IP4-4,6 substitution derivative compound

Abstract

The present invention provides substituted IP4-4,6 derivatives, methods for their synthesis, and uses thereof. In some embodiments, the IP4-4,6 derivatives are compounds of formula I, where R 1 , R 3 , R 7 , and R 11 is OPO 3 2- and R 5 and R 9 is -O(alkyl) n X, -O(alkyl) y Cy(alkyl 2 )yZ, -O(alkyl) y A(alkyl) y -Z', and thiophosphate analogs thereof. Also provided are methods, pharmaceutical compositions and formulations, methods of use, articles of manufacture, and kits for the treatment of diseases and conditions, such as diseases and conditions associated with pathologic crystallization.

Description

[Technical Field]

[0001] [1] The present invention relates to 4,6-substituted IP4 derivative compounds, methods for their synthesis, and uses. [Background technology]

[0002] [2] Inositol hexaphosphate (phytic acid, IP6, InsP6, inositol hexaphosphate, or myo-inositol-1,2,3,4,5,6-hexaphosphate) is a naturally occurring substance found uniquely in plant seeds. It is the major form of phosphorus found in edible plants such as grains, nuts, and legumes.

[0003] [3] IP6 is a potent inhibitor of calcium salt crystallization (Grases F et al., Anticancer Res. 1999;19:3717-3722). As a molecule with six phosphate groups, it exhibits a high affinity for divalent and trivalent metal ions such as calcium. This property allows IP6 to prevent, among other things, the development of pathological calcification, such as nephrolithiasis (Conte A et al., Arch. Esp. Urol. 1999;52:305-310) or cardiovascular calcification (Grases F et al., Front. Biosci. 2006;11:136-42). This property also allows it to chelate calcium ions in environments such as the intestinal tract, where it can prevent or treat Clostridium difficile infections (Kreimeyer I et al., Naunyn Schmiedebergs Arch Pharmacol. 2011;383(3):253-262).

[0004] [4] It has been described that some IP6 derivatives (e.g., those in which the phosphate group is replaced with sulfate, thiosulfate, or a water-soluble biopolymer such as polyethylene glycol (PEG)) can be used to treat diseases and conditions associated with pathological calcification, such as bacterial infections, or other diseases. See, for example, WO2017098047 and WO2017098033. However, there remains a need in the art for new and improved inositol phosphate derivatives (e.g., with varying degrees of crystallization inhibition ability, solubility, or resistance to degradation) that can be used medically to treat pathological calcification disorders and other conditions. Summary of the Invention [Means for solving the problem]

[0005] [5] The present invention relates to a compound of general formula I:

[0006] [ka]

[0007] or a pharmaceutically acceptable salt thereof, or a combination thereof, wherein R, R, R, and R 11 independently, OPO3 2- R5 and R9 each represent the formula -O(alkyl) n and X is a substituent corresponding to 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, -NHSOR, -NHCONRR', halogen, -CF, a carbocycle (saturated or unsaturated), and a heterocycle (saturated or unsaturated), and R and R' are H or an alkyl group.

[0008] [6] In some embodiments, R, R, R, and R 11 independently, OPO3 2- R5 and R9 each represent the formula -O(alkyl)y Cy(alkyl) y is a substituent corresponding to -Z, where y is an integer 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, -NHSOR, -NHCONRR', halogen, and -CF, and R and R' are H or alkyl groups.

[0009] [7] In some embodiments, R, R, R, and R 11 independently, OPO3 2- R5 and R9 each represent the formula -O(alkyl) y A (alkyl) y -Z' is a substituent corresponding to Z', where y is an integer from 0 to 10, A is a linker selected from the group consisting of -CONR-, -NHCOO-, -NHSO2, -NHCONR-, and -OCONR, -NHCO-, and the terminal group Z' is selected from the group consisting of -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSOR, -NHCONRR', carbocycle (saturated or unsaturated), heterocycle (saturated or unsaturated), and R and R' are H or alkyl groups.

[0010] [8] In some embodiments, R, R, R or R of the compound of Formula I 11 At least one of the thiophosphates (-OPSO2 2- ) group.

[0011] [9] 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.

[0012]

[10] In some embodiments, the alkyl moieties in the R5 and R9 substituents contain at least one double or triple carbon bond, i.e., form an alkenyl or 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 alkenyl or alkynyl chains. In some embodiments, the combination of alkenyl and alkynyl chains in the R5 and R9 substituents are the same. In some embodiments, the combination of alkenyl and alkynyl chains in the R5 and R9 substituents are different.

[0013]

[11] In some embodiments, the compound of Formula I is selected from the group consisting of Compound 1 to Compound 53.

[0014]

[12] 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 deca-sodium 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 deca-sodium salt.

[0015]

[13] The present invention also provides pharmaceutical compositions comprising the compounds of Formula I disclosed above and at least one pharmaceutically acceptable excipient.

[0016]

[14] Also provided is a method for inhibiting the formation or growth of calcium salts / crystals (e.g., calcium phosphate, hydroxyapatite (HAP)) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I, or a pharmaceutical composition disclosed herein.

[0017]

[15] Additionally, the present invention provides a method for treating or preventing a disease or condition associated with pathological crystallization in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I, or a pharmaceutical composition disclosed herein.

[0018]

[16] Also provided is a method of inhibiting the progression of a crystallization process in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I, or a pharmaceutical composition disclosed herein.

[0019]

[17] The present invention also provides a method of restoring or increasing blood perfusion in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I, or a pharmaceutical composition disclosed herein.

[0020]

[18] In some embodiments, the subject is a human. In some embodiments, administration is topical, enteral, or parenteral. In some embodiments, parenteral administration is intravenous. In some embodiments, intravenous administration is by bolus injection or infusion.

[0021]

[19] The present invention also provides kits or articles of manufacture comprising at least one compound of Formula I or a pharmaceutical composition comprising a compound of Formula I, and instructions for administration by any of the methods disclosed herein. In some embodiments, the kits or articles of manufacture may also include at least one compound selected from the group consisting of the compounds listed in Table 1.

[0022]

[20] In some embodiments, the present invention additionally provides a method for preparing a compound of Formula I (e.g., Compound 1 to Compound 53), comprising using at least one compound selected from the group consisting of the compounds listed in Table 1. [Brief explanation of the drawings]

[0023] [Figure 1]

[21] Figure 1 is a simplified schematic diagram of the physiochemical mechanism of action of the 4,6-substituted IP4 derivatives of the present invention, which inhibit hydroxyapatite (HAP) crystallization and are therefore useful for treating HAP-crystallization-mediated diseases. [Figure 2A]

[22] Figures 2A and 2B show representative structures of 4,6-substituted IP4 derivative compounds of Family A (e.g., compounds 1-30 and compounds 52-53). [Figure 2B] Figures 2A and 2B show representative structures of 4,6-substituted IP4 derivative compounds of Family A (e.g., compounds 1-30 and compounds 52-53). [Figure 3A]

[23] Figures 3A and 3B show representative structures of 4,6-substituted IP4 derivative compounds of Family B (e.g., compounds 31-44). [Figure 3B] Figures 3A and 3B show representative structures of 4,6-substituted IP4 derivative compounds of Family B (e.g., compounds 31-44). [Figure 4]

[24] Figure 4 shows representative structures of family C IP4-4,6-substituted derivative compounds (e.g., compounds 45–49). [Figure 5]

[25] Figure 5 shows representative structures of family D IP4-4,6-substituted derivative compounds (e.g., compounds 50-51). [Figure 6]

[26] Figure 6 is a schematic diagram of synthetic scheme 1. [Figure 7]

[27] Figure 7 is a schematic diagram of synthetic scheme 2. [Figure 8]

[28] Figure 8 is a schematic diagram of synthetic scheme 3. [Figure 9]

[29] Figure 9 is a schematic representation of synthetic scheme 4. [Figure 10]

[30] Figure 10 is a schematic representation of synthetic scheme 5. DETAILED DESCRIPTION OF THE INVENTION

[0024]

[31] The present invention provides 4,6-substituted IP4 derivatives, methods for their synthesis, and uses. In some embodiments, the 4,6-substituted IP4 derivatives are represented by the general formula I:

[0025] [ka]

[0026] (Wherein R1, R3, R7, and R 11 is OPO3 2- or OPSO2 2- and R5 and R9 are the same) or a pharmaceutically acceptable salt thereof, or a combination thereof. 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 octa-sodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, an octa-sodium salt, a nonasodium salt, or a deca-sodium salt. In some embodiments, the IP4-4,6 derivative is an octa-sodium salt.

[0027]

[32] Also provided are methods, pharmaceutical compositions and formulations, methods of use, articles of manufacture, and kits for the treatment of diseases and conditions, such as diseases and conditions associated with pathological crystallization.

[0028]

[33] 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 stated herein, each of the following terms has the meaning set forth below. Additional definitions are set forth throughout this application.

[0029] I. Definition

[34] 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.

[0030]

[35] 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, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd Edition, 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd Edition, 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, Revised Edition, 2000, Oxford University Press provide those skilled in the art with a general dictionary of many of the terms used in this invention.

[0031]

[36] Units, prefixes, and symbols are expressed in their International System of Units (SI) recognized form. Numerical ranges are inclusive of the numbers defining the range. When a range of values ​​is described, it is understood that each integer and each fraction between the upper and lower limit of that described range is also specifically disclosed, along with each subrange between such values. The upper and lower limits of any range can independently be included in or excluded from the range, and each range is also encompassed within the invention when either, neither, or both of these limits are included.

[0032]

[37] Where a value is explicitly recited, it is understood that values ​​that are approximately the same number or amount as the recited value are also within the scope of the invention. Where a combination is disclosed, each subcombination of some elements of that combination is also expressly disclosed and within the scope of the invention. Conversely, where different elements or groups of elements are individually disclosed, combinations thereof are also disclosed. Where any element of an invention is disclosed as having multiple alternatives, examples of the invention in which each alternative is excluded, alone or in any combination with other alternatives, are also disclosed herein; more than one element of an invention may include such an exclusion, and all combinations of elements including such exclusions are disclosed herein.

[0033]

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

[0034]

[39] When a specific value or composition is described in this application and claims, unless otherwise stated, the meaning of "about" should be assumed to be within an acceptable error range for that particular value or composition. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical range. Thus, "about 10 to 20" means "about 10 to about 20." In general, the term "about" can modify numerical values ​​above and below the stated value by, for example, a variance of 10 percent above or below.

[0035]

[40] And / or: When used herein, "and / or" should be construed as a specific invention of each of the two specified features or components (with or without the other). Thus, when the term "and / or" is used herein in phrases such as "A and / or B," it is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, when the term "and / or" is used herein in phrases such as "A, B, and / or C," it is intended to encompass each of the following embodiments: 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).

[0036]

[41] Approximately: As used herein, the term "approximately," when applied to one or more values ​​of interest, refers to a value similar to a 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 or less) of the stated reference value (excluding any value that such number could represent exceeding 100%), unless otherwise stated or apparent from the context.

[0037]

[42] Comprising: Whenever an embodiment is described herein with the term "comprising," it is understood that other similar embodiments described with "consisting of" and / or "consisting essentially of" are also provided.

[0038]

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

[0039] 44] Effective amount: As used herein, the term "effective amount" of a therapeutic agent, in reference to (i) a 4,6-substituted IP4 derivative of the present invention, (ii) any dosage form, pharmaceutical composition, or formulation disclosed herein containing at least one 4,6-substituted IP4 derivative of the present invention, or (iii) a combination of a 4,6-substituted IP4 derivative of the present invention with one or more additional therapeutic agents, is that amount sufficient to affect a beneficial or desired result. In some embodiments, the beneficial or desired result is, for example, a clinical result, so "effective amount" depends on the context in which it is applied. The term "effective amount" can be used interchangeably with "effective dose," "therapeutically effective amount," or "therapeutically effective dose."

[0040] The term "effective amount" refers to a specific use of a 4,6-substituted IP4 derivative. For example, if the 4,6-substituted IP4 derivative is used to inhibit the formation or growth of calcium salts / crystals (e.g., calcium phosphate, HAP), an effective amount is the amount of the 4,6-substituted IP4 derivative capable of achieving the desired effect (e.g., reducing HAP crystallization / formation in serum or plasma).

[0041] 46] Enteral administration: As used herein, the term "enteral administration" and the related term "enterally" refer to any administration of a 4,6-substituted IP4 derivative of the present invention or a pharmaceutical composition containing said derivative via the gastrointestinal tract. Enteral administration includes, but is not limited to, oral, sublingual, and rectal routes of administration.

[0042] 47] Prevention: As used herein, the term "prevention" refers to measures taken to maintain health, prevent or delay the onset of a disease or condition, or reduce the level and / or severity of symptoms. Thus, prophylactic use of a therapeutic agent disclosed herein, e.g., (i) a 4,6-substituted IP4 derivative of the present invention, or (ii) a combination thereof, or (iii) any dosage form containing at least one 4,6-substituted IP4 derivative of the present invention, or (iv) any formulation containing at least one 4,6-substituted IP4 derivative of the present invention, or (v) a combination of a 4,6-substituted IP4 derivative of the present invention with one or more additional therapeutic agents, corresponds to an amount thereof sufficient to affect a beneficial or desired result.

[0043]

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

[0044]

[49] 4,6-substituted IP4 derivatives of the present invention: As used herein, the term "4,6-substituted IP4 derivatives of the present invention" and grammatical variations thereof refer to compounds of formula I:

[0045] [ka]

[0046] (Wherein R1, R3, R7, and R 11 is OPO3 2- or OPSO2 2- wherein R5 and R9 may or may not be the same, and wherein the R5 and R9 substituents are those disclosed in compound families A, B, C, and D detailed below. and salts thereof (e.g., pharmaceutically acceptable salts thereof). In some embodiments, the term IP4-4,6-substituted derivatives of the present invention encompasses compounds 1-53, any salts thereof (e.g., sodium salts), and any combinations thereof. In some embodiments, the term IP4-4,6-substituted derivatives of the present invention encompasses compounds of Formula I that are intermediates in the synthesis of compounds 1-53, e.g., compounds selected from the group consisting of the compounds listed in Table 1, any salts thereof (e.g., sodium salts), and any combinations thereof. In some embodiments, the term IP4-4,6-substituted derivatives of the present invention encompasses compounds of Formula I that are compounds 1-53, as well as compounds selected from the group consisting of the compounds listed in Table 1, any salts thereof (e.g., sodium salts), and any combinations thereof.

[0047]

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

[0048]

[51] The group of compounds listed in Table 1: In the context of the present invention, reference to "the group of compounds listed in Table 1" refers to, for example, the group of intermediate compounds used in the synthesis of the 4,6-substituted IP4 derivatives of the present invention (e.g., compounds selected from the group consisting of Compounds 1 through 53), i.e., Intermediates II-1 through II-27, Intermediates III-1 through III-47, Intermediates IV-1 through IV-48, Intermediates VI'-1 through IV'-2, Intermediate V-1, Intermediate VI-1, Intermediates VII-1 through VII-2, Intermediates VIII-1 through VIII-5, Intermediates IX-1 through IX-5, Intermediates X-1 through X-3, Intermediates XI-1 through XI-2, Intermediates XII-1 through XII-2, and Intermediates XIII-1 through XIII-3. In some embodiments, the group of compounds listed in Table 1 also includes combinations thereof. In some embodiments, the 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.

[0049] 52 Parenteral administration: As used herein, the term "parenteral administration" and the related term "parenteral" refer to the administration of a 4,6-substituted IP4 derivative of the present invention characterized by a physical disruption of the target tissue, and the administration of the derivative through said disruption. Parenteral administration includes, but is not limited to, the administration of a 4,6-substituted IP4 derivative of the present invention (e.g., a compound selected from the group consisting of Compounds 1 through 53) or a pharmaceutical composition containing the derivative, for example, by application of the derivative or composition through a surgical incision or through a tissue-penetrating non-surgical wound. 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 administration routes.

[0050]

[53] Subject: "Subject" or "individual" or "animal" or "patient" or "mammal" refers to any subject for which diagnosis, prognosis, or treatment is desired, particularly a mammalian subject. Mammalian subjects include, but are not limited to, humans, domestic animals, farm animals, zoo animals, sport animals, and pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cows, and cows; primates such as apes, monkeys, orangutans, and chimpanzees; canines such as dogs and wolves; felines such as cats, lions, and tigers; equines, horses, donkeys, and zebras; bears; food animals such as cows, pigs, and sheep; ungulates such as deer and giraffes; rodents such as mice, rats, hamsters, and guinea pigs. 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.

[0051]

[54] Substantially: As used herein, the term "substantially" refers to a qualitative state indicating the total or nearly total extent or degree of a desired characteristic or property. Those skilled in the art of biology will understand that biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completion, or reach or avoid an absolute result. Thus, the term "substantially" is used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0052]

[55] Therapeutic Agent: As used herein, the term "therapeutic agent" is used broadly to include compositions containing a 4,6-substituted IP4 derivative of the present invention that can provide a significant therapeutic benefit to a subject in need thereof. In some embodiments, the subject in need thereof 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, a therapeutic agent according to the present invention can be a 4,6-substituted IP4 derivative of the present invention administered alone or in combination with one or more additional therapeutic agents in an amount sufficient for beneficial or desired results.

[0053]

[56] The term therapeutic agent also encompasses prophylactic, diagnostic, or imaging agents comprising the 4,6-substituted IP4 derivatives of the present invention, where the therapeutic agent is administered (i.e., topically, enterally, or parenterally). Therapeutic agents of the present invention include agents that can inhibit the formation or growth of calcium salts / crystals (e.g., calcium phosphate, HAP) and / or ameliorate and / or prevent symptoms associated with pathological crystallization.

[0054]

[57] Topical administration: As used herein, the term "topical administration" and the related term "topical" refer to any administration of a 4,6-substituted IP4 derivative of the present invention or a pharmaceutical composition containing said derivative by applying the derivative or composition to a specific location, such as the skin or mucous membrane, or internally. Topical administration includes, but is not limited to, otic, cutaneous, nasal, transdermal, urethral, ​​vaginal, and urethral routes of administration.

[0055]

[58] Treat, Treatment, Therapy: As used herein, the term "treat" or "treatment" or "therapy" refers to partially or completely alleviating, ameliorating, improving, relieving, delaying the onset of, inhibiting the progression of, reducing the severity of, or reducing the incidence of one or more symptoms or characteristics of a disease, or any combination thereof.

[0056]

[59] Treatments comprising the 4,6-substituted IP4 derivatives of the present invention can be administered to subjects who do not exhibit symptoms of a disease, disorder, and / or condition and / or who exhibit only early symptoms of a disease, disorder, and / or condition, for the purpose of, for example, (i) reducing the risk of developing symptoms associated with the disease, disorder, and / or condition; (ii) delaying the onset of the disease, disorder, and / or condition or symptoms associated with said disease, disorder, and / or condition; or (iii) alleviating the symptoms and / or sequelae of the disease, disorder, and / or condition or symptoms associated with said disease, disorder, and / or condition.

[0057]

[60] Thus, in general, the term "treatment" refers to (i) inhibiting a disease or pathological condition, in other words, slowing or halting its onset or progression; (ii) reversing a disease or pathological condition, in other words, causing regression of said disease or pathological condition or its symptoms; (iii) stabilizing a disease or pathological condition, and (iv) countering the resulting effects of a disease or pathological condition of interest in a subject, including any combination thereof.

[0058]

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

[0059] II. IP4-4,6-substituted derivatives

[62] The present invention provides 4,6-substituted IP4 derivatives, methods for their synthesis, and uses. In some embodiments, the 4,6-substituted IP4 derivatives are represented by the general formula I:

[0060] [ka]

[0061] (Wherein R1, R3, R7, and R 11 independently, 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 4,6-substituted IP4 derivatives of the present invention are acceptable salts (e.g., pharmaceutically acceptable salts) of compounds of Formula I, or combinations thereof.

[0062]

[63] In some embodiments, not all negative charges of the IP4-4,6 derivatives of the present invention are neutralized by the charges of positively charged ions. Thus, the IP4-4,6 derivatives of the present invention can be, for example, tetra-ionic salts (e.g., tetrasodium salts), penta-ionic salts (e.g., pentasodium salts), hexa-ionic salts (e.g., hexa-ionic salts), heptasodium salts (e.g., heptasodium salts), octa-ionic salts (e.g., octa-ionic salts), nona-ionic salts (e.g., nona-ionic salts), or deca-ionic salts (e.g., deca-ionic salts). In some embodiments, the presence of additional negatively charged groups in the IP4-4,6 substituted derivatives can result in the formation of complexes with additional ions. In some embodiments, the IP4-4,6 derivatives of the present invention are sodium salts. In some embodiments, the IP4-4,6 derivatives are tetra-, pentasodium, hexasodium, heptasodium, octa-, nonasodium, or deca-ionic salts. In some embodiments, the IP4-4,6 derivatives are tetra-, pentasodium, hexasodium, heptasodium, or octa-ionic salts. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, an octasodium salt, a nonasodium salt, or a deca-sodium salt. Formula I and the remaining formulas presented herein are meant to encompass any isomers of the compounds covered thereby.

[0063]

[64] The term "alkenyl" or "alkenyl chain," in the context of this invention, refers to a linear or branched alkyl chain (e.g., containing 2 to 10 carbon atoms) containing one or more double bonds, either substituted or unsubstituted. Examples include ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, and 1,3-butadienyl, among others.

[0064]

[65] The term "alkyl" or "alkyl chain," in the context of the present invention, refers to a saturated hydrocarbon moiety that may 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, n- or isobutyl, n- or cyclohexyl. The term alkyl can be extended to alkyl groups that are bonded or bridged by heteroatoms. Heteroatoms, in the context of the present invention, are nitrogen (N), sulfur (S), oxygen (O), and halogens.

[0065]

[66] The term "alkynyl" or "alkynyl chain," in the context of this invention, refers to a linear or branched alkyl chain (e.g., containing 2 to 10 carbon atoms) containing one or more triple bonds, either substituted or unsubstituted. Examples include ethynyl, propynyl, 1-butynyl, and 3-butynyl, among others.

[0066]

[67] An "amine functional group" or "amine group" is a functional group of the formula NRR', where R and R' are, for example, hydrogen (-H) and C1-C n and n is an integer from 0 to 20.

[0067]

[68] A "hydroxy functional group" or "hydroxy group" is OH.

[0068]

[69] A "carboxylic acid functional group" or "carboxylic acid group" is a functional group consisting of COOH or its anion, COO - is.

[0069]

[70] A "carboxylic acid amide" is CONRR' or NCOR, where R and R' are, for example, hydrogen (-H) and C1-C n and n is an integer from 0 to 20.

[0070]

[71] "Carbocycle" refers to a 3- to 10-membered carbocyclic ring that may be saturated, partially unsaturated, or aromatic and is attached to the rest of the molecule through any available C atom. The term includes carbocyclic rings substituted with one or more heteroatoms (e.g., N, O, halogen atoms).

[0071]

[72] "Heterocycle" refers to a 3- to 10-membered cyclic ring that may be saturated, partially unsaturated, or aromatic and that contains at least one heteroatom selected from among N, O, and S, bonded to the remainder of the molecule through any available C or N atom. The term includes heterocyclic rings substituted with one or more halogen atoms.

[0072]

[73] Examples of carbocycles and heterocycles include, among others, 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, pyrazinyl, pyrimidinyl, pyridazinyl, benzimidazolyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, benzothiazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, and aziridinyl.

[0073]

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

[0074]

[75] The term "OPO3 2- " in the context of the present invention is unclear. - and OPO3H2.

[0075]

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

[0076] 77] The 4,6-substituted IP4 derivatives of the present invention can be present in any form commonly used in the pharmaceutical arts. Specific embodiments include, but are not limited to, sodium salts, magnesium salts, potassium salts, ammonium salts, the free acid, or mixtures of the foregoing forms. Other pharmaceutically acceptable salts will be known to those skilled in the art and can be obtained by methods previously described (Haynes M et al., J. Pharmaceutical Sci. 2005;94:2111-2120).

[0077]

[78] In some embodiments, R, R, R, and R 11 are independently phosphate (-OPO3 2- ) and R5 / R9 represent a group of the formula -O(alkyl) n X (i.e., R5 / R9 are branched or unbranched alkyl chains), 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, -NHSOR, -NHCONRR', halogen, -CF3, carbocycle (saturated or unsaturated), and heterocycle (saturated or unsaturated), where R and R' are H or alkyl groups. Throughout this invention, this family of IP4-4,6-substituted derivatives is designated Family A.

[0078]

[79] In some embodiments, R, R, R, and R 11 are independently phosphate (-OPO3 2- ) and R5 / R9 represent a group of the formula -O(alkyl) y Cy(alkyl) ycorresponds to -Z (i.e., R5 / R9 comprise two alkyl chains connected by a cyclic linker interposed between the two alkyl chains), where each alkyl comprises y carbon (e.g., CH2) units, where y is an integer between 0 and 10, and the distal alkyl chain comprises a terminal group Z selected from the group consisting of alkyl, -COR, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSOR, -NHCONRR', halogen, and -CF3, where R and R' are H or alkyl groups. Throughout this invention, this family of IP4-4,6-substituted derivatives is designated Family B.

[0079]

[80] In some embodiments, R, R, R, and R 11 are independently phosphate (-OPO3 2- ) and R5 / R9 represent a group of the formula -O(alkyl) y A (alkyl) y The group corresponds to -Z' (i.e., two alkyl chains connected by a linker A interposed between the two alkyl chains), where each alkyl chain contains y carbon (e.g., CH) units, where y is an integer between 0 and 10; the linker A is selected from the group consisting of -CONR-, -NHCOO-, -NHSO-, -NHCONR-, -NHCO-, and -OCONR-; the distal alkyl chain contains a terminal group Z' selected from the group consisting of -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO-R, -NHCONRR', a carbocycle (saturated or unsaturated), or a heterocycle (saturated or unsaturated); R and R' are H or alkyl groups. Throughout this invention, this family of IP4-4,6-substituted derivatives is designated Family C.

[0080]

[81] In some embodiments, the 4,6-substituted IP4 derivatives of Family D are analogs of compounds from Family A, B, or C, and R, R, R, or R 11 At least one of the thiophosphates (-OPSO2 2-Throughout this invention, this family of 4,6-substituted IP4 derivatives is designated Family D.

[0081]

[82] In some embodiments of the 4,6-substituted IP4 derivatives of Family D, R, R, R or R in a compound from Family A, B or C 11 One of them is thiophosphate (-OPSO2 2- In some embodiments of the 4,6-substituted IP4 derivatives of Family D, R, R, R or R in a compound from Family A, B or C is 11 The two are thiophosphates (-OPSO2 2- In some embodiments of the 4,6-substituted IP4 derivatives of Family D, R, R, R or R in a compound from Family A, B or C is 11 The three are thiophosphates (-OPSO2 2- In some embodiments of the 4,6-substituted IP4 derivatives of Family D, R, R, R or R in a compound from Family A, B or C is 11 is a thiophosphate (-OPSO2 2- )

[0082]

[83] In some embodiments of the Family D IP4-4,6 substituted derivatives, the Family D compounds contain a thiophosphate (-OPSO2) only at position R1. 2- In some embodiments of the Family D IP4-4,6 substituted derivatives, the Family D compounds contain a thiophosphate (-OPSO2) only at position R3. 2- In some embodiments of the Family D IP4-4,6 substituted derivatives, the Family D compounds contain a thiophosphate (-OPSO2) at position R7 only. 2- In some embodiments of the Family D IP4-4,6 substituted derivatives, the Family D compound contains a 4,6-substituted IP4 at position R 11 Only in thiophosphate (-OPSO2 2- In some embodiments of the Family D IP4-4,6 substituted derivatives, the Family D compound contains at positions R1, R3, R7, and R 11 And thiophosphate (-OPSO22- In some embodiments of the Family D IP4-4,6 substituted derivatives, the Family D compounds contain a thiophosphate (-OPSO2) at positions R1 and R3. 2- In some embodiments of the Family D IP4-4,6 substituted derivatives, the Family D compounds contain thiophosphates (-OPSO2) at positions R1 and R7. 2- In some embodiments of the Family D IP4-4,6 substituted derivatives, the Family D compounds contain a 4,6 substituted IP4 at positions R and R 11 And thiophosphate (-OPSO2 2- In some embodiments of the Family D IP4-4,6 substituted derivatives, the Family D compounds contain thiophosphates (-OPSO2) at positions R3 and R7. 2- In some embodiments of the Family D IP4-4,6 substituted derivatives, the Family D compounds contain positions R3 and R 11 And thiophosphate (-OPSO2 2- In some embodiments of the Family D IP4-4,6 substituted derivatives, the Family D compounds contain a 4,6 substituted IP4 at positions R7 and R 11 And thiophosphate (-OPSO2 2- In some embodiments of the Family D IP4-4,6 substituted derivatives, the Family D compounds contain thiophosphates (-OPSO2) at positions R1, R3, and R7. 2- In some embodiments of the Family D IP4-4,6 substituted derivatives, the Family D compounds contain at positions R1, R3, and R 11 And thiophosphate (-OPSO2 2- In some embodiments of the Family D IP4-4,6 substituted derivatives, the Family D compounds contain at positions R3, R7, and R 11 And thiophosphate (-OPSO2 2- In some embodiments of the Family D IP4-4,6 substituted derivatives, the Family D compounds contain at positions R1, R7, and R 11 And thiophosphate (-OPSO2 2- ) contains.

[0083]

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

[0084]

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

[0085]

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

[0086]

[87] In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of Compound 1, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of Compound 2, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 3, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 4, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 5, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 6, where R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 7, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 8, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 9, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 10, wherein R, R, R, 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 (-OPSO2 2-In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 11, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 12, wherein R1, R3, R7 or R 11 ;R1, R3, R7, and R 11 ;R1 and R3;R1 and R7;R1 and R 11 ;R3 and R7;R3 and R 11 ;R7 and R 11 ;R1, R3, and R7;R1, R3, and R 11 ;R3, R7, and R 11 ; or R1, R7, and R 11 is a thiophosphate (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 13, wherein R, R, R, 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 (-OPSO2 2-In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 14, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 15, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 16, where R, R, R, 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 (-OPSO2 2-In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 17, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 18, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 19, wherein R, R, R, 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 (-OPSO2 2-In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 20, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 21, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 22, wherein R, R, R, 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 (-OPSO2 2-In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 23, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 24, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 25, wherein R, R, R, 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 (-OPSO2 2-In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 26, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 27, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 28, wherein R, R, R, 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 (-OPSO2 2-In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 29, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 30, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 31, wherein R, R, R, 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 (-OPSO2 2-In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 32, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 33, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 34, wherein R, R, R, 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 (-OPSO2 2-In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 35, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 36, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 37, wherein R, R, R, 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 (-OPSO2 2-In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 38, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 39, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 40, wherein R, R, R, 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 (-OPSO2 2-In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 41, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 42, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 43, wherein R, R, R, 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 (-OPSO2 2-In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 44, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 45, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 46, wherein R, R, R, 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 (-OPSO2 2-In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 47, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 48, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 49, wherein R, R, R, 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 (-OPSO2 2-In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 50, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 51, wherein R, R, R, 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 (-OPSO2 2- In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 52, wherein R, R, R, 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 (-OPSO2 2-In some embodiments, the 4,6-substituted IP4 derivatives of the present invention comprise or consist of an analog of compound 53, wherein R, R, R, 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 (-OPSO2 2- )

[0087]

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

[0088]

[89] In some embodiments, the 4,6-substituted IP4 derivatives of the present invention have the following formula:

[0089] [ka]

[0090] (wherein n is an integer from 1 to 20, alkyl is CH2, and X is -H) 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, 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. 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).

[0091]

[90] In some embodiments, the 4,6-substituted IP4 derivatives of the present invention have the following formula:

[0092] [ka]

[0093] wherein n is an integer from 1 to 20, alkyl is CH2, and X is selected from the group consisting of -OH and -OMe. The compound of formula (I) comprises or consists of the compound of formula (I). 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 octa-sodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, an octa-sodium salt, a nonasodium salt, or a deca-sodium salt. In some embodiments, the IP4-4,6 derivative is an octa-sodium 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).

[0094]

[91] In some embodiments, the 4,6-substituted IP4 derivatives of the present invention have the following formula:

[0095] [ka]

[0096] (wherein n is an integer from 1 to 20, alkyl is CH2, and X is an amine group). 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 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 octa-sodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, an octa-sodium salt, a nonasodium salt, or a deca-sodium 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 CH, and X is —NH (Compound 14). In some embodiments, n is 10, alkyl is CH, and X is —NH (Compound 15).

[0097]

[92] In some embodiments, the 4,6-substituted IP4 derivatives of the present invention have the following formula:

[0098] [ka]

[0099] (wherein n is an integer from 1 to 20, alkyl is CH2, and X is pyrazole or triazole). 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, 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. 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).

[0100]

[93] In some embodiments, the 4,6-substituted IP4 derivatives of the present invention have the following formula:

[0101] [ka]

[0102] (wherein n is an integer from 1 to 20, alkyl is CH2, and X is -COOH) 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, 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 or a 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 CH, and X is —COOH (Compound 19). In some embodiments, n is 3, alkyl is CH, and X is —COOH (Compound 52).

[0103]

[94] In some embodiments, the 4,6-substituted IP4 derivatives of the present invention have the following formula:

[0104] [ka]

[0105] (wherein n is an integer of 1 to 20, alkyl is CH2, and X is -CONRR', -NHCOR, -NHCOOR, -NHCONRR', or -CF3). 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, 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. 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).

[0106]

[0095] In some embodiments, the 4,6-substituted IP4 derivatives of the present invention have the following formula:

[0107] [ka]

[0108] (wherein n is an integer from 1 to 20, alkyl is CH2, and X is cyclopropane or cyclopentane). 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, 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. 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).

[0109]

[0096] In some embodiments, the 4,6-substituted IP4 derivatives of the present invention have the following formula:

[0110] [ka]

[0111] (wherein n is an integer of 1 to 20, alkyl is branched, and X is —H). 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, 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. In some embodiments, the substituted IP4-4,6 derivative of the present invention comprises or consists of compound 21, as shown in Figure 2B.

[0112]

[97] In some embodiments, the 4,6-substituted IP4 derivatives of the present invention have the following formula:

[0113] [ka]

[0114] (wherein n is an integer from 1 to 20, alkyl is an alkynyl chain, and X is —H). 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 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 octa-sodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, an octa-sodium salt, a nonasodium salt, or a deca-sodium salt. In some embodiments, the IP4-4,6 derivative is an octa-sodium salt. In some embodiments, the substituted IP4-4,6 derivative of the present invention comprises or consists of compound 53, as shown in Figure 2B.

[0115]

[0098] In some embodiments, the 4,6-substituted IP4 derivatives of the present invention have the following formula:

[0116] [ka]

[0117] wherein y and y' are integers from 0 to 10, alkyl is CH, 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 -COCH. The compound of formula (I) comprises or consists of the compound shown in Figure 3A. See Figure 3A. 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 octa-sodium salt. In some embodiments, the IP4-4,6 derivative is a hexasodium salt, an octa-sodium salt, a nonasodium salt, or a deca-sodium salt. In some embodiments, the IP4-4,6 derivative is an octa-sodium salt or a 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 CH, Cy is triazole-2, and Z is -OMe (Compound 32). In some embodiments, y is 1, y' is 6, alkyl is CH, Cy is triazole-2, and Z is -OMe (Compound 33). In some embodiments, y is 2, y' is 0, alkyl is CH, Cy is piperazine, and Z is -COCH (Compound 34). In some embodiments, y is 3, y' is 2, alkyl is CH, Cy is triazole-1, and Z is -COOH (Compound 35). In some embodiments, y is 3, y' is 1, alkyl is CH, Cy is triazole-1, and Z is -OMe (Compound 36). In some embodiments, y is 4, y' is 1, alkyl is CH, Cy is triazole-1, and Z is -OMe (Compound 37). In some embodiments, y is 5, y' is 1, alkyl is CH, Cy is triazole-1, and Z is -OMe (Compound 38). In some embodiments, y is 6, y' is 1, alkyl is CH, Cy is triazole-1, and Z is -OMe (Compound 39).In some embodiments, y is 6, y' is 0, alkyl is CH, Cy is triazole-1, and Z is -COOH (Compound 40). In some embodiments, y is 6, y' is 1 / 0, alkyl is CH, Cy is triazole-1, and Z is -OMe / -COOH (Compound 41).

[0118]

[0099] In some embodiments, the 4,6-substituted IP4 derivatives of the present invention have the following formula:

[0119] [ka]

[0120] wherein y and y' are integers from 0 to 10, alkyl is CH, 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 -CF. See Figure 3B. 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. 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 CH, Cy is 1,4-substituted phenyl, and Z is -Me (Compound 42). In some embodiments, y is 3, y' is 0, alkyl is CH, Cy is 1,4-substituted phenyl, and Z is -OMe (Compound 43). In some embodiments, y is 3, y' is 0, alkyl is CH, Cy is 1,3-substituted phenyl, and Z is -CF (Compound 44).

[0121] In some embodiments, the 4,6-substituted IP4 derivatives of the present invention have the following formula:

[0122] [ka]

[0123] wherein y and y' are integers from 0 to 10, alkyl is CH, 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. In some embodiments, the IP4-4,6 derivative comprises or consists of a compound of formula (I). 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 deca-sodium 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 deca-sodium salt. In some embodiments, the IP4-4,6 derivative is an octasodium salt or deca-sodium 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 CH, A is -NHCONH, and Z is phenyl (Compound 46). In some embodiments, y is 3, y' is 0, alkyl is CH, A is -NHCONH, and Z is cyclopentyl (Compound 47). In some embodiments, y is 5, y' is 0, alkyl is CH, A is -NHCO, and Z is phenyl (Compound 48). In some embodiments, y is 5, y' is 0, alkyl is CH, A is -NHCO, and Z is thiophenyl (Compound 49).

[0124] In some embodiments, the 4,6-substituted IP4 derivatives of the present invention have the following formula:

[0125] [ka]

[0126] wherein n is an integer from 1 to 20, alkyl is CH2, and X is selected from the group consisting of -H and -OMe. 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, 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. 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).

[0127] The IP4-4,6 derivatives of the present invention are disclosed in the myo form. However, the present invention is also meant to encompass all other isomers of the inositol backbone, such as the scyllo-, muco-, 1D-chiro-, 1L-chiro-, neo-, allo-, epi-, and cis- counterparts of the IP4-4,6 derivatives of the present invention.

[0128]

[0103] The present invention also provides chemical intermediate compounds useful for preparing the 4,6-substituted IP4 derivatives of the present invention (e.g., Compounds 1-53). In some embodiments, such intermediate compounds are compounds listed in Table 1. The intermediate compounds disclosed herein can be converted to the 4,6-substituted IP4 derivatives of the present invention using the procedures described herein. Thus, the present invention provides a method for producing the 4,6-substituted IP4 derivatives of the present invention (e.g., a compound selected from the group consisting of Compounds 1-53), comprising the step of utilizing an intermediate compound selected from the group consisting of the compounds listed in Table 1. The present invention also provides methods for producing the intermediate compounds disclosed herein. Thus, the present invention provides a method for producing the 4,6-substituted IP4 derivatives of the present invention (e.g., a compound selected from the group consisting of Compounds 1-53), comprising the step of utilizing an intermediate compound selected from the group consisting of the compounds listed in Table 1.

[0129] [Table 1-1]

[0130] [Table 1-2]

[0131] [Table 1-3]

[0132] [Table 1-4]

[0133] [Table 1-5]

[0134] [Table 1-6]

[0135] [Table 1-7]

[0136] [Table 1-8]

[0137] The 4,6-substituted IP4 derivatives of the present invention and intermediates for their synthesis can be synthesized using the methods described herein as well as other methods known in the art of organic chemistry. In some embodiments, the methods include, but are not limited to, the general procedures shown in Synthetic Schemes 1, 2, 3, and 4 described herein. Thus, in some embodiments, the present invention provides methods for preparing the 4,6-substituted IP4 derivatives of the present invention, comprising applying Synthetic Scheme 1 disclosed below. In some embodiments, the present invention provides methods for preparing the 4,6-substituted IP4 derivatives of the present invention, comprising applying Synthetic Scheme 2 disclosed below. In some embodiments, the present invention provides methods for preparing the 4,6-substituted IP4 derivatives of the present invention, comprising applying Synthetic Scheme 3 disclosed below. In some embodiments, the present invention provides methods for preparing the 4,6-substituted IP4 derivatives of the present invention, comprising applying Synthetic Scheme 4 disclosed below.

[0138] In some aspects, the present invention provides methods for preparing intermediates for the synthesis of 4,6-substituted IP4 derivatives of the present invention (e.g., compounds selected from the group consisting of Compounds 1 to 53), comprising the step of applying Synthetic Scheme 1 disclosed below. In some aspects, the present invention provides methods for preparing intermediates for the synthesis of 4,6-substituted IP4 derivatives of the present invention (e.g., compounds selected from the group consisting of Compounds 1 to 53), comprising the step of applying Synthetic Scheme 2 disclosed below. In some aspects, the present invention provides methods for preparing intermediates for the synthesis of 4,6-substituted IP4 derivatives of the present invention (e.g., compounds selected from the group consisting of Compounds 1 to 53), comprising the step of applying Synthetic Scheme 3 disclosed below. In some aspects, the present invention provides methods for preparing intermediates for the synthesis of 4,6-substituted IP4 derivatives of the present invention (e.g., compounds selected from the group consisting of Compounds 1 to 53), comprising the step of applying Synthetic Scheme 4 disclosed below.

[0139] Scheme 1: The 4,6-substituted IP4 derivatives of the present invention can be obtained, for example, by deprotection of intermediates of formula IV (e.g., intermediates IV-1 to IV-48) and intermediates of formula IV' (e.g., intermediates IV'-1 to IV'-2). See Scheme 1, Figure 6. The "protecting group" or PG can be, but is not limited to, benzyl, levulinylbenzyl, tert-butyl, o-xylenyl (e.g., by binding two PGs to the same phosphate), 9-fluorenylmethyl, cyanoethyl, and other suitable protecting groups in each case. Intermediates of formula IV (e.g., intermediates IV-1 to IV-48) can be obtained, for example, by phosphorylation of intermediates of formula III according to procedures described in the literature, for example, by reaction with a phosphoramidite derivative followed by oxidation with an oxidizing agent (e.g., m-CPBA, HO, tBuOOH). Intermediates of formula IV' (e.g., intermediates IV'-1 to IV'-2) can be obtained, for example, by thiophosphorylation of intermediates of formula III according to procedures described in the art, for example, by reaction with a phosphoramidite derivative followed by thiooxidation with sulfur. Similarly, intermediates of formula III (e.g., intermediates III-1 to III-47) can be obtained, for example, by hydrolysis of intermediates of formula II (e.g., intermediates II-1 to II-27) in an acidic medium. Finally, intermediates of formula II (e.g., intermediates II-1 to II-27) can be obtained, for example, by 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). The "leaving group" or LG can be, but is not limited to, chloride, bromide, iodide, toluenesulfonyl (Ts) or methylsulfonyl (Ms).

[0140] Scheme 2: As an alternative to Scheme 1, for example, when R5 and R9 contain a substituted 1,2,3-triazole, compounds of Formula I (i.e., 4,6-substituted IP4 derivatives of the present invention) can be obtained by following the alternative route described in Scheme 2 (Figure 7). In this method, intermediates of Formula III (e.g., intermediates III-20, III-26, and III-27) can be obtained via a click reaction, for example, by using an intermediate of Formula VI (e.g., intermediate VI-1) and any of the alkylating agents as starting materials. Intermediate VI (e.g., intermediate VI-1) can be achieved by alkylation of intermediate 2 with an appropriate reagent and hydrolysis.

[0141] Scheme 3: As an alternative to Schemes 1 and 2, for example, when R5 and R9 contain a substituted 1,2,3-triazole, compounds of Formula I (i.e., 4,6-substituted IP4 derivatives of the present invention) can be obtained by an alternative route described in Scheme 3 (FIG. 8). In this case, intermediates of Formula III (e.g., intermediates III-21 to III-25, III-42, and III-43) can be obtained via a click reaction, for example, by using intermediates of Formula IX (e.g., intermediates IX-1 to IX-5) and an alkynyl click agent as starting materials. Intermediate IX can be obtained by alkylation of compound 2 with an azide alkylating agent and hydrolysis. As an alternative to Scheme 1, when R5 and R9 contain an amine group, compounds of Formula I (i.e., 4,6-substituted IP4 derivatives of the present invention) can be obtained as shown in Scheme 3 (FIG. 8). Thus, intermediate IX (e.g., intermediates IX-1 to IX-5) can be phosphorylated to provide intermediate X (e.g., intermediates X-1 to X-3), which can then be deprotected to provide a compound of formula I.

[0142]

[0109] Scheme 4: As a further alternative to Scheme 1, when R5 and R9 contain a substituted amide, sulfonamide, carbamate, or urea, intermediate III (e.g., intermediates III-28, III-36 to III-41, and III-44 to III-46) can be obtained as shown in Figure 9. Thus, intermediate III (e.g., intermediates III-28, III-36 to III-41, and III-44 to III-46) can be achieved from intermediate VIII (e.g., intermediates VIII-1 to VIII-5) via azide reduction (e.g., intermediates XI-1 to XI-2), followed by deprotection (e.g., intermediate XII-1), and finally, reaction of intermediate XII (e.g., intermediate XII-1) with an appropriate reagent to form the amide / sulfonamide / urea or carbamate. Alternatively, the reaction sequence can be changed to first obtain the amide / sulfonamide / urea or carbamate from intermediate XIII (eg, intermediates XIII-1 to XIII-3), and then achieve intermediate III by hydrolysis.

[0143] Any alkylating or click agent (including azide or alkynyl) and reagents used for amide, sulfonamide, urea, or carbamate formation can be commercially available or can be obtained by the following reactions well known in the art of organic chemistry: In some embodiments, methods include, but are not limited to, the general procedure shown in Scheme 5 (Figure 10).

[0144] Representative 4,6-substituted IP4 derivatives of the invention (e.g., compounds selected from the group consisting of Compounds 1 through 53) are shown herein, all of which are in the myo conformation. However, it should be understood that any exemplary 4,6-substituted IP4 derivatives of the invention in the myo conformation are not limited to the representative conformation shown. Thus, for example, Compounds 1 through 53 and intermediates shown herein also encompass equivalents corresponding to 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 greatest number of hydroxyls are shifted to the equatorial positions furthest from each other. In this conformation, the naturally occurring myo isomer has a structure in which five of the six hydroxyls (the first, third, fourth, fifth, and sixth) are equatorial, while the second hydroxyl group is axial.

[0145] The present invention also provides a method for producing a medicament for the treatment of pathological crystallization, comprising the step of using an intermediate compound selected from the group consisting of the compounds listed in Table 1. Also provided is a compound of Formula I (e.g., selected from the group consisting of Compounds 1 to 53) for use as a medicament. Also provided is the use of a compound of Formula I (e.g., selected from the group consisting of Compounds 1 to 53) for the manufacture of a medicament for preventing or treating a disease associated with pathological crystallization.

[0146] III. Pharmaceutical Compositions The present invention also provides pharmaceutical compositions for use in methods for preventing and / or treating the diseases and conditions (e.g., pathological calcification) disclosed herein, the pharmaceutical compositions comprising at least one 4,6-substituted IP4 derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 through Compound 53). In some embodiments, the pharmaceutical compositions comprise a 4,6-substituted IP4 derivative of the present invention (e.g., a compound selected from the group consisting of Compound 1 through Compound 53), alone or in combination with one or more pharmaceutically acceptable excipients or carriers.

[0147]

[0114] The term "excipient," as used herein, refers to a substance that aids in the absorption of an element of a pharmaceutical composition, stabilizes said element, or 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 (e.g., benzalkonium chloride, metacresol, thimerosal), cosolvents (e.g., ethanol), buffers, tonicity agents (e.g., NaCl), and pH adjusters (e.g., carbonate, citrate, phosphate solutions).

[0148] As in the case of excipients, a "pharmaceutically acceptable vehicle" is a substance used in a composition to dilute any of the ingredients contained therein to a determined volume or weight (e.g., 0.9% (w / v) NaCl aqueous solution). A pharmaceutically acceptable vehicle is an inert substance or a substance that contains a similar effect on any of the elements comprising the pharmaceutical composition of the present invention. The role of the vehicle is to allow the incorporation of other elements, to allow for better dosing and administration, or to provide consistency and shape to the composition.

[0149] Pharmaceutical compositions may contain from about 1% to about 95% of the active ingredient. In some embodiments, for example, pharmaceutical compositions of the present invention may contain from about 20% to about 90% of the active ingredient (i.e., a 4,6-substituted IP4 derivative of the present invention, or a combination thereof, alone or in combination with, for example, one or more additional therapeutic agents).

[0150] Pharmaceutical compositions suitable for parenteral administration include the active ingredient, e.g., a 4,6-substituted IP4 derivative of the present invention (e.g., a compound selected from the group consisting of Compounds 1 through 53), combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline (e.g., 0.9% (w / v) NaCl solution). Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampoules or 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 may further comprise one or more additional ingredients, including, but not limited to, suspending agents, stabilizing agents, or dispersing agents.

[0151] In some embodiments, in formulations for parenteral administration, the active ingredient, e.g., a 4,6-substituted IP4 derivative of the present invention (e.g., a compound selected from the group consisting of Compounds 1 through 53), is provided in a dry (i.e., powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

[0152]

[0119] Pharmaceutical compositions can be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. These suspensions or solutions can be formulated according to conventional techniques and may contain, in addition to the active ingredient (e.g., the inositol phosphates of the present invention), additional ingredients such as dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable preparations 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 such as synthetic mono- or diglycerides.

[0153] Other useful administrable formulations include those containing the active ingredient in microcrystalline form, in a liposomal formulation, or as a component of a biodegradable polymer system. Sustained-release or implantable compositions may contain pharmaceutically acceptable polymeric or hydrophobic materials, such as emulsions, ion-exchange resins, sparingly soluble polymers, or sparingly soluble salts. Methods for making compositions and formulations for administering the 4,6-substituted IP4 derivatives of the present invention, including controlled- 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, 1999. Press; US6340475, US6488962, US6451808, US5972389, US5582837, and US5007790; US20030147952, US20030104062, US20030104053, US20030044466, US20030039688, and US20020051820; WO2003035041, WO200303504 0, WO2003035029, WO2003035177, WO2003035039, WO2002096404, WO2002032416, WO2001097783, WO2001056544, WO2001032217, WO1998055107, WO1998011879, WO1997047285, WO1993018755, and WO1990011757.

[0154]

[0121] The medicaments according to the present invention are manufactured by methods known in the art, inter alia, by conventional mixing, coating, granulating, dissolving, or lyophilizing processes.

[0155]

[0122] The present invention also provides a compound or a combination of compounds or a pharmaceutical formulation for use as a pharmaceutical according to any of the above-mentioned aspects of the invention, in the broadest definition given or as specified in any of the aspects presented above.

[0156]

[0123] The present invention also provides a compound or a combination of compounds or a pharmaceutical formulation for use in the treatment and / or prevention of a disease or condition disclosed herein in its broadest definition given or as specified in any of the aspects presented above, according to any of the above-mentioned aspects of the invention.

[0157]

[0124] The present invention also provides a compound or a combination of compounds or a pharmaceutical formulation for the manufacture of a medicament for preventing and / or treating a disease or condition disclosed herein in its broadest definition given or as specified in any of the aspects presented above, according to any of the above-mentioned aspects of the invention.

[0158] IV. Manufactured Articles and Kits The present invention also provides articles of manufacture and kits. Such articles of manufacture and kits may include a container (e.g., a box) containing one or more vials containing a formulation comprising one or more of the 4,6-substituted IP4 derivatives of the present invention (e.g., a compound selected from the group consisting of Compounds 1-53) and / or solvents, for pharmaceutical administration thereof according to the methods disclosed herein or for other uses.

[0159] Kits or articles of manufacture provided by the present invention may also include pamphlets or instructions describing the drug administration processes and dosages disclosed herein or the use of a 4,6-substituted IP4 derivative of the present invention (e.g., a compound selected from the group consisting of Compounds 1-53) in accordance with the methods disclosed herein. In some embodiments, the kit or article of manufacture may include multiple vials, each containing a single dose. In other embodiments, the kit or article of manufacture may include one or more vials, each containing two or more doses.

[0160] In some embodiments, the article of manufacture is a bag containing a solution of a 4,6-substituted IP4 derivative of the invention (e.g., a compound selected from the group consisting of Compound 1-53). In other embodiments, the article of manufacture is a bottle (e.g., a glass or plastic bottle) containing a solution of a 4,6-substituted IP4 derivative of the invention (e.g., a compound selected from the group consisting of Compound 1-53). In some embodiments, the article of manufacture is a bag containing a 4,6-substituted IP4 derivative of the invention (e.g., a compound selected from the group consisting of Compound 1-53) in powder form for reconstitution with an appropriate solvent. In other embodiments, the article of manufacture is a bottle (e.g., a glass or plastic bottle) containing a 4,6-substituted IP4 derivative of the invention (e.g., a compound selected from the group consisting of Compound 1-53) in powder form for reconstitution with an appropriate solvent.

[0161]

[0128] Kits and articles of manufacture may include instructions for carrying out one or more administrations of a 4,6-substituted IP4 derivative of the present invention (e.g., a compound selected from the group consisting of Compounds 1 through 53) according to the methods and dosages disclosed herein.

[0162]

[0129] Instructions included with kits and articles of manufacture can be affixed to packaging material or can be included in a package insert. Instructions are typically, but not limited to, written or printed. Any medium capable of storing such instructions and transmitting them to an end user is also contemplated. Such media include, but are not limited to, electronic storage media (e.g., magnetic disks, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. As used herein, the term "instructions" can include the address of an internet site that provides the instructions.

[0163] V. Uses of 4,6-substituted IP4 derivatives of formula I The present invention provides methods for using the 4,6-substituted IP4 derivatives of the present invention (e.g., compounds selected from the group consisting of Compounds 1-53) to treat diseases and conditions. In some aspects, the medical uses disclosed herein relate to the ability of the 4,6-substituted IP4 derivatives of the present invention (e.g., compounds selected from the group consisting of Compounds 1-53) to (i) inhibit the formation or growth of calcium salts / crystals (e.g., calcium phosphate, HAP) and / or (ii) restore or increase blood perfusion in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutical composition disclosed herein. Thus, the 4,6-substituted IP4 derivatives of the present invention (e.g., compounds selected from the group consisting of Compounds 1-53) can be used to treat and prevent diseases and conditions associated with pathological crystallization. See Figure 1.

[0164]

[0131] The present invention provides a method for treating and / or preventing pathological crystallization and / or its consequences in a subject in need thereof, comprising the step of administering a 4,6-substituted IP4 derivative of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53), wherein administration of the 4,6-substituted IP4 derivative effectively treats and / or prevents pathological crystallization and / or its consequences in the subject.

[0165] The present invention also provides a method for manufacturing a medicament for the treatment of pathological crystallization, comprising the step of using an intermediate compound selected from the group consisting of the compounds listed in Table 1. Also provided is a compound selected from the group consisting of Compound 1 to Compound 53 for treating pathological crystallization and / or its consequences in a subject in need thereof.

[0166]

[0133] In some embodiments, the 4,6-substituted IP4 derivatives of the present invention (eg, a compound selected from the group consisting of Compounds 1 to 53) can be administered topically, enterally, or parenterally.

[0167] A. Synthesis of Protected myo-Inositol Agents, Alkylating or Click Agents, and Activated Acids A.1. Synthesis of Protected myo-inositol Agents (1) and (2) 1,3,5-O-Methylidine-myo-inositol (1): The synthesis of (1) was previously described in the literature (Martin S et al., J. Org. Chem. 1994;59(17):4805-4820).

[0168] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methylidine-myo-inositol (2): The synthesis of (2) was previously described in the literature (Kadirvel M et al., Org. Biomol. Chem. 2008;6(11):1966-1972).

[0169] A.2. Synthesis of Alkylating or Click Agents (((10-Bromodecyl)oxy)methyl)benzene (4): The synthesis of (4) was previously described in the literature (Hanbali M. et al., Bioorg. Med. Chem. Letters 2006;16(10):2637-2640).

[0170] (((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).

[0171] 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%). 1H 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). 9-Methoxynonyl 4-methylbenzenesulfonate (7) 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) (83% yield). 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). 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 give 2.15 g of (7) (76%). 1H 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). 3-Azidopropyl 4-methylbenzenesulfonate (8): To a solution of 3-azidopropan-1-ol (1 g, 9.89 mmol) in DCM (0.2 M) at 0 °C was added 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 give 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). 5-Azidopentyl 4-methylbenzenesulfonate (10) 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 NaSO, filtered, and concentrated in vacuo to give 57 mg of (9) (50%). 1H 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). 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 was 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] + .

[0172] 10-Azidodecyl 4-methylbenzenesulfonate (12) 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 0.2 M DMF 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 NaSO, filtered, and concentrated in vacuo to give 388 mg of 11 (92%). 1 H 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). Step 2: 10-Azidodecyl 4-methylbenzenesulfonate (12): To a solution of (11) (388 mg, 1.95 mmol) in DCM (0.2 M) at 0 °C was added TEA (407 μL, 2.92 mmol) and Ts-Cl (371 mg, 1.95 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 Na SO , 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 H NMR (400 MHz, chloroform-d) δ 7.79 (d, J = 8.1 Hz, 2H), 7.34 (d, J =8.1 Hz, 2H), 4.02 (t, J = 6.4 Hz, 2H), 3.25 (t, J = 6.8 Hz, 2H), 2.45 (s, 3H),1.63 (p, J = 6.4 Hz, 2H), 1.59 (p, = 6.8 Hz, 2H), 1.35- 1.15 (m, 12H). 1-(5-Bromopentyl)-1H-pyrazole (13): To a mixture of 1H-pyrazole (0.78 g, 11.49 mmol) and CsCO (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]. + .

[0173] 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 CsCO (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 (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]. + .

[0174] Benzyl 3-azidopropanoate (15): To a solution of 3-azidopropanoic acid (1.62 mL, 17.38 mmol) in DMF (1 M) was added (bromomethyl)benzene (4.1 mL, 34.8 mmol), followed by the dropwise addition of TEA (7.3 mL, 52.1 mmol). After stirring at room temperature for 1 day, the mixture was concentrated, diluted with EtOAc, washed with NaCO (1×), water (3×), and brine (1×), dried over NaSO, 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). 6-Azidohexyl 4-methylbenzenesulfonate (17) 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 0.8 M DMF 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 NaSO, filtered, and concentrated in vacuo to give 470 mg of 16 (>99%). 1H 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). 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 NaHSO. The aqueous phase was extracted with EtOAc (3×). The combined layers were washed with a saturated aqueous solution of NaHCO and dried over anhydrous NaSO. 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 H 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) 4-Azidobutyl 4-methylbenzenesulfonate (19) 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 0.8 M DMF 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 NaSO, filtered, and concentrated in vacuo to give 213 mg of 18 (56%). 1H 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). 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. It was diluted with EtOAc and washed with a 10% aqueous solution of NaHCO. The aqueous phase was extracted with EtOAc (3×). The combined layers were dried over anhydrous NaSO. 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 H NMR (400 MHz, chloroform-d) δ 7.79 (d, J = 8 Hz, 2H),7.36 (d, J = 8Hz, 2H), 4.06 (td, J = 6.1, 0.8 Hz, 2H), 3.26 (t, J = 6.6 Hz, 2H), 2.46 (s,3H), 1.81-1.68 (m, 2H), 1.68-1.60 (m, 2H). 1-(4-(2-Chloroethyl)piperazin-1-yl)ethanone (20): To a solution of 1-(4-(2-hydroxyethyl)piperazin-1-yl)ethanone (1.74 g, 10.10 mmol) in DCM (0.2 M) at 0° C. was added TEA (2.1 mL, 15.15 mmol) and Ts-Cl (2.31 g, 12.12 mmol). The reaction mixture was stirred at room temperature for 72 h and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, DCM:MeOH 95:5) to give 1.28 g of 20 (66%). HPLC-MS (Condition A): RT=0.24 min; m / z: 191, 193 [M, M+2]. + .

[0175] 2-Cyclopropylethyl 4-methylbenzenesulfonate (21): To a solution of 2-cyclopropylethanol (3 mL, 34.0 mmol) in DCM (85 mL) was added TEA (7.10 mL, 50.9 mmol) and Ts-Cl (7.77 g, 40.8 mmol), and the resulting mixture was stirred for 18 h. Water was added to the reaction mixture, which was then extracted with DCM (2×). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hex-EtOAc, 4:1) to give 6.23 g of 21 (76%). 1 H NMR (400 MHz, chloroform-d) δ 7.78 (d, J = 8.2 Hz, 2H), 7.32 (d, J =8.2 Hz, 2H), 4.06 (t, J = 6.8 Hz, 2H), 2.43 (s, 3H), 1.51 (q, J = 6.8 Hz, 2H),0.63 (m, 1H), 0.38 (ddd, J = 8, 6, 4 Hz, 2H), -0.01 (dt, J = 6, 4 Hz, 2H). 2-Cyclopentylethyl 4-methylbenzenesulfonate (22): To a solution of 2-cyclopentylethanol (1.09 mL, 8.76 mmol) in DCM (22 mL) was added TEA (1.83 mL, 13.1 mmol) and Ts-Cl (2.00 g, 10.5 mmol), and the resulting mixture was stirred for 18 h. Water was added to the reaction mixture, which was then extracted with DCM (2×). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hex-EtOAc, 4:1) to give 1.53 g of 22 (65%). 1 H NMR (400 MHz, chloroform-d) δ 7.81 (d, J = 8 Hz, 2H), 7.37 (d, J = 8Hz, 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). 3-(4-Methoxyphenyl)propyl 4-methylbenzenesulfonate (23): To a solution of 3-(4-methoxyphenyl)propan-1-ol (0.96 mL, 6.02 mmol) in DCM (15 mL) was added TEA (1.26 mL, 9.02 mmol) and Ts-Cl (1.38 g, 7.22 mmol), and the resulting mixture was stirred for 18 h. Water was added to the reaction mixture, which was then extracted with DCM (2×). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hex-EtOAc, 4:1) to give 1.59 g of 23 (82%). 1 H NMR (400 MHz, chloroform-d) δ 7.81 (d, J = 8 Hz, 2H), 7.37 (d, J = 8Hz, 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). 3-(3-(trifluoromethyl)phenyl)propyl 4-methylbenzenesulfonate (24): To a solution of 3-(3-(trifluoromethyl)phenyl)propan-1-ol (0.91 mL, 4.90 mmol) in DCM (12 mL) was added TEA (1.02 mL, 7.35 mmol) and Ts-Cl (1.12 g, 5.88 mmol), and the resulting mixture was stirred for 18 h. Water was added to the reaction mixture, which was then extracted with DCM (2×). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hex-EtOAc, 4:1) to afford 1.53 g of 24 (87%). 1H 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, 7.6Hz, 2H), 2.29 (s, 3H), 1.81(ddt, J = 8.0, 7.6, 6.2 Hz, 2H). 3-(p-Tolyl)propyl 4-methylbenzenesulfonate (25): To a solution of 3-(p-tolyl)propan-1-ol (1 g, 6.66 mmol) in DCM (17 mL) was added TEA (1.39 mL, 9.99 mmol) and Ts-Cl (1.52 g, 7.99 mmol), and the resulting mixture was stirred for 18 h. Water was added to the reaction mixture, which was then extracted with DCM (2×). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hex-EtOAc, 4:1) to give 1.85 g of 25 (87%). 1 H 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). 19-Methoxynonadec-10-yn-1-yl 4-methylbenzenesulfonate (31) Step 1: 2-((9-Bromonoyl)oxy)tetrahydro-2H-pyran (26): To a solution of 9-bromononan-1-ol (6.17 g, 27.6 mmol) and 2,3-dihydro-2H-pyran (3.78 mL, 23 mmol) was added p-TSA (105 mg, 0.55 mmol). The mixture was stirred at room temperature for 18 h. The mixture was diluted with NaCO3 IN, extracted with ethyl ether (2x), dried over Na2SO4, filtered, and the solvent removed in vacuo. The filtrate was concentrated and purified by column chromatography (0-5% EtOAc in Hex) to give 6.31 g of 26 (74%). 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). Step 2: Dec-9-yn-1-yl methanesulfonate (27): To a stirred solution of dec-9-yn-1-ol (3.45 mL, 19.5 mmol) in THF (56 mL) was added TEA (3.52 mL, 25.3 mmol) and methanesulfonyl chloride (1.97 mL, 25.3 mmol) dropwise at 0° C. under a nitrogen atmosphere. The reaction was continued to stir 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 NaSO, filtered, and evaporated under reduced pressure to give 4.45 g of (27) (98%). HPLC-MS (Condition A): RT = 3.58 min.

[0176] Step 3: 10-Methoxydec-1-yne (28): To a stirred solution of sodium methoxide 5 M in MeOH, 27 (4.45 g, 19.1 mmol) was added and stirring continued at 45 °C for 18 h. The suspension was then dissolved in water and extracted with EtO (2x). The organic layer was dried over NaSO and evaporated to dryness. The crude product was purified by column chromatography (5% EtOAc in Hex) to give 28 (2.58 g, 80%). 1H 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). Step 4: 2-((19-Methoxynonadec-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 at −40° C., n-BuLi (15.5 mL, 24.8 mmol) was slowly added, followed by stirring for 30 min at the same temperature and another 30 min at 0° C. 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 for 10 min at the same temperature, the temperature was allowed to rise to room temperature. Stirring was continued for 18 h at the same temperature. With ice cooling (at 4° C.), 10% aqueous HCl was added, followed by extraction with tBuMeO (3×). The ether layer was washed with saturated brine and further dried over anhydrous MgSO4. After filtration, the solvent was evaporated under reduced pressure to give a yellow oil, and the residue was purified by column chromatography with EtOAc / Hex (1:20) to give 29 (2.36 g, 30%). 1 H NMR (400 MHz, chloroform-d) δ 4.55 (dd, J = 4.4, 2.8 Hz, 1H), 3.86-3.74 (m, 1H), 3.70 (dt, J = 9.6, 6.8 Hz, 1H), 3.52-3.46 (m, 1H), 3.39-3.33 (m, 3H), 3.31 (s, 3H), 2.11 (td, J = 7.2, 2.1 Hz, 2H), 1.86-1.78 (m, 1H), 1.74-1.65 (m, 1H), 1.53-1.26 (m, 31H), 0.86-0.83 (m, 1H). Step 5: 19-Methoxynonadec-10-yn-1-ol (30): To a solution of (29) (2.36 g, 6 mmol) in MeOH (10 mL) was added p-TSA (68 mg, 0.36 mmol) portionwise. The resulting solution was stirred at 60 °C for 16 h and then concentrated in vacuo. The residue was dissolved in saturated aqueous NaHCO and extracted with tBuMeO (2x). The combined organic extracts were washed with brine solution and dried over NaSO. No further purification was required to give 1.32 g of (30) (71%). 1 H NMR (400 MHz, chloroform-d) δ 3.62 (t, J = 6.6 Hz, 2H), 3.34 (t, J = 6.7 Hz, 2H), 3.31 (s, 3H), 2.15-2.09 (m, 4H), 1.54 (m, 6H), 1.50-1.40 (m, 5H), 1.40-1.22 (m, 16H). Step 6: 19-Methoxynonadec-10-yn-1-yl 4-methylbenzenesulfonate (31): To a solution of (30) (1.32 g, 4.25 mmol) in THF (8.5 mL) was added Ts-Cl (973 mg, 5.10 mmol) and NaOH 5M (1.020 mL, 5.10 mmol), and the resulting mixture was stirred for 18 h. Water was added to the reaction mixture, which was then extracted with tBuMeO (2x). The combined organic layers were washed with water, brine, dried over NaSO, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hex-EtOAc, 6:1) to give 1.69 g of (31) (86%). 1 H NMR (400 MHz, chloroform-d) δ 7.65 (d, J = 8.2 Hz, 2H), 7.20 (d, J =8.2 Hz, 2H), 3.87 (t, J = 6.5 Hz, 2H), 3.22 (t, J = 6.7 Hz, 2H), 3.18 (s, 3H),2.31 (s, 3H), 2.00-1.96 (m, 4H), 1.52-1.45 (m, 2H), 1.44-1.38 (m, 2H),1.34-1.27 (m, 4H), 1.27-1.05 (m, 18H). A.3. Activated acid synthesis 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 NaSO, 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] + .

[0177] 2,5-Dioxopyrrolidin-1-ylthiophene-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 extracted with DCM (2×). The combined organic layers were washed with brine, dried over NaSO, 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 Procedure A: To a solution of (2) (1 eq) in DMF (0.2 M) at 0° C. was added NaH (2.15 eq). When the addition was complete, the mixture was stirred at room temperature for 5 min. Finally, the alkylating agent was added. The reaction 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 give the pure compound.

[0178] Procedure B: To a solution of (2) (1 equiv.) in DMF (0.2 M) at 0° C., LiH was added. When the addition was complete, the mixture was stirred at room temperature for 5 minutes. Finally, an alkylating agent was added. The reaction 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 give the pure compound.

[0179] B.2. Hydrolysis Procedure Procedure C: Intermediate (II), (V), (VIII), (XI), or (XIII) (1 equivalent) was dissolved in a mixture of methanol / water / DCM / trifluoroacetic acid (3:1:1:1, 0.1 M), and the solution was stirred at room temperature overnight. Finally, the solvent and excess TFA were removed under vacuum to give the desired compound.

[0180] Procedure D: Intermediate (II), (V), (VIII), (XI), or (XIII) (1 equivalent) 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. The solvent and excess TFA were then removed under vacuum. Finally, the residue was dissolved in methanol (MeOH), treated with IRA-400 resin until the pH was basic, filtered, and the solvent was removed under vacuum to give the desired compound.

[0181] Procedure E: To a solution of intermediate (II), (V), (VIII), (XI), or (XIII) (1 equivalent) in THF (c=0.1 M) was added a solution of 0.1 M TBAF in THF (1.2 equivalents). The reaction mixture was stirred at room temperature for 18 hours, quenched with water, and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in a mixture of MeOH / water / DCM / TFA (3:1:1:1, 0.1 M), and the solution was stirred at room temperature overnight. The solvent and excess TFA were then removed in vacuo. Finally, the residue was dissolved in methanol (MeOH), treated with IRA-400 resin until the pH was basic, filtered, and the solvent was removed in vacuo to give the desired compound.

[0182] Procedure F: Intermediate (II), (V), (VIII), (XI), or (XIII) (1 equivalent) was dissolved in a mixture of DCM / TFA (4:1, 0.14 M), and the solution was stirred at room temperature for 1 hour. Water was then added (final concentration 0.1 M), and the reaction mixture was stirred at room temperature for 18 hours. Finally, the layers were separated, and the aqueous layer was concentrated in vacuo to give the desired compound.

[0183] Procedure S: Intermediate (II), (V), (VIII), (XI) or (XIII) (1 equivalent) was dissolved in a mixture of MeOH / HCl 1N (10:1, 0.1 M) and the solution was stirred overnight at 60° C. Finally, the solvent and excess HCl were removed under vacuum to give the desired compound.

[0184] B.3. Click reaction procedure Procedure K: To a suspension of intermediate (VI) (1 equiv.) and CuI (0.03 equiv.) in DCM (0.1 M) was added a solution of azide reagent (2 equiv.), DIPEA (0.07 equiv.) and AcOH (0.07 equiv.) in DCM / MeOH (1 M). The reaction mixture was stirred under inert atmosphere at 35° C. for 20 h and concentrated in vacuo to give the desired compound.

[0185] Procedure L: To a solution of intermediate (VI) (1 equiv.), CuSO 5H O (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 under an inert atmosphere at room temperature for 20 h, filtered through Celite, and concentrated in vacuo. The residue was treated with water / DCM. The organic layer was then dried over Na SO , filtered, and concentrated in vacuo to give the desired compound.

[0186] Procedure M: To a solution of intermediate (IX) (1 equiv.), CuSO 4 ·5H 2 O (0.4 equiv.), and sodium ascorbate (0.6 equiv.) in water (0.07 M) was added a solution of an alkynyl reagent (2 equiv.) in THF (0.35 M). The reaction mixture was stirred under an inert atmosphere at room temperature for 24 h, filtered through Celite, and concentrated in vacuo. The residue was dissolved in MeOH, treated with IRA-400 resin until the pH was basic, filtered, and the solvent was removed in vacuo to give the desired compound.

[0187] B.4. Group Transformation Procedures Procedure N: A mixture of intermediate (VII) (1 equiv.) and sodium methoxide 25% (3 equiv.) in MeOH (0.1 M) was stirred for 18 h at 40° C. The reaction mixture was diluted with water / DCM and the organic layer was dried over NaSO, filtered and concentrated in vacuo to give the desired compound.

[0188] B.5. Azide Reduction Procedure Procedure Q: To a solution of intermediate (VIII) (1 equivalent) in a mixture of THF / water (9:1, 0.08 M) was added DIPEA (3 equivalents) and PPh (2.6 equivalents). The reaction mixture was stirred at 60° C. for 4 hours, then quenched with water and washed with brine. The organic layer was dried over NaSO, filtered, and concentrated in vacuo to give the desired compound.

[0189] B.6. Amide Formation Procedure Procedure P: To a solution of intermediate (XI) or (XII) (1 equivalent) in DMF (0.1 M) was added TEA (4 equivalents) and activated acid (2 equivalents). The reaction mixture was stirred at room temperature for 4 hours and concentrated in vacuo. The residue was dissolved in MeOH, treated with IRA-400 resin until the pH was basic, filtered, and the solvent was removed in vacuo. Finally, the residue was purified by flash chromatography (silica gel) to give the pure compound.

[0190] B.7. Urea Formation Procedure Procedure H: Intermediate (XI) or (XII) (1 equivalent) was dissolved in MeOH, treated with IRA-400 resin until the pH was basic, filtered, and the solvent was removed in vacuo. The residue was dissolved in EtOH (0.1 M) and an isocyanate reagent (2 equivalents) was added. The reaction mixture was stirred at 60° C. for 24 hours and concentrated in vacuo to give the pure compound.

[0191] B.8. Carbamate Formation Procedure

[0187] Procedure V: Intermediate (XI) or (XII) (1 equivalent) was dissolved in MeOH and treated with IRA-400 resin until the pH was basic. The solution was then filtered, and the solvent was removed under vacuum. The residue was dissolved in MeOH (1 M) and dimethyl carbonate (40 equivalents), and tetrabutylammonium bromide (0.1 equivalents) and L-proline (0.1 equivalents) were added. The reaction mixture was stirred at 60°C for 48 hours and concentrated. The residue was treated with water and DCM, and the aqueous layer was concentrated in vacuo. The residue was dissolved in MeOH and treated with DOWEX resin until the pH was acidic. The solution was then filtered, and the solvent was removed under vacuum to give the desired compound.

[0192] B.9. Phosphorylation or Thiophosphorylation Procedures 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 reach 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 crystallization to give the pure compound.

[0193] 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. N,N-diethyl-1,5-dihydrobenzo[e][1,3,2]-dioxaphosphepin-3-amine (5-7.2 equivalents) was then 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 crystallization to give the pure compound.

[0194] B.10. Phosphate or Thiophosphate Deprotection Procedures Procedure I: Phosphorylated compound (IV) or (X) was dissolved in a mixture of THF / MeOH / water (3:1:1, 0.01 M), followed by the addition of excess palladium hydroxide 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. The compounds were purified on a Sephadex column (PD-10, G-25-M) by adding dilute aqueous NaOH (1N) to a pH of 9-10 and eluting the residue with water. All fractions were lyophilized and lyophilized. 1 The fractions containing the product were further purified on a reversed-phase cartridge (Sep-Pack® C18 cartridge, 1 g, Waters Corp., Milford, MA, USA) by eluting with water. All fractions were lyophilized and analyzed by H-RMN. 1 Analyzed by H-RMN.

[0195] Procedure J: Phosphorylated compound (IV) or (X) was dissolved in a mixture of THF / MeOH / water (3:1:1, 0.01 M), followed by the addition of excess palladium hydroxide 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. The compound was brought to pH 10 by the addition of dilute aqueous NaOH (1N), 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 lyophilized. 1 The fractions containing the product were further purified on a reversed-phase cartridge (Sep-Pack® C18 cartridge, 1 g, Waters Corp., Milford, MA, USA) by eluting with water. All fractions were lyophilized and analyzed by H-RMN. 1 Analyzed by H-RMN.

[0196] Procedure U: Phosphorylated or thiophosphorylated compound (IV), (IV'), or (X) was treated with thiophenol (40 equiv.), m-cresol (40 equiv.) in TFA (0.045 M). TBMSBr (40 equiv.) was then slowly added, and the mixture was stirred at room temperature for 4 h, quenched with water, and extracted with DCM (3x). The aqueous layer was concentrated in vacuo. The residue was purified on a Sephadex column (PD-10, G-25-M) by adding water and diluted aqueous NaOH (1N) to bring the pH to 9-10, and eluting the compound with water. All fractions were lyophilized and lyophilized. 1 The fractions containing the product were further purified on a reversed-phase cartridge (Sep-Pack® C18 cartridge, 1 g, Waters Corp., Milford, MA, USA) by eluting with water. All fractions were lyophilized and analyzed by H-RMN. 1 Analyzed by H-RMN.

[0197] C. Synthesis of Intermediates II-XIII C.1. Intermediate II 4,6-O-Bis(5-(benzyloxy)pentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidine-myo-inositol (II-1): General alkylation procedure A gave 202 mg of (II-1) (18.3%) from 1.04 mL (3 eq) of (((5-bromopentyl)oxy)methyl)benzene. HPLC-MS (Condition A): RT = 6.30 min; m / z: 657 [M+1] + , 679[M+23] + .

[0198] 4,6-O-bis(10-(benzyloxy)decyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidine-myo-inositol (II-2): General alkylation procedure A gave 75 mg of (II-2) (16%) from 408 mg (2 equivalents in 2 mL DMF) of (4). 1H NMR (400 MHz, chloroform-d) δ 7.39-7.25 (m, 10H), 5.53 (d, J = 1.2Hz, 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). 4,6-O-bis(14-(benzyloxy)tetradecyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidine-myo-inositol (II-3): General alkylation procedure A gave 37 mg of II-3 from 312 mg (2 equivalents in 1.4 mL DMF) of 5 (10%). 1 H 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). 2-O-tert-Butyldimethylsilyl-4,6-O-bis(3-methoxypropyl)-1,3,5-O-methylidine-myo-inositol (II-4): General alkylation procedure A gave 232 mg of (II-4) (52%) from 0.55 mL (5 equiv.) of 1-bromo-3-methoxypropane. HPLC-MS (Condition A): RT = 4.58 min; m / z: 449 [M+1] + , 471[M+23] + .

[0199] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(5-methoxypentyl)-1,3,5-O-methylidine-myo-inositol (II-5): General alkylation procedure A gave 21 mg of (II-5) (7%) from 241 mg (2.2 equiv., in 3 mL DMF) of 1-bromo-5-methoxypentane. HPLC-MS (Condition B): RT = 3.80 min; m / z: 505 [M+1] + , 527[M+23] + .

[0200] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(9-methoxynonyl)-1,3,5-O-methylidine-myo-inositol (II-6): General alkylation procedure A gave 194 mg of (II-6) (32%) from 803 mg (2.5 equiv. in 1.2 mL DMF) of (7). 1H 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). 2-O-tert-Butyldimethylsilyl-4,6-O-bis(7-methoxyheptyl)-1,3,5-O-methylidine-myo-inositol (II-7): General alkylation procedure A gave 398 mg of II-7 (47.6%) from 780 mg (2.5 equiv. in 1.5 mL DMF) of 6. HPLC-MS (Condition A): RT = 6.11 min; m / z: 561 [M+1] + , 583[M+23] + .

[0201] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methylidyne-4,6-O-dipropyl-myo-inositol (II-8): General alkylation procedure A gave 79.14 mg of (II-8) (21%) from 481 μL (5 equiv) of 1-iodopropane. 1H 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). 2-O-tert-Butyldimethylsilyl-1,3,5-O-methylidyne-4,6-O-dipentyl-myo-inositol (II-9): General alkylation procedure A gave 255 mg of (II-9) (58%) from 377 μL (3 equiv.) of 1-bromopentane. HPLC-MS (Condition A): RT = 6.38 min; m / z: 445 [M+1] + .

[0202] 2-O-tert-Butyldimethylsilyl-4,6-O-diheptyl-1,3,5-O-methylidine-myo-inositol (II-10): General alkylation procedure A gave 250 mg of (II-10) (70%) from 560 μL (5 equiv) of 1-bromoheptane. 1 H 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 = 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).

[0203] 2-O-tert-Butyldimethylsilyl-4,6-O-didecyl-1,3,5-O-methylidine-myo-inositol (II-11): General alkylation procedure A gave 272.6 mg of (II-11) (57%) from 511 μL (3 equiv.) of 1-bromodecane. 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 0.94 (s, 9H), 0.88 (t, J = 7.2 Hz6H), 0.14 (s, 6H).

[0204] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methylidyne-4,6-O-di(tetradecyl)-myo-inositol (II-12): General alkylation procedure A gave 350 mg of (II-12) (61%) from 670 μL (3 equiv.) of 1-bromotetradecane. 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 = 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).

[0205] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(5-ethoxycarbonylpentyl)-1,3,5-O-methylidine-myo-inositol (II-13): General alkylation procedure A was followed from 351 μL of ethyl 6-bromohexanoate (3 equiv.) to give 90 mg of (II-13) (23%). HPLC-MS (Condition A): RT = 5.46 min; m / z: 589 [M+1]. + , 611[M+23] + .

[0203]

[0206] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(10-ethoxycarbonyldecyl)-1,3,5-O-methylidine-myo-inositol (II-14): General alkylation procedure A gave 169 mg of (II-14) (34%) from 455 μL of ethyl 11-bromoundecanoate (2.5 equiv.). 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).

[0207] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methylidyne-4,6-O-bis(5-(1H-pyrazol-1-yl)pentyl)-myo-inositol (II-15): General alkylation procedure A gave 101 mg of II-15 (12%) from 450 mg of 12. HPLC-MS (Condition A): RT = 4.56 min; m / z: 578 [M+1]. + .

[0204]

[0208] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methylidyne-4,6-O-bis(5-(1H-1,2,4-triazol-1-yl)pentyl)-myo-inositol (II-16): General alkylation procedure A gave 60 mg of II-16 from 500 mg of 14 (6%). HPLC-MS (Condition A): RT = 3.70 min; m / z: 579 [M+1]. + .

[0205]

[0209] 4,6-O-bis(2-(4-acetylpiperazin-1-yl)ethyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidine-myo-inositol (II-17)

[0210] Step 1: rac-4-O-(2-(4-acetylpiperazin-1-yl)ethyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidine-myo-inositol (34): General alkylation procedure A gave 460 mg of 34 (68%) from 700 mg (2.5 equivalents in 7.3 mL of DMF) of 20 (2.5 equivalents in 7.3 mL of DMF). HPLC-MS (Condition A): RT = 1.90 min; m / z: 459 [M+1]. + .

[0206]

[0211] Step 2: 4,6-O-bis(2-(4-acetylpiperazin-1-yl)ethyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidine-myo-inositol (II-17): To a solution of 34 (279 mg, 0.61 mmol) in DMF (0.2 M) at 0 °C was added NaH (55.7 mg, 1.39 mmol). When the addition was complete, the mixture was stirred at room temperature for 5 min. Finally, a solution of 20 (309 mg, 1.62 mmol) in DMF (3.2 mL) was added. The reaction was warmed to 90 °C, stirred overnight, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, DCM:MeOH 95:5, 1% NH) to give 89 mg of II-17 (22%). HPLC-MS (Condition A): Room temperature = 1.56 min; m / z:613[M+1] + .

[0207]

[0212] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methylidyne-4,6-O-bis(4,4,4-trifluorobutyl)-myo-inositol (II-18): General alkylation procedure B gave 3.61 g of (II-18) (60% yield) from 4.2 mL (3 equiv.) of 4-bromo-1,1,1-trifluorobutane and 934 mg (10 equiv.) of LiH. HPLC-MS (Condition A): RT = 5.23 min; m / z: 525 [M+1]. + .

[0208]

[0213] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methylidyne-4,6-O-bis(6,6,6-trifluorohexyl)-myo-inositol (II-19): General alkylation procedure B gave 594 mg of (II-19) (48%) from 1.16 g (2.5 equiv.) of 6-bromo-1,1,1-trifluorohexane and 43 mg (2.5 equiv.) of LiH. HPLC-MS (Condition A): RT = 6.87 min; m / z: 573 [M+1]. + , 595[M+23] + .

[0209]

[0214] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methylidyne-4,6-O-bis(4-methylpentyl)-myo-inositol (II-20): General alkylation procedure B yielded 273 mg of (II-20) (20%) from 1 mL (2.5 equiv.) of 1-bromo-4-methylpentane and 58 mg (2.5 equiv.) of LiH. HPLC-MS (Condition A): RT = 5.77 min; m / z: 581 [M+1]. + .

[0210] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(19-methoxynonadec-10-yn-1-yl)-1,3,5-O-methylidine-myo-inositol (II-21): General alkylation procedure A gave 1.236 g of II-21 (55%) from 2.93 g (2.5 equiv.) of 31. 1H 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).

[0215] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(2-cyclopropylethyl)-1,3,5-O-methylidine-myo-inositol (II-22): General alkylation procedure B gave 3.1 g of II-22 (59.6%) from 6.24 g (2.2 equiv.) of 21 and 213 mg (2.2 equiv.) of LiH. HPLC-MS (Condition A): RT = 5.94 min; 441 [M+1] + , 563[M+23] + .

[0211]

[0216] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(2-cyclopentylethyl)-1,3,5-O-methylidine-myo-inositol (II-23): General alkylation procedure B gave 267 mg of II-23 (23.5%) from 1.53 g (2.5 equiv.) of 22 and 43 mg (2.5 equiv.) of LiH. HPLC-MS (Condition A): RT = 7.22 min; 497 [M+1]. + , 519[M+23] + .

[0212]

[0217] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(3-(4-methoxyphenyl)propyl)-1,3,5-O-methylidine-myo-inositol (II-24): General alkylation procedure B gave 60 mg of II-24 (5%) from 1.59 g (2.5 equiv.) of 23 and 41 mg (2.5 equiv.) of LiH. HPLC-MS (Condition A): RT = 5.80 min; 601.5 [M+1] + , 623.5[M+23] + .

[0213]

[0218] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methylidyne-4,6-O-bis(3-(3-(trifluoromethyl)phenyl)propyl)-myo-inositol (II-25): General alkylation procedure B gave 35 mg of II-25 (3%) from 1.53 g (2.5 equiv.) of 24 and 35 mg (2.5 equiv.) of LiH. HPLC-MS (Condition A): RT = 6.19 min; 677.4 [M+1] + , 699.4[M+23] + .

[0214]

[0219] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methylidyne-4,6-O-bis(3-(p-tolyl)propyl)-myo-inositol (II-26): General alkylation procedure B gave 261 mg of II-26 (19%) from 1.85 g (2.5 equiv.) of 25 and 50 mg (2.5 equiv.) of LiH. HPLC-MS (Condition A): RT = 6.45 min; 569.4 [M+1] + , 591.4[M+23] + .

[0215]

[0220] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(3-methoxycarbonylpropyl)-1,3,5-O-methylidine-myo-inositol (II-27): General alkylation procedure B gave 264 mg of (II-27) (15%) from 2.65 mL (6 equiv.) of methyl 4-bromobutanoate and 288 mg (10 equiv.) of LiH. HPLC-MS (Condition A): RT = 4.52 min; 505 [M+1] + .

[0216] C.2. Intermediate III

[0221] 4,6-O-bis(5-(benzyloxy)pentyl)-myo-inositol (III-1): General hydrolysis procedure C gave 163 mg of (III-1) from 202 mg of (II-1) (>99%). HPLC-MS (Condition A): RT = 3.59 min; m / z: 533 [M+1] + .

[0217]

[0222] 4,6-O-bis(5-methoxypentyl)-myo-inositol (III-2): General hydrolysis procedure C gave 348 mg of (III-2) from 510 mg of (II-5) (>99%). HPLC-MS (Condition A): RT = 2.69 min; m / z: 381 [M+1]. + , 403[M+23] + .

[0218]

[0223] 4,6-O-bis(10-(benzyloxy)decyl)-myo-inositol (III-3): General hydrolysis procedure D gave 51 mg of (III-3) from 75 mg of (II-2) (80%). 1H 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).

[0224] 4,6-O-bis(14-(benzyloxy)tetradecyl)-myo-inositol (III-4): General hydrolysis procedure D gave 14 mg of (III-4) from 16.5 mg of (II-3) (>99%). 1 H 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).

[0225] 4,6-O-bis(5-ethoxycarbonylpentyl)-myo-inositol (III-5): General hydrolysis procedure D gave 87.7 mg of III-5 (>99%) from 114 mg of II-13. HPLC-MS (Condition A): RT = 2.95 min; m / z: 465 [M+1] + .

[0219]

[0226] 4,6-O-bis(10-ethoxycarbonyldecyl)-myo-inositol (III-6): General hydrolysis procedure D gave 129 mg of III-6 from 166 mg of II-14 (94%). HPLC-MS (Condition A): RT = 4.47 min; m / z: 605 [M+1]. + .

[0220]

[0227] 4,6-O-bis(2-cyclopropylethyl)-myo-inositol (III-7): General hydrolysis procedure S gave 2.23 g of III-7 from 3.10 g of II-22 (100%). HPLC-MS (Condition A): RT = 2.82 min; m / z: 317 [M+1]. + , 339[M+23] + .

[0221]

[0228] 4,6-O-bis(2-cyclopentylethyl)-myo-inositol (III-8): General hydrolysis procedure S gave 201 mg of III-8 from 267 mg of II-23 (>99%). HPLC-MS (Condition A): RT = 3.50 min; m / z: 373 [M+1]. + , 395[M+23] + .

[0222]

[0229] 4,6-O-bis(5-(1H-pyrazol-1-yl)pentyl)-myo-inositol (III-9): General hydrolysis procedure D gave 67 mg of III-9 from 90 mg of II-15 (95%). HPLC-MS (Condition A): RT = 2.79 min; m / z: 453 [M+1] + .

[0223]

[0230] 4,6-O-bis(5-(1H-1,2,4-triazol-1-yl)pentyl)-myo-inositol (III-10): General hydrolysis procedure D gave 15 mg of III-10 from 19 mg of II-16 (>99%). HPLC-MS (Condition A): RT = 2.29 min; m / z: 455 [M+1]. + .

[0224]

[0231] 4,6-O-bis(2-(4-acetylpiperazin-1-yl)ethyl)-myo-inositol (III-11): General hydrolysis procedure C yielded 36 mg of III-11 from 45 mg of II-17 (>99%). HPLC-MS (Condition B): RT = 0.23 min; m / z: 489 [M+1]. + , 511[M+23] + .

[0225]

[0232] 4,6-O-bis(3-methoxypropyl)-myo-inositol (III-12): General hydrolysis procedure E gave 23 mg of III-12 from 232 mg of II-4 (13%). HPLC-MS (Condition A): RT = 1.83 min; m / z: 325 [M+1]. + .

[0226]

[0233] 4,6-O-bis(7-methoxyheptyl)-myo-inositol (III-13): General hydrolysis procedure E gave 321 mg of III-13 from 389 mg of II-7 (>99%). HPLC-MS (Condition A): RT = 3.14 min; m / z: 437 [M+1]. + .

[0227]

[0234] 4,6-O-bis(9-methoxynonyl)-myo-inositol (III-14): General hydrolysis procedure E gave 156 mg of III-14 from 194 mg of II-6 (>99%). HPLC-MS (Condition A): RT = 3.76 min; m / z: 493 [M+1]. + , 515[M+23] + .

[0228]

[0235] 4,6-O-Dipropyl-myo-inositol (III-15): General hydrolysis procedure E gave 26.3 mg of III-15 (49%) from 79 mg of II-8. HPLC-MS (Condition A): RT = 1.85 min; m / z: 265 [M+1] + , 287[M+23] + .

[0229]

[0236] 4,6-O-Dipentyl-myo-inositol (III-16): General hydrolysis procedure E gave 107 mg of III-16 (59%) from 255 mg of II-9. HPLC-MS (Condition A): RT = 3.00 min; m / z: 321 [M+1] + .

[0230]

[0237] 4,6-O-Diheptyl-myo-inositol (III-17): General hydrolysis procedure E gave 149 mg of III-17 (77%) from 250 mg of II-10. HPLC-MS (Condition A): RT = 3.89 min; m / z: 377 [M+1] + , 399[M+23] + .

[0231]

[0238] 4,6-O-Didecyl-myo-inositol (III-18): General hydrolysis procedure E gave 185 mg of III-18 (84%) from 272 mg of II-11. HPLC-MS (Condition A): RT = 5.36 min; m / z: 461 [M+1] + .

[0232]

[0239] 4,6-O-Di(tetradecyl)-myo-inositol (III-19): General hydrolysis procedure E gave 212 mg of (III-19) 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).

[0240] 4,6-O-bis((1-(2-(benzyloxycarbonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol (III-20): General click reaction procedure K was used to obtain 983 mg of (III-20) from 615 mg of (15) (98%). HPLC-MS (Condition A): RT = 3.18 min; m / z: 667 [M+1] + .

[0233]

[0241] 4,6-O-bis(3-(4-(2-(benzyloxycarbonyl)ethyl)-1H-1,2,3-triazol-1-yl)propyl)-myo-inositol (III-21): General click reaction procedure M gave 98 mg of III-21 (67%) from 70 mg of IX-3 and 76 mg of benzylpent-4-ynoate. Flash chromatography was used. HPLC-MS (condition B): room temperature = 2.37 min; m / z: 723 [M+1]. + .

[0234]

[0242] 4,6-O-bis(3-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)propyl)-myo-inositol (III-22): General click reaction procedure M yielded 35 mg of III-22 (61%) from 41 mg of IX-3 and 19 μL of 3-methoxypropion-1-yne. HPLC-MS (Condition A): room temperature = 2.32 min; m / z: 487 [M+1]. + .

[0235]

[0243] 4,6-O-bis(4-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)butyl)-myo-inositol (III-23): General click reaction procedure M yielded 13 mg of (III-23) (22%) from 43 mg of (IX-1) and 19 μL of 3-methoxypropion-1-yne. HPLC-MS (Condition A): room temperature = 2.40 min; m / z: 515 [M+1]. + .

[0236]

[0244] 4,6-O-bis(5-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-myo-inositol (III-24): General click reaction procedure M yielded 50 mg of III-24 (64%) from 58 mg of IX-4 and 12 μL of 3-methoxypropion-1-yne. HPLC-MS (Condition A): room temperature = 2.48 min; m / z: 543 [M+1]. + .

[0237]

[0245] 4,6-O-bis(6-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)hexyl)-myo-inositol (III-25): General click reaction procedure M gave 321 mg of (III-25) (12%) from 2 g of (IX-2) and 1.16 mL of 3-methoxypropion-1-yne. HPLC-MS (Condition A): room temperature = 2.65 min; m / z: 571 [M+1]. + Two other compounds were isolated from 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): room temperature = 2.78 min; m / z: 599 [M+1]. III-43: HPLC-MS (condition A): room temperature = 2.70 min; m / z: 585 [M+1].

[0238]

[0246] 4,6-O-bis((1-(3-methoxypropyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol (III-26): General group transformation procedure N gave 38 mg of (III-26) from 110 mg of (VII-1) (54%). HPLC-MS (Condition A): RT = 2.42 min; m / z: 487 [M+1] + .

[0239]

[0247] 4,6-O-bis((1-(6-methoxyhexyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol (III-27): General group transformation procedure N gave 59 mg of (III-27) from 160 mg of (VII-2) (55%). HPLC-MS (Condition A): RT = 2.88 min; m / z: 571 [M+1] + .

[0240]

[0248] 4,6-O-bis((3-(4-ethyloxycarbonylbutanamido)propyl))-myo-inositol (III-28): General amide formation procedure P was performed from 160 mg of XII-1 and 196 mg of 32 to give 57 mg of III-28 (34%). HPLC-MS (Condition B): RT = 1.45 min; m / z: 551 [M+1] + , 573[M+23] + .

[0241]

[0249] 4,6-O-bis(3-(4-methoxyphenyl)propyl)-myo-inositol (III-29): General hydrolysis procedure S gave 47 mg of III-29 from 60 mg of II-24 (>99%). HPLC-MS (Condition A): RT = 3.31 min; m / z: 477 [M+1]. + .

[0242]

[0250] 4,6-O-bis(3-(3-(trifluoromethyl)phenyl)propyl)-myo-inositol (III-30): General hydrolysis procedure S gave 212 mg of III-30 from 262 mg of II-25 (84%). HPLC-MS (Condition A): RT = 3.88 min; m / z: 553 [M+1] + , 575[M+23] + .

[0243]

[0251] 4,6-O-bis(3-(p-tolyl)propyl)-myo-inositol (III-31): General hydrolysis procedure S gave 57 mg of III-31 (85%) from 85 mg of II-26. HPLC-MS (Condition A): RT = 3.88 min; m / z: 445 [M+1] + , 467[M+23] + .

[0244]

[0252] 4,6-O-bis(4,4,4-trifluorobutyl)-myo-inositol (III-32): General hydrolysis procedure S gave 2.73 g of III-32 (99%) from 3.61 g of II-18. HPLC-MS (Condition A): RT = 3.01 min; m / z: 401 [M+1] + , 423[M+23] + .

[0245]

[0253] 4,6-O-bis(6,6,6-trifluorohexyl)-myo-inositol (III-33): General hydrolysis procedure S gave 457 mg of III-33 from 594 mg of II-19 (98%). HPLC-MS (Condition A): RT = 3.40 min; m / z: 457 [M+1] + .

[0246]

[0254] 4,6-O-bis(4-methylpentyl)-myo-inositol (III-34): General hydrolysis procedure S gave 193 mg of III-34 from 273 mg of II-20 (96%). HPLC-MS (Condition A): RT = 3.40 min; m / z: 349 [M+1]. + .

[0247]

[0255] 4,6-O-bis(19-methoxynonadeca-10-yn-1-yl)-myo-inositol (III-35): General hydrolysis procedure S gave 1.03 g of III-35 (>99%) from 1.2 g of II-21. HPLC-MS (Condition A): RT = 7.18 min; m / z: 765.6 [M+1] + , 787.7[M+23] + .

[0248]

[0256] 4,6-O-bis(3-(3-phenylureido)propyl)-myo-inositol (III-36): General urea formation procedure H yielded 90 mg of III-36 (>99%) from 89 mg of XII-1 and 39 μL of phenyl isocyanate. HPLC-MS (Condition A): RT = 2.70 min; m / z: 533 [M+1] + .

[0249]

[0257] 4,6-O-bis(3-(3-cyclopentylureido)propyl)-myo-inositol (III-37): General urea formation procedure H yielded 80 mg of III-37 (91%) from 89 mg of XII-1 and 40.2 μL of isocyanatocyclopentane. HPLC-MS (Condition A): RT = 2.79 min; m / z: 517 [M+1]. + .

[0250]

[0258] 4,6-O-bis(3-((methoxycarbonyl)amino)propyl)-myo-inositol (III-38): General carbamate formation procedure V gave 7 mg of III-38 from 74 mg of XII-1 (12%). HPLC-MS (Condition B): RT = 0.25 min; m / z: 411 [M+1] + , 433[M+23] + .

[0251]

[0259] 4,6-O-bis(5-acetamidopentyl)-myo-inositol (III-39): General hydrolysis procedure S gave 52 mg of III-39 (72%) from 93 mg of XIII-1. HPLC-MS (Condition B): RT = 0.25 min; m / z: 435 [M+1] + , 457[M+23] + .

[0252]

[0260] 4,6-O-bis(5-benzamidopentyl)-myo-inositol (III-40): General hydrolysis procedure S yielded 35 mg of III-40 from 43 mg of XIII-2 (>99%). HPLC-MS (Condition A): RT = 2.92 min; m / z: 559 [M+1]. + .

[0253]

[0261] 4,6-O-bis(5-(thiophene-2-carboxamido)pentyl)-myo-inositol (III-41): General amide formation procedure P was used to obtain 158 mg of III-41 (97%) from 121 mg of XII-2 and 129 mg of 33. HPLC-MS (Condition B): RT = 2.14 min; m / z: 571 [M+1]. + .

[0254]

[0262] 4,6-O-bis(4-amino-4-oxobutyl)-myo-inositol (III-44): 185 mg of (III-47) was dissolved in 1 mL of ammonia (37% aqueous solution), and the solution was stirred at 60 °C for 24 h. 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] + .

[0255]

[0263] 4,6-O-bis(5-(3-propylureido)pentyl)-myo-inositol (III-45): General urea formation procedure H yielded 120 mg of III-45 (91%) from 89 mg of XII-1 and 50 μL of 1-isocyanatopropane. HPLC-MS (Condition A): RT = 2.72 min; m / z: 521 [M+1]. + .

[0256]

[0264] 4,6-O-bis(5-((methoxycarbonyl)amino)pentyl)-myo-inositol (III-46): General hydrolysis procedure S gave 43 mg of III-46 from 54 mg of XIII-3 (>99%). HPLC-MS (Condition A): RT = 2.62 min; m / z: 467 [M+1]. + , 490[M+23] + .

[0257]

[0265] 4,6-O-bis(3-methoxycarbonylpropyl)-myo-inositol (III-47): General hydrolysis procedure S gave 200 mg of (III-47) 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 = 6.8Hz, 4H). C.3. Intermediates IV and IV'

[0266] 4,6-O-bis(5-(benzyloxy)pentyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-26): General phosphorylation procedure G gave 173 mg of IV-26 from 164 mg of III-1 (44.6%). HPLC-MS (Condition A): room temperature = 4.85 min; m / z: 1261 [M+1]. + .

[0258]

[0267] 4,6-O-bis(10-(benzyloxy)decyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-1): General phosphorylation procedure G was used to obtain 50 mg of (IV-1) from 50 mg of (III-3) (48%). HPLC-MS (Condition B): RT = 4.21 min; m / z: 1401 [M+1]. + .

[0259]

[0268] 4,6-O-bis(14-(benzyloxy)tetradecyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-2): General phosphorylation procedure G gave 8 mg of (IV-2) from 16 mg of (III-4) (26%).

[0260]

[0269] 4,6-O-bis(3-methoxypropyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-3): General phosphorylation procedure G gave 25 mg of IV-3 (21%) from 37 mg of III-12. HPLC-MS (Condition A): RT = 3.78 min; m / z: 1053 [M+1] + .

[0261]

[0270] 4,6-O-bis(5-methoxypentyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-4): General phosphorylation procedure G gave 326 mg of IV-4 (25%) from 444 mg of III-2. HPLC-MS (Condition A): RT = 4.03 min; m / z: 1109 [M+1]. + .

[0262]

[0271] 4,6-O-bis(7-methoxyheptyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-5): General phosphorylation procedure G gave 191 mg of IV-5 (19.6%) from 365 mg of III-13. HPLC-MS (Condition A): RT = 4.49 min; m / z: 1165 [M+1]. + .

[0263]

[0272] 4,6-O-bis(7-methoxynonyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-6): General phosphorylation procedure G gave 71 mg of IV-6 from 219 mg of III-14 (13.1%). HPLC-MS (Condition A): RT = 4.98 min; m / z: 1221.6 [M+1]. + .

[0264]

[0273] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4,6-O-dipropyl-myo-inositol (IV-7): General phosphorylation procedure G gave 24 mg of IV-7 from 26.3 mg of III-15 (24%). HPLC-MS (Condition A): RT = 3.99 min; m / z: 993 [M+1]. + .

[0265]

[0274] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4,6-O-dipentyl-myo-inositol (IV-8): General phosphorylation procedure G was used to obtain 143 mg of IV-8 (42%) from 105 mg of III-16. HPLC-MS (Condition A): RT = 4.39 min; m / z: 1049 [M+1] + .

[0266]

[0275] 4,6-O-Diheptyl-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-9): General phosphorylation procedure G was used to obtain 244 mg of IV-9 (55%) from 150 mg of III-17. HPLC-MS (Condition A): RT = 5.04 min; m / z: 1105 [M+1] + .

[0267]

[0276] 4,6-O-Didecyl-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-10): General phosphorylation procedure G gave 64 mg of IV-10 from 180 mg of III-18 (14%). 1 H 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).

[0277] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4,6-O-di(tetradecyl)-myo-inositol (IV-11): General phosphorylation procedure G gave 193 mg of IV-11 from 134 mg of III-19 (63%). HPLC-MS (Condition B): room temperature = 5.25 min; m / z: 1301 [M+1]. + .

[0268]

[0278] 4,6-O-bis(5-ethoxycarbonylpentyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-12): General phosphorylation procedure G was used to obtain 35.5 mg of IV-12 (15%) from 90 mg of III-5. HPLC-MS (Condition A): RT = 4.31 min; m / z: 1193 [M+1] + .

[0269]

[0279] 4,6-O-bis(10-ethoxycarbonyldecyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-13): General phosphorylation procedure G gave 161 mg of IV-13 (57%) from 129 mg of III-6. HPLC-MS (Condition A): RT = 5.38 min; m / z: 1333 [M+1] + .

[0270]

[0280] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4,6-O-bis(5-(1H-pyrazol-1-yl)pentyl)-myo-inositol (IV-14): General phosphorylation procedure G gave 26 mg of IV-14 (14%) from 70 mg of III-9. HPLC-MS (Condition A): RT = 3.89 min; m / z: 1182 [M+1]. + .

[0271]

[0281] 1,2,3,5-O-Tetrakis(3-oxido-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): General phosphorylation procedure G gave 8.8 mg of IV-15 from 19 mg of III-10. HPLC-MS (Condition A): RT = 3.46 min; m / z: 1184 [M+1]. + .

[0272]

[0282] 4,6-O-bis((1-(2-(benzyloxycarbonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-16): General phosphorylation procedure G gave 445 mg of IV-16 (50%) from 423 mg of III-20. HPLC-MS (Condition A): RT = 4.16 min; m / z: 1395 [M+1]+ .

[0273]

[0283] 4,6-O-bis((1-(3-methoxypropyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-17): General phosphorylation procedure G gave 64 mg of IV-17 from 62 mg of III-26 (41%). HPLC-MS (Condition A): RT = 3.64 min; m / z: 1215 [M+1]. + .

[0274]

[0284] 4,6-O-bis((1-(6-methoxyhexyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-18): General phosphorylation procedure G gave 15 mg of IV-18 from 59 mg of III-27 (11%). HPLC-MS (Condition A): room temperature = 3.95 min; m / z: 1299 [M+1]. + .

[0275]

[0285] 4,6-O-bis(3-(4-(2-(benzyloxycarbonyl)ethyl)-1H-1,2,3-triazol-1-yl)propyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-19): General phosphorylation procedure G gave 86 mg of IV-19 (43%) from 100 mg of III-21. HPLC-MS (Condition B): RT = 3.18 min; m / z: 1451 [M+1]. + .

[0276]

[0286] 4,6-O-bis(3-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)propyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-20): General phosphorylation procedure G gave 7.2 mg of (IV-20) (7%) from 40 mg of (III-22). HPLC-MS (Condition A): room temperature = 3.48 min; m / z: 1215 [M+1]. + .

[0277]

[0287] 4,6-O-bis(4-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)butyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-21): General phosphorylation procedure G gave 11 mg of IV-21 (23%) from 20 mg of III-23. HPLC-MS (Condition A): RT = 3.53 min; m / z: 1243 [M+1] + .

[0278]

[0288] 4,6-O-bis(5-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-22): General phosphorylation procedure G gave 9.7 mg of IV-22 (8%) from 54 mg of III-24. HPLC-MS (Condition A): RT = 3.59 min; m / z: 1271 [M+1]. + .

[0279]

[0289] 4,6-O-bis(6-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)hexyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-23): General phosphorylation procedure G gave 35.5 mg of IV-23 (18%) from 85 mg of III-25. HPLC-MS (Condition A): RT = 3.66 min; m / z: 1299 [M+1] + .

[0280]

[0290] 4,6-O-bis(2-(4-acetylpiperazin-1-yl)ethyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-24): General phosphorylation procedure G gave 16 mg of IV-24 (8%) from 81.5 mg of III-11. HPLC-MS (Condition B): RT = 1.92 min; m / z: 1217 [M+1] + .

[0281]

[0291] 4,6-O-bis((3-(4-ethyloxycarbonylbutanamido)propyl))-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-25): General phosphorylation procedure G gave 28 mg of IV-25 (21%) from 57 mg of III-28. HPLC-MS (Condition A): RT = 2.66 min; m / z: 1279 [M+1] + .

[0282]

[0292] 4,6-O-bis(2-cyclopropylethyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-27): General phosphorylation procedure G gave 3 g of IV-27 from 2.3 g of III-7 (39%). HPLC-MS (Condition A): RT = 4.30 min; m / z: 1045 [M+1]. +.

[0283]

[0293] 4,6-O-bis(2-cyclopentylethy)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-28): General phosphorylation procedure G was used to obtain 164 mg of IV-28 (28%) from 200 mg of III-8. HPLC-MS (Condition A): RT = 4.74 min; m / z: 1101 [M+1] + .

[0284]

[0294] 4,6-O-bis(3-(4-methoxyphenyl)propyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-29): General phosphorylation procedure G gave 36 mg of IV-29 (24%) from 60 mg of III-29. HPLC-MS (Condition A): RT = 4.20 min; m / z: 1206 [M+1]. + .

[0285]

[0295] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4,6-O-bis(3-(3-(trifluoromethyl)phenyl)propyl)-myo-inositol (IV-30): General phosphorylation procedure G gave 64 mg of IV-30 from 214 mg of III-30 (13%). HPLC-MS (Condition A): RT = 4.83 min; m / z: 1281 [M+1]. + .

[0286]

[0296] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4,6-O-bis(3-(p-tolyl)propyl)-myo-inositol (IV-31): General phosphorylation procedure G gave 19.1 mg of IV-31 from 54.7 mg of III-31 (13%). HPLC-MS (Condition A): RT = 4.76 min; m / z: 1274 [M+1]. + .

[0287]

[0297] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4,6-O-bis(4,4,4-trifluorobutyl)-myo-inositol (IV-32): General phosphorylation procedure G gave 2.34 g of IV-32 (51%) from 1.62 g of III-32. HPLC-MS (Condition A): RT = 4.29 min; m / z: 1129 [M+1] + .

[0288]

[0298] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4,6-O-bis(6,6,6-trifluorohexyl)-myo-inositol (IV-33): General phosphorylation procedure G gave 414 mg of IV-33 from 457 mg of III-33 (35%). HPLC-MS (Condition A): RT = 4.53 min; m / z: 1185 [M+1]. + .

[0289]

[0299] 4,6-O-bis(4-methylpentyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-34): General phosphorylation procedure G gave 168 mg of IV-34 (12%) from 457 mg of III-34. HPLC-MS (Condition A): RT = 4.568 min; m / z: 1077 [M+1] + .

[0290]

[0300] 4,6-O-bis(19-methoxynonadec-10-yn-1-yl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-35): General phosphorylation procedure G gave 939 mg of IV-35 (45%) from 1.03 g of III-35. HPLC-MS (Condition A): RT = 7.19 min; m / z: 1494 [M+1] + .

[0291]

[0301] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4,6-O-bis(3-(3-phenylureido)propyl)-myo-inositol (IV-36): General phosphorylation procedure G gave 187 mg of IV-36 (82%) from 96 mg of III-36. HPLC-MS (Condition A): RT = 4.02 min; m / z: 1262 [M+1] + .

[0292]

[0302] 4,6-O-bis(3-(3-cyclopentylureido)propyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-37): General phosphorylation procedure G gave 181 mg of IV-37 (94%) from 80 mg of III-37. HPLC-MS (Condition A): RT = 3.83 min; m / z: 1245 [M+1] + .

[0293]

[0303] 4,6-O-bis(3-((methoxycarbonyl)amino)propyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-38): General phosphorylation procedure G gave 3 mg of IV-38 from 10 mg of III-38 (11%). HPLC-MS (Condition B): RT = 2.90 min; m / z: 1139 [M+1]. + .

[0294]

[0304] 4,6-O-Bis(5-acetamidopentyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-39): General phosphorylation procedure G gave 110 mg of IV-39 (79%) from 52 mg of III-39. HPLC-MS (Condition B): RT = 2.69 min; m / z: 1163 [M+1]. + .

[0295]

[0305] 4,6-O-Bis(5-benzamidopentyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-40): General phosphorylation procedure G gave 38 mg of (IV-40) from 39 mg of (III-40) (42%). HPLC-MS (Condition A): RT = 4.04 min; m / z: 1288 [M+1]. + .

[0296]

[0306] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4,6-O-bis(5-(thiophene-2-carboxamido)pentyl)-myo-inositol (IV-41): General phosphorylation procedure G yielded 196 mg of IV-41 from 158 mg of III-41 (54%). HPLC-MS (Condition B): RT = 3.13 min; m / z: 1299 [M+1]. + .

[0297]

[0307] 4,6-O-(6-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)hexyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-42): General phosphorylation procedure G gave 34 mg of IV-42 from 278 mg of III-42 (5.5%). HPLC-MS (Condition A): RT = 3.86 min; m / z: 1327 [M+1]. + .

[0298]

[0308] 4-O-(6-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)hexyl)-6-O-(6-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)hexyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-43): General phosphorylation procedure G gave 101 mg of (IV-43) (10%) from 454 mg of (III-43). HPLC-MS (Condition A): room temperature = 3.76 min; m / z: 1313 [M+1]. + .

[0299]

[0309] 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): General phosphorylation procedure G gave 179 mg of IV-44 (59%) from 97.5 mg of III-44. HPLC-MS (Condition A): RT = 3.29 min; m / z: 1079.5 [M+1]. + .

[0300]

[0310] 1,2,3,5-O-Tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4,6-O-bis(5-(3-propylureido)pentyl)-myo-inositol (IV-45): General phosphorylation procedure G gave 210 mg of IV-45 (73%) from 120 mg of III-45. HPLC-MS (Condition A): RT = 3.73 min; m / z: 1250.5 [M+1]. + .

[0301]

[0311] 4,6-O-bis(5-((methoxycarbonyl)amino)pentyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-46): General phosphorylation procedure G gave 64 mg of IV-46 (50%) from 50 mg of III-46. HPLC-MS (Condition A): RT = 3.86 min; m / z: 1195 [M+1]. + .

[0302]

[0312] 4,6-O-bis(3-methoxycarbonylpropyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-47): General phosphorylation procedure G gave 40 mg of IV-47 from 70 mg of III-47 (19%). HPLC-MS (Condition A): RT = 3.77 min; m / z: 1109 [M+1]. + .

[0303]

[0313] 4,6-O-Dipropargyl-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV-48): General phosphorylation procedure G gave 4.69 g of IV-48 (32%) from 3.92 g of VI-1. HPLC-MS (Condition A): RT = 3.69 min; m / z: 985 [M+1] + .

[0304]

[0314] 4,6-O-Dipentyl-1,2,3,5-O-tetrakis(3-sulfido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV'-1): General thiophosphorylation procedure T gave 28 mg of IV'-1 from 64 mg of III-16 (13%). HPLC-MS (Condition A): RT = 5.94 min; m / z: 1113 [M+1]. + .

[0305]

[0315] 4,6-O-bis(5-methoxypentyl)-1,2,3,5-O-tetrakis(3-sulfido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV'-2): General thiophosphorylation procedure T gave 70 mg of IV'-2 (30%) from 76 mg of III-2. HPLC-MS (Condition A): RT = 5.49 min; m / z: 1173 [M+1] + .

[0306] C.4. Intermediate V

[0316] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methylidyne-4,6-O-dipropargyl-myo-inositol (V-1): General alkylation procedure A gave 1.2 g of (V-1) (>99%) from 1.0 mL of 3-bromoprop-1-yne in toluene (2.1 equiv., 80%). HPLC-MS (Condition A): RT = 4.36 min; m / z: 381 [M+1]. + .

[0307] C.5. Intermediate VI

[0317] 4,6-O-Dipropargyl-myo-inositol (VI-1): General hydrolysis procedure D gave 740 mg of (VI-1) from 1.2 g of (VI-1) (92%). 1H 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

[0318] 4,6-O-bis((1-(3-(tosyloxy)propyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol (VII-1): General click reaction procedure L was used to obtain 110 mg of (VII-1) (73%) from 100 mg of (8). HPLC-MS (Condition A): Room temperature = 3.30 min; m / z: 767 [M+1] + .

[0308]

[0319] 4,6-O-bis((1-(6-(tosyloxy)hexyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol (VII-2): General click reaction procedure L gave 162 mg of (VII-2) from 116 mg of (17) (98%). HPLC-MS (Condition A): Room temperature = 3.71 min.

[0309] C.7. Intermediate VIII

[0320] 4,6-O-Bis(3-azidopropyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidine-myo-inositol (VIII-1): General alkylation procedure A gave 249 mg of VIII-1 (22%) from 1.27 g (2.1 equivalents in 5.9 mL DMF) of 8. HPLC-MS (Condition A): RT = 5.12 min; m / z: 471 [M+1]. + .

[0310]

[0321] 4,6-O-Bis(5-azidopentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidine-myo-inositol (VIII-2): General alkylation procedure A gave 900 mg of VIII-2 (51%) from 2 g (2.1 equiv. in 8.4 mL DMF) of 10. HPLC-MS (Condition A): RT = 5.62 min; m / z: 527 [M+1]. + , 549[M+23] + .

[0311]

[0322] 4,6-O-Bis(10-azidodecyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidine-myo-inositol (VIII-3): General alkylation procedure A gave 57.5 mg of VIII-3 (27%) from 234 mg (2.05 equiv. in 2 mL 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).

[0323] 4,6-O-Bis(4-azidobutyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidine-myo-inositol (VIII-4): General alkylation procedure A gave 17 mg of VIII-4 (7%) from 245 mg (2 equivalents in 1.2 mL DMF) of 19. HPLC-MS (Condition A): RT = 5.33 min; m / z: 499 [M+1]. + , 521[M+1] + .

[0312]

[0324] 4,6-O-Bis(6-azidohexyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidine-myo-inositol (VIII-5): General alkylation procedure A gave 74 mg of VIII-5 (20%) from 200 mg (2 equivalents in 1.6 mL DMF) of 17. HPLC-MS (Condition A): RT = 5.97 min; m / z: 555 [M+1]. + , 577[M+1] + .

[0313] C.8. Intermediate IX

[0325] 4,6-O-bis(4-azidobutyl)-myo-inositol (IX-1): General hydrolysis procedure C with a slight modification (aqueous work-up) gave 8 mg of IX-1 from 16.7 mg of VIII-4 (64%). HPLC-MS (Condition A): RT = 2.76 min; m / z: 375 [M+1]. + , 397[M+23] + .

[0314]

[0326] 4,6-O-bis(6-azidohexyl)-myo-inositol (IX-2): General hydrolysis procedure C with a minor modification (aqueous workup) gave 40 mg of IX-2 from 74.7 mg of VIII-5 (69%). HPLC-MS (Condition A): RT = 3.29 min; m / z: 431 [M+1]. + , 453[M+23] + .

[0315]

[0327] 4,6-O-bis(3-azidopropyl)-myo-inositol (IX-3): General hydrolysis procedure E gave 174 mg of IX-3 (94%) from 250 mg of VIII-1. HPLC-MS (Condition A): RT = 2.45 min; m / z: 347 [M+1] + , 369[M+23] + .

[0316]

[0328] 4,6-O-Bis(5-azidopentyl)-myo-inositol (IX-4): General hydrolysis procedure D gave 6.8 mg of IX-4 from 8.9 mg of VIII-2 (>99%). HPLC-MS (Condition A): RT = 3.06 min; m / z: 403 [M+1]. + , 425[M+23] + .

[0317]

[0329] 4,6-O-bis(10-azidodecyl)-myo-inositol (IX-5): General hydrolysis procedure D gave 47 mg of (IX-5) 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

[0330] 4,6-O-bis(3-azidopropyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (X-1): General phosphorylation procedure G gave 148 mg of X-1 from 305 mg of IX-3 (16%). HPLC-MS (Condition A): RT = 4.01 min; m / z: 1075 [M+1] + .

[0318]

[0331] 4,6-O-Bis(5-azidopentyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (X-2): General phosphorylation procedure G was used to obtain 530 mg of X-2 (63%) from 300 mg of IX-4. HPLC-MS (Condition A): RT = 4.32 min; m / z: 1131 [M+1] + .

[0319]

[0332] 4,6-O-bis(10-azidodecyl)-1,2,3,5-O-tetrakis(3-oxido-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (X-3): General phosphorylation procedure G gave 63 mg of X-3 (27%) from 100 mg of IX-5. HPLC-MS (Condition B): RT = 3.86 min; m / z: 1271 [M+1]. + .

[0320] C.10. Intermediate XI

[0333] 4,6-O-Bis(3-aminopropyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidine-myo-inositol (XI-1): General azide reduction procedure Q gave 144 mg of (VIII-1) sufficiently pure (XI-1) to carry on without further purification. HPLC-MS (Condition B): RT = 2.43 min; m / z: 419 [M+1] + , 441[M+23] + .

[0321]

[0334] 4,6-O-Bis(5-aminopentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidine-myo-inositol (XI-2): General azide reduction procedure Q gave 1.4 g of XI-2 from 2.5 g of VIII-2 after column purification (62%). HPLC-MS (Condition A): RT = 2.73 min; m / z: 475 [M+1] + , 493[M+23] + .

[0322] C.11. Intermediate XII

[0335] 4,6-O-bis(3-aminopropyl)-myo-inositol·2TFA (XII-1): General hydrolysis procedure C with a slight modification (aqueous workup) gave 160 mg of XII-1 from 128 mg of XI-1 (>99%). HPLC-MS (Condition B): RT = 0.24 min; m / z: 295 [M+1]. + .

[0323]

[0336] 4,6-O-Bis(5-aminopentyl)-myo-inositol dihydrochloride (XII-2): General hydrolysis procedure S yielded 447 mg of XII-2 (54%) from 1.13 g of XI-2. HPLC-MS (Condition B): RT = 0.25 min; m / z: 351 [M+1] + .

[0324] C.12. Intermediate XIII

[0337] 4,6-O-Bis(5-acetamidopentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidine-myo-inositol (XIII-1): General amide formation procedure P yielded 93 mg of XIII-1 (69%) from 115 mg of XI-2 and 38 μL of acetyl chloride. HPLC-MS (Condition A): RT = 3.67 min; m / z: 559 [M+1] + .

[0325]

[0338] 4,6-O-Bis(5-benzamidopentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidine-myo-inositol (XIII-2): General amide formation procedure P was used to obtain 57 mg of XIII-2 (32%) from 125 mg of XIII-2 and 67 μL of benzoyl chloride. HPLC-MS (Condition B): RT = 3.56 min; m / z: 683 [M+1] + .

[0326]

[0339] 2-O-tert-Butyldimethylsilyl-4,6-O-bis(5-((methoxycarbonyl)amino)pentyl)-1,3,5-O-methylidine-myo-inositol (XIII-3): General carbamate formation procedure V gave 54 mg of XIII-3 (38%) from 127 mg of XI-2. HPLC-MS (Condition A): RT = 4.31 min; m / z: 591 [M+1] + .

[0327] D. Compound Characterization: Analytical and Spectroscopic Tests D.1.NMR

[0340] NMR spectra were recorded on an Agilent VNMRS-400 (400.10 MHz) 1 H, 162MHz 31 P). 1 In H-NMR, chemical shifts are expressed in ppm relative to TMS and coupling constants (J) are expressed in Hz. 31 For P NMR, no internal standard was used to collect phosphorus NMR spectra. The usual internal standard is phosphoric acid; 1 It was not used due to concerns about its effect on H-NMR.

[0328] D.2. HPLC-MS

[0341] Condition A: High-performance liquid chromatography (HPLC) was performed using a 2795 Alliance Waters Aquity system connected to an Agilent 1100 DAD detector and a Waters MS ESI triple quadrupole Quattro micro detector. 10 μL of sample was injected in MeOH. Mass spectrometry (MS) analysis was performed using flux injection analysis (FIA) on an LCT Premier orthogonal acceleration time-of-flight mass spectrometer. Data were acquired in positive mode using electrospray ionization (ESI). Spectra were scanned from 50 to 1500 Da at 0.2-second intervals, and peaks were reported as m / z (% of the base peak). Stationary phase: ZORBAX Extend-C18 3.5 μm 2.1 × 50 mm (T a 35℃).

[0329] [Table 2]

[0330] [Table 3]

[0331]

[0342] Condition B: HPLC-MS was performed using a Thermo Ultimate 3000SD (Thermo Scientific Dionex) high-performance liquid chromatograph equipped with a photodiode array detector and an LTQ XL ESI-ion trap mass spectrometer (Thermo Scientific). 5 μL to 20 μL of sample MeOH was injected (c = 0.5 mg / mL). Mass spectral data were analyzed by electrospray ionization in positive and negative modes, and peaks were given as m / z (% of the base peak). Stationary phase: ZORBAX Extend-C18 3.5 μm 2.1 × 50 mm (T a 35℃).

[0332] [Table 4]

[0333] [Table 5]

[0334]

[0343] Condition C: HPLC-MS was performed using a Thermo Ultimate 3000SD (Thermo Scientific Dionex) high-performance liquid chromatograph equipped with a photodiode array detector and an LTQ XL ESI-ion trap mass spectrometer (Thermo Scientific). Samples were injected in 5-20 μL MeOH (c = 0.5 mg / mL). Mass spectra were analyzed using electrospray ionization in positive and negative modes, and peaks were expressed as m / z (% of the base peak). Stationary phase: Xbridge BEH Amide 2.5 μm, 4.6 x 150 mm, XP.

[0335] [Table 6]

[0336] [Table 7]

[0337]

[0344] Condition D: HPLC-MS was performed using a Thermo Ultimate 3000SD (Thermo Scientific Dionex) high-performance liquid chromatograph equipped with a photodiode array detector and an LTQ XL ESI-ion trap mass spectrometer (Thermo Scientific). 5 μL to 20 μL of sample MeOH was injected (c = 0.5 mg / mL). Mass spectral data were analyzed by electrospray ionization in positive and negative modes, and peaks were given as m / z (% of the base peak). Stationary phase: ZORBAX Extend-C18 3.5 μm 2.1 × 50 mm (T a 35℃).

[0338] [Table 8]

[0339] [Table 9]

[0340]

[0345] Condition E: HPLC-MS was performed using a Thermo Ultimate 3000SD (Thermo Scientific Dionex) high-performance liquid chromatograph equipped with a photodiode array detector and an LTQ XL ESI-ion trap mass spectrometer (Thermo Scientific). 5 μL to 20 μL of sample MeOH was injected (c = 0.5 mg / mL). Mass spectral data were analyzed by electrospray ionization in positive and negative modes, and peaks were given as m / z (% of the base peak). Stationary phase: ZORBAX Extend-C18 3.5 μm 2.1 × 50 mm (T a 30℃).

[0341] [Table 10]

[0342] [Table 11]

[0343] Example 1 Synthesis and characterization of 4,6-O-bis(5-hydroxypentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 6)

[0346] General phosphate deprotection procedure I gave 38 mg of compound 6 (56.5%) from 100 mg of (IV-26). 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): Room temperature=10.06 min; m / z:673[M+1] + , 746[M+1+DEA] + , 819[M+1+2DEA] + .

[0344] Example 2 Synthesis and characterization of 4,6-O-bis(10-hydroxydecyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 7)

[0347] General phosphate deprotection procedure I gave 3.15 mg of compound 7 (10.9%) from 50 mg of (IV-1). 1 H 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). 31PNMR (162 MHz, D2O) δ 1.57, -0.15, -1.08.HPLC-MS (Condition C): Room temperature = 6.89 minutes; m / z:813[M+1] + , 886[M+1+DEA] + , 959[M+1+2DEA] + .

[0345] Example 3 Synthesis and characterization of 4,6-O-bis(14-hydroxytetradecyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 8)

[0348] General phosphate deprotection procedure I gave 0.6 mg of compound 8 from 8.3 mg of (IV-2) (8%). 1 H 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): Room temperature=6.8 minutes; m / z:998[M+1+DEA] + , 1071[M+1+2DEA] + .

[0346] Example 4 Synthesis and characterization of 4,6-O-bis(3-methoxypropyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 10)

[0349] General phosphate deprotection procedure I gave 17.7 mg of compound 10 (99%) from 23 mg of (IV-3). 1 H NMR (400 MHz, D2O) δ 4.35 (br, 4H), 4.14 (br, 2H), 3.82-3.73 (m, 4H), 3.59 (t, J = 6.7Hz, 4H), 3.36 (s, 6H), 1.90 (q, J = 6.7, Hz, 4H). 31 P NMR (162 MHz, D2O)δ 3.90 (br).HPLC-MS (Condition C): Room temperature=9.96 min; m / z:718[M+1+DEA]+ , 791[M+1+2DEA] + .

[0347] Example 5 Synthesis and characterization of 4,6-O-bis(5-methoxypentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 9)

[0350] General phosphate deprotection procedure I gave 193 mg of compound 9 (75%) from 326 mg of (IV-4). 1 H 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 P NMR (162 MHz, D2O) δ 7.46 (br), 6.71 (br).HPLC-MS (Condition C): Room temperature=9.59 min; m / z:774[M+1+DEA] + , 847[M+1+2DEA] + .

[0348] Example 6 Synthesis and characterization of 4,6-O-bis(7-methoxyheptyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 11)

[0351] General phosphate deprotection procedure I gave 29.8 mg of compound 11 (22%) from 169.5 mg of (IV-5). 1H 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): Room temperature=8.95 min; m / z:757[M+1] + , 830[M+1+DEA] + , 903[M+1+2DEA] + .

[0349] Example 7 Synthesis and characterization of 4,6-O-bis(9-methoxynonyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 12)

[0352] General phosphate deprotection procedure I gave 7.65 mg of compound 12 (14% yield) from 67 mg of (IV-6). 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 PNMR (162 MHz, D2O) δ 0.84, -0.36, -1.12.HPLC-MS (Condition C): Room temperature = 8.52 minutes; m / z:813[M+1] + , 886[M+1+DEA] + , 959[M+1+2DEA] + .

[0350] Example 8 Synthesis and characterization of 4,6-O-dipropyl-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 4)

[0353] General phosphate deprotection procedure I gave 3.8 mg of compound 4 (20%) from 24 mg of (IV-7). 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): Room temperature=10.09 min; m / z:731[M+1+2DEA] + .

[0351] Example 9 Synthesis and characterization of 4,6-O-dipentyl-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 1)

[0354] General phosphate deprotection procedure I gave 92 mg of compound 1 (83%) from 143 mg of (IV-8). 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): Room temperature = 6.16 min; m / z:714[M+1] + , 787[M+1+DEA] + , 860[M+1+2DEA] + .

[0352] Example 10 Synthesis and characterization of 4,6-O-diheptyl-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 5)

[0355] General phosphate deprotection procedure I gave 7.8 mg of compound 5 (4%) from 244 mg of (IV-9). 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): Room temperature=8.46 min; m / z:843[M+1+DEA] + , 916[M+1+2DEA] + .

[0353] Example 11 Synthesis and characterization of 4,6-O-didecyl-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 2)

[0356] General phosphate deprotection procedure I gave 1.6 mg of compound 2 (4%) from 63 mg of (IV-10). 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): Room temperature = 6.89 minutes; m / z:781[M+1] + , 854[M+1+DEA] + , 927[M+1+2DEA] + , 1000[M+1+2DEA] + .

[0354] Example 12 Synthesis and characterization of 4,6-O-di(tetradecyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 3)

[0357] General phosphate deprotection procedure I gave 656 mg of compound 3 (66.5%) from 1.5 g of (IV-11). 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 PNMR (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] + .

[0355] Example 13 Synthesis and characterization of 4,6-O-bis(3-aminopropyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 13)

[0358] General phosphate deprotection procedure I gave 5.6 mg of compound 13 (16.7%) from 45.6 mg of (X-1). HPLC-MS (condition C): room temperature = 10.73 min; m / z: 615 [M+1] + , 688[M+1+DEA] + .

[0356] Example 14 Synthesis and characterization of 4,6-O-bis(5-aminopentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 14)

[0359] General phosphate deprotection procedure I gave 11.3 mg of compound 14 from 145 mg of (X-2) (10%). 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 P NMR (162 MHz, D2O)δ 1.86, 0.46, 0.15.HPLC-MS (Condition C): Room temperature=10.77 min; m / z:671[M+1] + , 744[M+1+DEA] + .

[0357] Example 15 Synthesis and characterization of 4,6-O-bis(10-aminodecyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 15)

[0360] General phosphate deprotection procedure I gave 0.8 mg of compound 15 (2%) from 57.5 mg of (X-3). 1 H 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 P NMR (162 MHz, D2O) δ 2.04, -0.05, -1.00.HPLC-MS (Condition D): Room temperature = 6.48 minutes; m / z:811[M+1] + , 884[M+1+DEA] + , 958[M+1+2DEA] + .

[0358] 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)

[0361] General phosphate deprotection procedure I gave 8.5 mg of compound 16 (29%) from 36.6 mg of (IV-14). 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 (162MHz, D2O) δ4.91, 4.21.HPLC-MS (Condition C): Room temperature = 9.20 minutes; m / z:773[M+1] + , 846[M+1+DEA] + , 919[M+1+2DEA] + .

[0359] 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)

[0362] General phosphate deprotection procedure I gave 5.2 mg of compound 17 (74%) from 8.8 mg of (IV-15). 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): Room temperature = 9.86 minutes; m / z:776[M+1] + , 849[M+1+DEA] + , 922[M+1+2DEA] + .

[0360] 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) deca-sodium salt (compound 31)

[0363] General phosphate deprotection procedure I gave 72 mg of compound 31 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): Room temperature=10.62 min; m / z:807[M+1] + , 880[M+1+DEA] + , 953[M+1+2DEA] + .

[0361] 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)

[0364] General phosphate deprotection procedure I gave 22 mg of compound 32 (43%) from 64 mg of (IV-17). 1H 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): room temperature = 9.56 minutes; m / z:880[M+1+DEA] + .

[0362] 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)

[0365] General phosphate deprotection procedure I gave 1.8 mg of compound 33 from 15 mg of (IV-18) (15%). 1 H 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): Room temperature = 8.83 minutes; m / z:891[M+1] + , 964[M+1+DEA] + , 1037[M+1+2DEA] + .

[0363] 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)

[0366] General phosphate deprotection procedure I gave 1.7 mg of compound 36 (28%) from 7.2 mg of (IV-20). 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): Room temperature = 9.73 minutes; m / z:880[M+1+DEA] + .

[0364] 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)

[0367] General phosphate deprotection procedure I gave 1.2 mg of compound 37 (13%) from 11 mg of (IV-21). 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): Room temperature = 9.59 minutes; m / z:835[M+1] + , 908[M+1+DEA] + .

[0365] 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)

[0368] General phosphate deprotection procedure I gave 1.4 mg of compound 38 (16%) from 11 mg of (IV-22). 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): Room temperature = 9.53 minutes; m / z:936[M+1+DEA] + .

[0366] 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)

[0369] General phosphate deprotection procedure I gave 10 mg of compound 39 (34%) from 35.5 mg of (IV-23). 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 = 7.1Hz, 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): Room temperature=9.24 min; m / z:964[M+1+DEA] + .

[0367] 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)

[0370] General phosphate deprotection procedure I gave 6.2 mg of compound 34 (48%) from 16 mg of (IV-24). 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): Room temperature=10.26 min; m / z:882[M+1+DEA] + .

[0368] Example 26 Synthesis and characterization of 4,6-O-bis((3-(4-carboxybutanamido)propyl))-myo-inositol-1,2,3,5-tetrakis(phosphate) deca-sodium salt (compound 45)

[0371] General phosphate deprotection procedure I gave 4.4 mg of compound 45 (19%) from 28 mg of (IV-25). 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): room temperature = 10.18 min; m / z:916[M+1+DEA] + , 989[M+1+2DEA] + .

[0369] Example 27 Synthesis and characterization of 4,6-O-bis(5-carboxypentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) deca-sodium salt (compound 18)

[0372] General phosphate deprotection procedure J gave 6.8 mg of compound 18 (23%) from 35.5 mg of (IV-12).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 PNMR (162 MHz, D2O) δ 4.86, 4.21.HPLC-MS (Condition C): Room temperature = 10.37 minutes; m / z:802[M+1] + , 875[M+1+DEA] + , 948[M+1+2DEA] + .

[0370] Example 28 Synthesis and characterization of 4,6-O-bis(10-carboxydecyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) deca-sodium salt (compound 19)

[0373] General phosphate deprotection procedure J gave 34.6 mg of compound 19 (22.6%) from 187 mg of (IV-13). 1 H 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 P NMR (162 MHz, D2O) δ:4.79, 4.12, 4.00.HPLC-MS (Condition D): Room temperature = 6.26 minutes; m / z:942[M+1] + , 1015[M+1+DEA] + , 1088[M+1+2DEA] + .

[0371] 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) deca-sodium salt (compound 35)

[0374] General phosphate deprotection procedure J gave 11.8 mg of compound 35 (21%) from 74 mg of (IV-19). 1 H 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 P NMR (162 MHz, D2O) δ 1.94, 0.53.HPLC-MS (Condition C): Room temperature=10.17 min; m / z:936[M+1+DEA] + , 1009[M+1+2DEA] + .

[0372] Example 30 Synthesis and characterization of 4,6-O-bis(2-cyclopropylethyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 28)

[0375] General phosphate deprotection procedure I gave 710 mg of compound 28 (68%) from 1.34 g of (IV-27). 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). 31P NMR (162 MHz, D2O) δ3.79-(-0.54) (br).HPLC-MS (Condition C): Room temperature=9.51 min; m / z:637[M+1] + , 710[M+1+DEA] + , 783[M+1+2DEA] + .

[0373] Example 31 Synthesis and characterization of 4,6-O-bis(2-cyclopentylethyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 29)

[0376] General phosphate deprotection procedure I gave 22 mg of compound 29 (17%) from 164 mg of (IV-28). 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): Room temperature=8.76 min; m / z:693[M+1] + , 766[M+1+DEA] + , 839[M+1+2DEA] + .

[0374] 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)

[0377] General phosphate deprotection procedure I gave 10.8 mg of compound 43 (37%) from 36 mg of (IV-29). 1H NMR (400 MHz, D2O) δ7.02 (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): Room temperature = 8.55 min; m / z:797[M+1] + , 870[M+1+DEA] + , 943[M+1+2DEA] + .

[0375] 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)

[0378] General phosphate deprotection procedure I gave 11.9 mg of compound 44 (23%) from 64 mg of (IV-30). 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): Room temperature=7.84 min; m / z:873[M+1] + , 946[M+1+DEA] + , 1019[M+1+2DEA] + .

[0376] 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)

[0379] General phosphate deprotection procedure I gave 1.1 mg of compound 42 (7%) from 19 mg of (IV-31). 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): Room temperature = 8.35 minutes; m / z:911[M+1+2DEA] + .

[0377] 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)

[0380] General phosphate deprotection procedure I gave 820 mg of compound 22 (44%) from 2.32 g of (IV-32). 1 H 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 PNMR (162 MHz, D2O) δ 1.69, 0.17, -0.92.HPLC-MS (Condition C): Room temperature = 8.86 minutes; m / z:721[M+1] + , 794[M+1+DEA] + , 867[M+1+2DEA] + .

[0378] 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)

[0381] General phosphate deprotection procedure I gave 45 mg of compound 23 (22%) from 248 mg of (IV-33). 1 H 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): Room temperature = 8.27 minutes; m / z:923[M+1+2DEA] + .

[0379] Example 37 Synthesis and characterization of 4,6-O-bis(4-methylpentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 21)

[0382] General phosphate deprotection procedure I gave 4.6 mg of compound 21 (3.5%) from 167 mg of (IV-34). 1 H 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): room temperature = 8.74 min; m / z:742[M+1+DEA] + , 815[M+1+2DEA] + .

[0380] Example 38 Synthesis and characterization of 4,6-O-bis(19-methoxynonadec-10-yn-1-yl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 20)

[0383] General phosphate deprotection procedure I gave 4.3 mg of compound 20 (1.3%) from 410 mg of (III-35). 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 PNMR (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)

[0384] General phosphate deprotection procedure I gave 6.5 mg of compound 46 (4.3%) from 187 mg of (IV-36). 1 H 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): room temperature = 8.73 minutes; m / z:926[M+1+DEA] + , 999[M+1+2DEA] + .

[0381] 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)

[0385] General phosphate deprotection procedure I gave 26 mg of compound 47 (17.6%) from 181 mg of (IV-37). 1H NMR (400 MHz, D2O) δδ 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 (conditions C): room temperature = 8.98 minutes; m / z:837[M+1] + , 910[M+1+DEA] + , 983[M+1+2DEA] + .

[0382] 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)

[0386] General phosphate deprotection procedure I gave 1.7 mg of compound 24 (42%) from 5 mg of (IV-38). 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): Room temperature=9.69 min; m / z:804[M+1+DEA] + , 877[M+1+2DEA] + .

[0383] Example 42 Synthesis and characterization of 4,6-O-bis(5-acetamidopentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 27)

[0387] General phosphate deprotection procedure I gave 4.7 mg of compound 27 (5%) from 110 mg of (IV-39). 1H 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): room temperature = 9.71 min; m / z:828[M+1+DEA] + , 901[M+1+2DEA] + .

[0384] Example 43 Synthesis and characterization of 4,6-O-bis(5-benzamidopentyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 48)

[0388] General phosphate deprotection procedure I gave 15 mg of compound 48 (43%) from 43 mg of (IV-40). 1 H 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): Room temperature = 8.73 minutes; m / z:879[M+1] + , 952[M+1+DEA] + , 1025[M+1+2DEA] + .

[0385] 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)

[0389] General phosphate deprotection procedure U gave 19 mg of compound 49 (12%) from 196 mg of (IV-41). 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): Room temperature = 8.85 minutes; m / z:964[M+1+DEA] + , 1037[M+1+2DEA] + .

[0386] 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) deca-sodium salt (compound 40)

[0390] General phosphate deprotection procedure J gave 9.3 mg of compound 40 (33%) from 34 mg of (IV-42). 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 PNMR (162 MHz, D2O) δ 4.81-3.21 (bs).HPLC-MS (Condition C): Room temperature=10.27 min; m / z:964[M+1+DEA] + , 1037[M+1+2DEA] + .

[0387] 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)

[0391] General phosphate deprotection procedure J gave 35 mg of compound 41 (42%) from 101 mg of (IV-43). 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 PNMR (162 MHz, D2O) δ 4.83, 4.18, 4.10.HPLC-MS (Condition C): Room temperature = 9.65 minutes; m / z:891[M+1] + , 964[M+1+DEA] + , 1037[M+1+2DEA] + .

[0388] 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)

[0392] General phosphate deprotection procedure I gave 168 mg of (IV-44) to give 168 mg of compound 26 (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): Room temperature=10.47 minutes; 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)

[0393] General phosphate deprotection procedure I gave 100 mg of compound 30 (58%) from 210 mg of (IV-45). 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): Room temperature = 9.20 minutes; m / z:841[M+1] + , 914[M+1+DEA] + .

[0389] 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)

[0394] General phosphate deprotection procedure I gave 25 mg of compound 25 (61% yield) from 60 mg of (IV-46). 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): Room temperature = 9.33 minutes; m / z:787[M+1] + , 860[M+1+DEA] + , 932[M+1+2DEA] + .

[0390] Example 50 Synthesis and characterization of 4,6-O-dipentyl-myo-inositol-1,2,3,5-tetrakis(thiophosphate) octasodium salt (compound 50)

[0395] General phosphate deprotection procedure U gave 2.2 mg of compound 50 (3%) from 97 mg of (IV'-1). 1H 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): room temperature = 9.36 min; m / z:850[M+1+2DEA] + , 923[M+1+3DEA] + .

[0391] Example 51 Synthesis and characterization of 4,6-O-bis(5-methoxypentyl)-myo-inositol-1,2,3,5-tetrakis(thiophosphate) octasodium salt (compound 51)

[0396] General phosphate deprotection procedure U gave 2.2 mg of compound 51 (5%) from 54 mg of (IV'-2). 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): Room temperature=9.89 min; m / z:910[M+1+2DEA] + , 983[M+1+3DEA] + .

[0392] Example 52 Synthesis and characterization of 4,6-O-bis(3-carboxypropyl)-myo-inositol-1,2,3,5-tetrakis(phosphate) deca-sodium salt (compound 52)

[0397] General phosphate deprotection procedure J gave 11 mg of compound 52 (34%) from 40 mg of (IV-47). 1H 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): Room temperature=10.73 minutes; m / z:746[M+1+1DEA] + , 819[M+1+2DEA] + .

[0393] Example 53 Synthesis and characterization of 4,6-O-dipropargyl-myo-inositol-1,2,3,5-tetrakis(phosphate) octasodium salt (compound 53)

[0398] General phosphate deprotection procedure U gave 10 mg of compound 53 (35%) from 50 mg of (IV-48). 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): Room temperature=10.70 min; m / z:724[M+1+2DEA] + , 797[M+1+3DEA] + .

[0394] Pharmacological assays A. In vitro inhibition of calcium phosphate crystallization

[0399] The in vitro efficacy of 4,6-substituted IP4 derivatives of the present invention (e.g., compounds 1-53) in inhibiting calcium phosphate crystallization in human plasma samples was assessed by a spectrophotometric assay previously described in the art (Ferrer M et al., Sci Rep 2017;7:6858, doi:10.1038 / s41598-017-07203-x).

[0395]

[0400] A 96-well plate was used. Plasma was added with increasing concentrations of derivative ranging from 0 to 100 μM (1 volume of 4,6-substituted IP4 derivative of the present invention per 19 volumes of plasma). The plasma was then centrifuged at 10,000 g at room temperature and subsequently mixed with a mixture of 5 mM hydrogen phosphate and 41.67 mM calcium to reach 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.

[0396]

[0401] Calcium phosphate crystallization was monitored spectrophotometrically at room temperature for 30 min by measuring the absorbance increment at 550 nm using a Biotek Powerwave XS microplate spectrophotometer (BioTek Instruments, Inc., Winooski, VT, US). Plates were incubated at room temperature on an orbital shaker, and absorbance was measured every 3 min.

[0397]

[0402] Plasma crystallization was assessed based on slope measurements in the linear range of 6 to 24 minutes from a plot of the increase in absorbance versus the logarithm of time. The effectiveness of different myo-inositol phosphate derivatives in preventing the in vitro formation of calcium phosphate crystals was evaluated in human plasma samples using the slopes obtained from 6 to 24 minutes. Inhibition of crystallization was measured by comparing the slope of the control sample (blank plasma) with the slope of the sample containing the inhibitor, as shown below.

[0398]

[0403]

[0399]

number

[0400]

[0404] See Table 13.

[0401] [Table 12-1]

[0402] [Table 12-2]

[0403] B. In vivo effects of calcification and hemoperfusion

[0405] The effects of compounds 1, 6, 9, 14, 18, 31, and 39 on blood perfusion and tissue calcification after limb ischemia were examined using a rat model for 5 days. Limb ischemia was induced in all groups from Days 1 to 3, except for the sham group, in which ischemia was not induced. Animals were administered placebo and active agent formulations from Days 1 to 5. Observations were conducted at several points during the treatment period from Days 0 to 5. All animals were weighed daily before treatment.

[0404]

[0406] Seventy-two male Sprague Dawley (SD) rats (Envigo Corp., Huntingdon, GB) weighing approximately 150-200 g were used. The rats were fed the LASQCdiet® Rod14-H diet (LASvendi GmbH, Soest, DE). The rats were divided into nine groups with eight rats per group as follows:

[0405]

[0407] Group 1 - Control (Sham)

[0408] Group 2 - Saline solution

[0409] Group 3 - Compound 1

[0410] Group 4 - Compound 6

[0411] Group 5 - Compound 9

[0412] Group 6 - Compound 14

[0413] Group 7 - Compound 18

[0414] Group 8 - Compound 31

[0415] Group 9 - Compound 39

[0416] Limb ischemia was induced in rats in groups 2–9 by subcutaneous administration of 150,000 IU / kg of vitamin D3 (cholecalciferol, Duphafral D31000; Zoetis Inc., Parsippany, NJ, US) in saline solution (2 mL / kg) daily from D1 to D3. Rats in group 1 did not receive vitamin D3.

[0406]

[0417] Rats in groups 1 and 2 received 2 mL / kg of saline solution via the subcutaneous route daily from D1 to D5. Animals in groups 3 to 9 received 30 mg / kg of compounds 1, 6, 9, 14, 18, 31, and 39 subcutaneously in saline solution (2 mL / kg) daily from D1 to D5.

[0407]

[0418] Limb function and ischemic status were assessed in all groups on D0 and D5 using a laser Doppler perfusion imaging device, PeriCam PSI Normal Resolution (Perimed AB, Jarfalla, SE). Perfusion differences and perfusion ratios were calculated for each group by comparing baseline with either D0 or D5 readings. In addition, blood perfusion ratios for each treatment group (i.e., groups 2-9) relative to the sham group were also calculated. See Table 14.

[0408]

[0419] All rats in Groups 1-9 were sacrificed 30 min after dosing on D5 to determine their baseline calcium levels. Animals were anesthetized with isoflurane inhalation. The entire aorta, carotid artery, femoral artery, heart, and right kidney of each subject were collected for calcium content measurement. The tissues were freeze-dried for 48-72 h and weighed. The freeze-dried tissues were then digested using a 1:1 HNO3:HClO4 mixture in a dry bath incubator at 180°C for 2-4 h. The digested tissues were then diluted to a final volume of 5 mL (i.e., for the femoral artery and carotid artery) or 10 mL (i.e., for the heart, kidney, and aorta) using ultrapure MilliQ® water (MilliporeSigma (Merck KGaA), Burlington, MA, US). Calcium content was quantified via inductively coupled plasma optical emission spectroscopy (ICP-OES) using an Optima 7300 DV ICP-OES system analyzer (PerkinElmer, Inc., Waltham, MA, US) according to the manufacturer's instructions. The average recovery rate of hemoperfusion compared to vehicle and sham was also calculated. See Table 14. The recovery rate for sham was 100%. The calculated recovery rate of hemoperfusion was calculated using the following equation: 100-((BP sham - BP new drug) / (BP sham - BP vehicle)*100).

[0409] [Table 13]

[0410]

[0420] It should be understood that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections are not intended to limit the scope of the invention and the appended claims in any manner, as they may describe one or more, but not all, exemplary embodiments of the invention as contemplated by the inventors.

[0411]

[0421] The present invention has been described above using functional block diagrams illustrating the implementation of specified functions and their relationships. The boundaries of these functional blocks have been arbitrarily defined herein for the convenience of explanation. Alternative boundaries may be defined so long as the specified functions and their relationships can be appropriately implemented.

[0412]

[0422] The foregoing description of specific embodiments sufficiently reveals the general nature of the present invention, so that others, by applying knowledge within the skill of the art, can readily modify such specific embodiments and / or adapt such embodiments for various uses without undue experimentation and without departing from the general concept of the present invention. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology used herein is for the purpose of description and not of limitation, and that the terminology or terminology used herein should be understood by one of ordinary skill in the art in light of the teaching and guidance.

[0413]

[0423] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

Claims

1. General formula I: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, or a combination thereof, (i) R １ , R ３ , R ７ , and R １１ is an independent OPO ３ ２－ Represents; R ５ and R ９ each of the formula -O(alkyl) ｎ A substituent corresponding to 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 , carbocycle (saturated or unsaturated), and heterocycle (saturated or unsaturated), where R and R' are H or alkyl groups; (ii) R １ , R ３ , R ７ , and R １１ is an independent OPO ３ ２－ Represents; R ５ and R ９ each of the formula -O(alkyl) ｙ Cy(alkyl) ｙ -Z, where y is an integer from 0 to 10, Cy is a cyclic linker, and the terminal group Z is an alkyl, -COR, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO ２ R, -NHCONRR', halogen, and -CF ３ where R and R' are H or alkyl groups; (iii) R １ , R ３ , R ７ , and R １１ is an independent OPO ３ ２－ Represents; R ５ and R ９ each of the formula -O(alkyl) ｙ A (alkyl) ｙ -Z' is a substituent, where y is an integer from 0 to 10, and A is -CONR-, -NHCOO-, -NHSO ２ , -NHCONR-, -NHCO-, and -OCONR, and the terminal group Z' is -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO ２ is selected from the group consisting of R, -NHCONRR', carbocycle (saturated or unsaturated), heterocycle (saturated or unsaturated), where R and R' are H or alkyl groups; (iv) The compound of formula I is an analogue of (i), (ii) or (iii), wherein R １ , R ３ , R ７ Or R １１ At least one of the groups is a thiophosphate (-OPSO ２ ２－ ) is.

2. R ５ and R ９ The compound of claim 1 , wherein are the same substituents.

3. 3. The compound according to claim 1, wherein the pharma- ceutically acceptable salt is a sodium salt.

4. 4. The compound of claim 3, wherein the sodium salt is a tetrasodium salt, a pentasodium salt, a hexasodium salt, a heptasodium salt, an octasodium salt, a nonasodium salt or a deca-sodium salt.

5. 4. The compound of claim 3, wherein the sodium salt is a tetrasodium salt, a pentasodium salt, a hexasodium salt, a heptasodium salt or an octasodium salt.

6. 4. The compound of claim 3, wherein the sodium salt is a hexasodium salt, an octasodium salt, a nonasodium salt or a deca-sodium salt.

7. 4. The compound of claim 3, wherein the sodium salt is an octa- or nona-sodium salt.

8. The compound of any one of claims 1 to 7, selected from the group consisting of Compound 1 to Compound 53, and any combination thereof.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and at least one pharma- ceutically acceptable excipient.

10. A pharmaceutical composition as described in claim 9, wherein the pharmaceutical composition is for use in a method for inhibiting the formation or growth of calcium salts / crystals in a subject in need thereof, the method comprising administering an effective amount of the pharmaceutical composition to the subject.

11. 11. The pharmaceutical composition of claim 10, wherein the calcium salt / crystal is calcium phosphate.

12. 12. The pharmaceutical composition of claim 11, wherein the calcium phosphate is hydroxyapatite.

13. A pharmaceutical composition as described in claim 9, wherein the pharmaceutical composition is for use in a method for treating or preventing a disease or condition associated with pathological crystallization in a subject in need thereof, the method comprising administering an effective amount of the pharmaceutical composition to the subject.

14. A pharmaceutical composition as described in claim 9, wherein the pharmaceutical composition is for use in a method for inhibiting the progression of a crystallization process in a subject in need thereof, the method comprising administering an effective amount of the pharmaceutical composition to the subject.

15. A pharmaceutical composition as described in claim 9, wherein the pharmaceutical composition is for use in a method for restoring or increasing blood perfusion in a subject in need thereof, the method comprising administering an effective amount of the pharmaceutical composition to the subject.

16. The pharmaceutical composition according to any one of claims 10 to 15, wherein the subject is a human.

17. The pharmaceutical composition according to any one of claims 10 to 16, wherein said administration is topical, enteral or parenteral.

18. 18. The pharmaceutical composition of claim 17, wherein the parenteral administration is intravenous or subcutaneous.

19. A compound selected from the group consisting of the compounds listed in Table 1.

20. A kit or article of manufacture comprising at least one compound according to any one of claims 1 to 8, a pharmaceutical composition according to claim 9, or a compound according to claim 19.

21. A method for making a compound of formula I according to any one of claims 1 to 8, comprising the use of at least one compound according to claim 19.

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