IP4-4,6 substitution derivative compounds for use in the treatment, inhibition of progression, and prevention of ectopic calcification

Abstract

The present invention provides IP4-4,6 substitution derivatives for use in the prevention, inhibition of progression, and treatment of (a) heterotopic calcification and the resulting conditions, and (b) diseases and / or conditions associated with heterotopic calcification and the resulting conditions. Also provided are methods, pharmaceutical compositions and formulations, methods of use, articles of manufacture, and kits for use in the prevention, inhibition of progression, and treatment of (a) heterotopic calcification and the resulting conditions, and (b) diseases and / or conditions associated with heterotopic calcification and the resulting conditions.

Description

Technical Field

[0001] [1] The present invention relates to IP4-4,6 substituted derivative compounds for use in the treatment, inhibition of progression, and prevention of (a) ectopic calcification and (b) diseases and / or conditions associated with ectopic calcification. Pharmaceuticals and kits for such use are also provided.

Background Art

[0002] [2] Ectopic calcification (EC) is defined as inappropriate biomineralization that occurs in soft tissues (Cotran R et al., Pathological Basis of Disease, 5th Edition, edited by Robbins S et al., (WB Saunders, Philadelphia, PA, US, 1994, pp. 1-35)). EC is usually composed of calcium phosphate salts including hydroxyapatite (HAP), but may also consist of calcium oxalate and octacalcium phosphate as found in kidney stones (Pak C, Am J Kidney Dis, 1991; 18: 624-632). EC develops through a mechanism similar to physiological calcification, but may also appear independently in different locations (Giachelli C, Am J Pathol., 1999; 154(3): 671-67). The diversity of EC types is thought to be associated with having chronic or rare diseases. See Figure 1 (Kempf H et al., Front Cell Dev Biol. 2021; 9: 759702).

[0003] [3] Thus, EC can be found in soft tissues such as blood vessels, heart valves, lungs, kidneys, and the brain. This pathological calcification causes organ damage. Some of the most relevant pathologies associated with EC are listed below. See Table A.

[0004]

Table 1

[0005] [4]As listed above, there are over 30 pathologies related to EC in the vascular bed. The causes are diverse but can be grouped into four categories: [5](i) Genetic mutations (e.g., GACI1, CALJA, PH, FOP, PXE), [6](ii) Tissue repair responses and / or immunological responses associated with inflammation (e.g., cutaneous calcinosis), [7](iii) Imbalances in metabolic calcium and phosphate (e.g., renal diseases), and [8](iv) Idiopathic.

[0006] [9]Recent data suggest that many molecules can modulate this process. The research field of discovering biomarkers to identify and / or characterize these molecules is expanding (Nitschke Y et al., Am J Hum Genet. 2012;90(1):25 - 39).

[0007]

[10] From the list shown in Table A, the most important extra - skeletal ECs are those generated in the cardiovascular system, specifically ECs in arteries and heart valves, because these ECs are strong independent risk factors for increased mortality and cardiovascular events. In arteries, calcification is associated with CAD, atherosclerotic plaque burden, peripheral vascular disease, and poor prognosis after angioplasty (e.g., increased risk of dissection). In the heart, valves are particularly prone to calcification. Degenerative calcific aortic stenosis is the most common valvular lesion currently encountered in clinical cardiology and one of the most difficult to manage. It is estimated that approximately 1 - 2% of the elderly population is affected by this pathology, which is characterized by encrustation of the aortic valve leaflets by apatite mineral deposition and subsequent sclerosis, tearing, and mechanical failure. Congenital abnormalities, inflammatory changes, such as those seen in rheumatic fever, renal diseases, and age are all risk factors for aortic stenosis.

[0008]

[11] The definitive treatment for severe symptomatic aortic stenosis is aortic valve replacement. In the United States, more than 40,000 patients undergo valve replacement annually. In the case of bioprosthetic valves, the malfunction most often results from calcification of the graft. In fact, by 10 years after implantation, one-third of bioprosthetic valves require replacement, and this increases to two-thirds by 15 years after implantation. The prevalence of aortic stenosis in people aged >75 years in the European Union and the United States is 3.4%, which represents a significant public health problem.

[0009]

[12] Another important disease associated with EC is peripheral artery disease, which is particularly prominent in end-stage kidney disease (PAD-ESKD). This peripheral artery disease affects individuals with end-stage kidney disease who are undergoing hemodialysis. PAD-ESKD causes a decline in exercise capacity and pain in the lower limbs, and can lead to severe lower limb ischemia, gangrene, and amputation. The main etiological factor 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 causes narrowing and hardening of the arteries, which results in a reduction in arterial blood flow and distal ischemia. Risk factors for PAD-ESKD include aging, diabetes, hypertension, and smoking (Chen J et al., Nephrol Dial Transplant., 2016; 31(7): 1145-1151). The dialysis duration is an important risk factor for PAD-ESKD, and for the risk factors of hypertension and diabetes, the prevalence is higher and the control is more difficult in patients with ESKD than in the general population (Rajagopalan S et al., Circulation, 2006; 114(18): 1914-1922). Patients with ESKD have been excluded from previous clinical studies of medical treatment methods for PAD, so there is no treatment method specifically approved for patients with PAD-ESKD.

[0010]

[13] As knowledge of the mechanisms of ectopic calcification increases, this field is facing two major challenges: discovering biomarkers useful for the early detection of EC events, and more importantly, discovering effective treatments to block or reverse this pathological process that occurs in both chronic and rare diseases (see Kempf, 2021, supra).

[0011]

[14] Regarding potential targets for possible therapeutic interventions, little research has been conducted in this field. The potential of omega-3 therapy in the treatment of inflammation in aortic valve stenosis has been evaluated in mice for its anti-inflammatory efficacy (Artiach G et al., Circulation, 2020; 142: 776-789). Proteins modified with the synthetic peptide (GFOGER) have shown in vitro the content of extracellular vesicles released in calcified vascular tissue and the osteogenic exchange of cultured cells (Mansour A et al., Front. Cell Dev. Biol., 2020; 8: 58976130). However, these findings must be confirmed in animal models and ultimately in humans.

Summary of the Invention

Problems to be Solved by the Invention

[0012]

[15] Therefore, future research in this field needs to focus on (i) the development of new biomarkers to predict the progression of ectopic calcification, (ii) the characterization of new animal models and human pathology related to ectopic calcification, (iii) understanding the unknown mechanisms of action of some important regulators of EC mineralization, and most importantly, (iv) the development of effective treatments for the calcification of various types of "soft" tissues (see Kempf, 2021, supra). Therefore, there is a need in this field for new chemical substances that can be effective in the treatment and prevention of diseases and conditions related to soft tissue calcification.

Means for Solving the Problems

[0013]

[16] A compound of general formula I for use in the treatment, inhibition of progression, or prevention of heterotopic calcification or a condition resulting therefrom, in a subject in need thereof:

[0014] [Chemical formula]

[0015] its pharmaceutically acceptable salts, or combinations thereof [wherein, (i) R1, R3, R7, and R 11 each independently represents OPO3 2- ; R5 and R9 are each a substituent corresponding to the formula -O-(alkyl) n -X, where n is an integer from 1 to 20, and the terminal group X is selected from the group consisting of -H, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', halogen, -CF3, alkyl, alkenyl, alkynyl, carbocyclic (saturated or unsaturated), and heterocyclic (saturated or unsaturated), and R and R' are H or an alkyl group, (ii) R1, R3, R7, and R 11 each independently represents OPO3 2- ; R5 and R9 are each a substituent corresponding to the formula -O-(alkyl) y -Cy-(alkyl) y’ -Z, where y and y' are integers from 0 to 10, Cy is a cyclic linker, and the terminal group Z is selected from the group consisting of alkyl, -COR, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', halogen, and -CF3, and R and R' are H or an alkyl group, (iii) R1, R3, R7, and R 11 each independently represents OPO3 2- ; R5 and R9 are each a substituent corresponding to the formula -O-(alkyl) y -A-(alkyl) y’-Z’ is a substituent corresponding thereto, where y and y’ are integers from 0 to 10, A is a linker selected from the group consisting of -CONR-, -NHCOO-, -NHSO2, -NHCONR-, -NHCO-, and -OCONR, and the terminal group Z’ is selected from the group consisting of -OR, -NRR’, -COOR, -CONRR’, -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR’, a carbocyclic ring (saturated or unsaturated), and a heterocyclic ring (saturated or unsaturated), and R and R’ are H or an alkyl group. (iv) The compound of formula I is an analog of (i), (ii), or (iii), where at least one of R1, R3, R7, or R 11 is a thiophosphate ion (-OPSO2 2- ) is disclosed.

[0016]

[17] In some embodiments, the R5 and R9 substituents of the compound of formula I are the same. In some embodiments, the R5 and R9 substituents of the compound of formula I are different.

[18] In some embodiments, the alkyl portion in the R5 and R9 substituents contains at least one double bond or triple carbon bond, i.e., forms an alkenyl chain or an alkynyl chain, respectively. In some embodiments, the alkenyl chains in the R5 and R9 substituents are the same. In some embodiments, the alkenyl chains in the R5 and R9 substituents are different. In some embodiments, the alkynyl chains in the R5 and R9 substituents are the same. In some embodiments, the alkynyl chains in the R5 and R9 substituents are different. In some embodiments, the alkyl portion in the R5 and R9 substituents contains at least one carbon double bond and at least one carbon triple bond, forming a combination of an alkenyl chain and an alkynyl chain. In some embodiments, the combination of the alkenyl chain and the alkynyl chain in the R5 and R9 substituents is the same. In some embodiments, the combination of the alkenyl chain and the alkynyl chain in the R5 and R9 substituents is different.

[0017]

[19] In some embodiments, the compound of formula I is selected from the group consisting of Compounds 1 to 53.

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

[0018]

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

[22] Also provided are compounds or pharmaceutical compositions according to the present invention for use in the treatment, inhibition of progression, or prevention of a disease and / or condition associated with heterotopic calcification or a condition resulting therefrom in a subject in need thereof.

[0019]

[23] In some embodiments, the subject is human. In some embodiments, the administration is topical, enteral, or parenteral administration. In some embodiments, the parenteral administration is intravenous administration. In some embodiments, the intravenous administration is by intravenous infusion.

[0020]

[24] 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 administration according to the uses disclosed herein. In some embodiments, the kit or article of manufacture can also comprise at least one compound selected from the group consisting of the compounds listed in Table 1. BRIEF DESCRIPTION OF THE DRAWINGS

[0021]

Figure 1

[25] A simplified schematic diagram showing the cellular, extracellular, and systemic changes associated with heterotopic calcification and their connections to several chronic and rare diseases.

Figure 2

[26] This is a simplified schematic diagram of the physicochemical mechanism of action of the IP4-4,6 substitution derivatives of the present invention that inhibit the crystallization of hydroxyapatite (HAP) and are thus useful for the treatment of HAP crystallization-mediated diseases.

Figure 3A

[27] Figures 3A and 3B present the representative structures of the IP4-4,6 substitution derivative compounds of Family A (e.g., Compounds 1-30 and Compounds 52-53).

Figure 3B

Figure 4A

[28] Figures 4A and 4B present the representative structures of the IP4-4,6 substitution derivative compounds of Family B (e.g., Compounds 31-44).

Figure 4B

Figure 5

[29] Figure 5 presents the representative structure of the IP4-4,6 substitution derivative compounds of Family C (e.g., Compounds 45-49).

Figure 6

[30] Figure 6 presents the representative structure of the IP4-4,6 substitution derivative compounds of Family D (e.g., Compounds 50-51).

Figure 7

[31] Figure 7 is a schematic representation of Synthetic Scheme 1.

Figure 8

[32] Figure 8 is a schematic representation of Synthetic Scheme 2.

Figure 9

[33] Figure 9 is a schematic representation of Synthetic Scheme 3.

Figure 10

[34] Figure 10 is a schematic representation of Synthetic Scheme 4.

Figure 11

[35] Figure 11 is a schematic representation of Synthetic Scheme 5.

Figure 12A

[36] Figure 12 shows the mean calcium content (±SD) in (A) the aorta, (B) the heart, (C) the femoral artery, (D) the carotid artery, and (E) the kidneys of sham rats (without VitD3 treatment) and rats treated with vehicle or compound 27 (5, 15, and 45 mg / kg). For the femoral and carotid arteries, the mean values of calcium content in the left and right blood vessels were used. Statistical analysis: one-way ANOVA and Fisher's LSD test for post hoc comparison. (#) indicates a significant difference from the sham, (*) indicates a significant difference from the vehicle, (§) indicates a significant difference from compound 27 at 5 mg / kg (only applicable to the other doses of compound 27), (￥) indicates a significant difference from compound 27 at 15 mg / kg (only applicable to compound 27 at 45 mg / kg), p < 0.05. N = 7 - 12 animals / group.

Figure 12B

Figure 12C

Figure 12D

Figure 12E

Figure 13

[37] Figure 13 shows the normalized mean blood perfusion (±SD) in sham rats (without VitD3 treatment) and rats treated with vehicle, compound 27 (5, 15, and 45 mg / kg) at D13. Statistical analysis: One-way ANOVA and Fisher's LSD test for post hoc comparison. The result of ANOVA was p < 0.0001. (#) indicates a significant difference from the sham, (*) indicates a significant difference from the vehicle, (§) indicates a significant difference from compound 27 at 5 mg / kg (only applicable to the other doses of compound 27), p < 0.05. N = 10 - 12 animals / group.

Figure 14

[38] Figure 14 shows the mean maximum walking distance (±SD) in sham rats (without VitD3 treatment) and rats treated with vehicle, compound 27 (5, 15, and 45 mg / kg). Statistical analysis: One-way ANOVA and Fisher's LSD test for post hoc comparison. The result of ANOVA was p < 0.0001. (#) indicates a significant difference from the sham, (*) indicates a significant difference from the vehicle, (§) indicates a significant difference from compound 27 at 5 mg / kg (only applicable to the other doses of compound 27), (￥) indicates a significant difference from compound 27 at 15 mg / kg (only applicable to compound 27 at 45 mg / kg), (&) indicates a significant difference from compound 27 at 45 mg / kg, p < 0.05.

Figure 15A

[39] Figure 15 shows the culture of aortic valve interstitial cells (VIC) (n = 7, taken from calcified valve donors). The cells were maintained for 3 weeks in basic growth medium (control), osteogenic differentiation medium (Osteodiff), and osteogenic differentiation medium supplemented with (A) IP6, (B) Compound 1, (C) Compound 3, and (D) Compound 6 at various concentrations (1, 3, 10, 30, and 100 μM). Calcification was measured by alizarin red staining and quantified as relative calcification by spectrophotometry. Values are shown as dot plots using the mean value. Along with statistical analysis by Dunnett's post hoc test, one-way analysis of variance for parametric distribution (IP6) was performed. For non-normally distributed results (Compound 1, Compound 3, and Compound 6), non-parametric one-way analysis of variance (Kruskal-Wallis test) was applied along with Dunn's post hoc test. p < 0.05 was considered statistically significant.

Figure 15B

Figure 15C

Figure 15D

Figure 16

[40] Figure 16 shows the analysis of hypermineralization in 10 dpf abcc6a- / - zebrafish larvae using Alizarin Red staining. Larvae were maintained in E3 medium (n=20) and E3 medium supplemented with 1 mM Compound 27 (n=18) from 3 to 10 dpf. After treatment with Compound 27, a significant decrease in spinal cord hypermineralization (black squares) was observed in abcc6a- / - larvae. Quantification of calcified vertebrae in Compound 27-treated and untreated abcc6a- / - larvae via Image J analysis showed a significance of p<0.001. Scale bar: 500 μm. DETAILED DESCRIPTION OF THE INVENTION

[0022]

[41] The present invention provides 4,6-substituted IP4 derivative compounds of general formula I for use in the treatment, inhibition of progression, and prevention of ectopic calcification and resulting conditions:

[0023] [ka]

[0024] In some embodiments, nR1, R3, R7, and R8 are independently substituted or unsubstituted, or a pharmaceutically acceptable salt thereof, or a combination thereof. 11 is OPO3 2- or OPSO2 2- and R5 and R9 are the same. In some embodiments, R5 and R9 are not the same. In some embodiments, the IP4-4,6 derivative is a sodium salt. In some embodiments, 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 deca-sodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, a pentasodium salt, a hexasodium salt, a heptasodium salt, or an octasodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, an octasodium salt, a nonasodium salt, or a deca-sodium salt. In some embodiments, the IP4-4,6 derivative is an octasodium salt.

[0025]

[42] Methods, pharmaceutical compositions and formulations, methods of use, articles of manufacture, and kits for treating, inhibiting progression of, and treating ectopic calcification and resulting conditions, as well as diseases and / or conditions associated with ectopic calcification and resulting conditions, are also provided.

[0026]

[43] In order that the present invention may be more readily understood, certain terms are first defined below. As used in this application, unless otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout this application.

[0027] I. Definitions

[44] The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all, of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0028]

[45] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. For example, 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 Oxford Dictionary of Biochemistry and Molecular Biology, Revised Edition, 2000, Oxford University Press provide those skilled in the art with a general dictionary of many of the terms used in this invention.

[0029]

[46] Units, prefixes, and symbols are expressed in the form approved by these Systeme International d’Unites (SI). Numerical ranges include the numbers defining the limits of the range. When a range of values is recited, it is to be understood that each value between the upper and lower recited limits of such range, and each fraction thereof, as well as each subrange between such values, is also specifically disclosed. It should be understood that the upper and lower limits of any range may independently be included in or excluded from the range, and that ranges encompassing either, neither, or both of the boundaries are also included within the invention.

[0030]

[47] When values are explicitly recited, it is to be understood that values which are substantially the same quantity or amount as the recited values are also included within the scope of the invention. When a combination is disclosed, each subcombination of the elements of that combination is also specifically disclosed and is included within the scope of the invention. Conversely, when different elements or groups of elements are disclosed individually, combinations thereof are also disclosed. When any element of an invention is disclosed as having a plurality of alternative forms, examples of the invention in which each alternative is excluded, either individually or in any combination with other alternatives, are also disclosed herein. More than one element of an invention may have such exclusions, and all combinations of elements having such exclusions are disclosed herein.

[0031]

[48] About: As used herein, the term “about” refers to a value or composition within an acceptable error range for a particular value or composition as determined by one of ordinary skill in the art, which error range is dependent, in part, upon how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within one or more standard deviations, as determined by the conventions in the art. Alternatively, “about” can mean within a range of up to 20%. Further, especially with respect to biological systems or processes, the term can mean within up to one order of magnitude, or up to five-fold, of a value.

[0032]

[49] If a specific value or composition is provided in this application and the claims, unless otherwise stated, the meaning of "about" should be assumed to be within the allowable error range for that specific value or composition. When the term "about" is used in conjunction with a numerical range, this modifies the range by expanding the boundaries above and below the recited numerical values. Thus, "about 10 - 20" means "about 10 - about 20". Generally, the term "about" can modify a numerical value by, for example, plus or minus 10 percent (higher or lower) above and below the stated value.

[0033]

[50] And / or: As used herein, "and / or" when used in this specification, each of the two specified features or components is considered to be a part of the specific invention regardless of the presence of the other. Thus, the term "and / or" when used in this specification in a phrase such as "A and / or B", is intended to include "A and B", "A or B", "A" (alone), and "B" (alone). Similarly, when the term "and / or" is used in a phrase such as "A, B, and / or C", it is intended to include 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).

[0034]

[51] Angina: As used herein, the terms "angina" and "chronic stable angina" relate to chest pain or discomfort resulting from myocardial ischemia. This is a symptom that commonly appears among patients with coronary artery disease (CAD). It is estimated that approximately 9.8 million Americans suffer from angina each year, and 500,000 new cases of angina occur annually.

[0035]

[52] Approximately: As used herein, the term "approximately" when applied to one or more target values refers to a value similar to the stated reference value. In certain embodiments, the term "approximately" refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater than or less than) of the stated reference value, unless otherwise stated or apparent from the context (except when such numbers exceed 100% of the possible values).

[0036]

[53] 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.

[0037]

[54] Calcific aortic valve stenosis: As used herein, the terms "calcific aortic valve stenosis" and "CAVS" refer to one of the most prevalent cardiac valve disorders in developed countries, characterized by progressive fibrotic calcific remodeling and thickening of the aortic valve leaflets. This disease progresses over years and causes severe obstruction of the heart's outflow tract. In developed countries, CAVS is the third most frequent cardiovascular disease after coronary artery disease and systemic arterial hypertension, with a prevalence of 0.4% in the general population and 1.7% in the population >65 years old (Lindman B et al., Nat Rev Dis Primers., 2016; 2:16006).

[0038]

[55] Calciphylaxis: As used herein, the terms "calciphylaxis" and "CUA" refer to a severe, rare disease in which calcium accumulates in the small blood vessels of adipose and skin tissue. CUA can cause blood clots, painful skin ulcers, and severe infections that can lead to death. Subjects with CUA typically suffer from renal insufficiency and may require dialysis. This condition can also occur in people without kidney disease.

[0039]

[56] Cardiovascular diseases in chronic kidney disease: As used herein, the term "cardiovascular diseases in CKD patients" refers to the fact that CKD patients are at high risk of developing cardiovascular diseases such as coronary artery disease, heart failure, arrhythmia, and sudden cardiac death. 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, but it has been shown that the risk is significantly increased in patients with advanced CKD stages (CKD stages 4-5) (Jankowski J et al., Circulation, 2021; 143(11): 1157-1172).

[0040]

[57] Aging-related cardiovascular diseases: As used herein, the term "aging-related cardiovascular diseases" refers to the fact that adults over 65 years of age are at high risk of suffering from cardiovascular diseases such as heart failure, coronary artery disease, hypertension, cerebrovascular diseases, peripheral artery diseases, valvular diseases, and arrhythmias. Aging is associated with changes in the heart and blood vessels that increase the risk of developing cardiovascular diseases in humans (North B et al., Circ Res., 2012; 110(8): 1097-1108). Age is an established, independent risk factor for cardiovascular diseases.

[0041]

[58] Comprising: When an aspect is described herein with the language "comprising", it should always be understood that similar aspects described with "consisting of" and / or "consisting essentially of" are also provided.

[0042]

[59] Compound: As used herein, the term "compound" is intended to include any and all free bases, isomers, and isotopes of the structures shown. As used herein, the term "isomer" means any geometric isomer, tautomer, zwitterion, stereoisomer, enantiomer, or diastereomer of a compound. A compound can contain one or more chiral centers and / or double bonds and thus can 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 those in pure form as stereoisomers (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure form) as well as enantiomeric and stereoisomeric mixtures (e.g., racemates). Enantiomers and stereoisomeric mixtures of compounds and means for resolving them into their enantiomeric or stereoisomeric components are well known. The compounds, salts, or complexes of the present invention can form solvates and hydrates by conventional methods by preparation in combination with a solvent or water molecule. In some embodiments, the term compound is used to refer to the IP4-4,6 substituted derivatives of the present invention.

[0043]

[60] Resulting state: When the phrase "resulting state" refers to a disease or condition disclosed in this specification, it refers to symptoms, sequelae, complications, and combinations thereof related to the 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 in a subject. Generally, this term refers to any pathological phenomenon or deviation from normal in structure, function, or sensation experienced by the subject that suggests a disease. Symptoms are perceived or recognized by the individual experiencing the symptoms, but are not easily recognized by others. In some embodiments, symptoms can be mild, moderate, or severe. As used herein, the term "mild symptom" refers to a symptom that does not affect life and does not require hospitalization or intensive care treatment (e.g., treatment in an ICU of a hospital). As used herein, the term "moderate symptom" refers to a symptom that may affect life and may require hospitalization. As used herein, the term "severe symptom" refers to a symptom that affects life and requires intensive care treatment (e.g., treatment in an ICU of a hospital). As used herein, the term "complication" refers to a pathological process or event that occurs between diseases or conditions and is not a major part of the disease or condition, and complications can occur from the disease / condition or from independent causes. Thus, the term "complication" refers to medical / clinical problems observed in a subject diagnosed with a disease or condition disclosed in this specification. In some embodiments, complications can be temporary. In some embodiments, complications can be chronic or permanent. As used herein, the term "sequela" refers to long-term, chronic, or permanent complications.

[0044]

[61] Critical limb ischemia: As used herein, the terms "critical limb ischemia" and "CLI" refer to severe arterial occlusion that significantly reduces blood flow to the extremities and progresses to the stage of severe pain, skin ulcers, tingling pain, or gangrene. Critical limb ischemia is a very severe state of peripheral artery disease.

[0045]

[62] Heterotopic calcification: As used herein, the term "heterotopic calcification" refers to inappropriate biomineralization occurring in soft tissues. Heterotopic calcification is usually composed of calcium phosphate salts including hydroxyapatite, but may also consist of calcium oxalate and octacalcium phosphate as seen in kidney stones.

[0046]

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

[0047]

[64] The term "effective amount" relates to the specific use of an IP4-4,6 substitution derivative. For example, when an IP4-4,6 substitution derivative is used to inhibit the formation or growth of calcium salts / crystals (e.g., calcium phosphate, HAP), the effective amount is the amount of the IP4-4,6 substitution derivative capable of achieving the desired effect (e.g., a decrease in HAP crystallization / formation in serum or plasma).

[0048]

[65] Enteral administration: As used herein, the term "enteral administration" and the related term "enterally" refer to any administration of an IP4-4,6 substitution derivative of the present invention or a pharmaceutical composition containing said derivative via the gastrointestinal tract. Enteral administrations include, but are not limited to, oral, sublingual, and rectal administration routes.

[0049]

[66] Infantile systemic arterial calcification: As used herein, the terms "infantile systemic arterial calcification" and "GACI" refer to a disorder affecting the circulatory system that becomes apparent prenatally or within the first few months of life and is characterized by abnormal arterial calcification and arterial wall thickening. These changes lead to arterial stenosis and sclerosis, resulting in heart failure in some affected individuals, and the signs and symptoms include dyspnea, edema, cyanosis, hypertension, and cardiomegaly.

[0050]

[67] IP4-4,6 substitution derivatives of the present invention: As used herein, the term "IP4-4,6 substitution derivatives of the present invention" and its grammatical variations refer to the compounds of formula I:

[0051] [Chemical formula]

[0052] [Wherein, R1, R3, R7, and R 11 is OPO3 2- or OPSO2 2- and R5 and R9 may or may not be the same, and the R5 and R9 substituents are the substituents disclosed in the compounds of families A, B, C, and D, and their salts (e.g., their pharmaceutically acceptable salts) described in detail below. In some embodiments, the term "IP4-4,6 substitution derivatives of the present invention" includes compounds 1 to 53, any of their salts (e.g., sodium salts), and any combination thereof. In some embodiments, the term "IP4-4,6 substitution derivatives of the present invention" includes compounds of formula I that are intermediates in the synthesis of compounds 1 to 53, e.g., compounds selected from the group consisting of the compounds listed in Table 1, any of their salts (e.g., sodium salts), and any combination thereof. In some embodiments, the term "IP4-4,6 substitution derivatives of the present invention" includes compounds 1 to compound 53, compounds of formula I that are compounds selected from the group consisting of the compounds listed in Table 1, any of their salts (e.g., sodium salts), and any combination thereof.

[0053]

[68] Group consisting of Compounds 1 to 53: In the context of the present invention, the reference to the "group consisting of Compounds 1 to 53" refers to a group of compounds including Compounds 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 embodiments, the group consisting of Compounds 1 to 53 also includes combinations thereof. In some embodiments, a combination of compounds from the group consisting of Compounds 1 to 53 can include 2, 3, 4, 5, 6, 7, 8, 9, 10 or more compounds from the group consisting of Compounds 1 to 53.

[0054]

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

[0055]

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

[0056]

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

[0057] 72 Parenteral Administration: As used herein, the term "parenteral administration" and the related term "parenterally" refer to administration of a 4,6-substituted IP4 derivative of the present invention characterized by physical incision of a subject's tissue and administration of the derivative through said incision. Parenteral administration includes, but is not limited to, administration of a 4,6-substituted IP4 derivative of the present invention (e.g., a compound selected from the group consisting of Compounds 1-53) or a pharmaceutical composition comprising the derivative, for example, by application of the derivative or composition through a surgical incision or through a non-surgical trauma 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, spinal, subcutaneous, and subcutaneous depot routes of administration.

[0058]

[73] Peripheral arterial disease: As used herein, the terms "peripheral arterial disease" and "PAD" refer to the narrowing and / or hardening of the peripheral arteries to the legs (most common), stomach, arms, and head. Symptoms include intermittent claudication (leg pain that occurs during walking and resolves with rest), skin ulcers, bluish discoloration of the skin, coldness of the skin, or poor growth of nails and hair.

[0059]

[74] Prevention: As used herein, terms such as "prevent", "preventing", and "prevention" refer to inhibiting the onset or reducing the occurrence of a disease or condition in a subject (e.g., preventing ectopic calcification or a condition resulting therefrom in a subject).

[0060]

[75] Primary hyperoxaluria: As used herein, the term "primary hyperoxaluria" or "PH" refers to a disorder of glyoxylate metabolism characterized by excessive oxalate, resulting in kidney stones, nephrocalcinosis, and ultimately renal failure and systemic oxalosis. There are three types of PH. Primary hyperoxaluria type 1 (PH1) is caused by a deficiency of alanine:glyoxylate aminotransferase (AGT), a liver peroxisomal enzyme. This enzyme catalyzes the conversion of glyoxylate to glycine. In the absence of AGT activity, glyoxylate is converted to oxalate, which forms insoluble calcium oxalate crystals that accumulate in the kidneys and other organs. Primary hyperoxaluria type 2 (PH2), which is a genetic disorder caused by mutations in the GRHPR gene, results in the accumulation of excessive amounts of oxalate in the body due to the absence of certain liver enzymes. Primary hyperoxaluria type 3 (PH3) is characterized by recurrent calcium oxalate kidney stones that begin in childhood or adolescence, and in some cases, nephrocalcinosis or decreased renal function.

[0061]

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

[0062]

[77] Pseudoxanthoma elasticum: As used herein, the terms "pseudoxanthoma elasticum" and "PXE" refer to a genetic metabolic disorder with an autosomal recessive inheritance caused by mutations in the ABCC6 gene. The absence of functional ABCC6 protein results in the most obvious ectopic calcification 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, and is slightly more common in women.

[0063]

[78] Range: As described herein, any concentration range, percentage range, ratio range or integer range is considered to include any integer value within the recited range and, where appropriate, fractions thereof (e.g., tenths and hundredths of an integer), unless otherwise indicated.

[0064]

[79] Subject: "Subject" or "individual" or "animal" or "patient" or "mammal" means any subject for which a diagnosis, prognosis, or therapy is desired, particularly a mammalian subject. Mammalian subjects include, but are not limited to, humans, domestic animals, farm animals, zoo animals, sport animals, pets such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cows, dairy cows; primates such as apes, monkeys, orangutans, and chimpanzees; canids such as dogs and wolves; felids such as cats, lions, and tigers; equids such as horses, donkeys, and zebras; bears, food animals such as dairy cows, pigs, and sheep; ungulates such as deer and giraffes; rodents such as mice, rats, hamsters, and guinea pigs, etc. In certain embodiments, the mammal is a human subject. In other embodiments, the subject is a human patient. In certain embodiments, the subject is a human patient having or at risk of having pathological crystallization.

[0065]

[80] Substantially: As used herein, the term "substantially" refers to a qualitative state indicating a complete or nearly complete range or degree of a desired feature or characteristic. One of ordinary skill in the biological arts understands that biological and chemical phenomena rarely, if ever, reach or proceed completely to completion, or achieve or avoid absolute results. Thus, the term "substantially" is used herein to account for the potential lack of completeness inherent in many biological and chemical phenomena.

[0066]

[81] Therapeutic agent: As used herein, the term "therapeutic agent" is used in a broad sense to include compositions containing the IP4-4,6 substitution derivatives of the present invention that can bring about a significant therapeutic benefit to a subject in need of a therapeutic agent. In some embodiments, a subject in need of a therapeutic agent is a subject suffering from or at risk of developing a disease or condition associated with pathological crystallization (e.g., calcium phosphate or HAP crystallization). Thus, generally, the therapeutic agent according to the present invention can be the IP4-4,6 substitution derivative of the present invention alone or in combination with one or more additional therapeutic agents, and this therapeutic agent is administered in an amount sufficient to produce a beneficial or desired result.

[0067]

[82] The term "therapeutic agent" also encompasses prophylactic agents, diagnostic agents or contrast agents containing the IP4-4,6 substitution derivatives of the present invention, and the therapeutic agent is administered (i.e., topically, enterally or parenterally). The therapeutic agent according to the present invention includes agents that can inhibit the formation or growth of calcium salts / crystals (e.g., calcium phosphate, HAP) and / or improve and / or prevent any symptoms associated with pathological crystallization.

[0068]

[83] Topical administration: As used herein, the term "topical administration" and related terms "topically" refer to the administration of either the IP4-4,6 substitution derivatives of the present invention or a pharmaceutical composition containing said derivatives by applying the derivative or composition to a specific location on or within the body, e.g., the skin or mucosa. Examples of topical administration include, but are not limited to, administration routes such as ear, skin, nasal, transdermal, urethral, vaginal, and urethral.

[0069]

[84] Treatment: As used herein, the terms "treat", "treating", and "treatment" refer to the administration of a compound or pharmaceutical composition of the invention to (i) slow, (ii) inhibit the progression of, (iii) stop, or (iv) reverse the progression or condition of a disease after the clinical manifestations thereof have occurred. Control of disease progression is considered to mean a beneficial or desired clinical outcome, which includes, but is not limited to, reduction in symptoms, reduction in disease duration, stabilization of a pathological condition (especially to avoid additional worsening), delay in the progression of the disease, improvement and remission (both partial and complete) of the pathological condition. Control of disease progression also includes an extension of survival as compared to the expected survival in the absence of treatment. In the context of the present invention, the terms "treat" and "treatment" specifically (a) stop, reduce, inhibit the progression of, or reverse the development of heterotopic calcification and the resulting pathological conditions, (b) improve the motor or walking ability (e.g., speed, distance, endurance) in a subject to which the compound or pharmaceutical composition of the invention is administered, (c) refer to reducing or improving the quality of life in a subject to which the compound or pharmaceutical composition of the invention is administered.

[0070]

[85] ug, uM, uL: As used herein, the terms "ug", "uM", and "uL" are used interchangeably with "μg", "μM", and "μL", respectively.

[0071] II. IP4-4,6 Replacement Derivatives

[86] The present invention discloses IP4-4,6 substitution derivatives, methods for their synthesis, and their uses. In some embodiments, the IP4-4,6 substitution derivatives are compounds of general formula I:

[0072] [Chemical formula]

[0073] [wherein, R1, R3, R7, and R11 independently represents OPO3 2- or OPSO2 2- and R5 and R9 are substituents. In some embodiments, R5 and R9 are the same substituent. In some embodiments, R5 and R9 are not the same substituent. In some embodiments, the IP4-4,6 substituted derivative of the present invention is an acceptable salt (e.g., a pharmaceutically acceptable salt) of the compound of formula I or a combination thereof.

[0074]

[87] In some embodiments, not all of the negative charges in the IP4-4,6 derivative of the present invention are neutralized by the charge of a positively charged ion. Thus, the IP4-4,6 derivative of the present invention can be, for example, a tetraionic salt (e.g., a tetrasodium salt), a pentaionic salt (e.g., a pentasodium salt), a hexaionic salt (e.g., a hexasodium salt), a heptaionic salt (e.g., a heptasodium salt), an octaionic salt (e.g., an octasodium salt), a nonaionic salt (e.g., a nonasodium salt) or a decaionic salt (e.g., a decasodium salt). In some embodiments, the presence of an additional negatively charged group in the IP4-4,6 substituted derivative can result in the formation of a complex with an additional ion. In some embodiments, the IP4-4,6 derivative of the present invention is a sodium salt. In some embodiments, 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 embodiments, the IP4-4,6 derivative is a tetrasodium salt, a pentasodium salt, a hexasodium salt, a heptasodium salt or an octasodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, an octasodium salt, a nonasodium salt or a decasodium salt. Formula I and the remaining formulas presented in the present invention are intended to encompass all isomers of the compounds covered herein.

[0075]

[88] As used in the context of the present invention, the term "alkenyl" or "alkenyl chain" refers to a linear or branched alkyl chain (e.g., containing 2 to 10 carbon atoms) that is substituted or unsubstituted and contains one or more double bonds. By way of example, among others, ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, and 1,3-butadienyl may be mentioned.

[0076]

[89] As used in the context of the present invention, the term "alkyl" or "alkyl chain" refers to a saturated hydrocarbon moiety, which can be linear, branched, cyclic, or cyclic with linear or branched side chains. The term alkyl includes partially unsaturated hydrocarbons, such as propenyl. Examples are methyl, ethyl, propyl, isopropyl, n- or isobutyl, n- or cyclohexyl. The term alkyl can be extended to include alkyl groups bonded or bridged by heteroatoms. In the context of the present invention, heteroatoms are nitrogen (N), sulfur (S), oxygen (O), and halogen.

[0077]

[90] As used in the context of the present invention, the term "alkynyl" or "alkynyl chain" refers to a linear or branched alkyl chain (e.g., containing 2 to 10 carbon atoms) that is substituted or unsubstituted and contains one or more triple bonds. By way of example, among others, ethynyl, propynyl, 1-butynyl, and 3-butynyl may be mentioned.

[0078]

[91] "Amine functional group" or "amine group" is the functional group NRR', where R and R' are independently selected from, for example, hydrogen (-H) and alkyl groups, such as C1~C n alkyl (where n is an integer from 0 to 20).

[0079]

[92] "Hydroxy functional group" or "hydroxy group" is OH.

[93] "Carboxylic acid functional group" or "carboxylic acid group" is COOH or its anion, COO - -.

[0080]

[94] "Carboxamide" is CONRR' or NCOR, where R and R' are independently, for example, hydrogen (-H) and an alkyl group, such as C1-C n alkyl (where n is an integer from 0 to 20).

[0081]

[95] "Carbocyclic ring" can be saturated, partially unsaturated or aromatic (e.g., phenol, cyclopentane, cyclopropane), and refers to a 3- to 10-membered carbocyclic ring that is bonded to the rest of the molecule via any available C atom. This term includes carbocyclic rings substituted with one or more heteroatoms (e.g., N, O, halogen atoms).

[0082]

[96] "Heterocyclic ring" can be saturated, partially unsaturated or aromatic (e.g., triazole, piperazine, pyrazole, thiophene), and refers to a 3- to 10-membered cyclic ring containing at least one heteroatom selected from N, O, and S that is bonded to the rest of the molecule via any available C atom or N atom. This term includes heterocyclic rings substituted with one or more halogen atoms.

[0083]

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

[0084]

[98] "Halogen" group refers to fluorine, chlorine, bromine or iodine.

[99] "OPO3" 2- ", in the context of the present invention, also, although not explicitly, refers to OPO3H - and OPO3H2."

[0085]

[0100] In some embodiments, the IP4-4,6 substitution derivatives or intermediate compounds of the invention disclosed herein can be detected and / or quantified using the methods disclosed in US9612250. See also US8377909, US8778912, and US20070066574.

[0086]

[0101] The IP4-4,6 substitution derivatives of the invention can exist in any form commonly used in pharmaceutical technology. Specific embodiments 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 the methods described previously (Haynes M et al., J. Pharmaceutical Sci., 2005; 94:2111-2120).

[0087]

[0102] In some embodiments, R1, R3, R7, and R 11 each independently represent a phosphate ion (-OPO3 2- ), R5 / R9 corresponds to the formula -O-(alkyl) n -X (i.e., R5 / R9 is an alkyl chain with or without a branch), where n is an integer from 1 to 20, and the terminal group X is selected from the group consisting of -H, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', halogen, -CF3, alkyl, alkenyl, alkynyl, carbocyclic (saturated or unsaturated), and heterocyclic (saturated or unsaturated), and R and R' are H or an alkyl group. Throughout the present invention, this family of IP4-4,6 substitution derivatives is named Family A.

[0088]

[0103] In some embodiments, R1, R3, R7, and R 11 each independently represents a phosphate ion (-OPO3 2- ), and R5 / R9 corresponds to the formula -O-(alkyl) y -Cy-(alkyl) y’ -Z (i.e., R5 / R9 includes two alkyl chains linked by a cyclic linker inserted between the two alkyl chains), where each alkyl contains y carbon (e.g., CH2) units, y and y' are integers from 0 to 10, and the terminal alkyl chain contains 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 R and R' are H or an alkyl group. Throughout the present invention, this family of IP4-4,6 substitution derivatives is named Family B.

[0089]

[0104] In some embodiments, R1, R3, R7, and R 11 each independently represents a phosphate ion (-OPO3 2- ), and R5 / R9 corresponds to the formula -O-(alkyl) y -A-(alkyl) y’ -Z' (i.e., two alkyl chains linked by a linker A inserted between the two alkyl chains), where each alkyl chain contains y carbon (e.g., CH2) units, y and y' are integers from 0 to 10, the linker A is selected from the group consisting of -CONR-, -NHCOO-, -NHSO2-, -NHCONR-, -NHCO- and -OCONR-, and the terminal alkyl chain contains a terminal group Z' selected from the group consisting of -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', a carbocyclic ring (saturated or unsaturated), and a heterocyclic ring (saturated or unsaturated), and R and R' are H or an alkyl group. Throughout the present invention, this family of IP4-4,6 substitution derivatives is named Family C.

[0090]

[0105] In one aspect, the IP4-4,6 substitution derivatives of family D are analogs of the compounds of family A, B, or C, where at least one of R1, R3, R7, or R 11 is a thiophosphate ion (-OPSO2 2- ). Throughout the present invention, this family of IP4-4,6 substitution derivatives is named family D.

[0091]

[0106] In some aspects of the IP4-4,6 substitution derivatives of family D, in the compounds of family A, B, or C, one of R1, R3, R7, or R 11 is a thiophosphate ion (-OPSO2 2- ). In some aspects of the IP4-4,6 substitution derivatives of family D, in the compounds of family A, B, or C, two of R1, R3, R7, or R 11 are thiophosphate ions (-OPSO2 2- ). In some aspects of the IP4-4,6 substitution derivatives of family D, in the compounds of family A, B, or C, three of R1, R3, R7, or R 11 are thiophosphate ions (-OPSO2 2- ). In some aspects of the IP4-4,6 substitution derivatives of family D, in the compounds of family A, B, or C, R1, R3, R7, or R 11 is a thiophosphate ion (-OPSO2<U+ 2- ).

[0092]

[0107] In some aspects of the IP4-4,6 substitution derivatives of family D, the family D compound contains a thiophosphate ion (-OPSO2 2- ) only at the position of R1. In some aspects of the IP4-4,6 substitution derivatives of family D, the family D compound contains a thiophosphate ion (-OPSO2 2- ) only at the position of R3. In some aspects of the IP4-4,6 substitution derivatives of family D, the family D compound contains a thiophosphate ion (-OPSO2 2-contains. In some embodiments of the IP4-4,6 substitution derivatives of Family D, the Family D compound has thiophosphate ions (-OPSO2 11 ) only at the position of R 2- . In some embodiments of the IP4-4,6 substitution derivatives of Family D, the Family D compound has thiophosphate ions (-OPSO2 11 ) at the positions of R1, R3, R7, and R 2- . In some embodiments of the IP4-4,6 substitution derivatives of Family D, the Family D compound has thiophosphate ions (-OPSO2 2- ) at the positions of R1 and R3. In some embodiments of the IP4-4,6 substitution derivatives of Family D, the Family D compound has thiophosphate ions (-OPSO2 2- ) at the positions of R1 and R7. In some embodiments of the IP4-4,6 substitution derivatives of Family D, the Family D compound has thiophosphate ions (-OPSO2 11 ) at the positions of R1 and R 2- . In some embodiments of the IP4-4,6 substitution derivatives of Family D, the Family D compound has thiophosphate ions (-OPSO2 2- ) at the positions of R3 and R7. In some embodiments of the IP4-4,6 substitution derivatives of Family D, the Family D compound has thiophosphate ions (-OPSO2 11 ) at the positions of R3 and R 2- . In some embodiments of the IP4-4,6 substitution derivatives of Family D, the Family D compound has thiophosphate ions (-OPSO2 11 ) at the positions of R7 and R 2- . In some embodiments of the IP4-4,6 substitution derivatives of Family D, the Family D compound has thiophosphate ions (-OPSO2 2- ) at the positions of R1, R3, and R7. In some embodiments of the IP4-4,6 substitution derivatives of Family D, the Family D compound has thiophosphate ions (-OPSO2 11 ) at the positions of R1, R3, and R 2- . In some embodiments of the IP4-4,6 substitution derivatives of Family D, the Family D compound has thiophosphate ions (-OPSO2 11contains thiophosphate ion (-OPSO2 at the position of 2- ). In some embodiments of the IP4-4,6 substitution derivatives of Family D, the Family D compound contains thiophosphate ion (-OPSO2 at the position of R1, R7, and R 11 ). 2- ).

[0093]

[0108] In some embodiments, the IP4-4,6 substitution derivatives of the present invention include IP4-4,6 substitution derivatives of Family A, Family B, Family C, Family D, or a combination thereof.

[0094]

[0109] In some embodiments, the IP4-4,6 substitution derivatives of the present invention include IP4-4,6 substitution derivatives of Family A. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include IP4-4,6 substitution derivatives of Family B. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include IP4-4,6 substitution derivatives of Family C. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include IP4-4,6 substitution derivatives of Family D.

[0095]

[0110] In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of IP4-4,6 substitution derivatives selected from the group consisting of Compounds 1 to 53 and combinations thereof. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of IP4-4,6 substitution derivatives selected from the group consisting of Compounds 1 to 30 and combinations thereof. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of IP4-4,6 substitution derivatives selected from the group consisting of Compounds 31 to 44 and combinations thereof. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of IP4-4,6 substitution derivatives selected from the group consisting of Compounds 45 to 49 and combinations thereof. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of IP4-4,6 substitution derivatives selected from the group consisting of Compounds 50 to 51 and combinations thereof. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of Compound 1. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of Compound 2. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of Compound 3. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of Compound 4. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of Compound 5. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of Compound 6. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of Compound 7. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of Compound 8. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of Compound 9. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of Compound 10. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of Compound 11. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of Compound 12. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of Compound 13. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of Compound 14. In some embodiments, the IP4-4,6 substitution derivatives of the present invention include or consist of Compound 15.In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 16. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 17. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 18. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 19. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 20. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 21. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 22. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 23. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 24. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 25. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 26. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 27. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 28. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 29. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 30. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 31. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 32. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 33. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 34. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 35. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 36. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 37. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 38. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 39.In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 40. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 41. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 42. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 43. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 44. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 45. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 46. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 47. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 48. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 49. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 50. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 51. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 52. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 53.

[0096]

[0111] In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 1 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 2 analogs, where R1, R3, R7, or R11 ; 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 3 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 4 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 5 analogs, where 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 is a thiophosphate ion (-OPSO2 2- )). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of Compound 6 analogs, 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 is a thiophosphate ion (-OPSO2 2- )). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of Compound 7 analogs, 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 is a thiophosphate ion (-OPSO2 2- )). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of Compound 8 analogs, 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[[ID=*57]] 11 ; R1, R3, and R7; R1, R3, and R 11 It should be noted that there may be a minor error in the original text where " 11 " has an asterisk in the translated version which seems not correct in the context. But following the rules strictly, this is the translation result.; R3, R7, and R 11 ; or R1, R7, and R 11 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of Compound 9 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of Compound 10 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of Compound 11 analogs, where 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 is a thiophosphate ion (-OPSO2 2-) is. In some embodiments, the IP4-4,6 substituted derivative of the present invention comprises or consists of a compound 12 analog, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivative of the present invention comprises or consists of a compound 13 analog, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivative of the present invention comprises or consists of a compound 14 analog, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivative of the present invention comprises or consists of a compound 15 analog, where R1, R3, R7, or R11 ; 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 is a thiophosphate ion (-OPSO2 2- )). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of Compound 16 analogs, where 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 is a thiophosphate ion (-OPSO2 2- )). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of Compound 17 analogs, where 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 is a thiophosphate ion (-OPSO2 2- )). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of Compound 18 analogs, where 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 is a thiophosphate ion (-OPSO2 2- )). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 19 analogs, where 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 is a thiophosphate ion (-OPSO2 2- )). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 20 analogs, where 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 is a thiophosphate ion (-OPSO2 2- )). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 21 analogs, where 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 R11 ; R3, R7, and R 11 ; or R1, R7, and R 11 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivative of the present invention comprises or consists of a compound 22 analog, 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivative of the present invention comprises or consists of a compound 23 analog, 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivative of the present invention comprises or consists of a compound 24 analog, 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 11is the thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of Compound 25 analogs, where 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 is the thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of Compound 26 analogs, where 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 is the thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of Compound 27 analogs, where 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 is the thiophosphate ion (-OPSO2 2-) is. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of compound 28 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ) is. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of compound 29 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ) is. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of compound 30 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ) is. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of compound 31 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 32 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 33 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 34 analogs, where 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 R11 ; R7 and R 11 ; R1, R3, and R7; R1, R3, and R 11 ; R3, R7, and R 11 ; or R1, R7, and R 11 is a thiophosphate ion (-OPSO2 2- )). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 35 analogs, where 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 is a thiophosphate ion (-OPSO2 2- )). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 36 analogs, where 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 is a thiophosphate ion (-OPSO2 11 )). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 37 analogs, where R1, R3, R7, or R 2- ; 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 11; R3, R7, and R 11 ; or R1, R7, and R 11 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 38 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 39 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 40 analogs, where 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 is a thiophosphate ion (-OPSO2 2-) is. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 41 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ) is. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 42 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ) is. In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 43 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substitution derivatives of the present invention comprise or consist of Compound 44 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 45 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 46 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 47 analogs, where 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 R11 ; R7 and R 11 ; R1, R3, and R7; R1, R3, and R 11 ; R3, R7, and R 11 ; or R1, R7, and R 11 is a thiophosphate ion (-OPSO2 2- )). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 48 analogs, where 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 is a thiophosphate ion (-OPSO2 2- )). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 49 analogs, where 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 is a thiophosphate ion (-OPSO2 2- )). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 50 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 51 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 52 analogs, where 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 is a thiophosphate ion (-OPSO2 2- ). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 53 analogs, where 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 is a thiophosphate ion (-OPSO2 2-) is as follows.

[0097]

[0112] In some embodiments, the alkyl moieties in the R5 and R9 substituents of the IP4-4,6 substituted derivatives of the present invention each contain at least one double or triple carbon bond, i.e., form an alkenyl chain or an alkynyl chain, respectively. In some embodiments, the alkenyl chains in the R5 and R9 substituents are the same. In some embodiments, the alkenyl chains in the R5 and R9 substituents are different. In some embodiments, the alkynyl chains in the R5 and R9 substituents are the same. In some embodiments, the alkynyl chains in the R5 and R9 substituents are different. In some embodiments, the alkyl moieties in the R5 and R9 substituents contain at least one double carbon bond and at least one triple carbon bond, forming a combination of an alkenyl chain and an alkynyl chain. In some embodiments, the combination of the alkenyl chain and the alkynyl chain in the R5 and R9 substituents is the same. In some embodiments, the combination of the alkenyl chain and the alkynyl chain in the R5 and R9 substituents is different. In some embodiments, the IP4-4,6 substituted derivatives of the present invention in which the alkyl moiety of the R5 or R9 substituent contains at least one double or triple carbon bond are Family A compounds. In some embodiments, the Family A compounds containing at least one double or triple carbon bond are Compounds 1 to 30 and Compound 52.

[0098]

[0113] In some embodiments, the IP4-4,6 substituted derivatives of the present invention are compounds of the following formula:

[0099] [Chemical formula]

[0100] [wherein, n is an integer from 1 to 20, alkyl is CH2, and X is -H] is included or consists of. In some embodiments, 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 embodiments, the IP4-4,6 derivative is a sodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is an octasodium salt. In some embodiments, n is 5, alkyl is CH2, and X is -H (Compound 1). In some embodiments, n is 10, alkyl is CH2, and X is -H (Compound 2). In some embodiments, n is 14, alkyl is CH2, and X is -H (Compound 3). In some embodiments, n is 3, alkyl is CH2, and X is -H (Compound 4). In some embodiments, n is 7, alkyl is CH2, and X is -H (Compound 5).

[0101]

[0114] In some embodiments, the IP4-4,6 substituted derivative of the present invention is a compound of the following formula:

[0102]

Chemical formula

[0103] [wherein, n is an integer of 1 to 20, alkyl is CH2, and X is selected from the group consisting of -OH and -OMe], or consists of. In some embodiments, the IP4-4,6 derivative is a sodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is an octasodium salt. In some embodiments, 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 embodiments, n is 5, alkyl is CH2, and X is -OH (Compound 6). In some embodiments, n is 10, alkyl is CH2, and X is -OH (Compound 7). In some embodiments, n is 14, alkyl is CH2, and X is -OH (Compound 8). In some embodiments, n is 5, alkyl is CH2, and X is -OMe (Compound 9). In some embodiments, n is 3, alkyl is CH2, and X is -OMe (Compound 10). In some embodiments, n is 7, alkyl is CH2, and X is -OMe (Compound 11). In some embodiments, n is 9, alkyl is CH2, and X is -OMe (Compound 12). In some embodiments, n is 19, alkyl is CH2, and X is -OMe (Compound 20).

[0104]

[0115] In some embodiments, the IP4-4,6 substituted derivative of the present invention is a compound of the following formula:

[0105]

Chemical formula

[0106] [wherein, n is an integer from 1 to 20, alkyl is CH2, and X is an amine group] is included or consists of. In some embodiments, 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 embodiments, the IP4-4,6 derivative is a sodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt. In some embodiments, n is 3, alkyl is CH2, and X is -NH2 (Compound 13). In some embodiments, n is 5, alkyl is CH2, and X is -NH2 (Compound 14). In some embodiments, n is 10, alkyl is CH2, and X is -NH2 (Compound 15).

[0107]

[0116] In some embodiments, the IP4-4,6 substituted derivative of the present invention is a compound of the following formula:

[0108]

Chemical formula

[0109] [wherein, n is an integer from 1 to 20, alkyl is CH2, and X is pyrazole or triazole] is included or consists of. In some embodiments, 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 embodiments, the IP4-4,6 derivative is a sodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is an octasodium salt. In some embodiments, n is 5, alkyl is CH2, and X is pyrazole (Compound 16). In some embodiments, n is 5, alkyl is CH2, and X is triazole (Compound 17).

[0110]

[0117] In some embodiments, the IP4-4,6 substituted derivative of the present invention is a compound of the following formula:

[0111]

Chemical formula

[0112] [wherein, n is an integer from 1 to 20, alkyl is CH2, and X is -COOH] is included or consists of. In some embodiments, 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 embodiments, the IP4-4,6 derivative is a sodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is an octasodium salt or decasodium salt. In some embodiments, n is 5, alkyl is CH2, and X is -COOH (Compound 18). In some embodiments, n is 10, alkyl is CH2, and X is -COOH (Compound 19). In some embodiments, n is 3, alkyl is CH2, and X is -COOH (Compound 52).

[0113]

[0118] In some embodiments, the IP4-4,6 substituted derivative of the present invention is a compound of the following formula:

[0114]

Chemical formula

[0115] [wherein, n is an integer from 1 to 20, alkyl is CH2, and X is -CONRR’, -NHCOR, -NHCOOR, -NHCONRR’ or -CF3] is included or consists of. In some embodiments, 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 embodiments, the IP4-4,6 derivative is a sodium salt. In some embodiments, 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 embodiments, the IP4-4,6 derivative is a tetrasodium salt, a pentasodium salt, a hexasodium salt, a heptasodium salt or an octasodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, an octasodium salt, a nonasodium salt or a decasodium salt. In some embodiments, the IP4-4,6 derivative is an octasodium salt. In some embodiments, n is 3, alkyl is CH2, and X is -CF3 (Compound 22). In some embodiments, n is 5, alkyl is CH2, and X is -CF3 (Compound 23). In some embodiments, n is 3, alkyl is CH2, and X is -NHCOOMe (Compound 24). In some embodiments, n is 5, alkyl is CH2, and X is -NHCOOMe (Compound 25). In some embodiments, n is 3, alkyl is CH2, and X is -CONH2 (Compound 26). In some embodiments, n is 5, alkyl is CH2, and X is -NHCOMe (Compound 27). In some embodiments, n is 5, alkyl is CH2, and X is -NHCONHPr (Compound 30).

[0116]

[0119] In some embodiments, the IP4-4,6 substituted derivative of the present invention is a compound of the following formula:

[0117]

Chemical formula

[0118] [wherein n is an integer from 1 to 20, alkyl is CH2, and X is cyclopropane or cyclopentane] is included or consists of. In some embodiments, 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 embodiments, the IP4-4,6 derivative is a sodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is an octasodium salt. In some embodiments, n is 2, alkyl is CH2, and X is cyclopropane (Compound 28). In some embodiments, n is 2, alkyl is CH2, and X is cyclopentane (Compound 29).

[0119]

[0120] In some embodiments, the IP4-4,6 substituted derivative of the present invention is a compound of the following formula:

[0120]

Chemical formula

[0121] [wherein, n is an integer of 1 to 20, the alkyl is branched, and X is -H] is included or consists of. In some embodiments, 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 embodiments, the IP4-4,6 derivative is a sodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is an octasodium salt. In some embodiments, the IP4-4,6 substituted derivative of the present invention includes or consists of Compound 21 as shown in FIG. 3B.

[0122]

[0121] In some embodiments, the IP4-4,6 substituted derivative of the present invention is a compound of the following formula:

[0123]

Chemical formula

[0124] [wherein, n is an integer of 1 to 20, alkyl is an alkynyl chain, and X is -H] is included or consists of. In some embodiments, 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 embodiments, the IP4-4,6 derivative is a sodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is an octasodium salt. In some embodiments, the IP4-4,6 substituted derivative of the present invention includes or consists of compound 53 as shown in FIG. 3B.

[0125]

[0122] In some embodiments, the IP4-4,6 substituted derivative of the present invention is a compound of the following formula:

[0126]

Chemical formula

[0127] [wherein, y and y' are integers from 0 to 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] is included or consists of. See Figure 4A. In some embodiments, the IP4-4,6 derivative is a sodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, or octasodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP4-4,6 derivative is an octasodium salt or nonasodium salt. In some embodiments, y or y' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, y is 1, y' is 2, alkyl is CH2, Cy is triazole-2, and Z is -COOH (Compound 31). In some embodiments, y is 1, y' is 3, alkyl is CH2, Cy is triazole-2, and Z is -OMe (Compound 32). In some embodiments, y is 1, y' is 6, alkyl is CH2, Cy is triazole-2, and Z is -OMe (Compound 33). In some embodiments, y is 2, y' is 0, alkyl is CH2, Cy is piperazine, and Z is -COCH3 (Compound 34). In some embodiments, y is 3, y' is 2, alkyl is CH2, Cy is triazole-1, and Z is -COOH (Compound 35). In some embodiments, y is 3, y' is 1, alkyl is CH2, Cy is triazole-1, and Z is -OMe (Compound 36). In some embodiments, y is 4, y' is 1, alkyl is CH2, Cy is triazole-1, and Z is -OMe (Compound 37). In some embodiments, y is 5, y' is 1, alkyl is CH2, Cy is triazole-1, and Z is -OMe (Compound 38).In some embodiments, y is 6, y' is 1, alkyl is CH2, Cy is triazole-1, and Z is -OMe (Compound 39). In some embodiments, y is 6, y' is 0, alkyl is CH2, Cy is triazole-1, and Z is -COOH (Compound 40). In some embodiments, y is 6, y' is 1 / 0, alkyl is CH2, Cy is triazole-1, and Z is -OMe / -COOH (Compound 41).

[0128]

[0123] In some embodiments, the IP4-4,6 substituted derivative of the present invention is a compound of the following formula:

[0129]

Chemical formula

[0130] [wherein, y and y' are integers from 0 to 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] is included or consists of. See FIG. 4B. In some embodiments, the IP4-4,6 derivative is a sodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is an octasodium salt. In some embodiments, y or y' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some embodiments, y is 3, y' is 0, alkyl is CH2, Cy is 1,4-substituted phenyl, and Z is -Me (Compound 42). In some embodiments, y is 3, y' is 0, alkyl is CH2, Cy is 1,4-substituted phenyl, and Z is -OMe (Compound 43). In some embodiments, y is 3, y' is 0, alkyl is CH2, Cy is 1,3-substituted phenyl, and Z is -CF3 (Compound 44).

[0131]

[0124] In some embodiments, the IP4-4,6 substituted derivative of the present invention is a compound of the following formula:

[0132]

Chemical formula

[0133] [wherein, y and y' are integers from 0 to 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 thiophenyl] is included or consists of. In some embodiments, the IP4-4,6 derivative is a sodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt or octasodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt. In some embodiments, the IP4-4,6 derivative is an octasodium salt or decasodium salt. In some embodiments, y or y' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In some embodiments, y is 3, y' is 3, alkyl is CH2, A is -NHCO, and Z is -COOH (Compound 45). In some embodiments, y is 3, y' is 0, alkyl is CH2, A is -NHCONH, and Z is phenyl (Compound 46). In some embodiments, y is 3, y' is 0, alkyl is CH2, A is -NHCONH, and Z is cyclopentyl (Compound 47). In some embodiments, y is 5, y' is 0, alkyl is CH2, A is -NHCO, and Z is phenyl (Compound 48). In some embodiments, y is 5, y' is 0, alkyl is CH2, A is -NHCO, and Z is thiophenyl (Compound 49).

[0134]

[0125] In some embodiments, the IP4-4,6 substitution derivative of the present invention is a compound of the following formula:

[0135]

Chemical formula

[0136] [wherein n is an integer from 1 to 20, alkyl is CH2, and X is selected from the group consisting of -H and -OMe] is included or consists of. In some embodiments, 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 embodiments, the IP4-4,6 derivative is a sodium salt. In some embodiments, 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 embodiments, the IP4-4,6 derivative is a tetrasodium salt, a pentasodium salt, a hexasodium salt, a heptasodium salt or an octasodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, an octasodium salt, a nonasodium salt or a decasodium salt. In some embodiments, the IP4-4,6 derivative is an octasodium salt. In some embodiments, n is 5, alkyl is CH2, and X is -H (Compound 50). In some embodiments, n is 5, alkyl is CH2, and X is -OMe (Compound 51).

[0137]

[0126] The IP4-4,6 derivative of the present invention is disclosed in the myo form. However, the present invention is also intended to encompass other isomers of all inositol scaffolds, such as the scyllo, muco, 1D-chiro, 1L-chiro, neo, allo, epi, and cis equivalents of the IP4-4,6 derivative of the present invention.

[0138]

[0127] The present invention also provides chemical intermediate compounds useful for the preparation of the IP4-4,6 substituted derivatives of the present invention (e.g., Compounds 1 to 53). In some embodiments, such intermediates are the compounds listed in Table 1. The intermediate compounds disclosed herein can be converted into the IP4-4,6 substituted derivatives of the present invention by utilizing the procedures described herein. Thus, the present invention provides a method for producing an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53), which includes using an intermediate compound selected from the group consisting of the compounds listed in Table 1. The present invention also provides a method for producing the intermediate compounds disclosed herein. Accordingly, the present invention provides a method for producing an intermediate compound selected from the group consisting of the compounds listed in Table 1 for producing an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53).

[0139]

Table 2-1

[0140]

Table 2-2

[0141]

Table 2-3

[0142]

Table 2-4

[0143]

Table 2-5

[0144]

Table 2-6

[0145]

Table 2-7

[0146]

Table 2-8

[0147]

Table 2-9

[0148]

[0128] The IP4-4,6 substitution derivatives and intermediates of the present invention for these syntheses can be synthesized by using the methods described herein and other methods known in the field of organic chemistry. In some embodiments, the methods include, but are not limited to, the general procedures shown in Synthesis Schemes 1, 2, 3, and 4 described herein. Thus, in some embodiments, the present invention provides a method for producing an IP4-4,6 substitution derivative of the present invention, which includes applying Synthesis Scheme 1 disclosed below. In some embodiments, the present invention provides a method for producing an IP4-4,6 substitution derivative of the present invention, which includes applying Synthesis Scheme 2 disclosed below. In some embodiments, the present invention provides a method for producing an IP4-4,6 substitution derivative of the present invention, which includes applying Synthesis Scheme 3 disclosed below. In some embodiments, the present invention provides a method for producing an IP4-4,6 substitution derivative of the present invention, which includes applying Synthesis Scheme 4 disclosed below.

[0149] In some embodiments, the present invention provides a method for producing an intermediate for the synthesis of an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53), the method comprising applying Synthesis Scheme 1 disclosed below. In some embodiments, the present invention provides a method for producing an intermediate for the synthesis of an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53), the method comprising applying Synthesis Scheme 2 disclosed below. In some embodiments, the present invention provides a method for producing an intermediate for the synthesis of an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53), the method comprising applying Synthesis Scheme 3 disclosed below. In some embodiments, the present invention provides a method for producing an intermediate for the synthesis of an IP4-4,6 substituted derivative of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53), the method comprising applying Synthesis Scheme 4 disclosed below.

[0150]

[0130] Scheme 1: The IP4-4,6 substitution derivatives of the present invention can be obtained, for example, by deprotection of the intermediates of formula IV (e.g., intermediates IV-1 to IV-48) and the intermediates of formula IV' (e.g., intermediates IV'-1 to IV'-2). See Scheme 1, Figure 7. "Protecting group" or PG can be, without limitation, in any case, benzyl, levulinyl benzyl, tert-butyl, o-xylyl (e.g., by bonding of two PGs within the same phosphate ion), 9-fluorenylmethyl, cyanoethyl and other suitable protecting groups. The intermediates of formula IV (e.g., intermediates IV-1 to IV-48) can be achieved, for example, by phosphorylation of the intermediates of formula III according to the procedures described in the literature, for example, by reaction with a phosphoramidite derivative, and subsequent oxidation with an oxidizing agent (e.g., m-CPBA, H2O2, tBuOOH). The intermediates of formula IV' (e.g., intermediates IV'-1 to IV'-2) can be achieved, for example, by thiophosphorylation of the intermediates of formula III according to the procedures described in the art, for example, by reaction with a phosphoramidite derivative, and subsequent thiooxidation with sulfur. At the same time, the intermediates of formula III (e.g., intermediates III-1 to III-47) can be obtained, for example, by hydrolysis of the intermediates of formula II (e.g., intermediates II-1 to II-27) in an acidic medium. Finally, the intermediates of formula II (e.g., intermediates II-1 to II-27) can be obtained, for example, by alkylation of compound (2) with an alkylating agent. The preparation of (2) has been previously described in the literature (Martin S et al., J. Org. Chem., 1994; 59: 4805; Kardivel M, Org. & Biomolecular Chem., 2008; 6(11): 1966 - 72). "Leaving group" or LG can be, without limitation, chloride, bromide, iodide, toluenesulfonyl (Ts) or methylsulfonyl (Ms).

[0151]

[0131] Scheme 2: As an alternative to Scheme 1, for example, when R5 and R9 contain a substituted 1,2,3-triazole, the compound of formula I (i.e., the IP4-4,6 substituted derivative of the present invention) can be obtained by following the alternative route described in Scheme 2 (Figure 8). In such a manner, the intermediate of formula III (e.g., intermediate III-20, III-26, and III-27) can be obtained via a click reaction, for example, by using either the intermediate of formula VI (e.g., intermediate VI-1) and an alkyl agent as starting materials. Intermediate VI (e.g., intermediate VI-1) can be achieved by alkylation and hydrolysis of intermediate 2 using appropriate reagents.

[0152]

[0132] Scheme 3: As another alternative to Scheme 1 and Scheme 2, for example, when R5 and R9 contain a substituted 1,2,3-triazole, the compound of formula I (i.e., the IP4-4,6 substituted derivative of the present invention) can be obtained by the alternative route described in Scheme 3 (Figure 9). In this case, the intermediate of formula III (e.g., intermediate III-21~III-25, III-42, and III-43) can be obtained via a click reaction, for example, by using the intermediate of formula IX (e.g., intermediate IX-1~IX5) and an alkynyl click reagent as starting materials. Intermediate IX can be achieved by alkylation and hydrolysis of compound 2 using an azidoalkylating agent. As another alternative to Scheme 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 as shown in Scheme 3 (Figure 9). Thus, the intermediate IX (e.g., intermediate IX-1~IX-5) can be phosphorylated to obtain the intermediate X (e.g., intermediate X-1~X3), and then the intermediate X can be deprotected to obtain the compound of formula I.

[0153]

[0133] Scheme 4: As an additional alternative to Scheme 1, when R5 and R9 contain a substituted amide, sulfonamide, carbamate or urea, Intermediate III (e.g., Intermediate III-28, III-36 to III-41, and III-44 to III-46) can be obtained as shown in Figure 10. Thus, Intermediate III (e.g., Intermediate III-28, III-36 to III-41, and III-44 to III-46) can be achieved from Intermediate VIII (e.g., Intermediate VIII-1 to VIII-5) via azide reduction (e.g., Intermediate XI-1 to XI-2), subsequent deprotection (e.g., Intermediate XII-1), and finally, formation of an amide / sulfonamide / urea or carbamate by reaction of Intermediate XII (e.g., Intermediate XII-1) with an appropriate reagent. Alternatively, the order of the reactions can be changed, and an amide / sulfonamide / urea or carbamate can first be obtained from Intermediate XIII (e.g., Intermediate XIII-1 to XIII-3), and then Intermediate III can be achieved by hydrolysis.

[0154]

[0134] The use of any alkylating agent or click reagent (including azide or alkynyl) and reagents for amide, sulfonamide, urea or carbamate formation can be by using commercially available ones or can follow reactions well-known in the field of organic chemistry. In some embodiments, the method includes, but is not limited to, the general procedure shown in Scheme 5 (Figure 11).

[0155]

[0135] Representative IP4-4,6 substitution derivatives of the present invention (e.g., compounds selected from the group consisting of Compounds 1 to 53) are presented herein, and all of these are in the myo conformation. However, it should be understood that any exemplary myo conformation IP4-4,6 substitution derivative of the present invention is not limited to the representative conformations shown. Thus, for example, Compounds 1 to 53 and the intermediates presented herein also include the corresponding equivalents in the scyllo, muco, 1D-chiro, 1L-chiro, neo, allo, epi, and cis conformations. In its most stable conformation, the myo-inositol isomer assumes a chair conformation, in which the maximum number of hydroxyls are in the equatorial position and are located as far apart from each other as possible. In this conformation, the natural myo isomer has a structure in which 5 out of 6 hydroxyls (the 1st, 3rd, 4th, 5th, and 6th) are equatorial, while the 2nd hydroxyl group is axial.

[0156]

[0136] The present invention also provides a method for manufacturing a medicament for the treatment of pathological crystallization, the method comprising using an intermediate compound selected from the group consisting of the compounds listed in Table 1. Compounds of Formula I (e.g., compounds selected from the group consisting of Compounds 1 to 53) for use as medicaments are also provided. Use of a compound of Formula I (e.g., compounds selected from the group consisting of Compounds 1 to 53) for manufacturing a medicament for the prevention or treatment of diseases associated with pathological crystallization is also provided.

[0157] III. Pharmaceutical Compositions

[0137] The present invention also provides a pharmaceutical for use in the treatment, inhibition of progression, and prevention of (a) heterotopic calcification or a condition resulting therefrom, and (b) a disease and / or condition associated with heterotopic calcification and a condition resulting therefrom in a subject in need thereof, wherein the pharmaceutical composition comprises at least one IP4-4,6 substitution derivative of the present invention (for example, a compound selected from the group consisting of Compounds 1 to 53). In some embodiments, the pharmaceutical composition comprises an IP4-4,6 substitution derivative of the present invention (for example, a compound selected from the group consisting of Compounds 1 to 53) alone or together with one or more pharmaceutically acceptable excipients or carriers.

[0158]

[0138] As used herein, the term "excipient" refers to a substance that aids in the absorption of the elements of a pharmaceutical composition, stabilizes said elements, and activates or aids in the preparation of the composition. Thus, examples of excipients used in parenteral formulations include, but are not limited to, antibacterial agents (for example, benzalkonium chloride, metacresol, thimerosal), co-solvents (for example, ethanol), buffers, tonicity agents (for example, NaCl), and pH adjusting agents (for example, carbonate, citrate, phosphate solutions).

[0159]

[0139] As in the case of excipients, a "pharmaceutically acceptable vehicle" is a substance used in a composition to dilute any of the components contained therein to a determined volume or weight (for example, 0.9% (w / v) aqueous NaCl solution). A pharmaceutically acceptable vehicle is either an inert substance or a substance having an action similar to any of the elements constituting the pharmaceutical composition of the present invention. The role of said vehicle is to enable the incorporation of other elements, to enable better dosing and administration, or to provide consistency and shape to the composition.

[0160]

[0140] The pharmaceutical composition can contain approximately 1% to approximately 95% of the active ingredient. In some embodiments, for example, the pharmaceutical composition of the present invention can contain approximately 20% to approximately 90% of the active ingredient (i.e., the IP4-4,6 substitution derivatives of the present invention or combinations thereof, alone or in combination with, for example, one or more additional therapeutic agents).

[0161]

[0141] Formulations of pharmaceutical compositions suitable for parenteral administration combine an active ingredient, for example, an IP4-4,6 substitution derivative of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53), with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline (e.g., 0.9% (w / v) aqueous NaCl solution). Such formulations can be prepared, packaged, or sold in a form suitable for bolus or non-bolus administration. Injectable formulations can be prepared, packaged, or sold in unit dosage forms, such as ampoules, or in multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations can further contain one or more additional ingredients, including, but not limited to, suspending agents, stabilizers, or dispersing agents.

[0162]

[0142] In some embodiments, in formulations for parenteral administration, the active ingredient, for example, an IP4-4,6 substitution derivative of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53), is provided in a dry (i.e., powder or granule) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

[0163]

[0143] The pharmaceutical composition can be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution can be formulated according to known techniques and can contain, in addition to the active ingredient (e.g., the inositol phosphate of the present invention), additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations can be prepared using, for example, a non-toxic parenterally acceptable diluent or solvent 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, for example, synthetic monoglycerides or diglycerides.

[0164]

[0144] Other useful administrable formulations include those containing the active ingredient in microcrystalline form in liposomal preparations or as a component of biodegradable polymer systems. Compositions for sustained release or implantation can include pharmaceutically acceptable polymeric or hydrophobic materials, such as emulsions, ion exchange resins, poorly soluble polymers, or poorly soluble salts. Compositions and methods for making formulations for administering the IP4-4,6 substituted derivatives of the present invention, including controlled release or sustained release formulations containing the active agent, are described in the art. 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, WO2003035040, WO2003035029, WO2003035177, WO2003035039, WO2002096404, WO2002032416, WO2001097783, WO2001056544, WO2001032217, WO1998055107, WO1998011879, WO1997047285, WO1993018755, and WO1990011757.

[0165]

[0145] The medicaments according to the present invention are manufactured by methods known in the art, in particular by conventional mixing, coating, granulating, dissolving or freeze-drying.

[0146] The present invention also provides a compound or combination of compounds or a pharmaceutical formulation according to any of the above aspects of the present invention, for use as a medicament, in the broadest definition given or as specified in any of the aspects presented above.

[0166]

[0147] The present invention also provides a compound or combination of compounds or pharmaceutical formulation according to any of the above aspects of the invention, as defined in the broadest sense given or as specified in any of the aspects presented above, for use in the treatment and / or prevention of the diseases or conditions disclosed herein.

[0167]

[0148] The present invention also provides a compound or combination of compounds or pharmaceutical formulation according to any of the above aspects of the invention, as defined in the broadest sense given or as specified in any of the aspects presented above, for use in the manufacture of a medicament for the prevention and / or treatment of the diseases or conditions disclosed herein.

[0168] IV. Manufactured Articles and Kits

[0149] The present invention also provides a manufactured article and a kit. Such manufactured article and kit can include a container (e.g., a box) containing one or more vials containing a formulation that includes (a) one or more IP4-4,6 substitution derivatives of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53), (b) one or more pharmaceutical compositions of the present invention, and / or (c) a solvent for their medical administration or other use by the methods disclosed herein.

[0169]

[0150] The kit or manufactured article provided in accordance with the present invention can also include a booklet or instructions describing the process and dosage of medical administration disclosed herein or the use of the IP4-4,6 substitution derivatives of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53) by the methods disclosed herein. In some aspects, the kit or manufactured article can include a plurality of vials, each of which contains a single dose. In other aspects, the kit or manufactured article can include one or more vials, each of which contains more than one dose.

[0170]

[0151] In one aspect, the manufactured article is a bag containing a solution of an IP4-4,6 substitution derivative of the present invention (for example, a compound selected from the group consisting of Compounds 1 to 53). In another aspect, the manufactured article is a bottle (for example, a glass bottle or a plastic bottle) containing a solution of an IP4-4,6 substitution derivative of the present invention (for example, a compound selected from the group consisting of Compounds 1 to 53). In some aspects, the manufactured article is a bag containing the IP4-4,6 substitution derivative of the present invention (for example, a compound selected from the group consisting of Compounds 1 to 53) in powder form for reconstitution in a suitable solvent. In another aspect, the manufactured article is a bottle (for example, a glass bottle or a plastic bottle) containing the IP4-4,6 substitution derivative of the present invention (for example, a compound selected from the group consisting of Compounds 1 to 53) in powder form for reconstitution in a suitable solvent.

[0171]

[0152] The kit and the manufactured article can include instructions for carrying out one or more administrations of an IP4-4,6 substitution derivative of the present invention (for example, a compound selected from the group consisting of Compounds 1 to 53) according to the methods and dosages disclosed herein.

[0172]

[0153] The instructions included in the kit and the manufactured article can be attached to the packaging material or included as a package insert. The instructions are usually, but not limited to, a document or printed material. Any medium capable of storing such instructions and communicating them to the end user is envisioned. Such media include, but are not limited to, electronic storage media (for example, magnetic disks, tapes, cartridges, chips), optical media (for example, CDROM), etc. As used herein, the term "instructions" can include the address of an Internet site that provides the instructions.

[0173] V. Use of IP4-4,6 Replacement Derivatives of Formula I

[0154] In one aspect, the present invention relates to IP4-4,6-substituted derivative compounds of general formula I (for example, compounds selected from the group consisting of Compound 1 to Compound 53) for use in the treatment, inhibition of progression, or prevention of heterotopic calcification or a condition resulting therefrom in a subject in need thereof. In some aspects, the present invention relates to a method for the treatment, inhibition of progression, and prevention of heterotopic calcification or a condition resulting therefrom in a subject in need thereof, the method comprising administering a therapeutically effective amount of an IP4-4,6-substituted derivative compound of the present invention. In some aspects, the present invention refers to the use of an IP4-4,6-substituted derivative compound of the present invention for the manufacture of a medicament for the treatment, inhibition of progression, and prevention of heterotopic calcification or a condition resulting therefrom in a subject in need thereof. In some aspects, the IP4-4,6-substituted derivative is a compound of general 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 an IP4-4,6-substituted derivative of the present invention is administered to a subject in need thereof.

[0174]

[0155] In some aspects, the IP4-4,6-substituted derivative of the present invention (for example, a compound selected from the group consisting of Compound 1 to Compound 53) can be administered by local, enteral, or parenteral routes of administration. In some aspects, parenteral administration is via intravenous, intraperitoneal, intramuscular, intraarterial, or subcutaneous routes of administration. In some aspects, the compound can be administered as a component of a hemodialysis, hemofiltration, or peritoneal dialysis solution.

[0175]

[0156] In one aspect, the 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 any suitable method, e.g., a method that induces non-bolus release or action, e.g., intravascular (e.g., intravenous) injection, other parenteral administrations (e.g., subcutaneous, subcutaneous depot, intraperitoneal, intramuscular, intradermal, intrathecal, epidural, spinal or other methods known to those skilled in the art), topical administrations (e.g., intranasal, inhalation, intravaginal, transdermal or other methods known to those skilled in the art), enteral administrations (e.g., oral, sublingual, rectal), oral preparations, spinal preparations, intraperitoneal preparations or other methods known to those skilled in the art.

[0176]

[0157] In certain cases of patients being treated by dialysis, a suitable administration method consists of administering (e.g., non-bolus type) the IP4-4,6 substituted derivatives of the present invention (e.g., compounds selected from the group consisting of Compound 1 to Compound 53) via a dialysis device (before or after filtration), rather than directly injecting the IP4-4,6 substituted derivatives of the present invention into the patient's vein. Thus, as the blood leaves the patient and circulates through 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 that provides a series of advantages. In the case of dialysis patients, administering the IP4-4,6 substituted derivatives of the present invention (e.g., compounds selected from the group consisting of Compound 1 to Compound 53) via a dialysis device enables the blood to equilibrate with the dialysis fluid before being returned to the body.

[0177]

[0158] In some embodiments, the IP4-4,6 substitution derivatives of the present invention (e.g., compounds selected from the group consisting of Compounds 1 to 53) are administered intravenously via intravenous injection. In another embodiment, the IP4-4,6 substitution derivatives of the present invention are administered subcutaneously. In yet another embodiment, the IP4-4,6 substitution derivatives of the present invention are administered locally. In some embodiments, when the IP4-4,6 substitution derivatives of the present invention are administered to a patient undergoing dialysis, such administration (e.g., intravenous administration via injection) can be performed during dialysis treatment. In some embodiments, the IP4-4,6 substitution derivatives of the present invention are administered before dialysis treatment. In some embodiments, the IP4-4,6 substitution derivatives of the present invention are administered after dialysis treatment.

[0178]

[0159] In some embodiments, the present invention also refers to a pharmaceutical composition for use in the treatment, inhibition of progression, or prevention of ectopic calcification or a condition resulting therefrom in a subject in need thereof, comprising an IP4-4,6 substitution derivative of the present invention or any combination thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the IP4-4,6 substitution derivative is a compound of General Formulas II to XIV or any combination thereof. In some embodiments, the IP4-4,6 substitution derivative is Compound 1, Compound 3, Compound 6, Compound 27, or any combination thereof. In some embodiments, a therapeutically effective amount of the pharmaceutical composition of the present invention is administered to a subject in need thereof.

[0179]

[0160] The present invention also provides a method for manufacturing a medicament for the treatment, inhibition of progression, and prevention of ectopic calcification or a condition resulting therefrom, the method comprising using an intermediate compound selected from the group consisting of the compounds listed in Table 1.

[0180]

[0161] Heterotopic calcification (e.g., cutaneous, subcutaneous calcification) is associated with the pathological crystallization of calcium and occurs as a complication in many diseases and conditions. Heterotopic calcification often damages soft tissues such as the aorta, brain, carotid artery, thigh, heart, heart valve, joint, kidney, and lung. This is often regarded as a natural, age-dependent process, but recent data suggest that numerous molecules may modulate this process in an active manner (Nitschke Y et al., Trends Cardiovasc Med., 2012; 22(6):145-149). The IP4-4,6 substitution derivatives of the present invention act by binding to the growth sites of hydroxyapatite (HAP) crystals, thereby selectively inhibiting the common final step in the pathway of heterotopic calcification, including vascular calcification. Since the IP4-4,6 substitution derivatives of the present invention are effective in inhibiting vascular calcification in various types of soft tissues, the IP4-4,6 substitution derivatives of the present invention can be useful for treating diseases and / or conditions associated with heterotopic calcification of such specific types of soft tissues.

[0181]

[0162] In one aspect, the present invention refers to the IP4-4,6 substitution derivative compounds or pharmaceutical compositions of the present invention for use in the treatment, inhibition of progression, and prevention of diseases and / or conditions associated with heterotopic calcification or conditions resulting therefrom in a subject in need thereof.

[0182]

[0163] In one aspect, the diseases and / or conditions related to ectopic calcification according to the present invention, or the conditions resulting therefrom, include, but are not limited to, calcification in the adrenal glands and brain in familial cerebral cavernous malformations, osteomalacia, age-related macular degeneration (AMD) related to calcium deposition, bone cancer, bone mineral diseases, breast calcification, calcific band keratopathy, calcific tendinitis, calcification in osteoarthritis, calcification of articular cartilage in osteoarthritis, calcification of joints and arteries (CALJA), calcification of the seminal vesicles, cutaneous calcinosis, calciphylaxis (CUA), calcium pyrophosphate deposition disease (CPPD), cardiovascular diseases and / or related conditions, chondrocalcinosis, colorectal cancer, diabetic kidney disease, dystrophic calcification, renal transplant graft failure, familial cerebral cavernous malformation (FCCM), fibrodysplasia ossificans progressiva (FOP), hyperphosphatemic tumoral calcinosis syndrome (HHS), hyperphosphatemic familial tumoral calcinosis (HFTC), idiopathic cerebral calcification (Fahr's disease), idiopathic mesenteric phlebosclerosis (IMP), kidney stones (i.e., renal calculi), metastatic calcification, nephrocalcinosis, calcification related to neurocysticercosis, osteomalacia, osteoporosis, pineal calcification, sclerosing colitis, podagra, primary familial brain calcification (PFBC), primary oxaluria (PH), pseudoxantoma elasticum (PXE), rheumatoid arthritis, sialolithiasis, calcification of the parotid gland in Sjögren's syndrome, seminal vesicle stones, skin cancer, soft tissue calcification due to sarcoidosis, adrenal calcification in Wolman disease, and wound healing related to diabetic ulcers.

[0183]

[0164] In one aspect, cardiovascular diseases and / or related conditions associated with ectopic calcification according to the present invention, or conditions resulting therefrom, include, but are not limited to, acute ischemic stroke (ACS), aneurysm, angina pectoris (chronic stable angina), arterial calcification of the aorta, aortic calcification, aortic stenosis, aortic valve calcification, arrhythmia, arteriosclerosis, hardening of the arteries, arteriovenous fistula (AVF) insufficiency, atherosclerosis, calcific aortic valve stenosis (CAVS), cardiac death, heart disease, cardiovascular calcification, cardiovascular disease in patients with chronic kidney disease (CKD), age-related cardiovascular disease, death due to cardiovascular disease, cerebrovascular disease, congestive heart failure, coralline aortic (CRA), coronary artery calcification, coronary artery disease, coronary disease, critical limb ischemia (CLI), electrocardiogram abnormality, generalized arterial calcification of infancy (GACI), heart failure, hypertension, ischemia, left ventricular hypertrophy, major adverse cardiovascular events (MACE) in patients on hemodialysis (HD), Monckeberg's medial sclerosis (MMS), myocardial calcification, myocardial infarction, myocardial ischemia, pericardial calcification, peripheral artery disease (PAD), peripheral vascular disease (PVD), porcelain aorta and calcification at the anastomosis site after coronary artery bypass graft (CABG), portal vein calcification, stroke, thrombosis, valve calcification, and vascular calcification.

[0184] In one aspect, the present invention relates to an IP4-4,6 substituted derivative compound of general formula I of the present invention (for example, a compound selected from the group consisting of Compounds 1 to 53) or a pharmaceutical composition for use in the treatment, inhibition of progression, and prevention of heterotopic calcification or a condition resulting therefrom in a subject in need thereof, wherein the heterotopic calcification occurs or can occur in the aorta, brain, carotid artery, thigh, heart, heart valve, joint, kidney or lung tissue or any combination thereof. Examples of diseases and / or conditions associated with heterotopic calcification in aortic tissue or a condition resulting therefrom include, but are not limited to, arterial calcification of the aorta, aortic calcification, aortic stenosis, aortic valve calcification, arteriosclerosis, hardening of the arteries, atherosclerotic arteriosclerosis, calcific aortic valve stenosis (CAVS), age-related cardiovascular disease, death due to cardiovascular disease, coral reef aorta (CRA), electrocardiogram abnormalities, generalized arterial calcification of infancy (GACI), heart failure, peripheral arterial disease (PAD), and peripheral vascular disease (PVD). Examples of diseases and / or conditions associated with heterotopic calcification in brain tissue or a condition resulting therefrom include, but are not limited to, calcification in the adrenal gland and brain in familial cerebral cavernous malformation, cerebrovascular disease, familial cerebral cavernous malformation (FCCM), idiopathic cerebral calcification (Fahr's disease), pineal gland calcification, and primary familial brain calcification (PFBC). Examples of diseases and / or conditions associated with heterotopic calcification in carotid artery tissue or a condition resulting therefrom 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 heterotopic calcification in thigh tissue or a condition resulting therefrom include, but are not limited to, arteriosclerosis, hardening of the arteries, atherosclerotic arteriosclerosis, cardiovascular system calcification, cardiovascular disease in patients with chronic kidney disease (CKD), age-related cardiovascular disease, death due to cardiovascular disease, critical limb ischemia (CLI), generalized arterial calcification of infancy (GACI), ischemia, peripheral arterial disease (PAD), peripheral vascular disease (PVD), thrombosis, and vascular calcification.Examples of diseases and / or conditions associated with or resulting from ectopic calcification in cardiac and heart valve tissue include, but are not limited to, aneurysm, angina pectoris (chronic stable angina), aortic valve calcification, arrhythmia, arteriosclerosis, arterial sclerosis, atherosclerosis, calcific aortic valve stenosis (CAVS), cardiac death, heart disease, cardiovascular calcification, cardiovascular disease in patients with chronic kidney disease (CKD), age-related cardiovascular disease, death due to cardiovascular disease, cerebrovascular disease, congestive heart failure, coronary artery calcification, coronary artery disease, coronary disease, electrocardiogram abnormalities, generalized arterial calcification in infants (GACI), heart failure, hypertension, ischemia, left ventricular hypertrophy, myocardial infarction, and myocardial ischemia. Examples of diseases and / or conditions associated with or resulting from ectopic calcification in joint tissue include, but are not limited to, calcific tendinitis, calcification in osteoarthritis, calcification of articular cartilage in osteoarthritis, calcification of joints and arteries (CALJA), dystrophic calcification, and pseudogout. Examples of diseases and / or conditions associated with or resulting from ectopic calcification in kidney tissue include, but are not limited to, renal transplant graft failure, kidney stones (i.e., renal calculi), nephrocalcinosis, and primary hyperoxaluria (PH). Examples of diseases and / or conditions associated with or resulting from ectopic calcification in lung tissue include, but are not limited to, dystrophic calcification, and metastatic calcification. Examples of diseases and / or conditions associated with or resulting from ectopic calcification in skin tissue include, but are not limited to, calciphylaxis (CUA) and pseudoxanthoma elasticum (PXE). In some embodiments, the IP4-4,6 substitution derivatives are compounds of general formulas II-XIV or any combination thereof. In some embodiments, the IP4-4,6 substitution derivatives are compound 1, compound 3, compound 6, compound 27, or any combination thereof.

[0185] As shown above, administration of the IP4-4,6 substitution derivatives of the present invention to a subject inhibits the formation and / or growth of hydroxyapatite (HAP) crystals and their deposition in heterotopic calcification. This mechanism of action can mediate the treatment of many diseases and / or conditions associated with heterotopic calcification and the resulting pathological conditions. For example, when HAP formation is inhibited, arterial sclerosis is reduced, thus improving coronary artery perfusion during diastole and alleviating any symptoms associated with ischemia, such as angina pectoris. Similarly, the IP4-4,6 substitution derivatives of the present invention can also be effective in reducing the risk of cardiovascular events in a patient. By inhibiting HAP formation, the IP4-4,6 substitution derivatives of the present invention slow down the progression of coronary artery calcification (CAC). Since CAC is associated with an increased risk of death due to cardiovascular disease, a decrease in its rate of progression can reduce the risk of cardiovascular events. Furthermore, considering these inhibitory properties of the IP4-4,6 substitution derivatives of the present invention on HAP formation, they can further slow down the calcification of the aortic valve leaflets. Pseudoxanthoma elasticum (PXE) is characterized by heterotopic mineralization and fragmentation of elastic fibers in the skin, eyes, vascular system, and digestive system. Since the IP4-4,6 substitution derivatives of the present invention inhibit HAP formation, for example, the vision of PXE patients can be stabilized or improved.

[0186]

[0167] In one aspect, the present invention relates to the use of an IP4-4,6 substitution derivative compound of general formula I of the present invention (for example, a compound selected from the group consisting of Compounds 1 to 53) or a pharmaceutical composition for the treatment, inhibition of progression, and prevention of diseases and / or conditions associated with ectopic calcification or conditions resulting therefrom in a subject in need thereof, wherein (i) a therapeutically effective amount of the IP4-4,6 substitution derivative or the pharmaceutical composition of the present invention is administered to the subject, and (ii) the disease and / or condition is selected from the group consisting of angina pectoris (chronic stable angina), calcific aortic valve stenosis, calciphlaxis, cardiovascular diseases in CKD patients, peripheral arterial diseases, severe lower limb ischemia, infantile systemic arterial calcification, pseudogout, primary oxaluria, and elastic fibrovascular pseudoxanthoma. In some aspects, the IP4-4,6 substitution derivative is a compound of general formulas II to XIV or any combination thereof. In some aspects, the IP4-4,6 substitution derivative is Compound 1, Compound 3, Compound 6, Compound 27, or any combination thereof.

[0187]

[0168] In one aspect, the present invention relates to a method for the treatment, inhibition of progression, and prevention of ectopic calcification or conditions resulting therefrom in a subject in need of treatment, inhibition of progression, and prevention, the method comprising administering a therapeutically effective amount of an IP4-4,6 substitution derivative or the pharmaceutical composition of the present invention. In some aspects, an IP4-4,6 substitution derivative of formulas II and VII, or any combination thereof, is administered to the subject. In some further aspects, Compound 1, Compound 3, Compound 6, and Compound 27, or any combination thereof, is administered to the subject.

[0188]

[0169] In some embodiments, the results of ectopic calcification are, for example, (i) functional complications, (ii) pain, (iii) nutritional complications, (iv) infections, or (v) combinations thereof. In some embodiments, functional complications are, for example, limitations in range of motion and / or joint function. In some embodiments, nutritional complications are, for example, ischemia and / or lesions. In some embodiments, lesions are, for example, necrosis of the skin and / or subcutaneous tissue.

[0189]

[0170] In some embodiments, administration of a dose of an IP4-4,6 substitution derivative or a pharmaceutical composition of the present invention, determined by, for example, the Bates-Jensen Wound Assessment Tool or other methods known in the art (Bates-Jensen B, Decubitus, 1992; 5(6):20-28), to a subject in need thereof causes a decrease in lesions. In some embodiments, the decrease in lesions includes, for example, a decrease in lesion severity, a decrease in lesion size, and a decrease in lesion duration, or combinations thereof. In some embodiments, administration of a dose of an IP4-4,6 substitution derivative or a pharmaceutical composition of the present invention to a subject causes an improvement in lesion healing. In some embodiments, administration of an IP4-4,6 substitution derivative or a pharmaceutical composition of the present invention to a subject causes a decrease in pain. In some embodiments, the subject has renal insufficiency. In some embodiments, the subject is undergoing hemodialysis. In some embodiments, the subject is human.

[0190]

[0171] In some embodiments, administration of an IP4-4,6 substitution derivative or a pharmaceutical composition of the present invention to a subject in need thereof causes an improvement in the overall quality of life (QoL) related to wounds, determined by 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 embodiments, the subject has renal insufficiency. In some embodiments, the subject is undergoing hemodialysis. In some embodiments, the subject is human.

[0191]

[0172] Renal insufficiency, which is also known as renal dysfunction or kidney disease, is a disease that causes progressive loss of kidney function, accompanied by a simultaneous reduction in glomerular filtration rate (GFR) or index. Renal dysfunction, along with the treatment of the disease, leads to hypercalcemia and hyperphosphatemia. Hypercalcemia and hyperphosphatemia may cause calcification of the cardiovascular system, although this process may be delayed or accelerated due to deficiency of inhibitory factors (such as matrix Gla protein, osteopontin, fetuin, or vitamin K) or imbalance of promoting factors (such as vitamin D, FGF23, inflammatory cytokines, lipid deposition, apoptotic bodies, nuclear formation complexes). Patients with kidney dysfunction are generally characterized as CKD-MBD (Chronic Kidney Disease-Mineral and Bone Disorder) patients because the changes in kidney function trigger a chain of actions and also affect bone remodeling.

[0192]

[0173] In some embodiments, the IP4-4,6 substitution derivatives and the pharmaceutical compositions of the present invention can be used to treat, inhibit the progression of, and prevent some of the diseases and / or conditions associated with ectopic calcification or the resulting conditions listed above in patients with renal insufficiency. In some embodiments, the diseases and / or conditions associated with ectopic calcification or the resulting conditions are renal insufficiency-related diseases. In some embodiments, the patients with renal insufficiency are undergoing dialysis. In some embodiments, the IP4-4,6 substitution derivatives and the pharmaceutical compositions of the present invention are administered to patients with renal insufficiency via intravenous infusion. In some embodiments, the intravenous infusion is performed using a dialysis device. In some embodiments, the IP4-4,6 substitution derivative is a compound of general formulas II to XIV or any combination thereof. In some embodiments, the IP4-4,6 substitution derivative is compound 1, compound 3, compound 6, compound 27, or any combination thereof. In some embodiments, a therapeutically effective amount of the IP4-4,6 substitution derivative of the present invention is administered to patients with renal insufficiency.

[0193]

[0174] In one aspect, the IP4-4,6 substitution derivatives of the present invention can be used, for example, in a dialysis fluid during hemodialysis. Accordingly, the present invention also provides a hemodialysis fluid comprising a dialysis fluid, for example, an IP4-4,6 substitution derivative of the present invention (for example, a compound selected from the group consisting of Compounds 1 to 53), a pharmaceutically acceptable salt thereof, or any combination thereof, wherein administration of the IP4-4,6 substitution derivative, a pharmaceutically acceptable salt thereof, or a combination thereof to a subject in need of administration is effective for treating, inhibiting the progression of, and preventing (i) ectopic calcification and the resulting conditions or (ii) diseases and / or conditions associated with ectopic calcification and the resulting conditions.

[0194] 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)

[0175] 1,3,5-O-Methylidene-myo-inositol (1): The synthesis of (1) has been previously described in the literature (Martin S et al., J. Org. Chem., 1994; 59(17): 4805 - 4820).

[0195]

[0176] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (2): The synthesis of (2) has been previously described in the literature (Kadirvel M et al., Org. Biomol. Chem., 2008; 6(11): 1966 - 1972).

[0196] A.2. Synthesis of Alkylating Agents or Click Reagents

[0177] (((10-Bromodecyl)oxy)methyl)benzene (4): The synthesis of (4) has been previously described in the literature (Hanbali M. et al., Bioorg. Med. Chem. Lett., 2006; 16(10): 2637 - 2640).

[0197]

[0178] (((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).

[0198]

[0179] 1-Bromo-7-methoxyheptane (6): A mixture of 1,7-dibromoheptane (3.27 mL, 19.38 mmol) and sodium methoxide 5N (3.88 mL, 19.38 mmol) was stirred at 40 °C for 4 hours. 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 of (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).

[0180] 9-Methoxynonyl 4-methylbenzenesulfonate (7)

[0181] 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 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, Hex:EtOAc 4:1) to give 324 mg of (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).

[0182] Step 2: 9-Methoxynonyl 4-methylbenzenesulfonate (7): To a solution of (3) (1.5 g, 8.61 mmol) in dichloromethane (DCM, 28.7 mL) was added triethylamine (TEA (1.80 mL, 12.91 mmol) and tosyl 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 yield 2.15 g of (7) (76%). 1 H NMR (400 MHz, chloroform-d) δ 7.78 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 4.01 (t, J = 6.5 Hz, 2H), 3.35 (t, J = 6.6 Hz, 2H), 3.32 (s, 3H), 2.45 (s, 3H), 1.61 (dt, J = 8, 6.6 Hz, 2H), 1.56 - 1.51 (m, 2H), 1.32 - 1.22 (m, 10H).

[0183] 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, at 0 °C, TEA (2.07 mL, 14.84 mmol) and Ts-Cl (2.26 g, 11.87 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 yield 1.27 g of (8) (50%). 1 H NMR (400 MHz, chloroform-d) δ 7.80 (d, J = 8.3 Hz, 2H), 7.36 (dd, J = 8.3, 0.7 Hz, 2H), 4.11 (t, J = 6.3Hz, 2H), 3.38 (t, J = 6.3 Hz, 2H), 2.46 (s, 3H), 1.89 (p, J = 6.3 Hz, 2H).

[0184] 5-Azidopentyl 4-methylbenzenesulfonate (10)

[0185] 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 (3×). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give 57 mg of (9) (50%). 1 H NMR (400 MHz, chloroform-d) δ 3.63 (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).

[0186] 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 were added TEA (87 μL, 0.63 mmol) and Ts-Cl (80 mg, 0.42 mmol). 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 of (10) (78%). HPLC-MS (Condition A): rt = 3.00 min; m / z: 284 [M+1] + 。

[0199]

[0187] 10-Azidodecyl 4-methylbenzenesulfonate (12)

[0188] Step 1: 10-Azidodecan-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 (3×). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give 388 mg of (11) (92%).1 1H NMR (400 MHz, chloroform-d) δ 3.64 (t, J = 6.8 Hz, 2H), 3.25 (t, J = 6.8 Hz, 2H), 1.59 (p, J=6.8 Hz, 2H), 1.56 (p, J = 6.8 Hz, 2H), 1.44 - 1.19 (m, 12H).

[0189] Step 2: 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 of (12) (34%). 1 1H 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).

[0190] 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 of (13) (45%). HPLC-MS (Condition A): rt = 3.00 min; m / z: 218, 220 [M+1, M+3] + 。

[0200]

[0191] 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 of (14) (22%). HPLC-MS (Condition A): rt = 2.95 min; m / z: 218, 220 [M, M+2] + 。

[0201]

[0192] Benzyl 3-azidopropanoate (15): To a solution of 3-azidopropanoic acid (1.62 mL, 17.38 mmol) in DMF (1 M) was added dropwise (bromomethyl)benzene (4.1 mL, 34.8 mmol), followed by 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 (1×), water (3×), and brine (1×), dried over Na2SO4, and filtered. The solvent was removed in vacuo to give 2.90 g of (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).

[0193] 6-Azidohexyl 4-methylbenzenesulfonate (17)

[0194] 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 (3×). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give 470 mg of (16) (>99%). 11H 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).

[0195] Step 2: 6-Azidohexyl 4-methylbenzenesulfonate (17): At 0 °C, 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 dry DCM (0.6 M). The reaction mixture was stirred at room temperature overnight. It was diluted with EtOAc and washed with a 10% aqueous solution of NaHSO4. The aqueous phase was extracted with EtOAc (3×). The combined layers were washed with a saturated aqueous solution of NaHCO3 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 of (17) (62%). 1 1H NMR (400 MHz, chloroform-d) δ 7.79 (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).

[0196] 4-Azidobutyl 4-methylbenzenesulfonate (19)

[0197] 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 (3×). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to produce 213 mg of (18) (56%). 11H 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).

[0198] Step 2: 4-Azidobutyl 4-methylbenzenesulfonate (19): At 0 °C, 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 dry DCM (0.6 M). The reaction mixture was stirred at room temperature overnight. This was diluted with EtOAc and washed with a 10% aqueous solution of NaHCO3. The aqueous phase was extracted with EtOAc (3×). 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 of (19) (54%). 1 1H NMR (400 MHz, chloroform-d) δ 7.79 (d, J = 8 Hz, 2H), 7.36 (d, J = 8 Hz, 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).

[0199] 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) were added, at 0 °C, 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 of (20) (66%). HPLC-MS (Condition A): rt = 0.24 min; m / z: 191, 193 [M, M + 2] + 。

[0202] [

[0200] ]2-Cyclopropylethyl 4-methylbenzenesulfonate (21): To a solution of 2-cyclopropylethanol (3 mL, 34.0 mmol) in DCM (85 mL) were 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 the mixture was extracted with DCM (2×). 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 yield 6.23 g (76%) of (21). 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). [

[0201] ]2-Cyclopentylethyl 4-methylbenzenesulfonate (22): To a solution of 2-cyclopentylethanol (1.09 mL, 8.76 mmol) in DCM (22 mL) were 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 the mixture was extracted with DCM (2×). 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 yield 1.53 g (65%) of (22). 1 H 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).

[0202] 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) were 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 the mixture was extracted with DCM (2×). 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 yield 1.59 g (82%) of (23). 1 1H NMR (400 MHz, chloroform-d) δ 7.81 (d, J = 8 Hz, 2H), 7.37 (d, J = 8 Hz, 2H), 7.00 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 4.04 (t, J = 6 Hz, 2H), 3.80 (s, 3H), 2.61 (dd, J = 8.2, 6.8 Hz, 2H), 2.48 (s, 3H), 2.03 - 1.86 (ddt, J = 8.2, 6.8, 6 Hz, 2H).

[0203] 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) were 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 the mixture was extracted with DCM (2×). 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 yield 1.53 g (87%) of (24). 11H NMR (400 MHz, chloroform-d) δ 7.63 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 7.8 Hz, 1H), 7.21 - 7.16 (m, 2H), 7.19 (d, J = 8.5 Hz, 2H), 7.12 (, J = 7.8 Hz, 1H), 3.88 (t, J = 6.2 Hz, 2H), 2.56 (dd, 8.0, 7.6 Hz, 2H), 2.29 (s, 3H), 1.81 (ddt, J = 8.0, 7.6, 6.2 Hz, 2H).

[0204] 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) were 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 the mixture was extracted with DCM (2×). 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 yield 1.85 g (87%) of (25). 1 1H NMR (400 MHz, chloroform-d) δ 7.81 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 4.05 (t, J = 6.4 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.48 (s, 3H), 2.32 (s, 3H), 1.95 (tt, J = 7.5, 6.4 Hz, 2H).

[0205] 19-Methoxynonadec-10-yn-1-yl 4-methylbenzenesulfonate (31)

[0206] Step 1: 2-((9-Bromononyl)oxy)tetrahydro-2H-pyran (26): p-TSA (105 mg, 0.55 mmol) was added 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). The mixture was stirred at room temperature for 18 h. The mixture was diluted with 1N Na2CO3 and extracted with ethyl ether (2×), dried over Na2SO4, filtered, and the solvent was removed in vacuo. The filtrate was concentrated and purified by column chromatography (0 - 5% EtOAc in Hex) to yield 6.31 g (74%) of (26). 1 H NMR (400 MHz, chloroform-d) δ 4.56 (dd, J = 4.3, 2.7 Hz, 1H), 3.85 (td, J = 7.5, 3.8 Hz, 1H), 3.71 (dt, J = 9.6, 6.9 Hz, 1H), 3.52 - 3.32 (m, 4H), 1.88 - 1.24 (m, 20H).

[0207] Step 2: Dec-9-yn-1-yl methanesulfonate (27): TEA (3.52 mL, 25.3 mmol) and methanesulfonyl chloride (1.97 mL, 25.3 mmol) were added dropwise to a stirred solution of dec-9-yn-1-ol (3.45 mL, 19.5 mmol) in THF (56 mL) at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature for 18 h. The solvent was evaporated. Water was added to the reaction mixture, which was then extracted with DCM. The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure to give 4.45 g (98%) of (27). HPLC-MS (Condition A): rt = 3.58 min.

[0203]

[0208] Step 3: 10-Methoxydec-1-yne (28): (27) (4.45 g, 19.1 mmol) was added to a stirred solution of sodium methoxide 5M in MeOH and stirred at 45 °C for 18 h. The suspension was then dissolved in water and extracted with Et2O (2×). The organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was purified by column chromatography (5% EtOAc in Hex) to give (28) (2.58 g, 80%). 11H 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).

[0209] Step 4: 2-((19-Methoxynonadeca-10-yn-1-yl)oxy)tetrahydro-2H-pyran (29): To a solution of (28) (4 g, 23.8 mmol) in 30 mL of THF and 25 mL of HMPA cooled to -40 °C, n-BuLi (15.5 mL, 24.8 mmol) was slowly added, 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 of HMPA was slowly added. After stirring at the same temperature for 10 minutes, the temperature was increased to room temperature. Stirring was carried out at the same temperature for 18 hours. Under cooling with ice (4 °C), 10% aqueous HCl was added and extracted with tBuMeO (3×). 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 give a yellow oily substance. The residue was purified by column chromatography using EtOAc / Hex (1:20) to give (29) (2.36 g, 30%). 1 1H 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).

[0210] Step 5: 19-Methoxynonadec-10-yn-1-ol (30): p-TSA (68 mg, 0.36 mmol) was added portionwise to a solution of (29) (2.36 g, 6 mmol) in MeOH (10 mL). 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 (2×). The combined organic extracts were washed with brine solution and dried over Na2SO4. Further purification was not required and 1.32 g (71%) of (30) was produced. 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).

[0211] Step 6: 19-Methoxynonadec-10-yn-1-yl 4-methylbenzenesulfonate (31): Ts-Cl (973 mg, 5.10 mmol) and 5 M NaOH (1.020 mL, 5.10 mmol) were added to a solution of (30) (1.32 g, 4.25 mmol) in THF (8.5 mL) and the resulting mixture was stirred for 18 h. Water was added to the reaction mixture and the mixture was extracted with tBuMeO (2×). 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 yield 1.69 g (86%) of (31). 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). A.3. Synthesis of Activated Acids

[0212] Benzyl (2,5-dioxopyrrolidin-1-yl) glutarate (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 of (32) (64%). HPLC-MS (Condition B): rt = 2.55 min; m / z: 320 [M+1] + , 342 [M+23] + .

[0204]

[0213] 2,5-Dioxopyrrolidin-1-yl thiophene-2-carboxylate (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 the mixture was extracted with DCM (2×). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was used without further purification. 1 H NMR (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). B. General Procedures B.1. Alkylation Procedure

[0214] Procedure A: To a solution of (2) (1 equiv) in DMF (0.2 M), NaH (2.15 equiv) was added at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 5 minutes. Finally, the alkylating agent was added. The reaction mixture was stirred 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 yield the pure compound.

[0205]

[0215] Procedure B: To a solution of (2) (1 equiv) in DMF (0.2 M), LiH was added at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 5 minutes. Finally, the alkylating agent was added. The reaction mixture was stirred for different times and at different temperatures depending on the alkylating agent, 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 yield the pure compound.

[0206] B.2. Hydrolysis Procedure

[0216] Procedure C: Intermediate (II), (V), (VIII), (XI) or (XIII) (1 equiv) 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 yield the desired compound.

[0207]

[0217] Procedure D: Intermediate (II), (V), (VIII), (XI) or (XIII) (1 equiv) 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) and treated with IRA-400 resin until the pH became basic, filtered, and the solvent was removed under vacuum to yield the desired compound.

[0208]

[0218] Procedure E: To a solution of intermediate (II), (V), (VIII), (XI) or (XIII) (1 eq.) in THF (c = 0.1 M) was added a solution of 0.1 M 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 / H2O / DCM / TFA (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) and treated with IRA-400 resin until the pH was basic, filtered and the solvent was removed under vacuum to give the desired compound.

[0209]

[0219] 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 was added (final concentration 0.1 M) 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.

[0210]

[0220] Procedure S: Intermediate (II), (V), (VIII), (XI) or (XIII) (1 eq.) was dissolved in a mixture of MeOH / HCl 1 N (10:1, 0.1 M) and the solution was stirred at 60 °C overnight. Finally, the solvent and excess HCl were removed under vacuum to give the desired compound.

[0211] B.3. Click Reaction Procedure

[0221] Procedure K: To a suspension of intermediate (VI) (1 eq.) and CuI (0.03 eq.) in DCM (0.1 M) was added a solution of azide reagent (2 eq.), DIPEA (0.07 eq.) and AcOH (0.07 eq.) in DCM / MeOH (1 M). The reaction mixture was stirred at 35 °C for 20 h under an inert atmosphere and concentrated in vacuo to give the desired compound.

[0212]

[0222] Procedure L: To a solution of intermediate (VI) (1 equiv), CuSO4·5H2O (0.4 equiv), and sodium ascorbate (0.6 equiv) in water (0.07 M) was added a solution of azide reagent (2 equiv) in THF (0.35 M). The reaction mixture was stirred at room temperature for 20 h under an inert atmosphere, 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.

[0213]

[0223] Procedure M: To a solution of intermediate (IX) (1 equiv), CuSO4·5H2O (0.4 equiv), and sodium ascorbate (0.6 equiv) in a water mixture (0.07 M) was added a solution of alkynyl reagent (2 equiv) in THF (0.35 M). The reaction mixture was stirred at room temperature for 24 h under an inert atmosphere, filtered through celite, and concentrated in vacuo. The residue was dissolved in MeOH and treated with IRA-400 resin until the pH became basic, filtered, and the solvent was removed under vacuum to give the desired compound.

[0214] B.4. Group Conversion Procedure

[0224] Procedure N: A mixture of intermediate (VII) (1 equiv) and 25% sodium methoxide (3 equiv) 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 Na2SO4, filtered, and concentrated in vacuo to give the desired compound.

[0215] B.5. Reduction Procedure of Azide

[0225] Procedure Q: To a solution of intermediate (VIII) (1 equiv) in a THF / water mixture (9:1, 0.08 M) were added DIPEA (3 equiv) and PPh3 (2.6 equiv). 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.

[0216] B.6. Amide Formation Procedure

[0226] Procedure P: To a solution of intermediate (XI) or (XII) (1 eq) in DMF (0.1 M), TEA (4 eq) and activated acid (2 eq) were added. The reaction mixture was stirred at room temperature for 4 h and concentrated in vacuo. The residue was dissolved in MeOH and treated with IRA-400 resin until the pH became basic, filtered, and the solvent was removed under vacuum. Finally, the residue was purified by flash chromatography (silica gel) to give the pure compound.

[0217] B.7. Urea Formation Procedure

[0227] Procedure H: Intermediate (XI) or (XII) (1 eq) was dissolved in MeOH and treated with IRA-400 resin until the pH became basic, filtered, and the solvent was removed under vacuum. The residue was dissolved in EtOH (0.1 M) and 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.

[0218] B.8. Carbamate Formation Procedure

[0228] Procedure V: Intermediate (XI) or (XII) (1 eq) was dissolved in MeOH and treated with IRA-400 resin until the pH became 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 became acidic. Then the solution was filtered and the solvent was removed under vacuum to give the desired compound.

[0219] B.9. Phosphorylation or Thiophosphorylation Procedure

[0229] Procedure G: Intermediate (III), (VI-1) or (IX) (1 equivalent) was dissolved in DCM (0.02 M), and a solution of tetrazole in ACN (0.43 M) (10 - 14.4 equivalents) was added. The mixture was stirred at room temperature for 30 minutes. Then N,N-diethyl-1,5-dihydrobenzo[e][1,3,2]-dioxaphosphepin-3-amine (5 - 7.2 equivalents) was added and the mixture was stirred at room temperature overnight. Finally, the reaction mixture was cooled to 0 °C and a solution of tert-butyl hydroperoxide in hexane (5.5 M) (15 - 19.2 equivalents) was added. The solution was allowed to return to room temperature and stirred for 1 hour. 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 give the pure compound.

[0220]

[0230] Procedure T: Intermediate (III) or (IX) (1 equivalent) was dissolved in DCM (0.02 M), and a solution of tetrazole in ACN (0.43 M) (10 - 14.4 equivalents) was added. The mixture was stirred at room temperature for 30 minutes. Then, N,N-diethyl-1,5-dihydrobenzo[e][1,3,2]-dioxaphosphepin-3-amine (5 - 7.2 equivalents) was added and the mixture was stirred at room temperature overnight. Finally, pyridine (40 equivalents) and sulfur (40 equivalents) were added and the solution was stirred at room temperature for 24 hours. 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 give the pure compound.

[0221] B.10. Deprotection Procedure of Phosphate or Thiophosphate

[0231] 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 an excess of palladium hydroxide on 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. By the addition of aqueous dilute NaOH (1 N), the compound was brought to pH 9 - 10, and the residue was purified on a Sephadex column (PD - 10, G - 25 - M) by eluting with water. All fractions were lyophilized and 1 analyzed by H - NMR. The fractions containing the product were further purified on a reverse - phase cartridge (Sep - Pack® C18 cartridge, 1 g, Waters Corp., Milford, MA, USA) by eluting with water. All fractions were lyophilized and 1 analyzed by H - NMR.

[0222]

[0232] Procedure J: 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 an excess of palladium hydroxide on 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. By the addition of aqueous dilute NaOH (1 N), the compound was brought to pH 10 and the solution was stirred for 24 - 48 hours. Finally, the solution was purified on a Sephadex column (PD - 10, G - 25 - M) by eluting with water. All fractions were lyophilized and 1 analyzed by H - NMR. The fractions containing the product were further purified on a reverse - phase cartridge (Sep - Pack® C18 cartridge, 1 g, Waters Corp., Milford, MA, USA) by eluting with water. All fractions were lyophilized and 1 analyzed by H - NMR.

[0223]

[0233] Procedure U: The phosphorylated or thiophosphorylated compound (IV), (IV’) or (X) was treated with thiophenol (40 equiv), m-cresol (40 equiv) (0.045 M) in TFA. Then TBMSBr (40 equiv) was added slowly and the mixture was stirred at room temperature for 4 h, quenched with water and extracted with DCM (3×). The aqueous layer was concentrated in vacuo. By addition of water and aqueous dilute NaOH (1 N), the residue was brought to pH 9 - 10 and the compound was purified by eluting with water on a Sephadex column (PD-10, G-25-M). All fractions were lyophilized and 1 analyzed by 1H-RMN. The fractions containing the product were further purified on a reverse phase cartridge (Sep-Pack® C18 cartridge, 1 g, Waters Corp., Milford, MA, USA) by eluting with water. All fractions were lyophilized and 1 analyzed by 1H-RMN.

[0224] C. Synthesis of Intermediates II-XIII C.1. Intermediate II

[0234] 4,6-O-bis(5-(benzyloxy)pentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (II-1): According to the general alkylation procedure A, 202 mg of (II-1) was obtained from 1.04 mL (3 equiv) of (((5-bromopentyl)oxy)methyl)benzene (18.3%). HPLC-MS (condition A): rt = 6.30 min; m / z: 657 [M+1] + , 679 [M+23]+.

[0225]

[0235] 4,6-O-bis(10-(benzyloxy)decyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (II-2): According to the general alkylation procedure A, 75 mg of (II-2) was obtained from 408 mg (2 equiv, in 2 mL of DMF) of (4) (16%). 11H NMR (400 MHz, chloroform-d) δ 7.39 - 7.25 (m, 10H), 5.53 (d, J = 1.2 Hz, 1H), 4.50 (s, 4H), 4.36 (dt, J = 3.6, 1.6 Hz, 1H), 4.25 (q, J = 1.6 Hz, 1H), 4.16 (t, J = 3.6 Hz, 2H), 4.10 (dt, J = 3.6, 1.6 Hz, 2H), 3.53 (dt, J = 8.8, 6.4 Hz, 2H), 3.46 (t, J = 6.8 Hz, 4H), 3.50 (dt, J = 8.8, 6.4 Hz, 2H), 1.61 (p, J = 6.8 Hz, 4H), 1.54 - 1.48 (m, 4H), 1.44 - 1.16 (m, 24H), 0.94 (s, 9H), 0.14 (s, 6H).

[0236] 4,6 - O - Bis(14 - (benzyloxy)tetradecyl)-2 - O - tert - butyldimethylsilyl - 1,3,5 - O - methylidine - myo - inositol (II - 3): According to the general alkylation procedure A, 37 mg of (II - 3) was obtained (10%) from 312 mg (2 equivalents, in 1.4 mL of DMF) of (5). 1 1H NMR (400 MHz, chloroform-d) δ 7.34 - 7.21 (m, 10H), 5.53 (d, J = 1.6 Hz, 1H), 4.50 (s, 4H), 4.36 (h, J = 1.6 Hz, 1H), 4.25 (q, J = 1.6 Hz, 1H), 4.16 (t, J = 4 Hz, 2H), 4.11 (dd, J = 4, 1.6 Hz, 2H), 3.54 (dt, 8.8, 6.4 Hz, 2H), 3.56 (t, J = 6.8 Hz, 4H), 3.45 (dt, J = 8.8, 6.4 Hz, 2H), 1.61 (q, J = 6.8 Hz, 4H) 1.56 - 1.59 (m, 4H), 1.30 - 1.25 (m, 40H), 0.94 (s, 9H), 0.14 (s, 6H).

[0237] 2-O-tert-butyldimethylsilyl-4,6-O-bis(3-methoxypropyl)-1,3,5-O-methylidene-myo-inositol (II-4): According to the general alkylation procedure A, 232 mg of (II-4) was obtained from 0.55 mL (5 equivalents) of 1-bromo-3-methoxypropane (52%). HPLC-MS (Condition A): rt = 4.58 min; m / z: 449 [M+1] + , 471 [M+23] + .

[0226]

[0238] 2-O-tert-butyldimethylsilyl-4,6-O-bis(5-methoxypentyl)-1,3,5-O-methylidene-myo-inositol (II-5): According to the general alkylation procedure A, 21 mg of (II-5) was obtained from 241 mg (2.2 equivalents, in 3 mL of DMF) of 1-bromo-5-methoxypentane (7%). HPLC-MS (Condition B): rt = 3.80 min; m / z: 505 [M+1] + , 527 [M+23] + .

[0227]

[0239] 2-O-tert-butyldimethylsilyl-4,6-O-bis(9-methoxynonyl)-1,3,5-O-methylidene-myo-inositol (II-6): According to the general alkylation procedure A, 194 mg of (II-6) was obtained from 803 mg (2.5 equivalents, in 1.2 mL of DMF) of (7) (32%). 11H NMR (400 MHz, chloroform-d) δ 5.53 (d, J = 1.2 Hz, 1H), 4.36 (tt, J = 3.2, 1.6 Hz, 1H), 4.24 (dd, J = 3.2, 2.4 Hz, 1H), 4.16 (t, J = 3.6 Hz, 2H), 4.10 (dt, J = 4, 1.6 Hz, 2H), 3.53 (dt, J = 8.8, 6.4 Hz, 2H), 3.44 (dt, J = 8.8, 6.4 Hz, 2H), 3.36 (t, J = 6.4 Hz, 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).

[0240] 2-O-tert-butyldimethylsilyl-4,6-O-bis(7-methoxyheptyl)-1,3,5-O-methylidene-myo-inositol (II-7): According to the general alkylation procedure A, 398 mg of (II-7) was obtained from 780 mg (2.5 equivalents, in 1.5 mL of DMF) of (6) (47.6%). HPLC-MS (condition A): rt = 6.11 min; m / z: 561 [M+1] + , 583 [M+23] + 。

[0228]

[0241] 2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-4,6-O-dipropyl-myo-inositol (II-8): According to the general alkylation procedure A, 79.14 mg of (II-8) was obtained from 481 μL (5 equivalents) of 1-iodopropane (21%). 11H NMR (400 MHz, chloroform-d) δ 5.52 (d, J = 1.4 Hz, 1H), 4.37 (h, J = 1.6 Hz, 1H), 4.26 (q, J = 1.6 Hz, 1H), 4.16 (t, J = 4 Hz, 2H), 4.11 (dt, J = 4, 1.6 Hz, 2H), 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).

[0242] 2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-4,6-O-dipentyl-myo-inositol (II-9): According to the general alkylation procedure A, 255 mg of (II-9) was obtained from 377 μL (3 equivalents) of 1-bromopentane (58%). HPLC-MS (Condition A): rt = 6.38 minutes; m / z: 445 [M+1] + 。

[0229]

[0243] 2-O-tert-butyldimethylsilyl-4,6-O-diheptyl-1,3,5-O-methylidene-myo-inositol (II-10): According to the general alkylation procedure A, 250 mg of (II-10) was obtained from 560 μL (5 equivalents) of 1-bromoheptane (70%). 1 1H NMR (400 MHz, chloroform-d) δ 5.53 (d, J = 1.2 Hz, 1H), 4.36 (h, J = 1.6 Hz, 1H), 4.25 (d, J = 1.6 Hz, 1H), 4.16 (t, J = 4 Hz, 2H), 4.11 (dt, J = 4, 1.6 Hz, 2H), 3.54 (dt, J = 8.8, 6.4 Hz, 2H), 3.44 (dt, J = 8.8, 6.4 Hz, 2H), 1.57-1.49 (m, 4H), 1.37-1.17 (m, 16H), 0.94 (s, 9H), 0.88 (t, J = 6.8 Hz, 6H), 0.14 (s, 6H).

[0244] 2-O-tert-butyldimethylsilyl-4,6-O-didecyl-1,3,5-O-methylidene-myo-inositol (II-11): According to the general alkylation procedure A, 272.6 mg of (II-11) was obtained from 511 μL (3 equivalents) of 1-bromodecane (57%). 1 H NMR (400 MHz, chloroform-d) δ 5.53 (d, J = 1.2 Hz, 1H), 4.37 (h, J =1.6 Hz, 1H), 4.25 (q, J = 1.6 Hz, 1H), 4.16 (t, J = 4 Hz, 2H), 4.11 (dt, J = 4.0, 1.6 Hz, 2H), 3.54 (dt, J = 8.8, 6.4 Hz, 2H), 3.44 (dt, J = 8.8, 6.4 Hz, 2H), 1.55-1.50 (m, 4H), 1.37-1.22 (m, 28H), 0.94 (s, 9H), 0.88 (t, J = 7.2 Hz 6H), 0.14 (s, 6H).

[0245] 2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-4,6-O-di(tetradecyl)-myo-inositol (II-12): According to the general alkylation procedure A, 350 mg of (II-12) was obtained from 670 μL (3 equivalents) of 1-bromotetradecane (61%). 1 H NMR (400 MHz, chloroform-d) δ 5.53 (d, J = 1.6 Hz, 1H), 4.36 (h, J = 1.6 Hz, 1H), 4.25 (q, J = 1.6 Hz, 1H), 4.16 (t, J = 4 Hz, 2H), 4.11 (dt, J = 4, 1.6 Hz, 2H), 3.54 (dt, J = 8.8, 6.4 Hz, 2H), 3.44 (dt, J = 8.8, 6.4 Hz, 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).

[0246] 2-O-tert-butyldimethylsilyl-4,6-O-bis(5-ethoxycarbonylpentyl)-1,3,5-O-methylidene-myo-inositol (II-13): According to the general alkylation procedure A, 90 mg of (II-13) was obtained from 351 μL of ethyl 6-bromohexanoate (3 equivalents) (23%). HPLC-MS (Condition A): rt = 5.46 min; m / z: 589 [M+1] + , 611 [M+23] + .

[0230]

[0247] 2-O-tert-butyldimethylsilyl-4,6-O-bis(10-ethoxycarbonyldecyl)-1,3,5-O-methylidene-myo-inositol (II-14): According to the general alkylation procedure A, 169 mg of (II-14) was obtained from 455 μL of ethyl 11-bromoundecanoate (2.5 equivalents) (34%). 1 H NMR (400 MHz, chloroform-d) δ 5.50 (d, J = 1.6 Hz, 1H), 4.34 (h, J = 1.6 Hz, 1H), 4.23 (q, J = 1.6 Hz, 1H), 4.15 - 4.07 (m, 8H), 3.52 (dt, J = 8.8, 6.4 Hz, 2H), 3.42 (dt, J = 8.8, 6.4 Hz, 2H), 2.26 (t, J = 7.2 Hz, 4H), 1.59 (p, J = 7.2 Hz, 4H), 1.50 (p, J = 6.4 Hz, 4H), 1.37 - 1.17 (m, 30H), 0.92 (s, 9H), 0.12 (s, 6H).

[0248] 2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-4,6-O-bis(5-(1H-pyrazol-1-yl)pentyl)-myo-inositol (II-15): According to the general alkylation procedure A, 101 mg of (II-15) was obtained from 450 mg of (12) (12%). HPLC-MS (Condition A): rt = 4.56 min; m / z: 578 [M+1] + .

[0231]

[0249] 2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-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 of (II-16) was obtained from 500 mg of (14) (6%). HPLC-MS (condition A): rt = 3.70 min; m / z: 579 [M+1] + 。

[0232]

[0250] 4,6-O-bis(2-(4-acetylpiperazin-1-yl)ethyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (II-17)

[0251] Step 1: rac-4-O-(2-(4-acetylpiperazin-1-yl)ethyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (34): According to the general alkylation procedure A, 460 mg of (34) was obtained from 700 mg (2.5 equivalents, in 7.3 mL of DMF) of (20) (2.5 equivalents, in 7.3 mL of DMF) (68%). HPLC-MS (condition A): rt = 1.90 min; m / z: 459 [M+1] + 。

[0233]

[0252] Step 2: 4,6-O-bis(2-(4-acetylpiperazin-1-yl)ethyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-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). After the addition was complete, the mixture was stirred at room temperature for 5 minutes. Finally, a solution of (20) (309 mg, 1.62 mmol) in DMF (3.2 mL) was added. The reaction was warmed to 90 °C, stirred overnight, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, DCM:MeOH 95:5, 1% NH3) to yield 89 mg of (II-17) (22%). HPLC-MS (condition A): rt = 1.56 min; m / z: 613 [M+1] + 。

[0234]

[0253] 2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-4,6-O-bis(4,4,4-trifluorobutyl)-myo-inositol (II-18): According to the general alkylation procedure B, 3.61 g of (II-18) was obtained (60% yield) from 4.2 mL (3 equivalents) of 4-bromo-1,1,1-trifluorobutane and 934 mg (10 equivalents) of LiH. HPLC-MS (Condition A): rt = 5.23 min; m / z: 525 [M+1] + 。

[0235]

[0254] 2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-4,6-O-bis(6,6,6-trifluorohexyl)-myo-inositol (II-19): According to the general alkylation procedure B, 594 mg of (II-19) was obtained (48%) from 1.16 g (2.5 equivalents) of 6-bromo-1,1,1-trifluorohexane and 43 mg (2.5 equivalents) of LiH. HPLC-MS (Condition A): rt = 6.87 min; m / z: 573 [M+1] + 、595[M+23] + 。

[0236]

[0255] 2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-4,6-O-bis(4-methylpentyl)-myo-inositol (II-20): According to the general alkylation procedure B, 273 mg of (II-20) was obtained (20%) from 1 mL (2.5 equivalents) of 1-bromo-4-methylpentane and 58 mg (2.5 equivalents) of LiH. HPLC-MS (Condition A): rt = 5.77 min; m / z: 581 [M+1] + 。

[0237] 2-O-tert-butyldimethylsilyl-4,6-O-bis(19-methoxynonadec-10-yn-1-yl)-1,3,5-O-methylidene-myo-inositol (II-21): According to the general alkylation procedure A, 1.236 g of (II-21) was obtained (55%) from 2.93 g (2.5 equivalents) of (31). 11H NMR (400 MHz, chloroform-d) δ 5.53 (d, J = 1.3 Hz, 1H), 4.36 (tt, J = 3.6, 1.6 Hz, 1H), 4.25 (q, J = 1.6 Hz, 1H), 4.16 (t, J = 3.6 Hz, 2H), 4.11 - 4.09 (m, 2H), 3.53 (dt, J = 8.8, 6.4 Hz, 2H), 3.44 (dt, J = 8.8, 6.4 Hz, 2H), 3.36 (t, J = 6.8 Hz, 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).

[0256] 2-O-tert-butyldimethylsilyl-4,6-O-bis(2-cyclopropylethyl)-1,3,5-O-methylidene-myo-inositol (II-22): According to the general alkylation procedure B, 3.1 g of (II-22) was obtained (59.6%) from 6.24 g (2.2 equivalents) of (21) and 213 mg (2.2 equivalents) of LiH. HPLC-MS (Condition A): rt = 5.94 min; 441 [M+1] + , 563 [M+23] + 。

[0238]

[0257] 2-O-tert-butyldimethylsilyl-4,6-O-bis(2-cyclopentylethyl)-1,3,5-O-methylidene-myo-inositol (II-23): According to the general alkylation procedure B, 267 mg of (II-23) was obtained (23.5%) from 1.53 g (2.5 equivalents) of (22) and 43 mg (2.5 equivalents) of LiH. HPLC-MS (Condition A): rt = 7.22 min; 497 [M+1] + , 519 [M+23] + 。

[0239]

[0258] 2-O-tert-butyldimethylsilyl-4,6-O-bis(3-(4-methoxyphenyl)propyl)-1,3,5-O-methylidene-myo-inositol (II-24): According to the general alkylation procedure B, 60 mg of (II-24) was obtained (5%) from 1.59 g (2.5 equivalents) of (23) and 41 mg (2.5 equivalents) of LiH. HPLC-MS (Condition A): rt = 5.80 min; 601.5 [M+1] + 、623.5 [M+23] + 。

[0240]

[0259] 2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-4,6-O-bis(3-(3-(trifluoromethyl)phenyl)propyl)-myo-inositol (II-25): According to the general alkylation procedure B, 35 mg of (II-25) was obtained (3%) from 1.53 g (2.5 equivalents) of (24) and 35 mg (2.5 equivalents) of LiH. HPLC-MS (Condition A): rt = 6.19 min; 677.4 [M+1] + 、699.4 [M+23] + 。

[0241]

[0260] 2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-4,6-O-bis(3-(p-tolyl)propyl)-myo-inositol (II-26): According to the general alkylation procedure B, 261 mg of (II-26) was obtained (19%) from 1.85 g (2.5 equivalents) of (25) and 50 mg (2.5 equivalents) of LiH. HPLC-MS (Condition A): rt = 6.45 min; 569.4 [M+1] + 、591.4 [M+23] + 。

[0242]

[0261] 2-O-tert-butyldimethylsilyl-4,6-O-bis(3-methoxycarbonylpropyl)-1,3,5-O-methylidene-myo-inositol (II-27): According to the general alkylation procedure B, 264 mg of (II-27) was obtained (15%) from 2.65 mL (6 equivalents) of methyl 4-bromobutanoate and 288 mg (10 equivalents) of LiH. HPLC-MS (Condition A): rt = 4.52 minutes; 505 [M+1] + 。

[0243] C.2. Intermediate III

[0262] 4,6-O-bis(5-(benzyloxy)pentyl)-myo-inositol (III-1): According to the general hydrolysis procedure C, 163 mg of (III-1) was obtained from 202 mg of (II-1) (>99%). HPLC-MS (Condition A): rt = 3.59 minutes; m / z: 533 [M+1] + 。

[0244]

[0263] 4,6-O-bis(5-methoxypentyl)-myo-inositol (III-2): According to the general hydrolysis procedure C, 348 mg of (III-2) was obtained from 510 mg of (II-5) (>99%). HPLC-MS (Condition A): rt = 2.69 minutes; m / z: 381 [M+1] + 、403 [M+23] + 。

[0245]

[0264] 4,6-O-bis(10-(benzyloxy)decyl)-myo-inositol (III-3): According to the general hydrolysis procedure D, 51 mg of (III-3) was obtained from 75 mg of (II-2) (80%). 11H NMR (400 MHz, methanol-d4) δ 7.33 - 7.24 (m, 10H), 4.46 (s, 4H), 3.89 (t, J = 2.4 Hz, 1H), 3.77 (td, J = 6.8, 2.4 Hz, 4H), 3.46 (t, J = 6.8 Hz, 4H) 3.40 (t, J = 8.4 Hz, 2H), 3.38 (dd, J = 8.4, 2.4 Hz, 2H), 3.28 (t, J = 8.4 Hz, 1H), 1.65 - 1.52 (m, 8H), 1.26 - 1.27 (m, 24H).

[0265] 4,6 - O - Bis(14 - (benzyloxy)tetradecyl)-myo - inositol (III - 4): According to the general hydrolysis procedure D, 14 mg of (III - 4) was obtained from 16.5 mg of (II - 3) (>99%). 1 1H NMR (400 MHz, methanol-d4) δ 7.33 - 7.27 (m, 10H), 4.46 (s, 4H), 3.90 (t, J = 2.4 Hz, 1H), 3.77 (td, J = 6.6, 2.8 Hz, 4H), 3.48 (t, J = 6.6 Hz, 4H), 3.41 (t, J = 9.2 Hz, 2H), 3.35 (dd, J = 9.2, 2.8 Hz, 2H), 3.28 - 3.23 (m, 1H), 1.63 - 1.56 (m, 8H), 1.45 - 1.17 (m, 40H).

[0266] 4,6 - O - Bis(5 - ethoxycarbonylpentyl)-myo - inositol (III - 5): According to the general hydrolysis procedure D, 87.7 mg of (III - 5) was obtained from 114 mg of (II - 13) (>99%). HPLC - MS (condition A): rt = 2.95 min; m / z: 465 [M + 1] + 。

[0246]

[0267] 4,6-O-bis(10-ethoxycarbonyldecyl)-myo-inositol (III-6): According to the general hydrolysis procedure D, 129 mg of (III-6) was obtained from 166 mg of (II-14) (94%). HPLC-MS (Condition A): rt = 4.47 min; m / z: 605 [M+1] + 。

[0247]

[0268] 4,6-O-bis(2-cyclopropylethyl)-myo-inositol (III-7): According to the general hydrolysis procedure S, 2.23 g of (III-7) was obtained from 3.10 g of (II-22) (100%). HPLC-MS (Condition A): rt = 2.82 min; m / z: 317 [M+1] + , 339 [M+23] + 。

[0248]

[0269] 4,6-O-bis(2-cyclopentylethyl)-myo-inositol (III-8): According to the general hydrolysis procedure S, 201 mg of (III-8) was obtained from 267 mg of (II-23) (>99%). HPLC-MS (Condition A): rt = 3.50 min; m / z: 373 [M+1] + , 395 [M+23] + 。

[0249]

[0270] 4,6-O-bis(5-(1H-pyrazol-1-yl)pentyl)-myo-inositol (III-9): According to the general hydrolysis procedure D, 67 mg of (III-9) was obtained from 90 mg of (II-15) (95%). HPLC-MS (Condition A): rt = 2.79 min; m / z: 453 [M+1] + 。

[0250]

[0271] 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 of (III-10) was obtained from 19 mg of (II-16) (>99%). HPLC-MS (Condition A): rt = 2.29 min; m / z: 455 [M+1] + 。

[0251]

[0272] 4,6-O-bis(2-(4-acetylpiperazin-1-yl)ethyl)-myo-inositol (III-11): According to the general hydrolysis procedure C, 36 mg of (III-11) was obtained from 45 mg of (II-17) (>99%). HPLC-MS (Condition B): rt = 0.23 min; m / z: 489 [M+1] + , 511 [M+23] + .

[0252]

[0273] 4,6-O-bis(3-methoxypropyl)-myo-inositol (III-12): According to the general hydrolysis procedure E, 23 mg of (III-12) was obtained from 232 mg of (II-4) (13%). HPLC-MS (Condition A): rt = 1.83 min; m / z: 325 [M+1] + .

[0253]

[0274] 4,6-O-bis(7-methoxyheptyl)-myo-inositol (III-13): According to the general hydrolysis procedure E, 321 mg of (III-13) was obtained from 389 mg of (II-7) (>99%). HPLC-MS (Condition A): rt = 3.14 min; m / z: 437 [M+1] + .

[0254]

[0275] 4,6-O-bis(9-methoxynonyl)-myo-inositol (III-14): According to the general hydrolysis procedure E, 156 mg of (III-14) was obtained from 194 mg of (II-6) (>99%). HPLC-MS (Condition A): rt = 3.76 min; m / z: 493 [M+1] + , 515 [M+23] + .

[0255]

[0276] 4,6-O-dipropyl-myo-inositol (III-15): According to the general hydrolysis procedure E, 26.3 mg of (III-15) was obtained from 79 mg of (II-8) (49%). HPLC-MS (Condition A): rt = 1.85 min; m / z: 265 [M+1] + , 287 [M+23] + .

[0256]

[0277] 4,6-O-Dipentyl-myo-inositol (III-16): According to the general hydrolysis procedure E, 107 mg of (III-16) was obtained from 255 mg of (II-9) (59%). HPLC-MS (condition A): rt = 3.00 min; m / z: 321 [M+1] + .

[0257]

[0278] 4,6-O-Diheptyl-myo-inositol (III-17): According to the general hydrolysis procedure E, 149 mg of (III-17) was obtained from 250 mg of (II-10) (77%). HPLC-MS (condition A): rt = 3.89 min; m / z: 377 [M+1] + , 399 [M+23] + .

[0258]

[0279] 4,6-O-Didecyl-myo-inositol (III-18): According to the general hydrolysis procedure E, 185 mg of (III-18) was obtained from 272 mg of (II-11) (84%). HPLC-MS (condition A): rt = 5.36 min; m / z: 461 [M+1] + .

[0259]

[0280] 4,6-O-Di(tetradecyl)-myo-inositol (III-19): According to the general hydrolysis procedure E, 212 mg of (III-19) was obtained from 360 mg of (II-12) (69%). 1 H NMR (400 MHz, chloroform-d) δ 4.19-4.12 (m, 1H), 3.83 (dt, J = 9.2, 6.8 Hz, 2H), 3.65 (dt, J = 9.2, 6.8 Hz, 2H), 3.52-3.44 (m, 4H), 3.43-3.36 (m, 1H), 1.59 (p, J = 6.8 Hz, 4H), 1.33-1.25 (m, 44H), 0.88 (t, J = 6.8 Hz, 6H).

[0281] 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 of (III-20) was obtained from 615 mg of (15) (98%). HPLC-MS (Condition A): rt = 3.18 min; m / z: 667 [M+1] + .

[0260]

[0282] 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 of (III-21) was obtained from 70 mg of (IX-3) and 76 mg of benzyl penta-4-inoate (67%). In this case, flash chromatography was utilized. HPLC-MS (Condition B): rt = 2.37 min; m / z: 723 [M+1] +

[0283] 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 of (III-22) was obtained from 41 mg of (IX-3) and 19 μL of 3-methoxyprop-1-yne (61%). HPLC-MS (Condition A): rt = 2.32 min; m / z: 487 [M+1] +

[0284] 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 of (III-23) was obtained from 43 mg of (IX-1) and 19 μL of 3-methoxyprop-1-yne (22%). HPLC-MS (Condition A): rt = 2.40 min; m / z: 515 [M+1] +

[0285] 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 of (III-24) was obtained (64%) from 58 mg of (IX-4) and 12 μL of 3-methoxyprop-1-yne. HPLC-MS (Condition A): rt = 2.48 min; m / z: 543 [M+1] +

[0286] 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 of (III-25) was obtained (12%) from 2 g of (IX-2) and 1.16 mL of 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].

[0261]

[0287] 4,6-O-bis((1-(3-methoxypropyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol (III-26): According to the general group conversion procedure N, 38 mg of (III-26) was obtained (54%) from 110 mg of (VII-1). HPLC-MS (Condition A): rt = 2.42 min; m / z: 487 [M+1] +

[0288] 4,6-O-bis((1-(6-methoxyhexyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol (III-27): According to the general group conversion procedure N, 59 mg of (III-27) was obtained from 160 mg of (VII-2) (55%). HPLC-MS (Condition A): rt = 2.88 min; m / z: 571 [M+1] +

[0289] 4,6-O-bis((3-(4-ethyloxycarbonylbutanamide)propyl))-myo-inositol (III-28): According to the general amide formation procedure P, 57 mg of (III-28) was obtained from 160 mg of (XII-1) and 196 mg of (32) (34%). HPLC-MS (Condition B): rt = 1.45 min; m / z: 551 [M+1] + , 573 [M+23] + 。

[0262]

[0290] 4,6-O-bis(3-(4-methoxyphenyl)propyl)-myo-inositol (III-29): According to the general hydrolysis procedure S, 47 mg of (III-29) was obtained from 60 mg of (II-24) (>99%). HPLC-MS (Condition A): rt = 3.31 min; m / z: 477 [M+1] + 。

[0263]

[0291] 4,6-O-bis(3-(3-(trifluoromethyl)phenyl)propyl)-myo-inositol (III-30): According to the general hydrolysis procedure S, 212 mg of (III-30) was obtained from 262 mg of (II-25) (84%). HPLC-MS (Condition A): rt = 3.88 min; m / z: 553 [M+1] + , 575 [M+23] + 。

[0264]

[0292] 4,6-O-bis(3-(p-tolyl)propyl)-myo-inositol (III-31): According to the general hydrolysis procedure S, 57 mg of (III-31) was obtained from 85 mg of (II-26) (85%). HPLC-MS (Condition A): rt = 3.88 min; m / z: 445 [M+1] +, 467 [M + 23] + .

[0265]

[0293] 4,6 - O - bis(4,4,4 - trifluorobutyl) - myo - inositol (III - 32): According to the general hydrolysis procedure S, 2.73 g of (III - 32) was obtained from 3.61 g of (II - 18) (99%). HPLC - MS (Condition A): rt = 3.01 min; m / z: 401 [M + 1] + , 423 [M + 23] + .

[0266]

[0294] 4,6 - O - bis(6,6,6 - trifluorohexyl) - myo - inositol (III - 33): According to the general hydrolysis procedure S, 457 mg of (III - 33) was obtained from 594 mg of (II - 19) (98%). HPLC - MS (Condition A): rt = 3.40 min; m / z: 457 [M + 1] + .

[0267]

[0295] 4,6 - O - bis(4 - methylpentyl) - myo - inositol (III - 34): According to the general hydrolysis procedure S, 193 mg of (III - 34) was obtained from 273 mg of (II - 20) (96%). HPLC - MS (Condition A): rt = 3.40 min; m / z: 349 [M + 1] + .

[0268]

[0296] 4,6 - O - bis(19 - methoxynonadeca - 10 - yn - 1 - yl) - myo - inositol (III - 35): According to the general hydrolysis procedure S, 1.03 g of (III - 35) was obtained from 1.2 g of (II - 21) (>99%). HPLC - MS (Condition A): rt = 7.18 min; m / z: 765.6 [M + 1] + , 787.7 [M + 23] + .

[0269]

[0297] 4,6-O-bis(3-(3-phenylureido)propyl)-myo-inositol (III-36): According to the general urea formation procedure H, 90 mg of (III-36) was obtained from 89 mg of (XII-1) and 39 μL of phenyl isocyanate (>99%). HPLC-MS (Condition A): rt = 2.70 min; m / z: 533 [M+1] + .

[0270]

[0298] 4,6-O-bis(3-(3-cyclopentylureido)propyl)-myo-inositol (III-37): According to the general urea formation procedure H, 80 mg of (III-37) was obtained from 89 mg of (XII-1) and 40.2 μL of isocyanatocyclopentane (91%). HPLC-MS (Condition A): rt = 2.79 min; m / z: 517 [M+1] + .

[0271]

[0299] 4,6-O-bis(3-((methoxycarbonyl)amino)propyl)-myo-inositol (III-38): According to the general carbamate formation procedure V, 7 mg of (III-38) was obtained from 74 mg of (XII-1) (12%). HPLC-MS (Condition B): rt = 0.25 min; m / z: 411 [M+1] + , 433 [M+23] + .

[0272]

[0300] 4,6-O-bis(5-acetamidopentyl)-myo-inositol (III-39): According to the general hydrolysis procedure S, 52 mg of (III-39) was obtained from 93 mg of (XIII-1) (72%). HPLC-MS (Condition B): rt = 0.25 min; m / z: 435 [M+1] + , 457 [M+23] + .

[0273]

[0301] 4,6-O-bis(5-benzamidopentyl)-myo-inositol (III-40): According to the general hydrolysis procedure S, 35 mg of (III-40) was obtained from 43 mg of (XIII-2) (>99%). HPLC-MS (Condition A): rt = 2.92 min; m / z: 559 [M+1]+ .

[0274]

[0302] 4,6-O-bis(5-(thiophene-2-carboxamido)pentyl)-myo-inositol (III-41): According to the general amide formation procedure P, 158 mg of (III-41) was obtained from 121 mg of (XII-2) and 129 mg of (33) (97%). HPLC-MS (Condition B): rt = 2.14 min; m / z: 571 [M+1] + .

[0275]

[0303] 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), and the solution was stirred at 60 °C for 24 h. The solution was then concentrated in vacuo to give 98 mg of (III-44) (57%). HPLC-MS (Condition A): rt = 2.44 min; m / z: 381 [M+1] + , 403 [M+23] + .

[0276]

[0304] 4,6-O-bis(5-(3-propylureido)pentyl)-myo-inositol (III-45): According to the general urea formation procedure H, 120 mg of (III-45) was obtained from 89 mg of (XII-1) and 50 μL of 1-isocyanatopropane (91%). HPLC-MS (Condition A): rt = 2.72 min; m / z: 521 [M+1] + .

[0277]

[0305] 4,6-O-bis(5-((methoxycarbonyl)amino)pentyl)-myo-inositol (III-46): According to the general hydrolysis procedure S, 43 mg of (III-46) was obtained from 54 mg of (XIII-3) (>99%). HPLC-MS (Condition A): rt = 2.62 min; m / z: 467 [M+1] + , 490 [M+23] + .

[0278]

[0306] 4,6-O-bis(3-methoxycarbonylpropyl)-myo-inositol (III-47): According to the general hydrolysis procedure S, 200 mg of (III-47) was obtained from 274 mg of (II-27) (97%). 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). C.3. Intermediates IV and IV’

[0307] 4,6-O-bis(5-(benzyloxy)pentyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-26): According to the general phosphorylation procedure G, 173 mg of (IV-26) was obtained from 164 mg of (III-1) (44.6%). HPLC-MS (Condition A): rt = 4.85 min; m / z: 1261 [M+1] + 。

[0279]

[0308] 4,6-O-bis(10-(benzyloxy)decyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-1): According to the general phosphorylation procedure G, 50 mg of (IV-1) was obtained from 50 mg of (III-3) (48%). HPLC-MS (Condition B): rt = 4.21 min; m / z: 1401 [M+1] + 。

[0280]

[0309] 4,6-O-bis(14-(benzyloxy)tetradecyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-2): According to the general phosphorylation procedure G, 8 mg of (IV-2) was obtained from 16 mg of (III-4) (26%).

[0281]

[0310] 4,6-O-bis(3-methoxypropyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-3): According to the general phosphorylation procedure G, 25 mg of (IV-3) was obtained from 37 mg of (III-12) (21%). HPLC-MS (Condition A): rt = 3.78 min; m / z: 1053 [M+1] + 。

[0282]

[0311] 4,6-O-bis(5-methoxypentyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-4): According to the general phosphorylation procedure G, 326 mg of (IV-4) was obtained from 444 mg of (III-2) (25%). HPLC-MS (Condition A): rt = 4.03 min; m / z: 1109 [M+1] + 。

[0283]

[0312] 4,6-O-bis(7-methoxyheptyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-5): According to the general phosphorylation procedure G, 191 mg of (IV-5) was obtained from 365 mg of (III-13) (19.6%). HPLC-MS (Condition A): rt = 4.49 min; m / z: 1165 [M+1] + 。

[0284]

[0313] 4,6-O-bis(7-methoxynonyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-6): According to the general phosphorylation procedure G, 71 mg of (IV-6) was obtained from 219 mg of (III-14) (13.1%). HPLC-MS (Condition A): rt = 4.98 min; m / z: 1221.6 [M+1] + 。

[0285]

[0314] 1,2,3,5-O-Tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4,6-O-dipropyl-myo-inositol (IV-7): According to the general phosphorylation procedure G, 24 mg of (IV-7) was obtained from 26.3 mg of (III-15) (24%). HPLC-MS (Condition A): rt = 3.99 min; m / z: 993 [M+1] + 。

[0286]

[0315] 1,2,3,5-O-Tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4,6-O-dipentyl-myo-inositol (IV-8): According to the general phosphorylation procedure G, 143 mg of (IV-8) was obtained from 105 mg of (III-16) (42%). HPLC-MS (Condition A): rt = 4.39 min; m / z: 1049 [M+1] + 。

[0287]

[0316] 4,6-O-Diheptyl-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-9): According to the general phosphorylation procedure G, 244 mg of (IV-9) was obtained from 150 mg of (III-17) (55%). HPLC-MS (Condition A): rt = 5.04 min; m / z: 1105 [M+1] + 。

[0288]

[0317] 4,6-O-Didecyl-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-10): According to the general phosphorylation procedure G, 64 mg of (IV-10) was obtained from 180 mg of (III-18) (14%). 11H NMR (400 MHz, chloroform-d) δ 7.35 - 7.09 (m, 16H), 5.41 - 4.97 (m, 17H), 4.43 (t, J = 8.8 Hz, 2H), 4.37 (dt, J = 11.2, 4.8 Hz, 1H), 3.81 (t, J = 8.8 Hz, 2H), 3.64 (t, J = 7.2 Hz, 4H), 1.54 (p, J = 7.2 Hz, 4H), 1.25 - 1.11 (m, 28H), 0.79 (t, J = 7.2 Hz, 6H).

[0318] 1,2,3,5 - O - Tetrakis(3 - oxide - 1,5 - dihydrobenzo[e][1,3,2]dioxaphosphepin - 3 - yl) - 4,6 - O - di(tetradecyl) - myo - inositol (IV - 11): According to the general phosphorylation procedure G, 193 mg of (IV - 11) was obtained from 134 mg of (III - 19) (63%). HPLC - MS (Condition B): rt = 5.25 min; m / z: 1301 [M + 1] + 。

[0289]

[0319] 4,6 - O - Bis(5 - ethoxycarbonylpentyl) - 1,2,3,5 - O - tetrakis(3 - oxide - 1,5 - dihydrobenzo[e][1,3,2]dioxaphosphepin - 3 - yl) - myo - inositol (IV - 12): According to the general phosphorylation procedure G, 35.5 mg of (IV - 12) was obtained from 90 mg of (III - 5) (15%). HPLC - MS (Condition A): rt = 4.31 min; m / z: 1193 [M + 1] + 。

[0290]

[0320] 4,6 - O - Bis(10 - ethoxycarbonyldecyl) - 1,2,3,5 - O - tetrakis(3 - oxide - 1,5 - dihydrobenzo[e][1,3,2]dioxaphosphepin - 3 - yl) - myo - inositol (IV - 13): According to the general phosphorylation procedure G, 161 mg of (IV - 13) was obtained from 129 mg of (III - 6) (57%). HPLC - MS (Condition A): rt = 5.38 min; m / z: 1333 [M + 1] + 。

[0291]

[0321] 1,2,3,5 - O - Tetrakis(3 - oxide - 1,5 - dihydrobenzo[e][1,3,2]dioxaphosphepin - 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 of (IV - 14) was obtained from 70 mg of (III - 9) (14%). HPLC - MS (Condition A): rt = 3.89 min; m / z: 1182 [M + 1] + 。

[0292]

[0322] 1,2,3,5 - O - Tetrakis(3 - oxide - 1,5 - dihydrobenzo[e][1,3,2]dioxaphosphepin - 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 of (IV - 15) was obtained from 19 mg of (III - 10). HPLC - MS (Condition A): rt = 3.46 min; m / z: 1184 [M + 1] + 。

[0293]

[0323] 4,6 - O - Bis((1 - (2 - (benzyloxycarbonyl)ethyl) - 1H - 1,2,3 - triazol - 4 - yl)methyl) - 1,2,3,5 - O - tetrakis(3 - oxide - 1,5 - dihydrobenzo[e][1,3,2]dioxaphosphepin - 3 - yl) - myo - inositol (IV - 16): According to the general phosphorylation procedure G, 445 mg of (IV - 16) was obtained from 423 mg of (III - 20) (50%). HPLC - MS (Condition A): rt = 4.16 min; m / z: 1395 [M + 1] + 。

[0294]

[0324] 4,6-O-bis((1-(3-methoxypropyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-17): According to the general phosphorylation procedure G, 64 mg of (IV-17) was obtained from 62 mg of (III-26) (41%). HPLC-MS (Condition A): rt = 3.64 minutes; m / z: 1215 [M+1] + 。

[0295]

[0325] 4,6-O-bis((1-(6-methoxyhexyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-18): According to the general phosphorylation procedure G, 15 mg of (IV-18) was obtained from 59 mg of (III-27) (11%). HPLC-MS (Condition A): rt = 3.95 minutes; m / z: 1299 [M+1] + 。

[0296]

[0326] 4,6-O-bis(3-(4-(2-(benzyloxycarbonyl)ethyl)-1H-1,2,3-triazol-1-yl)propyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-19): According to the general phosphorylation procedure G, 86 mg of (IV-19) was obtained from 100 mg of (III-21) (43%). HPLC-MS (Condition B): rt = 3.18 minutes; m / z: 1451 [M+1] + 。

[0297]

[0327] 4,6-O-bis(3-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)propyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-20): According to the general phosphorylation procedure G, 7.2 mg of (IV-20) was obtained from 40 mg of (III-22) (7%). HPLC-MS (Condition A): rt = 3.48 min; m / z: 1215 [M+1] + 。

[0298]

[0328] 4,6-O-bis(4-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)butyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-21): According to the general phosphorylation procedure G, 11 mg of (IV-21) was obtained from 20 mg of (III-23) (23%). HPLC-MS (Condition A): rt = 3.53 min; m / z: 1243 [M+1] + 。

[0299]

[0329] 4,6-O-bis(5-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-22): According to the general phosphorylation procedure G, 9.7 mg of (IV-22) was obtained from 54 mg of (III-24) (8%). HPLC-MS (Condition A): rt = 3.59 min; m / z: 1271 [M+1] + 。

[0300]

[0330] 4,6-O-bis(6-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)hexyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-23): According to the general phosphorylation procedure G, 35.5 mg of (IV-23) was obtained from 85 mg of (III-25) (18%). HPLC-MS (Condition A): rt = 3.66 min; m / z: 1299 [M+1] + 。

[0301]

[0331] 4,6-O-bis(2-(4-acetylpiperazin-1-yl)ethyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-24): According to the general phosphorylation procedure G, 16 mg of (IV-24) was obtained from 81.5 mg of (III-11) (8%). HPLC-MS (Condition B): rt = 1.92 min; m / z: 1217 [M+1] + 。

[0302]

[0332] 4,6-O-bis((3-(4-ethyloxycarbonylbutanamide)propyl))-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-25): According to the general phosphorylation procedure G, 28 mg of (IV-25) was obtained from 57 mg of (III-28) (21%). HPLC-MS (Condition A): rt = 2.66 min; m / z: 1279 [M+1] + 。

[0303]

[0333] 4,6-O-bis(2-cyclopropylethyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-27): According to the general phosphorylation procedure G, 3 g of (IV-27) was obtained from 2.3 g of (III-7) (39%). HPLC-MS (Condition A): rt = 4.30 min; m / z: 1045 [M+1] +。

[0304]

[0334] 4,6-O-bis(2-cyclopentylethyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-28): According to the general phosphorylation procedure G, 164 mg of (IV-28) was obtained from 200 mg of (III-8) (28%). HPLC-MS (Condition A): rt = 4.74 min; m / z: 1101 [M+1] + 。

[0305]

[0335] 4,6-O-bis(3-(4-methoxyphenyl)propyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-29): According to the general phosphorylation procedure G, 36 mg of (IV-29) was obtained from 60 mg of (III-29) (24%). HPLC-MS (Condition A): rt = 4.20 min; m / z: 1206 [M+1] + 。

[0306]

[0336] 1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4,6-O-bis(3-(3-(trifluoromethyl)phenyl)propyl)-myo-inositol (IV-30): According to the general phosphorylation procedure G, 64 mg of (IV-30) was obtained from 214 mg of (III-30) (13%). HPLC-MS (Condition A): rt = 4.83 min; m / z: 1281 [M+1] + 。

[0307]

[0337] 1,2,3,5 - O - Tetrakis(3 - oxide - 1,5 - dihydrobenzo[e][1,3,2]dioxaphosphepin - 3 - yl) - 4,6 - O - bis(3 - (p - tolyl)propyl) - myo - inositol (IV - 31): According to the general phosphorylation procedure G, 19.1 mg of (IV - 31) was obtained from 54.7 mg of (III - 31) (13%). HPLC - MS (Condition A): rt = 4.76 min; m / z: 1274 [M + 1] + 。

[0308]

[0338] 1,2,3,5 - O - Tetrakis(3 - oxide - 1,5 - dihydrobenzo[e][1,3,2]dioxaphosphepin - 3 - yl) - 4,6 - O - bis(4,4,4 - trifluorobutyl) - myo - inositol (IV - 32): According to the general phosphorylation procedure G, 2.34 g of (IV - 32) was obtained from 1.62 g of (III - 32) (51%). HPLC - MS (Condition A): rt = 4.29 min; m / z: 1129 [M + 1] + 。

[0309]

[0339] 1,2,3,5 - O - Tetrakis(3 - oxide - 1,5 - dihydrobenzo[e][1,3,2]dioxaphosphepin - 3 - yl) - 4,6 - O - bis(6,6,6 - trifluorohexyl) - myo - inositol (IV - 33): According to the general phosphorylation procedure G, 414 mg of (IV - 33) was obtained from 457 mg of (III - 33) (35%). HPLC - MS (Condition A): rt = 4.53 min; m / z: 1185 [M + 1] + 。

[0310]

[0340] 4,6 - O - Bis(4 - methylpentyl) - 1,2,3,5 - O - tetrakis(3 - oxide - 1,5 - dihydrobenzo[e][1,3,2]dioxaphosphepin - 3 - yl) - myo - inositol (IV - 34): According to the general phosphorylation procedure G, 168 mg of (IV - 34) was obtained from 457 mg of (III - 34) (12%). HPLC - MS (Condition A): rt = 4.568 min; m / z: 1077 [M + 1] + 。

[0311]

[0341] 4,6-O-bis(19-methoxynonadeca-10-in-1-yl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-35): According to the general phosphorylation procedure G, 939 mg of (IV-35) was obtained from 1.03 g of (III-35) (45%). HPLC-MS (Condition A): rt = 7.19 min; m / z: 1494 [M+1] + 。

[0312]

[0342] 1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4,6-O-bis(3-(3-phenylureido)propyl)-myo-inositol (IV-36): According to the general phosphorylation procedure G, 187 mg of (IV-36) was obtained from 96 mg of (III-36) (82%). HPLC-MS (Condition A): rt = 4.02 min; m / z: 1262 [M+1] + 。

[0313]

[0343] 4,6-O-bis(3-(3-cyclopentylureido)propyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-37): According to the general phosphorylation procedure G, 181 mg of (IV-37) was obtained from 80 mg of (III-37) (94%). HPLC-MS (Condition A): rt = 3.83 min; m / z: 1245 [M+1] + 。

[0314]

[0344] 4,6-O-bis(3-((methoxycarbonyl)amino)propyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-38): According to the general phosphorylation procedure G, 3 mg of (IV-38) was obtained from 10 mg of (III-38) (11%). HPLC-MS (Condition B): rt = 2.90 min; m / z: 1139 [M+1] + 。

[0315]

[0345] 4,6-O-bis(5-acetamidopentyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-39): According to the general phosphorylation procedure G, 110 mg of (IV-39) was obtained from 52 mg of (III-39) (79%). HPLC-MS (Condition B): rt = 2.69 min; m / z: 1163 [M+1] + 。

[0316]

[0346] 4,6-O-bis(5-benzamidopentyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-40): According to the general phosphorylation procedure G, 38 mg of (IV-40) was obtained from 39 mg of (III-40) (42%). HPLC-MS (Condition A): rt = 4.04 min; m / z: 1288 [M+1] + 。

[0317]

[0347] 1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4,6-O-bis(5-(thiophene-2-carboxamido)pentyl)-myo-inositol (IV-41): According to the general phosphorylation procedure G, 196 mg of (IV-41) was obtained from 158 mg of (III-41) (54%). HPLC-MS (Condition B): rt = 3.13 min; m / z: 1299 [M+1] + 。

[0318]

[0348] 4,6-O-(6-(4-(Methoxycarbonyl)-1H-1,2,3-triazol-1-yl)hexyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-42): According to the general phosphorylation procedure G, 34 mg of (IV-42) was obtained from 278 mg of (III-42) (5.5%). HPLC-MS (Condition A): rt = 3.86 min; m / z: 1327 [M+1] + 。

[0319]

[0349] 4-O-(6-(4-(Methoxymethyl)-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-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-43): According to the general phosphorylation procedure G, 101 mg of (IV-43) was obtained from 454 mg of (III-43) (10%). HPLC-MS (Condition A): rt = 3.76 min; m / z: 1313 [M+1] + 。

[0320]

[0350] 4,6-O-bis(4-amino-4-oxobutyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-44): According to the general phosphorylation procedure G, 179 mg of (IV-44) was obtained from 97.5 mg of (III-44) (59%). HPLC-MS (Condition A): rt = 3.29 min; m / z: 1079.5 [M+1] + 。

[0321]

[0351] 1,2,3,5 - O - Tetrakis(3 - oxide - 1,5 - dihydrobenzo[e][1,3,2]dioxaphosphepin - 3 - yl)-4,6 - O - bis(5-(3 - propylureido)pentyl)-myo - inositol (IV - 45): According to the general phosphorylation procedure G, 210 mg of (IV - 45) was obtained from 120 mg of (III - 45) (73%). HPLC - MS (Condition A): rt = 3.73 min; m / z: 1250.5 [M + 1] + 。

[0322]

[0352] 4,6 - O - Bis(5 - ((methoxycarbonyl)amino)pentyl)-1,2,3,5 - O - tetrakis(3 - oxide - 1,5 - dihydrobenzo[e][1,3,2]dioxaphosphepin - 3 - yl)-myo - inositol (IV - 46): According to the general phosphorylation procedure G, 64 mg of (IV - 46) was obtained from 50 mg of (III - 46) (50%). HPLC - MS (Condition A): rt = 3.86 min; m / z: 1195 [M + 1] + 。

[0323]

[0353] 4,6 - O - Bis(3 - methoxycarbonylpropyl)-1,2,3,5 - O - tetrakis(3 - oxide - 1,5 - dihydrobenzo[e][1,3,2]dioxaphosphepin - 3 - yl)-myo - inositol (IV - 47): According to the general phosphorylation procedure G, 40 mg of (IV - 47) was obtained from 70 mg of (III - 47) (19%). HPLC - MS (Condition A): rt = 3.77 min; m / z: 1109 [M + 1] + 。

[0324]

[0354] 4,6 - O - Dipropargyl - 1,2,3,5 - O - tetrakis(3 - oxide - 1,5 - dihydrobenzo[e][1,3,2]dioxaphosphepin - 3 - yl)-myo - inositol (IV - 48): According to the general phosphorylation procedure G, 4.69 g of (IV - 48) was obtained from 3.92 g of (VI - 1) (32%). HPLC - MS (Condition A): rt = 3.69 min; m / z: 985 [M + 1] + 。

[0325]

[0355] 4,6 - O - Dipentyl - 1,2,3,5 - O - tetrakis(3 - sulfide - 1,5 - dihydrobenzo[e][1,3,2]dioxaphosphepin - 3 - yl) - myo - inositol (IV’ - 1): According to the general thiophosphorylation procedure T, 28 mg of (IV’ - 1) was obtained from 64 mg of (III - 16) (13%). HPLC - MS (Condition A): rt = 5.94 min; m / z: 1113 [M + 1] + 。

[0326]

[0356] 4,6 - O - Bis(5 - methoxypentyl) - 1,2,3,5 - O - tetrakis(3 - sulfide - 1,5 - dihydrobenzo[e][1,3,2]dioxaphosphepin - 3 - yl) - myo - inositol (IV’ - 2): According to the general thiophosphorylation procedure T, 70 mg of (IV’ - 2) was obtained from 76 mg of (III - 2) (30%). HPLC - MS (Condition A): rt = 5.49 min; m / z: 1173 [M + 1] + 。

[0327] C.4. Intermediate V

[0357] 2 - O - tert - Butyldimethylsilyl - 1,3,5 - O - methylidine - 4,6 - O - dipropargyl - myo - inositol (V - 1): According to the general alkylation procedure A, 1.2 g of (V - 1) was obtained from 1.0 mL of 3 - bromoprop - 1 - yne in toluene (2.1 equivalents, 80%) (>99%). HPLC - MS (Condition A): rt = 4.36 min; m / z: 381 [M + 1] + 。

[0328] C.5. Intermediate VI

[0358] 4,6 - O - Dipropargyl - myo - inositol (VI - 1): According to the general hydrolysis procedure D, 740 mg of (VI - 1) was obtained from 1.2 g of (V - 1) (92%). 11H NMR (400 MHz, methanol-d4) δ 4.48 (d, J = 2.4 Hz, 4H), 3.89 (t, J = 2.8 Hz, 1H), 3.56 (t, J = 9.6 Hz, 2H), 3.39 (dd, J = 9.6, 2.8 Hz, 2H), 3.33 (d, J = 9.6 Hz, 1H), 2.80 (t, J = 2.4 Hz, 2H). C.6. Intermediate VII

[0359] 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 of (VII-1) was obtained from 100 mg of (8) (73%). HPLC-MS (Condition A): rt = 3.30 min; m / z: 767 [M+1] + 。

[0329]

[0360] 4,6-O-Bis((1-(6-(tosyloxy)hexyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol (VII-2): According to the general click reaction procedure L, 162 mg of (VII-2) was obtained from 116 mg of (17) (98%). HPLC-MS (Condition A): rt = 3.71 min.

[0330] C.7. Intermediate VIII

[0361] 4,6-O-Bis(3-azidopropyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (VIII-1): According to the general alkylation procedure A, 249 mg of (VIII-1) was obtained from 1.27 g (2.1 eq, in 5.9 mL of DMF) of (8) (22%). HPLC-MS (Condition A): rt = 5.12 min; m / z: 471 [M+1] + 。

[0331]

[0362] 4,6-O-bis(5-azidopentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (VIII-2): According to the general alkylation procedure A, 900 mg of (VIII-2) was obtained (51%) from 2 g (2.1 equivalents, in 8.4 mL of DMF) of (10). HPLC-MS (Condition A): rt = 5.62 min; m / z: 527 [M+1] + , 549 [M+23] + .

[0332]

[0363] 4,6-O-bis(10-azidodecyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (VIII-3): According to the general alkylation procedure A, 57.5 mg of (VIII-3) was obtained (27%) from 234 mg (2.05 equivalents, in 2 mL of DMF) of (12). 1 H NMR (400 MHz, chloroform-d) δ 5.52 (d, J = 1.6 Hz, 1H), 4.36 (h, J = 1.6 Hz, 1H), 4.24 (q, J = 1.6 Hz, 1H), 4.16 (t, J = 4 Hz, 2H), 4.10 (dt, J = 4, 1.6 Hz, 2H), 3.53 (dt, J = 8.8, 6.4 Hz, 2H), 3.45 (dt, J = 8.8, 6.4 Hz, 2H), 3.25 (t, J = 7.0 Hz, 4H), 1.59 (p, J = 7.0 Hz, 4H), 1.57 - 1.46 (m, 4H), 1.38 - 1.26 (m, 24H), 0.94 (s, 9H), 0.14 (s, 6H).

[0364] 4,6-O-bis(4-azidobutyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (VIII-4): According to the general alkylation procedure A, 17 mg of (VIII-4) was obtained (7%) from 245 mg (2 equivalents, in 1.2 mL of DMF) of (19). HPLC-MS (Condition A): rt = 5.33 min; m / z: 499 [M+1] + , 521 [M+1] + .

[0333]

[0365] 4,6-O-bis(6-azidohexyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (VIII-5): According to the general alkylation procedure A, 74 mg of (VIII-5) was obtained (20%) from 200 mg (2 equivalents, in 1.6 mL of DMF) of (17). HPLC-MS (Condition A): rt = 5.97 min; m / z: 555 [M+1] + , 577 [M+1] + .

[0334] C.8. Intermediate IX

[0366] 4,6-O-bis(4-azidobutyl)-myo-inositol (IX-1): According to the general hydrolysis procedure C, with a slight modification (aqueous workup), 8 mg of (IX-1) was obtained (64%) from 16.7 mg of (VIII-4). HPLC-MS (Condition A): rt = 2.76 min; m / z: 375 [M+1] + , 397 [M+23] + .

[0335]

[0367] 4,6-O-bis(6-azidohexyl)-myo-inositol (IX-2): According to the general hydrolysis procedure C, with a slight modification (aqueous workup), 40 mg of (IX-2) was obtained (69%) from 74.7 mg of (VIII-5). HPLC-MS (Condition A): rt = 3.29 min; m / z: 431 [M+1] + , 453 [M+23] + .

[0336]

[0368] 4,6-O-bis(3-azidopropyl)-myo-inositol (IX-3): According to the general hydrolysis procedure E, 174 mg of (IX-3) was obtained (94%) from 250 mg of (VIII-1). HPLC-MS (Condition A): rt = 2.45 min; m / z: 347 [M+1] + , 369 [M+23]+.

[0337]

[0369] 4,6-O-bis(5-azidopentyl)-myo-inositol (IX-4): According to the general hydrolysis procedure D, 6.8 mg of (IX-4) was obtained from 8.9 mg of (VIII-2) (>99%). HPLC-MS (Condition A): rt = 3.06 min; m / z: 403 [M+1] + , 425 [M+23] + .

[0338]

[0370] 4,6-O-bis(10-azidodecyl)-myo-inositol (IX-5): According to the general hydrolysis procedure D, 47 mg of (IX-5) was obtained from 57.5 mg of (VIII-3) (>99%). 1 H NMR (400 MHz, methanol-d4) δ 3.92 (t, J = 2.6 Hz, 1H), 3.79 (m, 4H), 3.48 - 3.35 (m, 4H), 3.30 - 3.25 (m, 5H), 1.64 (p, J = 6.8 Hz, 4H), 1.61 (p, J = 7.2 Hz, 4H), 1.45 - 1.27 (m, 24H). C.9. Intermediate X

[0371] 4,6-O-bis(3-azidopropyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (X-1): According to the general phosphorylation procedure G, 148 mg of (X-1) was obtained from 305 mg of (IX-3) (16%). HPLC-MS (Condition A): rt = 4.01 min; m / z: 1075 [M+1] + .

[0339]

[0372] 4,6-O-bis(5-azidopentyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (X-2): According to the general phosphorylation procedure G, 530 mg of (X-2) was obtained from 300 mg of (IX-4) (63%). HPLC-MS (Condition A): rt = 4.32 min; m / z: 1131 [M+1] + .

[0340]

[0373] 4,6-O-bis(10-azidodecyl)-1,2,3,5-O-tetrakis(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (X-3): According to the general phosphorylation procedure G, 63 mg of (X-3) was obtained from 100 mg of (IX-5) (27%). HPLC-MS (condition B): rt = 3.86 min; m / z: 1271 [M+1] + 。

[0341] C.10. Intermediate XI

[0374] 4,6-O-bis(3-aminopropyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (XI-1): According to the general azide reduction procedure Q, (XI-1) was obtained from 144 mg of (VIII-1). Since its purity was sufficiently high, it was used continuously without purification. HPLC-MS (condition B): rt = 2.43 min; m / z: 419 [M+1] + , 441 [M+23] + 。

[0342]

[0375] 4,6-O-bis(5-aminopentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (XI-2): According to the general azide reduction procedure Q, 1.4 g of (XI-2) was obtained after column purification from 2.5 g of (VIII-2) (62%). HPLC-MS (condition A): rt = 2.73 min; m / z: 475 [M+1] + , 493 [M+23] + 。

[0343] C.11. Intermediate XII

[0376] 4,6-O-bis(3-aminopropyl)-myo-inositol·2TFA (XII-1): According to the general hydrolysis procedure C, with a slight modification (aqueous workup), 160 mg of (XII-1) was obtained from 128 mg of (XI-1) (>99%). HPLC-MS (condition B): rt = 0.24 min; m / z: 295 [M+1] + 。

[0344]

[0377] 4,6-O-bis(5-aminopentyl)-myo-inositol·2HCl (XII-2): According to the general hydrolysis procedure S, 447 mg of (XII-2) was obtained from 1.13 g of (XI-2) (54%). HPLC-MS (Condition B): rt = 0.25 min; m / z: 351 [M+1] + 。

[0345] C.12. Intermediate XIII

[0378] 4,6-O-bis(5-acetamidopentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (XIII-1): According to the general amide formation procedure P, 93 mg of (XIII-1) was obtained from 115 mg of (XI-2) and 38 μL of acetyl chloride (69%). HPLC-MS (Condition A): rt = 3.67 min; m / z: 559 [M+1] + 。

[0346]

[0379] 4,6-O-bis(5-benzamidopentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (XIII-2): According to the general amide formation procedure P, 57 mg of (XIII-2) was obtained from 125 mg of (XI-2) and 67 μL of benzoyl chloride (32%). HPLC-MS (Condition B): rt = 3.56 min; m / z: 683 [M+1] + 。

[0347]

[0380] 2-O-tert-butyldimethylsilyl-4,6-O-bis(5-((methoxycarbonyl)amino)pentyl)-1,3,5-O-methylidene-myo-inositol (XIII-3): According to the general carbamate formation procedure V, 54 mg of (XIII-3) was obtained from 127 mg of (XI-2) (38%). HPLC-MS (Condition A): rt = 4.31 min; m / z: 591 [M+1] + 。

[0348] D. Compound Characterization: Analytical and Spectroscopic Tests D.1. NMR

[0381] Agilent VNMRS-400( 1 H: 400.10 MHz and 31 P: 162 MHz) was used to record the NMR spectra. 1 In 1H-NMR, the chemical shifts were expressed in ppm with respect to TMS and the coupling constants (J) (unit: Hz). 31 In 31P NMR, no internal standard was used to collect the phosphorus NMR spectra. The usual internal standard is phosphoric acid, but 1 it was not used because there was a concern that it would affect 1H-NMR.

[0349] D.2. HPLC-MS

[0382] Condition A: High-performance liquid chromatography (HPLC) 2795 Alliance Waters Aquity connected to Detector DAD Agilent 1100 and Detector MS Waters ESI triple quadrupole Quattro micro, with a 10 μL sample in MeOH injected. Mass spectrometry (MS) was performed by FIA (flow injection analysis) connected to an LCT Premier orthogonal acceleration time-of-flight mass spectrometer, and data were acquired by positive-mode electrospray ionization (ESI). The spectra were scanned from 50 to 1500 Da, values were recorded every 0.2 seconds, and the peaks were assigned in m / z (% of the reference peak). Stationary phase: ZORBAX Extend-C18 3.5 μm 2.1 × 50 mm (T a 35 °C).

[0350]

Table 3

[0351]

Table 4

[0352]

[0383] Condition B: HPLC-MS was performed using a Thermo Ultimate 3000SD (Thermo Scientific Dionex) high-performance liquid chromatography connected to a photodiode array detector and a mass spectrometer LTQ XL ESI-ion trap (Thermo Scientific); 5 μL to 20 μL of sample MeOH was injected (c = 0.5 mg / mL). Data from the mass spectra were analyzed by electrospray ionization in positive and negative modes. Peaks are assigned in m / z (% of the reference peak). Stationary phase: ZORBAX Extend-C18 3.5 μm 2.1×50 mm (T a 35 °C).

[0353]

Table 5

[0354]

Table 6

[0355]

[0384] Condition C: HPLC-MS was performed using a Thermo Ultimate 3000SD (Thermo Scientific Dionex) high-performance liquid chromatography connected to a photodiode array detector and a mass spectrometer LTQ XL ESI-ion trap (Thermo Scientific). 5 μL to 20 μL of sample MeOH was injected (c = 0.5 mg / mL). Data from the mass spectra were analyzed by electrospray ionization in positive and negative modes. Peaks are assigned in m / z (% of the reference peak). Stationary phase: Xbridge BEH amide, 2.5 μm 4.6×150 mm XP.

[0356]

Table 7

[0357]

Table 8

[0358]

[0385] Condition D: HPLC-MS was performed using a high performance liquid chromatography 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 to 20 μL of sample MeOH was injected (c = 0.5 mg / mL). Data from the mass spectra were analyzed by electrospray ionization in positive and negative modes. Peaks are assigned in m / z (% of the reference peak). Stationary phase: ZORBAX Extend-C18 3.5 μm 2.1×50 mm (T a 35 °C).

[0359]

Table 9

[0360]

Table 10

[0361]

[0386] Condition E: HPLC-MS was performed using a high performance liquid chromatography 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 to 20 μL of sample MeOH was injected (c = 0.5 mg / mL). Data from the mass spectra were analyzed by electrospray ionization in positive and negative modes. Peaks are assigned in m / z (% of the reference peak). Stationary phase: ZORBAX Extend-C18 3.5 μm 2.1×50 mm (T a 30 °C).

[0362]

Table 11

[0363]

Table 12

Example

[0364] Example 1 Synthesis and Characterization of 4,6-O-bis(5-hydroxypentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) Octasodium Salt (Compound 6)

[0387] According to the general phosphate deprotection procedure I, 38 mg of compound 6 was obtained from 100 mg of (IV-26) (56.5%). 1 H NMR (400 MHz, D2O) δ 4.87-4.80 (m, 1H), 4.55-4-15 (m, 3H), 4.10-3.80 (m, 2H), 3.81-3.71 (m, 4H), 3.45 (t, J = 6.6 Hz, 4H), 1.66-1.55 (m, 8H), 1.40 (p, J = 7.2 Hz, 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] + .

[0365] Example 2 Synthesis and Characterization of 4,6-O-bis(10-hydroxydecyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) Octasodium Salt (Compound 7)

[0388] According to the general phosphate deprotection procedure I, 3.15 mg of compound 7 was obtained from 50 mg of (IV-1) (10.9%). 11H NMR (400 MHz, D2O) δ 5.08 - 5.01 (m, 1H), 4.10 - 4.02 (m, 3H), 3.81 - 3.75 (m, 6H), 3.60 (t, J = 6.6 Hz, 4H), 1.66 - 1.60 (m, 4H), 1.56 - 1.52 (m, 4H), 1.30 (br, 24H). 31 31P 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] + .

[0366] Example 3 Synthesis and Characterization of 4,6-O-bis(14-hydroxy-tetradecyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) Octasodium Salt (Compound 8)

[0389] According to the general phosphate deprotection procedure I, 0.6 mg of Compound 8 was obtained from 8.3 mg of (IV-2) (8%). 1 1H NMR (400 MHz, D2O) δ 4.25 - 3.71 (m, 3H), 3.69 - 3.50 (m, 6H), 3.44 (t, J = 6.7 Hz, 4H), 1.54 - 1.29 (m, 8H), 1.15 (m, 40H). HPLC-MS (Condition D): rt = 6.8 min; m / z: 998 [M + 1 + DEA] + , 1071 [M + 1 + 2DEA] + .

[0367] Example 4 Synthesis and Characterization of 4,6-O-bis(3-methoxypropyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) Octasodium Salt (Compound 10)

[0390] According to the general phosphate deprotection procedure I, 17.7 mg of Compound 10 was obtained from 23 mg of (IV-3) (99%). 11H NMR (400 MHz, D2O) δ 4.35 (br, 4H), 4.14 (br, 2H), 3.82 - 3.73 (m, 4H), 3.59 (t, J = 6.7 Hz, 4H), 3.36 (s, 6H), 1.90 (q, J = 6.7, Hz, 4H). 31 31P NMR (162 MHz, D2O) δ 3.90 (br). HPLC-MS (Condition C): rt = 9.96 min; m / z: 718 [M+1+DEA] + 、791 [M+1+2DEA] + 。

[0368] Example 5 Synthesis and Characterization of 4,6 - O - bis(5 - methoxypentyl) - myo - inositol - 1,2,3,5 - tetrakis(phosphate) Octasodium Salt (Compound 9)

[0391] According to the general phosphate deprotection procedure I, 193 mg of Compound 9 was obtained from 326 mg of (IV - 4) (75%). 1 1H NMR (400 MHz, D2O) δ 4.47 - 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 = 6.8 Hz, 4H), 3.35 (s, 6H), 1.66 - 154 (m, 8H), 1.38 (p, J = 7.6 Hz, 4H). 31 31P NMR (162 MHz, D2O) δ 7.46 (br), 6.71 (br). HPLC-MS (Condition C): rt = 9.59 min; m / z: 774 [M+1+DEA] + 、847 [M+1+2DEA] + 。

[0369] Example 6 Synthesis and Characterization of 4,6 - O - bis(7 - methoxyheptyl) - myo - inositol - 1,2,3,5 - tetrakis(phosphate) Octasodium Salt (Compound 11)

[0392] According to the general phosphate deprotection procedure I, 29.8 mg of compound 11 was obtained from 169.5 mg of (IV-5) (22%). 1 H NMR (400 MHz, D2O) δ 4.96 (d, J = 10.6 Hz, 1H), 4.07 (t, J = 9.2 Hz, 3H), 3.82 - 3.70 (m, 6H), 3.49 (t, J = 6.8 Hz, 4H), 3.34 (s, 6H), 1.63 (q, J = 7 Hz, 4H), 1.59 (q, J = 6.8 Hz, 4H), 1.18 (d, J = 4.5 Hz, 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] + 。

[0370] Example 7 Synthesis and characterization of 4,6-O-bis(9-methoxynonyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 12)

[0393] According to the general phosphate deprotection procedure I, 7.65 mg of compound 12 was obtained from 67 mg of (IV-6) (14% yield). 1 H NMR (400 MHz, D2O) δ 4.95 (d, J = 9.8 Hz, 1H), 4.11 - 4.02 (m, 3H), 3.89 - 3.71 (m, 6H), 3.49 (t, J = 6.8 Hz, 4H), 3.18 (s, 6H), 1.65 - 1.55 (m, 8H), 1.31 (br, 20H). 31 P NMR (162 MHz, D2O) δ 0.84, -0.36, -1.12. HPLC-MS (condition C): rt = 8.52 min; m / z: 813 [M+1] + , 886 [M+1+DEA] + , 959 [M+1+2DEA] + 。

[0371] Example 8 Synthesis and Characterization of 4,6-O-Dipropyl-myo-inositol-1,2,3,5-Tetrakis(phosphate) Octasodium Salt (Compound 4)

[0394] According to the general phosphate deprotection procedure I, 3.8 mg of Compound 4 was obtained from 24 mg of (IV-7) (20%). 1 H 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] + 。

[0372] Example 9 Synthesis and Characterization of 4,6-O-Dipentyl-myo-inositol-1,2,3,5-Tetrakis(phosphate) Octasodium Salt (Compound 1)

[0395] According to the general phosphate deprotection procedure I, 92 mg of Compound 1 was obtained from 143 mg of (IV-8) (83%). 1 H NMR (400 MHz, D2O) δ 5.01 - 4.91 (m, 1H), 4.10 - 4.00 (m, 3H), 3.84 - 3.72 (m, 6H), 1.63 (p, J = 7.2 Hz, 4H), 1.36 - 1.27 (m, 8H), 0.88 (p, J = 7.2 Hz, 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] +。

[0373] Example 10 Synthesis and Characterization of 4,6-O-Diheptyl-myo-inositol-1,2,3,5-Tetrakis(phosphate) Octasodium Salt (Compound 5)

[0396] Following the general phosphate deprotection procedure I, 7.8 mg of Compound 5 was obtained from 244 mg of (IV-9) (4%). 1 H NMR (400 MHz, D2O) δ 4.10 - 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 = 7.2 Hz, 6H). 31 P NMR (162 MHz, D2O) δ 1.96, 0.08, -0.89. HPLC-MS (Condition C): rt = 8.46 min; m / z: 843 [M + 1 + DEA] + , 916 [M + 1 + 2DEA] + 。

[0374] Example 11 Synthesis and Characterization of 4,6-O-Didecyl-myo-inositol-1,2,3,5-Tetrakis(phosphate) Octasodium Salt (Compound 2)

[0397] Following the general phosphate deprotection procedure I, 1.6 mg of Compound 2 was obtained from 63 mg of (IV-10) (4%). 1 H NMR (400 MHz, D2O) δ 5.02 (d, J = 8 Hz, 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 = 6.8 Hz, 6H). HPLC-MS (Condition D): rt = 6.89 min; m / z: 781 [M + 1] + , 854 [M + 1 + DEA] + , 927 [M + 1 + 2DEA] + , 1000 [M + 1 + 2DEA] + 。

[0375] Example 12 Synthesis and Characterization of 4,6-O-Di(tetradecyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) Octasodium Salt (Compound 3)

[0398] According to the general phosphate deprotection procedure I, 656 mg of Compound 3 was obtained from 1.5 g of (IV-11) (66.5%). 1 H NMR (400 MHz, D2O) δ 4.96 (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 = 6.8 Hz, 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] + .

[0376] Example 13 Synthesis and Characterization of 4,6-O-Bis(3-aminopropyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) Octasodium Salt (Compound 13)

[0399] According to the general phosphate deprotection procedure I, 5.6 mg of Compound 13 was obtained from 45.6 mg of (X-1) (16.7%). HPLC-MS (Condition C): rt = 10.73 min; m / z: 615 [M+1] + , 688 [M+1+DEA] + .

[0377] Example 14 Synthesis and Characterization of 4,6-O-Bis(5-aminopentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) Octasodium Salt (Compound 14)

[0400] According to the general phosphate deprotection procedure I, 11.3 mg of Compound 14 was obtained from 145 mg of (X-2) (10%).1 1H NMR (400 MHz, D2O) δ 4.95 (s, 1H), 4.07 - 4.05 (m, 3H), 3.94 (m, 2H), 3.84 - 3.70 (m, 7H), 3.02 (t, J = 6.7 Hz, 2H), 1.79 - 1.47 (m, 12H). 31 31P 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] + 。

[0378] Example 15 Synthesis and Characterization of 4,6 - O - bis(10 - aminodecyl)-myo - inositol - 1,2,3,5 - tetrakis(phosphate) Octasodium Salt (Compound 15)

[0401] According to the general phosphate deprotection procedure I, 0.8 mg of Compound 15 was obtained from 57.5 mg of (X - 3) (2%). 1 1H NMR (400 MHz, D2O) δ 4.95 (d, J = 10.3 Hz, 1H), 4.06 (t, J = 9.2 Hz, 3H), 3.89 - 3.67 (m, 7H), 3.59 (t, J = 6.8 Hz, 1H), 2.99 (t, J = 7.4 Hz, 2H), 1.76 - 1.57 (m, 8H), 1.45 - 1.19 (m, 24H). 31 31P NMR (162 MHz, D2O) δ 2.04, - 0.05, - 1.00. HPLC-MS (Condition D): rt = 6.48 min; m / z: 811 [M+1] + 、884 [M+1+DEA] + 、958 [M+1+2DEA] + 。

[0379] Example 16 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)

[0402] According to the general phosphate deprotection procedure I, 8.5 mg of compound 16 was obtained from 36.6 mg of (IV-14) (29%). 1 H NMR (400 MHz, D2O) δ 7.64 (d, J = 2.4 Hz, 2H), 7.52 (br, 2H), 6.31 (t, J = 2.4 Hz, 2H), 4.42 (m, 3H), 4.28 - 4.14 (m, 3H), 4.13 (t, J = 7 Hz, 4H), 3.66 (m, 4H), 1.82 (p, J = 7.0 Hz, 4H), 1.67 - 1.49 (m, 4H), 1.42 - 1.18 (m, 4H). 31 P NMR (162 MHz, D2O) δ4.91, 4.21. HPLC-MS (condition C): rt = 9.20 min; m / z: 773 [M + 1] + , 846 [M + 1 + DEA] + , 919 [M + 1 + 2DEA] + .

[0380] Example 17 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)

[0403] According to the general phosphate deprotection procedure I, 5.2 mg of compound 17 was obtained from 8.8 mg of (IV-15) (74%). 1 H NMR (400 MHz, D2O) δ 8.46 - 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 = 7.4 Hz, 4H). HPLC-MS (condition C): rt = 9.86 min; m / z: 776 [M + 1] + , 849 [M + 1 + DEA] + , 922 [M + 1 + 2DEA] + .

[0381] Example 18 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)

[0404] 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 (400 MHz, D2O) δ 8.22 (s, 2H), 5.08 (d, J = 11.6 Hz, 2H), 5.10 - 4.97 (m, 1H), 4.99 (d, J = 11.6 Hz, 2H), 4.70 (t, J = 7.2 Hz, 4H), 4.26 - 4.18 (m, 3H), 3.99 (t, J = 9.5 Hz, 2H), 2.88 (t, J = 7.2 Hz, 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] + .

[0382] Example 19 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)

[0405] According to the general phosphate deprotection procedure I, 22 mg of Compound 32 was obtained from 64 mg of (IV-17) (43%). 11H NMR (400 MHz, D2O) δ 8.40 - 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 = 6.2 Hz, 4H), 3.32 (s, 6H), 2.12 - 2.10 (m, 4H). HPLC-MS (Condition C): rt = 9.56 min; m / z: 880 [M + 1 + DEA] + 。

[0383] Example 20 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)

[0406] According to the general phosphate deprotection procedure I, 1.8 mg of Compound 33 was obtained from 15 mg of (IV - 18) (15%). 1 1H NMR (400 MHz, D2O) δ 8.08 (s, 2H), 4.87 (d, J = 11.6 Hz, 2H), 4.85 - 4.75 (m, 1H), 4.81 (d, J = 11.6 Hz, 2H), 4.27 (t, J = 7 Hz, 4H), 4.07 - 3.90 (m, 3H), 3.83 - 3.73 (m, 2H), 3.30 (t, J = 6.8 Hz, 4H), 3.17 (s, 6H), 1.76 (p, J = 7 Hz, 4H), 1.40 (p, J = 6.8 Hz, 4H), 1.17 (m, 8H). HPLC-MS (Condition C): rt = 8.83 min; m / z: 891 [M + 1] + , 964 [M + 1 + DEA] + , 1037 [M + 1 + 2DEA] + 。

[0384] Example 21 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)

[0407] Following the general phosphate deprotection procedure I, 1.7 mg of Compound 36 was obtained from 7.2 mg of (IV-20) (28%). 1 H NMR (400 MHz, D2O) δ 8.21 (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 = 9.73 min; m / z: 880 [M + 1 + DEA] + 。

[0385] Example 22 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)

[0408] Following the general phosphate deprotection procedure I, 1.2 mg of Compound 37 was obtained from 11 mg of (IV-21) (13%). 1 H NMR (400 MHz, D2O) δ 8.08 (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 = 9.59 min; m / z: 835 [M + 1], 908 [M + 1 + DEA] + , 908 [M + 1 + DEA] + 。

[0386] Example 23 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)

[0409] Following the general phosphate deprotection procedure I, 1.4 mg of Compound 38 was obtained from 11 mg of (IV-22) (16%). 1 H NMR (400 MHz, D2O) δ 8.07 (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 = 7.6 Hz, 4H), 1.67 (p, J = 7.6 Hz, 4H), 1.34 (p, J = 7.6 Hz, 4H). HPLC-MS (Condition C): rt = 9.53 min; m / z: 936 [M+1+DEA] + 。

[0387] Example 24 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)

[0410] Following the general phosphate deprotection procedure I, 10 mg of Compound 39 was obtained from 35.5 mg of (IV-23) (34%). 1 H NMR (400 MHz, D2O) δ 8.04 (s, 2H), 5.30 - 5.10 (br, 1H), 4.60 (s, 4H), 4.43 (t, J = 7.1 Hz, 4H), 4.15 - 3.97 (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 = 9.24 min; m / z: 964 [M+1+DEA] + 。

[0388] Example 25 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)

[0411] According to the general phosphate deprotection procedure I, 6.2 mg of compound 34 was obtained from 16 mg of (IV-24) (48%). 1 H NMR (400 MHz, D2O) δ 5.10 - 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). 31 P 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] + 。

[0389] Example 26 Synthesis and Characterization of 4,6-O-Bis((3-(4-carboxybutanamido)propyl))-myo-inositol-1,2,3,5-tetrakis(phosphate) Decasodium Salt (Compound 45)

[0412] According to the general phosphate deprotection procedure I, 4.4 mg of compound 45 was obtained from 28 mg of (IV-25) (19%). 1 H NMR (400 MHz, D2O) δ 5.29 - 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 = 10.18 min; m / z: 916 [M + 1 + DEA] + , 989 [M + 1 + 2DEA] + 。

[0390] Example 27 Synthesis and Characterization of Sodium 4,6-O-bis(5-carboxypentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) (Compound 18)

[0413] According to the general phosphate deprotection procedure J, 6.8 mg of Compound 18 was obtained from 35.5 mg of (IV-12) (23%). 1 H NMR (400 MHz, D2O) δ 4.31-4.24 (m, 3H), 4.12-4.08 (m, 1H), 4.01 (br, 2H), 3.58 (dt, J = 7.6, 7.2 Hz, 2H), 3.51 (dt, J = 7.6, 7.2 Hz, 2H), 2.03 (t, J = 7.6, 4H), 1.47 (p, J = 7.2 Hz, 4H), 1.42 (p, J = 7.6 Hz, 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] + .

[0391] Example 28 Synthesis and Characterization of Sodium 4,6-O-bis(10-carboxydecyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) (Compound 19)

[0414] According to the general phosphate deprotection procedure J, 34.6 mg of Compound 19 was obtained from 187 mg of (IV-13) (22.6%). 11H NMR (400 MHz, D2O) δ: 4.49 (d, J = 12.4 Hz, 1H), 4.42 (br, 1H), 4.40 (br, 1H), 4.25 (d, J = 12.4 Hz, 1H), 4.19 (s, 2H), 3.77 - 3.58 (m, 4H), 2.16 (t, J = 7.6 Hz, 4H), 1.66 - 1.49 (m, 8H), 1.36 - 1.25 (m, 24H). 31 31P NMR (162 MHz, D2O) δ: 4.79, 4.12, 4.00. HPLC-MS (Condition D): rt = 6.26 min; m / z: 942 [M+1] + , 1015 [M+1+DEA] + , 1088 [M+1+2DEA] + .

[0392] Example 29 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)

[0415] According to the general phosphate deprotection procedure J, 11.8 mg of Compound 35 was obtained from 74 mg of (IV-19) (21%). 1 1H NMR (400 MHz, D2O) δ 7.89 (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 = 7.8 Hz, 4H), 2.54 (t, J = 7.8 Hz, 4H), 2.24 - 2.15 (m, 4H). 31 31P 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] + .

[0393] Example 30 Synthesis and Characterization of 4,6-O-Bis(2-cyclopropylethyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) Octasodium Salt (Compound 28)

[0416] According to the general phosphate deprotection procedure I, 710 mg of compound 28 was obtained from 1.34 g of (IV-27) (68%). 1 H NMR (400 MHz, D2O) δ 4.51-4.20 (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 = 4.7 Hz, 4H). 31 P NMR (162 MHz, D2O) δ3.79-(-0.54) (br). HPLC-MS (Condition C): rt = 9.51 min; m / z: 637 [M+1] + , 710 [M+1+DEA] + , 783 [M+1+2DEA] + .

[0394] Example 31 Synthesis and Characterization of 4,6-O-Bis(2-cyclopentylethyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) Octasodium Salt (Compound 29)

[0417] According to the general phosphate deprotection procedure I, 22 mg of compound 29 was obtained from 164 mg of (IV-28) (17%). 1 H NMR (400 MHz, D2O) δ 4.39-4.19 (br, 3H), 4.11-3.95 (br, 2H), 3.65 (q, J = 8 Hz, 2H), 3.59 (q, J = 8 Hz, 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) δ4.99-3.20 (br). HPLC-MS (Condition C): rt = 8.76 min; m / z: 693 [M+1] +, 766 [M + 1 + DEA] + , 839 [M + 1 + 2DEA] + .

[0395] Example 32 Synthesis and Characterization of 4,6 - O - bis(3 - (4 - methoxyphenyl)propyl)-myo - inositol - 1,2,3,5 - tetrakis(phosphate) octasodium salt (Compound 43)

[0418] According to the general phosphate deprotection procedure I, 10.8 mg of Compound 43 was obtained from 36 mg of (IV - 29) (37%). 1 H NMR (400 MHz, D2O) δ 7.02 (d, J = 8.4 Hz, 4H), 6.72 (d, J = 8.4 Hz, 4H), 4.41 - 4.18 (m, 4H), 4.11 (br, 2H), 3.66 (s, 6H), 3.64 (t, J = 7.2 Hz, 4H), 2.47 (t, J = 8.0 Hz, 4H), 1.78 - 1.63 (m, 4H). 31 P NMR (162 MHz, D2O) δ 4.29 - 3.86 (br). HPLC - MS (Condition C): rt = 8.55 min; m / z: 797 [M + 1] + , 870 [M + 1 + DEA] + , 943 [M + 1 + 2DEA] + .

[0396] Example 33 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)

[0419] According to the general phosphate deprotection procedure I, 11.9 mg of Compound 44 was obtained from 64 mg of (IV - 30) (23%). 1 H NMR (400 MHz, D2O) δ 7.42 - 7.25 (m, 8H), 4.30 - 4.06 (m, 5H), 3.69 (s, 4H), 2.62 (t, J = 8.1 Hz, 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] + and 946 [M+1+DEA] + and 1019 [M+1+2DEA] + .

[0397] Example 34 Synthesis and Characterization of 4,6-O-bis(3-(p-tolyl)propyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) Octasodium Salt (Compound 42)

[0420] Following the general phosphate deprotection procedure I, 1.1 mg of Compound 42 was obtained from 19 mg of (IV-31) (7%). 1 H NMR (400 MHz, D2O) δ 7.13 (d, J = 7.4 Hz, 4H), 7.08 (d, J = 7.4 Hz, 4H), 4.02 - 3.90 (br, 3H), 3.81 - 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 = 8.35 min; m / z: 911 [M+1+2DEA] + .

[0398] Example 35 Synthesis and Characterization of 4,6-O-bis(4,4,4-trifluorobutyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) Octasodium Salt (Compound 22)

[0421] Following the general phosphate deprotection procedure I, 820 mg of Compound 22 was obtained from 2.32 g of (IV-32) (44%). 11H NMR (400 MHz, D2O) δ 4.84 (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 31P 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] + 。

[0399] Example 36 Synthesis and Characterization of 4,6-O-bis(6,6,6-trifluorohexyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) Octasodium Salt (Compound 23)

[0422] According to the general phosphate deprotection procedure I, 45 mg of Compound 23 was obtained from 248 mg of (IV-33) (22%). 1 1H NMR (400 MHz, D2O) δ 4.40 - 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 = 8.27 min; m / z: 923 [M+1+2DEA] + 。

[0400] Example 37 Synthesis and Characterization of 4,6-O-bis(4-methylpentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) Octasodium Salt (Compound 21)

[0423] According to the general phosphate deprotection procedure I, 4.6 mg of Compound 21 was obtained from 167 mg of (IV-34) (3.5%). 11H NMR (400 MHz, D2O) δ 4.44 - 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 = 6.6 Hz, 12H). HPLC-MS (Condition C): rt = 8.74 min; m / z: 742 [M+1+DEA] + , 815 [M+1+2DEA] + .

[0401] Example 38 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)

[0424] According to the general phosphate deprotection procedure I, 4.3 mg of Compound 20 was obtained from 410 mg of (III-35) (1.3%). 1 1H NMR (400 MHz, D2O) δ 4.50 - 4.26 (m, 3H), 4.19 - 4.02 (m, 2H), 3.70 - 3.47 (m, 4H), 3.38 - 3.26 (m, 4H), 3.22 (s, 6H), 1.49 - 1.41 (m, 8H), 1.25 - 1.16 (m, 60H). 31 31P NMR (162 MHz, D2O) δ 4.04 (bs), 3.73 (bs). Example 39 Synthesis and Characterization of 4,6-O-bis(3-(3-phenylureido)propyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) Octasodium Salt (Compound 46)

[0425] According to the general phosphate deprotection procedure I, 6.5 mg of Compound 46 was obtained from 187 mg of (IV-36) (4.3%). 11H NMR (400 MHz, D2O) δ 7.27 - 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] + and 999 [M + 1 + 2DEA] + .

[0402] Example 40 Synthesis and Characterization of 4,6 - O - bis(3 - (3 - cyclopentylureido)propyl)-myo - inositol - 1,2,3,5 - tetrakis(phosphate) octasodium salt (Compound 47)

[0426] Following the general phosphate deprotection procedure I, 26 mg of Compound 47 was obtained from 181 mg of (IV - 37) (17.6%). 1 1H NMR (400 MHz, D2O) δ δ 4.87 - 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 = 8.98 min; m / z: 837 [M + 1] + and 910 [M + 1 + DEA] + and 983 [M + 1 + 2DEA] + .

[0403] Example 41 Synthesis and Characterization of 4,6 - O - bis(3 - ((methoxycarbonyl)amino)propyl)-myo - inositol - 1,2,3,5 - tetrakis(phosphate) octasodium salt (Compound 24)

[0427] According to the general phosphate deprotection procedure I, 1.7 mg of compound 24 was obtained from 5 mg of (IV-38) (42%). 1 H NMR (400 MHz, D2O) δ 3.94 - 3.40 (m, 10H), 3.52 (s, 6H), 3.11 (m, 4H), 1.67 (m, 4H). HPLC-MS (condition C): rt = 9.69 min; m / z: 804 [M+1+DEA] + , 877 [M+1+2DEA] + 。

[0404] Example 42 Synthesis and characterization of 4,6-O-bis(5-acetamidopentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 27)

[0428] According to the general phosphate deprotection procedure I, 4.7 mg of compound 27 was obtained from 110 mg of (IV-39) (5%). 1 H NMR (400 MHz, D2O) δ 4.05 - 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 = 9.71 min; m / z: 828 [M+1+DEA] + , 901 [M+1+2DEA] + 。

[0405] Example 43 Synthesis and characterization of 4,6-O-bis(5-benzamidopentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 48)

[0429] According to the general phosphate deprotection procedure I, 15 mg of compound 48 was obtained from 43 mg of (IV-40) (43%). 11H NMR (400 MHz, D2O) δ 7.61 - 7.55 (m, 4H), 7.47 - 7.29 (m, 6H), 4.40 - 4.18 (m, 3H), 4.08 - 3.88 (m, 2H), 3.61 - 3.55 (m, 5H), 3.17 (t, J = 7 Hz, 4H), 1.56 - 1.41 (m, 8H), 1.33 - 1.23 (m, 4H). HPLC-MS (Condition C): rt = 8.73 min; m / z: 879 [M+1] + , 952 [M+1+DEA] + , 1025 [M+1+2DEA] + .

[0406] Example 44 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)

[0430] According to the general phosphate deprotection procedure U, 19 mg of Compound 49 was obtained from 196 mg of (IV-41) (12%). 1 1H NMR (400 MHz, D2O) δ 7.68 - 7.37 (m, 4H), 7.15 - 6.84 (m, 2H), 4.48 - 4.03 (m, 5H), 3.56 (t, J = 8.2, 6.7 Hz, 4H), 3.19 - 3.12 (m, 4H), 1.50 - 1.37 (m, 8H), 1.25 - 1.19 (m, 4H). HPLC-MS (Condition C): rt = 8.85 min; m / z: 964 [M+1+DEA] + , 1037 [M+1+2DEA] + .

[0407] Example 45 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)

[0431] Following the general phosphate deprotection procedure J, 9.3 mg of compound 40 was obtained from 34 mg of (IV-42) (33%). 1 H NMR (400 MHz, D2O) δ 8.08 (s, 2H), 4.32 - 4.22 (m, 8H), 4.10 - 3.96 (m, 2H), 3.65 - 3.54 (m, 4H), 1.76 (p, J = 7.5 Hz, 4H), 1.54 - 1.39 (m, 4H), 1.29 - 1.15 (m, 8H). 31 P NMR (162 MHz, D2O) δ 4.81 - 3.21 (bs). HPLC-MS (Condition C): rt = 10.27 min; m / z: 964 [M+1+DEA] + , 1037 [M+1+2DEA] + 。

[0408] Example 46 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)

[0432] Following the general phosphate deprotection procedure J, 35 mg of compound 41 was obtained from 101 mg of (IV-43) (42%). 1 H NMR (400 MHz, D2O) δ 8.05 (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] + .

[0409] Example 47 Synthesis and Characterization of 4,6 - O - bis(4 - amino - 4 - oxobutyl) - myo - inositol - 1,2,3,5 - tetrakis(phosphate) Octasodium Salt (Compound 26)

[0433] According to the general phosphate deprotection procedure I, mg of compound 26 was obtained from 168 mg of (IV - 44) (25%). 1 H NMR (400 MHz, D2O) δ 4.17 - 3.39 (m, 10H), 2.48 - 2.17 (m, 3H), 2.16 - 2.03 (m, 1H), 1.77 (p, J = 6.8 Hz, 4H). HPLC - MS (Condition C): rt = 10.47 min; m / z: 744 [M + 1 + DEA] + , 817 [M + 1 + 2DEA] + Example 48 Synthesis and Characterization of 4,6 - O - bis(5 - (3 - propylureido)pentyl) - myo - inositol - 1,2,3,5 - tetrakis(phosphate) Octasodium Salt (Compound 30)

[0434] According to the general phosphate deprotection procedure I, 100 mg of compound 30 was obtained from 210 mg of (IV - 45) (58%). 1 H NMR (400 MHz, D2O) δ 4.41 - 3.90 (m, 6H), 3.60 (t, J = 6.5 Hz, 4H), 3.04 - 2.85 (m, 8H), 1.61 - 1.18 (m, 16H), 0.75 (t, J = 7.4 Hz, 6H). HPLC - MS (Condition C): rt = 9.20 min; m / z: 841 [M + 1] + , 914 [M + 1 + DEA] + .

[0410] Example 49 Synthesis and Characterization of 4,6-O-bis(5-((Methoxycarbonyl)amino)pentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) Octasodium Salt (Compound 25)

[0435] According to the general phosphate deprotection procedure I, 25 mg of Compound 25 was obtained from 60 mg of (IV-46) (61% yield). 1 H NMR (400 MHz, D2O) δ 4.37 - 3.82 (m, 6H), 3.64 (m, 4H), 3.52 (s, 6H), 3.00 (t, J = 7.1 Hz, 4H), 1.64 - 1.46 (m, 4H), 1.45 - 1.33 (m, 4H), 1.33 - 1.17 (m, 4H). HPLC-MS (Condition C): rt = 9.33 min; m / z: 787 [M+1] + , 860 [M+1+DEA] + , 932 [M+1+2DEA] + .

[0411] Example 50 Synthesis and Characterization of 4,6-O-dipentyl-myo-inositol-1,2,3,5-tetrakis(thiophosphate) Octasodium Salt (Compound 50)

[0436] According to the general phosphate deprotection procedure U, 2.2 mg of Compound 50 was obtained from 97 mg of (IV’-1) (3%). 1 H NMR (400 MHz, D2O) 4.63 - 4.55 (m, 2H), 4.52 - 4.44 (m, 2H), 4.34 - 4.28 (m, 2H), 3.67 (t, J = 7.0 Hz, 4H), 1.59 - 1.48 (m, 4H), 1.27 - 1.18 (m, 8H), 0.77 (t, J = 6.8 Hz, 6H). HPLC-MS (Condition C): rt = 9.36 min; m / z: 850 [M+1+2DEA] + , 923 [M+1+3DEA] + .

[0412] Example 51 Synthesis and Characterization of 4,6-O-Bis(5-methoxypentyl)-myo-inositol-1,2,3,5-Tetrakis(thiophosphate) Octasodium Salt (Compound 51)

[0437] Following the general phosphate deprotection procedure U, 2.2 mg of Compound 51 was obtained from 54 mg of (IV’-2) (5%). 1 H NMR (400 MHz, D2O) δ 4.65 - 4.25 (m, 6H), 3.68 (m, 4H), 3.39 (t, J = 6.8 Hz, 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] + .

[0413] Example 52 Synthesis and Characterization of 4,6-O-Bis(3-carboxypropyl)-myo-inositol-1,2,3,5-Tetrakis(phosphate) Decasodium Salt (Compound 52)

[0438] Following the general phosphate deprotection procedure J, 11 mg of Compound 52 was obtained from 40 mg of (IV-47) (34%). 1 H NMR (400 MHz, D2O) δ 4.31 - 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 = 10.73 min; m / z: 746 [M + 1 + 1DEA] + , 819 [M + 1 + 2DEA] + .

[0414] Example 53 Synthesis and Characterization of 4,6-O-Dipropargyl-myo-inositol-1,2,3,5-Tetrakis(phosphate) Octasodium Salt (Compound 53)

[0439] Following the general phosphate deprotection procedure U, 10 mg of compound 53 was obtained from 50 mg of (IV-48) (35%). 1 H NMR (400 MHz, D2O) δ 4.89-4.81 (m, 1H), 4.43 (d, J = 1.9 Hz, 4H), 4.11-3.87 (m, 3H), 3.79-3.60 (m, 2H), 2.77 (t, J = 1.9 Hz, 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] + 。

[0415] Example 54 In vitro inhibition of calcium phosphate crystallization

[0440] According to the spectrophotometric assay previously described in the art, the in vitro efficacy of the IP4-4,6 substituted derivatives of the present invention (e.g., compounds 1 to 53) in inhibiting calcium phosphate crystallization in human plasma samples was evaluated (Ferrer M et al., Sci Rep 2017; 7: 6858, doi: 10.1038 / s41598-017-07203-x).

[0416]

[0441] A 96-well plate was used. The IP4-4,6 substituted derivative of the present invention (1 volume per 19 volumes of plasma) was added to the plasma, and the concentration of the derivative was gradually increased in the range of 0 to 100 μM. Then, the plasma was 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 achieve final concentrations of 1.5 mM phosphate and 12.5 mM calcium, respectively. All reagent solutions were filtered and the pH was adjusted to 7.4.

[0417]

[0442] The crystallization of calcium phosphate was monitored by spectrophotometry at room temperature for 30 minutes by measuring the increase in absorbance at 550 nm using a Biotek Powerwave XS microplate spectrophotometer (BioTek Instruments, Inc., Winooski, VT, US). The plates were incubated at room temperature in an orbital shaker, and the absorbance was measured every 3 minutes.

[0418]

[0443] Plasma crystallization was evaluated based on the measurement of the slope in the linear range of 6 - 24 minutes from the plot of the increase in absorbance versus the logarithm of time. The effectiveness of different phospho-myo-inositol derivatives in preventing the formation of calcium phosphate crystals in vitro was evaluated in human plasma samples using the slopes obtained between 6 and 24 minutes. The inhibition of crystallization was measured by comparing the slopes of the control samples (blank plasma). The values of the samples containing the inhibitor are as shown below:

[0444]

[0419]

Number

[0420]

[0445] See Table 13.

[0421]

Table 13 - 1

[0422]

Table 13 - 2

[0423] Example 55 Rat Models Corresponding to Multiple Heterotopic Calcification-Related Conditions

[0446] In this model, the effects of compound 27 on tissue calcification, blood perfusion, and walking ability in rats were evaluated over a 13-day period. Tissue calcification was induced in 2 - 5 groups at D1 - D3. In the animals with induced calcification, a placebo or active agent formulation was administered from D1 onwards to evaluate their effects on preventing calcification. The therapeutic effects on tissue calcification, blood perfusion, and walking ability were evaluated. Observations were recorded at several points during the treatment from D0 - D13. All animals were weighed daily before treatment.

[0424]

[0447] Fifty-eight male Sprague Dawley (SD) rats (Envigo Corp., Huntingdon, GB) with a body weight of approximately 275 - 300 g were used. The animals were given a standard LASQCdiet® Rod14-H4 diet (LASvendi, Soest, DE). The animals were divided into 5 groups of 10 - 12 animals per group as follows:

[0448] Group 1 - Control (vehicle), 10 animals

[0449] Group 2 - Physiological saline solution (placebo), 12 animals daily

[0450] Group 3 - Compound 27, 5 mg / kg, 12 animals daily

[0451] Group 4 - Compound 27, 15 mg / kg, 12 animals daily

[0452] Group 5 - Compound 27, 45 mg / kg, 12 animals daily

[0453] In the animals of Groups 2 to 5, calcification was induced by administering 120,000 IU / kg of vitamin D3 (cholecalciferol, Duphafral D3 1000; Zoetis Inc., Parsippany, NJ, US) subcutaneously daily in 0.9% (w / v) NaCl solution (2 mL / kg) of physiological saline from D1 to D3. In the animals of Group 1, a 2 mL / kg physiological saline solution was administered daily from D1 to D3 via the subcutaneous route, and vitamin D3 was not administered. In the animals of Group 2, a 2 mL / kg physiological saline solution was administered daily from D1 to D13 via the subcutaneous route. In the animals of Groups 3, 4, and 5, 5 mg / kg, 15 mg / kg, and 45 mg / kg of Compound 27 (754.45 g / mol free acid) in physiological saline solution (2 mL / kg) were administered daily from D1 to D13 via the subcutaneous route.

[0425]

[0454]

[0455] 1. Tissue Analysis

[0456]

[0457] On D13, all surviving animals of Groups 1 to 5 were sacrificed, and these Ca values in the tissues (i.e., aorta, carotid artery, thigh, heart, kidney) were determined.

[0426]

[0458] The animals were anesthetized and then sacrificed. These necropsies were performed, and the entire right and left femoral arteries, left and right carotid arteries, aorta, heart, and right kidney were collected and their calcium content was measured. The tissues were lyophilized for 24 hours and weighed. Subsequently, using a 1:1 mixture of HNO3:HClO4, the lyophilized tissues were decomposed in a drying oven incubator at 180 °C for 2 - 4 hours. Subsequently, the decomposed tissues were diluted to a final volume of 5 mL (for the thighs and carotid arteries) or 10 mL (for the heart, kidneys, and aorta) using ultrapure water Milli-Q water (MilliporeSigma, Merck KGaA, Burlington, MA, US). Following the manufacturer's instructions, the calcium content was quantified via inductively coupled plasma optical emission spectrometry (ICP-OES) using an Optima 7300 DV ICP-OES System spectrometer (PerkinElmer, Inc., Waltham, MA, US).

[0427]

[0459]

[0460] 2. Blood Perfusion

[0461]

[0462] Blood perfusion (BP) was evaluated by applying laser Doppler perfusion imaging to the hindlimbs of the animals using a PeriCam PSI Normal Resolution analyzer (Perimed AB, Jarfalla, SE). Measurements were taken for all groups at D0, D4, and D13. The perfusion ratio (i.e., the average of the two legs) was calculated by comparing the baseline with any of the D4 or D13 readings for each group. Additionally, the perfusion ratio was calculated by comparing Group 1 with Groups 2 - 5.

[0428]

[0463]

[0464] 3. Walking Ability

[0465]

[0466] A 2-lane touch screen treadmill device for rats (Cat. No. LE8709TS, Panlab, Harvard Biosciences, Inc., Holliston, MA, US) was used at a 15% gradient to evaluate the maximum walking time (MWT) and maximum walking distance (MWD) by a forced incremental treadmill running test. Measurements were taken for all groups at D0, D6, and D11.

[0429]

[0467] Animals were acclimated to the treadmill for 2 days before the test. On the first day, the treadmill speed was incrementally increased from 15 m / min to 24 m / min, and the animals were exercised for 5 - 10 minutes. On the second day, the animals were exercised as follows for 20 minutes: (a) 15 m / min for the first 5 minutes, (b) 19.8 m / min for the next 5 minutes, and (c) 24 m / min for the last 10 minutes. Pre-operative walking time and distance were recorded. Animals that did not conform to the protocol were excluded from the test. 48 rats were screened for the walking ability test. The day before test D0, the selected animals were exercised for an additional 5 - 10 minutes to ensure they were well accustomed to the treadmill. The protocols for MWT and MWD measurements at D0, D5, and D10 were as follows:

[0430]

Table 14

[0431]

[0468] For group 2, treadmill evaluation was started 15 minutes after dosing. For groups 2 - 5, treadmill evaluation was started 25 minutes after dosing. Rats continued running for 40 minutes or until fatigued. The test was stopped when the rat remained on the shock grid continuously for 5 seconds (i.e., fatigued). MWD (unit: meter) and MWT (unit: minute) were recorded for each animal.

[0432]

[0469] By administering Compound 27 at doses of 15 and 45 mg / kg, the walking ability of rats administered with vitamin D was improved in a dose-responsive manner as early as D5 after the induction of PAD disease. The results indicate that Compound 27 inhibits heterotopic calcification in all evaluated tissues. See Figures 12A - 12E.

[0433]

[0470] Inhibition of calcification in the aorta (Figure 12A) was observed at 45 mg / kg. These results indicate that Compound 27 can be used to treat conditions such as aortic calcification, aortic valve calcification, aortic stenosis, calcified aortic valve stenosis, atherosclerosis, arteriosclerosis, aneurysm, or coralliform aorta. Calcification of arteries leads to hardening of the blood vessels, indicating the potential use of Compound 27 in the hardening of arteries. Hardening of the aorta leads to a reduction in coronary vessel filling and a decrease in myocardial perfusion during diastole, indicating that Compound 27 can be used in coronary disease or coronary artery disease. Due to the reduction in coronary filling, the myocardium is unable to adequately respond to an increased oxygen demand, resulting in ischemia even in the absence of coronary occlusion. Inadequate response to an increased myocardial oxygen demand can cause symptoms of myocardial ischemia and angina. Therefore, since Compound 27 affects aortic calcification and, consequently, all downstream effects on ischemia and chest pain, it can be used in myocardial ischemia and angina (including chronic stable angina). Hardening of the arteries also forces the heart to pump stronger, causing hypertrophy, indicating that Compound 27 can be used in left ventricular hypertrophy. Ultimately, hardening of the arteries and heart hypertrophy can lead to arrhythmia, heart failure, congestive heart failure, heart disease, death due to cardiovascular disease, or cardiac death, indicating that Compound 27 can be used in these situations or conditions.

[0434]

[0471] Inhibition of calcification in the heart (Figure 12B) showed a dose-response effect starting from 5 mg / kg. This result indicated that compound 27 could be used in conditions related to cardiovascular calcification, coronary artery calcification, valvular calcification, calcific aortic stenosis, atherosclerosis, arteriosclerosis, myocardial infarction, aneurysm, coronary disease or coronary artery disease. Coronary artery calcification in the heart leads to hardening of the blood vessels, which indicates the potential use of compound 27 in arterial hardening. Hardening leads to a reduction in the filling of the coronary blood vessels during diastole and a decrease in myocardial perfusion, which indicates that compound 27 can be used in coronary disease or coronary artery disease. Due to the reduction in coronary artery filling, the myocardium is unable to adequately respond to an increased oxygen demand, and as a result, ischemia occurs even in the absence of coronary artery occlusion. Inadequate response to an increased myocardial oxygen demand can lead to symptoms of myocardial ischemia and angina. Therefore, compound 27 can be used in myocardial ischemia and angina (including chronic stable angina) because it affects coronary artery calcification in the heart and, consequently, all downstream effects on ischemia and chest pain. Arterial hardening also forces the heart to pump stronger, causing hypertrophy, which indicates that compound 27 can be used in left ventricular hypertrophy. Finally, coronary artery hardening and heart hypertrophy are the backgrounds for the occurrence of arrhythmia, heart failure, congestive heart failure, heart disease, death due to cardiovascular disease or cardiac death, which indicates that compound 27 can be used in these situations or conditions.

[0435]

[0472] Inhibition of calcification in the carotid artery (Figure 12D) was observed at 45 mg / kg. This result showed that compound 27 could be used in the situation or condition of atherosclerosis or arteriosclerosis. Arterial calcification leads to hardening of the blood vessels, which indicates the potential use of compound 27 in arterial hardening.

[0436]

[0473] Inhibition of calcification in the kidney (Figure 12E) showed a dose-response effect from 5 mg / kg. These results indicated that compound 27 can be used in situations or conditions with nephrocalcinosis or kidney stones (renal calculi).

[0437]

[0474] Inhibition of calcification in the femoral artery (Figure 12C), the effect on blood perfusion (Figure 13), and the effect on maximum walking distance (Figure 14) showed a dose-response effect from 5 mg / kg, and hindlimb blood perfusion recovered at doses of 15 and 45 mg / kg. These results indicate that compound 27 can be used in atherosclerotic or arteriosclerotic situations or conditions. Arterial calcification leads to hardening of the blood vessels, which indicates the potential use of compound 27 in arterial hardening. Arterial hardening in the lower limbs reduces blood supply and causes ischemic pain. The recovery of blood perfusion by compound 27 indicates that compound 27 can be used to treat PAD, including limb ischemia or severe lower limb ischemia. The overall results in femoral calcification and blood perfusion led to a functional improvement, as evaluated by the maximum walking distance, which indicates that compound 27 can be used in peripheral vascular disease or peripheral arterial disease.

[0438]

[0475] The overall effect on arterial calcification also indicates the potential use of compound 27 in PXE, a genetic condition among others that leads to arterial calcification. Example 56 Prevention and Treatment of Dermal Calcinosis and Calciphylaxis

[0476] The dose - response efficacy of IP4 - 4,6 derivatives in the prevention and treatment of skin calcinosis and calciphylaxis (CUA) induced by vitamin D3 and FeCl3 was investigated using a rat model. In this model, the effects of compound 27 and IP6 on the formation of calcified skin plaques in rats were evaluated over an 8 - day period. Animals were sensitized with low - concentration (LC, 35,000 IU / kg) and high - concentration (HC, 50,000 IU / kg) doses of vitamin D3. An FeCl3 solution (0.5 mg / kg) was used as a challenger to induce the formation of skin plaques. All animals were weighed daily before treatment.

[0439]

[0477] Eighty - six male Sprague Dawley (SD) rats (Envigo Corp., Huntingdon, GB) weighing approximately 250 - 300 g were used. The animals were fed a standard LASQCdiet® Rod14 - H diet (LASvendi, Soest, DE). The animals were divided into eight groups of 6 - 12 animals per group as follows:

[0440]

Table 15

[0441]

[0478] The following solutions were prepared: (a) vitamin D3 (cholecalciferol, Duphafral D31000; Zoetis Inc., Parsippany, NJ, US) at 17,500 IU / mL (LC) and 25,000 IU / mL (HC), (b) 0.3 mg / mL of FeCl3 (FeCl3·6H2O, 99%, Scharlab S.L., Barcelona, ES), (c) 30 mg / mL of IP6 (660 g / mol phytic acid, pH 6.5 - 7.7), and (d) 15, 30, and 50 mg / mL of compound 27 (754.45 g / mol free acid, pH 6.5 - 7.7). All solutions were prepared in 0.9% (w / v) physiological saline NaCl medium. An application volume of 2 mL / kg was utilized.

[0442]

[0479] Group 1 - Control (placebo), 6 animals. The animals in Group 1 were administered physiological saline (0.9% (w / v) NaCl solution) subcutaneously in the interscapular space daily from D1 to D3, and 0.9% physiological saline was injected once into each of two ventral sites in the chest on D4. The animals in Group 1 were not administered either Vit D or FeCl3 solution.

[0443]

[0480] Group 2 - Low-concentration physiological saline solution (vehicle LC): Vit D 35,000 IU / kg, 0.5 mg / kg FeCl3 solution, 10 animals. Vit D was administered subcutaneously at a dose of 35,000 IU / kg continuously for 3 days (D1, D2, D3), and 0.5 mg / kg FeCl3 was injected once into each of two ventral sites in the chest on D4. This group was given s.c. treatment with 0.9% physiological saline daily (D1 - D8).

[0444]

[0481] Group 3 - Compound 27, 60 mg / kg LC: Vit D 35,000 IU / kg, 0.5 mg / kg FeCl3, 10 animals. Vit D was administered subcutaneously at a dose of 35,000 IU / kg continuously for 3 days (D1, D2, D3), and 0.5 mg / kg FeCl3 was injected once into each of two ventral sites in the chest on D4. This group was given s.c. treatment with Compound 27 at a dose of 60 mg / kg daily (D1 - D8).

[0445]

[0482] Group 4 - High-concentration physiological saline solution (vehicle HC): Vit D 50,000 IU / kg, 0.5 mg / kg FeCl3, 12 animals. Vit D at a dose of 50,000 IU / kg was administered subcutaneously continuously for 3 days (D1, D2, D3), and 0.5 mg / kg FeCl3 was injected once into each of two ventral sites in the chest on D4. This group was given s.c. treatment with 0.9% physiological saline daily (D1 - D8).

[0446]

[0483] Group 5 - IP6, 60 mg / kg of HC, Vit D 50,000 IU / kg, 0.5 mg / kg of FeCl3, 12 animals. Vit D at a dose of 50,000 IU / kg was administered subcutaneously for 3 consecutive days (D1, D2, D3), and on D4, 0.5 mg / kg of FeCl3 was injected once into each of two ventral sites on the chest. In this group, daily s.c. treatment with IP6 was performed at a dose of 60 mg / kg (D1 - D8).

[0447]

[0484] Group 6 - Compound 27, 30 mg / kg of HC, Vit D 50,000 IU / kg, 0.5 mg / kg of FeCl 3、 12 animals. Vit D at a dose of 50,000 IU / kg was administered subcutaneously for 3 consecutive days (D1, D2, D3), and on D4, 0.5 mg / kg of FeCl3 was injected once into each of two ventral sites on the chest. In this group, daily s.c. treatment with Compound 27 was performed at a dose of 30 mg / kg (D1 - D8).

[0448]

[0485] Group 7 - Compound 27, 60 mg / kg of LC, Vit D 50,000 IU / kg, 0.5 mg / kg of FeCl3, 12 animals. Vit D at a dose of 50,000 IU / kg was administered subcutaneously for 3 consecutive days (D1, D2, D3), and on D4, 0.5 mg / kg of FeCl3 was injected once into each of two ventral sites on the chest. In this group, daily s.c. treatment with Compound 27 was performed at a dose of 60 mg / kg (D1 - D8).

[0449]

[0486] Group 8 - Compound 27, 100 mg / kg of HC, Vit D 50,000 IU / kg, 0.5 mg / kg of FeCl3, 12 animals. Vit D at a dose of 50,000 IU / kg was administered subcutaneously for 3 consecutive days (D1, D2, D3), and on D4, 0.5 mg / kg of FeCl3 was injected once into each of two ventral sites on the chest. In this group, daily s.c. treatment with Compound 27 was performed at a dose of 100 mg / kg (D1 - D8).

[0450]

[0487] In D8, all animals were anesthetized and then sacrificed. These necropsies were performed, and skin tissue plaques formed at the FeCl3 injection sites were collected for calcium content measurement. The tissues were washed with 0.15 M aqueous saline solution, freeze-dried for 48 - 72 hours, and weighed. Subsequently, using a 1:1 mixture of HNO3:HClO4, the freeze-dried tissues were decomposed in a drying oven incubator at 180 °C for 2 - 4 hours. Subsequently, using ultrapure water Milli-Q water (MilliporeSigma, Merck KGaA, Burlington, MA, US), the decomposed tissues were diluted to a final volume of 10 mL. According to the manufacturer's instructions, an Optima 7300 DV ICP-OES System spectrometer (PerkinElmer, Inc., Waltham, MA, US) was used to quantify the calcium content via inductively coupled plasma optical emission spectrometry (ICP-OES).

[0451]

[0488] The results show that the degree of inhibition achieved by compound 27 is higher than the degree of inhibition achieved by IP6 at the same dose. Furthermore, compound 27 inhibits the formation of skin plaques in a dose-responsive manner in rats, indicating that compound 27 can be used in conditions such as skin calcinosis and calciphylaxis. See Table 14. The effect on skin calcification also indicates the potential use of compound 27 in the treatment of PXE, a genetic condition among others that leads to skin calcification.

[0452]

[0489] Statistical analysis: One-way ANOVA using Tukey post-hoc test (p < 0.01 for LC group; p < 0.0001 for HC group). (#) Significance vs. placebo, (*) significance vs. corresponding vehicle, (§) significance vs. IP6 60 mg / kg (only applicable to compound 27 at the same dose), p < 0.05.

[0453]

Table 16

[0454] Example 57 Treatment of Calcified Human Aortic Valves

[0490] Using an in vitro model, the dose - response efficacy of IP4 - 4,6 derivatives in the treatment of calcified human aortic valves was analyzed (Zabirnyk A et al., Vasc Pharmacol, 2019; pp. 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 interstitial cells of human aortic valves (VIC).

[0455]

[0491] During aortic valve replacement, calcified human aortic valve leaflets were obtained and collected. After removal of valve endothelial cells, VICs were isolated. The leaflet portions 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 of collagenase II was added. The cells were incubated overnight at 37 °C and 5% CO2. The next day, the tissue that had been disassembled by pipetting with a serum pipette was homogenized, centrifuged at 300 g for 5 minutes, and the supernatant was carefully removed by suction.

[0456]

[0492] The pellet was washed with 10 mL of fresh DMEM and centrifuged as previously described. The supernatant was removed by suction, and the cell pellet was resuspended in basal growth medium and seeded into 75 cm 3 flasks. The VICs were cultured at 37 °C and 5% CO2 while changing the growth medium twice a week, and the culture was continued until they reached an approximate confluence of 90%. The cells were passaged, proliferated, and frozen at a ratio of 1:2.

[0457]

[0493]

[0494] 1. VIC Osteogenic Differentiation and Inhibition

[0495]

[0496] For osteogenic differentiation, VICs (n = 7) from calcified human aortic valves were seeded in 24 - well tissue culture plates at 30×10 4Cells were seeded in wells in basic growth medium and cultured overnight at 37°C and 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 3 weeks. The negative control group (without induction of mineralization) was cultured in basic growth medium for the same period and the medium was changed according to the same protocol.

[0458]

[0497] Concentration-response experiments were performed with the same VIC donor in all groups (n = 7 per concentration and test item). Starting from the first week of induced osteogenic differentiation, test items with increasing concentrations, compound 1, compound 3, and compound 6 (1, 3, 10, 30, and 100 μM) were incubated and compared with the activity of IP6. Tests for the positive control group (osteogenic medium without added inhibitor) were performed using VIC from the same donor.

[0459]

[0498]

[0499] 2. Calcium staining and quantification

[0500]

[0501] To evaluate mineralization, alizarin red staining was performed. The cell medium was removed, the cells were washed with PBS, and fixed with 70% ethanol at room temperature for 1 hour. The cells were then washed with Milli-Q water and stained with alizarin red according to the manufacturer's instructions. To quantify calcium accumulation, the alizarin red staining was extracted and measured by spectrophotometry. Briefly, for a 24-well plate, 200 μL of 10% acetic acid was added to each well and incubated at room temperature for 30 minutes with gentle stirring. Thereafter, a cell scraper was used to detach the cells, and the resulting suspension was transferred to a 1.5 mL microcentrifuge tube and vortexed vigorously for 30 seconds. The cells were then heated at 85 °C for 10 minutes, after which the tube was transferred to ice for 5 minutes to cool. The cells were then...

Claims

1. Compound of general formula I: 【Chemistry 1】 The pharmaceutically acceptable salt, or combination thereof [in the formula, (i) R １ , R ３ , R ７ , and R １１ each independently represents OPO ３ ２－ , R ５ and R ９ are each a substituent corresponding to the formula -O-(alkyl) ｎ -X, where n is an integer from 1 to 20, and the terminal group X is -H, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO ２ R, -NHCONRR', halogen, -CF ３ , alkyl, alkenyl, alkynyl, carbocycle, and heterocycle, and R and R' are H or an alkyl group (ii) R １ , R ３ , R ７ , and R １１ OPO operates independently. ３ ２－ Represents R ５ and R ９ Each of these is the formula -O-(alkyl) ｙ -Cy- (alkyl) ｙ’ -Z is a substituent corresponding to -Z, where y and y' are integers from 0 to 10, Cy is a cyclic linker, and the terminal group Z is alkyl, -COR, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO ２ R, -NHCONRR', halogen, and -CF ３ Selected from the group consisting of, where R and R' are H or alkyl groups, (iii) R １ , R ３ , R ７ , and R １１ OPO operates independently. ３ ２－ Represents R ５ and R ９ Each of these is the formula -O-(alkyl) ｙ -A- (Alkyl) ｙ’ -Z' is the substituent corresponding to -Z', where y and y' are integers from 0 to 10, and A is -CONR-, -NHCOO-, -NHSO ２ The linker is selected from the group consisting of -NHCONR-, -NHCO-, and -OCONR, and the terminal group Z' is -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO ２ Selected from the group consisting of R, -NHCONRR', a carbon ring, and a heterocycle, where R and R' are H or alkyl groups, (iv) The compound of formula I is an analog of (i), (ii), or (iii), where R １ , R ３ , R ７ or R １１ At least one of them is a thiophosphate ion (-OPSO ２ ２－ ) A pharmaceutical composition for use in treating, inhibiting the progression of, or preventing ectopic calcification or conditions resulting therefrom in subjects in need thereof.

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

3. The pharmaceutical composition according to any one of claims 1 to 2, wherein the compound is selected from the group consisting of compound 1 to compound 53 and any combination thereof.

4. The aforementioned compound has the following chemical structure: 【Chemistry 2】 The pharmaceutical composition according to claim 3, wherein compound 1 is compound 1.

5. The aforementioned compound has the following chemical structure: 【Transformation 3】 The pharmaceutical composition according to claim 3, wherein compound 3 is the compound 3.

6. The aforementioned compound has the following chemical structure: 【Chemistry 4】 The pharmaceutical composition according to claim 3, wherein the compound is 6.

7. The aforementioned compound has the following chemical structure: 【Transformation 5】 The pharmaceutical composition according to claim 3, wherein the compound 27 is the compound 27.

8. The pharmaceutical composition according to claim 1, further comprising at least one pharmaceutically acceptable excipient or carrier.

9. The pharmaceutical composition according to claim 1, wherein a therapeutically effective amount of the compound or pharmaceutical composition is administered to a subject in need thereof.

10. The pharmaceutical composition according to claim 1, for use in treating, inhibiting the progression of, and preventing diseases and / or conditions associated with ectopic calcification or conditions resulting therefrom, in subjects in need thereof.

11. The aforementioned ectopic calcification or the resulting conditions include: adrenal and cerebral calcification in familial spongiform malformation, asthenoid bone, age-related macular degeneration (AMD) associated with calcium deposition, bone cancer, bone mineral disorders, breast calcification, calcified corneal degeneration, calcifying tendinitis, calcification in osteoarthritis, articular cartilage calcification in osteoarthritis, articular and arterial calcification (CALJA), seminal vesicle calcification, cutaneous calcification, calciphylaxis (CUA), calcium pyrophosphate deposition disorder (CPPD), cardiovascular disease or related conditions, chondrocalcification, colorectal cancer, diabetic kidney disease, dystrophic calcification, kidney transplant graft failure, familial spongiform malformation (FCCM), fibrodysplasia ossificans (FO). P) The pharmaceutical composition according to claim 10, comprising osteoporosis-hyperphosphatemia syndrome (HHS), hyperphosphatemic familial neoplastic calcification (HFTC), idiopathic cerebral calcification (Faal's disease), idiopathic mesenteric venous sclerosis (IMP), kidney stones (i.e., nephrolithiasis), metastatic calcification, nephrocalcemia, neurocysticercosis-related calcification, osteomalacia, osteoporosis, pineal gland calcification, venous sclerosing colitis, foot gout, primary familial cerebral calcification (PFBC), primary oxaluria (PH), pseudoxanthoma elasticum (PXE), rheumatoid arthritis, sialolithiasis, parotid gland calcification in Sjögren's syndrome, seminal vesicle stones, skin cancer, soft tissue calcification due to sarcoidosis, adrenal calcification in Wolmann's disease, or wound healing associated with diabetic ulcers.

12. The cardiovascular disease or related condition is acute ischemic stroke (ACS), aneurysm, angina pectoris (chronic stable angina), aortic calcification, aortic calcification, aortic stenosis, aortic valve calcification, arrhythmia, arteriosclerosis, arteriosclerosis, arteriovenous fistula (AVF) failure, atherosclerosis, calcified aortic valve stenosis, cardiac death, heart disease, cardiovascular calcification, cardiovascular disease in patients with chronic kidney disease (CKD), age-related cardiovascular disease, death due to cardiovascular disease, cerebrovascular disease, congestive heart failure, coral reef aorta (CRA), coronary artery calcification, The pharmaceutical composition according to claim 11, comprising coronary artery disease, coronary disease, severe lower limb ischemia, electrocardiogram abnormalities, systemic arterial calcification in infants (GACI), heart failure, hypertension, ischemia, left ventricular hypertrophy, major adverse cardiovascular events (MACE) in hemodialysis (HD) patients, Mönkeberg type medial sclerosis (MMS), myocardial calcification, myocardial infarction, myocardial ischemia, pericardial calcification, peripheral artery disease (PAD), peripheral vascular disease (PVD), calcification of the anastomosis site after porcelain aorta and coronary artery bypass graft (CABG), portal vein calcification, stroke, thrombosis, valve calcification, or vascular calcification.

13. The pharmaceutical composition according to claim 1, wherein the subject has renal failure.

14. The pharmaceutical composition according to claim 1, wherein the subject is undergoing dialysis.

15. The pharmaceutical composition according to claim 9, wherein the administration is local, enteral, or parenteral.

16. The pharmaceutical composition according to claim 15, wherein the parenteral administration is administered intravenously, subcutaneously, intramuscularly, or by intravenous injection.

17. The pharmaceutical composition according to claim 16, wherein the intravenous infusion is administered using a dialysis machine.

18. The pharmaceutical composition according to claim 1, wherein the subject is a human.

19. A kit or manufactured article comprising the pharmaceutical composition described in claim 1.

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