-。在一些实施方案中，L 1表示-C(＝O)-。在一些实施方案中，L 1表示-S-或单键。
在一些实施方案中，本公开化合物中
Figure PCTCN2021091548-appb-000005
选自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或CHX-CHXCH(L 1-)CHX-CHX，其中“-”表示键。
在一些实施方案中，本公开化合物包含五元至七元环，其中至少四个环成员可以由式CH-X表示，且一个环成员可以由式-CH-L 1。
在一些实施方案中，本公开化合物包含五元环，其中四个环成员可以由式CH-X表示，且一个环成员可以由式-CH-L 1-。
在一些实施方案中，本公开化合物包含六元环，其中五个环成员可以由式CH-X表示，且一个环成员可以由式-CH-L 1-。
在一些实施方案中，本公开化合物包含七元环，其中六个环成员可以由式CH-X表示，且一个环成员可以由式-CH-L 1-。
在一些实施方案中，本公开化合物包含六元环，其中五个环成员可以由式CH-X表示，且一个环成员可以由式-CH-L 1-。
在一些实施方案中，式(I)化合物为：
Figure PCTCN2021091548-appb-000006
在一些实施方案中，本公开化合物包含式(D)所示部分如式(Da)或(Db)所示：
Figure PCTCN2021091548-appb-000007
其中，L 1、X如前述式(I)化合物中所定义。
聚甘油，如式R 4-O-(CH 2-CHOH-CH 2O) g-所示，其中R 4选自氢、甲基或乙基，g＝1-200，支链或超枝化聚甘油如式R 4-O-(CH 2-CHOR 5-CH 2O) g-所示，其中R 5选自氢、C 1-6烷基或甘油链，且R 4选自氢、甲基或乙基。
甘油链，如式R 4-O-(CH 2-CHOR 2-CH 2O) g-，其中R 2为氢。
聚乙二醇，如式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示，其中R 4选自氢、甲基或乙基，g＝1-200。
本公开中聚乙二醇或聚甘油的摩尔质量选自100g/mol至3000g/mol，特别是100g/mol至2500g/mol，更特别是100g/mol至2000g/mol，或者200g/mol至3000g/mol，特别是300g/mol至2500g/mol，更特别是400g/mol至2000g/mol。
在一些实施方案中，化合物至少一个X选自R 1，所述R 1选自或包含由式R 4-O-(CH 2-CHOH-CH 2O) g-所示的聚甘油，其中R 4选自氢、甲基或乙基，g＝1-200。在另一些实施方案中，g＝3-20。在另一些实施方案中，g＝10-20。在另一些实施方案中，g＝9-45。另一些实施方案提供式I所示化合物中g为2至100、2至50、2至20或2至10。
在一些实施方案中，化合物中至少一个X选自R 1，所述R 1选自或包含由R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的支链或超枝化聚甘油，其中R 5选自氢或甘油链，且R 4选自氢、甲基或乙基。在另一些实施方案中，化合物中有1、2、3、4或5个X选自R 1，所述R 1选自或包含由式R 4-O-(CH 2-CHOH-CH 2O) g-所示的聚甘油或者R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的支链或超枝化聚甘油，其中R 5选自氢或甘油链，且R 4选自氢、甲基或乙基，g＝1-200。在一些实施方案中，化合物 中X选自R 1，所述R 1选自或包含由式R 4-O-(CH 2-CHOH-CH 2O) g-所示的聚甘油或R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的支链或超枝化聚甘油，且摩尔质量为100g/mol至3000g/mol，特别是100g/mol至2500g/mol，更特别是约100g/mol至2000g/mol，或者200g/mol至3000g/mol，特别是300g/mol至2500g/mol，更特别是约400g/mol至2000g/mol。
在一些实施方案中，化合物中至少一个X选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，其中R 4选自氢、甲基或乙基，g＝1-200，所述聚乙二醇任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。在另一些实施方案中，g＝3-20。在另一些实施方案中，g＝10-20。在另一些实施方案中，g＝9-45。
在一些实施方案中，化合物中至少一个X选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或R 4O(CH 2-CHOH-CH 2O) g-所示的聚甘油或者R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的支链或超枝化聚甘油，其中g＝2-100，所述聚乙二醇任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。在另一些实施方案中，g＝7-50，在另一些实施方案中，g＝7-15。在另一些实施方案中，g＝40-50。另一些实施方案提供式I所示化合物中g为2至100、2至50、2至20或2至10。在一些实施方案中，化合物中有3个X选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，且在同一式(D)部分上，所述聚乙二醇任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在另一些实施方案中，化合物中1、2、3、4或5个X选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，其中R 4选自氢、甲基或乙基，g＝1-200，所述聚乙二醇任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在一些实施方案中，化合物中X选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，所述聚乙二醇任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代，且摩尔质量为100g/mol至3000g/mol，特别是100g/mol至2500g/mol，更特别是100g/mol至2000g/mol，或者200g/mol至3000g/mol，特别是300g/mol至2500g/mol，更特别是400g/mol至2000g/mol。
在一些实施方案中，前述化合物中至少2或3个X选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，所述聚乙二醇任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代，其余X都是OPO 3 2-或都是OPSO 2 2-或都是OSO 3 -。在另一些实施方案中， 前述化合物中至少2个X选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，所述聚乙二醇任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代，且在同一式(D)部分上，其余X都是OPO 3 2-或都是OPSO 2 2-或都是OSO 3 -。
在一些实施方案中，前述化合物中式(D)部分上至少1个X选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或由式R 4-O-(CH 2-CHOH-CH 2O) g-所示的聚甘油，其中R 4选自氢、甲基或乙基，g＝1-200，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在一些实施方案中，前述化合物中式(D)部分上至少2或3个X选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，其中R 4选自氢、甲基或乙基，g＝1-200，所述聚乙二醇任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。进一步地，聚乙二醇摩尔质量为100g/mol至3000g/mol，特别是100g/mol至2500g/mol，更特别是100g/mol至2000g/mol，或者200g/mol至3000g/mol，特别是300g/mol至2500g/mol，更特别是400g/mol至2000g/mol。
在一些实施方案中，前述化合物中式(D)部分上至少2或3个X选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，其中R 4选自氢、甲基或乙基，g＝1-200，所述聚乙二醇任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代；其余X都是OPO 3 2-或都是OPSO 2 2-或都是OSO 3 -。进一步地，聚乙二醇摩尔质量为100g/mol至3000g/mol，特别是100g/mol至2500g/mol，更特别是100g/mol至2000g/mol，或者200g/mol至3000g/mol，特别是300g/mol至2500g/mol，更特别是400g/mol至2000g/mol。
在一些实施方案中，前述化合物中式(D)部分上至少2或3个X选自R 1，所述R 1选自或包含由式R 4-O-(CH 2-CHOH-CH 2O) g-所示的聚甘油，其中R 4选自氢、甲基或乙基，g＝1-200，所述聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。进一步地，聚乙二醇摩尔质量为100g/mol至3000g/mol，特别是100g/mol至2500g/mol，更特别是100g/mol至2000g/mol，或者200g/mol至3000g/mol，特别是300g/mol至2500g/mol，更特别是400g/mol至2000g/mol。
在一些实施方案中，前述化合物中式(D)部分上至少2或3个X选自R 1，所述R 1选自或包含由式R 4-O-(CH 2-CHOH-CH 2O) g-所示的聚甘油，所述聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代，其余X都是OPO 3 2-或都是OPSO 2 2-或都是OSO 3 -，其中R 4选自氢、甲基 或乙基，g＝1-200。进一步地，聚乙二醇摩尔质量为100g/mol至3000g/mol，特别是100g/mol至2500g/mol，更特别是100g/mol至2000g/mol，或者200g/mol至3000g/mol，特别是300g/mol至2500g/mol，更特别是400g/mol至2000g/mol。
在一些实施方案中，本公开化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体为：
Figure PCTCN2021091548-appb-000008
进一步地，本公开化合物存在不同空间构型，在实施方案中，空间构型不同不影响化合物活性或抑制钙离子结晶效率。在可选实施方案中，式(III)化合物可以选自：
Figure PCTCN2021091548-appb-000009
在一些实施方案中，前述化合物如式(III)中L 2选自C 3-10直链或支链亚烷基、C 3-10直链或支链亚烷氧基，所述亚烷基或亚烷氧基任选被一个或多个选自羟基、卤素、氘、氨基、腈基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基或C 3-7亚环烷基所取代。在一些实施方案中，L 2选自C 3-5直链或支链亚烷基、C 3-5直链或支链亚烷氧基。在一些实施方案中，L 2选自C 4-8直链或支链亚烷基、C 4-8直链 或支链亚烷氧基。在一些实施方案中，L 2选自C 3-4直链或支链亚烷基、C 3-4直链或支链亚烷氧基。
在一些实施方案中，前述化合物如式(III)中L2选自
Figure PCTCN2021091548-appb-000010
其中r和s分别选自1至6之间整数，例如1、2或3，所述
Figure PCTCN2021091548-appb-000011
任选被一个或多个选自羟基、卤素、氘、氨基、腈基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基或C 3-7亚环烷基所取代；A如前述式(I)化合物中所定义，且当A部分选自氮原子时，A可任选被C 1-6烷基取代，例如甲基；L 1如式(I)化合物中所定义。
在一些实施方案中，前述化合物如式(III)中L2选自
Figure PCTCN2021091548-appb-000012
所述
Figure PCTCN2021091548-appb-000013
任选被一个或多个选自羟基、卤素、氘、氨基、腈基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基或C 3-7亚环烷基所取代，L 1选自-O-、-NH-、-C(＝O)-、-OC(＝O)-或-S-，A选自氧原子、氮原子、硫原子。
在一些实施方案中，前述化合物如式(III)中A选自氧原子、氮原子、硫原子或C 1-6烷基，且当A部分选自碳原子或氮原子时，A任选被C 1-6烷基，包括但不限于甲基、乙基、丙基或丁基。
在一些实施方案中，前述化合物如式(III)中L2选自
Figure PCTCN2021091548-appb-000014
其中r和s分别为2或3，所述
Figure PCTCN2021091548-appb-000015
任选被一个或多个选自羟基、卤素、氘、氨基、腈基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基或C 3-7亚环烷基所取代；L 1选自-O-、-OC(＝O)-；A选自氧原子、氮原子、硫原子或C 1-6烷基，且当A部分选自碳原子或氮原子时，A任选被C 1-6烷基，包括但不限于甲基、乙基、丙基或丁基。
在另一些实施方案中，前述化合物如式(III)中L 2选自-(OCH 2CH 2) eO-、-(OCH 2CH 2) e-或-O-(CH 2-CHOR 2-CH 2O) e-，e＝1-20之间整数，例如2、3、4、5、6、7、8，所述-(OCH 2CH 2) eO-、-(OCH 2CH 2) e-或-O-(CH 2-CHOR 2-CH 2O) e-任选被一个或多个选自羟基、卤素、氘、氨基、腈基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基或C 3-7亚环烷基所取代。
在另一些实施方案中，前述化合物如式(III)中L 1为单键，聚二乙醇摩尔质量小于2000g/mol。
在一些实施方案中，式(III)中L 2为-(OCH 2CH 2) eCH 2O-，e＝1-20，L 1为单键。
在另一些实施方案中，式(III)中L 2为-O-(CH 2-CHOH-CH 2O) e-，e＝1-20，L 1为单键。
在可选所述方案中，式(III)化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体为：
Figure PCTCN2021091548-appb-000016
X如权利要求1中所定义，进一步地，其中R 1优选自或包含R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-表示的聚乙二醇，且R 4优选自氢、甲基、乙基、三氟甲基或环丙基，所述聚乙二醇任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在一些实施方案中，前述化合物如式(III)中至少有二个有X选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，且在同一式(D)上，所述聚乙二醇任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代，其余X各自独立地选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -或CO 2 -。
在一些实施方案中，前述化合物如式(III)中有3个有X选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，且在同一式(D)上，所述聚乙二醇任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代，其余X各自独立地选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -或CO 2 -。
在一些实施方案中，前述化合物如式(III)中L 2选自：
-(OCH 2CH 2) hO-A-(OCH 2CH 2) jO-、-(OCH 2-CH 2) hCH 2O-A-(OCH 2-CH 2) jCH 2O-或-(OCH 2CH(OH)CH 2) hO-A-(OCH 2CH(OH)CH 2) jO-，所述A部分选自C 1-6烷基、C 3-7环烷基(包括，环丙基、正丁基、环戊基或环已基)、五元或六元杂环基或芳环基或杂芳环基(包括四氢呋喃基、吡咯基、吡啶基或苯基)，所述-(OCH 2CH 2) hO-A-(OCH 2CH 2) jO-、-(OCH 2-CH 2) h-A-(OCH 2-CH 2) j-或-(OCH 2CH(OR 2)CH 2) hO-A-(OCH 2CH(OR 2)CH 2) jO-任选被一个或多个选自羟基、卤 素、氘、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代；h或j为1至10之间整数，例如1、2、3或4。进一步地，L 1优选单键。
另一方面，在一些实施方案中，式I所示化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体为
Figure PCTCN2021091548-appb-000017
其中，X 1至X 5中至少一个独立地选自R 1，所述R 1选自包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或式R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的聚甘油，其余独立地选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -或CO 2 -；X 6至X 10各自独立选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -、CO 2 -或R 1，所述R 1选自包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或式R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的聚甘油，R 4、L 1至L 3如式I中所定义，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在一些实施方案中，式III-1中X 1至X 5中至少一个独立地选自R 1，所述R 1选自包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或式R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的聚甘油，其余独立地选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -或CO 2 -，X 6至X 10各自独立选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -、CO 2 -，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在一些实施方案中，式III-1中X 1至X 5中至少二个独立地选自R 1，所述R 1选自包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或式R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的聚甘油，其余独立地选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -或CO 2 -，X 6至X 10各自独立选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -、CO 2 -，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在一些实施方案中，式III-1中X 1至X 5中至少二个独立地选自R 1，所述R 1 选自包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或式R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的聚甘油，其余独立地选自OPO 3 2-，OPSO 2 2-，OSO 3 -或CO 2 -，X 6至X 10各自独立选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -、CO 2 -，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在一些实施方案中，式III-1中X 1至X 5中至少二个独立地选自R 1，所述R 1选自包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或式R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的聚甘油，其余独立地选自OPO 3 2-或CO 2 -，X 6至X 10各自独立选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -、CO 2 -，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在一些实施方案中，式III-1中X 1至X 5中至少二个独立地选自R 1，所述R 1选自包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，其余独立地选自OPO 3 2-或CO 2 -，X 6至X 10各自独立选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -、CO 2 -，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在一些实施方案中，式III-1中X 6至X 10中至少一个独立地选自R 1，所述R 1选自包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或式R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的聚甘油，其余独立地选自OPO 3 2-或CO 2 -，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在一些实施方案中，式III-1中X 6至X 10中至少一个独立地选自R 1，所述R 1选自包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，其余独立地选自OPO 3 2-或CO 2 -，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在一些实施方案中，式III-1中X 6至X 10中至少二个独立地选自R 1，所述R 1选自包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或式R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的聚甘油，其余独立地选自OPO 3 2-或CO 2 -，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在一些实施方案中，式III-1中X 6至X 10中至少二个独立地选自R 1，所述R 1选自包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，其余独立地选自OPO 3 2-或CO 2 -，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在一些实施方案中，式III-1中X 1至X 5中有一个独立地选自R 1，所述R 1 选自包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，其余独立地选自OPO 3 2-或CO 2 -，X 6至X 10中有一个独立地选自R 1，所述R 1选自包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，其余独立地选自OPO 3 2-或CO 2 -，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在一些实施方案中，式III-1中X 1至X 5中有二个独立地选自R 1，所述R 1选自包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，其余独立地选自OPO 3 2-或CO 2 -，X 6至X 10中有二个独立地选自R 1，所述R 1选自包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，其余独立地选自OPO 3 2-或CO 2 -，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
进一步地，式III-1存在不同空间构型，在实施方案中，空间构型不同不影响化合物活性或抑制钙离子结晶效率。在可选实施方案中，式(III)化合物可以选自：
Figure PCTCN2021091548-appb-000018
在一些实施方案中，式III-1中X 1至X 5中至少二个独立地选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或式R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的聚甘油，且X 6至X 10各自独立地选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -或CO 2 -，R 4、L 1至L 3如式I中所定义，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在一些实施方案中，式III-1中X 1至X 5中至少三个独立地选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或式R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的聚甘油，且X 6至X 10各自独立地选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -或CO 2 -，R 4、L 1至L 3如式I中所定义，所述聚乙二醇 或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在另一些实施方案中，式III-1中X 1、X 4选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或式R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的聚甘油，且X 2、X 4、X 5、X 6至X 10各自独立地选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -或CO 2 -，R 4、L 1至L 3如式I中所定义，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在另一些实施方案中，式III-1中X 2、X 4选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或式R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的聚甘油，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代，且X 1、X 4、X 5、X 6至X 10各自独立地选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -或CO 2 -，R 4、L 1至L 3如式I中所定义。
在某一些实施方案中，式III-1中X 6至X 10选自OPO 3 2-、OSO 3 -或CO 2 -。在一些实施方案中，式III-1中X 6至X 10选自OPO 3 2-或OSO 3 -。在一些实施方案中，式III-1中X 6至X 10选自OPO 3 2-。
进一步地，在一些实施方案中，式III-1中聚乙二醇任选被一个或多个选自羟基、卤素、氘、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。在某一些实施方案中，式III-1中聚乙二醇被一个或多个选自氘、C 1-6烷基所取代。在一些实施方案中，式III-1中聚乙二醇被一个或多个选自氘、甲基、乙基或丙基所取代。
在另一些实施方案中，式I所示化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体为
Figure PCTCN2021091548-appb-000019
其中X 1至X 10如式III-1中所定义。
在一些实施方案中，式I中L 2为连接于式(D)上的共用的中心连接子，包含C 2-20直链或支链亚烷基、C 2-20直链或支链亚烷氧基、-(OCH 2CH 2) eO-或-(OCH 2CH 2) e-，所述亚烷基、亚烷氧基、-(OCH 2CH 2) eO-或-(OCH 2CH 2) e-任选被一个或多个选自羟基、氘、氨基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基或C 3-7亚环烷基所取代。
在另一些实施方案中，式I中L 2为连接于式(D)上的共用的中心连接子，包含C 2-10直链或支链亚烷基、-(OCH 2CH 2) eO-或-(OCH 2CH 2) e-，所述亚烷基、-(OCH 2CH 2) eO-或-(OCH 2CH 2) e-任选被一个或多个选自羟基、氘、氨基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基或C 3-7亚环烷基所取代；L 1表示-O-或单键。在另一些实施方案中，式I中e为2至15、2至10、2至8或2至4。
另一方面，本公开化合物为：
Figure PCTCN2021091548-appb-000020
其中所述A部分选自氮原子、C 1-6烷基、C 3-7环烷基、五元或六元杂环基或芳环基或杂芳环基，所述C 1-6烷基、C 3-7环烷基、五元或六元杂环或芳环或杂芳环任选被卤素、羟基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、SR'、NR'(R”)、COOR'或CONR'(R”)所取代；
e＝3至8，例如3、4、5、6；
R'、R”、L 2如前述式(I)化合物中所定义。
一些实施方案提供的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体为：
Figure PCTCN2021091548-appb-000021
在一些实施方案中，本公开化合物如式(V)化合物中L 2选自：
Figure PCTCN2021091548-appb-000022
其中r、s、t各自独立选自1至6之间整数，例如1、2或3；A、R 3如前述式(I)化合物中所定义；L 1表示-O-、-NH-、-C(＝O)-、-OC(＝O)-、 -NHC(＝O)-、-S-或单键。
在一些实施方案中，本公开化合物如式(V)化合物中L 2选自：
Figure PCTCN2021091548-appb-000023
其中r、s、t各自独立选自1至6之间整数，例如1、2或3；A、R 3如前述式(I)化合物中所定义；L 1表示-O-、-NH-、-C(＝O)-、-OC(＝O)-或单键。
在一些实施方案中，本公开化合物如式(V)化合物中L 2选自：
Figure PCTCN2021091548-appb-000024
其中r、s、t各自独立选自1至6之间整数，例如1、2或3；A、R 3如前述式(I)化合物中所定义；L 1表示-O-、-OC(＝O)-；A选自氮原子、C 1-6烷基(包括但不限于甲基、乙基、丙基或丁基)。进一步地，R 3选自氢、羟基、C 1-6烷基(包括但不限于甲基、乙基、丙基或丁基)、C 1-6烷氧基(包括但不限于甲氧基、乙氧基、丙氧基或丁氧基)、C 3-7环烷基(包括但不限于环丙基、环丁基、环戊基)。
在一些实施方案中，本公开化合物如式(V)化合物中L 2选自：
Figure PCTCN2021091548-appb-000025
其中所述A部分选自氮原子、C 1-6烷基、C 3-7环烷基、五元或六元杂环基或芳环基或杂芳环基，所述碳原子、氮原子、C 3-7环烷基、五元或六元杂环或芳环或杂芳环任选被卤素、羟基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、SR'、NR'(R”)、COOR'或CONR'(R”)所取代，优选碳原子、氮原子或苯基，j、k、l各自独立选自1至6之间整数，例如1、2或3。进一步地，其中L 1选自-C(＝O)-、-OC(＝O)-、-NHC(＝O)-或单键；R 3如前述式(I)化合物中所定义。
在一些实施方案中，前述化合物如式(V)中R 3选自氢、C 1-6烷基(包括但限于，甲基、乙基、丙基或戊基)、C 1-6烷氧基(包括但限于，甲氧基、乙氧基、丙氧基或戊氧基)、C 3-7环烷基(包括但不限于，环丙基、环丁基、环戊基)、五元或六元杂环基(包括但不限于呋喃基)、五元或六元芳基(包括但不限于苯基)或五元或六元杂芳基(包括但不限于吡啶基)。
在一些实施方案中，前述化合物如式(V)中至少有二个X选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，且在同一式(D)上，所述聚乙二醇任选被一个或多个选自羟基、卤素、氘、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代，其余X各自独立地选自氢、-OH、OPO 3 2-， OPSO 2 2-，OSO 3 -或CO 2 -。
在另一些实施方案中，本公开化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体为：
Figure PCTCN2021091548-appb-000026
其中j、k、l各自独立选自1至6之间整数，例如1、2或3；X如式(I)中所定义。
在另一些实施方案中，本公开化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体为
Figure PCTCN2021091548-appb-000027
其中X选自R 1，所述R 1选自或包含R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-表示的聚乙二醇，所述聚乙二醇任选被一个或多个选自羟基、卤素、氘、C 1-6烷基、C 3-7 环烷基或C 3-7亚环烷基所取代，且R 4选自氢、甲基、乙基、三氟甲基或环丙基。
在一些实施方案中，前述化合物如式(Va)中R 3选自氢、羟基、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基。
在一些实施方案中，前述化合物如式(Va)中R 3选自C 1-6烷基，如甲基、乙基、丙基。在一些实施方案中，前述化合物如式(Va)中R 3选自C 1-6烷氧基，如甲氧基或乙氧基。
在一些实施方案中，前述化合物如式(Va)中R 3选自C 3-7环烷基，如甲氧基或乙氧基。
另一方面，本公开化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体为：
Figure PCTCN2021091548-appb-000028
其中X、L 1、L 2如前述化合物(I)中所定义
在一些实施方案中，前述化合物如式(VI)中L 1选自-C(＝O)-、-OC(＝O)-、-NHC(＝O)-或单键。
在一些实施方案中，前述化合物如式(VI)化合物中L 2选自：
Figure PCTCN2021091548-appb-000029
Figure PCTCN2021091548-appb-000030
其中所述A部分选自C 1-6烷基、C 3-7环烷基、五元或六元杂环基或芳环基或杂芳环基，所述碳原子、氮原子、C 3-7环烷基、五元或六元杂环或芳环或杂芳环任选被卤素、羟基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、SR'、NR'(R”)、COOR'或CONR'(R”)所取代，优选氮原子、C1-6烷基或苯基；r、s、t、v、j、k、l各自独立选自1至6之间整数， 例如1、2或3。
在一些实施方案中，前述化合物如(VI)中至少有二个X选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，且在同一式(D)上，所述聚乙二醇任选被一个或多个选自羟基、卤素、氘、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代，其余X各自独立地选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -或CO 2 -。
在一些实施方案中，前述式(VI)化合物中A选自C 1-6烷基(如甲基、乙基、丙基)、C 3-7环烷基(如正丁基、环戊基或环己基)、六元芳环基(如苯基)。
在一些实施方案中，化合物中A部分为
Figure PCTCN2021091548-appb-000031
其中X各自独立选自羟基、OPO 3 2-、OPSO 2 2-、OSO 3 -。
在一些实施方案中，化合物中A部分为
Figure PCTCN2021091548-appb-000032
其中X都是OPO 3 2-或都是OPSO 2 2-都是OSO 3 -。
在一些实施方案中，前述式(VI)化合物中L 2选自：
Figure PCTCN2021091548-appb-000033
在一些实施方案中，前述式(VI)化合物中R 1包含R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-表示的聚乙二醇，所述聚乙二醇任选被一个或多个选自羟基、卤素、氘、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代，且R 4选自氢、甲基、乙基、三氟甲基或环丙基。
另一方面，本公开化合物中n＝5或6。在一些实施方案中，其中L 2包含C 2-20直链或支链亚烷基、-(OCH 2CH 2) eO-、-(OCH 2CH 2) e-或-O-(CH 2-CHOR 2-CH 2O) e-，且包含A部分，所述A部分选自C 1-6烷基、C 3-7环烷基、五元或六元杂环基或芳环基或杂芳环基，所述亚烷基、-(OCH 2CH 2) eO-、-(OCH 2CH 2) e-或-O-(CH 2-CHOR 2-CH 2O) e-任选被一个或多个选自羟基、卤素、氘、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在一些实施方案中，化合物中A部分为
Figure PCTCN2021091548-appb-000034
其中X各自独立选自羟基、OPO 3 2-、OPSO 2 2-、OSO 3 -。
在一些实施方案中，化合物中A部分为
Figure PCTCN2021091548-appb-000035
在一些实施方案中，本公开化合物中n＝5，所述L 2选自：
Figure PCTCN2021091548-appb-000036
在一些实施方案中，本公开式(I)化合物中L 2包含C 2-10直链或支链亚烷基、C 2-10直链或支链亚烷氧基、C 2-10直链或支链亚烷氨基、C 2-10直链或支链亚烷巯基、C 2-10直链或支链亚烯基、C 2-10直链或支链亚烯氧基或C 2-10亚环烷基-(OCH 2CH 2) eO-、-(OCH 2CH 2) e-或-O-(CH 2-CHOR 2-CH 2O) e-，所述L 2进一步任选被一个或多个选自羟基、卤素、氘、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
在一些实施方案中，本公开式(I)化合物中所述R 3选自氢、羟基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、五元或六元杂环基或芳环基或杂芳环基。
在一些实施方案中，本公开式(I)化合物中L 1表示-O-、-C(＝O)-、-OC(＝O)-或单键。
在一些实施方案中，其中R 2或R 5选自氢、甲基或乙基。
在一些实施方案中，本公开式(I)化合物至少三个X各自独立地选自R 1，所述R 1选自或包含式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，其中R 4选自氢、甲基或乙基，g＝1-200，所述聚乙二醇任选被一个或多个选自羟基、卤素、氘、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代；其余X都是OPO 3 2-或都是OPSO 2 2-都是OSO 3 -。
在一些实施方案中，本公开式(I)化合物有三个X各自独立地选自R 1，所述R 1选自或包含式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，且X位于同一式(D)中，其中R 4选自氢、甲基或乙基，g＝1-200，所述聚乙二醇任选被一个或多个选自羟基、卤素、氘、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代；其余X都是OPO 3 2-或都是OPSO 2 2-都是OSO 3 -。
在一些实施方案中，本公开式(I)化合物中聚甘油或聚乙二醇摩尔质量选自100g/mol至3000g/mol，优选100g/mol至2500g/mol，更优选100g/mol至2000g/mol。
另一方面，本公开化合物中L 2选自：
-(OCH 2CH 2) 2O-、-(OCH 2CH 2) 3O-、-(OCH 2CH 2) 4O-、-(OCH 2CH 2) 5O-、
Figure PCTCN2021091548-appb-000037
Figure PCTCN2021091548-appb-000038
所述L 2进一步任选被一个或多个选自羟基、卤素、氘、氨基、腈基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基或C 3-7亚环烷基所取代。
本公开典型化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，包括但不限于：
Figure PCTCN2021091548-appb-000039
Figure PCTCN2021091548-appb-000040
Figure PCTCN2021091548-appb-000041
另一方面，本公开典型化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，包括但不限于：
Figure PCTCN2021091548-appb-000042
Figure PCTCN2021091548-appb-000043
另一方面，本公开还提供了下列化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体：
Figure PCTCN2021091548-appb-000044
Figure PCTCN2021091548-appb-000045
另一方面，本公开还提供一种药物组合物，包括至少一种治疗有效量的前述式(I)化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，和任选自药学上可接受的赋形剂中的至少一种的药用辅料。
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述式(I)化合物或其可药用盐。在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。
另一方面，本公开中提供上述方案中所述化合物或其可药用盐或其立体异构体、旋转异构体或互变异构体，或前述的药物组合物在制备用于治疗或预防与钙紊乱相关疾病的药物中用途，所述钙紊乱相关疾病选自肾结石，心血管钙化，心血管病，骨质疏松症，骨癌，足痛风，钙化性肌腱炎，皮肤钙质沉着症，类风湿关节炎，骨矿物质病，骨软症，动力缺失性骨病，钙过敏和心血管病。
本文公开的化合物可以以制药技术中常用的任何形式存在。具体的实施方式包括但不限于钠盐、镁盐、钾盐或前述形式的混合物。其它药学上可接受的盐是 本领域技术人员已知的，并且尤其可以获自Haynes等,J.Pharmaceutical Sci.94,2005,2111-2120.在一些实施方案中，前述化合物如式(I)化合物以其钠盐或钾盐或镁盐形式存在。
另一方面，本公开所述化合物的官能团中氢可被氘代，获得相应氘代化合物，氘代化合物保留了与氢类似物相当的选择性和潜力；氘键更稳定，使得"ADME"即"毒药物动力学"不同，从而提供临床上有益效果。
毒药物动力学，指机体对外源化学物的吸收(absorption)、分布(distribution)、代谢(metabolism)及排泄(excretion)过程。
术语解释：
“可药用赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
本公开中化合物可以含有一个或多个不对称中心，因此可以产生对映异构体、非对映异构体、及可以根据绝对立体化学定义为(R)-或(S)-或用于氨基酸的(D)-或(L)-的其它立体异构形式。本公开包括所有可能异构体以及其外消旋的和光学纯的形式。光学活性的(+)和(-)、(R)-和(S)-或(D)-和(L)-异构体可以使用手性合成子或手性试剂制备，或者可以使用常规方法例如色谱法和分级结晶制备。用于制备/分离各个对映体的常规方法包括从合适的的光学纯前体手性合成或使用例如手性高压液相色谱法(HPLC)的外消旋物(或盐或衍生物的外消旋物)拆分。当本文描述的化合物含有烯双键或其它几何不对称性中心，除非另有说明，否则其意味着所述化合物包括E和Z几何异构体。而且，所有的互变异构形式也意味着包括在内。
本公开还包括一些与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
本公开的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物 半衰期等优势。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少3000倍的丰度的氘(即，至少45％的氘掺入)。
“立体异构体”指通过相同的键键合但具有不同的三维结构的相同原子组成的化合物，其不可互换。本公开中预期各种立体异构体及其混合物，并且包括“对映异构体”，其指其分子彼此为不能重叠的镜像的两种立体异构体。
“互变异构体”指质子从分子的一个原子转移到同一分子的另一个原子。本公开中包括任何所述化合物的互变异构体。
本公开所述化合物的化学结构中，键
Figure PCTCN2021091548-appb-000046
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2021091548-appb-000047
可以为
Figure PCTCN2021091548-appb-000048
或
Figure PCTCN2021091548-appb-000049
或者同时包含
Figure PCTCN2021091548-appb-000050
和
Figure PCTCN2021091548-appb-000051
两种构型。虽然为简便起见将全部上述结构式画成某些异构体形式，但是本发明可以包括所有的异构体，如互变异构体、旋转异构体、几何异构体、非对映异构体、外消旋体和对映异构体。“一价基团”是指一个化合物从“形式上”消除一个单价的原子或基团。“亚基”则是指化合物从“形式上”消除两个单价或一个双价形成的原子或原子团。示例“烷基”是指由烷烃分子中去除1个氢原子后余下的部分，包括1至20个碳原子的直链和支链一价基团。含有1至6个碳原子的烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基及其各种支链异构体等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自芳基、杂芳基、卤素所取代。
“亚烷基(-CH 2-)”则表示烷烃分子中去除2个氢原子后余下的部分，包括1至20个碳原子的直链和支链亚基团。含有1至6个碳原子的亚烷基，非限制性实施例包括亚甲基(-CH 2-)、亚乙基(如-CH 2CH 2-或-CH(CH 3)-)、亚丙基(如-CH 2CH 2CH 2-或-CH(CH 2CH 3)-)、亚丁基(如-CH 2CH 2CH 2CH 2-)。亚烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自芳基、杂芳基、卤素所取代。
同理，“亚烷氧基”、“亚烷氨基”、“亚烷巯基”、“亚烯基”、“亚烯氧基”、“亚环烷基”、“亚聚乙二醇基”的定义如“亚烷基”。例如亚烷氧基，包括2至20个碳原子的直链或支链亚烷氧基，非限制性示例：-(CH 2OCH 2OCH 2OCH 2O)-、 -(OCH 2OCH 2OCH 2)-、-(CH 2O)-。亚烷巯基，包括2至20个碳原子的直链或支链亚烷巯基，非限制性示例：-(CH 2SCH 2SCH 2SCH 2S)-、-(SCH 2SCH 2SCH 2)-、-(SCH 2)-。“亚烷氨基”，包括2至20个碳原子的直链或支链亚烷氨基，非限制性示例：-(CH 2NCH 2NCH 2NCH 2N)-、-(NCH 2)-、-(NCH 2NCH 2NCH 2)-。
“烷基”指饱和的脂族烃基团，包括2至20个碳原子的直链烷基或2至20个碳原子的支链烷基。非限制性实施例包括正丁基、正戊基、正己基或正庚基，及其各种支链异构体等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选为一个或多个以下基团，独立地选自羟基、卤素、烷基、腈基、硝基、芳基、杂芳基或烯基。
“烯基”包括具有2至20个碳原子的支链和直链烯烃或含有脂族烃基团的烯烃。例如“C 2-6烯基”表示具有2、3、4、5或6个碳原子的烯基。烯基的实例包括但不限于，乙烯基、烯丙基、1-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基丁-2-烯基、3-甲基丁-1-烯基、1-戊烯基、3-戊烯基及4-己烯基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含2至20个碳原子，优选包含3至12个碳原子，更优选包含3至7个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含2至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) w(其中w是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2021091548-appb-000052
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至12元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2021091548-appb-000053
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基，优选苯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为6至12元，更优选为5元或6元。例如。其非限制性实例包括：咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪，
Figure PCTCN2021091548-appb-000054
等等。
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所 述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“卤代烷基”指被卤素取代的烷基，其中烷基如上所定义。
术语“卤代芳基”指被卤素取代的芳基，其中芳基如上所定义。
术语“卤代杂芳基”指被卤素取代的杂芳基，其中杂芳基如上所定义。
术语“卤代杂环基”指被卤素取代的杂环基，其中杂环基如上所定义。
术语“卤代环烷基”指被卤素取代的环基，其中环烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代”指＝O取代基。
术语“硫代”指＝S取代基。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。另一方面，取代基为“二价基团”时如亚环烷基，基团中的2个氢原子同时被亚环烷基所取代，形成环烷基。
本公开中数值为仪器测量值，存在一定程度的误差，一般而言，正负10％均属于合理误差范围内。当然需要考虑该数值所用之处的上下文，例如，聚乙二醇摩尔质量，该数值为测量后误差变化不超过正负10％，可以为正负9％、正负8％、正负7％、正负6％、正负5％、正负4％、正负3％、正负2％或正负1％，优选正负5％。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标 为四甲基硅烷(TMS)。化合物的光学异构体(异构体)空间构型可进一步通过测量单晶参数的方式确认。
HPLC的测定使用Waters ACQUITY ultra high performance LC、Shimadzu LC-20A systems、Shimadzu LC-2010HT series或安捷伦Agilent 1200LC高压液相色谱仪(ACQUITY UPLC BEH C18 1.7UM 2.1X50MM色谱柱、Ultimate XB-C18 3.0*150mm色谱柱或Xtimate C18 2.1*30mm色谱柱)。
MS的测定用Waters SQD2质谱仪，以正/负离子模式扫描，质量扫描范围为100～1200。
手性HPLC分析测定使用Chiralpak IC-3 100×4.6mm I.D.，3um、Chiralpak AD-3 150×4.6mm I.D.，3um、Chiralpak AD-3 50×4.6mm I.D.，3um、Chiralpak AS-3 150×4.6mm I.D.，3um、Chiralpak AS-3 100×4.6mm I.D.，3μm、ChiralCel OD-3 150×4.6mm I.D.，3um、Chiralcel OD-3 100×4.6mm I.D.，3μm、ChiralCel OJ-H 150×4.6mm I.D.，5um、Chiralcel OJ-3 150×4.6mm I.D.，3um色谱柱；
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
快速柱纯化系统使用Combiflash Rf150(TELEDYNE ISCO)或者Isolara one(Biotage)。
正向柱层析一般使用烟台黄海硅胶100～200目、200～300目或300～400目硅胶为载体，或者使用常州三泰预填预填超纯正相硅胶柱(40-63μm，60，12g,，25g，40g，80g或其他规格)。
反相柱层析一般使用常州三泰预填超纯C18硅胶柱(20-45μm，
Figure PCTCN2021091548-appb-000055
40g，80g，120g，220g或其他规格)。
高压柱纯化系统使用Waters AutoP，配合使用Waters XBridge BEH C18 OBD Prep Column，
Figure PCTCN2021091548-appb-000056
5μm，19mm X 150mm或者Atlantis T3 OBD Prep Column，
Figure PCTCN2021091548-appb-000057
5μm，19mm X 150mm。
手性制备柱使用DAICEL CHIRALPAK IC(250mm*30mm,10um)或Phenomenex-Amylose-1(250mm*30mm,5um)。
本公开中的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自上海泰坦科技，ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20OC～30OC。
实施例中的反应进程的监测采用薄层色谱法(TLC)。
具体实施方式
以下结合实施例进一步描述本公开中，但这些实施例并非限制本公开中的范围。
本公开中实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例1
Figure PCTCN2021091548-appb-000058
在250mL单口瓶中，加入化合物1-1(按照CN108367080A方法合成得到，3.04g,10mmol)以及DMF(30mL)，冰浴冷却，加入0.96gNaH(24mmol)，将6.03g的化合物1-2(按照US6645951方法合成得到)溶于30mLDMF里，滴入前面的反应体系里，反应室温搅拌至反应基本完全，MTBE萃取，有机相合并，无水硫酸钠干燥过滤，浓缩，经硅胶柱过柱纯化得2.15g化合物1-3。
Ms(ESI):m/z 509[M+H] +。
1H-NMR(400MHz,CDCl 3)：δ5.51(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).
Figure PCTCN2021091548-appb-000059
在100mL的塑料瓶中，加入化合物1-3(1.52g,2.99mmol)以及THF(15mL)，冰浴冷却，加入氟化氢吡啶(15mL,含65～70％HF)，室温反应12h。将反应液加入到饱和碳酸氢钠水溶液淬灭，用乙酸乙酯萃取，有机相合并，无水硫酸钠干燥过滤，浓缩得1.1g化合物1-4，Ms(ESI):m/z 395[M+H] +。
Figure PCTCN2021091548-appb-000060
在100mL的单口瓶中，加入化合物1-4(1.379g,3.5mmol)以及DMF(14mL)，冰浴冷却，加入120mgNaH，加完后，将1.75g化合物1-5(按照US4001279方法合成得到)溶于20mLDMF，随后滴入反应液里，反应至基本完全。将反应液用水(70mL)稀释，MTBE(35mL x 2)萃取，有机相合并，无水硫酸钠干燥过滤，浓缩，粗品过柱得1.43g化合物1-6.
Ms(ESI):m/z 637[M+H] +。
1H-NMR(400MHz,CDCl 3)：δ7.810-7.791(d,2H),7.356-7.337(d,2H),5.48(s,1H),4.47-4.16(m,6H),3.82-3.53(m,24H),3.37(s,6H),2.45(s,3H).
Figure PCTCN2021091548-appb-000061
在50mL的单口瓶中，加入化合物1-4(0.788g,2mmol)以及DMF(8mL)，冰浴冷却，加入120mgNaH，加完后，将1.271g化合物1-6溶于12mL的DMF，随后滴入反应液里。反应升到40℃至反应基本完全。将反应液用水(40mL)稀释，甲基叔丁基醚萃取，有机相合并，无水硫酸钠干燥过滤，浓缩，粗品过硅胶柱得1.08g化合物1-7。
Ms(ESI):m/z 859[M+H] +。
1H-NMR(400MHz,CDCl 3)：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).
在100mL的单口瓶中，加入化合物1-7(1.08g,1.26mmol)，MeOH(29mL)以及0.1N HCl(29mL)，加热到轻微回流。直接浓缩得1.06g粗品，Ms(ESI):m/z839[M+H] +。
Figure PCTCN2021091548-appb-000062
在50mL的单口瓶中，加入上一步产物(600mg,0.7161mmol)，四氮唑(451mg，6.444mmol)，溶于二氯甲烷/乙腈(5mL/18mL)，滴入2.223g化合物1-8，滴完后反应室温搅拌18h。反应降温到-50℃，加入1.312g间氯过氧苯甲酸，升到室温并搅拌反应基本完全，加入50mL水淬灭反应，甲基叔丁基醚萃取，有机相合并，无水硫酸钠干燥过滤后浓缩得粗品，过硅胶柱纯化得到453mg的化合物1-9(HPLC纯度>98％)。
1H-NMR(400MHz,CDCl 3)：δ7.30-7.26(m,60H),5.05-5.00(m,24H),4.27(s,2H),4.15-3.90(m,6H),3.81-3.74(m,16H),3.54-3.28(m,28H),3.16(s,12H).
Figure PCTCN2021091548-appb-000063
在25mL的单口瓶中，加入化合物1-9(162mg,0.06mmol)，Pd(OH) 2/C(50mg，湿)，EtOH/H 2O(5mL/5mL)，加入34mg碳酸氢钠。氢气氛围下反应8h，过滤，滤液浓缩除掉绝大部分有机溶剂，冻干得目标产物1a(87mg，收率：100％)。
1H-NMR(400MHz,D 2O)：δ4.21(s,2H),3.99-3.69(m,50H),3.34(s,12H).
实施例2
Figure PCTCN2021091548-appb-000064
在250mL的单口瓶中，加入化合物1-4(1.8g,4.57mmol)以及DMF(20mL)，冰浴冷却，加入220mg NaH，室温反应半小时。将3.35g化合物2-1溶于40mL DMF，滴入反应液里，升到40℃搅拌18h。将反应液用水(120mL)稀释淬灭，甲基叔丁基醚(60mL x 3)萃取，有机相合并，无水硫酸钠干燥过滤，浓缩，粗品过硅胶柱纯化得3g化合物2-2，Ms(ESI):m/z 835[M+H] +。
Figure PCTCN2021091548-appb-000065
在250mL的氢化瓶中，加入化合物2-2(2.8g,3.36mmol)，Pd(OH) 2/C(1.4g，湿)，THF(56mL)，氢气氛围下(1atm)加热到40℃反应12h。过滤，滤液浓缩，残余物经过硅胶柱纯化得化合物2-3(1.675g)，Ms:655[M+H] +。
1H-NMR(400MHz,CDCl 3)：δ5.50(s,2H),4.54(s,3H),4.47-4.24(m,10H),3.93-3.53(m,25H),3.38(s,6H).
再参照实施例1中步骤制备获得目标产物2a。
1H-NMR(400MHz,D 2O)：δ4.43-3.63(m,36H),3.37(s,6H).
实施例3
Figure PCTCN2021091548-appb-000066
在250mL的单口瓶中，加入化合物3-1(按照文献Organic and Biomolecular Chemistry,2014,13,866-875.方法合成，4.44g,12mmol)以及DMF(50mL)，冰浴冷却，加入0.624g NaH，然后将5.98g化合物3-2溶于60mL DMF，滴入反应液里。室温搅拌反应基本完全，将反应液用水(240mL)稀释淬灭，甲基叔丁基醚(30mL x 3)萃取，有机相合并，无水硫酸钠干燥过滤，浓缩，粗品过硅胶柱得3.36g化合物3-2。
Ms(ESI):m/z 811[M+H] +。
1H-NMR(400MHz,CDCl 3)：δ7.32-7.26(m,20H),5.50(s,2H),4.70-4.55(m,8H),4.43(s,2H),4.35-4.32(m,7H),4.13-4.11(m,1H),4.00-3.88(m,2H),3.69-3.62(m,8H).
Figure PCTCN2021091548-appb-000067
在250mL的氢化瓶中，加入化合物3-2(2.6g,3.21mmol)，Pd/C(1.3g，湿)，THF(52mL)，氢气(1atm)氛围下加热到40℃反应3h，过滤，滤液浓缩，过硅胶柱纯化得化合物3-3(1.4g，收率96.9％)。
Ms(ESI):m/z 451[M+H] +。
1H-NMR(400MHz,D 2O)：δ5.50(s,2H),4.50-4.44(m,4H),4.40-4.30(m,4H),4.25-4.24(m,2H),4.00-3.90(m,2H),3.82-3.80(m,4H),3.73-3.71(m,4H).
Figure PCTCN2021091548-appb-000068
在250mL的单口瓶中，加入化合物3-3(1.4g,3.11mmol)，MeOH(30mL)，加入0.5N HCl(30mL)，加热到65℃反应5h，反应液直接浓缩得1.14g的化合物3-4，Ms(ESI):m/z 431[M+H] +。
再参照实施例1中步骤制备获得目标产物3a。
1H-NMR(400MHz,D 2O)：δ4.50-4.40(m,4H),4.20-3.95(m,12H),3.62-3.60(m,4H).
实施例4
Figure PCTCN2021091548-appb-000069
在50mL的单口瓶中，加入化合物3-1(740mg,2mmol，按照文献Organic and Biomolecular Chemistry,2014,13,866-875方法合成),化合物4-1(1.377g,4mmol，按照文献Tetrahedron Asymmetry,1995,5,1097-1104方法合成)以及DMSO(15mL)，冰浴冷却，加入560mg KOH，反应在70℃下搅拌5h。将反应液用水(30mL)稀释淬灭，甲基叔丁基醚(40mL x 3)萃取，有机相合并，无水硫酸钠干燥过滤，浓缩，粗品过硅胶柱纯化得1.02g化合物4-2。
Ms(ESI):m/z 429[M+H] +。
Figure PCTCN2021091548-appb-000070
在100mL的单口瓶中，加入化合物1-4(1.64g,4.19mmol)以及DMF(5mL)，冰浴冷却，加入252mg NaH，室温反应半小时。将1.93g化合物4-3(按照文献Chemistry-A European Journal,2009,31,7534-7538方法合成)溶于17mL DMF，滴入反应液里，升到45℃搅拌5h。将反应液用水(44mL)稀释淬灭，甲基叔丁基醚(50mL x 3)萃取，有机相合并，无水硫酸钠干燥过滤，浓缩，粗品过硅胶柱纯化得2.08g化合物4-4。
Ms(ESI):m/z 529[M+H]+。
Figure PCTCN2021091548-appb-000071
在100mL的氢化瓶中，加入化合物4-4(2.08g,3.94mmol)，Pd(OH) 2/C(1g，湿)，THF(42mL)，氢气氛围下(1atm)加热到45℃反应5h。过滤，滤液浓缩得化合物4-5(1.632g)。
Ms(ESI):439[M+H] +。
Figure PCTCN2021091548-appb-000072
在100mL的单口瓶中，加入化合物4-5(1.632g,3.73mmol)，三乙胺(756mg，7.46mmol)以及32mL二氯甲烷，冰浴冷却，室温反应半小时，随后加入TsCl(851mg，4.48mmol)以及48mg DMAP，室温反应18h。反应液直接浓缩过硅胶柱纯化得2.08g化合物4-6。
Ms(ESI):m/z 593[M+H]+。
Figure PCTCN2021091548-appb-000073
在50mL的单口瓶中，加入化合物4-2(0.685g,1.74mmol)以及DMF(10mL)，冰浴冷却，加入139mg NaH，室温反应半小时。将1.922g化合物4-6溶 于10mL DMF，滴入反应液里，升到40℃搅拌18h。将反应液用水(40mL)稀释淬灭，甲基叔丁基醚(40mL x 3)萃取，有机相合并，无水硫酸钠干燥过滤，浓缩，粗品过硅胶柱纯化得1.627g化合物4-7。
Ms(ESI):m/z 849[M+H] +。
1H-NMR(400MHz,CDCl3)δ7.29-7.26(m,10H),5.49(s,2H),4.68-4.24(m,10H),3.93-3.51(m,25H),3.38(s,6H),1.18(d,J＝6.4Hz,6H).
Figure PCTCN2021091548-appb-000074
在100mL的氢化瓶中，加入化合物4-7(1.627g,1.92mmol)，Pd(OH) 2/C(0.82g，湿)，THF(33mL)，氢气氛围下(1atm)加热到45℃反应5h。过滤，滤液浓缩，残余物经过硅胶柱纯化得化合物4-8(740mg)。
Ms(ESI):m/z 669[M+H] +。
1H-NMR(400MHz,CDCl3)δ5.50(s,2H),4.55-4.24(m,11H),3.88-3.53(m,26H),3.38(s,6H),1.18(d,J＝6.4Hz,6H).
Figure PCTCN2021091548-appb-000075
在50mL的单口瓶中，加入化合物4-8(740mg,1.11mmol)，MeOH(15mL)以及0.5N HCl(15mL)，加热到回流，反应2h。直接浓缩得750mg的粗品化合物4-9。
Ms(ESI):m/z 649[M+H]+。
Figure PCTCN2021091548-appb-000076
在100mL的单口瓶中，加入化合物4-9(350mg,0.54mmol)，四氮唑(910mg，12.96mmol)，溶于二氯甲烷/乙腈(35mL/15mL)，反应20min后滴入2.24g化合物1-8，滴完后反应室温搅拌1h。反应降温到-50℃左右，加入1.98g间氯过氧苯甲酸，升到室温并搅拌2h，加入50mL水淬灭反应，甲基叔丁基醚萃取，有机相合并，无水硫酸钠干燥过滤后直接浓缩得粗品，过硅胶柱纯化得到700mg 化合物4-10(HPLC纯度>98％)。
1H-NMR(400MHz,CDCl3)δ7.40-7.12(m,80H),5.04-4.92(m,34H),4.52(s,1H),4.40-4.02(m,7H),3.81-3.72(m,9H),3.53-3.15(m,22H),1.07(d,J＝6Hz,3H).
Figure PCTCN2021091548-appb-000077
在50mL的单口瓶中，加入化合物4-10(537mg,0.197mmol)，20％Pd(OH) 2/C(179mg，湿)，EtOH/H 2O(16mL/16mL)，加入132mg碳酸氢钠。氢气氛围下反应3h，过滤，滤液浓缩除掉绝大部分有机溶剂，冻干得目标化合物4a(285mg，收率：100％)。
1H-NMR(400MHz,D 2O)δ4.54-4.49(m,2H),4.25-3.63(m,42H),3.42(s,6H),1.35-1.31(m,3H).
实施例5
Figure PCTCN2021091548-appb-000078
在100mL的单口瓶中，加入化合物3-1(0.9g,2.43mmol)以及DMAc(3.6mL)，冰浴冷却，加入t-BuONa(0.47g，2.0eq)，加完后，将10g化合物3-2(合成参照Organic and Biomolecular Chemistry,2006,4,2082–2087.)溶于27mL的DMAc，随后滴入反应液里，反应至基本完全。将反应液用水稀释，过滤，滤饼加入MTBE打浆洗涤，有机相合并，浓缩析晶，过滤除去滤饼，滤液浓缩，粗品过柱得1.1g化合物2-1，收率73.9％。
Ms(ESI):m/z 613[M+H] +。
1H-NMR(400MHz,CDCl3)：δ7.79-7.77(d,J＝8Hz,2H),7.32-7.26(m,12H),5.51(s,1H),4.70-4.67(d,J＝12Hz,2H),4.58-4.55(d,J＝12Hz,2H),4.45(s, 1H),4.36-4.32(m,4H),4.13-4.11(m,2H),3.94(s,1H),3.69-3.62(m,6H),2.42(s,3H).
Figure PCTCN2021091548-appb-000079
在250mL的反应瓶中，加入化合物5-1(0.50g,1.18mmol)和化合物2-1(1.09g,1.78mmol)以及DMSO(4mL)，溶解。室温下，加入0.17g叔丁醇钠，加完后反应3h，加入甲醇(0.2mL)，室温搅拌0.5h，将反应液加入到20％氯化铵溶液和甲基叔丁基醚，分液，水相用甲基叔丁基醚萃取，有机相合并，用水和饱和食盐水洗，无水硫酸钠干燥过滤，浓缩，粗品过硅胶柱得0.72g化合物5-2，收率：70.5％。
Ms(ESI):m/z 863[M+H] +。
1H-NMR(400MHz,CDCl3)δ7.29(s,10H),5.50(d,J＝2.2Hz,2H),4.68(d,J＝11.6Hz,2H),4.58(d,J＝11.6Hz,2H),4.49–4.42(m,2H),4.35-4.34(m,6H),4.30-4.28(m,2H),3.97(s,1H),3.82(s,1H),3.76–3.60(m,18H),3.41–3.27(m,10H),1.14(d,J＝6.3Hz,6H).
再参照实施例4中步骤制备获得目标产物5a。M+HM+H 1H-NMR(400MHz,D2O)δ4.42(d,J＝9.4Hz,2H),4.17-4.10(m,5H),4.00-3.74(m,23H),3.47–3.38(m,4H),3.31(s,6H),1.11(d,J＝6.4Hz,6H).
Figure PCTCN2021091548-appb-000080
在3L的三口瓶中，加入化合物a1(1.01g,11.3mmol)以及THF(10ml)，冰浴冷却，滴加NaHMDS(6.19ml,1.1eq)，冰浴反应2小时。冰浴将1.53g的化合物a2分批加入反应中，室温反应2h,反应基本结束。室温加入硫酸和水搅拌16h，过滤，滤液浓缩后粗品蒸馏得0.94g化合物a3，收率：62.3％。
Ms(ESI):m/z 135[M+H] +。
1H-NMR(400MHz,CDCl3)：δ3.72-3.64(m,4H),3.59-3.52(m,1H),3.40-3.32(m,5H),2.68(s,1H),1.13(d,3H,J＝6.4Hz).
Figure PCTCN2021091548-appb-000081
在1L的三口瓶中，加入化合物a4(0.72g,5.39mmol)，Et 3N(0.654g，6.46mmol)，DMAP(0.066g)和DCM(3.6mL)，冰浴冷却，将1.13g化合物TsCl溶 于3.6mL DCM，随后滴入反应液里，室温反应1小时，反应结束，加水，分液，有机层依次加稀盐酸和盐水洗涤，干燥、过滤，滤液浓缩，得1.55g化合物a5，收率：99.8％。
Ms(ESI):m/z 289[M+H] +。
1H-NMR(400MHz,CDCl3)：δ7.80(d,2H,J＝8.4Hz),7.33(d,2H,J＝8.0Hz),4.14(t,2H,J＝2.4Hz),3.71(t,2H,J＝2.6Hz),3.60-3.56(m,1H),3.35-3.25(m,5H),2.44(s,3H),1.08(d,3H,J＝6.4Hz).
Figure PCTCN2021091548-appb-000082
在1L三口反应瓶中，加入化合物1-1(0.30g,0.986mmol)、化合物1-2(0.71g,2.46mmol)以及THF(4.5mL)，滴加NaHMDS的THF溶液(1.7ml,3.45mmol)，反应至反应基本完全，反应液转入1L四氟瓶中，冰浴冷却，加入65-70％氢氟酸吡啶溶液(1.2ml)，室温反应，反应液经饱和碳酸氢钠洗涤，二氯甲烷萃取，合并有机相，盐水洗涤，无水硫酸钠干燥过滤，浓干，柱纯化得到0.165g化合物5-1，收率40％。
Ms:(ESI):m/z 423[M+H] +。
1H-NMR(400MHz,CDCl3)：δ5.46(s,1H),4.47-4.45(m,1H),4.30-4.23(m,4H),4.08(s,1H),3.76-3.71(m,2H),3.67-3.60(m,8H),3.41-3.31(m,11H),1.16-1.15(m,6H).
实施例6
Figure PCTCN2021091548-appb-000083
Figure PCTCN2021091548-appb-000084
将化合物6-1(0.85g，2.3mmol)溶于DMAc(3.5mL)中，冷却至0℃，加入t-BuONa(0.44g，4.6mmol)，滴加化合物6-2(7.7g，18.4mmol，按照专利WO200923233A1合成)的DMAc(26mL)溶液，反应至基本完全。将反应液用水(75mL)稀释，过滤，滤饼加入MTBE(80mL x 2)打浆洗涤，有机相合并，浓缩，过滤浓缩后经柱层析纯化得1g 6-3，收率70％。
MS-ESI:m/z 617.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.78(d,J＝8.3Hz,2H),7.35-7.24(m,12H),5.49(s,1H),4.68(d,J＝11.6Hz,2H),4.57(d,J＝11.6Hz,2H),4.47-4.42(m,1H),4.38-4.23(m,4H),3.94(d,J＝1.3Hz,1H),3.63(d,J＝24.6Hz,4H),2.42(s,3H).
Figure PCTCN2021091548-appb-000085
将化合物6-3(1g，1.62mmol)和5-1(0.57g，1.35mmol)溶于DMSO(6mL)中，加入叔丁醇钠(0.19g，2.0mmol)，室温反应3小时。加入甲醇(0.2mL)，室温搅拌0.5小时，将反应液加入到20％氯化铵溶液(100mL)和甲基叔丁基醚(100mL)中，分液，水相用甲基叔丁基醚(50mL)萃取，有机相合并，用水(100mL)和饱和食盐水(100mL)洗，无水硫酸钠干燥，过滤浓缩后经柱层析纯化得1.05g 6-4，收率90％。
MS-ESI:m/z 867.4[M+H] +。
1H NMR(400MHz,CDCl3)δ7.29(s,10H),5.50(d,J＝2.6Hz,2H),4.68(d,J＝11.7Hz,2H),4.58(d,J＝11.7Hz,2H),4.48-4.42(m,2H),4.41-4.25(m,8H),3.96(s,1H),3.81(s,1H),3.76-3.54(m,14H),3.41-3.28(m,9H),3.22(s,1H),1.14(d,J＝6.2Hz,6H).
再参照实施例4中步骤制备获得目标产物6a。
1H NMR(400MHz,D2O)δ4.38(dd,J＝19.1,9.6Hz,2H),4.19-3.59(m,24H),3.50-3.38(m,4H),3.31(s,6H),1.11(d,J＝6.4Hz,6H).
实施例7
Figure PCTCN2021091548-appb-000086
参照实施例4中步骤制备获得目标产物7a
1H NMR(400MHz,D2O)δ4.35(dd,J＝19.0,9.5Hz,2H),4.10-3.67(m,28H),3.44-3.36(m,4H),3.29(s,6H),1.09(d,J＝4.0Hz,6H).
实施例8
Figure PCTCN2021091548-appb-000087
将化合物b1(10.0g，11.1mmol)溶于THF(100mL)中，冷却至0℃，滴加NaHMDS(61mL，122.0mmol)，于0℃反应2小时。分批加入化合物a2(15.2g，122.0mmol)，室温反应2小时。室温加入硫酸(61mL)和水(61mL)，搅拌16小时。加入NaOH调pH至中性，过滤浓缩后残余物溶于二氯甲烷(70mL)中，室温下依次加入TEA(14.0g)和DMAP(1.4g)，冰浴下加入TsCl(24.2g)的二氯甲烷(70mL)溶液，室温反应2小时。依次加水、稀盐酸洗涤，有机相浓缩后经柱层析纯化得23g化合物b3，两步收率70％。
MS-ESI:m/z 289.1[M+H] +。
1H-NMR(400MHz,CDCl3)δ7.79(d,2H,J＝8.4Hz),7.32(d,2H,J＝8.4Hz),4.13(t,2H,J＝5.2Hz),3.70(t,2H,J＝5.2Hz),3.61-3.54(m,1H),3.32-3.24(m,5H),2.43(s,3H),1.07(d,3H,J＝6.4Hz).
Figure PCTCN2021091548-appb-000088
将化合物8-1(4.0g，11.6mmol，按照文献Carbohydrate Research,2002,337,2399–2410合成)和b3(7.0g，24.4mmol)溶于DMSO(40mL)中，室温加入叔丁醇钠(2.8g)，反应16小时。加入水和EA萃取分层，有机相浓缩后经柱层析纯化得3.8g化合物8-2，收率56％。
MS-ESI:m/z 577.2[M+H] +。
1H-NMR(400MHz,CDCl3)δ7.86(d,J＝8.4Hz,2H),7.35(d,J＝8.4Hz,2H),5.46(d,J＝0.8Hz,1H),5.04(d,J＝1.2Hz,1H),4.45-4.43(m,1H),4.27-4.21(m,4H),3.68-3.58(m,10H),3.41-3.30(m,10H),2.44(s,3H),1.15-1.13(m,6H).
Figure PCTCN2021091548-appb-000089
将化合物8-3(2.0g，3.47mmol)溶于甲醇(20mL)中，加入30％甲醇钠的甲醇溶液(10mL)，升至70℃反应3小时。旋去甲醇，残留物加水溶清后，用二氯甲烷提取，浓缩后得1.3g化合物8-4，收率88％。
MS-ESI:m/z 423.2[M+H] +。
再参照实施例4中步骤制备获得目标产物8a。
1H NMR(400MHz,D 2O)δ4.38(dd,J＝19.0,9.5Hz,2H),4.21-3.55(m,28H),3.47-3.35(m,4H),3.30(s,6H),1.09(d,J＝6.4Hz,6H).
测试例1
利用spectrophotometric pharmacodynamics(PD)assay测定待测化合物对人血浆羟磷灰石(HAP)生成的抑制作用。
实验方法
1.1试剂配制
1)经EDTA-K2抗凝的人血浆。
2)混合溶液：磷酸氢二钠5mM，氯化钙41.67mM，将pH调整为7.4并利用0.22um滤器过滤。
3)氯化钠溶液:0.15M，pH调整为7.4并利用0.22um滤器过滤。
2.1测试步骤
1)利用0.15M氯化钠溶液配制待测化合物。
2)人血浆样品再处理。取足量血浆，在室温10000g离心30min备用。
3)将血浆加入96孔板中，75μL/孔。
4)加入候选药物5μL/孔。
5)加入磷酸氢二钠和氯化钙混合液120μL/孔，预计终浓度分别为1.5mM和12.5mM。
6)将孔板置于shaker上(750转/分钟)室温(25℃)孵育，每3分钟测量一次550nm波长下的吸光度。
7)最终的读出值设定为在6-24min之间吸光度变化的斜率。
3计算公式
Figure PCTCN2021091548-appb-000090
4实验结果
样品 IC50(Mean±SD,nM)
INS 3001 1864±142
1a(实施例1) 306±104
2a(实施例2) 230±163
3a(实施例3) 343±154
注：INS 3001参照CN108367080中方法制备
测试例2
1实验目的
在Na 2HPO 4、NaCl缓冲液体系中，通过加入高浓度CaCl 2启动羟基磷灰石(HAP)的结晶过程，HAP晶体在波长550nm下具有最大吸收峰，其吸收峰强度与体系中HAP含量成正相关。化合物具有结合并抑制HAP晶体形成及生长的作用，因此通过测量无机盐溶液体系550nm下的OD值，来评价不同系列化合物对HAP结晶形成的抑制活性。
2实验步骤
1)配置无机盐体系：25mM CaCl 2溶液；55mM Na 2HPO 4·12H 2O溶液；1.5M NaCl溶液；
2)混合溶液：按体积比1:1:6分别加入55mM Na 2HPO 4·12H 2O、1.5M NaCl、ddH 2O，调节pH至7.4；
3)在96孔板中加入160μL混合溶液，分别加入不同浓度的化合物溶液20μL(浓度：100、30、10、3、1、0.3、0.1、0.01μM)；
4)分别加入25mM CaCl 2溶液，20μL/孔；
5)将孔板置于shaker上(300转/min)混匀30s；
6)常温下每3分钟测量一次550nm波长下的吸光度(测量前将孔板置于shaker上(300转/min)混匀30s)。测量时长为60min。
3实验结果
通过监测吸光度在96孔板中测量HAP晶体的形成，每隔3分钟在550nm波长下读取吸光度，并在板上不断震荡，持续1小时。对于每个实验孔读数期间的OD值求得两个线性方程：第一条代表基本吸光度且斜率接近0的直线，第二条代表基线吸光度增加的最大斜率。计算每个样品对HAP形成的诱导时间，即两条线之间的交点(基本吸光度和最大增加斜率)代表HAP晶体形成所需的时间。测量每种化合物不同浓度的诱导时间，并将其与对照诱导时间进行比较。使用GraphPad软件对时间-浓度曲线进行非线性拟合，求得IC50。
表1
化合物 IC50(μM)
1a 1.04±0.54
2a 4.04±2.55
3a 5.19±0.31
5a 1.13±0.26
7a 1.35±0.14
8a 1.73±0.57
参考文献：Mechanism of action of SNF472,a novel calcification inhibitor to treat vascular calcification and calciphylaxis[J].British Journal of Pharmacology,2020,177(19).

Claims (41)

  1. 式(I)所示化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体
    Figure PCTCN2021091548-appb-100001
    其为两个或多个式(D)所示的部分由共用的连接子L 2连接的，式(D)如下所示：
    Figure PCTCN2021091548-appb-100002
    其中，
    Figure PCTCN2021091548-appb-100003
    为
    Figure PCTCN2021091548-appb-100004
    o和q各自独立地选自0至2，且o+q的值为0、1或2，L 1表示-O-、-NH-、-C(＝O)-、-OC(＝O)-、-NHC(＝O)-、-S-或单键；
    至少一个X各自独立地选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或式R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的聚甘油，其余X各自独立地选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -或CO 2 -，且每个式(D)相同或不同，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、腈基、硝基、氨基、C 1-6烷基、C 1-6烷氧基、-OC(O)R 4、C 3-7环烷基或C 3-7亚环烷基所取代；
    L 2为连接于式(D)上的共用的中心连接子，包含C 2-20直链或支链亚烷基、C 2-20直链或支链亚烷氧基、C 2-20直链或支链亚烷氨基、C 2-20直链或支链亚烷巯基、C 2-20直链或支链亚烯基、C 2-20直链或支链亚烯氧基、C 2-20亚环烷基、-(OCH 2CH 2) eO-、-(OCH 2CH 2) e-或-O-(CH 2-CHOR 2-CH 2O) e-，且任选包含A部分，所述A部分选自氧原子、氮原子、硫原子、C 1-6烷基、C 3-7环烷基、五元或六元杂环基或芳环基或杂芳环基，其中所述亚烷基、亚烷氧基、亚烷氨基、亚烷巯基、亚烯基、亚烯氧基、亚环烷基、-(OCH 2CH 2) eO-、-(OCH 2CH 2) e-或-O-(CH 2-CHOR 2-CH 2O) e-任选被一个或多个选自羟基、卤素、氘、氨基、腈基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基或C 3-7亚环烷基所取代，所述C 1-6烷基、C 1-6烷氧基、C 3-7环烷基或C 3-7亚环烷基任选被卤素、羟基、氘、氨基、腈基或硝 基所取代；
    当A部分选自C 1-6烷基或氮原子时，A可任选被R 3所取代，R 3选自氢、羟基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、SR'、NR'(R”)、COOR'或CONR'(R”)，所述烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选被一个或多个选自烷基、烷氧基、环烷基、杂环基、烯基、炔基、芳基、杂芳基、硝基、腈基、羟基、卤素、卤代烷基、卤代烷氧基、卤代环烷基、卤代杂环基、卤代芳基、卤代杂芳基所取代；
    当A部分选自硫原子时，A可任选被氧取代；
    R 4选自氢、C 1-6烷基或C 3-7环烷基，所述C 1-6烷基或C 3-7环烷基任选被一个或多个选自氘、腈基、硝基、氨基、羟基或卤素所取代，进一步地，R 4优选氢、甲基、乙基、三氟甲基或环丙基；
    R 2或R 5各自独立选自氢、C 1-6烷基或甘油链，优选氢、甲基或乙基；
    R'或R”独立地选自氢、羟基、烷基、烷氧基、烯基、酰基、芳基或杂芳基，所述烷基、烷氧基、芳基或杂芳基任选被一个或多个选自卤素、烷基、环烷基、烷氧基、烯基、炔基、氧基、羟基、硝基、腈基或-R a所取代；R a选自芳基或杂芳基，所述芳基或杂芳基任选被一个或多个选自卤素、烷基、环烷基、烷氧基、烯基、炔基、氧基、羟基、芳基、杂芳基、硝基、腈基、卤代烷基、卤代烷氧基、卤代环烷基、卤代杂环基、卤代芳基或卤代杂芳基所取代；
    g＝1-200；
    n选自2至8，例如2、3、4、6、7和8；
    e＝1-20之间整数。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其为：
    Figure PCTCN2021091548-appb-100005
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中包含式(D)所示部分如式(Da)或(Db)所示
    Figure PCTCN2021091548-appb-100006
    其中，L 1、X如权利要求1中所定义。
  4. 根据权利要求1-3任一项所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其为：
    Figure PCTCN2021091548-appb-100007
    包括
    Figure PCTCN2021091548-appb-100008
  5. 根据权利要求4所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中L 2选自C 3-10直链或支链亚烷基、C 3-10直链或支链亚烷氧基或
    Figure PCTCN2021091548-appb-100009
    所述亚烷基、亚烷氧基或
    Figure PCTCN2021091548-appb-100010
    任选被一个或多个选自羟基、卤素、氘、氨基、腈基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基或C 3-7亚环烷基所取代，其中r和s分别选自1至6之间整数，例如1、2或3；A如权利要求1中所定义，且当A部分选自氮原子时，A可任选被C 1-6烷基取代，例如甲基；L 1如权利要求1中所定义取代。
  6. 根据权利要求5所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中A选自氧原子、氮原子、硫原子或C 1-6烷基，且当A部分选自碳原子或氮原子时，A任选被C 1-6烷基取代。
  7. 根据权利要求1-4任何一项所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中L 2选自-(OCH 2CH 2) eO-、-(OCH 2CH 2) e- 或-O-(CH 2-CHOR 2-CH 2O) e-，e＝1-20之间整数，例如2、3、4、5、6、7、8，所述-(OCH 2CH 2) eO-、-(OCH 2CH 2) e-或-O-(CH 2-CHOR 2-CH 2O) e-任选被一个或多个选自羟基、卤素、氘、氨基、腈基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基或C 3-7亚环烷基所取代。
  8. 根据权利要求7所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其为：
    Figure PCTCN2021091548-appb-100011
    X如权利要求1中所定义，进一步地，其中R 1优选或包含R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-表示的聚乙二醇，且R 4选自氢、甲基、乙基、三氟甲基或环丙基，所述聚乙二醇任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
  9. 根据权利要求7或8所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中化合物中至少有二个有X选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，且在同一式(D)上，其余X各自独立地选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -或CO 2 -，所述聚乙二醇任选被一个或多个选自羟基、卤素、氘、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
  10. 根据权利要求4所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中L 2选自：-(OCH 2CH 2) hO-A-(OCH 2CH 2) jO-、-(OCH 2-CH 2) h-A-(OCH 2-CH 2) j-或-(OCH 2CH(OR 2)CH 2) hO-A-(OCH 2CH(OR 2)CH 2) jO-，所述A部分选自C 1-6烷基、C 3-7环烷基、五元或六元杂环基或芳环基或杂芳环基，所述-(OCH 2CH 2) hO-A-(OCH 2CH 2) jO-、-(OCH 2-CH 2) h-A-(OCH 2-CH 2) j-或 -(OCH 2CH(OR 2)CH 2) hO-A-(OCH 2CH(OR 2)CH 2) jO-任选被一个或多个选自羟基、卤素、氘、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代；h或j为1至20之间整数，例如1、2、3或4。
  11. 根据权利要求1-3任一项所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其为：
    Figure PCTCN2021091548-appb-100012
    其中所述A部分选自氮原子、C 1-6烷基、C 3-7环烷基、五元或六元杂环基或芳环基或杂芳环基，所述C 1-6烷基、C 3-7环烷基、五元或六元杂环或芳环或杂芳环任选被卤素、羟基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、SR'、NR'(R”)、COOR'或CONR'(R”)所取代；
    R'、R”、L 2如权利要求1中所定义；
    f＝3至8，例如3、4、5、6。
  12. 根据权利要求1-3或11任一项所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其为：
    Figure PCTCN2021091548-appb-100013
    其中X如权利要求1中所定义；进一步地，L 2优选自：
    a)
    Figure PCTCN2021091548-appb-100014
    其中r、s、t各自独立选自1至6之间整数，例如1、2或3，进一步地，其中L 1选自-O-、-NH-、-C(＝O)-、-OC(＝O)-、-NHC(＝O)-、-S-或单键；
    b)
    Figure PCTCN2021091548-appb-100015
    其中所述A部分选自氮原子、C 1-6烷基、C 3-7环烷基、五元或六元杂环基或芳环基或杂芳环基，所述碳 原子、氮原子、C 3-7环烷基、五元或六元杂环或芳环或杂芳环任选被卤素、羟基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、SR'、NR'(R”)、COOR'或CONR'(R”)所取代，优选碳原子、氮原子或苯基；j、k、l各自独立选自1至6之间整数，例如1、2或3；进一步地，其中L 1选自-C(＝O)-、-OC(＝O)-、-NHC(＝O)-或单键。
  13. 根据权利要求12所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其为：
    Figure PCTCN2021091548-appb-100016
    其中X如权利要求1中所定义，进一步地，其中R 1优选包含R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-表示的聚乙二醇，且R 4选自氢、甲基、乙基、三氟甲基或环丙基，所述聚乙二醇任选被一个或多个选自羟基、卤素、氘、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
  14. 根据权利要求12或13所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中至少有二个X选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，且在同一式(D)上，其余X各自独立地选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -或CO 2 -，所述聚乙二醇任选被一个或多个选自羟基、卤素、氘、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
  15. 根据权利要求12-14任一项所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中R 3选自氢、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、五元或六元杂环基或芳环基或杂芳环基。
  16. 根据权利要求1-3或11任一项所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其为：
    Figure PCTCN2021091548-appb-100017
    其中X、L 1、L 2如权利要求1中所定义；进一步地，其中R 1优选或包含R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-表示的聚乙二醇，且R 4选自氢、甲基、乙基、三氟甲基或环丙基，所述聚乙二醇任选被一个或多个选自羟基、卤素、氘、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代；L 2优选自：
    Figure PCTCN2021091548-appb-100018
    Figure PCTCN2021091548-appb-100019
    其中所述A部分选自C 1-6烷基、C 3-7环烷基、五元或六元杂环基或芳环基或杂芳环基，所述C 3-7环烷基、五元或六元杂环或芳环或杂芳环任选被卤素、羟基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、SR'、NR'(R”)、COOR'或CONR'(R”)所取代，优选氮原子、C 1-6烷基或苯基；r、s、t、j、k、l、v各自独立选自1至6之间整数，例如1、2或3。
  17. 根据权利要求1-13任一项所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中至少有二个X选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，R 4选自氢、甲基、乙基、三氟甲基或环丙基，且在同一式(D)上，其余X各自独立地选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -或CO 2 -，所述聚乙二醇任选被一个或多个选自羟基、卤素、氘、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
  18. 根据权利要求1-3任一项所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中n＝5或6，进一步地，其中L 2包含C 2-20直链或支链亚烷基、-(OCH 2CH 2) eO-、-(OCH 2CH 2) e-或-O-(CH 2-CHOR 2-CH 2O) e-，且包含A部分，所述A部分选自C 1-6烷基、C 3-7环烷基、五元或六元杂环基或芳 环基或杂芳环基，所述亚烷基、-(OCH 2CH 2) eO-、-(OCH 2CH 2) e-或-O-(CH 2-CHOR 2-CH 2O) e-任选被一个或多个选自羟基、卤素、氘、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
  19. 根据权利要求18所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中所述A部分选自：
    Figure PCTCN2021091548-appb-100020
  20. 根据权利要求1所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中所述R 3选自氢、羟基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、五元或六元杂环基或芳环基或杂芳环基，优选C 1-6烷基，更优选甲基、乙基或丙基。
  21. 根据权利要求1所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中L 1表示-O-、-C(＝O)-、-OC(＝O)-或单键。
  22. 根据权利要求1所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中R 2或R 5选自氢、甲基或乙基。
  23. 根据权利要求1所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中至少三个X各自独立地选自R 1，所述R 1选自或包含式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，其中R 4选自氢、甲基或乙基，g＝1-200，所述聚乙二醇任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代；其余X都是OPO 3 2-或都是OPSO 2 2-或都是OSO 3 -。
  24. 根据权利要求1所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中有三个X各自独立地选自R 1，所述R 1选自或包含式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，且X位于同一式(D)中，其中R 4选自氢、甲基或乙基，g＝1-200，所述聚乙二醇任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代；其余X都是OPO 3 2-或都是OPSO 2 2-或都是OSO 3 -。
  25. 根据权利要求1所述的化合物或其药学上可接受的盐或它们的立体异构 体、旋转异构体或互变异构体，其中L 2包含C 2-10直链或支链亚烷基、C 2-10直链或支链亚烷氧基、C 2-10直链或支链亚烷氨基、C 2-10直链或支链亚烷巯基、C 2-10直链或支链亚烯基、C 2-10直链或支链亚烯氧基、C 2-10亚环烷基、-(OCH 2CH 2) eO-、-(OCH 2CH 2) e-或-O-(CH 2-CHOR 2-CH 2O) e-，所述亚烷基、亚烷氧基、亚烷氨基、亚烷巯基、亚烯基、亚烯氧基、亚环烷基、-(OCH 2CH 2) eO-、-(OCH 2CH 2) e-或-O-(CH 2-CHOR 2-CH 2O) e-任选被一个或多个选自羟基、卤素、氘、氨基、腈基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基或C 3-7亚环烷基所取代。
  26. 根据权利要求1-25任一项所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中式(D)部分上至少1个X选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或由式R 4-O-(CH 2-CHOH-CH 2O) g-所示的聚甘油，其中R 4选自氢、甲基或乙基，g＝1-200，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代。
  27. 根据权利要求1-26任一项所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中聚甘油或聚乙二醇摩尔质量选自100g/mol至3000g/mol，优选100g/mol至2500g/mol，更优选100g/mol至2000g/mol。
  28. 根据权利要求1-27任一项所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中g＝2-100，优选g＝7-50，更优选g＝7-15或40-50。
  29. 根据权利要求1-28所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中L 2选自：
    -(OCH 2CH 2) 2O-、-(OCH 2CH 2) 3O-、-(OCH 2CH 2) 4O-、-(OCH 2CH 2) 5O-、
    Figure PCTCN2021091548-appb-100021
    Figure PCTCN2021091548-appb-100022
    所述L 2进一步任选被一个或多个选自羟基、卤素、氘、氨基、腈基、硝基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基或C 3-7亚环烷基所取代。
  30. 根据权利要求4-10任一项所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其为
    Figure PCTCN2021091548-appb-100023
    其中，X 1至X 5中至少一个独立地选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或式R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的聚甘油，其余各自独立选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -或CO 2 -；X 6至X 10各自独立选自氢、-OH、OPO 3 2-，OPSO 2 2-，OSO 3 -、CO 2 -或R 1，所述R 1选自包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇或式R 4-O-(CH 2-CHOR 5-CH 2O) g-所示的聚甘油，所述聚乙二醇或聚甘油任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代，R 4、L 1至L 3如权利要求1中所定义。
  31. 根据权利要求4-10或30任一项所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其为
    Figure PCTCN2021091548-appb-100024
    其中X 1至X 10如权利要求30中所定义。
  32. 根据权利要求31所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中X 1至X 5中至少二个独立地选自R 1，所述R 1选自或包含由式R 4-(OCH 2CH 2) gO-或R 4-(OCH 2CH 2) g-所示的聚乙二醇，R 4选自氢、甲基、乙基、三氟甲基或环丙基，所述聚乙二醇任选被一个或多个选自羟基、氘、卤素、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代，其余选自OPO 3 2-，OPSO 2 2-，OSO 3 -或CO 2 -，g如权利要求1中定义。
  33. 根据权利要求30-32任一项所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中X 6至X 10选自OPO 3 2-、OSO 3 -或CO 2 -，优选OPO 3 2-或OSO 3 -，更优选OPO 3 2-。
  34. 根据权利要求30-33任一项所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中所述聚乙二醇任选被一个或多个选自羟基、卤素、氘、C 1-6烷基、C 3-7环烷基或C 3-7亚环烷基所取代，优选被一个或多个选自氘、C 1-6烷基或C 3-7环烷基所取代。
  35. 根据权利要求1-34任一项所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中g为2至100、2至50、2至20或2至10。
  36. 根据权利要求1所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中L 2为连接于式(D)上的共用的中心连接子，包含C 2-20直链或枝链亚烷基、C 2-20直链或支链亚烷氧基、-(OCH 2CH 2) eO-或-(OCH 2CH 2) e-，所述亚烷基、亚烷氧基、-(OCH 2CH 2) eO-或-(OCH 2CH 2) e-任选被一个或多个选自羟基、氘、氨基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基或C 3-7亚环烷基所取代，e如权利要求1中所定义。
  37. 根据权利要求1所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中L 2为连接于式(D)上的共用的中心连接子，包含C 2-10直链或枝链亚烷基、-(OCH 2CH 2) eO-或-(OCH 2CH 2) e-，所述亚烷基、-(OCH 2CH 2) eO-或-(OCH 2CH 2) e-任选被一个或多个选自羟基、氘、氨基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基或C 3-7亚环烷基所取代，e如权利要求1中所定义；L 1表示-O-或单键。
  38. 根据权利要求1-37任一项所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其中e为2至15、2至10、2至8或2至4。
  39. 根据权利要求1所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体，其为：
    Figure PCTCN2021091548-appb-100025
    Figure PCTCN2021091548-appb-100026
    Figure PCTCN2021091548-appb-100027
  40. 一种药物组合物，含有权利要求1-39任一项所述的化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体和任选自药学上可接受的赋形剂中的至少一种的药用辅料。
  41. 根据权利要求1-39任一项所述的化合物化合物或其药学上可接受的盐或它们的立体异构体、旋转异构体或互变异构体或权利要求40所述药物组合物在制备用于治疗或预防与钙紊乱相关疾病的药物中用途，所述钙紊乱相关疾病选自肾结石，心血管钙化，心血管病，骨质疏松症，骨癌，足痛风，钙化性肌腱炎，皮肤钙质沉着症，类风湿关节炎，骨矿物质病，骨软症，动力缺失性骨病，钙过敏和心血管病。
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