IP4-4, 6 substituted derivative compounds for treating, inhibiting progression and preventing ectopic calcification

Abstract

The present invention provides IP4-4, 6 substituted derivatives for preventing, inhibiting the progression of, and treating (a) ectopic calcification and their consequences, and (b) diseases and / or conditions associated with ectopic calcification and their consequences. The invention also provides methods, pharmaceutical compositions and formulations, methods of use, articles of manufacture, and kits for preventing, inhibiting progression of, and treating (a) ectopic calcification and consequences thereof, and (b) diseases and / or conditions associated with ectopic calcification and consequences thereof.

Description

Technical Field

[0001] The present invention relates to IP4-4,6 substituted derivative compounds useful for preventing, inhibiting the progression of and treating (a) ectopic calcification and its consequences and (b) diseases and / or conditions associated with ectopic calcification and its consequences. The present invention also relates to medicaments and kits for such uses. Background Art

[0002] Ectopic calcification (EC) is defined as inappropriate biomineralization occurring in soft tissues (Cotran R et al., Pathological Basis of Disease, 5th ed., Robbins S et al., eds., (WB Saunders, Philadelphia, PA, US, 1994, pp 1-35). EC is usually composed of calcium phosphate salts, including hydroxyapatite (HAP), but can also be composed of calcium oxalate and octacalcium phosphate, as seen in kidney stones (Pak C, Am J Kidney Dis 1991; 18: 624-632). EC can manifest independently in different locations, but develops through mechanisms similar to physiological calcification (Giachelli C, Am J Pathol. 1999; 154(3): 671-67). The diversity of EC types is thought to be associated with chronic or rare diseases. See Figure 1 (Kempf H et al., Front Cell Dev Biol. 2021;9:759702).

[0003] Thus, EC can be found in soft tissues such as blood vessels, heart valves, lungs, kidneys, and brain. This pathological calcification can lead to organ damage. Some of the most relevant pathologies associated with EC are listed below. See Table A.

[0004] Table A

[0005]

[0006]

[0007] As mentioned above, there are more than 30 pathologies associated with EC in the vascular bed. The etiologies are varied but can be divided into the following 4 categories:

[0008] (i) Gene mutations (e.g., GACI1, CALJA, PH, FOP, PXE),

[0009] (ii) tissue repair responses associated with inflammatory and / or immune responses (e.g., calcinosis cutis),

[0010] (iii) disturbances in metabolic calcium and phosphate balance (e.g., renal disease), and

[0011] (iv) Idiopathic.

[0012] Recent data indicate that a number of molecules can modulate this process. Discovery of biomarkers for identification and / or characterization of these molecules is an expanding area of ​​research (Nitschke Y et al., Am J Hum Genet. 2012; 90(1): 25-39).

[0013] As can be seen from the list shown in Table A, the most important extraosseous ECs are generated in the cardiovascular system, especially in the arteries and heart valves, as they are strong independent risk factors for increased mortality and cardiovascular events. In the arteries, calcification is associated with CAD, atherosclerotic plaque burden, peripheral vascular disease, and worse outcomes after angioplasty (e.g., increased risk of dissection). In the heart, valves are particularly susceptible to calcification. Degenerative calcific aortic stenosis is the most common valvular lesion currently seen in clinical cardiology and one of the most difficult to treat. It is estimated that approximately 1-2% of the elderly population has this disease, which is characterized by apatite mineral deposits in the aortic valve leaflets, which subsequently become hardened, tear, and mechanically fail. Congenital anomalies, rheumatic fever, renal disease, and inflammatory changes such as age are all risk factors for aortic stenosis.

[0014] The definitive treatment for severe symptomatic aortic stenosis is aortic valve replacement. In the United States, more than 40,000 patients undergo valve replacement each year. In the case of bioprosthetic valves, the most common cause of failure is graft calcification. In fact, by 10 years, one-third of bioprosthetic valves require replacement, increasing to two-thirds 15 years after implantation. In the European Union and the United States, the prevalence of aortic stenosis in people over 75 years of age is 3.4%, making it a serious public health problem.

[0015] Another important disease associated with EC is peripheral arterial disease, which is particularly evident in end-stage renal disease (PAD-ESKD). It affects patients with end-stage renal disease who are receiving hemodialysis. PAD-ESKD causes decreased mobility, lower limb pain, and may lead to severe limb ischemia, gangrene, and amputation. The key cause of PAD-ESKD is the accelerated deposition of calcium phosphate in the form of HAP in the media and intima of the peripheral arteries of the lower limbs. This calcification leads to arterial stenosis and sclerosis, resulting in reduced arterial blood flow and distal ischemia. Risk factors for PAD-ESKD include older age, diabetes, hypertension, and smoking (Chen J et al., Nephrol Dial Transplant. 2016; 31(7): 1145-1151). The duration of dialysis is an important risk factor for PAD-ESKD, and the risk factors of hypertension and diabetes are more common and more difficult to control in ESKD patients than in the general population (Rajagopalan S et al., Circulation 2006; 114(18): 1914-1922). ESKD patients have been excluded from previous clinical studies of PAD drug treatments, so there are no approved therapies specifically for PAD-ESKD patients.

[0016] As the mechanisms of ectopic calcification become more understood, the field faces two key challenges: finding useful biomarkers for early detection of EC events and, more importantly, finding effective treatments to block or reverse this pathological process occurring in chronic and rare diseases (Kempf, 2021, supra).

[0017] There is little research in this area regarding potential targets for possible treatments. Due to its anti-inflammatory benefits, the potential of omega-3 therapy for the treatment of aortic stenosis inflammation has been evaluated in mice (Artiach G et al., Circulation 2020; 142: 776-789). Synthetic peptide (GFOGER) modified proteins showed the extracellular vesicle content released in calcified vascular tissue and osteogenic conversion of cells cultured in vitro (Mansour A et al., Front. Cell Dev. Biol. 2020; 8: 58976130). However, these findings need to be confirmed in animal models and ultimately in humans.

[0018] Therefore, future work in this field needs to focus on (i) developing new biomarkers to predict the progression of ectopic calcification, (ii) characterizing new animal models and human pathologies associated with ectopic calcification, (iii) understanding the as yet unknown mechanisms of action of some key regulators of EC mineralization, and most importantly (iv) developing effective therapies for different types of "soft" tissue calcification (Kempf, 2021, supra). Therefore, there is a need in the art for new chemical entities that can effectively treat and prevent diseases and conditions associated with soft tissue calcification. Summary of the invention

[0019] The present invention discloses a compound of general formula I:

[0020]

[0021] Its pharmaceutically acceptable salt, or a combination thereof, wherein

[0022] (i) R1, R3, R7 and R 11 Independently expressed OPO3 2- ; R5 and R9 are substituents, each of which corresponds to the formula -O-(alkyl) n -X, wherein n is an integer between 1 and 20, wherein the terminal group X is selected from: -H, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHS02R, -NHCONRR', halogen, -CF3, alkyl, alkenyl, alkynyl, carbocycle (saturated or unsaturated) and heterocycle (saturated or unsaturated), and wherein R and R' are H or alkyl groups;

[0023] (ii) R1, R3, R7 and R 11 Independently expressed OPO3 2- ; R5 and R9 are substituents, each of which corresponds to the formula -O-(alkyl) y -Cy-(alkyl) y' -Z, wherein y and y' are integers between 0 and 10, wherein Cy is a cyclic linker, wherein the terminal group Z is selected from: alkyl, -COR, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', halogen and -CF3, and wherein R and R' are H or alkyl groups;

[0024] (iii) R1, R3, R7 and R 11 Independently expressed OPO3 2- ; R5 and R9 are substituents, each of which corresponds to the formula -O-(alkyl) y -A-(alkyl) y'-Z', wherein y and y' are integers between 0 and 10, wherein A is a linker selected from the group consisting of: -CONR-, -NHCOO-, -NHSO2, -NHCONR-, -NHCO-, and -OCONR, wherein the terminal group Z' is selected from the group consisting of: -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', carbocycle (saturated or unsaturated), heterocycle (saturated or unsaturated), and wherein R and R' are H or an alkyl group; and

[0025] (iv) The compound of formula I is an analog of (i), (ii) or (iii), wherein R1, R3, R7 or R 11 At least one of them is a phosphorothioate (-OPSO2 2- ) for treating, inhibiting the progression of, and preventing ectopic calcification or its consequences in a subject in need thereof.

[0026] In some aspects, the R5 and R9 substituents of the compound of Formula I are the same. In some aspects, the R5 and R9 substituents of the compound of Formula I are different.

[0027] In some aspects, the alkyl moiety in the R5 and R9 substituents includes at least one carbon double bond or triple bond, that is, an alkenyl chain or an alkynyl chain is formed respectively. In some aspects, the alkenyl chains in the R5 and R9 substituents are the same. In some aspects, the alkenyl chains in the R5 and R9 substituents are different. In some aspects, the alkynyl chains in the R5 and R9 substituents are the same. In some aspects, the alkynyl chains in the R5 and R9 substituents are different. In some aspects, the alkyl moiety in the R5 and R9 substituents includes at least one carbon double bond and at least one carbon triple bond, forming a combination of alkenyl chains and alkynyl chains. In some aspects, the combination of alkenyl chains and alkynyl chains in the R5 and R9 substituents is the same. In some aspects, the combination of alkenyl chains and alkynyl chains in the R5 and R9 substituents is different.

[0028] In some aspects, the compound of Formula I is selected from: Compound 1 to Compound 53.

[0029] In some aspects, the pharmaceutically acceptable salt is a sodium salt. In some aspects, the sodium salt is a tetrasodium salt, a pentasodium salt, a hexasodium salt, a heptasodium salt, an octasodium salt, a nonasodium salt, or a decasodium salt. In some aspects, the sodium salt is a tetrasodium salt, a pentasodium salt, a hexasodium salt, a heptasodium salt, or an octasodium salt. In some aspects, the sodium salt is a hexasodium salt, an octasodium salt, a nonasodium salt, or a decasodium salt.

[0030] The present invention also provides a pharmaceutical composition comprising the compound of formula I disclosed above and at least one pharmaceutically acceptable excipient or carrier.

[0031] The present invention also provides a compound or pharmaceutical composition according to the present invention for use in treating, inhibiting the progression of and preventing diseases and / or conditions associated with ectopic calcification or their consequences in a subject in need thereof.

[0032] In some aspects, the subject is a human. In some aspects, administration is topical, enteral, or parenteral. In some aspects, parenteral administration is intravenous. In some aspects, intravenous administration is by intravenous infusion.

[0033] The present invention also provides a kit or article of manufacture comprising at least one compound of Formula I or a pharmaceutical composition comprising a compound of Formula I and instructions for use according to the uses disclosed herein. In some aspects, the kit or article of manufacture may further comprise at least one compound selected from the group consisting of the compounds listed in Table 1. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 A simplified schematic diagram of the cellular, extracellular, and systemic changes associated with ectopic calcification and their relationship to several chronic and rare diseases.

[0035] Figure 2 is a simplified schematic diagram of the physiochemical mechanism of action by which the IP4-4,6 substituted derivatives of the present invention inhibit hydroxyapatite (HAP) crystallization and are therefore useful in treating HAP crystallization-mediated diseases.

[0036] Figure 3A and Figure 3B Representative structures of IP4-4,6 substituted derivative compound family A (eg, compounds 1 to 30 and compounds 52 to 53) are shown.

[0037] Figure 4A and Figure 4B Representative structures of IP4-4,6 substituted derivative compound family B (eg, compounds 31 to 44) are shown.

[0038] Figure 5 Representative structures of IP4-4,6 substituted derivative compound family C (eg, compounds 45 to 49) are shown.

[0039] Figure 6 Representative structures of IP4-4,6 substituted derivative compound family D (eg, compounds 50 to 51) are shown.

[0040] Figure 7 is a schematic diagram of synthetic route 1.

[0041] Figure 8is a schematic diagram of synthetic route 2.

[0042] Fig. 9 is a schematic diagram of synthetic route 3.

[0043] Fig.10 is a schematic diagram of synthetic route 4.

[0044] Fig.11 is a schematic diagram of synthetic route 5.

[0045] Figure 12 shows the mean calcium content (±SD) of (A) aorta, (B) heart, (C) femoral artery, (D) carotid artery and (E) kidney in sham-operated rats (no VitD3 treatment) and rats treated with vehicle or compound 27 (5, 15 and 45 mg / kg). For the femoral artery and carotid artery, the mean value of the calcium content of the left and right vessels was used. Statistical analysis: One-way ANOVA combined with Fisher LSD test was used for post hoc comparison. (#) indicates a significant difference compared with the sham-operated group, (*) indicates a significant difference compared with the vehicle group, (§) indicates a significant difference compared with compound 27 5 mg / kg (applied only to other compound 27 doses), (￥) indicates a significant difference compared with compound 27 15 mg / kg (applied only to compound 27 45 mg / kg), p<0.05. N=7-12 animals / group.

[0046] Fig.13 The mean normalized blood perfusion (±SD) in sham-operated rats (no VitD3 treatment) and rats treated with vehicle, compound 27 (5, 15 and 45 mg / kg) at D13 is shown. Statistical analysis: One-way ANOVA combined with Fisher's LSD test was used for post hoc comparisons. The result of ANOVA was p<0.0001. (#) indicates a significant difference compared with the sham-operated group, (*) indicates a significant difference compared with the vehicle group, (§) indicates a significant difference compared with compound 27 5 mg / kg (applicable only to other compound 27 doses), p<0.05. N=10-12 animals / group.

[0047] Fig.14The mean maximum walking distance (±SD) in sham-operated rats (no VitD3 treatment) and rats treated with vehicle, compound 27 (5, 15 and 45 mg / kg) is shown. Statistical analysis: One-way ANOVA combined with Fisher's LSD test was used for post hoc comparisons. The result of ANOVA was p<0.0001. (#) indicates a significant difference compared with the sham-operated group, (*) indicates a significant difference compared with the vehicle group, (§) indicates a significant difference compared with compound 27 5 mg / kg (applicable only to other compound 27 doses), (￥) indicates a significant difference compared with compound 27 15 mg / kg (applicable only to compound 27 45 mg / kg), It indicates that there is a significant difference compared with compound 27 45 mg / kg, p<0.05.

[0048] Figure 15 shows cultures of aortic valve interstitial cells (VIC) (n=7, from calcified valve donors) cultured for 3 weeks in basal growth medium (control), osteodifferentiation medium (Osteodiff), and osteodifferentiation medium supplemented with different concentrations (1, 3, 10, 30, and 100 μM) of (A) IP6, (B) Compound 1, (C) Compound 3, and (D) Compound 6. Calcification was measured by Alizarin Red staining and quantified as relative calcification spectrophotometrically. Values ​​are shown as dot plots with mean values. One-way ANOVA analysis was performed for parametric distribution (IP6), and DMS post hoc test statistical analysis was performed. For non-normally distributed results (Compound 1, Compound 3, and Compound 6), non-parametric one-way ANOVA analysis (Kruskal-Wallis test) was used in combination with Dunn's post hoc test, and p<0.05 was considered statistically significant.

[0049] Fig.16 Alizarin red staining of 10 dpf abcc6a - / - Analysis of hypermineralization in zebrafish larvae. Larvae from 3 to 10 dpf were maintained in E3 medium (n=20) and E3 medium supplemented with 1 mM compound 27 (n=18). After treatment with compound 27, abcc6a was observed - / - The hypermineralization of the spinal cord (black box) was significantly reduced in the larvae. Image J analysis showed that abcc6a treated with compound 27 and untreated abcc6a - / - Quantification of calcified vertebrae in larvae revealed significance at p<0.001, scale bar 500 μm. DETAILED DESCRIPTION

[0050] The present invention relates to IP4-4,6 substituted derivative compounds of the general formula I:

[0051]

[0052] A pharmaceutically acceptable salt thereof, or a combination thereof, for use in treating ectopic calcification and its consequences, inhibiting the progression of ectopic calcification and its consequences, and preventing ectopic calcification and its consequences. In some aspects, n R1, R3, R7 and R 11 OPO3 2- or OPSO2 2- , and R5 and R9 are the same. In some aspects, R5 and R9 are different. In some aspects, IP4-4,6 derivatives are sodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts, octasodium salts, nonasodium salts or decasodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts or octasodium salts. In some aspects, IP4-4,6 derivatives are hexasodium salts, octasodium salts, nonasodium salts or decasodium salts. In some aspects, IP4-4,6 derivatives are octasodium salts.

[0053] The present invention also provides methods, pharmaceutical compositions and formulations, methods of use, products and kits for treating ectopic calcification and its consequences and diseases and / or conditions associated with ectopic calcification and its consequences, inhibiting the progression of ectopic calcification and its consequences and diseases and / or conditions associated with ectopic calcification and its consequences, and treating ectopic calcification and its consequences and diseases and / or conditions associated with ectopic calcification and its consequences.

[0054] In order to make it easier to understand the present invention, specific terms are first defined below. As used in this application, unless otherwise expressly stated herein, the following terms should have the meanings set forth below. Other definitions are set forth throughout the application.

[0055] I. Definitions

[0056] The invention includes aspects wherein one member of the group is present in, employed in, or relevant to a given product or method. The invention includes aspects wherein more than one or all members of the group are present in, employed in, or relevant to a given product or method.

[0057] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention relates. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd edition, 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd edition, 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, revised in 2000, Oxford University Press provide a general dictionary of many of the terms used in the present invention for those skilled in the art.

[0058] Units, prefixes and symbols are expressed in the form accepted by the International System of Units (SI). Numerical ranges include numbers that define ranges. In the case of a range of recorded values, it is understood that each intermediate integer value and each fraction thereof between the recorded upper and lower limits of the range and each subrange between these values ​​are also specifically disclosed. The upper and lower limits of any range may be independently included in the range or excluded therefrom, and each range including any one endpoint value, not including two endpoint values ​​or including two endpoint values ​​is also encompassed within the present invention.

[0059] Where a value is explicitly stated, it is understood that values ​​of approximately the same quantity or amount as the stated value are also within the scope of the present invention. Where a combination is disclosed, each subcombination of the elements of the combination is also specifically disclosed and is within the scope of the present invention. Conversely, where different elements or groups of elements are disclosed separately, combinations thereof are also disclosed. Where any element of the present invention is disclosed as having multiple alternatives, examples of the invention in which each alternative is excluded individually or in any combination with other alternatives are also therefore disclosed; more than one inventive element may have such an exclusion, and all combinations of elements having such an exclusion are also therefore disclosed.

[0060] About: As used herein, the term "about" refers to a value or composition that is within an acceptable error range for a particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., on the limitations of the measurement system. For example, according to the practice in the art, "about" can mean within 1 or more than 1 standard deviation. Alternatively, "about" can mean a range of up to 20%. In addition, particularly with respect to biological systems or methods, the term can mean up to an order of magnitude or up to 5 times the value.

[0061] When a specific value or composition is provided in the present application and claims, unless otherwise stated, the meaning of "about" should be assumed to be within the acceptable error range of the specific value or composition. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the numerical values. Thus, "about 10-20" means "about 10 to about 20". In general, the term "about" can modify a numerical value above or below the stated value with a variance of, for example, 10% above or below (higher or lower).

[0062] And / or: "and / or" as used herein is taken as a specific invention of each of the two specified features or components with or without the other. Therefore, the term "and / or" used in phrases such as "A and / or B" herein is intended to include "A and B", "A or B", "A" (alone), and "B" (alone). Similarly, the term "and / or" used in phrases such as "A, B, and / or C" is intended to cover each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0063] Angina: As used herein, the terms "angina" and "chronic stable angina" relate to chest pain or discomfort caused by myocardial ischemia. It is a common symptom in patients with coronary artery disease (CAD). It is estimated that approximately 9.8 million Americans suffer from angina each year, with 500,000 new cases of angina each year.

[0064] Approximately: As used herein, the term "approximately" as applied to one or more target values ​​refers to a value similar to the reference value. In certain aspects, the term "approximately" refers to a value that falls within a range of 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater or less) of the reference value, unless otherwise specified or it is obvious from the context (except for the case where the number will exceed 100% of the possible value).

[0065] Bolus administration: As used herein, the terms "bolus administration" and "bolus injection" refer to a rapid intravenous injection lasting less than 10 seconds, or an intravenous infusion lasting less than 3 minutes.

[0066] Calcific aortic stenosis: As used herein, the terms "calcific aortic stenosis" and "CAVS" refer to one of the most common valvular heart diseases in developed countries, characterized by progressive fibrocalcific remodeling and thickening of the aortic valve leaflets. Over the years, this disease can evolve to severely obstruct cardiac outflow. In developed countries, CAVS is the third most common cardiovascular disease after coronary artery disease and systemic arterial hypertension, with a prevalence of 0.4% in the general population and 1.7% in people over 65 years of age (Lindman B et al., Nat Rev Dis Primers. 2016; 2: 16006).

[0067] Calciuria: As used herein, the terms "calciuria" and "CUA" refer to a serious, uncommon disease in which calcium accumulates in small blood vessels in fat and skin tissue. CUA causes blood clots, painful skin ulcers, and can lead to serious infections that can ultimately lead to death. CUA subjects often suffer from kidney failure and may require dialysis. This condition can also occur in people without kidney disease.

[0068] Cardiovascular disease in chronic kidney disease: As used herein, the term "cardiovascular disease in patients with CKD" refers to the higher risk of CKD patients developing cardiovascular disease, such as, for example, coronary artery disease, heart failure, arrhythmias, and sudden cardiac death. Although the incidence and prevalence of cardiovascular events are already significantly higher in patients with early CKD stages (CKD stages 1-3) compared to the general population, patients with late CKD stages (CKD stages 4-5) show a significantly increased risk (Jankowski J et al., Circulation 2021; 143(11): 1157-1172).

[0069] Cardiovascular disease associated with aging: As used herein, the term "cardiovascular disease associated with aging" refers to the high risk of cardiovascular disease, such as heart failure, coronary artery disease, hypertension, cerebrovascular disease, peripheral arterial disease, valvular disease and arrhythmias, in adults over the age of 65. Aging is associated with changes in the heart and blood vessels that increase a person's risk of developing cardiovascular disease (North B et al., Circ Res. 2012; 110(8): 1097-1108). Age is a recognized independent risk factor for cardiovascular disease.

[0070] Comprising: It is to be understood that in any aspect described herein with the language "comprising," other similar aspects described as "consisting of" and / or "consisting essentially of" are also provided.

[0071] Compound: As used herein, the term "compound" is meant to include any and all free bases, isomers, and isotopes of the described structure. As used herein, the term "isomer" means any geometric isomer, tautomer, zwitterion, stereoisomer, enantiomer, or diastereomer of a compound. Compounds may include one or more chiral centers and / or double bonds, and thus may exist as stereoisomers such as double bond isomers (i.e., geometric E / Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). The present invention encompasses any and all isomers of the compounds described herein, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure), as well as enantiomers and stereoisomeric mixtures (e.g., racemates). Enantiomers and stereoisomeric mixtures of compounds and means for resolving them into their component enantiomers or stereoisomers are well known. The compounds, salts or complexes of the invention can be prepared by combining with solvents or water molecules to form solvates and hydrates by conventional methods. In some aspects, the term compound is used to refer to the IP4-4,6 substituted derivatives of the invention.

[0072] Its consequences: When referring to a disease or condition disclosed herein, the phrase "its consequences" refers to symptoms, sequelae, complications, and combinations thereof associated with a disease or condition. As used herein, the term "symptom" refers to subjective or physical signs, indications, or evidence of a disease or physical disorder observed by a subject. In general, the term refers to any morbid phenomenon or deviation from normal experienced by a subject in structure, function, or sensation, indicating the presence of a disease. Symptoms are felt or noticed by the person experiencing the symptoms, but others may not easily notice them. In some aspects, symptoms may be mild symptoms, moderate symptoms, or severe symptoms. As used herein, the term "mild symptoms" refers to symptoms that are not life-threatening and do not require hospitalization or intensive care treatment (e.g., in a hospital ICU). As used herein, the term "moderate symptoms" refers to symptoms that may become life-threatening and may require hospitalization. As used herein, the term "severe symptoms" refers to symptoms that are life-threatening and require intensive care treatment (e.g., in a hospital ICU). As used herein, the term "complication" refers to a pathological process or event that occurs during a disease or condition, but is not an important component of the disease or condition; wherein it may be caused by the disease / condition or an independent cause. Thus, the term complication refers to a medical / clinical problem observed in a subject diagnosed with a disease or condition disclosed herein. In some aspects, a complication may be temporary. In some aspects, a complication may be chronic or permanent. As used herein, the term "sequelae" refers to a long-term, chronic, or permanent complication.

[0073] Critical limb ischemia: As used herein, the term "critical limb ischemia" or "CLI" refers to a severe blockage of an artery that significantly reduces blood flow to the limbs and progresses to the point of severe pain and even skin ulcers, sores, or gangrene. Critical limb ischemia is a very serious condition of peripheral arterial disease.

[0074] Ectopic calcification: As used herein, the term "ectopic calcification" refers to inappropriate biomineralization that occurs in soft tissues. Ectopic calcification is usually composed of calcium phosphate salts, including hydroxyapatite, but can also be composed of calcium oxalate and octacalcium phosphate, as seen in kidney stones.

[0075] Effective amount: As used herein, with respect to (i) IP4-4,6 substituted derivatives of the present invention, (ii) any dosage form, pharmaceutical composition or formulation disclosed herein, which comprises at least one of the IP4-4,6 substituted derivatives of the present invention, or (iii) a combination of the IP4-4,6 substituted derivatives of the present invention and one or more other therapeutic agents, the term "effective amount" of a therapeutic agent is an amount sufficient to produce a beneficial or desired result. In some aspects, the beneficial or desired result is, for example, a clinical result, and thus the "effective amount" depends on the context in which it is applied. The term "effective amount" can be used interchangeably with "effective dose", "therapeutically effective dose" or "therapeutically effective dose".

[0076] The term effective amount relates to the specific use of the IP4-4,6 substituted derivatives. For example, when the IP4-4,6 substituted derivatives are used to inhibit the formation or growth of calcium salts / crystals (e.g., calcium phosphate, HAP), the effective amount will be the amount of IP4-4,6 substituted derivatives that can achieve the desired effect (e.g., reducing HAP crystallization / formation in serum or plasma).

[0077] Enteral administration: As used herein, the term "enteral administration" and the related term "enteral" refer to any administration of the IP4-4,6 substituted derivatives of the present invention or pharmaceutical compositions comprising the derivatives via the gastrointestinal tract. Enteral administration includes, but is not limited to, oral, sublingual, and rectal administration routes.

[0078] Systemic Arterial Calcification of Infancy: As used herein, the terms "systemic arterial calcification of infancy" and "GACI" refer to a condition that affects the circulatory system that becomes apparent before birth or within the first few months of life and is characterized by abnormal calcification of the arteries and thickening of the arterial walls. These changes cause the arteries to narrow and stiffen, leading to heart failure in some affected individuals, with signs and symptoms including difficulty breathing, edema, cyanosis, hypertension, and cardiac hypertrophy.

[0079] IP4-4,6 substituted derivatives of the present invention: As used herein, the term "IP4-4,6 substituted derivatives of the present invention" and grammatical variations thereof refer to compounds of Formula I:

[0080]

[0081] Among them, R1, R3, R7 and R 11 OPO3 2- or OPSO2 2- , and R5 and R9 may be the same or different, and wherein R5 and R9 substituents are those substituents disclosed in compound families A, B, C and D and their salts (e.g., pharmaceutically acceptable salts) described in detail below. In some aspects, the term IP4-4,6 substituted derivatives of the present invention encompass compounds 1 to 53, any salt thereof (e.g., sodium salt), and any combination thereof. In some aspects, the term IP4-4,6 substituted derivatives of the present invention encompass compounds of formula I, which are intermediates in the synthesis of compounds 1 to 53, for example, compounds selected from the group consisting of compounds listed in Table 1, any salt thereof (e.g., sodium salt), and any combination thereof. In some aspects, the term IP4-4,6 substituted derivatives of the present invention encompass compounds of formula I, which are compounds 1 to compound 53 and compounds selected from the group consisting of compounds listed in Table 1, any salt thereof (e.g., sodium salt), and any combination thereof.

[0082] The group consisting of Compound 1 to Compound 53: In the context of the present invention, reference to the "group consisting of Compound 1 to Compound 53" refers to a group of compounds comprising Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, and 53. In some aspects, the group consisting of Compound 1 to Compound 53 also includes combinations thereof. In some aspects, the combination of compounds from the group consisting of Compound 1 to Compound 53 can include 2, 3, 4, 5, 6, 7, 8, 9, 10 or more compounds from the group consisting of Compound 1 to Compound 53.

[0083] The group consisting of the compounds listed in Table 1: In the context of the present invention, reference to the group consisting of the compounds listed in Table 1 refers to the group of intermediate compounds used, for example, to synthesize the IP4-4,6-substituted derivatives of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53), i.e., intermediates II-1 to II-27, intermediates III-1 to III-47, intermediates IV-1 to IV-48, intermediates VI'-1 to IV'-2, intermediates V-1, intermediates VI-1, intermediates VII-1 to VII-2, intermediates VIII-1 to VIII-5, intermediates IX-1 to IX-5, intermediates X-1 to X-3, intermediates XI-1 to XI-2, intermediates XII-1 to XII-2, and intermediates XIII-1 to XIII-3. In some aspects, the group consisting of the compounds listed in Table 1 also includes combinations thereof. In some aspects, the combination of compounds consisting of the group consisting of compounds listed in Table 1 can include 2, 3, 4, 5, 6, 7, 8, 9, 10 or more compounds from the group consisting of compounds listed in Table 1.

[0084] Renal failure-related diseases: As used herein, the term "renal failure-related diseases" refers to a wide variety of disease processes in individuals with renal impairment, and may refer to, but is not limited to, any disease associated with calcium or calcium metabolism disorders, such as bone insufficiency, bone cancer, bone mineral disease, calcific tendinitis, calcinosis cutis, calcisensitization, nephrolithiasis, cardiovascular calcification, cardiovascular disease, osteomalacia, osteoporosis, gout and rheumatoid arthritis. Other diseases associated with renal failure may be of the cardiovascular type, including, but not limited to, aneurysms, angina pectoris, arteriosclerosis, atherosclerosis, heart disease, cardiovascular disease associated with aging, cerebrovascular disease, coronary artery disease, heart failure, hypertension, myocardial infarction, peripheral vascular disease and thrombosis. Patients with renal impairment may also suffer from cardiovascular accidents, events or diseases (e.g., ischemia, arrhythmia, myocardial infarction, stroke).

[0085] Non-bolus administration: As used herein, the terms "non-bolus" and "non-bolus administration" refer to an intravenous injection lasting 10 seconds or more or an intravenous infusion lasting 3 minutes or more.

[0086] Parenteral administration: As used herein, the term "parenteral administration" and the related term "parenteral" refer to the administration of IP4-4,6 substituted derivatives of the present invention characterized by destruction of the subject's body tissue, and the administration of the derivatives through the destruction in the tissue. Parenteral administration includes, but is not limited to, administering the IP4-4,6 substituted derivatives of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) or a pharmaceutical composition comprising the derivative by administering the derivative or composition through, for example, a surgical incision or through a non-surgical wound that penetrates the tissue. In particular, parenteral administration includes, but is not limited to, epidural, intraarterial, intradermal, intrathecal, intramuscular, intraperitoneal, intrasternal injection, intravascular, intravenous, intravenous infusion, intraspinal, subcutaneous, and subcutaneous reservoir administration routes.

[0087] Peripheral Arterial Disease: As used herein, the terms "peripheral arterial disease" and "PAD" refer to the narrowing and / or hardening of the peripheral arteries of the legs (most commonly), stomach, arms, and head. Symptoms include intermittent claudication (leg pain when walking that is relieved by rest), skin ulcers, bluish skin, cool skin, or poor nail and hair growth.

[0088] Prevent: As used herein, the terms "prevent," "preventing," and "prevention" refer to inhibiting the onset of or reducing the occurrence of a disease or condition in a subject (eg, avoiding ectopic calcification or its consequences in a subject).

[0089] Primary hyperoxaluria: As used herein, the term "primary hyperoxaluria" or "PH" refers to a disorder of glyoxylate metabolism characterized by excess oxalate leading to kidney stones, nephrocalcinosis, and ultimately renal failure and systemic oxalic acidosis. There are three types of PH. Primary hyperoxaluria type 1 (PH1) is caused by a deficiency in the liver peroxidase alanine:glyoxylate aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is absent, glyoxylate is converted to oxalate, which forms insoluble calcium oxalate crystals that accumulate in the kidneys and other organs. Primary hyperoxaluria type 2 (PH2), caused by mutations in the GRHPR gene, is a genetic disorder in which a lack of a specific liver enzyme causes excess oxalate to accumulate in the body. Primary hyperoxaluria type 3 (PH3) is characterized by recurrent calcium oxalate stones beginning in childhood or adolescence, sometimes accompanied by nephrocalcinosis or decreased renal function.

[0090] Pseudogout: As used herein, the term "pseudogout," also known as "calcium pyrophosphate dihydrate (CPPD) crystal deposition disease" or "pyrophosphate arthropathy," refers to a rheumatic disease believed to be caused by the accumulation of calcium pyrophosphate crystals in connective tissue, particularly in joints such as the knee.

[0091] Pseudoxanthoma elasticum: As used herein, the terms "pseudoxanthoma elasticum" and "PXE" refer to an autosomal recessive inherited metabolic disease caused by mutations in the ABCC6 gene. The absence of functional ABCC6 protein results in ectopic calcifications that are most evident in the elastic tissues of the skin, eyes, and blood vessels. The clinical prevalence of PXE is estimated to be between 1 in 100,000 and 1 in 25,000, with a slight female predominance.

[0092] Ranges: As described herein, any concentration range, percentage range, ratio range, or integer range is to be understood to include any integer value within the recited range, and fractions thereof (such as tenths and hundredths of integers) where appropriate, unless otherwise indicated.

[0093] Subject: "Subject" or "individual" or "animal" or "patient" or "mammal" means any subject, particularly a mammalian subject, for whom diagnosis, prognosis or treatment is desired. Mammalian subjects include, but are not limited to, humans, livestock, farm animals, zoo animals, sports animals, pet animals, such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows; primates, such as apes, monkeys, gorillas and chimpanzees; canines, such as dogs and wolves; felines, such as cats, lions and tigers; equines, such as horses, donkeys and zebras; bears; edible animals, such as cows, pigs and sheep; ungulates, such as deer and giraffes; rodents, such as mice, rats, hamsters and guinea pigs, etc. In certain aspects, the mammal is a human subject. In other aspects, the subject is a human patient. In a specific aspect, the subject is a human patient suffering from or at risk of suffering from pathological calcification.

[0094] Substantially: As used herein, the term "substantially" refers to the qualitative condition of exhibiting a full or nearly full degree or measure of a characteristic or property of interest. One of ordinary skill in the biological arts will appreciate that biological and chemical phenomena rarely, if ever, reach completion and / or proceed to completeness, or achieve or avoid an absolute result. Thus, the term "substantially" is used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0095] Therapeutic agent: As used herein, the term "therapeutic agent" is used in a broad sense to include compositions comprising IP4-4,6 substituted derivatives of the present invention, which can provide significant therapeutic benefits to subjects in need thereof. In some aspects, subjects in need thereof are subjects suffering from or at risk of developing a disease or condition associated with pathological crystals (e.g., calcium phosphate or HAP crystals). Therefore, in general, the therapeutic agent according to the present invention can be an IP4-4,6 substituted derivative of the present invention, alone or in combination with one or more other therapeutic agents, which is administered in an amount sufficient to produce a beneficial or desired result.

[0096] The term therapeutic agent also encompasses a preventive, diagnostic or imaging agent comprising an IP4-4,6 substituted derivative of the invention, wherein the therapeutic agent is administered (i.e., topically, enterally or parenterally). The therapeutic agents of the invention include agents that inhibit calcium salt / crystal (e.g., calcium phosphate, HAP) formation or growth and / or can improve and / or prevent any symptoms associated with pathological crystals.

[0097] Topical administration: As used herein, the term "topical administration" and the related term "topically" refer to any administration of the IP4-4,6 substituted derivatives of the present invention or pharmaceutical compositions comprising the derivatives by applying the derivatives or the compositions to a specific location on or in the body (such as the skin or mucous membrane). Topical administration includes, but is not limited to, ear, skin, nasal, transdermal, urethral, ​​vaginal and urethral administration routes.

[0098] Treatment: As used herein, the terms "treat", "treating" and "treatment" refer to the administration of a compound or pharmaceutical composition of the present invention for (i) slowing down, (ii) inhibiting progression, (iii) stopping or (iv) reversing the progression of a disease or condition after the onset of clinical symptoms. Control of disease progression is understood to mean beneficial or desired clinical results, including but not limited to alleviation of symptoms, shortening of disease duration, stabilization of pathological state (particularly to avoid further deterioration), delay of disease progression, improvement of pathological state and remission (partial and complete). Control of disease progression also involves prolonging survival compared to the expected survival when treatment is not applied. In the context of the present invention, the terms "treat" and "treatment" specifically refer to (a) stopping, reducing, inhibiting the progression of ectopic calcification or reversing its development and its consequences, (b) improving the mobility or walking ability (e.g., speed, distance, endurance) of a subject to which a compound or pharmaceutical composition of the present invention is administered, and (c) reducing or improving the quality of life of a subject to which a compound or pharmaceutical composition of the present invention is administered.

[0099] μg, μM, μL: As used herein, the terms "μg," "μM," and "μL" are used interchangeably with "μg," "μM," and "μL," respectively.

[0100] II. IP4-4,6 substituted derivatives

[0101] The present invention discloses IP4-4,6 substituted derivatives, their synthesis methods and uses. In some aspects, the IP4-4,6 substituted derivatives are compounds of formula I:

[0102]

[0103] Among them, R1, R3, R7 and R11 Independently expressed OPO3 2- or OPSO2 2- , and R5 and R9 are substituents. In some aspects, R5 and R9 are the same substituents. In some aspects, R5 and R9 are different substituents. In some aspects, the IP4-4,6 substituted derivatives of the present invention are acceptable salts (e.g., pharmaceutically acceptable salts) of compounds of Formula I or combinations thereof.

[0104] In some aspects, the charge of the positively charged ion cannot compensate for all negative charges in the IP4-4,6 derivatives of the present invention. Therefore, the IP4-4,6 derivatives of the present invention can be, for example, tetraionic salts (e.g., tetrasodium salts), pentaionic salts (e.g., pentasodium salts), hexaionic salts (e.g., hexasodium salts), heptaionic salts (e.g., heptasodium salts), octaionic salts (e.g., octasodium salts), nonaionic salts (e.g., nonaionic salts) or decaionic salts (e.g., decaionic salts). In some aspects, the presence of additional negatively charged groups in the derivatives substituted with IP4-4,6 can lead to complex formation with additional ions. In some aspects, the IP4-4,6 derivatives of the present invention are sodium salts. In some aspects, the IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts, octasodium salts, nonaionic salts or decaionic salts. In some aspects, the IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts or octasodium salts. In some aspects, the IP4-4,6 derivative is a hexasodium salt, an octasodium salt, a nonasodium salt, or a decasodium salt. Formula I and the remaining formulae presented in the present invention are meant to encompass any isomer of the compounds covered thereby.

[0105] In the context of the present invention, the term "alkenyl" or "alkenyl chain" refers to a substituted or unsubstituted straight or branched alkyl chain (e.g., containing between 2 and 10 carbon atoms) containing one or more double bonds. Examples include ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, and 1,3-butadienyl, and the like.

[0106] In the context of the present invention, the term "alkyl" or "alkyl chain" refers to a saturated hydrocarbon portion, which can be a straight chain, branched, cyclic or cyclic saturated hydrocarbon portion with a straight chain or branched side chain. The term alkyl includes partially unsaturated hydrocarbons, such as propenyl. Examples are methyl, ethyl, n-butyl or isobutyl, n-hexyl or cyclohexyl. The term alkyl can be extended to alkyl groups connected or bridged by heteroatoms. In the context of the present invention, heteroatoms are nitrogen (N), sulfur (S), oxygen (O) and halogen.

[0107] In the context of the present invention, the term "alkynyl" or "alkynyl chain" refers to a substituted or unsubstituted straight or branched alkyl chain (e.g., containing between 2 and 10 carbon atoms) containing one or more triple bonds. Examples include ethynyl, propynyl, 1-butynyl and 3-butynyl, and the like.

[0108] An "amine functional group" or "amine group" is a functional group NRR', wherein R and R' are independently selected from, for example, hydrogen (-H) and alkyl, such as C1-C n Alkyl, wherein n is an integer between 0 and 20.

[0109] A "hydroxyl functional group" or "hydroxyl group" is OH.

[0110] A "carboxylic acid functional group" or "carboxylic acid group" is COOH or its anion COO - .

[0111] "Carboxamide" is CONRR' or NCOR, R and R' are independently selected from, for example, hydrogen (-H) and alkyl, such as C1-C n Alkyl, wherein n is an integer between 0 and 20.

[0112] "Carbocycle" refers to a three- to 10-membered carbon ring that may be saturated, partially unsaturated or aromatic (e.g., phenol, cyclopentane, cyclopropane) and is bonded to the remainder of the molecule through any available C atom. The term includes carbocycles substituted with one or more heteroatoms (e.g., N, O, halogen atoms).

[0113] "Heterocycle" refers to a three- to ten-membered ring containing at least one heteroatom selected from N, O and S, which may be saturated, partially unsaturated or aromatic (e.g., triazole, piperazine, pyrazole, thiophene), and is bonded to the rest of the molecule through any available C or N atom. The term includes heterocycles substituted with one or more halogen atoms.

[0114] "Cy" refers to a cyclic linker, which includes a carbocyclic ring or a heterocyclic ring. Examples of carbocyclic and heterocyclic rings include 1,3-phenyl, 1,4-phenyl, naphthyl, thienyl, furanyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzimidazolyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothienyl, benzothiazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, and aziridinyl.

[0115] A "halogen" group refers to fluorine, chlorine, bromine or iodine.

[0116] In the context of the present invention, the term "OPO3 2- "It is not clear that OPO3H - and OPO3H2.

[0117] In some aspects, the IP4-4,6 substituted derivatives of the present invention or the intermediate compounds disclosed herein can be detected and / or quantified using the methods disclosed in US9612250. See also, US8377909, US8778912 and US20070066574.

[0118] The IP4-4,6 substituted derivatives of the present invention may be present in any form commonly used in pharmaceutical technology. Specific aspects include, but are not limited to, sodium salts, magnesium salts, potassium salts, ammonium salts, free acids, or mixtures of the foregoing forms. Other pharmaceutically acceptable salts are known to those skilled in the art and can be obtained by methods previously described (Haynes M et al., J. Pharmaceutical Sci. 2005; 94: 2111-2120).

[0119] In some aspects, R1, R3, R7 and R 11 Independently represents phosphate (-OPO3 2- ) and R5 / R9 correspond to the formula -O-(alkyl) n -X (i.e., R5 / R9 is an alkyl chain with or without branches), wherein n is an integer between 1 and 20, wherein the terminal group X is selected from the group consisting of: -H, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHS02R, -NHCONRR', halogen, -CF3, alkyl, alkenyl, alkynyl, carbocyclic (saturated or unsaturated) and heterocyclic (saturated or unsaturated), and wherein R and R' are H or alkyl. Throughout the present invention, this family of IP4-4,6 substituted derivatives is designated as Family A.

[0120] In some aspects, R1, R3, R7 and R 11 Independently represents phosphate (-OPO3 2- ) and R5 / R9 correspond to the formula -O-(alkyl) y -Cy(alkyl) y'-Z (i.e., R5 / R9 comprises two alkyl chains connected by a cyclic linker inserted between the two alkyl chains), wherein each alkyl comprises y carbon (e.g., CH2) units, wherein y and y' are integers between 0 and 10, wherein the distal alkyl chain comprises a terminal group Z selected from the group consisting of alkyl, -COR, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', halogen, and -CF3, and wherein R and R' are H or alkyl. Throughout the present invention, this family of IP4-4,6 substituted derivatives is designated as Family B.

[0121] In some aspects, R1, R3, R7 and R 11 Independently represents phosphate (-OPO3 2- ) and R5 / R9 correspond to the formula -O-(alkyl) y -A-(alkyl) y' -Z' (i.e., two alkyl chains connected by a linker A inserted between the two alkyl chains), wherein each alkyl chain comprises y carbon (e.g., CH2) units, wherein y and y' are integers between 0 and 10, wherein linker A is selected from the group consisting of: -CONR-, -NHCOO-, -NHSO2-, -NHCONR-, -NHCO-, and -OCONR-, wherein the distal alkyl chain comprises a terminal group Z', which is selected from the group consisting of: -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', carbocyclic (saturated or unsaturated), heterocyclic (saturated or unsaturated), and wherein R and R' are H or alkyl. Throughout the present invention, this family of IP4-4,6 substituted derivatives is designated as Family C.

[0122] In some aspects, the substituted derivatives of IP4-4,6 of Family D are analogs of compounds from Family A, B, or C, wherein R1, R3, R7, or R 11 At least one of them is a phosphorothioate (-OPSO2 2- Throughout the present invention, this family of IP4-4,6 substituted derivatives is designated as Family D.

[0123] In some aspects of the IP4-4,6 substituted derivatives of Family D, R1, R3, R7 or R8 of compounds from Family A, B or C are 11 One of them is phosphorothioate (-OPSO2 2- In some aspects of IP4-4,6 substituted derivatives of Family D, R1, R3, R7 or R8 of compounds from Family A, B or C are 11Two of them are phosphorothioates (-OPSO2 2- In some aspects of IP4-4,6 substituted derivatives of Family D, R1, R3, R7 or R8 of compounds from Family A, B or C are 11 Three of them are phosphorothioates (-OPSO2 2- In some aspects of IP4-4,6 substituted derivatives of Family D, R1, R3, R7 or R1 of compounds from Family A, B or C 11 It is phosphorothioate (-OPSO2 2- ).

[0124] In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compounds contain only a phosphorothioate (-OPSO2 2- In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compounds contain only a phosphorothioate (-OPSO2 2- In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compounds contain only a phosphorothioate (-OPSO2 2- In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compounds have only one substituted residue at position R. 11 Contains phosphorothioate (-OPSO2 2- In some aspects of IP4-4,6 substituted derivatives of Family D, Family D compounds have at positions R1, R3, R7 and R 11 Contains phosphorothioate (-OPSO2 2- In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compounds contain phosphorothioates (-OPSO2 2- In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compounds contain phosphorothioates (-OPSO2 2- In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compounds have at positions R1 and R 11 Contains phosphorothioate (-OPSO2 2- In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compounds contain phosphorothioates (-OPSO2 2- In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compounds have at positions R3 and R 11 Contains phosphorothioate (-OPSO2 2-In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compounds have at positions R7 and R 11 Contains phosphorothioate (-OPSO2 2- In some aspects of the IP4-4,6 substituted derivatives of Family D, the Family D compounds contain phosphorothioates (-OPSO2 2- In some aspects of IP4-4,6 substituted derivatives of Family D, Family D compounds have at positions R1, R3 and R 11 Contains phosphorothioate (-OPSO2 2- In some aspects of IP4-4,6 substituted derivatives of Family D, Family D compounds have at positions R3, R7 and R 11 Contains phosphorothioate (-OPSO2 2- In some aspects of IP4-4,6 substituted derivatives of Family D, Family D compounds have at positions R1, R7 and R 11 Contains phosphorothioate (-OPSO2 2- ).

[0125] In some aspects, the IP4-4,6 substituted derivatives of the present invention include IP4-4,6 substituted derivatives from Family A, Family B, Family C, Family D, or a combination thereof.

[0126] In some aspects, the IP4-4,6 substituted derivatives of the present invention include IP4-4,6 substituted derivatives from Family A. In some aspects, the IP4-4,6 substituted derivatives of the present invention include IP4-4,6 substituted derivatives from Family B. In some aspects, the IP4-4,6 substituted derivatives of the present invention include IP4-4,6 substituted derivatives from Family C. In some aspects, the IP4-4,6 substituted derivatives of the present invention include IP4-4,6 substituted derivatives from Family D.

[0127] In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of IP4-4,6 substituted derivatives selected from the group consisting of compounds 1 to 53 and combinations thereof. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of IP4-4,6 substituted derivatives selected from the group consisting of compounds 1 to 30 and combinations thereof. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of IP4-4,6 substituted derivatives selected from the group consisting of compounds 31 to 44 and combinations thereof. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of IP4-4,6 substituted derivatives selected from the group consisting of compounds 45 to 49 and combinations thereof. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of IP4-4,6 substituted derivatives selected from the group consisting of compounds 50 to 51 and combinations thereof. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 1. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 2. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 3. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 4. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 5. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 6. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 7. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 8. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 9. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 10. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 11. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 12. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 13. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 14. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 15. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 16. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 17. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 18.In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 19. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 20. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 21. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 22. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 23. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 24. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 25. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 26. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 27. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 28. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 29. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 30. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 31. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 32. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 33. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 34. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 35. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 36. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 37. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 38. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 39. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 40. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 41. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 42. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 43. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 44. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 45.In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 46. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 47. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 48. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 49. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 50. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 51. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 52. In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of compound 53.

[0128] In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of Compound 1, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 2, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 3, wherein R1, R3, R7 or R 11 ;

[0129] R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 4, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 5, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 6, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 7, wherein R1, R3, R7 or R 11; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 8, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 9, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 10, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2-). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 11, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 12, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 13, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 14, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 15, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 16, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 17, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 18, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 19, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 20, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 21, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 22, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 23, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 24, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 25, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2-). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 26, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 27, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 28, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 29, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 30, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 31, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 32, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 33, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 34, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 35, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 36, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 37, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ). In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 38, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 39, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 40, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2-In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 41, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 42, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 43, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 44, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 45, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 46, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 47, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 48, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 49, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 50, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 51, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 52, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of analogs of compound 53, wherein R1, R3, R7 or R 11 ; R1, R3, R7 and R 11 ; R1 and R3; R1 and R7; R1 and R 11 ; R3 and R7; R3 and R 11 ; R7 and R 11 ; R1, R3 and R7; R1, R3 and R 11 ; R3, R7 and R 11 ; or R1, R7 and R 11 It is phosphorothioate (-OPSO2 2- ).

[0130] In some aspects, the alkyl moieties in the R5 and R9 substituents of the IP4-4,6 substituted derivatives of the present invention include at least one carbon double bond or carbon triple bond, i.e., forming alkenyl or alkynyl chains, respectively. In some aspects, the alkenyl chains in the R5 and R9 substituents are the same. In some aspects, the alkenyl chains in the R5 and R9 substituents are different. In some aspects, the alkynyl chains in the R5 and R9 substituents are the same. In some aspects, the alkynyl chains in the R5 and R9 substituents are different. In some aspects, the alkyl moieties in the R5 and R9 substituents include at least one double bond and at least one triple bond, forming a combination of alkenyl and alkynyl chains. In some aspects, the combination of alkenyl and alkynyl chains in the R5 and R9 substituents is the same. In some aspects, the combination of alkenyl and alkynyl chains in the R5 and R9 substituents is different. In some aspects, the IP4-4,6 substituted derivatives of the present invention including at least one carbon double bond or carbon triple bond in the alkyl moieties of the R5 and R9 substituents are family A compounds. In some aspects, the Family A compounds comprising at least one carbon double bond or carbon triple bond are Compounds 1 to 30 and Compound 52.

[0131] In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of the compound represented by the following formula:

[0132]

[0133]

[0134] Wherein n is an integer between 1 and 20, alkyl is CH2 and X is -H. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some aspects, IP4-4,6 derivatives are sodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts, octasodium salts, nonasodium salts or decasodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts or octasodium salts. In some aspects, IP4-4,6 derivatives are hexasodium salts, octasodium salts, nonasodium salts or decasodium salts. In some aspects, IP4-4,6 derivatives are octasodium salts. In some aspects, n is 5, alkyl is CH2 and X is -H (Compound 1). In some aspects, n is 10, alkyl is CH2 and X is -H (Compound 2). In some aspects, n is 14, alkyl is CH2 and X is -H (Compound 3). In some aspects, n is 3, alkyl is CH2 and X is -H (Compound 4). In some aspects, n is 7, alkyl is CH2 and X is -H (Compound 5).

[0135] In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of the compound represented by the following formula:

[0136]

[0137] Wherein n is an integer between 1 and 20, alkyl is CH2 and X is selected from the group consisting of: -OH and -OMe. In some aspects, IP4-4,6 derivatives are sodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts, octasodium salts, nonasodium salts or decasodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts or octasodium salts. In some aspects, IP4-4,6 derivatives are hexasodium salts, octasodium salts, nonasodium salts or decasodium salts. In some aspects, IP4-4,6 derivatives are octasodium salts. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some aspects, n is 5, alkyl is CH2 and X is -OH (Compound 6). In some aspects, n is 10, alkyl is CH2 and X is -OH (Compound 7). In some aspects, n is 14, alkyl is CH2 and X is -OH (Compound 8). In some aspects, n is 5, alkyl is CH2 and X is -OMe (Compound 9). In some aspects, n is 3, alkyl is CH2 and X is -OMe (Compound 10). In some aspects, n is 7, alkyl is CH2 and X is -OMe (Compound 11). In some aspects, n is 9, alkyl is CH2 and X is -OMe (Compound 12). In some aspects, n is 19, alkyl is CH2 and X is -OMe (Compound 20).

[0138] In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of the compound represented by the following formula:

[0139]

[0140] Wherein n is an integer between 1 and 20, alkyl is CH2 and X is an amine group. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some aspects, IP4-4,6 derivatives are sodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts, octasodium salts, nonasodium salts or tensodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts or eightsodium salts. In some aspects, IP4-4,6 derivatives are hexasodium salts, eight sodium salts, nine sodium salts or ten sodium salts. In some aspects, IP4-4,6 derivatives are hexasodium salts. In some aspects, n is 3, alkyl is CH2 and X is -NH2 (Compound 13). In some aspects, n is 5, alkyl is CH2 and X is -NH2 (Compound 14). In some aspects, n is 10 and X, alkyl is CH2 is -NH2 (Compound 15).

[0141] In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of the compound represented by the following formula:

[0142]

[0143] Wherein n is an integer between 1 and 20, alkyl is CH2 and X is pyrazole or triazole. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some aspects, IP4-4,6 derivatives are sodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts, octasodium salts, nonasodium salts or tensodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts or eightsodium salts. In some aspects, IP4-4,6 derivatives are hexasodium salts, eight sodium salts, nine sodium salts or ten sodium salts. In some aspects, IP4-4,6 derivatives are eight sodium salts. In some aspects, n is 5, alkyl is CH2 and X is pyrazole (Compound 16). In some aspects, n is 5, alkyl is CH2 and X is triazole (Compound 17).

[0144] In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of the compound represented by the following formula:

[0145]

[0146] Wherein n is an integer between 1 and 20, alkyl is CH2 and X is -COOH. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some aspects, IP4-4,6 derivatives are sodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts, octasodium salts, nonasodium salts or tenasodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts or eightasodium salts. In some aspects, IP4-4,6 derivatives are hexasodium salts, eightasodium salts, nineasodium salts or tenasodium salts. In some aspects, IP4-4,6 derivatives are eightasodium salts or tenasodium salts. In some aspects, n is 5, alkyl is CH2 and X is -COOH (Compound 18). In some aspects, n is 10, alkyl is CH2 and X is -COOH (Compound 19). In some aspects, n is 3, alkyl is CH2 and X is -COOH (Compound 52).

[0147] In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of the compound represented by the following formula:

[0148]

[0149] Wherein n is an integer between 1 and 20, alkyl is CH2 and X is -CONRR', -NHCOR, -NHCOOR, -NHCONRR' or -CF3. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some aspects, IP4-4,6 derivatives are sodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts, octasodium salts, nonasodium salts or decasodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts or octasodium salts. In some aspects, IP4-4,6 derivatives are hexasodium salts, octasodium salts, nonasodium salts or decasodium salts. In some aspects, IP4-4,6 derivatives are octasodium salts. In some aspects, n is 3, alkyl is CH2 and X is -CF3 (Compound 22). In some aspects, n is 5, alkyl is CH2 and X is -CF3 (Compound 23). In some aspects, n is 3, alkyl is CH2 and X is -NHCOOMe (Compound 24). In some aspects, n is 5, alkyl is CH2 and X is -NHCOOMe (Compound 25). In some aspects, n is 3, alkyl is CH2 and X is -CONH2 (Compound 26). In some aspects, n is 5, alkyl is CH2 and X is -NHCOMe (Compound 27). In some aspects, n is 5, alkyl is CH2 and X is -NHCONHPr (Compound 30).

[0150] In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of the compound represented by the following formula:

[0151]

[0152] Wherein n is an integer between 1 and 20, alkyl is CH2 and X is cyclopropane or cyclopentane. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some aspects, IP4-4,6 derivatives are sodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts, octasodium salts, nonasodium salts or tensodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts or eightsodium salts. In some aspects, IP4-4,6 derivatives are hexasodium salts, eight sodium salts, nine sodium salts or ten sodium salts. In some aspects, IP4-4,6 derivatives are eight sodium salts. In some aspects, n is 2, alkyl is CH2 and X is cyclopropane (Compound 28). In some aspects, n is 2, alkyl is CH2 and X is cyclopentane (Compound 29).

[0153] In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of the compound represented by the following formula:

[0154]

[0155] Wherein n is an integer between 1 and 20, the alkyl group is branched and X is -H. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some aspects, the IP4-4,6 derivative is a sodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, a pentasodium salt, a hexasodium salt, a heptasodium salt, an octasodium salt, a nonasodium salt or a decasodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, a pentasodium salt, a hexasodium salt, a heptasodium salt or an octasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt, an octasodium salt, a nonasodium salt or a decasodium salt. In some aspects, the IP4-4,6 derivative is an octasodium salt. In some aspects, the IP4-4,6 substituted derivatives of the present invention include such as Figure 3B The compound 21 shown in or consisting of the compound 21.

[0156] In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of the compound represented by the following formula:

[0157]

[0158] Wherein n is an integer between 1 and 20, alkyl is an alkynyl chain and X is -H. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some aspects, the IP4-4,6 derivative is a sodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, a pentasodium salt, a hexasodium salt, a heptasodium salt, an octasodium salt, a nonasodium salt or a decasodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, a pentasodium salt, a hexasodium salt, a heptasodium salt or an octasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt, an octasodium salt, a nonasodium salt or a decasodium salt. In some aspects, the IP4-4,6 derivative is an octasodium salt. In some aspects, the IP4-4,6 substituted derivatives of the present invention include such as Figure 3B The compound 53 shown in or consisting of the compound 53.

[0159] In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of the compound represented by the following formula:

[0160]

[0161] wherein y and y' are integers between 0 and 10, alkyl is CH2, Cy is selected from the group consisting of piperazine, triazole-1 and triazole-2, and Z is selected from the group consisting of -COOH, -OMe and -COCH3. Figure 4A. In some aspects, the IP4-4,6 derivative is a sodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, a pentasodium salt, a hexasodium salt, a heptasodium salt, an octasodium salt, a nonasodium salt or a decasodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, a pentasodium salt, a hexasodium salt, a heptasodium salt or an octasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt, an octasodium salt, a nonasodium salt or a decasodium salt. In some aspects, the IP4-4,6 derivative is an octasodium salt or a nonasodium salt. In some aspects, y or y' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some aspects, y is 1, y' is 2, alkyl is CH2, Cy is triazole-2, and Z is -COOH (Compound 31). In some aspects, y is 1, y' is 3, alkyl is CH2, Cy is triazole-2, and Z is -OMe (Compound 32). In some aspects, y is 1, y' is 6, alkyl is CH2, Cy is triazole-2, and Z is -OMe (Compound 33). In some aspects, y is 2, y' is 0, alkyl is CH2, Cy is piperazine, and Z is -COCH3 (Compound 34). In some aspects, y is 3, y' is 2, alkyl is CH2, Cy is triazole-1, and Z is -COOH (Compound 35). In some aspects, y is 3, y' is 1, alkyl is CH2, Cy is triazole-1, and Z is -OMe (Compound 36). In some aspects, y is 4, y' is 1, alkyl is CH2, Cy is triazole-1, and Z is -OMe (Compound 37). In some aspects, y is 5, y' is 1, alkyl is CH2, Cy is triazole-1, and Z is -OMe (Compound 38). In some aspects, y is 6, y' is 1, alkyl is CH2, Cy is triazole-1, and Z is -OMe (Compound 39). In some aspects, y is 6, y' is 0, alkyl is CH2, Cy is triazole-1, and Z is -COOH (Compound 40). In some aspects, y is 6, y' is 1 / 0, alkyl is CH2, Cy is triazole-1, and Z is -OMe / -COOH (Compound 41).

[0162] In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of the compound represented by the following formula:

[0163]

[0164] wherein y and y' are integers between 0 and 10, alkyl is CH2, Cy is selected from the group consisting of 1,3-substituted phenyl and 1,4-substituted phenyl, and Z is selected from the group consisting of -Me, -OMe and -CF3. Figure 4B. In some aspects, the IP4-4,6 derivative is a sodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, a pentasodium salt, a hexasodium salt, a heptasodium salt, an octasodium salt, a nonasodium salt or a decasodium salt. In some aspects, the IP4-4,6 derivative is a tetrasodium salt, a pentasodium salt, a hexasodium salt, a heptasodium salt or an octasodium salt. In some aspects, the IP4-4,6 derivative is a hexasodium salt, an octasodium salt, a nonasodium salt or a decasodium salt. In some aspects, the IP4-4,6 derivative is an octasodium salt. In some aspects, y or y' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some aspects, y is 3, y' is 0, alkyl is CH2, Cy is a 1,4-substituted phenyl, and Z is -Me (Compound 42). In some aspects, y is 3, y' is 0, alkyl is CH2, Cy is 1,4-substituted phenyl, and Z is -OMe (Compound 43). In some aspects, y is 3, y' is 0, alkyl is CH2, Cy is 1,3-substituted phenyl, and Z is -CF3 (Compound 44).

[0165] In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of the compound represented by the following formula:

[0166]

[0167] Wherein y and y' are integers between 0 and 10, alkyl is CH2, A is selected from the group consisting of: -NHCO and -NHCONH, and Z is selected from the group consisting of: -COOH, phenyl, cyclopentyl and thienyl. In some aspects, IP4-4,6 derivatives are sodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts, octasodium salts, nonasodium salts or tensodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts or eightsodium salts. In some aspects, IP4-4,6 derivatives are hexasodium salts, eight sodium salts, nine sodium salts or ten sodium salts. In some aspects, IP4-4,6 derivatives are eight sodium salts or ten sodium salts. In some aspects, y or y' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some aspects, y is 3, y' is 3, alkyl is CH2, A is -NHCO, and Z is -COOH (Compound 45). In some aspects, y is 3, y' is 0, alkyl is CH2, A is -NHCONH, and Z is phenyl (Compound 46). In some aspects, y is 3, y' is 0, alkyl is CH2, A is -NHCONH, and Z is cyclopentyl (Compound 47). In some aspects, y is 5, y' is 0, alkyl is CH2, A is -NHCO, and Z is phenyl (Compound 48). In some aspects, y is 5, y' is 0, alkyl is CH2, A is -NHCO, and Z is thienyl (Compound 49).

[0168] In some aspects, the IP4-4,6 substituted derivatives of the present invention include or consist of the compound represented by the following formula:

[0169]

[0170] Wherein n is an integer between 1 and 20, alkyl is CH2 and X is selected from the group consisting of: -H and -OMe. In some aspects, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In some aspects, IP4-4,6 derivatives are sodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts, octasodium salts, nonasodium salts or tensodium salts. In some aspects, IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts or eightsodium salts. In some aspects, IP4-4,6 derivatives are hexasodium salts, eight sodium salts, nine sodium salts or ten sodium salts. In some aspects, IP4-4,6 derivatives are eight sodium salts. In some aspects, n is 5, alkyl is CH2 and X is -H (Compound 50). In some aspects, n is 5, alkyl is CH2 and X is -OMe (Compound 51).

[0171] The IP4-4,6 derivatives of the present invention are disclosed in myo form. However, the present invention is also intended to cover all other isomers of the inositol skeleton, such as scyllo-inositol, muco-inositol, 1D-chiro-inositol, 1L-chiro-inositol, neo-inositol, iso-inositol, epi-inositol and cis-inositol counterparts of the IP4-4,6 derivatives of the present invention.

[0172] The present invention also provides chemical intermediate compounds (e.g., compounds 1 to compounds 53) for preparing IP4-4,6 substituted derivatives of the present invention. In some aspects, such intermediates are compounds listed in Table 1. The intermediate compounds disclosed herein can be converted into IP4-4,6 substituted derivatives of the present invention by utilizing the procedures described herein. Therefore, the present invention provides a method for preparing IP4-4,6 substituted derivatives of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53), which includes utilizing an intermediate compound selected from the group consisting of the compounds listed in Table 1. The present invention also provides a method for preparing an intermediate compound disclosed herein. Therefore, the present invention provides a method for preparing an intermediate compound selected from the group consisting of the compounds listed in Table 1 for preparing IP4-4,6 substituted derivatives of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53).

[0173] Table 1 Intermediates

[0174]

[0175]

[0176]

[0177]

[0178]

[0179] The IP4-4,6 substituted derivatives of the present invention and the intermediates for synthesizing them can be synthesized by using the methods described herein and other methods known in the field of organic chemistry. In some aspects, the method is not limited to the general procedures shown in Synthetic Schemes 1, 2, 3 and 4 described herein. Therefore, in some aspects, the present invention provides a method for preparing the IP4-4,6 substituted derivatives of the present invention, which includes the application of Synthetic Scheme 1 disclosed below. In some aspects, the present invention provides a method for preparing the IP4-4,6 substituted derivatives of the present invention, which includes the application of Synthetic Scheme 2 disclosed below. In some aspects, the present invention provides a method for preparing the IP4-4,6 substituted derivatives of the present invention, which includes the application of Synthetic Scheme 3 disclosed below. In some aspects, the present invention provides a method for preparing the IP4-4,6 substituted derivatives of the present invention, which includes the application of Synthetic Scheme 4 disclosed below.

[0180] In some aspects, the present invention provides a method for preparing an intermediate for synthesizing an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53), which comprises applying Synthetic Route 1 disclosed below. In some aspects, the present invention provides a method for preparing an intermediate for synthesizing an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53), which comprises applying Synthetic Route 2 disclosed below. In some aspects, the present invention provides a method for preparing an intermediate for synthesizing an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53), which comprises applying Synthetic Route 3 disclosed below. In some aspects, the present invention provides a method for preparing an intermediate for synthesizing an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53), which comprises applying Synthetic Route 4 disclosed below.

[0181] Route 1: The IP4-4,6 substituted derivatives of the present invention can be obtained by, for example, removing the protecting groups of the intermediates of formula IV (eg, intermediates IV-1 to IV-48) and intermediates of formula IV' (eg, IV'-1 to IV'-2). See Route 1, Figure 7. In each case, "protecting group" or PG can be, but is not limited to, benzyl, levulinic acid benzyl, tert-butyl, o-xylyl (e.g., by combining 2 PGs in the same phosphate), 9-fluorenylmethyl, cyanoethyl and other suitable protecting groups. Formula IV intermediates (e.g., intermediates IV-1 to IV-48) can be, for example, phosphorylated according to the procedure described in the literature, for example, by reacting with aminophosphite derivatives and then oxidizing with an oxidant (e.g., m-CPBA, H2O2, tBuOOH). Formula IV' intermediates (e.g., intermediates IV'-1 to IV'-2) can be, for example, phosphorothioated according to the procedure described in the prior art, for example, by reacting with aminophosphite derivatives and then oxidizing with sulfur. At the same time, formula III intermediates (e.g., intermediates III-1 to III-47) can be, for example, obtained by hydrolyzing formula II intermediates (e.g., intermediates II-1 to II-27) in an acidic medium. Finally, intermediates of formula II (e.g., intermediates II-1 to II-27) can be obtained, for example, by alkylating compound (2) with an alkylating agent. The preparation of (2) has been described previously in the literature (Martin S et al., J. Org. Chem. 1994; 59: 4805; Kardivel M, Org. & Biomolecular Chem. 2008; 6 (11): 1966-72). The "leaving group" or LG can be, but is not limited to, chloride, bromide, iodide, tosyl (Ts) or mesyl (Ms).

[0182] Route 2: As an alternative to Route 1, for example, when R5 and R9 contain substituted 1,2,3-triazole, the compound of Formula I (ie, the IP4-4,6 substituted derivative of the present invention) can be prepared by following Route 2 ( Figure 8 ) is obtained by the alternative route described in. In this way, the intermediates of formula III (e.g., intermediates III-20, III-26 and III-27) can be obtained, for example, by click reaction, by using the intermediates of formula VI (e.g., intermediate VI-1) and alkyl reagents as starting materials. Intermediate VI (e.g., intermediate VI-1) can be achieved by alkylating and hydrolyzing intermediate 2 with appropriate reagents.

[0183] Route 3: As another alternative to Route 1 and Route 2, for example, when R5 and R9 contain substituted 1,2,3-triazole, the compound of Formula I (ie, the IP4-4,6 substituted derivative of the present invention) can be prepared by following Route 3 ( Fig. 9) is obtained by the alternative route described in . In this case, the intermediate of formula III (e.g., intermediates III-21 to III-25, III-42 and III-43) can be obtained, for example, by a click reaction, by using the intermediate of formula IX (e.g., intermediates IX-1 to IX5) and an alkynyl click agent as a starting material. Intermediate IX can be achieved by alkylating and hydrolyzing compound 2 with an azide alkylating agent. As another alternative to route 1, when R5 and R9 contain an amine group, the compound of formula I (i.e., the IP4-4,6 substituted derivative of the present invention) can be obtained by route 3 ( Fig. 9 Thus, intermediate IX (e.g., intermediates IX-1 to IX-5) can be phosphorylated to obtain intermediate X (e.g., X-1 to X3), and intermediate X can then be deprotected to obtain a compound of formula I.

[0184] Route 4: As another alternative to Route 1, when R5 and R9 contain substituted amides, sulfonamides, carbamates or ureas, intermediates III (e.g., intermediates III-28, III-36 to III-41, and III-44 to III-46) can be prepared as follows: Fig.10 Obtained as shown in. Therefore, intermediate III (e.g., intermediate III-28, III-36 to III-41, and III-44 to III-46) can be by intermediate VIII (e.g., VIII-1 to VIII-5) by azide reduction (e.g., intermediate XI-1 to XI-2), then deprotection (e.g., intermediate XII-1) and finally by intermediate XII (e.g., intermediate XII-1) with the reaction of appropriate reagents to form amide / sulfonamide / urea or carbamate to achieve. Alternatively, the reaction order can be changed, first from intermediate XIII (e.g., intermediate XIII-1 to XIII-3) to obtain amide / sulfonamide / urea or carbamate, and then by hydrolysis to obtain intermediate III.

[0185] Any alkylating agent or click agent (including azide or alkynyl) and reagents for amide, sulfonamide, urea or carbamate formation may be commercially available or may be obtained using reactions well known in the art of organic chemistry. In some aspects, methods include but are not limited to Scheme 5 ( Fig.11 ) as shown in the general procedure.

[0186] Representative IP4-4,6 substituted derivatives of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53) are shown herein and all of them are myo configurations. However, it should be understood that any exemplary IP4-4,6 substituted derivatives of the present invention in myo configuration are not limited to the representative configurations shown. Therefore, for example, compounds 1 to 53 and the intermediates shown herein will also cover the corresponding equivalents of scyllo-inositol, muco-inositol, 1D-chiro-inositol, 1L-chiro-inositol, neo-inositol, iso-inositol, table-inositol and cis-inositol configurations. The most stable configuration of myo-inositol isomers takes a chair configuration, which moves the maximum number of hydroxyls to the equatorial position (equatorial), where they are farthest from each other. In this configuration, natural myo isomers have a structure in which five of the six hydroxyls (the first, third, fourth, fifth and sixth) are equatorial, and the second hydroxyl is axial.

[0187] The present invention also provides a method for preparing a drug for treating pathological crystallization, which comprises using an intermediate compound selected from the group consisting of the compounds listed in Table 1. The present invention also provides a compound of formula I (e.g., selected from the group consisting of compound 1 to compound 53) for use as a drug. The present invention also provides the use of a compound of formula I (e.g., selected from the group consisting of compound 1 to compound 53) for preparing a drug for preventing or treating a disease associated with pathological crystallization.

[0188] III. Pharmaceutical Compositions

[0189] The present invention also provides a pharmaceutical composition for treating, inhibiting the progression of, and preventing (a) ectopic calcification or its consequences and (b) diseases and / or conditions associated with ectopic calcification and its consequences in a subject in need thereof, wherein the pharmaceutical composition comprises at least one IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53). In some aspects, the pharmaceutical composition comprises an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) used alone or together with one or more pharmaceutically acceptable excipients or carriers.

[0190] The term "excipient" as used herein refers to a substance that aids in the absorption of an element of the pharmaceutical composition, stabilizes the element, activates or aids in the preparation of the composition. Thus, examples of excipients used in parenteral formulations include, but are not limited to, antimicrobial agents (e.g., benzalkonium chloride, metacresol, thimerosal), cosolvents (e.g., ethanol), buffers, tonicity agents (e.g., NaCl), and pH adjusting factors (e.g., carbonate, citrate, phosphate solutions).

[0191] As in the case of excipients, a "pharmaceutically acceptable carrier" is a substance used in a composition to dilute any component contained therein to a defined volume or weight (e.g., 0.9% (w / v) NaCl aqueous solution). A pharmaceutically acceptable carrier is an inert substance, or a substance having a similar effect to any element comprising the pharmaceutical composition of the present invention. The role of the carrier is to allow the incorporation of other elements, to allow for better dosage and administration, or to provide consistency and shape to the composition.

[0192] The pharmaceutical composition may contain about 1% to about 95% active ingredient. In some aspects, for example, the pharmaceutical composition of the invention may contain about 20% to about 90% active ingredient (i.e., IP4-4,6 substituted derivatives of the invention or combinations thereof, alone or, for example, in combination with one or more other therapeutic agents).

[0193] The formulation of a pharmaceutical composition suitable for parenteral administration comprises an active ingredient, such as an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53), in combination with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline (e.g., 0.9% (w / v) NaCl aqueous solution). Such formulations can be prepared, packaged or sold in a form suitable for push administration or non-pull administration. Injectable formulations can be prepared, packaged or sold in unit dosage form, such as in ampoules or multi-dose containers containing preservatives. Preparations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions, ointments, and implantable sustained-release or biodegradable formulations in oily or aqueous carriers. Such formulations may further comprise one or more other ingredients, including but not limited to suspending agents, stabilizing or dispersing agents.

[0194] In some aspects, in formulations for parenteral administration, the active ingredient, e.g., an IP4-4,6 substituted derivative of the invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) is provided in dry form (i.e., powder or granules) for reconstitution with a suitable carrier (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

[0195] Pharmaceutical compositions can be prepared, packaged or sold in the form of sterile injectable aqueous or oily suspensions or solutions. The suspensions or solutions can be prepared according to known techniques and, in addition to active ingredients (e.g., inositol phosphates of the present invention), can also include other ingredients, such as dispersants, wetting agents or suspending agents as described herein. For example, such sterile injection preparations can be prepared using nontoxic parenteral acceptable diluents or solvents, such as water or 1,3-butanediol. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution and fixed oils, such as synthetic monoglycerides or diglycerides.

[0196] Other useful parenteral formulations include those containing the active ingredient in microcrystalline form, in liposomal formulations, or as components of a biodegradable polymer system. Compositions for sustained release or implantation may include pharmaceutically acceptable polymers or hydrophobic materials, such as emulsions, ion exchange resins, slightly soluble polymers, or slightly soluble salts. Compositions and methods for preparing formulations for administering IP4-4,6 substituted derivatives of the present invention are described in the art, including controlled or sustained release formulations containing the active agent. See, for example, Remington: The Science and Practice of Pharmacy, 23rd edition, 2021, Academic Press; US6340475, US6488962, US6451808, US5972389, US5582837 and US5007790; US20030147952, US20030104062, US20030104053, US20030044466, US20030039688 and US20020051820; WO2003035041, WO2003035 040, WO2003035029, WO2003035177, WO2003035039, WO2002096404, WO2002032416, WO2001097783, WO2001056544, WO2001032217, WO1998055107, WO1998011879, WO1997047285, WO1993018755 and WO1990011757.

[0197] The medicaments according to the invention are prepared by methods known in the art, in particular by conventional mixing, coating, granulating, dissolving or lyophilizing.

[0198] The invention also provides a compound or combination of compounds or a pharmaceutical preparation according to any of the above aspects of the invention in the broadest definition given, or as specified in any of the above aspects, for use as a medicament.

[0199] The invention also provides a compound or combination of compounds or a pharmaceutical formulation according to any of the above aspects of the invention in the broadest definition given, or as specified in any of the above aspects, for use in the treatment and / or prevention of a disease or condition disclosed herein.

[0200] The invention also provides a compound or combination of compounds or a pharmaceutical formulation according to any of the above aspects of the invention in the broadest definition given, or as specified in any of the above aspects, for use in the preparation of a medicament for the prevention and / or treatment of a disease or condition disclosed herein.

[0201] IV. Products and Kits

[0202] The present invention also provides articles and kits. Such articles and kits may comprise a container (e.g., a box) comprising one or more vials containing a formulation comprising (a) one or more IP4-4,6 substituted derivatives of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53), (b) one or more pharmaceutical compositions of the present invention and / or (c) a solvent for its medical administration or other use according to the methods disclosed herein.

[0203] The kit or article provided according to the present invention may also include a manual or instructions describing the medical administration methods and dosages disclosed herein, or using the IP4-4,6 substituted derivatives of the present invention (e.g., compounds selected from the group consisting of Compound 1 to Compound 53) according to the methods disclosed herein. In some aspects, the kit or article may include multiple vials, each of which contains a single dose. In other aspects, the kit or article may include one or more vials, each of which contains more than one dose.

[0204] In some aspects, the article is a bag containing a solution of an IP4-4,6 substituted derivative of the invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53). In other aspects, the article is a bottle containing a solution of an IP4-4,6 substituted derivative of the invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53). In some aspects, the article is a bag containing an IP4-4,6 substituted derivative of the invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) in powder form for reconstitution in a suitable solvent. In other aspects, the article is a bottle (e.g., a glass bottle or a plastic bottle) containing an IP4-4,6 substituted derivative of the invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) in powder form for reconstitution in a suitable solvent.

[0205] Kits and articles of manufacture may include instructions for administering one or more of the IP4-4,6 substituted derivatives of the invention (eg, a compound selected from the group consisting of Compound 1 to Compound 53) according to the methods and dosages disclosed herein.

[0206] The instructions included in the kits and articles of manufacture may be attached to the packaging material or may be included as a drug package insert. Although the instructions are typically written or printed materials, they are not limited thereto. Any medium capable of storing such instructions and communicating them to an end user is contemplated. Such media include, but are not limited to, electronic storage media (e.g., disks, tapes, cassettes, chips), optical media (e.g., CD ROM), etc. As used herein, the term "instructions" may include the address of an Internet website that provides the instructions.

[0207] V. Use of IP4-4,6 substituted derivatives of formula I

[0208] In one aspect, the present invention relates to IP4-4,6 substituted derivative compounds of general formula I (e.g., compounds selected from the group consisting of compounds 1 to compound 53) for treating ectopic calcification or its consequences, inhibiting the progression of ectopic calcification or its consequences, and preventing ectopic calcification or its consequences in subjects in need thereof. In some aspects, the present invention relates to a method for inhibiting ectopic calcification or its consequences, inhibiting the progression of ectopic calcification or its consequences, and preventing ectopic calcification or its consequences in subjects in need thereof, comprising administering a therapeutically effective amount of IP4-4,6 substituted derivative compounds of the present invention. In some aspects, the present invention relates to the use of IP4-4,6 substituted derivative compounds of the present invention for the preparation of drugs for treating ectopic calcification or its consequences, inhibiting the progression of ectopic calcification or its consequences, and preventing ectopic calcification or its consequences in subjects in need thereof. In some aspects, IP4-4,6 substituted derivatives are compounds of general formula II to XIV or any combination thereof. In some aspects, IP4-4,6 substituted derivatives are compound 1, compound 3, compound 6, compound 27, or any combination thereof. In some aspects, a therapeutically effective amount of an IP4-4,6 substituted derivative of the invention is administered to a subject in need thereof.

[0209] In some aspects, IP4-4,6 substituted derivatives of the present invention (e.g., compounds selected from the group consisting of Compound 1 to Compound 53) can be administered by topical, enteral or parenteral administration. In some aspects, parenteral administration is by intravenous, intraperitoneal, intramuscular, intraarterial or subcutaneous administration. In some aspects, the compound can be administered as a component of hemodialysis, hemofiltration or peritoneal dialysis solution.

[0210] In some aspects, the IP4-4,6 substituted derivatives of the invention (e.g., compounds selected from the group consisting of Compound 1 to Compound 53) can be administered by any appropriate method, for example, methods that induce a non-bolus release or effect, such as intravascular (e.g., intravenous) infusion, other parenteral (e.g., subcutaneous, subcutaneous reservoir, intraperitoneal, intramuscular, intradermal, intrathecal, epidural, spinal, or other methods known to those skilled in the art), topical (e.g., intranasal, inhalation, intravaginal, transdermal, or other methods known to those skilled in the art), enteral (e.g., oral, sublingual, rectal) administration, oral, spinal, intraperitoneal formulations, or other methods known to those skilled in the art.

[0211] In the particular case of patients receiving dialysis treatment, an appropriate method of administration includes administering (e.g., non-bolus) the IP4-4,6 substituted derivatives of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53) through a dialysis device (before or after the filter), rather than directly injecting the IP4-4,6 substituted derivatives of the present invention intravenously into the patient. Thus, when the blood leaves the patient and circulates in the dialysis circuit, the blood can be treated with the IP4-4,6 substituted derivatives of the present invention, and when the blood containing the IP4-4,6 substituted derivatives of the present invention is returned to the body, the IP4-4,6 substituted derivatives are introduced into the blood in a manner having a series of advantages. In the case of dialysis patients, administration of the IP4-4,6 substituted derivatives of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53) through a dialysis device allows the blood to equilibrate with the dialysate before returning to the body.

[0212] In some aspects, IP4-4,6 substituted derivatives of the present invention (e.g., compounds selected from the group consisting of compound 1 to compound 53) are administered intravenously by intravenous infusion. In another aspect, IP4-4,6 substituted derivatives of the present invention are administered subcutaneously. In yet another aspect, IP4-4,6 substituted derivatives of the present invention are administered topically. In some aspects, when IP4-4,6 substituted derivatives of the present invention are administered to patients receiving dialysis, such administration (e.g., administered intravenously by infusion) can occur during dialysis treatment. In some aspects, IP4-4,6 substituted derivatives of the present invention are administered before dialysis treatment. In some aspects, IP4-4,6 substituted derivatives of the present invention are administered after dialysis treatment.

[0213] In some aspects, the present invention also relates to a pharmaceutical composition for treating ectopic calcification or its consequences, inhibiting the progression of ectopic calcification or its consequences and preventing ectopic calcification or its consequences in a subject in need thereof, comprising an IP4-4,6 substituted derivative of the present invention or any combination thereof, and at least one pharmaceutically acceptable excipient. In some aspects, the IP4-4,6 substituted derivative is a compound of formula II to XIV or any combination thereof. In some aspects, the IP4-4,6 substituted derivative is compound 1, compound 3, compound 6, compound 27 or any combination thereof. In some aspects, a therapeutically effective amount of the pharmaceutical composition of the present invention is administered to a subject in need thereof.

[0214] The present invention also provides a method for preparing a medicament for treating ectopic calcification or its consequences, inhibiting the progression of ectopic calcification or its consequences, and preventing ectopic calcification or its consequences, which comprises using an intermediate compound selected from the group consisting of the compounds listed in Table 1.

[0215] Ectopic calcification (e.g., skin, subcutaneous calcification) is associated with pathological crystallization of calcium and occurs as a complication in many diseases and conditions. Ectopic calcification typically damages soft tissues such as the aorta, brain, carotid artery, femur, heart, heart valves, joints, kidneys, and lungs. It is generally considered to be an age-dependent process, but recent data suggest that a large number of molecules may regulate this process in a positive manner (Nitschke Y et al., Trends Cardiovasc Med. 2012; 22 (6): 145-149). The IP4-4,6 substituted derivatives of the present invention are selective calcification inhibitors that act by binding to the growth sites of hydroxyapatite (HAP) crystals, thereby selectively inhibiting the last common step in the ectopic calcification (including vascular calcification) pathway. Since the IP4-4,6 substituted derivatives of the present invention effectively inhibit vascular calcification in various types of soft tissues, they can be used to treat diseases and / or conditions associated with ectopic calcification of such specific types of soft tissues.

[0216] In one aspect, the present invention relates to the use of an IP4-4,6 substituted derivative compound or pharmaceutical composition of the present invention for treating, inhibiting the progression of, and preventing diseases and / or conditions associated with ectopic calcification or its consequences in a subject in need thereof.

[0217] In some aspects, diseases and / or conditions associated with ectopic calcification or its consequences according to the present invention include, but are not limited to, adrenal and intracranial calcification in familial cavernous malformations, asthenic bone disease, calcium deposition-related age-related macular degeneration (AMD), bone cancer, bone mineral disease, breast calcification, calcific band keratopathy, calcific tendinitis, calcification in osteoarthritis, cartilage calcification in osteoarthritic joints, calcification of joints and arteries (CALJA), seminal vesicle calcification, calcinosis cutis, calcisensitization (CUA), calcium pyrophosphate deposition disease (CPPD), cardiovascular disease or related conditions, chondrocalcinosis, colon cancer, diabetic nephropathy, malnutrition calcification, renal transplant failure, familial cavernous malformations (FCCM), progressive fibrodysplasia ossificans progressiva (FOP), hyperosteogenetic-hyperphosphatemic syndrome (HHS), hyperphosphatemic familial tumoral calcification (HFTC), idiopathic brain calcification (Fahr's disease), idiopathic mesenteric venous sclerosis (IMP), kidney stones (i.e., nephrolithiasis), metastatic calcification, nephrocalcinosis, calcification associated with neurocysticercosis, osteomalacia, osteoporosis, pineal calcification, venous sclerosing colitis, podagra, primary familial brain calcification (PFBC), primary hyperoxaluria (PH), pseudoxanthoma elasticum (PXE), rheumatoid arthritis, sialolithiasis, parotid calcification in Sjorgen's syndrome, seminal vesicle stones, skin cancer, soft tissue calcification due to sarcoidosis, adrenal calcification in Wolman's disease, and wound healing associated with diabetic ulcers.

[0218] In some aspects, cardiovascular diseases and / or related conditions associated with ectopic calcification or its consequences according to the present invention include, but are not limited to, acute ischemic stroke (ACS), aneurysm, angina pectoris (chronic stable angina), aortic calcification, large artery calcification, aortic stenosis, aortic valve calcification, arrhythmias, atherosclerosis, arteriosclerosis, arteriovenous fistula (AVF) dysfunction, atherosclerosis, calcific aortic stenosis, cardiac death, heart disease, cardiovascular calcification, cardiovascular disease in patients with chronic kidney disease (CKD), cardiovascular disease associated with aging, cardiovascular death, cerebrovascular disease, congestive heart failure, coral reef aorta (CRA), coronary artery calcification, coronary artery disease, coronary heart disease, critical limb ischemia, electrocardiogram abnormalities, systemic arterial calcification in infancy (GACI), heart failure, hypertension, ischemia, left ventricular hypertrophy, major adverse cardiovascular events (MACE) in patients on hemodialysis (HD), medial sclerosis (MMS), myocardial calcification, myocardial infarction, myocardial ischemia, pericardial calcification, peripheral artery disease (PAD), peripheral vascular disease (PVD), porcelain aorta and anastomotic calcification after coronary artery bypass grafting (CABG), portal vein calcification, stroke, thrombosis, valvular calcification and vascular calcification.

[0219] In some aspects, the present invention relates to the use of IP4-4,6 substituted derivative compounds of the general formula I of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53) or pharmaceutical compositions for treating ectopic calcification or its consequences, inhibiting the progression of ectopic calcification or its consequences, and preventing ectopic calcification or its consequences in subjects in need thereof, wherein the ectopic calcification occurs or may occur in the aorta, brain, carotid artery, femur, heart, heart valve, joint, kidney or lung tissue or any combination thereof. Examples of diseases and / or conditions associated with ectopic calcification or its consequences in aortic tissue include, but are not limited to, aortic calcification, large artery calcification, aortic stenosis, aortic valve calcification, atherosclerosis, arteriosclerosis, atherosclerosis, calcific aortic stenosis (CAVS), cardiovascular disease associated with aging, cardiovascular death, coral reef aorta (CRA), electrocardiogram abnormalities, systemic arterial calcification in infancy (GACI), heart failure, peripheral arterial disease (PAD) and peripheral vascular disease (PVD). Examples of diseases and / or conditions associated with ectopic calcification or its consequences in brain tissue include, but are not limited to, adrenal and intracranial calcification in familial cavernous malformations, cerebrovascular disease, familial cavernous malformations (FCCM), idiopathic brain calcification (Fahr's disease), pineal calcification, and primary familial brain calcification (PFBC). Examples of diseases and / or conditions associated with ectopic calcification or its consequences in carotid artery tissue include, but are not limited to, ischemia, peripheral arterial disease (PAD), peripheral vascular disease (PVD), stroke, and thrombosis. Examples of diseases and / or conditions associated with ectopic calcification or its consequences in femoral tissue include, but are not limited to, arteriosclerosis, arteriosclerosis, atherosclerosis, cardiovascular calcification, cardiovascular disease in patients with chronic kidney disease (CKD), cardiovascular disease associated with aging, cardiovascular death, critical limb ischemia (CLI), systemic arterial calcification in infancy (GACI), ischemia, peripheral arterial disease (PAD), peripheral vascular disease (PVD), thrombosis, and vascular calcification. Examples of diseases and / or conditions associated with ectopic calcification or its consequences in heart and heart valve tissue include, but are not limited to, aneurysms, angina pectoris (chronic stable angina), aortic valve calcification, arrhythmias, atherosclerosis, arteriosclerosis, atherosclerosis, calcific aortic stenosis (CAVS), cardiac death, heart disease, cardiovascular calcification, cardiovascular disease in patients with chronic kidney disease (CKD), cardiovascular disease associated with aging, cardiovascular death, cardiovascular disease, congestive heart failure, coronary artery calcification, coronary artery disease, coronary heart disease, electrocardiogram abnormalities, systemic arterial calcification in infancy (GACI), heart failure, hypertension, ischemia, left ventricular hypertrophy, myocardial infarction, and myocardial ischemia.Examples of diseases and / or conditions associated with ectopic calcification or its consequences in joint tissue include, but are not limited to, calcific tendinitis, calcification in osteoarthritis, calcification of articular cartilage in osteoarthritis, joint and arterial calcification (CALJA), malnutrition calcification, and pseudogout. Examples of diseases and / or conditions associated with ectopic calcification or its consequences in renal tissue include, but are not limited to, renal transplant failure, kidney stones (i.e., nephrolithiasis), renal calcinosis, and primary hyperoxaluria (PH). Examples of diseases and / or conditions associated with ectopic calcification or its consequences in lung tissue include, but are not limited to, malnutrition calcification and metastatic calcification. Examples of diseases and / or conditions associated with ectopic calcification or its consequences in skin tissue include, but are not limited to, calcisensitivity (CUA) and pseudoxanthoma elasticum (PXE). In some aspects, IP4-4,6-substituted derivatives are compounds of formula II to XIV or any combination thereof. In some aspects, IP4-4,6-substituted derivatives are compound 1, compound 3, compound 6, compound 27, or any combination thereof.

[0220] As shown above, administering the IP4-4,6 substituted derivatives of the present invention to a subject inhibits the formation and / or growth of hydroxyapatite (HAP) crystals and their deposition in ectopic calcification. This mechanism of action can mediate the treatment of many diseases and / or conditions associated with ectopic calcification and their consequences. For example, due to the inhibition of HAP formation, arteriosclerosis will be reduced, thereby improving diastolic coronary artery perfusion and alleviating any associated ischemic symptoms, such as angina. Similarly, the IP4-4,6 substituted derivatives of the present invention can also effectively reduce the risk of cardiovascular events in patients. By inhibiting HAP formation, the IP4-4,6 substituted derivatives of the present invention will slow the progression of coronary artery calcification (CAC). Since CAC is associated with increased cardiovascular mortality, reducing its rate of progression may reduce the risk of cardiovascular events. In addition, given its inhibitory effect on HAP formation, the IP4-4,6 substituted derivatives of the present invention may also slow the calcification of the aortic valve leaflets. Pseudoxanthoma elasticum (PXE) is characterized by ectopic mineralization and fragmentation of elastic fibers in the skin, eyes, blood vessels, and gastrointestinal system. Because the IP4-4,6 substituted derivatives of the present invention inhibit HAP formation, the vision of, for example, PXE patients may be stabilized or improved.

[0221] In some aspects, the present invention relates to the use of IP4-4,6 substituted derivative compounds of formula I of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53) or pharmaceutical compositions for treating diseases and / or conditions associated with ectopic calcification or its consequences, inhibiting the progression of diseases and / or conditions associated with ectopic calcification or its consequences, and preventing diseases and / or conditions associated with ectopic calcification or its consequences in subjects in need thereof, wherein (i) a therapeutically effective amount of IP4-4,6 substituted derivatives or pharmaceutical compositions of the present invention is administered to the subject and (ii) the disease and / or condition is selected from: angina pectoris (chronic stable angina), calcific aortic stenosis, calcisensitivity, cardiovascular disease in CKD patients, critical limb ischemia, systemic arterial calcification in infancy, pseudogout, primary hyperoxaluria, and pseudoxanthoma elasticum. In some aspects, the IP4-4,6 substituted derivative is a compound of formula II to XIV or any combination thereof. In some aspects, the IP4-4,6 substituted derivative is Compound 1, Compound 3, Compound 6, Compound 27, or any combination thereof.

[0222] In some aspects, the present invention relates to a method for treating ectopic calcification or its consequences, inhibiting the progression of ectopic calcification or its consequences and preventing ectopic calcification or its consequences in a subject in need thereof, comprising administering a therapeutically effective amount of IP4-4,6 substituted derivatives or pharmaceutical compositions of the present invention. In some aspects, IP4-4,6 substituted derivatives of formula II and VII or any combination thereof are administered to the subject. In some further aspects, Compound 1, Compound 3, Compound 6 and Compound 27 or any combination thereof are administered to the subject.

[0223] In some aspects, the result of ectopic calcification is, for example, (i) functional complications, (ii) pain, (iii) nutritional complications, (iv) infection, or (v) combinations thereof. In some aspects, functional complications are, for example, limited range of motion and / or joint function. In some aspects, nutritional complications are, for example, ischemia and / or injury. In some aspects, injury is, for example, necrosis of the skin and / or subcutaneous tissue.

[0224] In some aspects, the dose of the IP4-4,6 substituted derivative or pharmaceutical composition of the present invention administered to a subject in need thereof reduces the damage, for example, as determined by the Bates-Jensen wound assessment tool or other methods known in the art (Bates-Jensen B, Decubitus 1992; 5 (6): 20-28). In some aspects, the damage reduction includes, for example, a reduction in the severity of the damage, a reduction in the size of the damage, and a shortened duration of the damage, or a combination thereof. In some aspects, the dose of the IP4-4,6 substituted derivative or pharmaceutical composition of the present invention administered to a subject in need thereof improves the healing of the damage. In some aspects, the IP4-4,6 substituted derivative or pharmaceutical composition of the present invention administered to a subject in need thereof reduces pain. In some aspects, the subject suffers from renal failure. In some aspects, the subject is undergoing hemodialysis. In some aspects, the subject is a human.

[0225] In some aspects, the IP4-4,6 substituted derivatives or pharmaceutical compositions of the present invention administered to a subject in need thereof improve overall wound quality of life (QoL), as determined using a validated wound-related QoL questionnaire or other methods known in the art (Augustin M et al., Int Wound J. 2017; 14(6): 1299-1304). In some aspects, the subject suffers from renal failure. In some aspects, the subject is undergoing hemodialysis. In some aspects, the subject is a human.

[0226] Renal failure, also known as renal injury or kidney disease, is a disorder that results in a progressive loss of renal function with an associated decrease in the glomerular filtration rate (GFR) or GFR index. Renal injury, coupled with treatment of the disease, results in hypercalcemia and hyperphosphatemia. Hypercalcemia and hyperphosphatemia may contribute to cardiovascular calcification, but deficiencies in inhibitory factors (e.g., matrix Gla protein, osteopontin, fetuin, or vitamin K) or imbalances in promoting factors (e.g., vitamin D, FGF23, inflammatory cytokines, lipid deposition, apoptotic bodies, nuclear complexes) may delay or accelerate this process. Patients with renal impairment are often described as CKD-MBD (chronic kidney disease-mineral bone disease) patients because altered renal function triggers a cascade of effects that also affect bone remodeling.

[0227] In some aspects, the IP4-4,6 substituted derivatives and pharmaceutical compositions of the present invention can be used to treat some of the diseases and / or conditions listed above in patients with renal failure, inhibit the progression of some of the diseases and / or conditions listed above in patients with ectopic calcification or its results, and prevent some of the diseases and / or conditions listed above in patients with ectopic calcification or its results. In some aspects, the disease and / or condition associated with ectopic calcification or its consequences is a renal failure-related disease. In some aspects, patients with renal failure are undergoing dialysis. In some aspects, IP4-4,6 substituted derivatives and pharmaceutical compositions of the present invention are administered to patients with renal failure by intravenous infusion. In some aspects, intravenous infusion is performed using a dialysis device. In some aspects, IP4-4,6 substituted derivatives are compounds of formula II or XIV or any combination thereof. In some aspects, IP4-4,6 substituted derivatives are compound 1, compound 3, compound 6, compound 27 or any combination thereof. In some aspects, a therapeutically effective amount of an IP4-4,6 substituted derivative of the invention is administered to a patient with renal failure.

[0228] In some aspects, the IP4-4,6 substituted derivatives of the present invention can be used in dialysates, for example, during hemodialysis. Therefore, the present invention also provides a dialysate (e.g., a hemodialysate) comprising an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53), a pharmaceutically acceptable salt thereof, or any combination thereof, wherein the IP4-4,6 substituted derivative, a pharmaceutically acceptable salt thereof, or a combination thereof is administered to a subject in need thereof to effectively treat, inhibit, and prevent the following: (i) ectopic calcification and its consequences or (ii) diseases and / or conditions associated with ectopic calcification or its consequences.

[0229] A. Synthesis of Protected Myo-Inositol Agents, Alkylating Agents or Click Reagents and Activated Acids A.1. Synthesis of Protected Myo-Inositol Agents (1) and (2)

[0230] 1,3,5-O-Methyl-myo-inositol (1): The synthesis of (1) has been described previously in the literature (Martin S et al., J. Org. Chem. 1994; 59(17): 4805-4820).

[0231] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methy1-myo-inositol (2): The synthesis of (2) has been described previously in the literature (Kadirvel M et al., Org. Biomol. Chem. 2008; 6(11): 1966-1972).

[0232] A.2. Synthesis of alkylating agents or click reagents

[0233] (((10-bromodecyl)oxy)methyl)benzene (4): The synthesis of (4) was previously described in the literature (Hanbali M. et al., Bioorg. Med. Chem. Letters 2006; 16(10): 2637-2640).

[0234] (((14-Bromotetradecyl)oxy)methyl)benzene (5): The synthesis of (5) was previously described in the literature (Hitosugi S et al., Organic Letters 2014; 16(3):844-847).

[0235] 1-Bromo-7-methoxyheptane (6): 1,7-dibromoheptane (3.27 mL, 19.38 mmol) and sodium methoxide 5N (3.88 mL, 19.38 mmol) were stirred at 40 °C for 4 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, hexane (Hex): ethyl acetate (EtOAc) 10:1) to give 1.4 g (6) (34.5%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.40 (t, J = 6.9 Hz, 2H), 3.36 (t, J = 6.6 Hz, 2H), 3.33 (s, 3H), 1.89–1.82 (m, 2H), 1.60–1.53 (m, 2H), 1.47–1.40 (m, 2H), 1.39–1.32 (m, 4H).

[0236] 4-Methylbenzenesulfonic acid 9-methoxynonyl ester (7)

[0237] Step 1: 9-Methoxynonan-1-ol (3): A mixture of 9-bromononan-1-ol (0.5 g, 2.24 mmol) and sodium methoxide 4N (25 mL, 100 mmol) was stirred at 40 °C for 18 h. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, Hex: EtOAc) 4:1 to give 324 mg (3) (yield 83%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.63 (t, J = 6.6 Hz, 2H), 3.36 (t, J = 6.6 Hz, 2H), 3.33 (s, 3H), 1.59-1.52 (m, 4H), 1.29 (m, 10H).

[0238] Step 2: 9-Methoxynonyl 4-methylbenzenesulfonate (7): To a solution of (3) (1.5 g, 8.61 mmol) in dichloromethane (DCM, 28.7 mL) were added triethylamine (TEA (1.80 mL, 12.91 mmol) and toluenesulfonyl chloride (Ts-Cl, 2.13 g, 11.19 mmol). The reaction mixture was stirred at room temperature for 24 h, then quenched with water and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, Hex:EtOAc 4:1) to give 2.15 g of (7) (76%). 1 H NMR (400MHz, chloroform-d) δ7.78(d,J=8.3Hz,2H),7.34(d,J=8.3Hz,2H),4.01(t,J=6.5Hz,2H),3.35(t,J=6. 6Hz, 2H), 3.32 (s, 3H), 2.45 (s, 3H), 1.61 (dt, J = 8, 6.6Hz, 2H), 1.56-1.51 (m, 2H), 1.32-1.22 (m, 10H).

[0239] 3-Azidopropyl 4-methylbenzenesulfonate (8): To a solution of 3-azidopropan-1-ol (1 g, 9.89 mmol) in DCM (0.2 M) was added TEA (2.07 mL, 14.84 mmol) and Ts-Cl (2.26 g, 11.87 mmol) at 0°C. The reaction mixture was stirred at room temperature for 24 h, then quenched with water and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, Hex:EtOAc 4:1) to give 1.27 g (8) (50%). 1 HNMR (400MHz, chloroform-d) δ7.80 (d, J=8.3Hz, 2H), 7.36 (dd, J=8.3, 0.7Hz, 2H), 4.1 1(t,J=6.3Hz,2H), 3.38(t,J=6.3Hz,2H), 2.46(s,3H), 1.89(p,J=6.3Hz,2H).

[0240] 4-Methylbenzenesulfonic acid 5-azidopentyl ester (10)

[0241] Step 1: 5-Azidopentan-1-ol (9): A solution of 5-bromopentan-1-ol (0.10 mL, 0.89 mmol) and sodium azide (63 mg, 0.98 mmol) in dimethylformamide (DMF, 0.2 M) was stirred at 80 °C for 18 h. The reaction mixture was then quenched with water / EtOAc and washed with brine (3x). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford 57 mg (9) (50%). 1 H NMR (400MHz, chloroform-d) δ3.63 (t, J = 6.8 Hz, 2H), 3.26 (t, J = 6.8 Hz, 2H), 1.61 (p, J = 7.2 Hz, 2H), 1.58 (p, J = 6.8 Hz, 2H), 1.52–1.36 (m, 2H).

[0242] Step 2: 5-Azidopentyl 4-methylbenzenesulfonate (10): To a solution of (9) (54 mg, 0.42 mmol) in DCM (0.2 M) at 0°C, TEA (87 μL, 0.63 mmol) and Ts-Cl (80 mg, 0.42 mmol) were added. The reaction mixture was stirred at room temperature for 60 h, then quenched with water / DCM and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give 92 mg (10) (78%). HPLC-MS (Condition A): rt = 3.00 min; m / z: 284 [M+1] + .

[0243] 4-Methylbenzenesulfonic acid 10-azidodecyl ester (12)

[0244] Step 1: 10-Azidodec-1-ol (11): A solution of 10-bromodecan-1-ol (0.42 mL, 2.11 mmol) and sodium azide (151 mg, 2.32 mmol) in DMF (0.2 M) was stirred at 80 °C for 18 h. The reaction mixture was then quenched with water / EtOAc and washed with brine (3x). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford 388 mg (11) (92%). 1 H NMR (400MHz, chloroform-d) δ3.64(t,J=6.8Hz,2H), 3.25(t,J=6.8Hz,2H), 1.59(p,J=6.8Hz,2H), 1.56(p,J=6.8Hz,2H), 1.44–1.19(m,12H).

[0245] Step 2: 4-methylbenzenesulfonic acid 10-azidodecyl ester (12): To a solution of (11) (388 mg, 1.95 mmol) in DCM (0.2 M) was added TEA (407 μL, 2.92 mmol) and Ts-Cl (371 mg, 1.95 mmol) at 0°C. The reaction mixture was stirred at room temperature for 60 h, then quenched with water / DCM and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, Hex:EtOAc 1:1) to give 234 mg (12) (34%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.79 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 4.02 (t, J = 6.4 Hz, 2H), 3.25 (t, J = 6.8 Hz, 2H), 2.45 (s, 3H), 1.63 (p, J = 6.4 Hz, 2H), 1.59 (p, = 6.8 Hz, 2H), 1.35–1.15 (m, 12H).

[0246] 1-(5-Bromopentyl)-1H-pyrazole (13): To a mixture of 1H-pyrazole (0.78 g, 11.49 mmol) and Cs2CO3 (3.74 mg, 11.49 mmol) in ACN (57 mL) was added 1,5-dibromopentane (1.56 mL, 11.49 mmol). The mixture was stirred at room temperature for 18 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, Hex:EtOAc 1:1) to give 1.1 g (13) (45%). HPLC-MS (Condition A): rt = 3.00 min; m / z: 218, 220 [M+1, M+3] + .

[0247] 1-(5-Bromopentyl)-1H-1,2,4-triazole (14): To a mixture of 1H-1,2,4-triazole (0.79 g, 11.50 mmol) and Cs2CO3 (3.74 mg, 11.50 mmol) in ACN (57 mL) was added 1,5-dibromopentane (1.56 mL, 11.49 mmol). The mixture was stirred at room temperature for 18 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, hexane:EtOAc (1:5) to give 0.55 g (14) (22%). HPLC-MS (Condition A): rt = 2.95 min; m / z: 218, 220 [M, M+2] + .

[0248] Benzyl 3-azidopropanoate (15): To a solution of 3-azidopropionic acid (1.62 mL, 17.38 mmol) in DMF (1 M) was added (bromomethyl)benzene (4.1 mL, 34.8 mmol) followed by dropwise addition of TEA (7.3 mL, 52.1 mmol). After stirring at room temperature for 1 day, the mixture was concentrated, diluted with EtOAc, washed with Na2CO3 (1x), water (3x) and brine (1x), dried over Na2SO4 and filtered. The solvent was removed in vacuo to give 2.90 g (15) (81%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.46–7.29 (m, 5H), 5.17 (s, 2H), 3.60 (t, J = 6.5 Hz, 2H), 2.63 (t, J = 6.5 Hz, 2H).

[0249] 4-Methylbenzenesulfonic acid 6-azidohexyl ester (17)

[0250] Step 1: 6-Azidohexan-1-ol (16): A solution of 6-bromohexan-1-ol (428 μL, 3.27 mmol) and sodium azide (850 mg, 13.08 mmol) in DMF (0.8 M) was stirred at 80 °C for 18 h. The reaction mixture was then quenched with water / EtOAc and washed with brine (3x). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give 470 mg (16) (>99%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.65 (t, J = 6.8 Hz, 2H), 3.27 (t, J = 6.8 Hz, 2H), 1.70–1.56 (m, 4H), 1.40 (m, 4H).

[0251] Step 2: 6-azidohexyl 4-methylbenzenesulfonate (17): p-Ts-Cl (720 mg, 3.78 mmol) was added to a solution of (16) (515 mg, 3.60 mmol) and TEA (1.5 mL, 10.79 mmol) in anhydrous DCM (0.6 M) at 0°C. The reaction mixture was stirred at room temperature overnight. It was diluted with EtOAc and washed with 10% NaHSO4 aqueous solution. The aqueous phase was extracted with EtOAc (3x). The combined layers were washed with saturated NaHCO3 aqueous solution and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, Hex:EtOAc 6:1) to give 666 mg (17) (62%). 1HNMR (400 MHz, CHLOROFORM-d) δ7.79 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 4.03 (t, J=6.4 Hz, 2H), 3.23 (t, J=6.8 Hz, 2H), 2.45 (s, 3H), 1.66 (p, J=6.4 Hz, 2H), 1.55 (p, J=6.4 Hz, 2H), 1.41–1.18 (m, 4H).

[0252] 4-Methylbenzenesulfonic acid 4-azidobutyl ester (19)

[0253] Step 1: 4-Azidobutan-1-ol (18): A solution of 4-bromobutan-1-ol (298 μL, 3.27 mmol) and sodium azide (850 mg, 13.08 mmol) in DMF (0.8 M) was stirred at 80 °C for 18 h. The reaction mixture was then quenched with water / EtOAc and washed with brine (3x). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give 213 mg (18) (56%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.69 (t, J = 5.9 Hz, 2H), 3.33 (t, J = 6.4 Hz, 2H), 1.76–1.59 (m, 4H).

[0254] Step 2: 4-Azidobutyl 4-methylbenzenesulfonate (19): Ts-Cl (370 mg, 1.94 mmol) was added to a solution of (18) (213 mg, 1.85 mmol) and TEA (774 μL, 5.55 mmol) in anhydrous DCM (0.6 M) at 0°C. The reaction mixture was stirred at room temperature overnight. It was diluted with EtOAc and washed with 10% aqueous NaHCO3. The aqueous phase was extracted with EtOAc (3x). The combined layers were dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, Hex:EtOAc 6:1) to give 271 mg (19) (54%). 1 H NMR (400MHz, chloroform-d) δ7.79 (d, J = 8Hz, 2H), 7.36 (d, J = 8Hz, 2H), 4.06 (td, J = 6.1, 0.8 Hz, 2H), 3.26 (t, J = 6.6 Hz, 2H), 2.46 (s, 3H), 1.81–1.68 (m, 2H), 1.68–1.60 (m, 2H).

[0255] 1-(4-(2-Chloroethyl)piperazin-1-yl)ethanone (20): To a solution of 1-(4-(2-hydroxyethyl)piperazin-1-yl)ethanone (1.74 g, 10.10 mmol) in DCM (0.2 M) at 0 °C was added TEA (2.1 mL, 15.15 mmol) and Ts-Cl (2.31 g, 12.12 mmol). The reaction mixture was stirred at room temperature for 72 h and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, DCM:MeOH 95:5) to give 1.28 g (20) (66%). HPLC-MS (Condition A): rt = 0.24 min; m / z: 191, 193 [M, M+2] + .

[0256] 2-Cyclopropylethyl 4-methylbenzenesulfonate (21): To a solution of 2-cyclopropylethanol (3 mL, 34.0 mmol) in DCM (85 mL) was added TEA (7.10 mL, 50.9 mmol) and Ts-Cl (7.77 g, 40.8 mmol) and the resulting mixture was stirred for 18 h. Water was added to the reaction mixture and extracted with DCM (2x). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hex-EtOAc, 4:1) to give 6.23 g (21) (76%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.78 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 4.06 (t, J = 6.8 Hz, 2H), 2.43 (s, 3H), 1.51 (q, J = 6.8 Hz, 2H), 0.63 (m, 1H), 0.38 (ddd, J = 8, 6, 4 Hz, 2H), -0.01 (dt, J = 6, 4 Hz, 2H).

[0257] 2-Cyclopentylethyl 4-methylbenzenesulfonate (22): To a solution of 2-cyclopentylethanol (1.09 mL, 8.76 mmol) in DCM (22 mL) was added TEA (1.83 mL, 13.1 mmol) and Ts-Cl (2.00 g, 10.5 mmol), and the resulting mixture was stirred for 18 h. Water was added to the reaction mixture and extracted with DCM (2x). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hex-EtOAc, 4:1) to give 1.53 g (22) (65%). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.81 (d, J = 8 Hz, 2H), 7.37 (d, J = 8 Hz, 2H), 4.06 (t, J = 6.7 Hz, 2H), 2.47 (s, 3H), 1.89–1.76 (m, 1H), 1.76–1.43 (m, 8H), 1.10–0.99 (m, 2H).

[0258] 3-(4-Methoxyphenyl)propyl 4-methylbenzenesulfonate (23): To a solution of 3-(4-methoxyphenyl)propan-1-ol (0.96 mL, 6.02 mmol) in DCM (15 mL) was added TEA (1.26 mL, 9.02 mmol) and Ts-Cl (1.38 g, 7.22 mmol), and the resulting mixture was stirred for 18 h. Water was added to the reaction mixture and extracted with DCM (2x). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hex-EtOAc, 4:1) to give 1.59 g (23) (82%). 1 H NMR (400MHz, chloroform-d) δ7.81(d,J=8Hz,2H),7.37(d,J=8Hz,2H),7.00(d,J=8.6Hz,2H),6.80(d,J=8.6Hz,2H),4.0 4(t,J=6Hz,2H),3.80(s,3H),2.61(dd,J=8.2,6.8Hz,2H),2.48(s,3H),2.03–1.86(ddt,J=8.2,6.8,6Hz,2H).

[0259] 3-(3-(trifluoromethyl)phenyl)propyl 4-methylbenzenesulfonate (24): To a solution of 3-(3-(trifluoromethyl)phenyl)propan-1-ol (0.91 mL, 4.90 mmol) in DCM (12 mL) was added TEA (1.02 mL, 7.35 mmol) and Ts-Cl (1.12 g, 5.88 mmol) and the resulting mixture was stirred for 18 h. Water was added to the reaction mixture and extracted with DCM (2x). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hex-EtOAc, 4:1) to give 1.53 g (24) (87%). 1H NMR (400MHz, chloroform-d) δ7.63(d,J=8.5Hz,2H),7.28(d,J=7.8Hz,1H),7.21-7.16(m.2H),7.19(d,J=8.5Hz,2H),7.12 (,J=7.8Hz,1H),3.88(t,J=6.2Hz,2H),2.56(dd,8.0,7.6Hz,2H),2.29(s,3H),1.81(ddt,J=8.0,7.6,6.2Hz,2H).

[0260] 3-(p-Tolyl)propyl 4-methylbenzenesulfonate (25): To a solution of 3-(p-tolyl)propan-1-ol (1 g, 6.66 mmol) in DCM (17 mL) was added TEA (1.39 mL, 9.99 mmol) and Ts-Cl (1.52 g, 7.99 mmol), and the resulting mixture was stirred for 18 h. Water was added to the reaction mixture and extracted with DCM (2x). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hex-EtOAc, 4:1) to give 1.85 g (25) (87%). 1 H NMR (400MHz, chloroform-d) δ7.81(d,J=8.0Hz,2H),7.37(d,J=8.0Hz,2H),7.07(d,J=8.0Hz,2H),6.98(d,J=8.0Hz ,2H),4.05(t,J=6.4Hz,2H),2.62(t,J=7.5Hz,2H),2.48(s,3H),2.32(s,3H),1.95(tt,J=7.5,6.4Hz,2H).

[0261] 4-Methylbenzenesulfonic acid 19-methoxynonadeca-10-yn-1-yl ester (31)

[0262] Step 1: 2-((9-Bromononyl)oxy)tetrahydro-2H-pyran (26): To a solution of 9-bromononan-1-ol (6.17 g, 27.6 mmol) and 2,3-dihydro-2H-pyran (3.78 mL, 23 mmol) was added p-TSA (105 mg, 0.55 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with Na2CO3 1N, extracted with ether (2x), dried over Na2SO4, filtered and the solvent removed in vacuo. The filtrate was concentrated and purified by column chromatography (0 to 5% EtOAc in Hex) to give 6.31 g (26) (74%). 1H NMR (400MHz, chloroform-d) δ4.56 (dd, J = 4.3, 2.7Hz, 1H), 3.85 (td, J = 7.5, 3.8Hz, 1H), 3.71 (dt, J = 9.6, 6.9Hz, 1H), 3.52–3.32 (m, 4H), 1.88-1.24 (m, 20H).

[0263] Step 2: Methanesulfonic acid dec-9-yn-1-yl ester (27): To a stirred solution of dec-9-yn-1-ol (3.45 mL, 19.5 mmol) in THF (56 mL) was added TEA (3.52 mL, 25.3 mmol) and methanesulfonyl chloride (1.97 mL, 25.3 mmol) dropwise at 0°C under nitrogen atmosphere. The reaction was kept stirring at room temperature for 18 h. The solvent was evaporated; water was added to the reaction mixture and then extracted with DCM. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give 4.45 g (27) (98%). HPLC-MS (Condition A): rt = 3.58 min.

[0264] Step 3: 10-Methoxydec-1-yne (28): To a stirred solution of 5M sodium methoxide in MeOH was added (27) (4.45 g, 19.1 mmol) and kept stirring at 45°C for 18 h. The suspension was then dissolved in water and extracted with Et2O (2x). The organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was purified by column chromatography (5% EtOAc in Hex) to afford (28) (2.58 g, 80%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.34 (t, J = 5.2 Hz, 2H), 3.31 (s, 3H), 2.16 (td, J = 7.2, 2.1 Hz, 2H), 1.91 (t, J = 3.2 Hz, 1H), 1.53-1.48 (m, 4H), 1.40-1.27 (m, 8H).

[0265] Step 4: 2-((19-methoxynadeca-10-yn-1-yl)oxy)tetrahydro-2H-pyran (29): To a solution of (28) (4 g, 23.8 mmol) in 30 mL THF and 25 mL HMPA cooled at -40°C was slowly added n-BuLi (15.5 mL, 24.8 mmol), followed by stirring at the same temperature for 30 minutes and further stirring at 0°C for 30 minutes. After cooling to -20°C, a solution of (26) (6.09 g, 19.81 mmol) in 25 mL HMPA was slowly added. After stirring at the same temperature for 10 minutes, the temperature was raised to room temperature. Stirring was carried out at the same temperature for 18 hours. Under ice cooling (at 4°C), 10% aqueous HCl solution was added and extracted with tBuMeO (3x). The ether layer was washed with saturated brine and further dried over anhydrous MgSO4. After filtration, the solvent was distilled off under reduced pressure to obtain a yellow oil. The residue was purified by column chromatography using EtOAc / Hex (1:20) to afford (29) (2.36 g, 30%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.55 (dd, J = 4.4, 2.8 Hz, 1H), 3.86-3.74 (m, 1H) 3.70 (dt, J = 9.6, 6.8 Hz, 1H), 3.52-3.46 (m, 1H), 3.39-3.33 (m, 3H), 3.31 (s, 3H), 2.11 (td, J = 7.2, 2.1 Hz, 2H), 1.86-1.78 (m, 1H), 1.74-1.65 (m, 1H), 1.53-1.26 (m, 31H), 0.86-0.83 (m, 1H).

[0266] Step 5: 19-methoxy nonadeca-10-yn-1-ol (30): To a solution of (29) (2.36 g, 6 mmol) in MeOH (10 mL) was added p-TSA (68 mg, 0.36 mmol) portionwise. The resulting solution was stirred at 60 °C for 16 h and then concentrated in vacuo. The residue was dissolved in saturated aqueous NaHCO3 and extracted with tBuMeO (2x). The combined organic extracts were washed with brine solution and dried over Na2SO4. No further purification was required to afford 1.32 g (30) (71%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.62 (t, J = 6.6 Hz, 2H), 3.34 (t, J = 6.7 Hz, 2H), 3.31 (s, 3H), 2.15–2.09 (m, 4H), 1.54 (m, 6H), 1.50–1.40 (m, 5H), 1.40–1.22 (m, 16H).

[0267] Step 6: 4-Methylbenzenesulfonic acid 19-methoxynadeca-10-yn-1-yl ester (31): To a solution of (30) (1.32 g, 4.25 mmol) in THF (8.5 mL) was added Ts-Cl (973 mg, 5.10 mmol) and NaOH 5M (1.020 mL, 5.10 mmol) and the obtained mixture was stirred for 18 h. Water was added to the reaction mixture and extracted with tBuMeO (2x). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hex-EtOAc, 6:1) to afford 1.69 g (31) (86%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 7.65 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 3.87 (t, J = 6.5 Hz, 2H), 3.22 (t, J = 6.7 Hz, 2H), 3.18 (s, 3H), 2.31 (s, 3H), 2.00-1.96 (m, 4H), 1.52-1.45 (m, 2H), 1.44-1.38 (m, 2H), 1.34-1.27 (m, 4H), 1.27-1.05 (m, 18H).

[0268] A.3. Activated acid synthesis

[0269] Benzyl (2,5-dioxopyrrolidin-1-yl)pentanedioate (32): To a solution of 5-(benzyloxy)-5-oxopentanoic acid (285 mg, 1.28 mmol) and (2,5-dioxopyrrolidin-1-yl) carbonate (600 mg, 2.34 mmol) in DCM (0.05 M) was added TEA (357 μL, 2.56 mmol). The reaction mixture was stirred at room temperature for 24 h, then quenched with water and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, Hex:EtOAc 1:1) to give 254 mg (32) (64%). HPLC-MS (Condition B): rt = 2.55 min; m / z: 320 [M+1] + ,342[M+23] + .

[0270] Thiophene-2-carboxylic acid 2,5-dioxopyrrolidin-1-yl ester (33): To a solution of thiophene-2-carboxylic acid (300 mg, 2.34 mmol) and di(N-succinimidyl) carbonate (600 mg, 2.34 mmol) in DCM (4 mL) was added TEA (653 μL, 4.68 mmol). The mixture was stirred at room temperature for 18 h. Water was added to the reaction mixture and extracted with DCM (2x). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was used without further purification. 1 HNMR (400 MHz, chloroform-d) δ 8.06 (dd, J = 4.8, 0.8 Hz, 1H), 7.80 (dd, J = 4.8, 0.8 Hz, 1H), 7.23 (dd, J = 4.8 Hz, 1H), 2.88 (br, 4H).

[0271] B. General Procedures

[0272] B.1. Alkylation Procedure

[0273] Procedure A: To a solution of (2) (1 eq) in DMF (0.2 M) was added NaH (2.15 eq) at 0°C. When the addition was complete, the mixture was stirred at room temperature for 5 minutes. Finally, the alkylating agent was added. The reaction was allowed to stir overnight, then quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel) to give the pure compound.

[0274] Procedure B: To a solution of (2) (1 eq) in DMF (0.2 M) was added LiH at 0°C. When the addition was complete, the mixture was stirred at room temperature for 5 minutes. Finally, an alkylating agent was added. Depending on the alkylating agent, the reaction was stirred for different times at different temperatures, then quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel) to give the pure compound.

[0275] B.2. Hydrolysis procedure

[0276] Procedure C: Intermediate (II), (V), (VIII), (XI) or (XIII) (1 eq) was dissolved in a mixture of methanol / water / DCM / trifluoroacetic acid (3:1:1:1, 0.1 M) and the solution was stirred at room temperature overnight. Finally, the solvent and excess TFA were removed under vacuum to give the desired compound.

[0277] Procedure D: Intermediate (II), (V), (VIII), (XI) or (XIII) (1 eq) was dissolved in a mixture of methanol / water / DCM / trifluoroacetic acid (3:1:1:1, 0.1 M) and the solution was stirred at room temperature overnight. Then, the solvent and excess TFA were removed under vacuum. Finally, the residue was dissolved in methanol (MeOH), treated with IRA-400 resin until the pH was basic, filtered and the solvent was removed under vacuum to give the desired compound.

[0278] Procedure E: To a solution of intermediate (II), (V), (VIII), (XI) or (XIII) (1 eq) in THF (c = 0.1 M) was added a 0.1 M solution of TBAF in THF (1.2 eq). The reaction mixture was stirred at room temperature for 18 h, quenched with water, and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in a mixture of MeOH / water / DCM / TFA (3:1:1:1, 0.1 M) and the solution was stirred at room temperature overnight. The solvent and excess TFA were then removed under vacuum. Finally, the residue was dissolved in methanol (MeOH), treated with IRA-400 resin until the pH was basic, filtered, and the solvent was removed under vacuum to give the desired compound.

[0279] Procedure F: Intermediate (II), (V), (VIII), (XI) or (XIII) (1 eq) was dissolved in a mixture of DCM / TFA (4:1, 0.14 M) and the solution was stirred at room temperature for 1 h. Then, water (final concentration 0.1 M) was added and the reaction mixture was stirred at room temperature for 18 h. Finally, the layers were separated and the aqueous layer was concentrated in vacuo to give the desired compound.

[0280] Procedure S: Intermediate (II), (V), (VIII), (XI) or (XIII) (1 eq) was dissolved in a mixture of MeOH / HCl 1N (10:1, 0.1 M) and the solution was stirred overnight at 60° C. Finally, the solvent and excess HCl were removed under vacuum to give the desired compound.

[0281] B.3. Click reaction procedure

[0282] Procedure K: To a suspension of intermediate (VI) (1 eq) and CuI (0.03 eq) in DCM (0.1 M) was added azide reagent (2 eq), DIPEA (0.07 eq) and AcOH (0.07 eq) in DCM / MeO (1 M). The reaction mixture was stirred at 35 °C for 20 h under inert atmosphere and concentrated in vacuo to give the desired compound.

[0283] Procedure L: To a solution of intermediate (VI) (1 eq), CuSO4·5H2O (0.4 eq) and sodium ascorbate (0.6 eq) in water (0.07 M) was added a solution of azide reagent (2 eq) in THF (0.35 M). The reaction mixture was stirred at room temperature under an inert atmosphere for 20 h, filtered through celite and concentrated in vacuo. The residue was treated with water / DCM. The organic layer was then dried over Na2SO4, filtered and concentrated in vacuo to give the desired compound.

[0284] Procedure M: To a solution of intermediate (IX) (1 eq), CuSO4·5H2O (0.4 eq) and sodium ascorbate (0.6 eq) in mixed water (0.07 M) was added a solution of azide reagent (2 eq) in THF (0.35 M). The reaction mixture was stirred at room temperature under an inert atmosphere for 24 h, filtered through celite and concentrated in vacuo. The residue was dissolved in MeOH, treated with IRA-400 resin until the pH was basic, filtered and the solvent removed in vacuo to give the desired compound.

[0285] B.4. Group transformation procedures

[0286] Procedure N: A mixture of intermediate (VII) (1 eq) and 25% sodium methoxide (3 eq) in MeOH (0.1 M) was stirred at 40° C. for 18 h. The reaction mixture was diluted in water / DCM, the organic layer was dried over Na 2 SO 4 , filtered and concentrated in vacuo to give the desired compound.

[0287] B.5. Azide Reduction Procedure

[0288] Procedure Q: To a solution of intermediate (VIII) (1 eq) in a mixture of THF / water (9:1, 0.08 M) was added DIPEA (3 eq) and PPh3 (2.6 eq). The reaction mixture was stirred at 60 °C for 4 h, then quenched with water and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the desired compound.

[0289] B.6. Amide Formation Procedure

[0290] Procedure P: To a solution of intermediate (XI) or (XII) (1 eq) in DMF (0.1 M) was added TEA (4 eq) and activated acid (2 eq). The reaction mixture was stirred at room temperature for 4 h and concentrated in vacuo. The residue was dissolved in MeOH, treated with IRA-400 resin until the pH was basic, filtered and the solvent was removed in vacuo. Finally, the residue was purified by flash chromatography (silica gel) to give the pure compound.

[0291] B.7. Urea Formation Procedure

[0292] Procedure H: Intermediate (XI) or (XII) (1 eq) was dissolved in MeOH and treated with IRA-400 resin until pH was basic, filtered and the solvent removed in vacuo. The residue was dissolved in EtOH (0.1 M) and the isocyanate reagent (2 eq) was added. The reaction mixture was stirred at 60 °C for 24 h and concentrated in vacuo to give the pure compound.

[0293] B.8. Carbamate Formation Procedure

[0294] Procedure V: Intermediate (XI) or (XII) (1 eq) was dissolved in MeOH and treated with IRA-400 resin until the pH was basic. Then, the solution was filtered and the solvent was removed under vacuum. The residue was dissolved in MeOH (1 M) and dimethyl carbonate (40 eq), tetrabutylammonium bromide (0.1 eq) and L-proline (0.1 eq) were added. The reaction mixture was stirred at 60°C for 48 h and concentrated. The residue was treated with water and DCM and the aqueous layer was concentrated in vacuo. The residue was dissolved in MeOH and treated with DOWEX resin until the pH was acidic. Then, the solution was filtered and the solvent was removed under vacuum to give the desired compound.

[0295] B.9. Phosphorylation or thiophosphorylation procedures

[0296] Procedure G: Intermediate (III), (VI-1) or (IX) (1 eq) was dissolved in DCM (0.02 M) and a solution of tetrazole in ACN (0.43 M) (10-14.4 eq) was added. Stir at room temperature for 30 min. Then, N,N-diethyl-1,5-dihydrobenzo[e][1,3,2]-dioxaphosphinane-3-amine (5-7.2 eq) was added and the mixture was stirred at room temperature overnight. Finally, the reaction mixture was cooled at 0°C and a solution of tert-butyl hydroperoxide in hexane (5.5 M) (15-19.2 eq) was added. The solution was allowed to reach room temperature and stirred for 1 h. The mixture was washed with dilute sodium sulfite and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel) or by crystallization to obtain the pure compound.

[0297] Procedure T: Intermediate (III) or (IX) (1 eq) was dissolved in DCM (0.02 M) and a solution of tetrazole in ACN (0.43 M) (10-14.4 eq) was added. The mixture was stirred at room temperature for 30 min. Then, N,N-diethyl-1,5-dihydrobenzo[e][1,3,2]-dioxaphosphinane-3-amine (5-7.2 eq) was added and the mixture was stirred at room temperature overnight. Finally, pyridine (40 eq) and sulfur (40 eq) were added and the solution was stirred at room temperature for 24 h. The mixture was washed with dilute sodium sulfite and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel) or by crystallization to obtain pure compounds.

[0298] B.10. Phosphate or Phosphorothioate Deprotection Procedure

[0299] Procedure I: The phosphorylated compound (IV) or (X) was dissolved in a mixture of THF / MeOH / water (3:1:1, 0.01 M), followed by the addition of excess palladium hydroxide / carbon. The mixture was placed under a hydrogen atmosphere and stirred at room temperature for 2 days. The mixture was then purged with nitrogen, filtered, and concentrated. The pH of the compound was adjusted to 9-10 by adding dilute aqueous NaOH solution (1 N), and the residue was purified by eluting with water in a Sephadex column (PD-10, G-25-M). All fractions were lyophilized and purified by 1 H-RMN analysis. The fractions containing the product were further purified by elution with water on a reverse phase cartridge ( C18 cartridge, 1 g, Waters Corp., Milford, MA, USA). All fractions were lyophilized and purified by 1 H-RMN analysis.

[0300] Procedure J: The phosphorylated compound (IV) or (X) was dissolved in a mixture of THF / MeOH / water (3:1:1, 0.01 M), and then an excess of palladium hydroxide / carbon was added. The mixture was placed under a hydrogen atmosphere and stirred at room temperature for 2 days. The mixture was then purged with nitrogen, filtered, and concentrated. The pH of the compound was brought to 10 by adding a dilute aqueous NaOH solution (1 N), and the solution was stirred for 24-48 h. Finally, the solution was purified on a dextran gel column (PD-10, G-25-M) by eluting with water. All fractions were lyophilized and purified by 1 H-RMN analysis. The fractions containing the product were further purified by elution with water on a reverse phase cartridge ( C18 cartridge, 1 g, Waters Corp., Milford, MA, USA). All fractions were lyophilized and purified by 1 H-RMN analysis.

[0301] Procedure U: Phosphorylated or thiophosphorylated compound (IV), (IV') or (X) was treated with thiophenol (40 eq), m-cresol (40 eq) in TFA (0.045 M). Then, TBMSBr (40 eq) was slowly added and the mixture was stirred at room temperature for 4 h, quenched with water and extracted with DCM (3x). The aqueous layer was concentrated in vacuo. The pH of the residue was brought to 9-10 by adding water and dilute aqueous NaOH (1 N) and the compound was purified by eluting with water on a Sephadex column (PD-10, G-25-M). All fractions were lyophilized and purified by 1 H-RMN analysis. The fractions containing the product were further purified by elution with water on a reverse phase cartridge ( C18 cartridge, 1 g, Waters Corp., Milford, MA, USA). All fractions were lyophilized and purified by 1 H-RMN analysis.

[0302] C. Synthesis of Intermediates II-XIII

[0303] C.1. Intermediate II

[0304] 4,6-O-bis(5-(benzyloxy)pentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methy1-myo-inositol (II-1): According to the general alkylation procedure A, 202 mg (II-1) (18.3%) was obtained from 1.04 mL (3 eq) (((5-bromopentyl)oxy)methyl)benzene. HPLC-MS (Condition A): rt = 6.30 min; m / z: 657 [M+1] + ,679[M+23] + .

[0305] 4,6-O-Bis(10-(benzyloxy)decyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methy1-myo-inositol (II-2): According to the general alkylation procedure A, 75 mg (II-2) (16%) was obtained from 408 mg (2 eq in 2 mL DMF) of (4). 1H NMR (400MHz, chloroform-d) δ7.39–7.25 (m, 10H), 5.53 (d, J = 1.2Hz, 1H), 4.50 (s, 4H), 4.36 (dt, J=3.6,1.6Hz,1H),4.25(q,J=1.6Hz,1H),4.16(t,J=3.6Hz,2H),4.10(dt,J=3.6,1.6Hz ,2H),3.53(dt,J=8.8,6.4Hz,2H),3.46(t,J=6.8Hz,4H),3.50(dt,J=8.8,6.4Hz,2H),1 .61(p,J=6.8Hz,4H),1.54–1.48(m,4H),1.44–1.16(m,24H),0.94(s,9H),0.14(s,6H).

[0306] 4,6-O-Bis(14-(benzyloxy)tetradecyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methy1-myo-inositol (II-3): According to the general alkylation procedure A, 37 mg (II-3) (10%) was obtained from 312 mg (2 eq in 1.4 mL DMF) of (5). 1 H NMR (400MHz, chloroform-d) δ7.34–7.21(m,10H),5.53(d,J=1.6Hz,1H),4.50(s,4H),4.36( h,J=1.6Hz,1H),4.25(q,J=1.6Hz,1H),4.16(t,J=4Hz,2H),4.11(dd,J=4,1.6Hz,2H ),3.54(dt,8.8,6.4Hz,2H),3.56(t,J=6.8Hz,4H),3.45(dt,J=8.8,6.4Hz,2H),1.6 1(q,J=6.8Hz,4H)1.56-1.59(m,4H),1.30-1.25(m,40H),0.94(s,9H),0.14(s,6H).

[0307] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(3-methoxypropyl)-1,3,5-O-methylene-myo-inositol (II-4): According to the general alkylation procedure A, 232 mg (II-4) (52%) was obtained from 0.55 mL (5 eq) of 1-bromo-3-methoxypropane. HPLC-MS (Condition A): rt = 4.58 min; m / z: 449 [M+1] + ,471[M+23] + .

[0308] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(5-methoxypentyl)-1,3,5-O-methylin-myo-inositol (II-5): According to the general alkylation procedure A, 21 mg (II-5) (7%) was obtained from 241 mg (2.2 eq, in 3 mL DMF) of 1-bromo-5-methoxypentane. HPLC-MS (condition B): rt = 3.80 min; m / z: 505 [M+1] + ,527[M+23] + .

[0309] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(9-methoxynonyl)-1,3,5-O-methy1-myo-inositol (II-6): According to the general alkylation procedure A, 194 mg (II-6) (32%) was obtained from 803 mg (2.5 eq in 1.2 mL DMF) (7). 1 H NMR (400MHz, chloroform-d) δ5.53 (d, J=1.2Hz, 1H), 4.36 (tt, J=3.2, 1.6Hz, 1H), 4.24 (dd,J=3.2,2,4Hz,1H),4.16(t,J=3.6Hz,2H),4.10(dt,J=4,1.6Hz,2H),3.53 (dt,J=8.8,6.4Hz,2H),3.44(dt,J=8.8,6.4Hz,2H),3.36(t,J=6.4Hz,4H),3 .33(s,6H),1.59–1.48(m,8H),1.35–1.26(m,20H),0.94(s,9H),0.14(s,6H).

[0310] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(7-methoxyheptyl)-1,3,5-O-methylin-myo-inositol (II-7): According to the general alkylation procedure A, 398 mg (II-7) (47.6%) was obtained from 780 mg (2.5 eq, in 1.5 mL DMF) (6). HPLC-MS (Condition A): rt = 6.11 min; m / z: 561 [M+1] + ,583[M+23] + .

[0311] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methy1-4,6-O-dipropyl-myo-inositol (II-8): According to the general alkylation procedure A, 79.14 mg (II-8) (21%) was obtained from 481 μL (5 eq) 1-iodopropane. 1H NMR (400MHz, chloroform-d) δ5.52(d,J=1.4Hz,1H),4.37(h,J=1.6Hz,1H),4.26(q,J=1.6Hz,1H),4.16(t,J=4Hz,2H),4.11(dt,J=4,1.6Hz,2 H), 3.51 (dt, J = 8.8, 6.8 Hz, 2H), 3.41 (dt, J = 8.8, 6.8 Hz, 3H), 1.55 (h, J = 6.8 Hz, 4H), 0.93 (s, 9H), 0.90 (t, J = 6.8 Hz, 6H), 0.13 (s, 6H).

[0312] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methy1-4,6-O-dipentyl-myo-inositol (II-9): According to the general alkylation procedure A, 255 mg (II-9) (58%) was obtained from 377 μL (3 eq) 1-bromopentane. HPLC-MS (condition A): rt = 6.38 min; m / z: 445 [M+1] + .

[0313] 2-O-tert-Butyldimethylsilyl-4,6-O-diheptyl-1,3,5-O-methy1-myo-inositol (II-10): According to the general alkylation procedure A, 250 mg (II-10) (70%) was obtained from 560 μL (5 eq) 1-bromoheptane. 1 H NMR (400MHz, chloroform-d) δ5.53(d,J=1.2Hz,1H),4.36(h,J=1.6Hz,1H),4.25(d,J=1.6Hz,1H),4.16(t,J=4Hz,2H),4.11(dt,J=4,1.6Hz,2H),3.54 (dt,J=8.8,6.4Hz,2H),3.44(dt,J=8.8,6.4Hz,2H),1.57–1.49(m,4H),1.37–1.17(m,16H),0.94(s,9H),0.88(t,J=6.8Hz,6H),0.14(s,6H).

[0314] 2-O-tert-Butyldimethylsilyl-4,6-O-didecyl-1,3,5-O-methy1-myo-inositol (II-11): According to the general alkylation procedure A, 272.6 mg (II-11) (57%) was obtained from 511 μL (3 eq) 1-bromodecane. 1H NMR (400MHz, chloroform-d) δ5.53(d,J=1.2Hz,1H),4.37(h,J=1.6Hz,1H),4.25(q,J=1.6Hz,1H),4.16(t,J=4Hz,2H),4.11(dt,J=4.0,1.6Hz,2H),3.5 4(dt,J=8.8,6.4Hz,2H),3.44(dt,J=8.8,6.4Hz,2H),1.55-1.50(m,4H),1.37–1.22(m,28H),0.94(s,9H),0.88(t,J=7.2Hz6H),0.14(s,6H).

[0315] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methy1-4,6-O-ditetradecyl-myo-inositol (II-12): According to the general alkylation procedure A, 350 mg (II-12) (61%) was obtained from 670 μL (3 eq) 1-bromotetradecane. 1 HNMR (400MHz, chloroform-d) δ5.53(d,J=1.6Hz,1H),4.36(h,J=1.6Hz,1H),4.25(q,J=1.6Hz,1H),4.16(t,J=4Hz,2H),4.11(dt,J=4,1.6Hz,2H),3. 54(dt,J=8.8,6.4Hz,2H),3.44(dt,J=8.8,6.4Hz,2H),1.60–1.45(m,4H),1.32-126(m,44H),0.94(s,9H),0.88(t,J=6.8,6H),0.14(s,6H).

[0316] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(5-ethoxycarbonylpentyl)-1,3,5-O-methy-myo-inositol (II-13): According to the general alkylation procedure A, 90 mg (II-13) (23%) was obtained from 351 μL 6-bromohexanoic acid ethyl ester (3 eq). HPLC-MS (condition A): rt = 5.46 min; m / z: 589 [M+1] + ,611[M+23] + .

[0317] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(10-ethoxycarbonyldecyl)-1,3,5-O-methy1-myo-inositol (II-14): According to the general alkylation procedure A, 169 mg (II-14) (34%) was obtained from 455 μL of 11-bromondecanoic acid ethyl ester (2.5 eq). 1H NMR (400MHz, chloroform-d) δ5.50(d,J=1.6Hz,1H),4.34(h,J=1.6Hz,1H),4.23(q,J=1.6Hz,1H),4.15–4.07(m,8H),3.52(dt,J=8.8,6.4Hz,2H),3.4 2(dt,J=8.8,6.4Hz,2H),2.26(t,J=7.2Hz,4H),1.59(p,J=7.2Hz,4H),1.50(p,J=6.4Hz,4H),1.37–1.17(m,30H),0.92(s,9H),0.12(s,6H).

[0318] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methy1-4,6-O-bis(5-(1H-pyrazol-1-yl)pentyl)-myo-inositol (II-15): According to the general alkylation procedure A, 101 mg (II-15) (12%) was obtained from 450 mg (12). HPLC-MS (condition A): rt = 4.56 min; m / z: 578 [M+1] + .

[0319] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methy1-4,6-O-bis(5-(1H-1,2,4-triazol-1-yl)pentyl)-myo-inositol (II-16): According to the general alkylation procedure A, 60 mg (II-16) (6%) was obtained from 500 mg (14). HPLC-MS (condition A): rt = 3.70 min; m / z: 579 [M+1] + .

[0320] 4,6-O-Bis(2-(4-acetylpiperazin-1-yl)ethyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylene-myo-inositol (II-17)

[0321] Step 1: rac-4-O-(2-(4-acetylpiperazin-1-yl)ethyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methy1-myo-inositol (34): According to the general alkylation procedure A, 460 mg (34) (68%) was obtained from 700 mg (2.5 eq in 7.3 mL DMF) (20). HPLC-MS (Condition A): rt = 1.90 min; m / z: 459 [M+1] + .

[0322] Step 2: 4,6-O-bis(2-(4-acetylpiperazin-1-yl)ethyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methy1-myo-inositol (II-17): To a solution of (34) (279 mg, 0.61 mmol) in DMF (0.2 M) at 0°C was added NaH (55.7 mg, 1.39 mmol). When the addition was complete, the mixture was stirred at room temperature for 5 min. Finally, a solution of (20) (309 mg, 1.62 mmol) in DMF (3.2 mL) was added. The reaction was warmed at 90°C, stirred overnight and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, DCM:MeOH 95:5, 1% NH3) to give 89 mg (II-17) (22%). HPLC-MS (Condition A): rt = 1.56 min; m / z: 613 [M+1] + .

[0323] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methy1-4,6-O-bis(4,4,4-trifluorobutyl)-myo-inositol (II-18): According to the general alkylation procedure B, 4.2 mL (3 eq) 4-bromo-1,1,1-trifluorobutane and 934 mg (10 eq) LiH were used to obtain 3.61 g (II-18) (yield 60%). HPLC-MS (condition A): rt = 5.23 min; m / z: 525 [M+1] + .

[0324] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methy1-4,6-O-bis(6,6,6-trifluorohexyl)-myo-inositol (II-19): According to the general alkylation procedure B, 594 mg (II-19) (48%) was obtained from 1.16 g (2.5 eq) 6-bromo-1,1,1-trifluorohexane and 43 mg (2.5 eq) LiH. HPLC-MS (condition A): rt = 6.87 min; m / z: 573 [M+1] + ,595[M+23] + .

[0325] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methy1-4,6-O-bis(4-methylpentyl)-myo-inositol (II-20): According to the general alkylation procedure B, 273 mg (II-20) (20%) was obtained from 1 mL (2.5 eq) 1-bromo-4-methylpentane and 58 mg (2.5 eq) LiH. HPLC-MS (condition A): rt = 5.77 min; m / z: 581 [M+1] + .

[0326] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(19-methoxynonadeca-10-yn-1-yl)-1,3,5-O-methy1-myo-inositol (II-21): According to the general alkylation procedure A, 1.236 g (II-21) (55%) was obtained from 2.93 g (2.5 eq) of (31). 1 H NMR (400MHz, chloroform-d) δ5.53(d,J=1.3Hz,1H),4.36(tt,J=3.6,1.6Hz,1H),4.25(q ,J=1.6Hz,1H),4.16(t,J=3.6Hz,2H),4.11-4.09(m,2H),3.53(dt,J=8.8,6.4H z,2H),3.44(dt,J=8.8,6.4Hz,2H),3.36(t,J=6.8Hz,4H),3.33(s,6H),2.19–2 .07(m,8H),1.55-1.43(m,14H),1.38-1.26(m,38H),0.94(s,9H),0.14(s,6H).

[0327] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(2-cyclopropylethyl)-1,3,5-O-methy-myo-inositol (II-22): According to the general alkylation procedure B, 3.1 g (II-22) (59.6%) was obtained from 6.24 g (2.2 eq) (21) and 213 mg (2.2 eq) LiH. HPLC-MS (Condition A): rt = 5.94 min; 441 [M+1] + ,563[M+23] + .

[0328] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(2-cyclopentylethyl)-1,3,5-O-methy1-myo-inositol (II-23): According to the general alkylation procedure B, 267 mg (II-23) (23.5%) was obtained from 1.53 g (2.5 eq) (22) and 43 mg (2.5 eq) LiH. HPLC-MS (Condition A): rt = 7.22 min; 497 [M+1] + ,519[M+23] + .

[0329] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(3-(4-methoxyphenyl)propyl)-1,3,5-O-methy-myo-inositol (II-24): According to the general alkylation procedure B, 60 mg (II-24) (5%) was obtained from 1.59 g (2.5 eq) (23) and 41 mg (2.5 eq) LiH. HPLC-MS (Condition A): rt = 5.80 min; 601.5 [M+1] + ,623.5[M+23] + .

[0330] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methy1-4,6-O-bis(3-(3-(trifluoromethyl)phenyl)propyl)-myo-inositol (II-25): According to the general alkylation procedure B, 35 mg (II-25) (3%) was obtained from 1.53 g (2.5 eq) (24) and 35 mg (2.5 eq) LiH. HPLC-MS (Condition A): rt = 6.19 min; 677.4 [M+1] + ,699.4[M+23] + .

[0331] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methy1-4,6-O-bis(3-(p-methylphenyl)propyl)-myo-inositol (II-26): According to the general alkylation procedure B, 261 mg (II-26) (19%) was obtained from 1.85 g (2.5 eq) (25) and 50 mg (2.5 eq) LiH. HPLC-MS (Condition A): rt = 6.45 min; 569.4 [M+1] + ,591.4[M+23] + .

[0332] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(3-methoxycarbonylacrylamido)-1,3,5-O-methy-myo-inositol (II-27): According to the general alkylation procedure B, 264 mg (II-27) (15%) was obtained from 2.65 mL (6 eq) methyl 4-bromobutyrate and 288 mg (10 eq) LiH. HPLC-MS (condition A): rt = 4.52 min; 505 [M+1] + .

[0333] C.2. Intermediate III

[0334] 4,6-O-Bis(5-(benzyloxy)pentyl)-myo-inositol (III-1): According to the general hydrolysis procedure C, 163 mg (III-1) (>99%) was obtained from 202 mg (II-1). HPLC-MS (condition A): rt = 3.59 min; m / z: 533 [M+1] + .

[0335] 4,6-O-Bis(5-methoxypentyl)-myo-inositol (III-2): According to the general hydrolysis procedure C, 348 mg (III-2) (>99%) was obtained from 510 mg (II-5). HPLC-MS (condition A): rt = 2.69 min; m / z: 381 [M+1] + ,403[M+23] + .

[0336] 4,6-O-Bis(10-(benzyloxy)decyl)-myo-inositol (III-3): According to the general hydrolysis procedure D, 51 mg (III-3) (80%) was obtained from 75 mg (II-2). 1 H NMR (400MHz, methanol-d4) δ7.33–7.24(m,10H),4.46(s,4H),3.89(t,J=2.4Hz,1H),3.77(td,J=6.8,2.4Hz,4H),3.46(t,J=6.8 Hz,4H)3.40(t,J=8.4Hz,2H),3.38(dd,J=8.4,2.4Hz,2H),3.28(t,J=8.4Hz,1H),1.65-1.52(m,8H),1.26–1.27(m,24H).

[0337] 4,6-O-Bis(14-(benzyloxy)tetradecyl)-myo-inositol (III-4): According to the general hydrolysis procedure D, 14 mg (III-4) (>99%) was obtained from 16.5 mg (II-3). 1 H NMR (400MHz, methanol-d4) δ7.33–7.27(m,10H),4.46(s,4H),3.90(t,J=2.4Hz,1H),3.77(td,J=6.6,2.8Hz,4H),3.48(t,J=6. 6Hz, 4H), 3.41 (t, J = 9.2Hz, 2H), 3.35 (dd, J = 9.2, 2.8Hz, 2H), 3.28–3.23 (m, 1H), 1.63–1.56 (m, 8H), 1.45–1.17 (m, 40H).

[0338] 4,6-O-Bis(5-ethoxycarbonylpentyl)-myo-inositol (III-5): According to the general hydrolysis procedure D, 87.7 mg (III-5) (>99%) was obtained from 114 mg (II-13). HPLC-MS (condition A): rt = 2.95 min; m / z: 465 [M+1] + .

[0339] 4,6-O-Bis(10-ethoxycarbonyldecyl)-myo-inositol (III-6): According to the general hydrolysis procedure D, 129 mg (III-6) (94%) was obtained from 166 mg (II-14). HPLC-MS (condition A): rt = 4.47 min; m / z: 605 [M+1] + .

[0340] 4,6-O-Bis(2-cyclopropylethyl)-myo-inositol (III-7): According to the general hydrolysis procedure S, 2.23 g (III-7) (100%) was obtained from 3.10 g (II-22). HPLC-MS (condition A): rt = 2.82 min; m / z: 317 [M+1] + ,339[M+23] + .

[0341] 4,6-O-Bis(2-cyclopentylethyl)-myo-inositol (III-8): According to the general hydrolysis procedure S, 201 mg (III-8) (>99%) was obtained from 267 mg (II-23). ​​HPLC-MS (condition A): rt = 3.50 min; m / z: 373 [M+1] + ,395[M+23] + .

[0342] 4,6-O-Bis(5-(1H-pyrazol-1-yl)pentyl)-myo-inositol (III-9): According to the general hydrolysis procedure D, 67 mg (III-9) (95%) was obtained from 90 mg (II-15). HPLC-MS (condition A): rt = 2.79 min; m / z: 453 [M+1] + .

[0343] 4,6-O-Bis(5-(1H-1,2,4-triazol-1-yl)pentyl)-myo-inositol (III-10): According to the general hydrolysis procedure D, 15 mg (III-10) (>99%) was obtained from 19 mg (II-16). HPLC-MS (condition A): rt = 2.29 min; m / z: 455 [M+1] + .

[0344] 4,6-O-Bis(2-(4-acetylpiperazin-1-yl)ethyl)-myo-inositol (III-11): According to the general hydrolysis procedure C, 36 mg (III-11) (>99%) was obtained from 45 mg (II-17). HPLC-MS (condition B): rt = 0.23 min; m / z: 489 [M+1] + ,511[M+23] + .

[0345] 4,6-O-bis(3-methoxypropyl)-myo-inositol (III-12): According to the general hydrolysis procedure E, 232 mg (II-4) was used to obtain 23 mg (III-12) (13%). HPLC-MS (condition A): rt = 1.83 min; m / z: 325 [M+1] + .

[0346] 4,6-O-Bis(7-methoxyheptyl)-myo-inositol (III-13): According to the general hydrolysis procedure E, 321 mg (III-13) (>99%) was obtained from 389 mg (II-7). HPLC-MS (condition A): rt = 3.14 min; m / z: 437 [M+1] + .

[0347] 4,6-O-Bis(9-methoxynonyl)-myo-inositol (III-14): According to the general hydrolysis procedure E, 156 mg (III-14) (>99%) was obtained from 194 mg (II-6). HPLC-MS (condition A): rt = 3.76 min; m / z: 493 [M+1] + ,515[M+23] + .

[0348] 4,6-O-dipropyl-myo-inositol (III-15): According to the general hydrolysis procedure E, 26.3 mg (III-15) (49%) was obtained from 79 mg (II-8). HPLC-MS (condition A): rt = 1.85 min; m / z: 265 [M+1] + ,287[M+23] + .

[0349] 4,6-O-dipentyl-myo-inositol (III-16): According to the general hydrolysis procedure E, 107 mg (III-16) (59%) was obtained from 255 mg (II-9). HPLC-MS (condition A): rt = 3.00 min; m / z: 321 [M+1] + .

[0350] 4,6-O-Diheptyl-myo-inositol (III-17): According to the general hydrolysis procedure E, 149 mg (III-17) (77%) was obtained from 250 mg (II-10). HPLC-MS (condition A): rt = 3.89 min; m / z: 377 [M+1] + ,399[M+23] + .

[0351] 4,6-O-didecyl-myo-inositol (III-18): According to the general hydrolysis procedure E, 185 mg (III-18) (84%) was obtained from 272 mg (II-11). HPLC-MS (condition A): rt = 5.36 min; m / z: 461 [M+1] + .

[0352] 4,6-O-ditetradecyl-myo-inositol (III-19): According to the general hydrolysis procedure E, 212 mg (III-19) (69%) was obtained from 360 mg (II-12). 1 H NMR (400MHz, chloroform-d) δ4.19–4.12(m,1H),3.83(dt,J=9.2,6.8Hz,2H),3.65(dt,J=9.2,6.8Hz,2H),3.5 2–3.44(m,4H),3.43–3.36(m,1H),1.59(p,J=6.8Hz,4H),1.33-1.25(m,44H),0.88(t,J=6.8Hz,6H).

[0353] 4,6-O-Bis((1-(2-(benzyloxycarbonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol (III-20): According to the general click reaction procedure K, 983 mg (III-20) (98%) was obtained from 615 mg (15). HPLC-MS (condition A): rt = 3.18 min; m / z: 667 [M+1] + .

[0354] 4,6-O-Bis(3-(4-(2-(benzyloxycarbonyl)ethyl)-1H-1,2,3-triazol-1-yl)propyl)-myo-inositol (III-21): According to the general click reaction procedure M, 98 mg (III-21) (67%) was obtained from 70 mg (IX-3) and 76 mg pent-4-ynoic acid benzyl ester. In this case, flash chromatography was used. HPLC-MS (condition B): rt = 2.37 min; m / z: 723 [M+1] + .

[0355] 4,6-O-bis(3-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)propyl)-myo-inositol (III-22): According to the general click reaction procedure M, 35 mg (III-22) (61%) was obtained from 41 mg (IX-3) and 19 μL 3-methoxyprop-1-yne. HPLC-MS (condition A): rt = 2.32 min; m / z: 487 [M+1] + .

[0356] 4,6-O-bis(4-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)butyl)-myo-inositol (III-23): According to the general click reaction procedure M, 13 mg (III-23) (22%) was obtained from 43 mg (IX-1) and 19 μL 3-methoxyprop-1-yne. HPLC-MS (condition A): rt = 2.40 min; m / z: 515 [M+1] + .

[0357] 4,6-O-bis(5-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-myo-inositol (III-24): According to the general click reaction procedure M, 50 mg (III-24) (64%) was obtained from 58 mg (IX-4) and 12 μL 3-methoxyprop-1-yne. HPLC-MS (condition A): rt = 2.48 min; m / z: 543 [M+1] + .

[0358] 4,6-O-bis(6-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)hexyl)-myo-inositol (III-25): According to the general click reaction procedure M, 321 mg (III-25) (12%) was obtained from 2 g (IX-2) and 1.16 mL 3-methoxyprop-1-yne. HPLC-MS (condition A): rt = 2.65 min; m / z: 571 [M+1] +. Two other compounds were isolated in this reaction: 278 mg of 4,6-O-(6-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)hexyl)-myo-inositol (III-42, 10%) and 454 mg of 4-O-(6-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)hexyl)-6-O-(6-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)hexyl)-myo-inositol (III-43, 17%). III-42: HPLC-MS (Condition A): rt = 2.78 min; m / z: 599 [M+1]. III-43: HPLC-MS (Condition A): rt = 2.70 min; m / z: 585 [M+1].

[0359] 4,6-O-bis((1-(3-methoxypropyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol (III-26): According to the general radical conversion procedure N, 38 mg (III-26) (54%) was obtained from 110 mg (VII-1). HPLC-MS (condition A): rt = 2.42 min; m / z: 487 [M+1] + .

[0360] 4,6-O-bis((1-(6-methoxyhexyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol (III-27): According to the general radical conversion procedure N, 59 mg (III-27) (55%) was obtained from 160 mg (VII-2). HPLC-MS (condition A): rt = 2.88 min; m / z: 571 [M+1] + .

[0361] 4,6-O-bis((3-(4-ethyloxycarbonylbutyramido)propyl))-myo-inositol (III-28): According to the general amide formation procedure P, 57 mg (III-28) (34%) was obtained from 160 mg (XII-1) and 196 mg (32). HPLC-MS (condition B): rt = 1.45 min; m / z: 551 [M+1] + ,573[M+23] + .

[0362] 4,6-O-Bis(3-(4-methoxyphenyl)propyl)-myo-inositol (III-29): According to the general hydrolysis procedure S, 47 mg (III-29) (>99%) was obtained from 60 mg (II-24). HPLC-MS (condition A): rt = 3.31 min; m / z: 477 [M+1] + .

[0363] 4,6-O-Bis(3-(3-(trifluoromethyl)phenyl)propyl)-myo-inositol (III-30): According to the general hydrolysis procedure S, 212 mg (III-30) (84%) was obtained from 262 mg (II-25). HPLC-MS (condition A): rt = 3.88 min; m / z: 553 [M+1] + ,575[M+23] + .

[0364] 4,6-O-Bis(3-(p-methylphenyl)propyl)-myo-inositol (III-31): According to the general hydrolysis procedure S, 57 mg (III-31) (85%) was obtained from 85 mg (II-26). HPLC-MS (condition A): rt = 3.88 min; m / z: 445 [M+1] + ,467[M+23] + .

[0365] 4,6-O-Bis(4,4,4-trifluorobutyl)-myo-inositol (III-32): According to the general hydrolysis procedure S, 2.73 g (III-32) (99%) was obtained from 3.61 g (II-18). HPLC-MS (condition A): rt = 3.01 min; m / z: 401 [M+1] + ,423[M+23] + .

[0366] 4,6-O-Bis(6,6,6-trifluorohexyl)-myo-inositol (III-33): According to the general hydrolysis procedure S, 457 mg (III-33) (98%) was obtained from 594 mg (II-19). HPLC-MS (condition A): rt = 3.40 min; m / z: 457 [M+1] + .

[0367] 4,6-O-Bis(4-methylpentyl)-myo-inositol (III-34): According to the general hydrolysis procedure S, 193 mg (III-34) (96%) was obtained from 273 mg (II-20). HPLC-MS (condition A): rt = 3.40 min; m / z: 349 [M+1] + .

[0368] 4,6-O-Bis(19-methoxynonadeca-10-yn-1-yl)-myo-inositol (III-35): According to the general hydrolysis procedure S, 1.03 g (III-35) (>99%) was obtained from 1.2 g (II-21). HPLC-MS (condition A): rt = 7.18 min; m / z: 765.6 [M+1] +,787.7[M+23] + .

[0369] 4,6-O-Bis(3-(3-phenylureido)propyl)-myo-inositol (III-36): According to the general urea formation procedure H, 90 mg (III-36) (>99%) was obtained from 89 mg (XII-1) and 39 μL phenyl isocyanate. HPLC-MS (condition A): rt = 2.70 min; m / z: 533 [M+1] + .

[0370] 4,6-O-bis(3-(3-cyclopentylureido)propyl)-myo-inositol (III-37): According to the general urea formation procedure H, 80 mg (III-37) (91%) was obtained from 89 mg (XII-1) and 40.2 μL isocyanatocyclopentane. HPLC-MS (condition A): rt = 2.79 min; m / z: 517 [M+1] + .

[0371] 4,6-O-Bis(3-((methoxycarbonyl)amino)propyl)-myo-inositol (III-38): According to the general carbamate formation procedure V, 7 mg (III-38) (12%) was obtained from 74 mg (XII-1). HPLC-MS (Condition B): rt = 0.25 min; m / z: 411 [M+1] + ,433[M+23] + .

[0372] 4,6-O-bis(5-acetamidopentyl)-myo-inositol (III-39): According to the general hydrolysis procedure S, 52 mg (III-39) (72%) was obtained from 93 mg (XIII-1). HPLC-MS (condition B): rt = 0.25 min; m / z: 435 [M+1] + ,457[M+23] + .

[0373] 4,6-O-Bis(5-benzamidopentyl)-myo-inositol (III-40): According to the general hydrolysis procedure S, 35 mg (III-40) (>99%) was obtained from 43 mg (XIII-2). HPLC-MS (condition A): rt = 2.92 min; m / z: 559 [M+1] + .

[0374] 4,6-O-bis(5-(thiophene-2-carboxamido)pentyl)-myo-inositol (III-41): According to the general amide formation procedure P, 158 mg (III-41) (97%) was obtained from 121 mg (XII-2) and 129 mg (33). HPLC-MS (condition B): rt = 2.14 min; m / z: 571 [M+1] + .

[0375] 4,6-O-bis(4-amino-4-oxobutyl)-myo-inositol (III-44): 185 mg of (III-47) was dissolved in 1 mL of ammonia (37% aqueous solution) and the solution was stirred at 60°C for 24 h. Then, the solution was concentrated in vacuo to obtain 98 mg of (III-44) (57%). HPLC-MS (condition A): rt = 2.44 min; m / z: 381 [M+1] + ,403[M+23] + .

[0376] 4,6-O-Bis(5-(3-propylureido)pentyl)-myo-inositol (III-45): According to the general urea formation procedure H, 120 mg (III-45) (91%) was obtained from 89 mg (XII-1) and 50 μL 1-isocyanatopropane. HPLC-MS (Condition A): rt = 2.72 min; m / z: 521 [M+1] + .

[0377] 4,6-O-Bis(5-((methoxycarbonyl)amino)pentyl)-myo-inositol (III-46): According to the general hydrolysis procedure S, 43 mg (III-46) (>99%) was obtained from 54 mg (XIII-3). HPLC-MS (condition A): rt = 2.62 min; m / z: 467 [M+1] + ,490[M+23] + .

[0378] 4,6-O-Bis(3-methoxycarbonylpropyl)-myo-inositol (III-47): According to the general hydrolysis procedure S, 200 mg (III-47) (97%) was obtained from 274 mg (II-27). 1 H NMR (400 MHz, methanol-d4) δ 3.79 (br, 1H), 3.74–3.60 (m, 4H), 3.31–3.25 (m, 4H), 3.22 (s, 6H), 2.26-2.19 (m, 4H), 1.76 (p, J=6.8 Hz, 4H).

[0379] C.3. Intermediates IV and IV'

[0380] 4,6-O-bis(5-(benzyloxy)pentyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-26): According to the general phosphorylation procedure G, 173 mg (IV-26) (44.6%) was obtained from 164 mg (III-1). HPLC-MS (condition A): rt = 4.85 min; m / z: 1261 [M+1] + .

[0381] 4,6-O-bis(10-(benzyloxy)decyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-1): According to the general phosphorylation procedure G, 50 mg (IV-1) (48%) was obtained from 50 mg (III-3). HPLC-MS (condition B): rt = 4.21 min; m / z: 1401 [M+1] + .

[0382] 4,6-O-Bis(14-(benzyloxy)tetradecyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphine-3-yl)-myo-inositol (IV-2): According to the general phosphorylation procedure G, 8 mg (IV-2) (26%) was obtained from 16 mg (III-4).

[0383] 4,6-O-bis(3-methoxypropyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphocycloheptan-3-yl)-myo-inositol (IV-3): According to the general phosphorylation procedure G, 25 mg (IV-3) (21%) was obtained from 37 mg (III-12). HPLC-MS (condition A): rt = 3.78 min; m / z: 1053 [M+1] + .

[0384] 4,6-O-bis(5-methoxypentyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-4): According to the general phosphorylation procedure G, 326 mg (IV-4) (25%) was obtained from 444 mg (III-2). HPLC-MS (condition A): rt = 4.03 min; m / z: 1109 [M+1] + .

[0385] 4,6-O-bis(7-methoxyheptyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-5): According to the general phosphorylation procedure G, 191 mg (IV-5) (19.6%) was obtained from 365 mg (III-13). HPLC-MS (condition A): rt = 4.49 min; m / z: 1165 [M+1] + .

[0386] 4,6-O-bis(7-methoxynonyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-6): According to the general phosphorylation procedure G, 71 mg (IV-6) (13.1%) was obtained from 219 mg (III-14). HPLC-MS (condition A): rt = 4.98 min; m / z: 1221.6 [M+1] + .

[0387] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphocycloheptan-3-yl)-4,6-O-dipropyl-myo-inositol (IV-7): According to the general phosphorylation procedure G, 24 mg (IV-7) (24%) was obtained from 26.3 mg (III-15). HPLC-MS (condition A): rt = 3.99 min; m / z: 993 [M+1] + .

[0388] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-4,6-O-dipentyl-myo-inositol (IV-8): According to the general phosphorylation procedure G, 143 mg (IV-8) (42%) was obtained from 105 mg (III-16). HPLC-MS (condition A): rt = 4.39 min; m / z: 1049 [M+1] + .

[0389] 4,6-O-diheptyl-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-9): According to the general phosphorylation procedure G, 244 mg (IV-9) (55%) was obtained from 150 mg (III-17). HPLC-MS (condition A): rt = 5.04 min; m / z: 1105 [M+1] + .

[0390] 4,6-O-Didecyl-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphocycloheptan-3-yl)-myo-inositol (IV-10): According to the general phosphorylation procedure G, 64 mg (IV-10) (14%) was obtained from 180 mg (III-18). 1 H NMR (400MHz, chloroform-d) δ7.35–7.09(m,16H),5.41–4.97(m,17H),4.43(t,J=8.8Hz,2H),4.37(dt,J=11.2,4.8Hz,1H) ,3.81(t,J=8.8Hz,2H),3.64(t,J=7.2Hz,4H),1.54(p,J=7.2Hz,4H),1.25-1.11(m,28H),0.79(t,J=7.2Hz,6H).

[0391] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-4,6-O-di(tetradecyl)-myo-inositol (IV-11): According to the general phosphorylation procedure G, 193 mg (IV-11) (63%) was obtained from 134 mg (III-19). HPLC-MS (condition B): rt = 5.25 min; m / z: 1301 [M+1] + .

[0392] 4,6-O-bis(5-ethoxycarbonylpentyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-12): According to the general phosphorylation procedure G, 35.5 mg (IV-12) (15%) was obtained from 90 mg (III-5). HPLC-MS (condition A): rt = 4.31 min; m / z: 1193 [M+1] + .

[0393] 4,6-O-bis(10-ethoxycarbonyldecyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-13): According to the general phosphorylation procedure G, 161 mg (IV-13) (57%) was obtained from 129 mg (III-6). HPLC-MS (condition A): rt = 5.38 min; m / z: 1333 [M+1] + .

[0394] 1,2,3,5-O-Tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-4,6-O-bis(5-(1H-pyrazol-1-yl)pentyl)-myo-inositol (IV-14): According to the general phosphorylation procedure G, 26 mg (IV-14) (14%) was obtained from 70 mg (III-9). HPLC-MS (condition A): rt = 3.89 min; m / z: 1182 [M+1] + .

[0395] 1,2,3,5-O-Tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-4,6-O-bis(5-(1H-1,2,4-triazol-1-yl)pentyl)-myo-inositol (IV-15): According to the general phosphorylation procedure G, 8.8 mg (IV-15) was obtained from 19 mg (III-10). HPLC-MS (condition A): rt = 3.46 min; m / z: 1184 [M+1] + .

[0396] 4,6-O-bis((1-(2-(benzyloxycarbonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-16): According to the general phosphorylation procedure G, 445 mg (IV-16) (50%) was obtained from 423 mg (III-20). HPLC-MS (Condition A): rt = 4.16 min; m / z: 1395 [M+1] + .

[0397] 4,6-O-bis((1-(3-methoxypropyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-17): According to the general phosphorylation procedure G, 64 mg (IV-17) (41%) was obtained from 62 mg (III-26). HPLC-MS (condition A): rt = 3.64 min; m / z: 1215 [M+1] + .

[0398] 4,6-O-bis((1-(6-methoxyhexyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-18): According to the general phosphorylation procedure G, 15 mg (IV-18) (11%) was obtained from 59 mg (III-27). HPLC-MS (condition A): rt = 3.95 min; m / z: 1299 [M+1] + .

[0399] 4,6-O-bis(3-(4-(2-(benzyloxycarbonyl)ethyl)-1H-1,2,3-triazol-1-yl)propyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-19): According to the general phosphorylation procedure G, 86 mg (IV-19) (43%) was obtained from 100 mg (III-21). HPLC-MS (Condition B): rt = 3.18 min; m / z: 1451 [M+1] + .

[0400] 4,6-O-bis(3-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)propyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-20): According to the general phosphorylation procedure G, 7.2 mg (IV-20) (7%) was obtained from 40 mg (III-22). HPLC-MS (Condition A): rt = 3.48 min; m / z: 1215 [M+1] + .

[0401] 4,6-O-bis(4-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)butyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-21): According to the general phosphorylation procedure G, 11 mg (IV-21) (23%) was obtained from 20 mg (III-23). ​​HPLC-MS (condition A): rt = 3.53 min; m / z: 1243 [M+1] + .

[0402] 4,6-O-bis(5-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-22): According to the general phosphorylation procedure G, 9.7 mg (IV-22) (8%) was obtained from 54 mg (III-24). HPLC-MS (Condition A): rt = 3.59 min; m / z: 1271 [M+1] + .

[0403] 4,6-O-bis(6-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)hexyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-23): According to the general phosphorylation procedure G, 35.5 mg (IV-23) (18%) was obtained from 85 mg (III-25). HPLC-MS (Condition A): rt = 3.66 min; m / z: 1299 [M+1] + .

[0404] 4,6-O-bis(2-(4-acetylpiperazin-1-yl)ethyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-24): According to the general phosphorylation procedure G, 16 mg (IV-24) (8%) was obtained from 81.5 mg (III-11). HPLC-MS (condition B): rt = 1.92 min; m / z: 1217 [M+1] + .

[0405] 4,6-O-bis((3-(4-ethyloxycarbonylbutyramido)propyl))-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-25): According to the general phosphorylation procedure G, 28 mg (IV-25) (21%) was obtained from 57 mg (III-28). HPLC-MS (condition A): rt = 2.66 min; m / z: 1279 [M+1] + .

[0406] 4,6-O-bis(2-cyclopropylethyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-27): According to the general phosphorylation procedure G, 3 g (IV-27) (39%) was obtained from 2.3 g (III-7). HPLC-MS (condition A): rt = 4.30 min; m / z: 1045 [M+1] + .

[0407] 4,6-O-Bis(2-cyclopentylethyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-28): According to the general phosphorylation procedure G, 164 mg (IV-28) (28%) was obtained from 200 mg (III-8). HPLC-MS (condition A): rt = 4.74 min; m / z: 1101 [M+1] + .

[0408] 4,6-O-bis(3-(4-methoxyphenyl)propyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-29): According to the general phosphorylation procedure G, 36 mg (IV-29) (24%) was obtained from 60 mg (III-29). HPLC-MS (condition A): rt = 4.20 min; m / z: 1206 [M+1] + .

[0409] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphocycloheptan-3-yl)-4,6-O-bis(3-(3-(trifluoromethyl)phenyl)propyl)-myo-inositol (IV-30): According to the general phosphorylation procedure G, 64 mg (IV-30) (13%) was obtained from 214 mg (III-30). HPLC-MS (Condition A): rt = 4.83 min; m / z: 1281 [M+1] + .

[0410] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphocycloheptan-3-yl)-4,6-O-bis(3-(p-methylphenyl)propyl)-myo-inositol (IV-31): According to the general phosphorylation procedure G, 19.1 mg (IV-31) (13%) was obtained from 54.7 mg (III-31). HPLC-MS (condition A): rt = 4.76 min; m / z: 1274 [M+1] + .

[0411] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-4,6-O-bis(4,4,4-trifluorobutyl)-myo-inositol (IV-32): According to the general phosphorylation procedure G, 2.34 g (IV-32) (51%) was obtained from 1.62 g (III-32). HPLC-MS (Condition A): rt = 4.29 min; m / z: 1129 [M+1] + .

[0412] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphocycloheptan-3-yl)-4,6-O-bis(6,6,6-trifluorohexyl)-myo-inositol (IV-33): According to the general phosphorylation procedure G, 414 mg (IV-33) (35%) was obtained from 457 mg (III-33). HPLC-MS (condition A): rt = 4.53 min; m / z: 1185 [M+1] + .

[0413] 4,6-O-bis(4-methylpentyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-34): According to the general phosphorylation procedure G, 168 mg (IV-34) (12%) was obtained from 457 mg (III-34). HPLC-MS (condition A): rt = 4.568 min; m / z: 1077 [M+1] + .

[0414] 4,6-O-bis(19-methoxynonadeca-10-yn-1-yl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-35): According to the general phosphorylation procedure G, 939 mg (IV-35) (45%) was obtained from 1.03 g (III-35). HPLC-MS (condition A): rt = 7.19 min; m / z: 1494 [M+1] + .

[0415] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-4,6-O-bis(3-(3-phenylureido)propyl)-myo-inositol (IV-36): According to the general phosphorylation procedure G, 187 mg (IV-36) (82%) was obtained from 96 mg (III-36). HPLC-MS (Condition A): rt = 4.02 min; m / z: 1262 [M+1] + .

[0416] 4,6-O-bis(3-(3-cyclopentylureido)propyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-37): According to the general phosphorylation procedure G, 181 mg (IV-37) (94%) was obtained from 80 mg (III-37). HPLC-MS (condition A): rt = 3.83 min; m / z: 1245 [M+1] + .

[0417] 4,6-O-bis(3-((methoxycarbonyl)amino)propyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphocycloheptan-3-yl)-myo-inositol (IV-38): According to the general phosphorylation procedure G, 3 mg (IV-38) (11%) was obtained from 10 mg (III-38). HPLC-MS (condition B): rt = 2.90 min; m / z: 1139 [M+1] + .

[0418] 4,6-O-bis(5-acetamidopentyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-39): According to the general phosphorylation procedure G, 110 mg (IV-39) (79%) was obtained from 52 mg (III-39). HPLC-MS (condition B): rt = 2.69 min; m / z: 1163 [M+1] + .

[0419] 4,6-O-bis(5-benzoylaminopentyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphocycloheptan-3-yl)-myo-inositol (IV-40): According to the general phosphorylation procedure G, 38 mg (IV-40) (42%) was obtained from 39 mg (III-40). HPLC-MS (condition A): rt = 4.04 min; m / z: 1288 [M+1] + .

[0420] 1,2,3,5-O-Tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-4,6-O-bis(5-(thiophene-2-carboxamido)pentyl)-myo-inositol (IV-41): According to the general phosphorylation procedure G, 196 mg (IV-41) (54%) was obtained from 158 mg (III-41). HPLC-MS (condition B): rt = 3.13 min; m / z: 1299 [M+1] + .

[0421] 4,6-O-(6-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)hexyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-42): According to the general phosphorylation procedure G, 34 mg (IV-42) (5.5%) was obtained from 278 mg (III-42). HPLC-MS (condition A): rt = 3.86 min; m / z: 1327 [M+1] + .

[0422] 4-O-(6-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)hexyl)-6-O-(6-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)hexyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-43): According to the general phosphorylation procedure G, 101 mg (IV-43) (10%) was obtained from 454 mg (III-43). HPLC-MS (Condition A): rt = 3.76 min; m / z: 1313 [M+1] + .

[0423] 4,6-O-bis(4-amino-4-oxobutyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-44): According to the general phosphorylation procedure G, 179 mg (IV-44) (59%) was obtained from 97.5 mg (III-44). HPLC-MS (condition A): rt = 3.29 min; m / z: 1079.5 [M+1] + .

[0424] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-4,6-O-bis(5-(3-propylureido)pentyl)-myo-inositol (IV-45): According to the general phosphorylation procedure G, 210 mg (IV-45) (73%) was obtained from 120 mg (III-45). HPLC-MS (Condition A): rt = 3.73 min; m / z: 1250.5 [M+1] + .

[0425] 4,6-O-bis(5-((methoxycarbonyl)amino)pentyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-46): According to the general phosphorylation procedure G, 64 mg (IV-46) (50%) was obtained from 50 mg (III-46). HPLC-MS (condition A): rt = 3.86 min; m / z: 1195 [M+1] + .

[0426] 4,6-O-bis(3-methoxycarbonylpropyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (IV-47): According to the general phosphorylation procedure G, 40 mg (IV-47) (19%) was obtained from 70 mg (III-47). HPLC-MS (condition A): rt = 3.77 min; m / z: 1109 [M+1] + .

[0427] 4,6-O-dipropynyl-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphocycloheptan-3-yl)-myo-inositol (IV-48): According to the general phosphorylation procedure G, 4.69 g (IV-48) (32%) was obtained from 3.92 g (VI-1). HPLC-MS (condition A): rt = 3.69 min; m / z: 985 [M+1] + .

[0428] 4,6-O-dipentyl-1,2,3,5-O-tetrakis(3-thio-1,5-dihydrobenzo[e][1,3,2]dioxaphosphocycloheptan-3-yl)-myo-inositol (IV'-1): According to the general phosphorothioation procedure T, 28 mg (IV'-1) (13%) was obtained from 64 mg (III-16). HPLC-MS (condition A): rt = 5.94 min; m / z: 1113 [M+1] + .

[0429] 4,6-O-bis(5-methoxypentyl)-1,2,3,5-O-tetra(3-thio-1,5-dihydrobenzo[e][1,3,2]dioxaphosphocycloheptan-3-yl)-myo-inositol (IV'-2): According to the general phosphorothioation procedure T, 70 mg (IV'-2) (30%) was obtained from 76 mg (III-2). HPLC-MS (Condition A): rt = 5.49 min; m / z: 1173 [M+1] + .

[0430] C.4. Intermediate V

[0431] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methy1-4,6-O-dipropynyl-myo-inositol (V-1): According to the general alkylation procedure A, 1.2 g (V-1) (>99%) was obtained from 1.0 mL of toluene containing 3-bromoprop-1-yne (2.1 eq, 80%). HPLC-MS (condition A): rt = 4.36 min; m / z: 381 [M+1] + .

[0432] C.5. Intermediate VI

[0433] 4,6-O-Dipropynyl-myo-inositol (VI-1): According to the general hydrolysis procedure D, 740 mg (VI-1) (92%) was obtained from 1.2 g (V-1). 1 H NMR (400MHz, methanol-d4) δ4.48(d,J=2.4Hz,4H),3.89(t,J=2.8Hz,1H),3.56(t,J=9.6 Hz,2H),3.39(dd,J=9.6,2.8Hz,2H),3.33(d,J=9.6Hz,1H),2.80(t,J=2.4Hz,2H).

[0434] C.6. Intermediate VII

[0435] 4,6-O-Bis((1-(3-(tosyloxy)propyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol (VII-1): According to the general click reaction procedure L, 110 mg (VII-1) (73%) was obtained from 100 mg (8). HPLC-MS (condition A): rt = 3.30 min; m / z: 767 [M+1] + .

[0436] 4,6-O-Bis((1-(6-(tosyloxy)hexyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol (VII-2): According to General Click Reaction Procedure L, 162 mg (VII-2) (98%) was obtained from 116 mg (17). HPLC-MS (Condition A): rt = 3.71 min.

[0437] C.7. Intermediate VIII

[0438] 4,6-O-bis(3-azidopropyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methy1-myo-inositol (VIII-1): According to the general alkylation procedure A, 249 mg (VIII-1) (22%) was obtained from 1.27 g (2.1 eq in 5.9 mL DMF) (8). HPLC-MS (Condition A): rt = 5.12 min; m / z: 471 [M+1] + .

[0439] 4,6-O-bis(5-azidopentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methy1-myo-inositol (VIII-2): According to the general alkylation procedure A, 900 mg (VIII-2) (51%) was obtained from 2 g (2.1 eq in 8.4 mL DMF) (10). HPLC-MS (Condition A): rt = 5.62 min; m / z: 527 [M+1] + ,549[M+23] + .

[0440] 4,6-O-Bis(10-azidodecyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methy1-myo-inositol (VIII-3): According to the general alkylation procedure A, 57.5 mg (VIII-3) (27%) was obtained from 234 mg (2.05 eq in 2 mL DMF) (12). 1 H NMR (400MHz, chloroform-d) δ5.52(d,J=1.6Hz,1H),4.36(h,J=1.6Hz,1H),4.24(q,J =1.6Hz,1H),4.16(t,J=4Hz,2H),4.10(dt,J=4,1.6Hz,2H),3.53(dt,J=8.8, 6.4Hz,2H),3.45(dt,J=8.8,6.4Hz,2H),3.25(t,J=7.0Hz,4H),1.59(p,J=7 .0Hz,4H),1.57–1.46(m,4H),1.38–1.26(m,24H),0.94(s,9H),0.14(s,6H).

[0441] 4,6-O-bis(4-azidobutyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methy1-myo-inositol (VIII-4): According to the general alkylation procedure A, 17 mg (VIII-4) (7%) was obtained from 245 mg (2 eq in 1.2 mL DMF) (19). HPLC-MS (Condition A): rt = 5.33 min; m / z: 499 [M+1] + ,521[M+1] + .

[0442] 4,6-O-bis(6-azidohexyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methy1-myo-inositol (VIII-5): According to the general alkylation procedure A, 74 mg (VIII-5) (20%) was obtained from 200 mg (2 eq in 1.6 mL DMF) (17). HPLC-MS (Condition A): rt = 5.97 min; m / z: 555 [M+1] + ,577[M+1] + .

[0443] C.8. Intermediate IX

[0444] 4,6-O-Bis(4-azidobutyl)-myo-inositol (IX-1): According to the general hydrolysis procedure C with slight modifications (water treatment), 8 mg (IX-1) (64%) was obtained from 16.7 mg (VIII-4). HPLC-MS (Condition A): rt = 2.76 min; m / z: 375 [M+1] + ,397[M+23] + .

[0445] 4,6-O-Bis(6-azidohexyl)-myo-inositol (IX-2): According to the general hydrolysis procedure C with slight modifications (water treatment), 40 mg (IX-2) (69%) was obtained from 74.7 mg (VIII-5). HPLC-MS (Condition A): rt = 3.29 min; m / z: 431 [M+1] + ,453[M+23] + .

[0446] 4,6-O-Bis(3-azidopropyl)-myo-inositol (IX-3): According to the general hydrolysis procedure E, 174 mg (IX-3) (94%) was obtained from 250 mg (VIII-1). HPLC-MS (Condition A): rt = 2.45 min; m / z: 347 [M+1] + ,369[M+23]+ .

[0447] 4,6-O-Bis(5-azidopentyl)-myo-inositol (IX-4): According to the general hydrolysis procedure D, 6.8 mg (IX-4) (>99%) was obtained from 8.9 mg (VIII-2). HPLC-MS (condition A): rt = 3.06 min; m / z: 403 [M+1] + ,425[M+23] + .

[0448] 4,6-O-Bis(10-azidodecyl)-myo-inositol (IX-5): According to the general hydrolysis procedure D, 47 mg (IX-5) (>99%) was obtained from 57.5 mg (VIII-3). 1 H NMR(400MHz, methanol-d4)δ3.92(t,J=2.6Hz,1H),3.79(m,4H),3.48–3.35(m,4H),3.3 0-3.25(m,5H),1.64(p,J=6.8Hz,4H),1.61(p,J=7.2Hz,4H),1.45–1.27(m,24H).

[0449] C.9. Intermediate X

[0450] 4,6-O-bis(3-azidopropyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (X-1): According to the general phosphorylation procedure G, 148 mg (X-1) (16%) was obtained from 305 mg (IX-3). HPLC-MS (condition A): rt = 4.01 min; m / z: 1075 [M+1] + .

[0451] 4,6-O-bis(5-azidopentyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (X-2): According to the general phosphorylation procedure G, 530 mg (X-2) (63%) was obtained from 300 mg (IX-4). HPLC-MS (condition A): rt = 4.32 min; m / z: 1131 [M+1] + .

[0452] 4,6-O-Bis(10-azidodecyl)-1,2,3,5-O-tetra(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphin-3-yl)-myo-inositol (X-3): According to the general phosphorylation procedure G, 63 mg (X-3) (27%) was obtained from 100 mg (IX-5). HPLC-MS (condition B): rt = 3.86 min; m / z: 1271 [M+1] + .

[0453] C.10. Intermediate XI

[0454] 4,6-O-Bis(3-aminopropyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylin-myo-inositol (XI-1): According to the general azide reduction procedure Q, (XI-1) was obtained from 144 mg of (VIII-1) in sufficient purity to be used further without purification. HPLC-MS (condition B): rt = 2.43 min; m / z: 419 [M+1] + ,441[M+23] + .

[0455] 4,6-O-bis(5-aminopentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylin-myo-inositol (XI-2): According to the general azide reduction procedure Q, 1.4 g (XI-2) (62%) was obtained from 2.5 g (VIII-2) after column purification. HPLC-MS (Condition A): rt = 2.73 min; m / z: 475 [M+1] + ,493[M+23] + .

[0456] C.11. Intermediate XII

[0457] 4,6-O-Bis(3-aminopropyl)-myo-inositol·2TFA (XII-1): According to the general hydrolysis procedure C with slight modifications (water treatment), 160 mg (XII-1) (>99%) was obtained from 128 mg (XI-1). HPLC-MS (Condition B): rt = 0.24 min; m / z: 295 [M+1] + .

[0458] 4,6-O-Bis(5-aminopentyl)-myo-inositol·2HCl (XII-2): According to the general hydrolysis procedure S, 447 mg (XII-2) (54%) was obtained from 1.13 g (XI-2). HPLC-MS (condition B): rt = 0.25 min; m / z: 351 [M+1] + .

[0459] C.12. Intermediate XIII

[0460] 4,6-O-bis(5-acetamidopentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methy1-myo-inositol (XIII-1): According to the general amide formation procedure P, 93 mg (XIII-1) (69%) was obtained from 115 mg (XI-2) and 38 μL acetyl chloride. HPLC-MS (condition A): rt = 3.67 min; m / z: 559 [M+1] + .

[0461] 4,6-O-bis(5-benzamidopentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methy1-myo-inositol (XIII-2): According to the general amide formation procedure P, 57 mg (XIII-2) (32%) was obtained from 125 mg (XI-2) and 67 μL benzoyl chloride. HPLC-MS (condition B): rt = 3.56 min; m / z: 683 [M+1] + .

[0462] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(5-((methoxycarbonyl)amino)pentyl)-1,3,5-O-methylin-myo-inositol (XIII-3): According to the general carbamate formation procedure V, 54 mg (XIII-3) (38%) was obtained from 127 mg (XI-2). HPLC-MS (Condition A): rt = 4.31 min; m / z: 591 [M+1] + .

[0463] D. Characterization of Compounds: Analytical and Spectroscopic Testing

[0464] D.1.NMR

[0465] In the Agilent VNMRS-400 (at 400.10 MHz 1 H and at 162MHz 31 NMR spectra were recorded on 1 In H-NMR, chemical shifts are expressed in ppm relative to TMS, and coupling constants (J) are expressed in Hz. 31 In P NMR, phosphorus NMR spectra are collected without an internal standard. Phosphoric acid is often used as an internal standard, but there is concern that it may affect 1 H-NMR, so it was not used.

[0466] D.2.HPLC-MS

[0467] Condition A: High performance liquid chromatography (HPLC) 2795 Alliance Waters Aquity connected to detector DAD Agilent1100 and detector MS Waters ESI triple cuadrupolo Quattro micro, inject 10 μL of MeOH containing sample. Mass spectra (MS) were analyzed by FIA (flux injection analysis) connected to LCT Premier orthogonal acceleration time-of-flight mass spectrometer, and data were obtained in positive mode by electrospray ionization (ESI). The spectrum was scanned between 50 and 1500 Da, with values ​​taken every 0.2 seconds, and peaks are shown in m / z (% of base peak). Stationary phase: ZORBAX extended-C18 3.5 μm 2.1x 50mm (T a 35℃).

[0468] Table 3: Condition A, mobile phase

[0469] Mobile phase A Mobile phase B 1 Water + 0.05 formic acid Acetonitrile + 0.05 formic acid

[0470] Table 4: Condition A, gradient

[0471]

[0472] Condition B: HPLC-MS was performed using a high performance liquid chromatograph Thermo Ultimate 3000SD (Thermo Scientific Dionex) connected to a photodiode array detector and a mass spectrometer LTQ XL ESI-ion trap (Thermo Scientific); 5 μL-20 μL of sample MeOH (c=0.5 mg / mL) was injected. Mass spectral data were analyzed by electrospray ionization in positive and negative modes and peaks are expressed as m / z (% of base peak). Stationary phase: ZORBAX Extended-C18 3.5 μm 2.1 x 50 mm (T a 35℃).

[0473] Table 5: Condition B, mobile phase

[0474] Mobile phase A Mobile phase B 1 Water + 0.05 formic acid Acetonitrile + 0.05 formic acid

[0475] Table 6: Condition B, gradient

[0476]

[0477]

[0478] Condition C: HPLC-MS was performed using a high performance liquid chromatograph Thermo Ultimate 3000SD (Thermo Scientific Dionex) connected to a photodiode array detector and a mass spectrometer LTQ XL ESI-ion trap (Thermo Scientific); 5 μL-20 μL of sample MeOH (c=0.5 mg / mL) was injected. Mass spectral data were analyzed by electrospray ionization in positive and negative modes and peaks are expressed as m / z (% of base peak). Stationary phase: Xbridge BEH Amide 2.5 μm 4.6x150 mm XP.

[0479] Table 7: Condition C, mobile phase

[0480] Mobile phase A Mobile phase B 1 <![CDATA[H2O + 0.1%DEA+40mM AcONH4]]> AHr

[0481] Table 8: Condition C, gradient

[0482]

[0483] Condition D: HPLC-MS was performed using a high performance liquid chromatograph Thermo Ultimate 3000SD (Thermo Scientific Dionex) connected to a photodiode array detector and a mass spectrometer LTQ XL ESI-ion trap (Thermo Scientific); 5 μL-20 μL of sample MeOH (c=0.5 mg / mL) was injected. Mass spectral data were analyzed by electrospray ionization in positive and negative modes and peaks are expressed as m / z (% of base peak). Stationary phase: ZORBAX Extend-C18 3.5 μm 2.1x50 mm (T a 35℃).

[0484] Table 9: Condition D, mobile phase

[0485] Mobile phase A Mobile phase B 1 <![CDATA[H2O + 0.1%DEA+40mM AcONH4]]> AHr

[0486] Table 10: Condition D, gradient

[0487]

[0488] Condition E: HPLC-MS was performed using a high performance liquid chromatograph Thermo Ultimate 3000SD (Thermo Scientific Dionex) connected to a photodiode array detector and a mass spectrometer LTQ XL ESI-ion trap (Thermo Scientific); 5 μL-20 μL of sample MeOH (c=0.5 mg / mL) was injected. Mass spectral data were analyzed by electrospray ionization in positive and negative modes and peaks are expressed as m / z (% of base peak). Stationary phase: ZORBAX Extend-C18 3.5 μm 2.1x50 mm (T a 30℃).

[0489] Table 11: Condition E, mobile phase

[0490] Mobile phase A Mobile phase B 1 <![CDATA[Water containing 0.1% NH4OH (30%)]]> <![CDATA[ACN containing 0.1% NH4OH (30%)]]>

[0491] Table 12: Condition E, gradient

[0492]

[0493] Example 1

[0494] Synthesis and characterization of 4,6-O-bis(5-hydroxypentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 6)

[0495] According to the general phosphate deprotection procedure I, 38 mg of compound 6 (56.5%) was obtained from 100 mg of (IV-26). 1 HNMR(400MHz,D2O)δ4.87-4.80(m,1H),4.55-4-15(m,3H),4.10-3.80(m,2H),3. 81-3.71(m,4H),3.45(t,J=6.6Hz,4H),1.66–1.55(m,8H),1.40(p,J=7.2Hz,4H). 31 P NMR (162 MHz, D2O) δ 4.85, 4.41, 4.21. HPLC-MS (condition C): rt = 10.06 min; m / z: 673 [M+1] + ,746[M+1+DEA] + ,819[M+1+2DEA] + .

[0496] Example 2

[0497] Synthesis and characterization of 4,6-O-bis(10-hydroxydecyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 7)

[0498] According to the general phosphate deprotection procedure I, 3.15 mg of compound 7 (10.9%) was obtained from 50 mg of (IV-1). 1 HNMR(400MHz,D2O)δ5.08-5.01(m,1H),4.10-4.02(m,3H),3.81-3.75(m,6H) ,3.60(t,J=6.6Hz,4H),1.66-1.60(m,4H),1.56–1.52(m,4H),1.30(br,24H). 31 P NMR (162 MHz, D2O) δ 1.57, -0.15, -1.08. HPLC-MS (condition C): rt = 6.89 min; m / z: 813 [M+1] + ,886[M+1+DEA] + ,959[M+1+2DEA] + .

[0499] Example 3

[0500] Synthesis and characterization of 4,6-O-bis(14-hydroxytetradecyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 8)

[0501] According to the general phosphate deprotection procedure I, 0.6 mg of compound 8 (8%) was obtained from 8.3 mg of (IV-2). 1 H NMR(400MHz,D2O)δ4.25-3.71(m,3H),3.69-3.50(m,6H),3.44(t,J=6.7Hz,4H),1.54-1.29(m,8H),1.15(m,40H). HPLC-MS (Condition D): rt=6.8min; m / z:998[M+1+DEA] + ,1071[M+1+2DEA] + .

[0502] Example 4

[0503] Synthesis and characterization of 4,6-O-bis(3-methoxypropyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 10)

[0504] According to the general phosphate deprotection procedure I, 17.7 mg of compound 10 (99%) was obtained from 23 mg of (IV-3). 1H NMR (400MHz, D2O) δ4.35 (br, 4H), 4.14 (br, 2H), 3.82-3.73 (m, 4H), 3.59 (t, J = 6.7Hz, 4H), 3.36 (s, 6H), 1.90 (q, J = 6.7, Hz, 4H). 31 P NMR (162MHz, D2O) δ3.90 (br). HPLC-MS (condition C): rt=9.96min; m / z:718[M+1+DEA] + ,791[M+1+2DEA] + .

[0505] Example 5

[0506] Synthesis and characterization of 4,6-O-bis(5-methoxypentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 9)

[0507] According to the general phosphate deprotection procedure I, 193 mg of compound 9 (75%) was obtained from 326 mg of (IV-4). 1 H NMR(400MHz,D2O)δ4.47-4.36(m,3H),4.31-4.21(br,1H)4.20-4.13(br,2H),3.74–3. 66(m,4H),3.50(t,J=6.8Hz,4H),3.35(s,6H),1.66-154(m,8H),1.38(p,J=7.6Hz,4H). 31 PNMR(162MHz,D2O)δ7.46(br),6.71(br). HPLC-MS (condition C): rt=9.59min; m / z:774[M+1+DEA] + ,847[M+1+2DEA] + .

[0508] Example 6

[0509] Synthesis and characterization of 4,6-O-bis(7-methoxyheptyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 11)

[0510] According to the general phosphate deprotection procedure I, 29.8 mg of compound 11 was obtained from 169.5 mg of (IV-5) (22%). 1HNMR(400MHz,D2O)δ4.96(d,J=10.6Hz,1H),4.07(t,J=9.2Hz,3H),3.82–3.70(m,6H),3.49(t, J=6.8Hz, 4H), 3.34 (s, 6H), 1.63 (q, J= 7Hz, 4H), 1.59 (q, J= 6.8Hz, 4H), 1.18 (d, J= 4.5Hz, 12H). 31 P NMR (162 MHz, D2O) δ 1.92, -0.04, -1.03. HPLC-MS (condition C): rt = 8.95 min; m / z: 757 [M+1] + ,830[M+1+DEA] + ,903[M+1+2DEA] + .

[0511] Example 7

[0512] Synthesis and characterization of 4,6-O-bis(9-methoxynonyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 12)

[0513] According to the general phosphate deprotection procedure I, 7.65 mg of compound 12 was obtained from 67 mg of (IV-6) (yield 14%). 1 HNMR(400MHz,D2O)δ4.95(d,J=9.8Hz,1H),4.11-4.02(m,3H),3.89-3.71(m ,6H),3.49(t,J=6.8Hz,4H),3.18(s,6H),1.65-1.55(m,8H),1.31(br,20H). 31 P NMR (162MHz, D2O) δ0.84, -0.36, -1.12. HPLC-MS (condition C): rt=8.52min; m / z:813[M+1] + ,886[M+1+DEA] + ,959[M+1+2DEA] + .

[0514] Example 8

[0515] Synthesis and characterization of 4,6-O-dipropyl-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 4)

[0516] According to the general phosphate deprotection procedure I, 3.8 mg of compound 4 (20%) was obtained from 24 mg of (IV-7). 1H NMR (400 MHz, D2O) δ 4.96 (d, J = 10.6 Hz, 1H), 4.20–3.96 (m, 3H), 3.75 (t, J = 7.2 Hz, 4H), 3.75-371 (m, 2H), 1.63 (sextet, J = 7.2 Hz, 4H), 0.90 (t, J = 7.2 Hz, 6H). 31 P NMR (162 MHz, D2O) δ 1.32, -0.26, -1.18. HPLC-MS (condition C): rt = 10.09 min; m / z: 731 [M+1+2DEA] + .

[0517] Example 9

[0518] Synthesis and characterization of 4,6-O-dipentyl-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 1)

[0519] According to the general phosphate deprotection procedure I, 92 mg of compound 1 (83%) was obtained from 143 mg of (IV-8). 1 H NMR (400MHz, D2O) δ5.01-4.91(m,1H),4.10-4.00(m,3H),3.84-3.72(m,6H),1.63(p,J=7.2Hz,4H),1.36-1.27(m,8H),0.88(p,J=7.2Hz,6H). 31 P NMR (162 MHz, D2O) δ 1.32, -0.31, -1.13. HPLC-MS (condition D): rt = 6.16 min; m / z: 714 [M+1] + ,787[M+1+DEA] + ,860[M+1+2DEA] + .

[0520] Example 10

[0521] Synthesis and characterization of 4,6-O-diheptyl-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 5)

[0522] According to the general phosphate deprotection procedure I, 7.8 mg of compound 5 (4%) was obtained from 244 mg of (IV-9). 1 H NMR (400MHz, D2O) δ4.10-4.03 (s, 3H), 3.81-3.71 (m, 6H), 1.68-1.59 (m, 4H), 1.41–1.18 (m, 16H), 0.87 (t, J = 7.2Hz, 6H). 31P NMR (162MHz, D2O) δ1.96, 0.08, -0.89. HPLC-MS (condition C): rt=8.46min; m / z:843[M+1+DEA] + ,916[M+1+2DEA] + .

[0523] Embodiment 11

[0524] Synthesis and characterization of 4,6-O-didecyl-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 2)

[0525] According to the general phosphate deprotection procedure I, 1.6 mg of compound 2 was obtained from 63 mg of (IV-10) (4%). 1 H NMR (400MHz, D2O) δ5.02 (d, J = 8Hz, 1H), 4.15-3.95 (m, 3H), 3.85-3.70 (m, 6H), 1.67-1.60 (m, 4H), 1.35-1.24 (m, 28H), 0.86 (t, J = 6.8Hz, 6H). HPLC-MS (Condition D): rt=6.89min; m / z:781[M+1] + ,854[M+1+DEA] + ,927[M+1+2DEA] + ,1000[M+1+2DEA] + .

[0526] Example 12

[0527] Synthesis and characterization of 4,6-O-di(tetradecyl)-myo-inositol-1,2,3,5-tetra(phosphate) octasodium salt (Compound 3)

[0528] According to the general phosphate deprotection procedure I, 656 mg of compound 3 (66.5%) was obtained from 1.5 g of (IV-11). 1 HNMR (400MHz, D2O) δ4.96 (d, J = 8.8 Hz, 1H), 4.14-4.02 (m, 3H), 3.84-3.67 (m, 6H), 1.70-1.58 (m, 4H), 1.34-1.26 (m, 44H), 0.86 (t, J = 6.8Hz, 6H). 31 P NMR (162 MHz, D2O) δ 4.01, 3.39, 3.02. HPLC-MS (condition D): 966 [M+1] + ,1039[M+1+DEA] + ,1111[M+1+2DEA] + .

[0529] Example 13

[0530] Synthesis and characterization of 4,6-O-bis(3-aminopropyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 13)

[0531] According to the general phosphate deprotection procedure I, 5.6 mg of compound 13 (16.7%) was obtained from 45.6 mg of (X-1). HPLC-MS (condition C): rt = 10.73 min; m / z: 615 [M+1] + ,688[M+1+DEA] + .

[0532] Embodiment 14

[0533] Synthesis and characterization of 4,6-O-bis(5-aminopentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 14)

[0534] According to the general phosphate deprotection procedure I, 11.3 mg of compound 14 (10%) was obtained from 145 mg of (X-2). 1 H NMR (400MHz, D2O) δ4.95 (s, 1H), 4.07-4.05 (m, 3H), 3.94 (m, 2H), 3.84-3.70 (m, 7H), 3.02 (t, J = 6.7Hz, 2H), 1.79–1.47 (m, 12H). 31 P NMR (162 MHz, D2O) δ 1.86, 0.46, 0.15. HPLC-MS (condition C): rt = 10.77 min; m / z: 671 [M+1] + ,744[M+1+DEA] + .

[0535] Embodiment 15

[0536] Synthesis and characterization of 4,6-O-bis(10-aminodecyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 15)

[0537] According to the general phosphate deprotection procedure I, 0.8 mg of compound 15 (2%) was obtained from 57.5 mg of (X-3). 1H NMR(400MHz,D2O)δ4.95(d,J=10.3Hz,1H),4.06(t,J=9.2Hz,3H),3.89–3.67(m,7H), 3.59(t,J=6.8Hz,1H), 2.99(t,J=7.4Hz,2H), 1.76–1.57(m,8H), 1.45–1.19(m,24H). 31 PNMR(162MHz,D2O)δ2.04,-0.05,-1.00. HPLC-MS (condition D): rt=6.48min; m / z:811[M+1] + ,884[M+1+DEA] + ,958[M+1+2DEA] + .

[0538] Example 16

[0539] Synthesis and characterization of 4,6-O-bis(5-(1H-pyrazol-1-yl)pentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 16)

[0540] According to the general phosphate deprotection procedure I, 8.5 mg of compound 16 (29%) was obtained from 36.6 mg of (IV-14). 1 HNMR(400MHz,D2O)δ7.64(d,J=2.4Hz,2H),7.52(br,2H),6.31(t,J=2.4Hz,2H),4.42(m,3H),4.28–4.1 4(m,3H),4.13(t,J=7Hz,4H),3.66(m,4H),1.82(p,J=7.0Hz,4H),1.67-1.49(m,4H),1.42–1.18(m,4H). 31 P NMR (162 MHz, D2O) δ 4.91, 4.21. HPLC-MS (condition C): rt = 9.20 min; m / z: 773 [M+1] + ,846[M+1+DEA] + ,919[M+1+2DEA] + .

[0541] Embodiment 17

[0542] Synthesis and characterization of 4,6-O-bis(5-(1H-1,2,4-triazol-1-yl)pentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 17)

[0543] According to the general phosphate deprotection procedure I, 5.2 mg of compound 17 (74%) was obtained from 8.8 mg of (IV-15). 1 HNMR(400MHz,D2O)δ8.46-8.45(m,2H),8.03-8.01(m,2H),4.32–4.23(m,5H),4.12–3 .88(m,3H),3.85-3.55(m,6H),1.89(m,4H),1.75-1.53(m,4H),1.31(p,J=7.4Hz,4H). HPLC-MS (condition C): rt=9.86min; m / z:776[M+1] + ,849[M+1+DEA] + ,922[M+1+2DEA] + .

[0544] Embodiment 18

[0545] Synthesis and characterization of 4,6-O-bis((1-(2-carboxyethyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) decasodium salt (Compound 31)

[0546] According to the general phosphate deprotection procedure I, 72 mg of compound 31 was obtained from 315 mg of (IV-16) (39%). 1 H NMR(400MHz,D2O)δ8.22(s,2H),5.08(d,J=11.6Hz,2H),5.10–4.97(m,1H),4.99(d,J=11.6Hz ,2H),4.70(t,J=7.2Hz,4H),4.26-4.18(m,3H),3.99(t,J=9.5Hz,2H),2.88(t,J=7.2Hz,4H). 31 P NMR (162 MHz, D2O) δ 1.57, 0.29, -1.00. HPLC-MS (condition C): rt = 10.62 min; m / z: 807 [M+1] + ,880[M+1+DEA] + ,953[M+1+2DEA] + .

[0547] Embodiment 19

[0548] Synthesis and characterization of 4,6-O-bis((1-(3-methoxypropyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 32)

[0549] According to the general phosphate deprotection procedure I, 22 mg of compound 32 (43%) was obtained from 64 mg of (IV-17). 1 H NMR(400MHz,D2O)δ8.40-7.75(br,2H),5.06-4.80(m,5H),4.55-4.44(m,4H ),4.40–3.82(m,5H),3.43(q,J=6.2Hz,4H),3.32(s,6H),2.12-2.10(m,4H). HPLC-MS (condition C): rt=9.56min; m / z:880[M+1+DEA] + .

[0550] Embodiment 20

[0551] Synthesis and characterization of 4,6-O-bis((1-(6-methoxyhexyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 33)

[0552] According to the general phosphate deprotection procedure I, 1.8 mg of compound 33 was obtained from 15 mg of (IV-18) (15%). 1 H NMR(400MHz,D2O)δ8.08(s,2H),4.87(d,J=11.6Hz,2H),4.85–4.75(m,1H),4.81(d,J=11.6Hz,2H),4.27(t,J=7Hz,4H),4.07 -3.90(m,3H),3.83-3.73(m,2H),3.30(t,J=6.8Hz,4H),3.17(s,6H),1.76(p,J=7Hz,4H),1.40(p,J=6.8Hz,4H),1.17(m,8H). HPLC-MS (condition C): rt=8.83min; m / z:891[M+1] + ,964[M+1+DEA] + ,1037[M+1+2DEA] + .

[0553] Embodiment 21

[0554] Synthesis and characterization of 4,6-O-bis(3-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)propyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 36)

[0555] According to the general phosphate deprotection procedure I, 1.7 mg of compound 36 was obtained from 7.2 mg of (IV-20) (28%). 1HNMR(400MHz,D2O)δ8.21(s,2H),5.20(br,1H),4.90-4.61(m,4H),4.61(s, 4H),4.20–3.92(m,5H),3.83-3.70(m,4H),3.39(s,6H),2.27-2.18(m,4H). HPLC-MS (condition C): rt=9.73min; m / z:880[M+1+DEA] + .

[0556] Embodiment 22

[0557] Synthesis and characterization of 4,6-O-bis(4-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)butyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 37)

[0558] According to the general phosphate deprotection procedure I, 1.2 mg of compound 37 (13%) was obtained from 11 mg of (IV-21). 1 H NMR(400MHz,D2O)δ8.08(s,2H),5.20(br,1H),4.61(s,4H),4.55-4.38(m,4H),4.10 –3.85(m,5H),3.83-3.70(m,4H),3.39(s,6H),2.05-1.91(m,4H),1.49-1.70(m,4H). HPLC-MS (condition C): rt=9.59min; m / z:835[M+1] + ,908[M+1+DEA] + .

[0559] Embodiment 23

[0560] Synthesis and characterization of 4,6-O-bis(5-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 38)

[0561] According to the general phosphate deprotection procedure I, 1.4 mg of compound 38 (16%) was obtained from 11 mg of (IV-22). 1H NMR(400MHz,D2O)δ8.07(s,2H),5.05(br,1H),4.61(s,4H),4.45(t,J=7.6Hz,4H),4.03(m,3H),3. 80-3.70(m,6H),3.39(s,6H),1.93(p,J=7.6Hz,4H),1.67(p,J=7.6Hz,4H),1.34(p,J=7.6Hz,4H). HPLC-MS (condition C): rt=9.53min; m / z: 936[M+1+DEA] + .

[0562] Embodiment 24

[0563] Synthesis and characterization of 4,6-O-bis(6-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)hexyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 39)

[0564] According to the general phosphate deprotection procedure I, 10 mg of compound 39 (34%) was obtained from 35.5 mg of (IV-23). 1 HNMR(400MHz,D2O)δ8.04(s,2H),5.30-5.10(br,1H),4.60(s,4H),4.43(t,J=7.1Hz,4H),4.15-3.9 7(m,3H),3.83-3.68(m,6H),3.39(s,6H),1.96-1.86(m,4H),1.67-1.57(m,4H),1.41-1.24(m,8H). HPLC-MS (Condition C): rt=9.24min; m / z: 964[M+1+DEA] + .

[0565] Embodiment 25

[0566] Synthesis and characterization of 4,6-O-bis(2-(4-acetylpiperazin-1-yl)ethyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 34)

[0567] According to the general phosphate deprotection procedure I, 6.2 mg of compound 34 (48%) was obtained from 16 mg of (IV-24). 1 H NMR (400MHz, D2O) δ5.10-5.03(m,1H),4.35–4.25(m,3H),4.11-3.85(m,12H),3.65-3.55(m,6H),3.33–3.14(m,8H),2.18(s,6H). 31P NMR (162 MHz, D2O) δ 1.32, 0.86, 0.70, 0.24. HPLC-MS (condition C): rt = 10.26 min; m / z: 882 [M+1+DEA] + .

[0568] Embodiment 26

[0569] Synthesis and characterization of 4,6-O-bis((3-(4-carboxybutyramido)propyl))-myo-inositol-1,2,3,5-tetrakis(phosphate) decasodium salt (Compound 45)

[0570] According to the general phosphate deprotection procedure I, 4.4 mg of compound 45 (19%) was obtained from 28 mg of (IV-25). 1 H NMR(400MHz,D2O)δ5.29–4.90(br,1H),4.18–3.92(m,3H),3.89-3.77(m,4H) ,3.73-360(m,2H),3.37-3.22(m,4H),2.29-2-17(m,8H),1.87-1.70(m,8H). HPLC-MS (condition C): rt=10.18min; m / z:916[M+1+DEA] + ,989[M+1+2DEA] + .

[0571] Embodiment 27

[0572] Synthesis and characterization of 4,6-O-bis(5-carboxypentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) decasodium salt (Compound 18)

[0573] According to the general phosphate deprotection procedure I, 6.8 mg of compound 18 (23%) was obtained from 35.5 mg of (IV-12). 1 HNMR(400MHz,D2O)δ4.31-4.24(m,3H),4.12-4.08(m,1H),4.01(br,2H),3.58(dt,J=7.6,7.2Hz,2H),3.51( dt,J=7.6,7.2Hz,2H),2.03(t,J=7.6,4H),1.47(p,J=7.2Hz,4H),1.42(p,J=7.6Hz,4H),1.30-1.11(m,4H). 31 P NMR (162 MHz, D2O) δ 4.86, 4.21. HPLC-MS (condition C): rt = 10.37 min; m / z: 802 [M+1] + ,875[M+1+DEA] +,948[M+1+2DEA] + .

[0574] Embodiment 28

[0575] Synthesis and characterization of 4,6-O-bis(10-carboxydecyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) decasodium salt (Compound 19)

[0576] According to the general phosphate deprotection procedure J, 34.6 mg of compound 19 (22.6%) was obtained from 187 mg of (IV-13). 1 HNMR(400MHz,D2O)δ:4.49(d,J=12.4Hz,1H),4.42(br,1H),4.40(br,1H),4.25(d,J=12.4Hz,1H ),4.19(s,2H),3.77–3.58(m,4H),2.16(t,J=7.6Hz,4H),1.66–1.49(m,8H),1.36-1.25(m,24H). 31 P NMR (162MHz, D2O) δ: 4.79, 4.12, 4.00. HPLC-MS (condition D): rt=6.26min; m / z:942[M+1] + ,1015[M+1+DEA] + ,1088[M+1+2DEA] + .

[0577] Embodiment 29

[0578] Synthesis and characterization of 4,6-O-bis(3-(4-(2-carboxyethyl)-1H-1,2,3-triazol-1-yl)propyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) decasodium salt (Compound 35)

[0579] According to the general phosphate deprotection procedure I, 11.8 mg of compound 35 (21%) was obtained from 74 mg of (IV-19). 1 HNMR(400MHz,D2O)δ7.89(s,2H),5.28(br,1H),4.66-4.49(m,4H),4.24-3.86(m,5H) ,3.85–3.55(m,4H),2.94(t,J=7.8Hz,4H),2.54(t,J=7.8Hz,4H),2.24–2.15(m,4H). 31 P NMR (162 MHz, D2O) δ 1.94, 0.53. HPLC-MS (condition C): rt = 10.17 min; m / z: 936 [M+1+DEA] +,1009[M+1+2DEA] + .

[0580] Embodiment 30

[0581] Synthesis and characterization of 4,6-O-bis(2-cyclopropylethyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 28)

[0582] According to the general phosphate deprotection procedure I, 710 mg of compound 28 (68%) was obtained from 1.34 g of (IV-27). 1 HNMR(400MHz,D2O)δ4.51-4.20(br,2H),4.10-3.91(br,2H),3.85-3.63(br,5H) ,1.46-1.41(m,4H),0.72-0.63(m,2H),0.35-0.31(m,4H),0.00(q,J=4.7Hz,4H). 31 P NMR(162MHz,D2O)δ3.79-(-0.54)(br). HPLC-MS (condition C): rt=9.51min; m / z: 637[M+1] + ,710[M+1+DEA] + ,783[M+1+2DEA] + .

[0583] Embodiment 31

[0584] Synthesis and characterization of 4,6-O-bis(2-cyclopentylethyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 29)

[0585] According to the general phosphate deprotection procedure I, 22 mg of compound 29 (17%) was obtained from 164 mg of (IV-28). 1 H NMR(400MHz,D2O)δ4.39-4.19(br,3H),4.11-3.95(br,2H),3.65(q,J=8Hz,2H) ,3.59(q,J=8Hz,2H),1.76–1.59(m,6H),1.56–1.29(m,12H),1.03–0.97(m,4H). 31 P NMR (162 MHz, D2O) δ 4.99-3.20 (br). HPLC-MS (condition C): rt = 8.76 min; m / z: 693 [M+1] + ,766[M+1+DEA] + ,839[M+1+2DEA] + .

[0586] Embodiment 32

[0587] Synthesis and characterization of 4,6-O-bis(3-(4-methoxyphenyl)propyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 43)

[0588] According to the general phosphate deprotection procedure I, 10.8 mg of compound 43 (37%) was obtained from 36 mg of (IV-29). 1 HNMR(400MHz,D2O)δ7.02(d,J=8.4Hz,4H),6.72(d,J=8.4Hz,4H),4.41-4.18(m,4H),4.1 1(br,2H),3.66(s,6H),3.64(t,J=7.2Hz,4H),2.47(t,J=8.0Hz,4H),1.78-1.63(m,4H). 31 PNMR(162MHz,D2O)δ4.29-3.86(br). HPLC-MS (condition C): rt=8.55min; m / z:797[M+1] + ,870[M+1+DEA] + ,943[M+1+2DEA] + .

[0589] Embodiment 33

[0590] Synthesis and characterization of 4,6-O-bis(3-(3-(trifluoromethyl)phenyl)propyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 44)

[0591] According to the general phosphate deprotection procedure I, 11.9 mg of compound 44 (23%) was obtained from 64 mg of (IV-30). 1 HNMR(400MHz,D2O)δ7.42-7.25(m,8H),4.30-4.06(m,5H),3.69(s,4H),2.62(t,J=8.1Hz,4H),1.87-1.70(m,4H). 31 P NMR (162 MHz, D2O) δ 5.09-2.92 (br). HPLC-MS (condition C): rt = 7.84 min; m / z: 873 [M+1] + ,946[M+1+DEA] + ,1019[M+1+2DEA] + .

[0592] Embodiment 34

[0593] Synthesis and characterization of 4,6-O-bis(3-(p-methylphenyl)propyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 42)

[0594] According to the general phosphate deprotection procedure I, 1.1 mg of compound 42 (7%) was obtained from 19 mg of (IV-31). 1 H NMR(400MHz,D2O)δ7.13(d,J=7.4Hz,4H),7.08(d,J=7.4Hz,4H),4.02-3.90(br,3H),3.8 1-3.70(br,4H),3.66-3.57(br,2H),2.57-2.53(m,4H),2.18(s,6H),1.84-1.77(m,4H). HPLC-MS (condition C): rt=8.35min; m / z: 911[M+1+2DEA] + .

[0595] Embodiment 35

[0596] Synthesis and characterization of 4,6-O-bis(4,4,4-trifluorobutyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 22)

[0597] According to the general phosphate deprotection procedure I, 820 mg of compound 22 (44%) was obtained from 2.32 g of (IV-32). 1 HNMR (400MHz, D2O) δ4.84 (d, J = 10.6 Hz, 1H), 3.97-3.90 (m, 3H), 3.74 (t, J = 6.5 Hz, 4H), 3.60 (t, J = 9.6 Hz, 2H), 2.28-2.15 (m, 4H), 1.79-1.72 (m, 4H). 31 P NMR (162 MHz, D2O) δ 1.69, 0.17, -0.92. HPLC-MS (condition C): rt = 8.86 min; m / z: 721 [M+1] + ,794[M+1+DEA] + ,867[M+1+2DEA] + .

[0598] Embodiment 36

[0599] Synthesis and characterization of 4,6-O-bis(6,6,6-trifluorohexyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 23)

[0600] According to the general phosphate deprotection procedure I, 45 mg of compound 23 (22%) was obtained from 248 mg of (IV-33).1 H NMR(400MHz,D2O)δ4.40-3.78(m,5H),3.69–3.56(m,4H),2.13–2.01(m,4H),1.57-1.43(m,8H),1.35-1.28(m,4H). HPLC-MS (condition C): rt=8.27min; m / z:923[M+1+2DEA] + .

[0601] Embodiment 37

[0602] Synthesis and characterization of 4,6-O-bis(4-methylpentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 21)

[0603] According to the general phosphate deprotection procedure I, 4.6 mg of compound 21 (3.5%) was obtained from 167 mg of (IV-34). 1 HNMR(400MHz,D2O)δ4.44-4.34(m,2H),4.25-4.19(m,2H),3.91-3.80(m,1H),3 .72-3.50(m,4H),1.68-1.39(m,6H),1.19-1.04(m,4H),0.76(d,J=6.6Hz,12H). HPLC-MS (condition C): rt=8.74min; m / z:742[M+1+DEA] + ,815[M+1+2DEA] + .

[0604] Embodiment 38

[0605] Synthesis and characterization of 4,6-O-bis(19-methoxynonadeca-10-yn-1-yl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 20)

[0606] According to the general phosphate deprotection procedure I, 4.3 mg of compound 20 (1.3%) was obtained from 410 mg of (III-35). 1 HNMR(400MHz,D2O)δ4.50–4.26(m,3H),4.19-4.02(m,2H),3.70–3.47(m,4 H),3.38-3.26(m,4H),3.22(s,6H),1.49-1.41(m,8H),1.25-1.16(m,60H). 31 P NMR (162MHz, D2O) δ4.04(bs), 3.73(bs).

[0607] Embodiment 39

[0608] Synthesis and characterization of 4,6-O-bis(3-(3-phenylureido)propyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 46)

[0609] According to the general phosphate deprotection procedure I, 6.5 mg of compound 46 (4.3%) was obtained from 187 mg of (IV-36). 1 HNMR (400MHz, D2O) δ7.27-7.20 (m, 8H), 6.98-6.91 (s, 2H), 4.96–4.78 (m, 1H), 4.03-3.83 (m, 3H), 3.82-3.67 (m, 4H), 3.64-3.45 (m, 2H), 3.27-3.07 (m, 4H), 1.72-1.61 (bs, 4H). HPLC-MS (condition C): rt = 8.73 min; m / z: 926 [M+1+DEA] + ,999[M+1+2DEA] + .

[0610] Embodiment 40

[0611] Synthesis and characterization of 4,6-O-bis(3-(3-cyclopentylureido)propyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 47)

[0612] According to the general phosphate deprotection procedure I, 26 mg of compound 47 (17.6%) was obtained from 181 mg of (IV-37). 1 HNMR(400MHz,D2O)δδ4.87-4.73(bs,1H),3.78-3.64(m,5H),3.62-3.52(m,2H),3.14-3.02(m,4H ),1.80-1.71(m,4H),1.65-1.59(m,4H),1.58-1.51(m,4H),1.46-1.39(m,4H),1.32-1.24(m,4H). HPLC-MS (condition C): rt=8.98min; m / z:837[M+1] + ,910[M+1+DEA] + ,983[M+1+2DEA] + .

[0613] Embodiment 41

[0614] Synthesis and characterization of 4,6-O-bis(3-((methoxycarbonyl)amino)propyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 24)

[0615] According to the general phosphate deprotection procedure I, 1.7 mg of compound 24 (42%) was obtained from 5 mg of (IV-38). 1 H NMR(400MHz,D2O)δ3.94-3.40(m,10H),3.52(s,6H),3.11(m,4H),1.67(m,4H). HPLC-MS (condition C): rt=9.69min; m / z:804[M+1+DEA] + ,877[M+1+2DEA] + .

[0616] Embodiment 42

[0617] Synthesis and characterization of 4,6-O-bis(5-acetylaminopentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 27)

[0618] According to the general phosphate deprotection procedure I, 4.7 mg of compound 27 (5%) was obtained from 110 mg of (IV-39). 1 H NMR(400MHz,D2O)δ4.05-3.83(m,3H),3.78–3.43(m,7H),3.05(t,J=27.7,6.7 Hz,4H),1.86(s,6H),1.58-1.47(m,4H),1.46-1.38(m,4H),1.34–1.18(m,4H). HPLC-MS (condition C): rt=9.71min; m / z:828[M+1+DEA] + ,901[M+1+2DEA] + .

[0619] Embodiment 43

[0620] Synthesis and characterization of 4,6-O-bis(5-benzamidopentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 48)

[0621] According to the general phosphate deprotection procedure I, 15 mg of compound 48 (43%) was obtained from 43 mg of (IV-40). 1 H NMR(400MHz,D2O)δ7.61–7.55(m,4H),7.47-7.29(m,6H),4.40-4.18(m,3H),4.08-3.8 8(m,2H),3.61-3.55(m,5H),3.17(t,J=7Hz,4H),1.56-1.41(m,8H),1.33–1.23(m,4H). HPLC-MS (condition C): rt=8.73min; m / z:879[M+1] +,952[M+1+DEA] + ,1025[M+1+2DEA] + .

[0622] Embodiment 44

[0623] Synthesis and characterization of 4,6-O-bis(5-(thiophene-2-carboxamido)pentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 49)

[0624] According to the general phosphate deprotection procedure U, 19 mg of compound 49 (12%) was obtained from 196 mg of (IV-41). 1 H NMR(400MHz,D2O)δ7.68–7.37(m,4H),7.15–6.84(m,2H),4.48–4.03(m,5H),3.5 6(t,J=8.2,6.7Hz,4H),3.19–3.12(m,4H),1.50-1.37(m,8H),1.25-1.19(m,4H). HPLC-MS (Condition C): rt=8.85min; m / z:964[M+1+DEA] + ,1037[M+1+2DEA] + .

[0625] Embodiment 45

[0626] Synthesis and characterization of 4,6-O-(6-(4-carboxy-1H-1,2,3-triazol-1-yl)hexyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) decasodium salt (Compound 40)

[0627] According to the general phosphate deprotection procedure I, 9.3 mg of compound 40 (33%) was obtained from 34 mg of (IV-42). 1 H NMR(400MHz,D2O)δ8.08(s,2H),4.32-4.22(m,8H),4.10-3.96(m,2H),3.65 -3.54(m,4H),1.76(p,J=7.5Hz,4H),1.54-1.39(m,4H),1.29–1.15(m,8H). 31 P NMR (162MHz, D2O) δ4.81-3.21 (bs). HPLC-MS (condition C): rt=10.27min; m / z:964[M+1+DEA] + ,1037[M+1+2DEA] + .

[0628] Embodiment 46

[0629] Synthesis and characterization of 4-O-(6-(4-carboxy-1H-1,2,3-triazol-1-yl)hexyl)-6-O-(6-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)hexyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) nonasodium salt (Compound 41)

[0630] According to the general phosphate deprotection procedure I, 35 mg of compound 41 (42%) was obtained from 101 mg of (IV-43). 1 H NMR(400MHz,D2O)δ8.05(s,1H),7.86(s,1H),4.42(s,2H),4.37–4.16(m,7H),4.13-4.08(m,1H),4.05(s,2H) ,3.62–3.50(m,4H),3.22(s,3H),1.83–1.64(m,4H),1.56–1.33(m,4H),1.29–1.19(m,4H),1.18-1.08(m,4H). 31 P NMR (162 MHz, D2O) δ 4.83, 4.18, 4.10. HPLC-MS (condition C): rt = 9.65 min; m / z: 891 [M+1] + ,964[M+1+DEA] + ,1037[M+1+2DEA] + .

[0631] Embodiment 47

[0632] Synthesis and characterization of 4,6-O-bis(4-amino-4-oxobutyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 26)

[0633] According to the general phosphate deprotection procedure I, mg compound 26 (25%) was obtained from 168 mg of (IV-44). 1 H NMR (400MHz, D2O) δ4.17–3.39 (m, 10H), 2.48–2.17 (m, 3H), 2.16–2.03 (m, 1H), 1.77 (p, J = 6.8Hz, 4H). HPLC-MS (condition C): rt=10.47min; m / z:744[M+1+DEA] + ,817[M+1+2DEA] + .

[0634] Embodiment 48

[0635] Synthesis and characterization of 4,6-O-bis(5-(3-propylureido)pentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 30)

[0636] According to the general phosphate deprotection procedure I, 100 mg of compound 30 (58%) was obtained from 210 mg of (IV-45). 1 HNMR(400MHz,D2O)δ4.41–3.90(m,6H),3.60(t,J=6.5Hz,4H),3.04–2.85(m,8H),1.61–1.18(m,16H),0.75(t,J=7.4Hz,6H). HPLC-MS (condition C): rt=9.20min; m / z:841[M+1] + ,914[M+1+DEA] + .

[0637] Embodiment 49

[0638] Synthesis and characterization of 4,6-O-bis(5-((methoxycarbonyl)amino)pentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 25)

[0639] According to the general phosphate deprotection procedure I, 25 mg of compound 25 was obtained from 60 mg of (IV-46) (yield 61%). 1 HNMR(400MHz,D2O)δ4.37–3.82(m,6H),3.64(m,4H),3.52(s,6H),3.00(t,J=7.1Hz,4H),1.64–1.46(m,4H),1.45–1.33(m,4H),1.33–1.17(m,4H). HPLC-MS (condition C): rt=9.33min; m / z:787[M+1] + ,860[M+1+DEA] + ,932[M+1+2DEA] + .

[0640] Embodiment 50

[0641] Synthesis and characterization of 4,6-O-dipentyl-myo-inositol-1,2,3,5-tetrakis(phosphorothioate) octasodium salt (Compound 50)

[0642] According to the general phosphate deprotection procedure U, 2.2 mg of compound 50 (3%) was obtained from 97 mg of (IV'-1). 1H NMR(400MHz,D2O)4.63-4.55(m,2H),4.52-4.44(m,2H),4.34-4.28(m,2H),3.6 7(t,J=7.0Hz,4H),1.59-1.48(m,4H),1.27-1.18(m,8H),0.77(t,J=6.8Hz,6H). HPLC-MS (Condition C): rt=9.36min; m / z:850[M+1+2DEA] + ,923[M+1+3DEA] + .

[0643] Embodiment 51

[0644] Synthesis and characterization of 4,6-O-bis(5-methoxypentyl)-myo-inositol-1,2,3,5-tetrakis(phosphorothioate) octasodium salt (Compound 51)

[0645] According to the general phosphate deprotection procedure U, 2.2 mg of compound 51 (5%) was obtained from 54 mg of (IV'-2). 1 H NMR (400MHz, D2O) δ4.65-4.25(m,6H),3.68(m,4H),3.39(t,J=6.8Hz,4H),3.23(s,6H),1.60-1.47(m,8H),1.30(m,4H). 31 P NMR (162 MHz, D2O) δ 45.82, 45.22, 44.23. HPLC-MS (condition C): rt = 9.89 min; m / z: 910 [M+1+2DEA] + ,983[M+1+3DEA] + .

[0646] Embodiment 52

[0647] Synthesis and characterization of 4,6-O-bis(3-carboxypropyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) decasodium salt (Compound 52)

[0648] According to the general phosphate deprotection procedure J, 11 mg of compound 52 (34%) was obtained from 40 mg of (IV-47). 1 H NMR(400MHz,D2O)δ4.31-4.24(m,3H),4.12-4.08(m,1H),4.01(br,2H),3.58(m,4H),2.11(m,4H),1.72(m,4H). HPLC-MS (Condition C): rt=10.73min; m / z:746[M+1+1DEA] + ,819[M+1+2DEA]+ .

[0649] Embodiment 53

[0650] Synthesis and characterization of 4,6-O-dipropynyl-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (Compound 53)

[0651] According to the general phosphate deprotection procedure U, 10 mg of compound 53 (35%) was obtained from 50 mg of (IV-48). 1 H NMR (400MHz, D2O) δ4.89–4.81(m,1H),4.43(d,J=1.9Hz,4H),4.11–3.87(m,3H),3.79-3.60(m,2H),2.77(t,J=1.9Hz,2H). 31 P NMR (162 MHz, D2O) δ 1.22, 0.47, -0.86. HPLC-MS (condition C): rt = 10.70 min; m / z: 724 [M+1+2DEA] + ,797[M+1+3DEA] + .

[0652] Embodiment 54

[0653] Inhibition of calcium phosphate crystallization in vitro

[0654] The in vitro potency of IP4-4,6 substituted derivatives of the present invention (eg, compounds 1 to 53) in inhibiting calcium phosphate crystallization in human plasma samples was evaluated according to a spectrophotometric assay previously described in the art (Ferrer M et al., Sci Rep 2017; 7:6858, doi: 10.1038 / s41598-017-07203-x).

[0655] A 96-well plate was used. Derivatives were added to plasma at increasing concentrations in the range of 0-100 μM (1 volume of IP4-4,6 substituted derivatives of the invention was added to every 19 volumes of plasma). The plasma was then centrifuged at 10,000 g at room temperature and subsequently mixed with a mixture of 5 mM hydrogen phosphate and 41.67 mM calcium to reach a final concentration of 1.5 mM phosphate and 12.5 mM calcium, respectively. All reagent solutions were filtered and the pH was adjusted to 7.4.

[0656] Calcium phosphate crystallization was monitored spectrophotometrically for 30 min at room temperature by measuring the increase in absorbance at 550 nm using a Biotek Powerwave XS microplate reader (BioTek Instruments, Inc., Winooski, VT, US). The plate was incubated on an orbital shaker at room temperature and the absorbance was measured every 3 min.

[0657] Plasma crystallization was assessed based on the slope measurements in the linear range between 6 and 24 min according to the curve of absorbance increase relative to the logarithm of time. The effectiveness of different myo-inositol phosphate derivatives in preventing the formation of calcium phosphate crystals in vitro was assessed in human plasma samples using the slopes obtained between 6 and 24 min. The inhibition of crystallization was measured by comparing the slopes of control samples (blank plasma) with those samples containing inhibitors as shown below:

[0658]

[0659] See Table 13.

[0660] Table 13

[0661]

[0662]

[0663]

[0664] legend:

[0665] +++-EC 50 ≤5μM

[0666] ++-5μM <EC 50 ≤10μM

[0667] +-EC 50 >10μM

[0668] Embodiment 55

[0669] Rat models for various conditions associated with ectopic calcification

[0670] This model evaluates the effect of compound 27 on rat tissue calcification, blood perfusion and walking ability for 13 days. From D1 to D3, tissue calcification was induced in groups 2-5. From D1 day, placebo or active agent preparations were administered to animals induced with calcification to assess their effect in preventing calcification. The effects of treatment on tissue calcification, blood perfusion and walking ability were evaluated. Observations were performed at several time points during treatment from D0 to D13. All animals were weighed daily before treatment.

[0671] Fifty-eight male Sprague Dawley (SD) rats (Envigo Corp., Huntingdon, GB) weighing approximately 275-300 g were used. The animals were fed with Rod14-H4 diet (LASvendi, Soest, DE). The animals were divided into 5 groups of 10 to 12 animals each as follows:

[0672] Group 1 – Control (sham treatment), 10 animals

[0673] Group 2 – Normal saline solution (placebo), daily, 12 animals

[0674] Group 3 - Compound 27, 5 mg / kg, daily, 12 animals

[0675] Group 4 - Compound 27, 15 mg / kg, daily, 12 animals

[0676] Group 5 - Compound 27, 45 mg / kg, daily, 12 animals

[0677] Calcification was induced in animals of groups 2-5 by daily subcutaneous administration of 120,000 IU / kg vitamin D3 (cholecalciferol, Duphafral D31000; Zoetis Inc., Parsippany, NJ, US) in saline 0.9% (w / v) NaCl solution (2 mL / kg) from D1 to D3. Animals of group 1 were administered 2 mL / kg of saline solution without vitamin D3 by subcutaneous route every day from D1 to D3. Animals of group 2 were administered 2 mL / kg of saline solution by subcutaneous route every day from D1 to D13. Animals of groups 3, 4, and 5 were administered 5 mg / kg, 15 mg / kg, and 45 mg / kg of compound 27 (754.45 g / mol free acid) by subcutaneous route every day from D1 to D13, respectively.

[0678] 1. Organizational Analysis

[0679] On D13, all surviving animals in Groups 1-5 were sacrificed to determine calcium values ​​in their tissues (ie, aorta, carotid artery, femur, heart, kidney).

[0680] Animals were bled before being killed. Autopsy was performed, and the whole left and right femoral arteries, left and right carotid arteries, aorta, heart and right kidney thereof were collected for calcium content measurement. Tissue was freeze-dried for 24 h and weighed. Then, freeze-dried tissue was digested for 2-4 h in a dry bath incubator at 180 ° C with 1:1 HNO3: HClO4 mixture. The digested tissue was subsequently diluted with ultrapure Milli-Q water (MilliporeSigma, MerckKGaA, Burlington, MA, US) to obtain a final volume of 5 mL (for femur and carotid artery) or 10 mL (for heart, kidney and aorta). According to the instructions of the manufacturer, Optima 7300DVICP-OES system spectrometer (PerkinElmer, Inc., Waltham, MA, US) was used to quantify calcium content by inductively coupled plasma optical emission spectrometry (ICP-OES).

[0681] 2. Blood Perfusion

[0682] The images were obtained using a PeriCam PSI normal resolution analyzer (Perimed AB, Laser Doppler perfusion imaging (LSE) was performed on the hind limbs of the animals to evaluate blood perfusion (BP). Measurements were performed on all groups at D0, D4, and D13. The perfusion ratio (i.e., the average of the two legs) was calculated by comparing the baseline and D4 or D13 readings of each group. In addition, the perfusion ratio was calculated by comparing Group 1 with Groups 2-5.

[0683] 3. Walking ability

[0684] Maximum walking time (MWT) and maximum walking distance (MWD) were assessed by forced incremental treadmill running test at 15% incline using a rat dual lane touch screen treadmill apparatus (Cat. No. LE8709TS, Panlab, Harvard Biosciences, Inc., Holliston, MA, US). All groups were measured at D0, D6 and D11.

[0685] Prior to testing, the animals were acclimated to the treadmill for two days. On the first day, the animals were trained for 5 to 10 minutes with the treadmill speed gradually changing from 15 m / min to 24 m / min. On the second day, the animals were trained for 20 minutes as follows: (a) 15 m / min for the first 5 minutes, (b) 19.8 m / min for the second 5 minutes and (c) 24 m / min for the last 10 minutes. The walking time and distance before the start of the experiment were obtained. Animals that did not comply with the protocol were excluded from testing. Forty-eight (48) rats were screened for walking ability testing. On the day before the D0 test, the selected animals were further trained for 5-10 minutes to ensure their acclimation to the treadmill. The protocol for MWT and MWD measurements at D0, D5 and D10 is as follows:

[0686] Speed(m / min) 15 19.8 24 Time (min) 0-5 5-10 10-40

[0687] For Group 2, treadmill assessment began 15 min after dosing. For Groups 2-5, treadmill assessment began 25 min after dosing. The rats were allowed to run for 40 min or until fatigue. The test was stopped when the rat was on the shock net for 5 consecutive seconds (i.e., fatigue). MWD (meters) and MWT (minutes) were recorded for each animal.

[0688] Administration of compound 27 at doses of 15 and 45 mg / kg improved the walking ability of rats administered with vitamin D in a dose-dependent manner as early as D5 after induction of PAD disease. The results showed that compound 27 inhibited ectopic calcification in all tissues evaluated. FIG. 12A to FIG. 12E .

[0689] At 45 mg / kg, inhibition of aortic calcification was observed ( Fig. 12A). The results indicate that compound 27 can be used to treat conditions such as aortic calcification, aortic valve calcification, aortic stenosis, calcified aortic stenosis, atherosclerosis, atherosclerosis, aneurysm or coral reef aorta. Arterial calcification leads to vascular hardening, indicating the potential use of compound 27 in atherosclerosis. Aortic hardening leads to reduced coronary vascular filling and reduced myocardial perfusion during diastole, indicating that compound 27 can be used for coronary heart disease or coronary artery disease. Reduced coronary filling may cause the myocardium to be unable to respond adequately to increased oxygen demand, resulting in ischemia, even in the absence of coronary artery obstruction. Inadequate response to increased myocardial oxygen demand can lead to myocardial ischemia and angina symptoms. Therefore, compound 27 can be used for myocardial ischemia and angina (including chronic stable angina) because it has an effect on aortic calcification, thereby affecting all downstream effects on ischemia and chest pain. Atherosclerosis also forces the heart to pump blood and hypertrophy more vigorously, indicating that compound 27 can be used for left ventricular hypertrophy. Ultimately, arteriosclerosis and cardiac hypertrophy may lead to arrhythmias, heart failure, congestive heart failure, heart disease, cardiovascular death, or cardiac death, suggesting that compound 27 may be useful in these situations or conditions.

[0690] Inhibits cardiac calcification ( Fig. 12B ) showed a dose response effect from 5mg / kg. The results show that compound 27 can be used for conditions associated with cardiovascular calcification, coronary artery calcification, valvular calcification, calcified aortic stenosis, atherosclerosis, atherosclerosis, myocardial infarction, aneurysm, coronary heart disease or coronary artery disease. Cardiac coronary artery calcification leads to vascular sclerosis, indicating the potential use of compound 27 in atherosclerosis. Sclerosis leads to reduced diastolic coronary artery vascular filling and reduced myocardial perfusion, indicating that compound 27 can be used for coronary heart disease or coronary artery disease. Reduced coronary artery filling may cause the myocardium to be unable to fully respond to increased oxygen demand, resulting in ischemia, even in the absence of coronary artery obstruction. Insufficient response to increased myocardial oxygen demand can lead to myocardial ischemia and angina symptoms. Therefore, compound 27 can be used for myocardial ischemia and angina (including chronic stable angina) because it has an effect on aortic calcification, thereby affecting all downstream effects for ischemia and chest pain. Arteriosclerosis also forces the heart to pump harder and enlarge, suggesting that compound 27 may be useful for left ventricular hypertrophy. Ultimately, arteriosclerosis and cardiac hypertrophy may lead to arrhythmias, heart failure, congestive heart failure, heart disease, cardiovascular death, or cardiac death, suggesting that compound 27 may be useful for these situations or conditions.

[0691] Inhibition of carotid artery calcification was observed at 45 mg / kg ( Fig.12D). This result indicates that compound 27 can be used in the case or condition of atherosclerosis or arteriosclerosis. Arterial calcification leads to vascular hardening, indicating the potential use of compound 27 in arteriosclerosis.

[0692] Inhibits renal calcification ( Fig.12E ) showed a dose response effect from 5 mg / kg. This result suggests that compound 27 is useful in cases or conditions of nephrocalcinosis or nephrolithiasis (kidney stones).

[0693] Inhibit femoral artery calcification ( Fig. 12C ), affecting blood perfusion ( Fig.13 ) and the maximum walking distance affected ( Fig.14 ) showed a dose response effect from 5 mg / kg, and at doses of 15 mg / kg and 45 mg / kg, hind limb blood perfusion was restored. These results indicate that compound 27 can be used for situations or conditions of atherosclerosis or arteriosclerosis. Arterial calcification leads to vascular hardening, indicating the potential use of compound 27 in arteriosclerosis. Lower limb arteriosclerosis reduces blood supply and causes ischemic pain. Restoring blood perfusion using compound 27 indicates that it can be used to treat PAD, including limb ischemia or critical limb ischemia. The overall results of femoral calcification and blood perfusion, as assessed by maximum walking distance, led to improved function, indicating that compound 27 can be used to treat peripheral vascular disease or peripheral arterial disease.

[0694] The overall effect on arterial calcification also suggests the potential use of compound 27 in PXE, a genetic disease that causes arterial calcification, among other sites.

[0695] Embodiment 56

[0696] Prevention and treatment of skin calcification and calcium allergy

[0697] IP4-4,6 derivatives were investigated for the prevention and treatment of skin calcification and calcium hypersensitivity (CUA) induced by vitamin D3 and FeCl3 in rat models. The model evaluated the effects of compound 27 and IP6 on the formation of calcified skin plaques in rats for 8 days. Animals were sensitized with vitamin D3 at low concentrations (LC, 35,000IU / kg) and high concentrations (HC, 50,000IU / kg). FeCl3 solution (0.5mg / kg) was used as a challenger to induce the formation of skin plaques. All animals were weighed daily before treatment.

[0698] 86 male Sprague Dawley (SD) rats (Envigo Corp., Huntingdon, GB) weighing approximately 250-300 g were used. The animals were fed with Rod14-H4 diet (LASvendi, Soest, DE). The animals were divided into 8 groups of 6 to 12 animals each as follows:

[0699]

[0700] The following solutions were prepared: (a) 17,500 IU / mL (LC) and 25,000 IU / mL (HC) vitamin D3 (cholecalciferol, Duphafral D3 1000; Zoetis Inc., Parsippany, NJ, US), (b) 0.3 mg / mL FeCl3 (FeCl3·6H2O, 99%, Scharlab SL, Barcelona, ​​ES), (c) 30 mg / mL IP6 (660 g / mol phytic acid, pH 6.5-7.7), and (d) 15, 30, and 50 mg / mL compound 27 (754.45 g / mol free acid, pH 6.5-7.7). All solutions were prepared in 0.9% (w / v) physiological salt NaCl medium. An application volume of 2 mL / kg was used.

[0701] Group 1 - Control (sham treatment), 6 animals. Animals in Group 1 were administered saline (0.9% (w / v) NaCl solution) subcutaneously daily in the interscapular space from D1 to D3, and injected once with 0.9% saline in two ventral sites of the chest on D4. Animals in Group 1 were not administered vitamin D or FeCl3 solution.

[0702] Group 2 - Physiological saline low concentration (vehicle LC): Vitamin D 35,000 IU / kg, 0.5 mg / kg FeCl3 solution, 10 animals. Vitamin D was administered subcutaneously for 3 consecutive days (D1, D2, D3) at a dose of 35,000 IU / kg and FeCl3 0.5 mg / kg was injected once in both ventral sites of the chest on D4. This group received daily saline 0.9% sc treatment (D1 to D8).

[0703] Group 3 - Compound 27 60 mg / kg LC: Vitamin D 35,000 IU / kg, 0.5 mg / kg FeCl3, 10 animals. Vitamin D was administered subcutaneously at a dose of 35,000 IU / kg for 3 consecutive days (D1, D2, D3), and 0.5 mg / kg FeCl3 was injected once in both ventral sites of the chest at D4. This group received daily treatment with 60 mg / kg of Compound 27 s.c. (D1 to D8).

[0704] Group 4 - Physiological saline high concentration (vehicle HC): Vitamin D 50,000 IU / kg, 0.5 mg / kg FeCl3, 12 animals. Vitamin D was administered subcutaneously for 3 consecutive days (D1, D2, D3) at a dose of 50,000 IU / kg and FeCl3 was injected once in both ventral sites of the chest on D4. This group received daily saline 0.9% sc treatment (D1 to D8).

[0705] Group 5 - IP6 60 mg / kg HC, Vitamin D 50,000 IU / kg, 0.5 mg / kg FeCl3, 12 animals. Vitamin D was administered subcutaneously at a dose of 50,000 IU / kg for 3 consecutive days (D1, D2, D3) and FeCl3 was injected once in two ventral sites of the chest at D4. This group received IP6 sc treatment at a dose of 60 mg / kg daily (D1 to D8).

[0706] Group 6 - Compound 27 30 mg / kg HC, Vitamin D 50,000 IU / kg, 0.5 mg / kg FeCl3, 12 animals. Vitamin D was administered subcutaneously at a dose of 50,000 IU / kg for 3 consecutive days (D1, D2, D3), and 0.5 mg / kg FeCl3 was injected once in both ventral sites of the chest at D4. This group received daily treatment with 30 mg / kg of Compound 27 s.c. (D1 to D8).

[0707] Group 7 - Compound 27 60 mg / kg LC, Vitamin D 50,000 IU / kg, 0.5 mg / kg FeCl3, 12 animals. Vitamin D was administered subcutaneously at a dose of 50,000 IU / kg for 3 consecutive days (D1, D2, D3), and 0.5 mg / kg FeCl3 was injected once in both ventral sites of the chest at D4. This group received daily treatment with Compound 27 s.c. at a dose of 60 mg / kg (D1 to D8).

[0708] Group 8 - Compound 27 100 mg / kg HC, Vitamin D 50,000 IU / kg, 0.5 mg / kg FeCl3, 12 animals. Vitamin D was administered subcutaneously at a dose of 50,000 IU / kg for 3 consecutive days (D1, D2, D3), and 0.5 mg / kg FeCl3 was injected once in both ventral sites of the chest at D4. This group received daily treatment with Compound 27 s.c. at a dose of 100 mg / kg (D1 to D8).

[0709] At D8, all animals were bled and then killed. Their autopsies were performed and the skin tissue plaques formed at the FeCl3 injection site were collected for calcium content measurement. The tissue was cleaned with 0.15M saline, freeze-dried for 48-72h and weighed. Then, the freeze-dried tissue was digested using a 1:1HNO3:HClO4 mixture in a dry bath incubator for 2-4h at 180°C. The digested tissue was subsequently diluted to a final volume of 10mL with ultrapure Milli-Q water (MilliporeSigma, Merck KGaA, Burlington, MA, US). According to the manufacturer's instructions, the calcium content was quantified by inductively coupled plasma optical emission spectroscopy (ICP-OES) using an Optima7300DVICP-OES system spectrometer (PerkinElmer, Inc., Waltham, MA, US).

[0710] The results show that at the same dose, compound 27 achieved a higher degree of inhibition than IP6. Moreover, compound 27 inhibited rat skin plaque formation in a dose-responsive manner, indicating that compound 27 can be used for conditions such as calcinosis cutis and calcisensitization. See Table 14. The effect on skin calcification also suggests the potential use of compound 27 in the treatment of PXE, a genetic disease that causes arterial calcification in addition to other locations.

[0711] Statistical analysis: One-way ANOVA (for LC group: p<0.01; for HC group: p<0.0001), combined with Tukey post hoc test. (#) Significant difference compared with the sham group, (*) Significant difference compared with the corresponding vehicle group, (§) Significant difference compared with IP6 60 mg / kg (at the same dose, only applied to compound 27), p<0.05.

[0712] Table 14

[0713]

[0714] Embodiment 57

[0715] Treatment of calcified human aortic valve

[0716] The dose-response efficacy of IP4-4,6 derivatives in treating calcified human aortic valves was analyzed using an in vitro model (Zabirnyk A et al., Vasc Pharmacol 2019; 122-123, 106583, doi: 10.1016 / j.vph.2019.106583). The model evaluated the effects of IP6, compound 1, compound 3, and compound 6 on the calcification of human aortic valve interstitial cells (VIC).

[0717] Human calcified aortic valve leaflets were obtained and harvested during aortic valve replacement. VICs were isolated after removal of valvular endothelial cells. The leaflets were placed in 30 mL of basal growth medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 50 μg / mL gentamicin, and 1 mg / mL collagenase II was added. The cells were incubated overnight at 37°C, 5% CO2. The next day, the digested tissue was homogenized by pipetting with a serological pipette and centrifuged at 300g for 5 min, and the supernatant was carefully removed by aspiration.

[0718] The pellet was washed in 10 mL of fresh DMEM and centrifuged as previously described. The supernatant was removed by aspiration, and the cell pellet was resuspended in basal growth medium and plated in 75 cm 3 VICs were cultured at 37°C and 5% CO2 with growth medium changed twice a week until ~90% confluence was reached. Cells were passaged at a 1:2 ratio, expanded, and cryopreserved.

[0719] 1.VIC osteogenic differentiation and inhibition

[0720] For osteogenic differentiation, VICs of calcified human aortic valves (n=7) were plated at 30×10 4 Cells / well were seeded in basal growth medium in 24-well tissue culture plates and cultured overnight at 37°C, 5% CO2. The next day, osteogenic differentiation was induced by supplementing the medium with 50 μM ascorbic acid, 0.1 μM dexamethasone, and 10 mM β-glycerophosphate. The osteogenic medium was changed twice a week for three weeks. The negative control group (calcium differentiation was not induced) was cultured in basal medium for the same period of time, and the medium was changed according to the same protocol.

[0721] The same VIC donor was used in all groups (n=7, each concentration and test item) for concentration response studies. Starting from the first week of induction of osteogenic differentiation, the test items Compound 1, Compound 3 and Compound 6 (1, 3, 10, 30 and 100 μM) were cultured at increasing concentrations and compared with the activity of IP6. VIC from the same donor was used for the positive control group (osteogenic medium without the addition of inhibitors).

[0722] 2. Calcium Staining and Quantification

[0723] Alizarin red staining was performed to assess calcification. Cell culture medium was removed, cells were washed with PBS, and fixed with 70% ethanol for 1 h at room temperature. Then, cells were washed with Milli-Q water and stained with Alizarin red according to the manufacturer's instructions. To quantify calcium accumulation, Alizarin red stain was extracted and measured spectrophotometrically. Briefly, for a 24-well plate, 200 μL of 10% acetic acid was added to each well, gently stirred and incubated at room temperature for 30 min. Afterwards, cells were detached using a cell scraper, and the resulting suspension was transferred to a 1.5 mL microcentrifuge tube and vortexed vigorously for 30 s. Then, cells were heated to 85 °C for 10 min, and the tubes were then transferred to ice for 5 min and cooled. Then, cells were centrifuged at 15000 g for 15 min. The supernatant was transferred to a new 1.5 mL microcentrifuge tube, and 75 μL of 1 M NaOH was added to each tube to obtain a pH between 4.1 and 4.5. Finally, 50 μL from the tube was transferred to a clear bottom 96-well plate and the absorbance at 405 nm was measured on a microplate reader.

[0724] Statistical analysis was performed using GraphPad Prism (version 9, Dotmatics, Boston, MA, US). VIC cultures that failed to differentiate and calcify under osteodifferentiation medium were excluded. The normality of the data was assessed using the Shapiro-Wilk test. For normally distributed results, a normally distributed one-way ANOVA with a DMS post-test was applied. For non-normally distributed results, a nonparametric one-way ANOVA (Kruskal–Wallis test) with a Dunn post-test was applied. Relative calcification results are shown as dot plots and mean values. Values ​​of p<0.05 were considered statistically significant.

[0725] The results showed that IP4-4,6 derivatives Compound 1, Compound 3 and Compound 6 effectively inhibited VIC calcification in a dose-dependent manner in vitro. FIG. 15A to FIG. 15D These results suggest that these compounds may be useful in situations or conditions such as valve calcification, valve stenosis, or calcific aortic stenosis. Calcified valves may lead to cardiac hypertrophy, suggesting that these compounds may be useful in treating or preventing left ventricular hypertrophy. Ultimately, cardiac hypertrophy may lead to arrhythmias, heart failure, congestive heart failure, heart attack, cardiovascular death, or cardiac death, suggesting that these compounds may be useful in these situations or conditions.

[0726] Embodiment 58

[0727] Treatment of Pseudoxanthoma Elasticum

[0728] Using stable CRISPR / Cas9 abcc6a characterized by spine hypermineralization - / -A zebrafish model was used to determine the efficacy of compound 27 in the treatment of pseudoxanthoma elasticum (PXE; Van Gils M et al., J Invest Dermatol 2022; 138: 2333-2342).

[0729] Abcc6a - / - The larvae were treated with different concentrations (i.e., 100 μM, 300 μM, and 1 mM) of compound 27 for 7 days, and the medium containing the dissolved compound was replaced every day starting from 3 days after fertilization (dpf). At 10 dpf, the larvae were killed and stained with alizarin red, and the spinal hypermineralization was visualized using a Leica M165 FC microscope (Leica Microsystems GmbH, Wetzlar, DE). Calcification was semi-quantified by ImageJ image processing using ImageJ (Rasband W, Research Services Branch, NIH, Bethesda, MD, US). The results showed that treatment with 1 mM of compound 27 significantly reduced abcc6a - / - The juvenile spine was hypermineralized, with an average reduction of 60% (relative calcification area 35.2 vs. 14.17; p<0.001), while retaining physiological calcification and bone formation, thus indicating the potential of compound 27 in PXE treatment. Fig.16 .

[0730] It should be understood that the Detailed Description section, rather than the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections may set forth one or more but not all exemplary embodiments of the present invention contemplated by the inventors, and therefore, are not intended to limit the present invention and the appended claims in any way.

[0731] The present invention has been described above with the aid of functional building blocks that can illustrate the implementation of specific functions and their relationships. For ease of description, the boundaries of these functional building blocks have been arbitrarily defined here. Other boundaries can be defined as long as the specified functions and their relationships are appropriately performed.

[0732] The foregoing description of specific embodiments will reveal the general nature of the invention so fully that others can easily modify and / or adapt to various applications such as specific embodiments by applying the knowledge of those skilled in the art without departing from the general concept of the invention, without undue experimentation. Therefore, based on the teachings and guidance set forth herein, such adaptations and modifications are intended to be within the meaning and scope of the equivalent forms of the disclosed embodiments. It should be understood that the wording or terminology herein is for the purpose of description rather than limitation, and thus the terms or wording of this specification will be interpreted by the skilled person based on the teachings and guidance.

[0733] The breadth and scope of the present invention should not be limited by any of the above-described examples, but should be defined only in accordance with the following claims and their equivalents.

Claims

1. A compound of formula I: Its pharmaceutically acceptable salt, or a combination thereof, wherein (i) R1, R3, R7 and R 11 Independently expressed OPO3 2- ; R5 and R9 are substituents, each of which corresponds to the formula -O-(alkyl) n -X, wherein n is an integer between 1 and 20, wherein the terminal group X is selected from: -H, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', halogen, -CF3, alkyl, alkenyl, alkynyl, carbocycle and heterocycle, and wherein R and R' are H or alkyl groups; (ii) R1, R3, R7 and R 11 Independently expressed OPO3 2- ; R5 and R9 are substituents, each of which corresponds to the formula -O-(alkyl) y -Cy-(alkyl) y' -Z, wherein y and y' are integers between 0 and 10, wherein Cy is a cyclic linker, wherein the terminal group Z is selected from: alkyl, -COR, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', halogen and -CF3, and wherein R and R' are H or alkyl groups; (iii) R1, R3, R7 and R 11 Independently expressed OPO3 2- ; R5 and R9 are substituents, each of which corresponds to the formula -O-(alkyl) y -A-(alkyl) y' -Z', wherein y and y' are integers between 0 and 10, wherein A is a linker selected from the group consisting of: -CONR-, -NHCOO-, -NHSO2, -NHCONR-, -NHCO-, and -OCONR, wherein the terminal group Z' is selected from the group consisting of: -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', carbocycle, heterocycle, and wherein R and R' are H or alkyl groups; and (iv) The compound of formula I is an analog of (i), (ii) or (iii), wherein R1, R3, R7 or R 11 At least one of them is a phosphorothioate (-OPSO2 2- ) for treating, inhibiting the progression of, and preventing ectopic calcification or its consequences in a subject in need thereof.

2. The compound for use according to claim 1, wherein the compound is a compound of formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV, and any combination thereof.

3. The compound for use according to any one of claims 1 to 2, wherein the compound is selected from: Compound 1 to Compound 53, and any combination thereof.

4. The compound for use according to claim 3, wherein the compound is compound 1 having the following chemical structure:

5. The compound for use according to claim 3, wherein the compound is compound 3 having the following chemical structure:

6. The compound for use according to claim 3, wherein the compound is compound 6 having the following chemical structure:

7. The compound for use according to claim 3, wherein the compound is compound 27 having the following chemical structure:

8. A pharmaceutical composition for treating ectopic calcification or its consequences, inhibiting the progression of ectopic calcification or its consequences or preventing ectopic calcification or its consequences in a subject in need thereof, comprising a compound for use according to any one of claims 1 to 7 and any combination thereof, and at least one pharmaceutically acceptable excipient or carrier.

9. The compound or pharmaceutical composition for use according to any one of the preceding claims, wherein a therapeutically effective amount of the compound or pharmaceutical composition is administered to the subject in need thereof.

10. A compound or pharmaceutical composition for use according to any one of the preceding claims, comprising treating, inhibiting the progression of and preventing diseases and / or conditions associated with ectopic calcification or its consequences in a subject in need thereof.

11. A compound or pharmaceutical composition for use according to claim 10, wherein the ectopic calcification or its consequences include adrenal and intracranial calcification in familial cavernous malformation, asthenic bone disease, calcium deposition-related age-related macular degeneration (AMD), bone cancer, bone mineral disease, breast calcification, calcific band keratopathy, calcific tendinitis, calcification in osteoarthritis, calcification of articular cartilage in osteoarthritis, calcification of joints and arteries (CALJA), seminal vesicle calcification, cutaneous calcification, calcisensitization (CUA), calcium pyrophosphate deposition disease (CPPD), cardiovascular disease or related conditions, chondrocalcinosis, colon cancer, diabetic nephropathy, malnutrition calcification, renal transplant failure, familial cavernous malformation (FCCM), induction fibrodysplasia ossificans progressiva (FOP), hyperosteogenetic-hyperphosphatemic syndrome (HHS), hyperphosphatemic familial tumoral calcification (HFTC), idiopathic brain calcification (Fahr's disease), idiopathic mesenteric venous sclerosis (IMP), kidney stones (i.e., nephrolithiasis), metastatic calcification, nephrocalcinosis, calcification associated with neurocysticercosis, osteomalacia, osteoporosis, pineal calcification, venous sclerosing colitis, podagra, primary familial brain calcification (PFBC), primary hyperoxaluria (PH), pseudoxanthoma elasticum (PXE), rheumatoid arthritis, sialolithiasis, parotid calcification in Sjorgen's syndrome, seminal vesicle stones, skin cancer, soft tissue calcification due to sarcoidosis, adrenal calcification in Wolman's disease, and wound healing associated with diabetic ulcers.

12. The compound or pharmaceutical composition for use according to claim 11, wherein the cardiovascular disease or related condition comprises acute ischemic stroke (ACS), aneurysm, angina pectoris (chronic stable angina), aortic calcification, large artery calcification, aortic stenosis, aortic valve calcification, arrhythmia, atherosclerosis, arteriosclerosis, arteriovenous fistula (AVF) dysfunction, atherosclerosis, calcific aortic stenosis, cardiac death, heart disease, cardiovascular calcification, cardiovascular disease in patients with chronic kidney disease (CKD), cardiovascular disease associated with aging, cardiovascular death, cerebrovascular disease, congestive heart failure, coral reef aorta (CRA), coronary artery calcification, coronary artery disease, coronary heart disease, critical limb ischemia, electrocardiogram abnormalities, systemic arterial calcification in infancy (GACI), heart failure, hypertension, ischemia, left ventricular hypertrophy, major adverse cardiovascular events (MACE) in patients on hemodialysis (HD), medial sclerosis (MMS), myocardial calcification, myocardial infarction, myocardial ischemia, pericardial calcification, peripheral artery disease (PAD), peripheral vascular disease (PVD), porcelain aorta and anastomotic calcification after coronary artery bypass grafting (CABG), portal vein calcification, stroke, thrombosis, valvular calcification and vascular calcification.

13. A compound or pharmaceutical composition for use according to any one of the preceding claims, wherein the subject suffers from renal failure.

14. A compound or pharmaceutical composition for use according to any preceding claim, wherein the subject is undergoing dialysis.

15. A compound or pharmaceutical composition for use according to any one of the preceding claims, wherein the administration is topical, enteral or parenteral.

16. The compound or pharmaceutical composition for use according to claim 15, wherein the parenteral administration is intravenous, subcutaneous, intramuscular or by intravenous infusion.

17. The compound or pharmaceutical composition for use according to claim 16, wherein the intravenous infusion is administered using a dialysis device.

18. A compound or pharmaceutical composition for use according to any one of the preceding claims, wherein the subject is a human.

19. A kit or article of manufacture comprising at least one compound or pharmaceutical composition for use according to any one of the preceding claims, and any combination thereof.

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