IP5 replacement compound

Abstract

The present invention provides IP5-substituted compounds of general formula I, methods for their synthesis, and their use. The IP5-substituted compounds of the present invention have -O(alkyl) at the positions of R1, R2, R4, and R5 n X and -O(alkyl) y Cy(alkyl) y’ -Z chain. Methods, pharmaceutical compositions and formulations, methods of use, products, and kits for the treatment of diseases and disorders, such as those associated with pathological crystallization, are also provided.

Description

Technical Field

[0001] [1] The present invention relates to IP5-substituted compounds, methods for their synthesis, and their use.

Background Art

[0002] [2] Crystallization and precipitation of calcium salts are common phenomena. Usually, these processes are physiologically necessary for the health of an individual. However, sometimes they can become abnormal and / or pathological and cause a variety of diseases and disorders that affect the angio-renal system, and can also have devastating consequences (Khan S et al., Pathological crystallization of calcium oxalate and calcium phosphate, Hydroxyapatite and Related Materials, 1st Edition, edited by Brown P et al. (CRC Press, Boca Raton, FL, US, 1994, Ch.5)). Hydroxyapatite (HAP), a calcium phosphate of the formula Ca 10 (PO4)6(OH)2, has been identified as a substance involved in pathological crystallization (Grases F et al., Cir J 2007;71:1152-1156).

[0003] [3]Several crystallization inhibitors that can affect the formation and growth of HAP, such as pyrophosphate, bisphosphonates (e.g., etidronate, alendronate, ibandronate), and phytate, have already been described in the art (Lomashvili K et al., J Am Soc Nephrol 2004;15:1392 - 1401, Bevilacqua M et al., Lupus 2005;14:773 - 779, Price P et al., Arterioscler Thromb Vasc Biol 2001;21:817 - 824. Price P et al., J Nutr 2001;131:2910 - 2915, Grases F et al., Front Biosci 2006;11:136 - 142). More recently, a number of phytate - related compounds, such as myo - inositol pentakisphosphate (IP5) substitution derivatives, have been proposed for various applications, including, among other things, the inhibition of HAP and / or the prevention and treatment of pathological crystallization. For example, WO2011064559 and Wang H et al., Chem Biol 2014;21:689 - 699 disclose the use of IP5 derivatives for the treatment of cancer. WO2009061393 and Huang X et al., ACS Appl Mater Interfaces 2017;9:10435 - 10445 describe the use of IP5 derivatives as biological tools and calcium chelating agents, respectively. Furthermore, WO2021219135, WO2017098047, and WO2020058321 describe the use of these compounds for the treatment of calcium - related lesions. However, there is still a need in the art for new IP5 substitution derivatives that may be effective in inhibiting the formation and growth of HAP and / or pathological crystallization.

Summary of the Invention

Means for Solving the Problems

[0004] [4]The present invention relates to the general formula I:

[0005]

Chemical formula

[0006] a compound, a pharmaceutically acceptable salt thereof, or a combination thereof (wherein, (i) R1, R2, R3, R5, and R6 each independently represent -OPO3H2, R4 is a substituent of formula II or formula III, or R1, R2, R3, R4, and R5 each independently represent -OPO3H2, and R6 is a substituent of formula II or formula III,

[0007]

Chemical formula

[0008] (ii) R1, R3, R4, R5, and R6 each independently represent -OPO3H2, and R2 is a substituent of formula II or formula III, (iii) R1, R2, R3, R4, and R6 each independently represent -OPO3H2, and R5 is a substituent of formula II or formula III, (iv) R2, R3, R4, R5, and R6 each independently represent -OPO3H2, and R1 is a substituent of formula II, or R1, R2, R4, R5, and R6 each independently represent -OPO3H2, and R3 is a substituent of formula II or formula III, For formula II, n is an integer from 1 to 30, the terminal group X is selected from the group consisting of -H, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', halogen, -CF3, alkyl, alkenyl, alkynyl, carbocyclic ring (substituted or unsubstituted), and heterocyclic ring (substituted or unsubstituted), R and R' are H or an alkyl group, for formula III, y and y' are integers from 0 to 10, Cy is a cyclic linker, and the terminal group Z is selected from the group consisting of alkyl, -COR, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', halogen, and -CF3, and R and R' are H or an alkyl group) is disclosed.

[0009] [5] In some embodiments, the compound of formula I is selected from the group consisting of Compounds 1 to 53. [6] In some embodiments, the pharmaceutically acceptable salt is a sodium salt or a magnesium 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, a decasodium salt, or an undecasodium salt.

[0010] [7] The present invention also provides a pharmaceutical composition comprising the compound of formula I disclosed above and at least one pharmaceutically acceptable excipient. [8] A method of inhibiting the formation or growth of calcium salts / crystals (such as calcium phosphate, hydroxyapatite (HAP)) in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of formula I, or the pharmaceutical composition disclosed herein.

[0011] [9] Further, the present invention provides a method of treating or preventing a disease or disorder associated with pathological crystallization in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of formula I, or the pharmaceutical composition disclosed herein.

[0012]

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

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

[0013]

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

[0014]

[13] The present invention also provides a kit or product comprising at least one compound of formula I or a pharmaceutical composition comprising a compound of formula I, and instructions for use for administration according to any of the methods disclosed herein. In some embodiments, the kit or product may also comprise at least one compound selected from the group consisting of the compounds listed in Table 1.

[0015]

[14] In some embodiments, the present invention further provides a method for the production of a compound of formula I (e.g., Compound 1 to Compound 53) comprising the step of using at least one compound selected from the group consisting of the compounds listed in Table 1.

Brief Description of the Drawings

[0016]

Figure 1A

[15] Figures 1A and 1B are diagrams representing the representative structures of Compound I_A: IP5-4 substituted compounds.

Figure 1B

Figure 2A

[16] Figures 2A and 2B are diagrams representing the representative structures of Compound I_B: IP5-2 substituted compounds.

Figure 2B

Figure 3

[17] A diagram representing the representative structure of Compound I_C: IP5-5 substituted compounds.

Figure 4

[18] A diagram representing the representative structure of Compound I_D: IP5-1 substituted compounds.

Figure 5

[19] A schematic diagram of Synthetic Scheme 1.

Figure 6

[20] Schematic diagram of synthetic scheme 2.

Figure 7A

[21] Figures 7A and 7B are schematic diagrams of synthetic schemes 3 and 6, respectively.

Figure 7B

Figure 8A

[22] Figures 8A and 8B are schematic diagrams of synthetic schemes 4 and 7, respectively.

Figure 8B

Figure 9A

[23] Figures 9A and 9B are schematic diagrams of synthetic schemes 5 and 8, respectively.

Figure 9B

[0017]

[24] The present invention provides IP5-substituted compounds, methods for their synthesis, and their use. In some embodiments, the IP5-substituted compound has the general formula I:

[0018] **CHEMICAL FORMULA**

[0019] or a pharmaceutically acceptable salt thereof, or a combination thereof (wherein, (i) R1, R2, R3, R5, and R6 independently represent -OPO3H2, R4 is a substituent of formula II or formula III, or R1, R2, R3, R4, and R5 independently represent -OPO3H2 and R6 is a substituent of formula II or formula III (see Figures 1A, 1B),

[0020] **CHEMICAL FORMULA**

[0021] (ii) R1, R3, R4, R5, and R6 each independently represent -OPO3H2, and R2 is a substituent of Formula II or Formula III (see Figures 2A and 2B). (iii) R1, R2, R3, R4, and R6 each independently represent -OPO3H2, and R5 is a substituent of Formula II or Formula III (see Figure 3). (iv) R2, R3, R4, R5, and R6 each independently represent -OPO3H2, and R1 is a substituent of Formula II, or R1, R2, R4, R5, and R6 each independently represent -OPO3H2, and R3 is a substituent of Formula II or Formula III (see Figure 4). For Formula II, n is an integer from 1 to 30, and the terminal group X is selected from the group consisting of -H, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', halogen, -CF3, alkyl, alkenyl, alkynyl, carbocyclic (substituted or unsubstituted), and heterocyclic (substituted or unsubstituted), where R and R' are H or an alkyl group. For Formula III, y and y' are integers from 1 to 10, Cy is a cyclic linker, and the terminal group Z is selected from the group consisting of alkyl, -COR, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', halogen, and -CF3, where R and R' are H or an alkyl group). In some embodiments, the IP-substituted compound is of Formula IV, V, VI, VII, VII, VIII, IX, X, or XI.

[0022]

[25] In some embodiments, the IP5-substituted compound is a sodium salt or a magnesium salt. In some embodiments, the IP5-substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt, decasodium salt, or undecasodium salt.

[0023]

[26] Methods, pharmaceutical compositions and formulations, methods of use, products, and kits for the treatment of diseases and disorders, such as diseases and disorders associated with pathological crystallization, are also provided.

[27] To more readily understand the present invention, certain terms are first defined below. As used in this application, unless otherwise expressly indicated herein, each of the following terms should have the meaning set forth below. Further definitions are set forth throughout the application.

[0024] I. Definitions

[28] The present invention includes aspects in which exactly one element of a group is present in, used in, or related to a given product or method. The present invention includes aspects in which two or more, or all, of the elements of a group are present in, used in, or related to a given product or method.

[0025]

[29] 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, 2000, Oxford University Press provide many of the basic dictionaries for terms used in this invention to one of ordinary skill in the art.

[0026]

[30] Units, prefixes, and symbols are shown in the form approved by the International System of Units (SI). Numerical ranges include the numbers defining the range. When a range of values is indicated, it is understood that each intervening integer value between the indicated upper and lower limits of that range, and each fraction thereof, is also clearly disclosed, along with each subrange between such values. It is possible for the upper and lower limits of any range to be independently included in or excluded from the range, and each range including either limit, neither limit, or both limits is also encompassed within the scope of the present invention.

[0027]

[31] When a value is clearly indicated, it is understood that values of approximately the same quantity or amount as the indicated value are also within the scope of the present invention. When a combination is disclosed, each subcombination of the elements of that combination is also clearly disclosed and is within the scope of the present invention. Conversely, when different elements or groups of elements are disclosed individually, their combination is also disclosed. When any element of an invention is disclosed as having a number of alternatives, embodiments of that invention in which each alternative is excluded, either alone or in any combination with other alternatives, are also disclosed by the present invention, two or more elements of the invention can have such exclusions, and all combinations of elements having such exclusions are disclosed herein.

[0028]

[32] About: As used herein, the term "about" refers to a value or composition within an acceptable error range for a particular value or composition determined by one of ordinary skill in the art, which depends to some extent on the limits of the measuring system, i.e., how the value or composition is measured or determined. For example, "about" can mean within one standard deviation or greater than one standard deviation, depending on the convention in the art. Alternatively, "about" can mean a range up to 20%. Further, particularly with respect to biological systems or methods, the term can mean up to one order of magnitude or up to fivefold of the value.

[0029]

[33] When a specific value or composition is provided in the present application and claims, unless otherwise stated, the meaning of "about" should be considered within the acceptable error range for that specific value or composition. When the term "about" is used with a numerical range, it modifies that range by extending the boundaries above or below the indicated numerical values. Thus, "about 10 to 20" means "about 10 to about 20". Generally, the term "about" can change the numerical value above or below the stated value by a change of, for example, 10 percent in either the upward or downward (higher or lower) direction.

[0030]

[34] And / or: As used herein, "and / or" is considered to be each specific invention of two specific features or components, regardless of the presence or absence of others. Thus, the term "and / or" as used in a phrase such as "A and / or B" herein is intended to include "A and B", "A or B", "A" (only), and "B" (only). Similarly, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to include each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (only); B (only); and C (only).

[0031]

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

[0032]

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

[0033]

[37] Comprising: It is understood that any aspect described herein using the word "comprising" also provides other similar aspects described in terms of "consisting of" and / or "consisting essentially of".

[0034]

[38] Compound: As used herein, the term "compound" is meant to include any and all free bases, isomers, and isotopes of the indicated structure. As used herein, the term "isomer" means any geometric isomer, tautomer, zwitterion, stereoisomer, enantiomer, or diastereomer of a compound. A compound can contain one or more chiral centers and / or double bonds and thus can exist as stereoisomers, such as double bond isomers (i.e., geometric E / Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). The present invention encompasses any and all isomers of the compounds described herein, in stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereoisomerically pure), as well as enantiomeric and stereoisomeric mixtures (e.g., racemic compounds). Means for separating enantiomeric and stereoisomeric mixtures of compounds, and their separation into enantiomeric or stereoisomeric components, are well known. The compounds, salts, or complexes of the present invention can be prepared in combination with a solvent or water molecule to form solvates and hydrates by conventional methods. In some aspects, the term compound is used to refer to the IP5-substituted compounds of the present invention.

[0035]

[39] Effective amount: As used herein, the term "effective amount" of a therapeutic agent is an amount sufficient to produce a beneficial or desired result with respect to (i) an IP5-substituted compound of the invention, (ii) any dosage form, pharmaceutical composition, or formulation disclosed herein that comprises at least one IP5-substituted compound of the invention, or (iii) a combination of one or more additional therapeutic agents with an IP5-substituted compound of the invention. In some embodiments, the beneficial or desired result is, for example, a clinical result, and thus the "effective amount" depends on the circumstances to which it is applied. The term "effective amount" can be used interchangeably with "effective dose", "therapeutically effective amount", or "therapeutically effective dose".

[0036]

[40] The term effective amount relates to the particular use of an IP5-substituted compound. For example, if an IP5-substituted compound is used to inhibit the formation or growth of calcium salts / crystals (e.g., calcium phosphate, HAP), the effective amount is the amount of the IP5-substituted compound that can achieve the desired effect (e.g., a decrease in the crystallization / formation of HAP in serum or plasma).

[0037]

[41] Enteral administration: As used herein, the terms "enteral administration" and the related term "enterally" refer to any administration of an IP5-substituted compound of the invention or a pharmaceutical composition comprising said compound via the gastrointestinal tract. Enteral administration includes, but is not limited to, oral, sublingual, and rectal routes of administration.

[0038]

[42] Prevention: As used herein, the term "prevention" refers to measures taken to maintain health and prevent or delay the onset of a disease or disorder, or to reduce its extent and / or the severity of its symptoms. Thus, the prophylactic use of the therapeutic agents disclosed herein, for example, (i) the IP5-substituted compounds of the present invention, or (ii) combinations thereof, or (iii) any dosage form containing at least one IP5-substituted compound of the present invention, or (iv) any formulation containing at least one IP5-substituted compound of the present invention, or (v) combinations of an IP5-substituted compound of the present invention with one or more additional therapeutic agents, corresponds to an amount sufficient to produce a beneficial or desired result.

[0039]

[43] Range: As described herein, any concentration range, percentage range, ratio range, or integer range is understood to include any integer value within the stated range and, where appropriate, a portion thereof (e.g., one-tenth and one-hundredth of an integer), unless otherwise indicated.

[0040]

[44] IP5-Substituted Compounds of the Present Invention: As used herein, the terms "IP5-substituted compounds of the present invention" and their grammatically correct variants refer to compounds of formula I, the substituents of which are those disclosed in compound families I_A, I_B, I_C, and I_D detailed below, and their salts (e.g., their pharmaceutically acceptable salts). In some embodiments, the term IP5-substituted compounds of the present invention includes compounds 1-53, any of their salts (e.g., sodium salts), and any combinations thereof. In some embodiments, the term IP5-substituted compounds of the present invention includes compounds of formula I that are compounds selected from the group consisting of the intermediates in the synthesis of compounds 1-53, e.g., the compounds listed in Table 1, any of their salts (e.g., sodium salts), and any combinations thereof. In some embodiments, the term IP5-substituted compounds of the present invention includes compounds of formula I that are compounds selected from the group consisting of compounds 1-compound 53 and the compounds listed in Table 1, any of their salts (e.g., sodium salts), and any combinations thereof.

[0041]

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

[0042]

[46] Group consisting of the compounds listed in Table 1: In the context of the present invention, a reference to the "group consisting of the compounds listed in Table 1" refers to, for example, intermediate compounds used in the synthesis of the IP5-substituted compounds of the present invention (e.g., compounds selected from the group consisting of Compounds 1 to 53), namely Intermediate II_A, II_B, II_B', II_C, and II_D, Intermediate III_A, III_B, III_C, and III_D, Intermediate IV_A, IV_B, IV_C, and IV_D, Intermediate V_A, V_B, V_C, and V_D, Intermediate VI_A, Intermediate VII_A, Intermediate VIII_B and VIII_B', Intermediate IX_D, and Intermediate X_D. In some embodiments, the group consisting of the compounds listed in Table 1 also includes combinations thereof. In some embodiments, a combination of compounds from the group consisting of the compounds listed in Table 1 can include 2, 3, 4, 5, 6, 7, 8, 9, 10 or more compounds from the group consisting of the compounds listed in Table 1.

[0043]

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

[0044]

[48] Parenteral administration: As used herein, the terms "parenteral administration" and related terms "parenterally" refer to the administration of the IP5-substituted compounds of the present invention characterized by physical penetration of the target tissue and the administration of the compound through said penetration of the tissue. Parenteral administration includes, but is not limited to, the administration of the IP5-substituted compounds of the present invention (e.g., compounds selected from the group consisting of Compounds 1 to 53) or formulations containing the compound by application of the compound or composition through, for example, a surgical incision or through a non-surgical trauma that penetrates the tissue. In particular, parenteral administration includes, but is not limited to, the administration routes of epidural, intra-arterial, intradermal, subarachnoid, intramuscular, intraperitoneal, intrasternal injection, intravascular, intravenous, intravenous infusion, spinal, subcutaneous, and subcutaneous depot.

[0045]

[49] Subject: By "subject" or "individual" or "animal" or "patient" or "mammal" is meant 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, sports animals, pets such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, beef cattle, dairy cows; primates such as apes, monkeys, orangutans, and chimpanzees; canids such as dogs and wolves; felids such as cats, lions, and tigers; equids such as horses, donkeys, and zebras; bears, food animals such as dairy cows, pigs, and sheep; ungulates such as deer and giraffes; rodents such as mice, rats, hamsters, and guinea pigs; etc. In certain embodiments, the mammal is a human subject. In other embodiments, the subject is a human patient. In a particular embodiment, the subject is a human patient with or at risk of having pathological crystallization.

[0046]

[50] Substantially: As used herein, the term "substantially" refers to a qualitative state indicating the entire or near-entire degree or extent of a targeted feature or characteristic. One of ordinary skill in the biological arts understands that biological and chemical phenomena rarely, if ever, complete and / or move towards completeness or obtain absolute results. Thus, the term "substantially" is used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0047]

[51] Therapeutic agent: As used herein, the term "therapeutic agent" is used in a broad sense to include compositions comprising the IP5-substituted compounds 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 disorder associated with pathological crystallization (e.g., crystallization of calcium phosphate or HAP). Thus, generally, a therapeutic agent according to the present invention can be an IP5-substituted compound of the present invention administered alone or in combination with one or more additional therapeutic agents in an amount sufficient to produce a beneficial or desired result.

[0048]

[52] The term therapeutic agent also encompasses prophylactic agents, diagnostic agents, or contrast agents comprising the IP5-substituted compounds of the present invention, where the therapeutic agent is administered (i.e., topically, enterally, or parenterally). A therapeutic agent of the present invention includes substances that can inhibit the formation or growth of calcium salts / crystals (e.g., calcium phosphate, HAP) and / or improve and / or prevent any symptoms associated with pathological crystallization.

[0049]

[53] Local administration: As used herein, the terms "local administration" and related terms "locally" refer to any administration of an IP5-substituted compound of the present invention or a pharmaceutical composition containing said compound by applying the compound or composition to a specific location on or within the body, such as the skin or mucosa. Local administration includes, but is not limited to, administration routes such as ear, skin, nose, transdermal, urethral, vaginal, and urethral.

[0050]

[54] Treating, treatment, therapy: As used herein, the terms "treating" or "treatment" or "therapy" refer to partially or completely reducing, ameliorating, improving, alleviating, delaying the onset of, inhibiting the progression of, reducing the severity of, or decreasing the incidence of one or more symptoms or characteristics of a disease, or any combination thereof.

[0051]

[55] Treatment with an IP5-substituted compound of the present invention can, for example, (i) reduce the risk of developing a lesion associated with a disease, disorder, and / or condition, (ii) delay the onset of a disease, disorder, and / or condition, or a lesion associated with said disease, disorder, and / or condition, or (iii) reduce the symptoms and / or consequences of a disease, disorder, and / or condition, or a lesion associated with said disease, disorder, and / or condition, for the purpose of treating subjects who do not exhibit signs of a disease, disorder, and / or condition, and / or subjects who exhibit only early signs of a disease, disorder, and / or condition.

[0052]

[56] Thus, generally, the term "treatment" refers to (i) inhibiting a disease or pathological condition, i.e., delaying or arresting their onset or progression; (ii) alleviating a disease or pathological condition, i.e., regressing said disease or pathological condition, or their symptoms; (iii) stabilizing a disease or pathological condition; and (iv) counteracting the effects resulting from a target disease or pathological condition in a subject, including any combination thereof.

[0053]

[57] ug, uM, uL: As used herein, the terms “ug,” “uM,” and “uL” are used interchangeably with “μg,” “μΜ,” and “μL,” respectively. II. IP5 Substituted Compounds

[58] The present invention provides IP5 substituted compounds, methods for their synthesis, and their use. In some embodiments, the IP5 substituted compound has the general formula I:

[0054]

Chemical Formula

[0055] a compound of, a pharmaceutically acceptable salt thereof, or a combination thereof (wherein,

[59] R1, R2, R3, R5, and R6 independently represent -OPO3H2, R4 is a substituent of formula II or formula III, or R1, R2, R3, R4, and R5 independently represent -OPO3H2, and R6 is a substituent of formula II or formula III,

[0056]

Chemical Formula

[0057]

[60] R1, R3, R4, R5, and R6 independently represent -OPO3H2, and R2 is a substituent of formula II or formula III,

[61] R1, R2, R3, R4, and R6 independently represent -OPO3H2, and R5 is a substituent of formula II or formula III,

[62] R2, R3, R4, R5, and R6 each independently represent -OPO3H2, R1 is a substituent of formula II, or R1, R2, R4, R5, and R6 each independently represent -OPO3H2, and R3 is a substituent of formula II or formula III,

[63] For formula II, n is an integer from 1 to 30, and the terminal group X is selected from the group consisting of -H, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', halogen, -CF3, alkyl, alkenyl, alkynyl, carbocycle (substituted or unsubstituted), and heterocycle (substituted or unsubstituted), R and R' are H or an alkyl group; for formula III, y and y' are integers from 1 to 10, Cy is a cyclic linker, and the terminal group Z is selected from the group consisting of alkyl, -COR, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', halogen, and -CF3, and R and R' are H or an alkyl group). In some embodiments, the IP-substituted compound is of formula IV, V, VI, VII, VII, VIII, IX, X, or XI.

[0058]

[64] In some embodiments, all the negative charges in the IP5-substituted compound of the present invention are ions having a positive charge (e.g., Na + , Ca ++ , Mg ++) is not compensated by the charge. Therefore, the IP5-substituted compound of the present invention can be, for example, a tetraionic salt (e.g., tetrasodium salt), a pentaionic salt (e.g., pentasodium salt), a hexaionic salt (e.g., hexasodium salt), a heptaionic salt (e.g., heptasodium salt), an octaionic salt (e.g., octasodium salt), a nonaionic salt (e.g., nonasodium salt), a decaionic salt (e.g., decasodium salt), or an undecaionic salt (e.g., undecasodium salt). In some embodiments, the presence of a group having an additional negative charge in the IP5-substituted compound can result in the formation of a complex with an additional ion. In some embodiments, the IP5-substituted compound of the present invention is a sodium salt. In some embodiments, the IP5-substituted compound is a tetrasodium salt, a pentasodium salt, a hexasodium salt, a heptasodium salt, an octasodium salt, a nonasodium salt, a decasodium salt, or an undecasodium salt. In some embodiments, the IP5-substituted compound is a tetrasodium salt, a pentasodium salt, a hexasodium salt, a heptasodium salt, or an octasodium salt. In some embodiments, the IP5-substituted compound is a hexasodium salt, an octasodium salt, a nonasodium salt, or a decasodium salt. Formula I and the remaining parts of the formulas shown in the present invention are meant to encompass any isomers of the compounds thereby covered.

[0059]

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

[0060]

[66] In the context of the present invention, the term "alkyl" or "alkyl chain" refers to a hydrocarbon moiety that can be saturated, partially unsaturated, straight-chain, branched-chain, cyclic, or cyclic with a straight-chain or branched-chain side chain containing from 1 to 30 carbon atoms. Examples include, but are not limited to, C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, n- or isobutyl, and cycloalkyl such as cyclohexyl. The term alkyl can be extended to include alkyl groups linked or bridged by heteroatoms. In the context of the present invention, heteroatoms are nitrogen (N), sulfur (S), oxygen (O), and halogen.

[0061]

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

[0062]

[68] An "amine functional group" or "amine group" is a functional group NRR' where R and R' are independently selected, for example, from hydrogen (-H) and alkyl groups, such as C1-C n alkyl where n is an integer from 0 to 30.

[0063]

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

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

[0064]

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

[0065]

[72] The term "carbon ring" refers to a 3- to 10-membered carbon ring that can be saturated, partially unsaturated, or aromatic (e.g., phenyl, cyclopentyl, cyclopropyl), and is bonded to the rest of the molecule via available C atoms.

[0066]

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

[0067]

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

[0068]

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

[76] In the context of the present invention, the term "-OPO3 2- " also refers indistinguishably to -OPO3H - and -OPO3H2.

[0069]

[77] In some embodiments, the IP5 substituted compounds of the present invention or the intermediate compounds disclosed herein can be detected and / or quantified using the methods disclosed in US9612250. See also US8377909, US8778912, and US20070066574.

[0070]

[78] The IP5 substituted compounds of the present invention can exist in any form commonly used in pharmaceutical technology. Specific embodiments include, but are not limited to, sodium salts, magnesium salts, potassium salts, ammonium salts, free acids, or mixtures of the foregoing forms. Other pharmaceutically acceptable salts are known to those skilled in the art and can be obtained by the methods already described (Haynes M et al., J. Pharmaceutical Sci. 2005;94:2111-2120).

[0071]

[79] In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, IP5-substituted compounds selected from the group consisting of Compounds 1-53 and combinations thereof. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 1. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 2. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 3. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 4. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 5. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 6. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 7. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 8. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 9. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 10. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 11. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 12. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 13. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 14. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 15. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 16. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 17. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 18. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 19. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, Compound 20.In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 21. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 22. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 23. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 24. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 25. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 26. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 27. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 28. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 29. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 30. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 31. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 32. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 33. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 34. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 35. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 36. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 37. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 38. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 39. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 40. In some embodiments, the IP5-substituted compound of the present invention comprises or consists of Compound 41.In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, compound 42. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, compound 43. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, compound 44. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, compound 45. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, compound 46. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, compound 47. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, compound 48. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, compound 49. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, compound 50. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, compound 51. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, compound 52. In some embodiments, the IP5-substituted compounds of the present invention comprise, or consist of, compound 53.

[0072]

[80] The IP5-substituted compounds of the present invention are disclosed in the myo form.

[81] The present invention also provides chemical intermediate compounds useful for the preparation of the IP5-substituted compounds of the present invention (e.g., Compounds 1 to 53). In some embodiments, such intermediates are the compounds listed in Table 1. The intermediate compounds disclosed herein can be converted to the IP5-substituted compounds of the present invention by utilizing the procedures disclosed herein. Accordingly, the present invention provides a method for producing an IP5-substituted compound of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 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 a method for producing the intermediate compounds disclosed herein. Accordingly, the present invention provides a method for producing an intermediate compound selected from the group consisting of the compounds listed in Table 1 for producing an IP5-substituted compound of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53).

[0073]

[82] In some embodiments, the IP5-substituted compounds of the present invention have the following formula:

[0074] [Chemical formula]

[0075] comprising or consisting of the compound (wherein n is an integer from 1 to 30, alkyl is CH2, and X is -H, -OH, -OMe, pyrazole, triazole, -COOH, CONRR’, -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR’, -CF3, alkyl, cyclopropane, cyclopentane, or pyrazole). See Figure 1A. In some embodiments, n is an integer from 1 to 20. In some embodiments, n is an integer from 1 to 10. 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 IP5-substituted compound is the sodium salt. In some embodiments, the IP5-substituted compound is the tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP5-substituted compound is the tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, or octasodium salt. In some embodiments, the IP5-substituted compound is the hexasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP5-substituted compound is the octasodium salt. In some embodiments, n is 5, alkyl is CH2, and X is -H (Compound 1). In some embodiments, n is 3, alkyl is CH2, and X is -H (Compound 24). In some embodiments, n is 1, alkyl is CH2, and X is -H (Compound 22). In some embodiments, n is 5, alkyl is CH2, and X is -OH (Compound 2). In some embodiments, n is 10, alkyl is CH2, and X is -OH (Compound 21). In some embodiments, n is 5, alkyl is CH2, and X is -OMe (Compound 3). In some embodiments, n is 7, alkyl is CH2, and X is -OMe (Compound 23). In some embodiments, n is 5, alkyl is CH2, and X is -COOH (Compound 4). In some embodiments, n is 10, alkyl is CH2, and X is -COOH (Compound 20). In some embodiments, n is 3, alkyl is CH2, and X is -CH(CH3)2 (Compound 12).In some embodiments, n is 5, alkyl is CH2, and X is -CF3 (Compound 13). In some embodiments, n is 5, alkyl is CH2, and X is -NHCOMe (Compound 19). In some embodiments, n is 2, alkyl is CH2, and X is cyclopentane (Compound 16). In some embodiments, n is 2, alkyl is CH2, and X is cyclopropane (Compound 17). In some embodiments, n is 5, alkyl is CH2, and X is pyrazole (Compound 18). In some embodiments, n is 5, alkyl is CH2, and X is -CONH2 (Compound 33).

[0076]

[83] In some embodiments, n is an integer from 3 to 30, alkyl is CH2, and X is an amine group. See Figure 1A; Wang, 2014, supra. In some embodiments, n is an integer from 3 to 20. In some embodiments, n is an integer from 3 to 10. In some embodiments, n is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, the IP5-substituted compound is a sodium salt. In some embodiments, the IP5-substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP5-substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, or octasodium salt. In some embodiments, the IP5-substituted compound is a hexasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP5-substituted compound is an octasodium salt. In some embodiments, n is 3, alkyl is CH2, and X is -NH2 (Compound 27). In some embodiments, n is 6, alkyl is CH2, and X is -NH2 (Compound 28).

[0077]

[84] In some embodiments, the IP5-substituted compound of the present invention has the following formula:

[0078]

Chemical formula

[0079] comprises or consists of the compound(s) of.

[85] In the formula, n is an integer from 1 to 30, alkyl is CH2, and X is -H, -OH, -OMe, an amine group, pyrazole, triazole, -COOH, CONRR’, -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR’, -CF3, cyclopropane, cyclopentane, pyrazole, or an alkynyl group. See Figure 2A. In some embodiments, n is an integer from 1 to 20. In some embodiments, n is an integer from 1 to 10. In some embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In some embodiments, the IP5-substituted compound is a sodium salt. In some embodiments, the IP5-substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP5-substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, or octasodium salt. In some embodiments, the IP5-substituted compound is a hexasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP5-substituted compound is an octasodium salt. In some embodiments, n is 5, alkyl is CH2, and X is -H (Compound 6). In some embodiments, n is 3, alkyl is CH2, and X is -H (Compound 34). In some embodiments, n is 5, alkyl is CH2, and X is -OH (Compound 40). In some embodiments, n is 5, alkyl is CH2, and X is -OMe (Compound 7). In some embodiments, n is 9, alkyl is CH2, and X is -OMe (Compound 8). In some embodiments, n is 19, alkyl is CH2, and X is -OMe (Compound 9). In some embodiments, n is 29, alkyl is CH2, and X is -OMe (Compound 10). In some embodiments, n is 5, alkyl is CH2, and X is -NHCOMe (Compound 35). In some embodiments, n is 5, alkyl is CH2, and X is -CF3 (Compound 36).In some embodiments, n is 5, alkyl is CH2, and X is -CONH2 (Compound 37). In some embodiments, n is 2, alkyl is CH2, and X is cyclopentane (Compound 38). In some embodiments, n is 2, alkyl is CH2, and X is cyclopropane (Compound 39). In some embodiments, n is 1, alkyl is CH2, and X is C≡CH (Compound 43).

[0080]

[86] In some embodiments, the IP5-substituted compounds of the present invention have the following formula:

[0081]

Chemical formula

[0082] include or consist of compounds of:

[87] In the formula, n is an integer from 1 to 30, alkyl is CH2, and X is -H, -OH, -OMe, an amine group, pyrazole, triazole, -COOH, CONRR’, -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR’, -CF3, cyclopropane, cyclopentane, or pyrazole. See Figure 3A. In some embodiments, n is an integer from 1 to 20. In some embodiments, n is an integer from 1 to 10. 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 IP5-substituted compound is a sodium salt. In some embodiments, the IP5-substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP5-substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, or octasodium salt. In some embodiments, the IP5-substituted compound is a hexasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP5-substituted compound is an octasodium salt. In some embodiments, n is 3, alkyl is CH2, and X is -H (Compound 29). In some embodiments, n is 9, alkyl is CH2, and X is -OMe (Compound 31). In some embodiments, n is 5, alkyl is CH2, and X is -OMe (Compound 44). In some embodiments, n is 5, alkyl is CH2, and X is -CF3 (Compound 45). In some embodiments, n is 2, alkyl is CH2, and X is cyclopropane (Compound 30).

[0083]

[88] In some embodiments, the IP5-substituted compound of the present invention has the following formula:

[0084] [Chemical formula]

[0085] and includes or consists of the compounds of these.

[89] In the formula, n is an integer from 1 to 30, alkyl is CH2, and X is -H, -OH, -OMe, an amine group, pyrazole, triazole, -COOH, CONRR’, -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR’, -CF3, cyclopropane, cyclopentane, or pyrazole. See Figure 4. In some embodiments, n is an integer from 1 to 20. In some embodiments, n is an integer from 1 to 10. 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 IP5-substituted compound is a sodium salt. In some embodiments, the IP5-substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP5-substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, or octasodium salt. In some embodiments, the IP5-substituted compound is a hexasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP5-substituted compound is an octasodium salt. In some embodiments, n is 3, alkyl is CH2, and X is -H (Compound 32). In some embodiments, n is 9, alkyl is CH2, and X is -OMe (Compound 47). In some embodiments, n is 5, alkyl is CH2, and X is -NHCOMe (Compound 49). In some embodiments, n is 5, alkyl is CH2, and X is -CF3 (Compound 50). In some embodiments, n is 2, alkyl is CH2, and X is cyclopropane (Compound 48). In some embodiments, n is 2, alkyl is CH2, and X is cyclopentane (Compound 51).

[0086]

[90] In some embodiments, the IP5-substituted compound of the present invention has the following formula:

[0087]

Chemical formula

[0088] comprises or consists of the compounds of

[91] wherein y and y’ are integers from 0 to 10, alkyl is CH2, Cy is selected from the group consisting of 1,3-substituted phenyl, 1,4-substituted phenyl, piperazine, triazole-1, and triazole-2, and Z is selected from the group consisting of -CH3, -OMe, -CF3, COCH3, and -COOH3. See Figure 1B. In some embodiments, the IP5-substituted compound is the sodium salt. In some embodiments, the IP5-substituted compound is the tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP5-substituted compound is the tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, or octasodium salt. In some embodiments, the IP5-substituted compound is the hexasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP5-substituted compound is the octasodium salt or nonasodium salt. In some embodiments, y or y’ is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, y is 3, y’ is 0, alkyl is CH2, Cy is 1,4-substituted phenyl, and Z is -CH3 (Compound 11). In some embodiments, y is 3, y’ is 0, alkyl is CH2, Cy is 1,4-substituted phenyl, and Z is -OMe (Compound 14). In some embodiments, y is 3, y’ is 0, alkyl is CH2, Cy is 1,3-substituted phenyl, and Z is -CF3 (Compound 15). In some embodiments, y is 2, y’ is 0, alkyl is CH2, Cy is piperazine, and Z is -COCH3 (Compound 5). In some embodiments, y is 3, y’ is 2, alkyl is CH2, Cy is triazole-1, and Z is -COOH (Compound 25). In some embodiments, y is 6, y’ is 0, alkyl is CH2, Cy is triazole-1, and Z is -COOH (Compound 26).

[0089]

[92] In some embodiments, the IP5-substituted compound of the present invention has the following formula:

[0090]

Chem.

[0091] comprises or consists of the compound of.

[93] In the formula, y and y’ are integers from 0 to 10, alkyl is CH2, Cy is selected from the group consisting of 1,3-substituted phenyl, 1,4-substituted phenyl, piperazine, triazole-1, and triazole-2, and Z is selected from the group consisting of -CH3, -OMe, -CF3, COCH3, and -COOH3. See Figure 2B. In some embodiments, the IP5-substituted compound is a sodium salt. In some embodiments, the IP5-substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP5-substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, or octasodium salt. In some embodiments, the IP5-substituted compound is a hexasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP5-substituted compound is an octasodium salt or nonasodium salt. In some embodiments, y or y’ is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, y is 5, y’ is 1, alkyl is CH2, Cy is triazole-1, and Z is -OMe (Compound 41). In some embodiments, y is 1, y’ is 2, alkyl is CH2, Cy is triazole-2, and Z is -COOH (Compound 46).

[0092]

[94] In some embodiments, the IP5-substituted compound of the present invention has the following formula:

[0093]

Chem.

[0094] comprises or consists of the compound of.

[95] In the formula, y and y’ are integers from 0 to 10, alkyl is CH2, Cy is selected from the group consisting of 1,3-substituted phenyl, 1,4-substituted phenyl, piperazine, triazole-1, and triazole-2, and Z is selected from the group consisting of -CH3, -OMe, -CF3, COCH3, and -COOH3. See Figure 3. In some embodiments, the IP5-substituted compound is a sodium salt. In some embodiments, the IP5-substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP5-substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, or octasodium salt. In some embodiments, the IP5-substituted compound is a hexasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP5-substituted compound is an octasodium salt or nonasodium salt. In some embodiments, y or y’ is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, y is 5, y’ is 1, alkyl is CH2, Cy is triazole-1, and Z is -OMe (Compound 42).

[0095]

[96] In some embodiments, the IP5-substituted compound of the present invention has the following formula:

[0096] [Chemical formula]

[0097] comprises or consists of the compound of.

[97] In the formula, y and y' are integers from 0 to 10, alkyl is CH2, Cy is selected from the group consisting of 1,3-substituted phenyl, 1,4-substituted phenyl, piperazine, triazole-1, and triazole-2, and Z is selected from the group consisting of -CH3, -OMe, -CF3, COCH3, and -COOH3. See Figure 4. In some embodiments, the IP5-substituted compound is a sodium salt. In some embodiments, the IP5-substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP5-substituted compound is a tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, or octasodium salt. In some embodiments, the IP5-substituted compound is a hexasodium salt, octasodium salt, nonasodium salt, or decasodium salt. In some embodiments, the IP5-substituted compound is an octasodium salt or nonasodium salt. In some embodiments, y or y' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, y is 5, y' is 1, alkyl is CH2, Cy is triazole-1, and Z is -OMe (Compound 52). In some embodiments, y is 1, y' is 2, alkyl is CH2, Cy is triazole-2, and Z is -COOH (Compound 53).

[0098]

Table 1-1

[0099]

Table 1-2

[0100]

Table 1-3

[0101]

Table 1-4

[0102]

Table 1-5

[0103]

Table 1-6

[0104]

[98] The IP5-substituted compounds of the present invention and the intermediates for their synthesis can be synthesized by using the methods described herein and other methods known in the field of organic chemistry. In some embodiments, the methods include, but are not limited to, the general procedures shown in Synthesis Schemes 1, 2, 3, 4, 5, 6, 7, and 8 described herein. Accordingly, in some embodiments, the present invention provides a method for producing an IP5-substituted compound of the present invention, which includes the step of applying Synthesis Scheme 1 disclosed below. In some embodiments, the present invention provides a method for producing an IP5-substituted compound of the present invention, which includes the step of applying Synthesis Scheme 2 disclosed below. In some embodiments, the present invention provides a method for producing an IP5-substituted compound of the present invention, which includes the step of applying Synthesis Scheme 3 disclosed below. In some embodiments, the present invention provides a method for producing an IP5-substituted compound of the present invention, which includes the step of applying Synthesis Scheme 4 disclosed below. In some embodiments, the present invention provides a method for producing an IP5-substituted compound of the present invention, which includes the step of applying Synthesis Scheme 5 disclosed below. In some embodiments, the present invention provides a method for producing an IP5-substituted compound of the present invention, which includes the step of applying Synthesis Scheme 6 disclosed below. In some embodiments, the present invention provides a method for producing an IP5-substituted compound of the present invention, which includes the step of applying Synthesis Scheme 7 disclosed below. In some embodiments, the present invention provides a method for producing an IP5-substituted compound of the present invention, which includes the step of applying Synthesis Scheme 8 disclosed below.

[0105]

[99] In some embodiments, the present invention provides a method for producing an intermediate for the synthesis of an IP5-substituted compound of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53), which comprises applying any one of the synthetic schemes 1, 2, 3, 4, 5, 6, 7, or 8 disclosed below when applicable.

[0106]

[0100] Scheme 1: Generally, the IP5-substituted compound of the present invention (i.e., Compound I_A) can be obtained by deprotecting the intermediate of Formula IV_A (Scheme 1). The "protecting group" or GP can be, without limitation, benzyl, levulinylbenzyl, tert-butyl, o,o'-xylyl (by the bonding of two PGs of the same phosphate), 9-fluorenylmethyl, cyanoethyl, and other suitable protecting groups in each case. The intermediate of Formula IV_A may be obtained by phosphorylation of the intermediate of Formula III_A according to the procedures described in the literature, for example, reaction with a phosphoramidite derivative and subsequent oxidation. At the same time, the intermediate of Formula III_A can be obtained by hydrolysis of the intermediate of Formula II_A in an acidic medium. Finally, the intermediate of Formula II_A may be obtained by alkylation of the intermediate (2) with an alkylating agent. The preparation of (2) has already been described in the literature (Martin S et al., J Org Chem 1994;59(17):4805 - 4820, Kardivel M, Org Biomol Chem 2008;6(11):1966 - 1972). The "leaving group" or LG can be, without limitation, chloride, bromide, iodide, toluenesulfonyl (Ts), or methylsulfonyl (Ms). See Figure 5.

[0107]

[0101] Scheme 2: As an alternative to Scheme 1, when R4 or R6 contains a substituted 1,2,3-triazole, the compound of formula I_A can be obtained by following the alternative route described in Scheme 2. In this method, the intermediate of formula III_A can be obtained via a click reaction using the intermediate of formula VI_A and an alkynyl “click agent” as starting materials. The intermediate VI_A can be obtained by alkylation and hydrolysis of intermediate 2 with appropriate reagents. As another alternative, when R4 or R6 contains a terminal amine group, the compound of formula I_A can be obtained by phosphorylation of the compound VI_A to obtain compound VII_A, and subsequent deprotection / reduction of such a compound. See Figure 6.

[0108]

[0102] Scheme 3: Compound I_B may be obtained using a synthetic route similar to that used for compound I_A. Thus, compound I_B may be obtained by deprotecting the intermediate of formula IV_B (Scheme 3). The intermediate of formula IV_B may be obtained by phosphorylating the intermediate of formula III_B. At the same time, the intermediate of formula III_B can be obtained by hydrolysis of the intermediate of formula II_B or VIII_B in an acidic medium. The intermediate of formula VIII_B may be obtained by benzylation of intermediate II_B’. Finally, the intermediate of formula II_B or B’ may be obtained by alkylation of intermediate (3) or (4) with an alkylating agent, respectively. The preparation of (3) and (4) has already been described in the art (Aiba T et al., Org Biomol Chem 2016;14(28):6672 - 6675 and Chen W et al., Eur J Med Chem 2015;93:172 - 181). Alternatively, when R2 contains a substituted 1,2,3-triazole, the compound of formula I_B can be obtained by following an alternative route. In this method, the intermediate of formula III_B can also be obtained via a click reaction using the alkynyl intermediate of formula III_B and an azide “click agent” as starting materials. See Figure 7A.

[0109]

[0103] Scheme 4: Compound I_C can be obtained by deprotection of the intermediate of formula IV_C (Scheme 4). The intermediate of formula IV_C may be obtained by phosphorylating the intermediate of formula IV_C. The intermediate of formula III_C can be obtained by benzylation of intermediate II_C. Finally, the intermediate of formula II_C may be obtained by alkylation of intermediate (33) with an appropriate alkylating agent. The preparation of (33) has already been described in the art (Phenix C. et al., ChemBioChem 2008;9(10):1591-1602). See Figure 8A.

[0110]

[0104] Scheme 5: Compound I_D may be obtained by deprotection of the intermediate of formula IV_D (Scheme 5). The intermediate of formula IV_D may be obtained by phosphorylating the intermediate of formula III_D. The intermediate of formula III_D can be obtained by benzylation of intermediate IX_D. Intermediate IX_D can be obtained by hydrolysis of intermediate II_D. Finally, the intermediate of formula II_D may be obtained by alkylation of intermediate (34) with an appropriate alkylating agent. The preparation of the racemic compound (34) is in the art (Chen, 2015, supra). Alternatively, when R2 contains a substituted 1,2,3-triazole, the compound of formula I_D can be obtained by following an alternative route. In this method, the intermediate of formula IX_D can also be obtained via a click reaction using an alkynyl intermediate of formula IX_D and an azide "click agent" as starting materials. See Figure 9A.

[0111]

[0105] Scheme 6: As an alternative to Scheme 3, when R2 contains a substituted 1,2,3-triazole or an acylamine, the compound of formula I_B can be obtained by following the alternative route described in Scheme 6. In this method, the intermediate of formula III_B can also be obtained via a click reaction using an azide intermediate of formula V_B and an alkynyl "click agent" as starting materials. Intermediate V_B can be obtained by alkylation of intermediate 3 with an appropriate reagent. As another alternative, when R2 contains a terminal acylamine group, the compound of formula III_B can be obtained by amidation of the corresponding amino compound III_B. See Figure 7B.

[0112]

[0106] Scheme 7: As an alternative to Scheme 4, when R5 contains a substituted 1,2,3-triazole, the compound of formula I_C can be obtained by following the alternative route described in Scheme 7. In this method, the intermediate of formula II_C can also be obtained via a click reaction using the azide intermediate of formula V_C and an alkynyl "click agent" as starting materials. Intermediate V_C can be obtained by alkylation of intermediate 33 with appropriate reagents. See Figure 8B.

[0113]

[0107] Scheme 8: As an alternative to Scheme 5, when R1 or R3 contains a substituted 1,2,3-triazole, the compound of formula I_D can be obtained by following the alternative route described in Scheme 8. In this method, the intermediate of formula IX_D can also be obtained via a click reaction using the alkynyl intermediate of formula V_C (when X is a triple bond) and an azide "click agent" as starting materials. Intermediate V_C (when X is a triple bond) can be obtained by alkylation of intermediate 34 and subsequent hydrolysis of such an alkenyl-protected compound II_D. As another alternative, when R1 or R3 contains an alkyl group, the intermediate of formula III_D having an alkyl as R1 can be obtained via debenzylation of intermediate IX_D where X corresponds to a triple bond. See Figure 9A.

[0114]

[0108] Representative IP5-substituted compounds of the present invention (for example, compounds selected from the group consisting of Compounds 1 to 53) are shown herein, and all of them are in the myo conformation. However, it is understood that any exemplary IP5-substituted compound of the present invention in the myo conformation is not limited to the representative conformations shown. Thus, for example, Compounds 1 to 53 and the intermediates shown herein are in the myo conformation. In this conformation, the natural myo isomer has a structure in which 5 out of 6 hydroxyls (the 1st, 3rd, 4th, 5th, and 6th) are equatorial and the 2nd hydroxyl group is axial.

[0115]

[0109] The present invention also provides a method for manufacturing a medicament for the treatment of pathological crystallization, which comprises a step of using an intermediate compound selected from the group consisting of the compounds listed in Table 1. Compounds of formula I for use as medicaments (e.g., selected from the group consisting of Compound 1 to Compound 53) are also provided. The use of compounds of formula I (e.g., selected from the group consisting of Compound 1 to Compound 53) for the manufacture of medicaments for the prevention or treatment of diseases associated with pathological crystallization is also provided.

[0116] III. Pharmaceutical Compositions

[0110] The present invention also provides a method for the prevention and / or treatment of the diseases and disorders disclosed herein (e.g., pathological crystallization), wherein the pharmaceutical composition comprises at least one IP5-substituted compound of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53), and provides a pharmaceutical composition for use in the method. In some embodiments, the pharmaceutical composition comprises the IP5-substituted compound of the present invention (e.g., a compound selected from the group consisting of Compound 1 to Compound 53) alone or together with one or more pharmaceutically acceptable excipients or carriers.

[0117]

[0111] As used herein, the term "excipient" refers to a substance that aids in the absorption of the components of a pharmaceutical composition, stabilizes those components, and activates or aids in the preparation of the composition. Thus, examples of excipients used in parenteral formulations include, but are not limited to, antibacterial agents (e.g., benzalkonium chloride, metacresol, thimerosal), co-solvents (e.g., ethanol), buffers, tonicity agents (e.g., NaCl), and pH regulators (e.g., carbonate, citrate, phosphate solutions).

[0118] As in the case of excipients, a "pharmaceutically acceptable vehicle" is a substance used in a composition to dilute any of the components contained therein to a determined volume or weight (e.g., 0.9% (w / v) aqueous NaCl solution). A pharmaceutically acceptable vehicle is an inert substance or a substance having an action similar to any of the components including the pharmaceutical composition of the present invention. The role of the vehicle is to enable the incorporation of other components, to enable better dosing and administration, or to impart viscosity and shape to the composition.

[0119]

[0113] The pharmaceutical composition can contain approximately 1% to approximately 95% of the active ingredient. In some embodiments, for example, the pharmaceutical composition of the present invention can contain approximately 20% to approximately 90% of the active ingredient (i.e., the IP5-substituted compound of the present invention or a combination thereof, alone or in combination with one or more additional therapeutic agents, for example).

[0120]

[0114] Formulations of pharmaceutical compositions suitable for parenteral administration include the active ingredient, for example, the IP5-substituted compound of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53), combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline (e.g., 0.9% (w / v) aqueous NaCl solution). Such formulations can be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations can be prepared, packaged, or sold in unit dosage form, for example, in ampoules, or in multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations can further contain one or more additional components including, but not limited to, suspending agents, stabilizers, or dispersing agents.

[0121]

[0115] In some embodiments, in a formulation for parenteral administration, the active ingredient, for example, an IP5 substituted compound of the present invention (for example, a compound selected from the group consisting of Compounds 1 to 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.

[0122]

[0116] The pharmaceutical composition can be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution can be formulated according to known techniques and may contain, in addition to the active ingredient (e.g., an inositol phosphate of the present invention), further ingredients such as a dispersing agent, wetting agent, or suspending agent described herein. Such sterile injectable formulations can be prepared using 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.

[0123]

[0117] Other useful administrable formulations include those containing the active ingredient in microcrystalline form, in liposomal formulations, or as components of biodegradable polymer systems. Compositions for sustained release or implantation can contain pharmaceutically acceptable polymer materials or hydrophobic materials such as emulsions, ion exchange resins, poorly soluble polymers, or poorly soluble salts. Methods for making compositions and formulations for administering the IP5-substituted compounds of the present invention, including controlled release or sustained release formulations containing the active agent, are described in the art. See, for example, Remington: The Science and Practice of Pharmacy, 23rd Edition, 2021, Academic Press; US6340475, US6488962, US6451808, US5972389, US5582837, and US5007790; US20030147952, US20030104062, US20030104053, US20030044466, US20030039688, and US20020051820; WO2003035041, WO2003035040, WO2003035029, WO2003035177, WO2003035039, WO2002096404, WO2002032416, WO2001097783, WO2001056544, WO2001032217, WO1998055107, WO1998011879, WO1997047285, WO1993018755, and WO1990011757.

[0124]

[0118] The medicaments of the present invention are manufactured by methods known in the art, in particular by conventional mixing, coating, granulation, dissolution, or lyophilization.

[0119] The present invention also provides a compound or combination of compounds or a formulation according to any of the above aspects of the present invention in the broadest definition given for use as a medicament, or as defined in any of the aspects shown above.

[0125]

[0120] The present invention also provides a compound, a combination of compounds, or a formulation according to any of the above aspects of the present invention in the broadest definition given, or as defined by any of the aspects shown above, for use in the treatment and / or prevention of the diseases or disorders disclosed herein.

[0126]

[0121] The present invention also provides a compound, a combination of compounds, or a formulation according to any of the above aspects of the present invention in the broadest definition given, or as defined by any of the aspects shown above, for use in the manufacture of a medicament for the prevention and / or treatment of the diseases or disorders disclosed herein.

[0127] IV. Products and Kits

[0122] The present invention also provides products and kits. Such products and kits can include a container (e.g., a box) containing one or more vials containing a formulation comprising one or more of the IP5-substituted compounds of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53) and / or a solvent for its medical administration or other use according to the methods disclosed herein.

[0128]

[0123] The kit or product provided according to the present invention can also include a pamphlet or instruction manual describing the process and dosage of medical administration disclosed herein, or the use of the IP5-substituted compounds of the present invention (e.g., a compound selected from the group consisting of Compounds 1 to 53) according to the methods disclosed herein. In some aspects, the kit or product can include a number of vials, each containing a single dose. In other aspects, the kit or product can include one or more vials, each containing two or more doses.

[0129]

[0124] In some embodiments, the product is a bag containing a solution of an IP5-substituted compound of the invention (e.g., a compound selected from the group consisting of Compounds 1 to 53). In other embodiments, the product is a bottle (e.g., a glass bottle or a plastic bottle) containing a solution of an IP5-substituted compound of the invention (e.g., a compound selected from the group consisting of Compounds 1 to 53). In some embodiments, the product is a bag containing an IP5-substituted compound of the invention (e.g., a compound selected from the group consisting of Compounds 1 to 53) in powder form for reconstitution in a suitable solvent. In other embodiments, the product is a bottle (e.g., a glass bottle or a plastic bottle) containing an IP5-substituted compound of the invention (e.g., a compound selected from the group consisting of Compounds 1 to 53) in powder form for reconstitution in a suitable solvent.

[0130]

[0125] The kits and products can include instructions for use for carrying out one or more administrations of an IP5-substituted compound of the invention (e.g., a compound selected from the group consisting of Compounds 1 to 53) according to the methods and dosages disclosed herein.

[0131]

[0126] The instructions for use included in the kits and products may be affixed to the packaging material or included as an accompanying document. The instructions for use are typically a document or in print, but are not limited thereto. Any medium capable of storing such instructions for use and communicating them to the end user is 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), etc. As used herein, the term "instructions for use" can include the address of an Internet site that provides instructions for use.

[0132] V. Use of the IP5-Substituted Compounds of Formula I

[0127] The present invention provides a method for treating diseases and disorders using the IP5 substituted compounds of the present invention (e.g., compounds selected from the group consisting of compound 1 to compound 53). In some embodiments, the medical uses disclosed herein relate to the ability of the IP5 substituted compounds of the present invention (e.g., compounds selected from the group consisting of compound 1 to compound 53) to inhibit the formation or growth of calcium salts / crystals (e.g., calcium phosphate, HAP) in a subject in need thereof, which ability comprises administering to the subject an effective amount of a compound of formula I or a pharmaceutical composition disclosed herein. Accordingly, the IP5 substituted compounds of the present invention (e.g., compounds selected from the group consisting of compound 1 to compound 53) can be used for treating and preventing diseases and disorders associated with pathological crystallization.

[0133]

[0128] The present invention is a method for treating and / or preventing pathological crystallization and / or its consequences in a subject in need thereof, which method comprises the step of administering an IP5 substituted compound of the present invention (e.g., a compound selected from the group consisting of compound 1 to compound 53), wherein the administration of the IP5 substituted compound effectively treats and / or prevents pathological crystallization and / or its consequences in the subject.

[0134]

[0129] The present invention also provides a method for manufacturing a medicament for treating pathological crystallization, which method comprises the step of using an intermediate compound selected from the group consisting of the compounds listed in Table 1. Compounds 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 are also provided.

[0135]

[0130] In some embodiments, the IP5 substituted compounds of the present invention (e.g., compounds selected from the group consisting of compound 1 to compound 53) can be administered topically, enterally, or parenterally.

[0136] A. Synthesis of Protected Myo-Inositol Agents, Alkylating Agents or Click Agents, and Reactive Acids A.1. Synthesis of Protected Myo-Inositol Agents (1), (2), (3), (4), (31), (32), (33), and (34)

[0131] 1,3,5-O-Methylidene-myo-inositol (1): The synthesis of (1) has already been described in the literature (Martin S et al., J. Org. Chem. 1994; 59(17): 4805 - 4820).

[0137]

[0132] 2-O-tert-Butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (2): The synthesis of (2) has already been described in the literature (Kadirvel, 2008, supra).

[0138]

[0133] 4,6-Bis-O-(4-methoxybenzyl)-1,3,5-O-methylidene-myo-inositol (3): The synthesis of (3) has already been described in the literature (Aiba, 2016, supra).

[0139]

[0134] 4,6-Di-O-benzyl-1,3,5-O-methylidene-myo-inositol (4): The synthesis of (4) has already been described in the literature (Chen, 2015, supra).

[0140]

[0135] 2,4,6-Tri-O-benzyl-1,3,5-O-methylidene-myo-inositol (31): The synthesis of (31) has already been described in the literature (Song F et al., Org Biomol Chem 2012; 10: 3642 - 3654).

[0141]

[0136] 2,4,6-Tri-O-benzyl-myo-inositol (32): The synthesis of (32) has already been described in the literature (Chen, 2015, supra).

[0137] 1,2,3,4,6-Penta-O-benzyl-myo-inositol (33): The synthesis of (33) has already been described in the literature (Gurale B et al., Carbohydrate Res 2018;461:38-44).

[0142]

[0138] rac-2,4,6-Tri-O-benzyl-3,5-O-ethylidene-myo-inositol (34): The synthesis of (34) has already been described in the literature (Song, 2012, supra).

[0143] A.2. Synthesis of Alkylating Agents or Click Agents

[0139] 1-(4-(2-Chloroethyl)piperazin-1-yl)ethanone (5): To a solution of 1-(4-(2-hydroxyethyl)piperazin-1-yl)ethanone (1.74 g, 10.10 mmol) in dichloromethane (DCM, 0.2 M) at 0 °C, triethylamine (TEA, 2.1 mL, 15.15 mmol) and Ts-Cl (2.31 g, 12.12 mmol) were added. 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 (5) (yield 66%). HPLC-MS (Condition A): rt = 0.24 min; m / z: 191, 193 [M, M+2] + 。

[0144]

[0140] 9-Methoxynonyl 4-methylbenzenesulfonate (7):

[0145]

Chemical formula

[0146]

[0141] Step 1: 9-Methoxynonan-1-ol (6): A mixture of 9-bromononan-1-ol (0.5 g, 2.24 mmol) and sodium methoxide 4N (25 mL, 100 mmol) was stirred at 40 °C for 18 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, hexane (Hex):ethyl acetate (EtOAc) 4:1) to afford 324 mg of (6) (83% yield). 1H 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).

[0142] Step 2: 9-Methoxynonyl 4-methylbenzenesulfonate (7): To a solution of (6) (1.5 g, 8.61 mmol) in (28.7 mL), TEA (1.80 mL, 12.91 mmol) and Ts-Cl (2.13 g, 11.19 mmol) were added. 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 afford 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).

[0143] 19-Methoxynonadeca-10-yn-1-yl 4-methylbenzenesulfonate (13):

[0147]

Chemical formula

[0148]

[0144] Step 1: 2-((9-Bromononyl)oxy)tetrahydro-2H-pyran (8): To a mixture of 9-bromononan-1-ol (2.18 g, 9.77 mmol) and p-TsOH (37 mg, 0.19 mmol), 3,4-dihydro-2H-pyran (1.3 mL, 14.65 mmol) was added. The reaction mixture was stirred at 60 °C for 3.5 days. The mixture was diluted with water, extracted with ethyl ether (2×), dried over Na2SO4, filtered, and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, Hex:EtOAc 9:1) to give 2.4 g of (8) (yield 80%). 1 1H-NMR was identical to that already described in the literature (Grube A et al., Eur J Org Chem 2006;1285 - 1295).

[0149]

[0145] Step 2: Dec-9-yn-1-yl methanesulfonate (9): To a solution of dec-9-yn-1-ol (5.22 g, 33.8 mmol) in THF (0.35 M) at 0 °C, TEA (6.3 mL, 44 mmol) and Ms-Cl (3.5 mL, 44 mmol) were added. The reaction mixture was stirred at room temperature for 16 h, diluted with water, extracted with DCM (×2), dried over Na2SO4, filtered, and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, Hex:EtOAc (20:1) to give 8.1 of (9) (yield >99%). 1 1H-NMR was identical to that already described in the literature (Langmuir: the ACS journal of surfaces and colloids., 2013, Vol. 29(2), pp. 570 - 580).

[0150]

[0146] Step 3: 10-Methoxydec-1-yne (10) (8.17 g, 35.2 mmol) was added to a 5 M solution of sodium methoxide in MeOH (35.2 mL, 176 mmol). The reaction mixture was stirred at 45 °C for 18 h. The mixture was diluted with water, extracted with ethyl ether (2×), dried over Na2SO4, filtered, and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, Hex:EtOAc 20:1) to give 4 g of (10) (yield 67%). 1 H NMR (400 MHz, chloroform-d) δ 3.34 (td, J = 6.6, 1.0 Hz, 2H), 3.31 (s, 3H), 2.15 (tdd, J = 7.1, 2.7, 1.0 Hz, 2H), 1.91 (td, J = 2.7, 1 Hz, 1H), 1.62 - 1.45 (m, 4H), 1.41 - 1.23 (m, 8H).

[0147] Step 4: 2-((19-Methoxynonadec-10-yn-1-yl)oxy)tetrahydro-2H-pyran (11): A mixed solution of (10) (1.41 g, 8.42 mmol) in tetrahydrofuran (THF) and hexamethylphosphoramide (HMPA) (1.2:1) cooled to -40 °C was slowly added to a 1.6 M hexane solution of n-BuLi (7.45 mL, 11.93 mmol), and then stirred at the same temperature for 30 min and further stirred at 0 °C for 30 min. After cooling to -20 °C, a HMPA solution of (8) (2.16 g, 7.02 mmol) was slowly added. After stirring at the same temperature for 10 min, the temperature was raised to room temperature. Stirring was carried out at the same temperature for 22 h. Under ice-cooling (4 °C), 1 N aqueous HCl and tBuMeO were added, and then washed with saturated NaHCO3 solution and saturated brine, and further dried over anhydrous Na2SO4. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by flash chromatography (silica gel, Hex:EtOAc 10:1) to give 1.28 g of (11) (yield 46%). 11H NMR (400 MHz, chloroform-d) δ 4.55 (dd, J = 4.4, 2.8 Hz, 1H), 3.85 (ddd, J = 10.8, 7.6, 3.6 Hz, 1H), 3.71 (dt, J = 9.6, 6.8 Hz, 1H), 3.51 - 3.45 (m, 1H), 3.35 (dt, J = 9.6, 6.8 Hz, 1H), 3.34 (t, J = 6.8 Hz, 2H), 3.31 (s, 3H), 2.14 - 2.08 (m, 4H), 1.82 (tdd, J = 10.8, 7.6, 4.6 Hz, 1H), 1.71 (dt, J = 12.8, 2.8 Hz, 1H), 1.63 - 1.40 (m, 10H), 1.39 - 1.21 (m, 16H), 0.90 - 0.79 (m, 4H).

[0148] Step 5: To a solution of (11) (3.28 g, 8.31 mmol) in MeOH (0.6 M) was added p-TsOH (95 mg, 0.5 mmol). The reaction mixture was stirred at 60 °C for 3.5 days. The mixture was diluted with water, extracted with ethyl ether (2×), dried over Na2SO4, filtered, and the solvent was removed in vacuo. The filtrate was concentrated to give 2.6 g of (12) (yield >99%). 1 1H NMR (400 MHz, chloroform-d) 3.61 (t, J = 6.6 Hz, 2H), 3.34 (t, J = 6.6 Hz, 2H), 3.31 (s, 3H), 2.11 (t, J = 7.2 Hz, 4H), 1.56 - 1.30 (m, 26H).

[0149] Step 6: 19-Methoxynonadec-10-yn-1-yl 4-methylbenzenesulfonate (13): To a solution of (12) (2.6 g, 8.37 mmol) in DCM (0.5 M) at 0 °C were added TEA (1.4 mL, 10.05 mmol), DMAP (102 mg, 0.83 mmol) and Ts-Cl (1.92 g, 10.05 mmol). The reaction mixture was stirred at room temperature for 6 h and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, Hex:EtOAc 10:1) to afford 2.45 g of (13) (yield 63%). HPLC-MS (Condition B): rt = 5.20 min; m / z: 465 [M+1] + , 482 [M+23] + .

[0151]

[0150] 29-Methoxynonacosa-9,20-dien-1-yl 4-methylbenzenesulfonate (16):

[0152]

Chemical formula

[0153]

[0151] Step 1: 19-Bromo-1-methoxynonadec-9-yne (14): A solution of lithium bromide (0.318 g, 3.66 mmol) in anhydrous THF (0.1 M) was placed in a reaction flask and dried over 3A molecular sieves (300 mg, pre-activated at 400 °C for 24 h). After stirring this solution for 20 min, a solution of (13) (0.85 g, 1.829 mmol) in anhydrous THF (2 mL + 2 mL) was added to the previous reaction flask. The solution was stirred for 4 h while refluxing. Then, the reaction mixture was brought to room temperature and diluted with tBuMeO. The organic layer was washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give a yellow oil. The residue was purified by flash chromatography (silica gel, Hex:EtOAc 10:1) to afford 467 mg of (14) (yield 68%). 11H NMR (400 MHz, chloroform-d) δ 3.39 (t, J = 6.8 Hz, 2H), 3.34 (t, J = 6.8 Hz, 2H), 3.31 (s, 3H), 2.12 (t, J = 6.6 Hz, 4H), 1.83 (q, J = 7.2 Hz, 2H), 1.57 - 1.51 (m, 2H), 1.49 - 1.22 (m, 24H).

[0152] Step 2: 29-Methoxynonacosa-9,20-dien-1-ol (15): A 1.6 M solution of n-BuLi (1.9 mL, 3.09 mmol) in n-hexane was slowly added to a mixed solution of dec-9-en-1-ol (230 mg, 1.48 mmol) in THF / HMPA (1.2:1) cooled to -40 °C. Then, the mixture was stirred at the same temperature for 30 minutes and further stirred at 0 °C for 30 minutes. After cooling to -20 °C, a solution of (14) (462 mg, 1.24 mmol) in HMPA was slowly added. After stirring at the same temperature for 10 minutes, the temperature was raised to room temperature. Stirring was carried out at the same temperature for 22 hours. Under ice-cooling (4 °C), 1N aqueous HCl and tBuMeO were added, and then the mixture was washed successively with saturated NaHCO3 solution and saturated brine, and further dried over anhydrous Na2SO4. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by flash chromatography (silica gel + 5% AgNO3, Hex:EtOAc 4:1) to obtain 69.7 mg of (15) (yield 12%). 1 1H NMR (400 MHz, heavy water) δ 3.64 (t, J = 6.6 Hz, 2H), 3.36 (t, J = 6.6 Hz, 2H), 3.33 (s, 3H), 2.13 (t, J = 7.0 Hz, 8H), 1.58 - 1.52 (d, J = 8.2 Hz, 4H), 1.51 - 1.41 (m, 8H), 1.41 - 1.23 (m, 26H).

[0153] Step 3: 29-Methoxynonacosa-9,20-dien-1-yl 4-methylbenzenesulfonate (16): To a solution of (15) (69.7 mg, 0.156 mmol) in DCM (0.1 M) at 0 °C were added TEA (43 μL, 0.325 mmol), DMAP (3.3 mg, 0.027 mmol) and Ts-Cl (62 mg, 0.325 mmol). The reaction mixture was then diluted with water and tBuMeO. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give a yellow oil. The residue was purified by flash chromatography (silica gel, Hex:EtOAc 10:1) to afford 63.3 mg of (16) (67% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.77 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 3.99 (t, J = 6.6 Hz, 2H), 3.34 (t, J = 6.6 Hz, 2H), 3.30 (s, 3H), 2.43 (s, 3H), 2.12 - 2.10 (m, 8H), 1.66 - 1.49 (m, 4H), 1.48 - 1.39 (m, 8H), 1.39 - 1.12 (m, 26H).

[0154] Bromo-7-methoxyheptane (17): 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 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, Hex:EtOAc 10:1) to afford 1.4 g of (17) (34.5%). 1 H NMR (400 MHz, chloroform-d) δ 3.40 (t, J = 6.9 Hz, 2H), 3.36 (t, J = 6.6 Hz, 2H), 3.33 (s, 3H), 1.89 - 1.82 (m, 2H), 1.60 - 1.53 (m, 2H), 1.47 - 1.40 (m, 2H), 1.39 - 1.32 (m, 4H).

[0155] 3-Azidopropyl 4-methylbenzenesulfonate (18): 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 afford 1.27 g of (18) (50%). 1 1H 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).

[0156] 1-(5-Bromopentyl)-1H-pyrazole (19): To a mixture of 1H-pyrazole (0.78 g, 11.49 mmol) and Cs2CO3 (3.74 mg, 11.49 mmol) in acetonitrile (CAN, 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 afford 1.1 g of (19) (45%). HPLC-MS (Condition A): rt = 3.00 min; m / z: 218, 220 [M+1, M+3] + 。

[0154]

[0157] Benzyl penta-4-enoate (20): A solution of penta-4-enoic acid (5.02 g, 51.2 mmol) in DMF (102 mL) was treated with K2CO3 (10.61 g, 77 mmol) and benzyl bromide (6.09 mL, 51.2 mmol), stirred for 72 h, then diluted with water (200 mL) and extracted with diethyl ether (3 × 150 mL). The combined organic layers were dried (MgSO4) and filtered. The solvent was removed in vacuo to give 9.9 g of (20) (>99%). HPLC-MS (condition A): rt = 3.70 min.

[0155]

[0158] 6-Azidohexyl 4-methylbenzenesulfonate (22):

[0156]

Chem.

[0157]

[0159] Step 1: 6-Azidohexan-1-ol (21): A solution of 6-bromohexan-1-ol (428 μL, 3.27 mmol) and sodium azide (850 mg, 13.08 mmol) in DMF (0.8 M) was stirred at 80 °C for 18 h. The reaction mixture was then quenched with water / EtOAc and washed with brine (3×). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give 470 mg of (21) (>99%). 1 H NMR (400 MHz, chloroform-d) δ 3.65 (t, J = 6.8 Hz, 2H), 3.27 (t, J = 6.8 Hz, 2H), 1.70 - 1.56 (m, 4H), 1.40 (m, 4H).

[0160] Procedure 2: 6-azidohexyl 4-methylbenzenesulfonate (22): At 0 °C, p-Ts-Cl (720 mg, 3.78 mmol) was added to a solution of (21) (515 mg, 3.60 mmol) and TEA (1.5 mL, 10.79 mmol) in dry DCM (0.6 M). The reaction mixture was stirred overnight at room temperature. It was diluted with EtOAc and washed with 10% aqueous NaHSO4. The aqueous layer was extracted with EtOAc (3×). The combined layers were washed with saturated aqueous NaHCO3 and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, Hex:EtOAc 6:1) to afford 666 mg of (22) (62%). 1 1H NMR (400 MHz, chloroform-d) δ 7.79 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.03 (t, J = 6.4 Hz, 2H), 3.23 (t, J = 6.8 Hz, 2H), 2.45 (s, 3H), 1.66 (p, J = 6.4 Hz, 2H), 1.55 (p, J = 6.4 Hz, 2H), 1.41 - 1.18 (m, 4H).

[0161] 2-cyclopropylethyl 4-methylbenzenesulfonate (23): To a solution of 2-cyclopropylethanol (3 mL, 34.0 mmol) in DCM (85 mL) were added TEA (7.10 mL, 50.9 mmol) and Ts-Cl (7.77 g, 40.8 mmol), and the resulting mixture was stirred for 18 h. Water was added to the reaction mixture and the mixture was extracted with DCM (2×). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hex-EtOAc, 4:1) to afford 6.23 g (76%) of (23). 11H 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).

[0162] 2-Cyclopentylethyl 4-methylbenzenesulfonate (24): To a solution of 2-cyclopentylethanol (1.09 mL, 8.76 mmol) in DCM (22 mL) was added TEA (1.83 mL, 13.1 mmol) and Ts-Cl (2.00 g, 10.5 mmol), and the resulting mixture was stirred for 18 h. Water was added to the reaction mixture and extracted with DCM (2×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hex-EtOAc, 4:1) to give 1.53 g (65%) of (24). 1 1H NMR (400 MHz, chloroform-d) δ 7.81 (d, J = 8 Hz, 2H), 7.37 (d, J = 8 Hz, 2H), 4.06 (t, J = 6.7 Hz, 2H), 2.47 (s, 3H), 1.89-1.76 (m, 1H), 1.76-1.43 (m, 8H), 1.10-0.99 (m, 2H).

[0163] 3-(4-Methoxyphenyl)propyl 4-methylbenzenesulfonate (25): To a solution of 3-(4-methoxyphenyl)propan-1-ol (0.96 mL, 6.02 mmol) in DCM (15 mL) were added TEA (1.26 mL, 9.02 mmol) and Ts-Cl (1.38 g, 7.22 mmol), and the resulting mixture was stirred for 18 h. Water was added to the reaction mixture, and the mixture was extracted with DCM (2×). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hex-EtOAc, 4:1) to afford 1.59 g (82%) of (25). 1 H NMR (400 MHz, chloroform-d) δ 7.81 (d, J = 8 Hz, 2H), 7.37 (d, J = 8 Hz, 2H), 7.00 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 4.04 (t, J = 6 Hz, 2H), 3.80 (s, 3H), 2.61 (dd, J = 8.2, 6.8 Hz, 2H), 2.48 (s, 3H), 2.03-1.86 (ddt, J = 8.2, 6.8, 6 Hz, 2H).

[0164] 3-(3-(Trifluoromethyl)phenyl)propyl 4-methylbenzenesulfonate (26): To a solution of 3-(3-(trifluoromethyl)phenyl)propan-1-ol (0.91 mL, 4.90 mmol) in DCM (12 mL) were added TEA (1.02 mL, 7.35 mmol) and Ts-Cl (1.12 g, 5.88 mmol), and the resulting mixture was stirred for 18 h. Water was added to the reaction mixture, and the mixture was extracted with DCM (2×). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hex-EtOAc, 4:1) to afford 1.53 g (87%) of (26). 11H NMR (400 MHz, chloroform-d) δ 7.63 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 7.8 Hz, 1H), 7.21 - 7.16 (m, 2H), 7.19 (d, J = 8.5 Hz, 2H), 7.12 (, J = 7.8 Hz, 1H), 3.88 (t, J = 6.2 Hz, 2H), 2.56 (dd, 8.0, 7.6Hz, 2H), 2.29 (s, 3H), 1.81 (ddt, J = 8.0, 7.6, 6.2 Hz, 2H).

[0165] 3-(p-Tolyl)propyl 4-methylbenzenesulfonate (27): To a solution of 3-(p-tolyl)propan-1-ol (1 g, 6.66 mmol) in DCM (17 mL) were added TEA (1.39 mL, 9.99 mmol) and Ts-Cl (1.52 g, 7.99 mmol), and the resulting mixture was stirred for 18 h. Water was added to the reaction mixture, and the mixture was extracted with DCM (2×). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Hex-EtOAc, 4:1) to give 1.85 g (87%) of (27). 1 1H NMR (400 MHz, chloroform-d) δ 7.81 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 4.05 (t, J = 6.4 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H), 2.48 (s, 3H), 2.32 (s, 3H), 1.95 (tt, J = 7.5, 6.4 Hz, 2H).

[0166] 5-Acetamidopentyl 4-methylbenzenesulfonate (29):

[0158]

Chemical formula

[0159]

[0167] Procedure 1: N-(5-Hydroxypentyl)acetamide (28): To a solution of 5-aminopentan-1-ol (50 g, 485 mmol) and 2,5-dioxopyrrolidin-1-yl acetate (75 g, 485 mmol) in dimethylformamide (DMF, 0.5 M) was added TEA (101 mL, 727 mmol), and the solution was stirred at 60 °C for 18 h. The solvent was then evaporated using a high-vacuum rotary evaporator, the residue was dissolved in MeOH, treated with IRA-410 to a basic pH (ca. 10), filtered, and evaporated to dryness to afford 70.4 g of (28) (100%). This crude product was used without further purification. 1 H NMR (400 MHz, CD3OD) δ 3.57 (t, J = 6.5 Hz, 2H), 3.18 (t, J = 7.0 Hz, 2H), 1.94 (s, 3H), 1.65 - 1.47 (m, 4H), 1.49 - 1.32 (m, 2H).

[0168] Procedure 2: 5-Acetamidopentyl 4-methylbenzenesulfonate (29): To a solution of (28) (70.4 g, 485 mmol) in DCM (0.5 M) were added TEA (101 mL, 727 mmol) and Ts-Cl (92 g, 485 mmol). The reaction mixture was stirred at room temperature for 18 h, then quenched with water / DCM and washed with saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford 92.45 g of (29) (63%). 1 H NMR (400 MHz, chloroform-d): δ 7.84 - 7.74 (m, 2H), 7.37 (d, J = 8.1 Hz, 2H), 5.59 (s, 1H), 4.04 (t, J = 6.3 Hz, 2H), 3.21 (q, J = 6.8 Hz, 2H), 2.47 (s, 3H), 1.98 (s, 3H), 1.68 (dt, J = 7.8, 6.6 Hz, 2H), 1.57-1.43 (m, 2H), 1.39 (qd, J = 7.3, 3.0 Hz, 2H). HPLC-MS (Condition A): rt = 3.42 min; m / z: 300 [M+1] + 。

[0160]

[0169] (((10-Bromodecyl)oxy)methyl)benzene (30): The synthesis of (4) has already been described in the literature (Hanbali M. et al., Bioorg Med Chem Letters 2006;16(10):2637 - 2640).

[0161]

[0170] 5-(Benzyloxy)pentyl 4-methylbenzenesulfonate (35): To a solution of 5-(benzyloxy)pentan-1-ol (11.2 g, 57.7 mmol) in dichloromethane (DCM, 0.4 M) at 0 °C, triethylamine (TEA, 12 mL, 86 mmol) and Ts-Cl (11 g, 57.7 mmol) were added. The reaction mixture was stirred at room temperature for 18 h and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, Hex / OEtAc (4:1)) to afford 15.32 g of (35) (76% yield). HPLC-MS (Condition A): rt = 4.55 min; m / z: 349 [M + 1], + 371 [M + 23] +

[0162]

Chemical formula

[0163]

[0171] 5-Azidopentyl 4-methylbenzenesulfonate (37)

[0172] Step 1: 5-Azidopentan-1-ol (36): A solution of 5-bromopentan-1-ol (0.10 mL, 0.89 mmol) and sodium azide (63 mg, 0.98 mmol) in dimethylformamide (DMF, 0.2 M) was stirred at 80 °C for 18 h. The reaction mixture was then quenched with water / EtOAc and washed with brine (3×). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford 57 mg of (36) (50%). 11H 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 (37) *csc_san_02_N37: To a solution (0.2 M) of (36) (54 mg, 0.42 mmol) in DCM 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 stirred with Na2SO4, filtered, and concentrated in vacuo to give 92 mg of (37) (78%). HPLC-MS (Condition A): rt = 3.00 min; m / z: 284 [M+1] + 。

[0164]

[0173] Methyl 3-azidopropanoate (38): A mixture of methyl 3-bromopropanoate (10.70 ml, 98 mmol) and sodium azide (8.92 g, 137 mmol) was dissolved in DMSO (volume: 49.0 ml). The solution was heated to 45 °C and stirred for 18 h. After the mixture was cooled to room temperature, it was extracted with diethyl ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated on a rotary evaporator to give azidopropanoate as a colorless liquid. 1 1H NMR (400 MHz, chloroform-d) δ 3.62 (s, 3H), 3.47 (t, J = 6.3 Hz, 2H), 2.87 (t, J = 6.6 Hz, 2H). B. General Procedure B.1. Alkylation Procedure

[0174] Procedure A: Sodium hydride (2.15 equiv) was added to a solution of (2), (3), (4), (33), or (34) (1 equiv) in dimethylformamide (DMF, 0.2 M) at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 5 minutes. Finally, the alkylating agent was added. The reaction mixture was stirred overnight, then quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel) to obtain the pure compound.

[0165]

[0175] Procedure B: Sodium hydride (1.2 equiv) was added to a solution of (2), (3), (4), (33), or (34) (1 equiv) in DMF (c = 0.15 M) at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 5 minutes. Finally, the alkylating agent was added. The reaction mixture was stirred overnight, then quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel) to obtain the pure compound.

[0166]

[0176] Procedure N: LiH was added to a solution of (2), (3), (4), (33), or (34) (1 equiv) in DMF (0.2 M) at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 5 minutes. Finally, the alkylating agent was added. The reaction mixture was stirred for different times and at different temperatures depending on the alkylating agent, then quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel) to obtain the pure compound.

[0167] B.2. Benzyl Deprotection Procedure

[0177] Procedure K: The alkyl-inositol derivative (II_B’, II_C, VIII_B’, or IX_D) was dissolved in a mixture of THF / MeOH (7:3, 0.05 M), and then an excess amount of palladium hydroxide on carbon was added. The mixture was placed under a hydrogen atmosphere and stirred at room temperature for 2 days. Then, the mixture was purged with nitrogen, filtered, and concentrated to obtain the desired compound.

[0168] B.3. Hydrolysis Procedure

[0178] Procedure C: The alkyl-inositol derivative (II_A, II_B, II_B’, II_D, V_A, V_B, V_D, or VIII_B) was dissolved in a mixture of MeOH / H2O / 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 obtain the desired compound.

[0169]

[0179] Procedure D: The alkyl-inositol derivative (II_A, II_B, II_B’, II_D, V_A, V_B, V_D, or VIII_B) was dissolved in a mixture of MeOH / H2O / DCM / trifluoroacetic acid (3:1:1:1, 0.1 M), and the solution was stirred at room temperature overnight. Then, the solvent and excess TFA were removed under vacuum. Finally, the residue was dissolved in MeOH, treated with IRA-400 resin to make the pH basic, filtered, and the solvent was removed under vacuum to obtain the desired compound.

[0170]

[0180] Procedure E: To a solution of the alkyl-inositol derivative (II_A or V_A) in tetrahydrofuran (THF) (c = 0.1 M), a solution of TBAF in THF 0.1 M (1.2 equiv) was added. The reaction mixture was stirred at room temperature for 18 h, quenched with water, and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in a mixture of MeOH / H2O / DCM / trifluoroacetic acid (3:1:1:1, 0.1 M), and the solution was stirred at room temperature overnight. Then, the solvent and excess TFA were removed under vacuum. Finally, the residue was dissolved in MeOH (MeOH), treated with IRA-400 resin to make the pH basic, filtered, and the solvent was removed under vacuum to obtain the desired compound.

[0171]

[0181] Procedure F: The alkyl-inositol derivative (II_A, II_B, II_B’, II_D, V_A, V_B, V_D, or VIII_B) was dissolved in a mixture of DCM / trifluoroacetic acid (4:1, 0.14 M), and the solution was stirred at room temperature for 1 hour. Then, water was 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.

[0172]

[0182] Procedure S: The alkyl-inositol derivative (II_A, II_B, II_B’, II_D, V_A, V_B, V_D, or VIII_B) was dissolved in a mixture of MeOH / HCl 1N (10:1, 0.1 M), and the solution was stirred at room temperature or 60 °C for 48 hours. Finally, the solvent and excess HCl were removed under vacuum. Finally, the residue was dissolved in MeOH, treated with IRA-400 resin to make the pH basic, filtered, and the solvent was removed under vacuum to give the desired compound.

[0173] B.4. Click reaction procedure

[0183] Procedure M: To a solution (0.07 M) in water of the intermediate (VI_A, V_C, or X_D) (1 equiv), CuSO4·5H2O (0.4 equiv) and sodium ascorbate (0.6 equiv), a solution (0.35 M) of the alkynyl reagent in THF was added. The reaction mixture was stirred at room temperature for 24 hours and at 60 °C under an inert atmosphere, filtered through celite, and concentrated in vacuo. The residue was dissolved in MeOH, treated with IRA-400 resin to make the pH basic, filtered, and the solvent was removed under vacuum to give the desired compound.

[0174]

[0184] Procedure L: To a solution (0.07 M) in water of the intermediate (III_B or IX_D) (1 equiv), CuSO4·5H2O (0.4 equiv) and sodium ascorbate (0.6 equiv), a solution (0.35 M) of the azide reagent (2 equiv) in THF was added. The reaction mixture was stirred at room temperature for 20 hours under an inert atmosphere, filtered through celite, and concentrated in vacuo. The residue was treated with water / DCM. Then, the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the desired compound.

[0175] B.5. Azide Reduction Procedure

[0185] Procedure P: To a solution of intermediate (V_B or X_D) (1 equivalent) in a mixture of THF / water (9:1, 0.08 M), DIPEA (3 equivalents) and PPh3 (2.6 equivalents) were added. 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 Na2SO4, filtered, and concentrated in vacuo to obtain the desired compound. Purification was not performed.

[0176] B.6. Amide Formation Procedure

[0186] Procedure Q: To a solution of intermediate (II_A, III_B or IX_D) (1 equivalent) in DMF (0.1 M), TEA (4 equivalents) and active acid (2 equivalents) were added. 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 to make the pH basic, filtered, and the solvent was removed under vacuum. Finally, the residue was filtered by flash chromatography (silica gel) to obtain the pure compound.

[0177] B.5. Phosphorylation Procedure

[0187] Procedure G: An alkyl-inositol derivative (III_A, VI_A, III_B, III_C, or III_D) (1 equivalent) was dissolved in DCM (0.02 M), and a solution of tetrazole in ACN (0.43 M) (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]-dioxaphosphepine-3-amine (7.2 equivalents) was added and stirred overnight at room temperature. Finally, the reaction mixture was cooled to 0 °C, and a solution of tert-butyl hydroperoxide in hexane (5.5 M) (19.2 equivalents) was added. The solution was brought to room temperature and stirred for 1 hour. The mixture was washed with dilute sodium sulfite and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel) to obtain the pure compound.

[0178]

[0188] Procedure H: An alkyl-inositol derivative (III_A, VI_A, III_B, III_C, or III_D) (1 equivalent) was dissolved in DCM (0.02 M), and a solution of tetrazole in ACN (0.43 M) (18 equivalents) was added. The mixture was stirred at room temperature for 30 minutes. Then, N,N-diethyl-1,5-dihydrobenzo[e][1,3,2]-dioxaphosphepine-3-amine (9 equivalents) was added, and the mixture was stirred overnight at room temperature. Finally, the reaction mixture was cooled to 0 °C, and a solution of tert-butyl hydroperoxide in hexane (5.5 M) (24 equivalents) was added. The solution was brought to room temperature and stirred for 1 hour. The mixture was washed with dilute sodium sulfite and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel) to obtain the pure compound.

[0179]

[0189] Procedure R: An alkyl-inositol derivative (III_A, VI_A, III_B, III_C, or III_D) (1 equivalent) was dissolved in DCM (0.05 M), and a solution of phenyltetrazole in DMF (5 M) (18 equivalents) was added. The mixture was stirred at room temperature for 30 minutes. Then, N,N-diethyl-1,5-dihydrobenzo[e][1,3,2]-dioxaphosphepine-3-amine (9 equivalents) was added, and the mixture was stirred overnight at room temperature. Finally, the reaction mixture was cooled to 0 °C, and a solution of tert-butyl hydroperoxide in hexane (5.5 M) (24 equivalents) was added. The solution was brought to room temperature and stirred for 1 hour. The mixture was washed with dilute sodium sulfite and extracted with EtOAc (×2). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel) to obtain the pure compound.

[0180] B.6. Phosphate Deprotection Procedure

[0190] Procedure I: The phosphorylated compound (IV_A, VII-A, IV_B, IV_C, or IV_D) was dissolved in a mixture of THF / MeOH / water (3:1:1, 0.01 M), and then an excess amount of palladium hydroxide on carbon or palladium on carbon was added. The mixture was placed under a hydrogen atmosphere and stirred at room temperature for 2 days. Then, the mixture was purged with nitrogen, filtered, and concentrated. The compound was brought to pH 7 by adding dilute NaOH (1N) water, and the residue was purified on a sephadex column (PD-10, G-25-M) by eluting with water. All fractions were lyophilized, 1 and analyzed by H-RMN. The fractions containing the product were further purified on a reverse-phase cartridge (Sep-Pack, Waters, 1 g, C18) by eluting with water. All fractions were lyophilized, 1 and analyzed by H-RMN.

[0181]

[0191] Procedure J: The phosphorylated compound (IV_A, VII-A, IV_B, IV_C, or IV_D) was dissolved in a mixture of THF / MeOH / water (3:1:1, 0.01 M), and then an excess amount of palladium hydroxide on carbon or palladium on carbon was added. The mixture was placed under a hydrogen atmosphere and stirred at room temperature for 2 days. Then, the mixture was purged with nitrogen, filtered, and concentrated. The compound was brought to pH 10 by adding dilute NaOH (1N) water, 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, 1 and analyzed by H-RMN. The fractions containing the product were further purified on a reverse-phase cartridge (Sep-Pack, Waters, 1 g, C18) by eluting with water. All fractions were lyophilized, 1 and analyzed by H-RMN.

[0182]

[0192] Procedure T: The phosphorylated compound (IV_A, VII-A, IV_B, IV_C, or IV_D) was treated with thiophenol (40 equivalents) and m-cresol (40 equivalents) in TFA (0.045 M). Then, TBMSBr (40 equivalents) was added slowly, and the mixture was stirred at room temperature for 4 hours, quenched with water, and extracted with DCM (3×). The aqueous layer was concentrated in vacuo. The residue was adjusted to pH 9 - 10 by adding water and diluted NaOH (1 N) aqueous solution, and the compound was purified by eluting with water on a sephadex column (PD-10, G-25-M). All fractions were lyophilized, 1 and analyzed by 1H-RMN. The fractions containing the product were further purified by eluting with water on a reverse-phase cartridge (Sep-Pack® C18 cartridge, 1 g, Waters Corp., Milford, MA, USA). All fractions were lyophilized, 1 and analyzed by 1H-RMN.

[0183] C. Synthesis of Intermediate II-X C.1. Intermediate II_A, II_B, II_B’, II_C, and II_D

[0193] rac-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-4-O-pentyl-myo-inositol (II_A-1): 48 mg of (II_A-1) was obtained from 377 μL (3 equivalents) of 1-bromopentane according to the general alkylation procedure A (yield 13%). HPLC-MS (Condition A): rt = 4.90 min; m / z: 375 [M+1] + 。

[0184]

[0194] rac-4-O-(5-(benzyloxy)pentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (II_A-2): 183 mg of (II_A-2) was obtained from 1.04 mL (3 equivalents) of (((5-bromopentyl)oxy)methyl)benzene according to the general alkylation procedure A (yield 22.8%). HPLC-MS (Condition A): rt = 4.99 min; m / z: 481 [M+1] + , 503 [M+23]+.

[0185]

[0195] rac-2-O-tert-butyldimethylsilyl-4-O-(5-methoxypentyl)-1,3,5-O-methylidene-myo-inositol (II_A-3): According to the general alkylation procedure A, 26 mg of (II_A-3) was obtained from 241 mg (2.2 equivalents, in 3 mL of DMF) of 1-bromo-5-methoxypentane (yield 11%). HPLC-MS (condition B): rt = 3.22 min; m / z: 405 [M+1] + 。

[0186]

[0196] rac-2-O-tert-butyldimethylsilyl-4-O-(5-ethoxycarbonylpentyl)-1,3,5-O-methylidene-myo-inositol (II_A-4): According to the general alkylation procedure A, 107 mg of (II_A-4) was obtained from 351 μL of ethyl 6-bromohexanoate (3 equivalents) (yield 36%). HPLC-MS (condition A): rt = 4.99 min; m / z: 447 [M+1] + 。

[0187]

[0197] rac-4-O-(2-(4-acetylpiperazin-1-yl)ethyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (II_A-5): According to the general alkylation procedure A, 460 mg of (II_A-5) was obtained from 700 mg (2.5 equivalents, in 7.3 mL of DMF) of (5) (2.5 equivalents, in 7.3 mL of DMF) (yield 68%). HPLC-MS (condition A): rt = 1.90 min; m / z: 459 [M+1] + 。

[0188]

[0198] 4,6-bis-O-(4-methoxybenzyl)-1,3,5-O-methylidene-2-O-pentyl-myo-inositol (II_B-1): According to the general alkylation procedure B, 142 mg of (II_B-1) was obtained from 200 mg of (3) and 87 μL (1.5 equivalents) of 1-bromopentane (yield 61%). HPLC-MS (condition B): rt = 3.43 min; m / z: 501 [M+1] + , 523 [M+23] + 。

[0189]

[0199] 4,6-Bis-O-(4-methoxybenzyl)-2-O-(5-methoxypentyl)-1,3,5-O-methylidene-myo-inositol (II_B-2): According to the general alkylation procedure B, 180 mg of (II_B-2) was obtained from 400 mg of (3) and 505 mg (3 equivalents) of 1-bromo-5-methoxypentane (yield 36.5%). HPLC-MS (Condition A): rt = 4.26 min; m / z: 531 [M+1] + , 553 [M+23] + .

[0190]

[0200] 4,6-Bis-O-(4-methoxybenzyl)-2-O-(9-methoxynonyl)-1,3,5-O-methylidene-myo-inositol (II_B-3): According to the general alkylation procedure B, 430 mg of (II_B-3) was obtained from 500 mg of (3) and 420 mg (1.1 equivalents) of (7) (yield 63%). 1 H NMR (400 MHz, chloroform-d) δ 7.20 (d, J = 8.6 Hz, 4H), 6.82 (d, J = 8.6 Hz, 4H), 5.48 (d, J = 1.2 Hz, 1H), 4.60 (d, J = 11.3 Hz, 2H), 4.47 (d, J = 11.3 Hz, 2H), 4.38-4.35 (m, 1H), 4.30 (t, J = 3.6 Hz, 2H), 4.24-4.22 (m, 2H), 3.82 (q, J = 1.6 Hz, 1H), 3.79 (s, 6H), 3.47 (t, J = 6.8 Hz, 2H), 3.34 (t, J = 6.8 Hz, 2H), 3.31 (s, 3H), 1.64-1.50 (m, 8H), 1.33-1.21 (m, 6H).

[0201] 4,6-Di-O-benzyl-2-O-(19-methoxynonadeca-10-yn-1-yl)-1,3,5-O-methylidene-myo-inositol (II_B’-1): According to the general alkylation procedure B, 504 mg of (II_B’-1) was obtained from 437 mg of (4) and 631 mg (1.1 equivalents) of (13) (yield 66%).1 1H NMR (400 MHz, chloroform-d) δ 7.28 (s, 10H), 5.49 (d, J = 1.3 Hz, 1H), 4.68 (d, J = 11.8 Hz, 3H), 4.55 (d, J = 11.8 Hz, 2H), 4.45 - 4.40 (m, 1H), 4.34 (t, J = 3.6 Hz, 2H), 4.27 (m, 2H), 3.85 (q, J = 1.6 Hz, 1H), 3.48 (t, J = 6.8 Hz, 2H), 3.34 (t, J = 6.8 Hz, 2H), 3.31 (s, 3H), 2.11 (t, J = 7.0 Hz, 4H), 1.60 (q, J = 7.0 Hz, 2H), 1.54 - 1.51 (m, 2H), 1.44 (q, J = 7.0 Hz, 4H), 1.37 - 1.24 (m, 16H).

[0202] 4,6 - Di - O - benzyl - 2 - O - (29 - methoxynonacosa - 9,20 - diyn - 1 - yl) - 1,3,5 - O - methylidene - myo - inositol (II_B’ - 2): According to the general alkylation procedure B, 776 mg of (II_B’ - 2) was obtained from 404 mg of (4) and 721 mg (1.1 equivalents) of (16) (yield 89%). 1 1H NMR (400 MHz, chloroform-d) δ 7.28 (s, 10H), 5.49 (d, J = 1.3 Hz, 1H), 4.68 (d, J = 11.8 Hz, 2H), 4.55 (d, J = 11.8 Hz, 2H), 4.44 - 4.42 (m, 1H), 4.34 (t, J = 3.7 Hz, 2H), 4.27 (m, 2H), 3.85 (q, J = 1.7 Hz, 1H), 3.47 (t, J = 6.8 Hz, 2H), 3.34 (t, J = 6.8 Hz, 2H), 3.31 (s, 3H), 2.11 (t, J = 7.2 Hz, 8H), 1.61 (p, J = 6.9 Hz, 2H), 1.55 - 1.50 (m, 2H), 1.45 (p, J = 7.0 Hz, 8H), 1.38 - 1.25 (m, 26H).

[0203] rac-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-4-O-(3-(p-tolyl)propyl)-myo-inositol (II_A-6): According to the general alkylation procedure N, 374 mg of (II_A-6) was obtained from 1.848 g (2.5 equivalents) of (27) (yield 35%). HPLC-MS (Condition A): rt = 4.99 minutes; m / z: 437 [M+1] + , 459 [M+23] + .

[0191]

[0204] rac-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-4-O-(4-methylpentyl)-myo-inositol (II_A-7): According to the general alkylation procedure N, 781 mg of (II_A-7) was obtained from 1 mL (2.5 equivalents) of 1-bromo-4-methylpentane (yield 71%). HPLC-MS (Condition A): rt = 5.09 minutes; m / z: 389 [M+1] + , 411 [M+23] + .

[0192]

[0205] rac-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-4-O-(6,6,6-trifluorohexyl)-myo-inositol (II_A-8): According to the general alkylation procedure N, 574 mg of (II_A-8) was obtained from 1.158 g (2.5 equivalents) of 6-bromo-1,1,1-trifluorohexane (yield 61%). HPLC-MS (Condition A): rt = 4.73 minutes; m / z: 443 [M+1] + , 465 [M+23] + .

[0193]

[0206] rac-2-O-tert-butyldimethylsilyl-4-O-(3-(4-methoxyphenyl)propyl)-1,3,5-O-methylidene-myo-inositol (II_A-9): According to the general alkylation procedure N, 457 mg of (II_A-9) was obtained from 1.59 g (2.5 equivalents) of (25) (yield 51%). HPLC-MS (Condition A): rt = 4.72 minutes; m / z: 453 [M+1] + , 455 [M+23]+ .

[0194]

[0207] rac-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-4-O-(3-(3-(trifluoromethyl)phenyl)propyl)-myo-inositol (II_A-10): According to the general alkylation procedure N, 807 mg of (II_A-10) was obtained from 1.53 g (2.5 equivalents) of (26) (yield 96%). HPLC-MS (Condition A): rt = 4.99 minutes; m / z: 491 [M+1] + .

[0195]

[0208] rac-2-O-tert-butyldimethylsilyl-4-O-(2-cyclopentylethyl)-1,3,5-O-methylidene-myo-inositol (II_A-11): According to the general alkylation procedure N, 50 mg of (II_A-11) was obtained from 1.53 g (2.5 equivalents) of (24) (yield 5%). HPLC-MS (Condition A): rt = 5.26 minutes; m / z: 401 [M+1] + , 423 [M+23] + .

[0196]

[0209] rac-2-O-tert-butyldimethylsilyl-4-O-(2-cyclopropylethyl)-1,3,5-O-methylidene-myo-inositol (II_A-12): According to the general alkylation procedure A, 552 mg of (II_A-12) was obtained from 1.45 g (1 equivalent) of (23) (yield 25%). HPLC-MS (Condition A): rt = 4.65 minutes; m / z: 373 [M+1] + , 395 [M+23] + .

[0197]

[0210] rac-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-4-O-(5-(1H-pyrazol-1-yl)pentyl)-myo-inositol (II_A-13): According to the general alkylation procedure A, 174 mg of (II_A-13) was obtained from 214 mg of (19) (yield 60%). HPLC-MS (Condition A): rt = 4.11 minutes; m / z: 441 [M+1] + .

[0198]

[0211] rac-4-O-(5-Acetamidopentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (II_A-14): According to the general alkylation procedure N, 241 mg of (II_A-14) was obtained from 1 g (3 equivalents) of (29) (yield 50%). HPLC-MS (Condition A): rt = 3.78 min; m / z: 432 [M+1] + 。

[0199]

[0212] rac-2-O-tert-butyldimethylsilyl-4-O-(10-ethoxycarbonyl decyl)-1,3,5-O-methylidene-myo-inositol (II_A-15): According to the general alkylation procedure A, 50 mg of (II_A-15) was obtained from 500 mg (2.5 equivalents) of ethyl 11-bromoundecanoate (yield 14%). 1 H NMR (400 MHz, chloroform-d) δ 1H NMR (400 MHz, chloroform-d) δ 5.47 (d, J = 1.6 Hz, 1H), 4.39 (ddt, J = 10.1, 4.1, 2.8 Hz, 1H), 4.24 (t, J = 2.8 Hz, 2H), 4.18 (dt, J = 5.2, 2.1 Hz, 1H), 4.14 (q, J = 1.6 Hz, 1H), 4.11-4.08 (m, 1H), 4.09 (q, J = 7.1 Hz, 1H), 3.70 (d, J = 10.1 Hz, 1H), 3.59 (td, J = 9,5, 6.5 Hz, 1H), 3.58 (td, J = 9,5, 6.5 Hz, 1H), 2.25 (t, J = 7.6 Hz, 2H), 1.58 (p, J = 6.8 Hz, 2H), 1.55 (p, J = 6.8 Hz, 2H), 1.30-1.23 (m, 12H), 1.22 (t, J = 7.1 Hz, 3H), 0.92 (s, 9H), 0.13 (s, 6H).

[0213] rac-4-O-(10-(Benzyloxy)decyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (II_A-16): According to the general alkylation procedure A, 44.5 mg of (II_A-16) was obtained from 407.9 mg (2.1 equivalents) of (30) (yield 14%). HPLC-MS (Condition A): rt = 6.13 minutes; m / z: 551 [M+1] + 。

[0200]

[0214] rac-2-O-tert-butyldimethylsilyl-4-O-methyl-1,3,5-O-methylidene-myo-inositol (II_A-17): According to the general alkylation procedure A, 50 mg of (II_A-17) was obtained from 0.1 mL (1 equivalent) of methyl iodide (yield 10%). HPLC-MS (Condition A): rt = 3.83 minutes; m / z: 319 [M+1] + 、341 [M+23] + 。

[0201]

[0215] rac-2-O-tert-butyldimethylsilyl-4-O-(7-methoxyheptyl)-1,3,5-O-methylidene-myo-inositol (II_A-18): According to the general alkylation procedure A, 163 mg of (II_A-18) was obtained from 780 mg (2.5 equivalents) of (17) (yield 25%). HPLC-MS (Condition A): rt = 4.79 minutes; m / z: 433 [M+1] + 、455 [M+23] + 。

[0202]

[0216] rac-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-4-O-propyl-myo-inositol (II_A-19): According to the general alkylation procedure A, 139 mg of (II_A-19) was obtained from 481 uL (5 equivalents) of 1-iodopropane (yield 41%). HPLC-MS (Condition A): rt = 4.41 minutes; m / z: 347 [M+1] + 、369 [M+23] + 。

[0203]

[0217] 1,2,3,4,6-Penta-O-benzyl-5-O-prop-2-ynyl-myo-inositol (II_C-1): According to the general alkylation procedure B, 107 mg of (II_C-1) was obtained from 200 mg of (33) and 3-bromoprop-1-yne (3 equiv., 80%) in 141 μL of toluene (yield 50%). HPLC-MS (condition A): rt = 5.98 min; m / z: 670 [M+1] + , 692 [M+23] + .

[0204]

[0218] 1,2,3,4,6-Penta-O-benzyl-5-O-(2-cyclopropylethyl)-myo-inositol (II_C-2): According to the general alkylation procedure B, 108 mg of (II_C-2) was obtained from 200 mg of (33) and 114 mg (1.5 equiv.) of (23) (yield 49%). HPLC-MS (condition A): rt = 6.56 min; m / z: 700 [M+1] + , 722 [M+23] + .

[0205]

[0219] 1,2,3,4,6-Penta-O-benzyl-5-O-(9-methoxynonyl)-myo-inositol (II_C-3): According to the general alkylation procedure B, 127 mg of (II_C-3) was obtained from 200 mg of (33) and 156 mg (1.5 equiv.) of (7) (yield 51%). HPLC-MS (condition A): rt = 7.11 min; m / z: 789 [M+1] + , 810 [M+23] + .

[0206]

[0220] rac-2,4,6-Tri-O-benzyl-3,5-O-ethylidene-1-O-prop-2-ynyl-myo-inositol (II_D-1): According to the general alkylation procedure B, 146 mg of (II_C-1) was obtained from 162 mg of (34) and 3-bromoprop-1-yne (3 equiv., 80%) in 152 μL of toluene (yield 83%). HPLC-MS (condition A): rt = 5.08 min; m / z: 537 [M+23] + .

[0207]

[0221] rac-2-O-tert-butyldimethylsilyl-4-O-(5-carboxypentyl)-1,3,5-O-methylidene-myo-inositol (II_A-20): To a solution (0.15 M) of intermediate (II_A-4) (1.58 g, 3.56 mmol) in MeOH / THF, a solution of lithium hydride (1 M, 11 mL, 10.96 mmol) was added. The solution was stirred at room temperature for 18 h, then quenched with 1 M HCl in DCM and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, Hex / EtOAc 1:1) to give 575 mg of (II_A-20) (38%). HPLC-MS (condition A): rt = 3.91 min; m / z: 419 [M+1] + 。

[0208]

[0222] rac-4-O-(6-amino-6-oxohexyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (II_A-21): To a mixture (0.15 M) of intermediate (II_A-20) (80 mg, 0.19 mmol), TEA (53 μL, 0.38 mmol) and bis(2,5-dioxopyrrolidin-1-yl) carbonate (59 mg, 0.23 mmol) in DCM, a solution of ammonia in dioxane (2.8 mL, 1.91 mmol) was added. The solution was stirred at room temperature for 18 h, then quenched with water / DCM and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give 72 mg of (II_A-21) (90%). HPLC-MS (condition A): rt = 3.66 min; m / z: 418 [M+1] + 。

[0209]

[0223] 4,6-bis-O-(4-methoxybenzyl)-2-O-prop-2-ynyl-myo-inositol (II_B-4): According to the general alkylation procedure A, 184 mg of (II_B-4) was obtained from 248 mg of (3) and 171 mg (2 equiv) of propargyl bromide (yield 68%). HPLC-MS (condition A): rt = 4.07 min; m / z: 469 [M+1] + 。

[0210]

[0224] 2-O-(5-(Benzyloxy)pentyl)-4,6-bis-O-(4-methoxybenzyl)-1,3,5-O-methylidene-myo-inositol (II_B-5): According to the general alkylation procedure A, 179 mg of (II_B-5) was obtained from 162 mg of (3) and 262 mg (2 equivalents) of (35) (yield 78%). HPLC-MS (condition A): rt = 4.90 min; m / z: 607 [M+1] + , 629 [M+23] + .

[0211]

[0225] 2-O-(5-Aminopentyl)-4,6-bis-O-(4-methoxybenzyl)-1,3,5-O-methylidene-myo-inositol (II_B-6): According to the general azide reduction procedure P, 203 mg of (II_B-6) was obtained from 110 mg of (V_B-1) (100%). HPLC-MS (condition A): rt = 3.24 min; m / z: 516 [M+1] + .

[0212]

[0226] 4,6-Bis-O-(4-methoxybenzyl)-2-O-(5-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-1,3,5-O-methylidene-myo-inositol (II_B-7): According to the general click reaction procedure M, 142 mg of (II_B-7) was obtained from 126 mg of (V_B-1) and 16 mg (1 equivalent) of 3-methoxyprop-1-yne (100%). HPLC-MS (condition A): rt = 3.97 min; m / z: 612 [M+1] + .

[0213]

[0227] 4,6-Di-O-benzyl-2-O-(6,6,6-trifluorohexyl)-O-1,3,5-methylidene-myo-inositol (II_B’-3): According to the general alkylation procedure B, 89.9 mg of (II_B’-3) was obtained from 200 mg of (4) and 142 mg (1.2 equivalents) of 6-bromo-1,1,1-trifluorohexane (yield 33%). HPLC-MS (condition A): rt = 4.90 min; m / z: 509 [M+1] +, 532[M + 23] + .

[0214]

[0228] 2 - O-(6 - Amino - 6 - oxohexyl)-4,6 - di - O - benzyl - 1,3,5 - O - methylidine - myo - inositol (II_B’ - 4): According to the general alkylation procedure B, 70 mg of (II_B’ - 4) was obtained from 200 mg of (4) and 126 mg (1.2 equivalents) of 6 - bromohexanamide (yield 27%). HPLC - MS (Condition A): rt = 3.75 min; m / z: 484[M + 1] + .

[0215]

[0229] 4,6 - di - O - benzyl - 2 - O-(2 - cyclopentylethyl)-1,3,5 - O - methylidine - myo - inositol (II_B’ - 5): According to the general alkylation procedure B, 184 mg of (II_B’ - 5) was obtained from 175 mg of (4) and 152 mg (1.2 equivalents) of (24) (yield 83%). HPLC - MS (Condition A): rt = 5.20 min; m / z: 467[M + 1] + .

[0216]

[0230] 4,6 - di - O - benzyl - 2 - O-(2 - cyclopropylethyl)-1,3,5 - O - methylidine - myo - inositol (II_B’ - 6): According to the general alkylation procedure B, 230 mg of (II_B’ - 6) was obtained from 200 mg of (4) and 195 mg (1.5 equivalents) of (23) (yield >99%). HPLC - MS (Condition A): rt = 4.74 min; m / z: 439[M + 1] + , 461[M + 23] + .

[0217]

[0231] 1,2,3,4,6 - penta - O - benzyl - 5 - O-(5 - methoxypentyl)-myo - inositol (II_C - 4): According to the general alkylation procedure A, 46 mg of (II_C - 4) was obtained from 250 mg of (33) and 144 mg (1.5 equivalents) of 1 - bromo - 5 - methoxypentane (yield 16%). HPLC - MS (Condition A): rt = 6.36 min; m / z: 732[M + 1] + . 754[M + 23]+ .

[0218]

[0232] 1,2,3,4,6-Penta-O-benzyl-5-O-(6,6,6-trifluorohexyl)-myo-inositol (II_C-5): According to the general alkylation procedure A, 162 mg of (II_C-5) was obtained from 250 mg of (33) and 174 mg (2 equivalents) of 6-bromo-1,1,1-trifluorohexane (yield 53%). HPLC-MS (condition A): rt = 6.38 min; m / z: 770 [M+1] + , 792 [M+23] + .

[0219]

[0233] 1,2,3,4,6-Penta-O-benzyl-5-O-(5-(4-(methoxymethyl)-1,2,3-triazol-1-yl)pentyl)-myo-inositol (II_C-6): According to the general click reaction procedure M, 102 mg of (II_C-6) was obtained from 110 mg of (V_C-1) and 21 mg (2 equivalents) of 3-methoxyprop-1-yne (85%). HPLC-MS (condition A): rt = 5.59 min; m / z: 813 [M+1] + .

[0220]

[0234] rac-2,4,6-Tri-O-benzyl-3,5-O-ethylidene-1-O-(9-methoxynonyl)-myo-inositol (II_D-2): According to the general alkylation procedure B, 270 mg of (II_D-2) was obtained from 203 mg of (34) and 210 mg (1.5 equivalents) of (7) (yield >99%). HPLC-MS (condition A): rt = 6.06 min; m / z: 656 [M+23] + .

[0221]

[0235] rac-2,4,6-Tri-O-benzyl-1-O-(2-cyclopropylethyl)-3,5-O-ethylidene-myo-inositol (II_D-3): According to the general alkylation procedure B, 246 mg of (II_D-3) was obtained from 215 mg of (34) and 163 mg (1.5 equivalents) of (23) (yield >99%). HPLC-MS (condition A): rt = 5.53 min; m / z: 568 [M+23]+ .

[0222]

[0236] rac-2,4,6-tri-O-benzyl-3,5-O-ethylidene-2-O-prop-2-ynyl-myo-inositol (II_D-4): According to the general alkylation procedure A, 232 mg of (II_D-4) was obtained from 215 mg of (34) and 201 mg (3 equivalents) of propargyl bromide (yield > 99%). HPLC-MS (condition A): rt = 4.97 min; m / z: 537 [M+23] + .

[0223]

[0237] rac-2,4,6-tri-O-benzyl-3,5-O-ethylidene-1-O-(6,6,6-trifluorohexyl)-myo-inositol (II_D-5): According to the general alkylation procedure A, 107 mg of (II_D-5) was obtained from 250 mg of (34) and 230 mg (2 equivalents) of 6-bromo-1,1,1-trifluorohexane (yield 33%). HPLC-MS (condition A): rt = 5.62 min; m / z: 637 [M+23] + .

[0224]

[0238] rac-2,4,6-tri-O-benzyl-1-O-(2-cyclopentylethyl)-3,5-O-ethylidene-myo-inositol (II_D-6): According to the general alkylation procedure A, 124 mg of (II_D-6) was obtained from 250 mg of (34) and 211 mg (1.5 equivalents) of (24) (yield 41%). HPLC-MS (condition A): rt = 6.06 min; m / z: 596 [M+23] + .

[0225] C.2. Intermediates III_A, III_B, III_C, and III_D

[0239] rac-4-O-pentyl-myo-inositol (III_A-1): According to the general hydrolysis procedure E, 16.6 mg of (III_A-1) was obtained from 48 mg of (II_A-1) (yield 53%).

[0226]

[0240] rac-4-O-(5-(Benzyloxy)pentyl)-myo-inositol (III_A-2): According to the general hydrolysis procedure C, 20.71 mg of (III_A-2) was obtained from 48 mg of (II_A-2) (yield 58%). HPLC-MS (Condition B): rt = 1.83 min; m / z: 357 [M+1] + 。

[0227]

[0241] rac-4-O-(5-Methoxypentyl)-myo-inositol (III_A-3): According to the general hydrolysis procedure C, 12.3 mg of (III_A-3) was obtained from 26 mg of (II_A-3) (yield 68%). HPLC-MS (Condition B): rt = 0.53 min; m / z: 281 [M+1] + 、303 [M+23] + 。

[0228]

[0242] rac-4-O-(5-Methoxycarbonylpentyl)-myo-inositol (III_A-4): According to the general hydrolysis procedure C with slight modification (aqueous workup), 42 mg of (III_A-4) was obtained from 100 mg of (II_A-4) (yield 61%). HPLC-MS (Condition B): rt = 0.92 min; m / z: 309 [M+1] + 。

[0229]

[0243] rac-4-O-(2-(4-Acetylpiperazin-1-yl)ethyl)-myo-inositol (III_A-5): According to the general hydrolysis procedure C, 24 mg of (III_A-5) was obtained from 38 mg of (II_A-5) (yield 86%). HPLC-MS (Condition B): rt = 0.23 min; m / z: 335 [M+1] + 。

[0230]

[0244] 2-O-Pentyl-myo-inositol (III_B-1): According to the general hydrolysis procedure F, 55.5 mg of (III_B-1) was obtained from 127 mg of (II_B-1) (yield 87%). HPLC-MS (Condition A): rt = 1.65 min; m / z: 251 [M+1] + 、273 [M+23] + 。

[0231]

[0245] 2-O-(5-Methoxypentyl)-myo-inositol (III_B-2): According to the general hydrolysis procedure F, 84 mg of (III_B-2) was obtained from 180 mg of (II_B-2) (yield 88%). 1 H NMR (400 MHz, MeOH-d4) δ 374 (t, J = 6.4 Hz, 2H), 3.67 (t, J = 2.6 Hz, 1H), 3.56 (t, J = 9.6 Hz, 2H), 3.37 (t, J = 6.4 Hz, 2H), 3.35 (dd, 9.6, 2.6 Hz, 2H, 2H), 3.29 (s, 3H), 3.11 (t, J = 9.6 Hz, 1H), 1.62-1.53 (m, 4H), 1.44 - 1.36 (m, 2H).

[0246] 2-O-(9-Methoxynonyl)-myo-inositol (III_B-3): According to the general hydrolysis procedure F, 240 mg of (III_B-3) was obtained from 430 mg of (II_B-3) (yield 97%). HPLC-MS (condition B): rt = 2.53 min; m / z: 337 [M+1] + 。

[0232]

[0247] 2-O-(19-Methoxynonadecyl)-myo-inositol (III_B-4): According to the general hydrolysis procedure C, 200 mg of (III_B-4) was obtained from 337 mg of (VIII_B-1) (yield 60%). HPLC-MS (condition B): rt = 4.43 min; m / z: 477 [M+1] + 。

[0233]

[0248] 2-O-(29-Methoxynonacosyl)-myo-inositol (III_B-5): According to the general hydrolysis procedure C, 75 mg of (III_B-5) was obtained from 284 mg of (VIII_B-2) (yield 27%).

[0234]

[0249] rac-4-O-(3-(p-Tolyl)propyl)-myo-inositol (III_A-6): According to the general hydrolysis procedure S, 166.4 mg of (III_A-6) was obtained from 344 mg of (II_A-6) (yield 67%). HPLC-MS (Condition A): rt = 2.87 min; m / z: 313 [M+1] + 。

[0235]

[0250] rac-4-O-(4-Methylpentyl)-myo-inositol (III_A-7): According to the general hydrolysis procedure S, 225 mg of (III_A-7) was obtained from 767 mg of (II_A-7) (yield 43%). HPLC-MS (Condition A): rt = 2.60 min; m / z: 265 [M+1] + 。

[0236]

[0251] rac-4-O-(6,6,6-Trifluorohexyl)-myo-inositol (III_A-8): According to the general hydrolysis procedure S, 274 mg of (III_A-8) was obtained from 424 mg of (II_A-8) (yield 90%). HPLC-MS (Condition A): rt = 2.66 min; m / z: 319 [M+1] + 。

[0237]

[0252] rac-4-O-(3-(4-Methoxyphenyl)propyl)-myo-inositol (III_A-9): According to the general hydrolysis procedure S, 196 mg of (III_A-9) was obtained from 409 mg of (II_A-9) (yield 66%). HPLC-MS (Condition A): rt = 2.66 min; m / z: 329 [M+1] + 。

[0238]

[0253] rac-4-O-(3-(3-(Trifluoromethyl)phenyl)propyl)-myo-inositol (III_A-10): According to the general hydrolysis procedure S, 146 mg of (III_A-10) was obtained from 209 mg of (II_A-10) (yield 93%). HPLC-MS (Condition A): rt = 3.01 min; m / z: 367 [M+1] + 。

[0239]

[0254] rac-4-O-(2-Cyclopentylethyl)-myo-inositol (III_A-11): According to the general hydrolysis procedure S, 45 mg of (III_A-11) was obtained from 68 mg of (II_A-11) (yield 96%). HPLC-MS (condition A): rt = 2.65 min; m / z: 277 [M+1] + 。

[0240]

[0255] rac-4-O-(2-Cyclopropylethyl)-myo-inositol (III_A-12): According to the general hydrolysis procedure S, 355 mg of (III_A-12) was obtained from 486 mg of (II_A-12) (yield 96%). HPLC-MS (condition A): rt = 1.09 min; m / z: 249 [M+1] + 。

[0241]

[0256] rac-4-O-(5-(1H-Pyrazol-1-yl)pentyl)-myo-inositol (III_A-13): According to the general hydrolysis procedure S, 77 mg of (III_A-13) was obtained from 137 mg of (II_A-13) (yield 78%). HPLC-MS (condition A): rt = 1.65 min; m / z: 317 [M+1] + 。

[0242]

[0257] rac-4-O-(5-Acetamidopentyl)-myo-inositol (III_A-14): According to the general hydrolysis procedure S, 180 mg of (III_A-14) was obtained from 254 mg of (II_A-14) (yield >99%). HPLC-MS (condition A): rt = 2.71 min; m / z: 308 [M+1] + 。

[0243]

[0258] rac-4-O-(10-Methoxycarbonyldecyl)-myo-inositol (III_A-15): According to the general hydrolysis procedure S, 30 mg of (III_A-15) was obtained from 63 mg of (II_A-15) (yield 64%). HPLC-MS (condition A): rt = 3.11 min; m / z: 379 [M+1] + 。

[0244]

[0259] rac-4-O-(10-(Benzyloxy)decyl)-myo-inositol (III_A-16): According to the general hydrolysis procedure S, 19 mg of (III_A-16) was obtained from 25 mg of (II_A-16) (yield 98%). HPLC-MS (Condition A): rt = 3.54 min; m / z: 427 [M+1] + 。

[0245]

[0260] rac-4-O-Methyl-myo-inositol (III_A-17): According to the general hydrolysis procedure S, 27 mg of (III_A-17) was obtained from 58 mg of (II_A-17) (yield 76%). 1 1H NMR (400 MHz, chloroform-d) δ 1H NMR (400 MHz, MeOH-d4) δ 3.87 (t, J = 2.8 Hz, 1H), 3.55 (s, 3H), 3.36 (dd, ii = 9.6, 2.8 Hz, 1H), 3.30 - 3.22 (m, 3H), 3.15 (t, J = 9.2 Hz, 1H).

[0261] rac-4-O-(7-Methoxyheptyl)-myo-inositol (III_A-18): According to the general hydrolysis procedure S, 103 mg of (III_A-18) was obtained from 167 mg of (II_A-18) (yield 87%). HPLC-MS (Condition A): rt = 2.57 min; m / z: 309 [M+1] + 。

[0246]

[0262] rac-4-O-Propyl-myo-inositol (III_A-19): According to the general hydrolysis procedure S, 66 mg of (III_A-19) was obtained from 128 mg of (II_A-19) (yield 80%). 1H NMR (400 MHz, MeOH-d4) δ 3.88 (t, J = 2.4 Hz, 1H), 3.69 (td, J = 9.2, 7.2 Hz, 1H), 3.68 (td, J = 9.2, 7.2 Hz, 1H), 3.56 (t, J = 9.5 Hz, 1H), 3.39 - 3.33 (m, 2H), 3.30 - 3.23 (m, 1H), 3.19 - 3.12 (m, 1H), 1.58 (h, J = 7.2 Hz, 2H), 0.87 (t, J = 7.2 Hz, 3H).

[0263] rac-4-O-(3-(4-(2-(Benzyloxycarbonyl)ethyl)-1H-1,2,3-triazol-1-yl)propyl)-myo-inositol (III_A-20): According to the general click reaction procedure M, 34 mg of (III_A-20) was obtained from 57 mg of (VI_A-1) and 61.3 mg (1.5 equivalents) of (20) (35%). In this case, flash chromatography was used. HPLC-MS (Condition A): rt = 2.84 min; m / z: 452 [M+1] + 。

[0247]

[0264] rac-4-O-(6-(4-(Methoxycarbonyl)-1H-1,2,3-triazol-1-yl)hexyl)-myo-inositol (III_A-21): According to the general click reaction procedure M, 109 mg of (III_A-21) was obtained from 99 mg of (VI_A-2) and 27 mg (1 equivalent) of methyl propiolate (86%). HPLC-MS (Condition A): rt = 2.39 min; m / z: 390 [M+1] + 。

[0248]

[0265] 5-O-Propyl-myo-inositol (III_C-1): According to the general debenzylation procedure K, 15 mg of (III_C-1) was obtained from 107 mg of (II_C-1) (yield 42%). 11H NMR (400 MHz, MeOH-d4) δ 3.84 (t, J = 2.8, 1H), 3.64 (t, J = 7.4 Hz, 2H), 3.56 (t, J = 9.6 Hz, 2H), 3.24 (dd, J = 9.6, 2.8 Hz, 2H), 2.86 (t, J = 9.6 Hz, 1H), 1.54 (q, J = 7.4 Hz, 3H), 0.83 (t, J = 7.4 Hz, 4H).

[0266] 5-O-(2-Cyclopropylethyl)-myo-inositol (III_C-2): According to the general debenzylation procedure K, 15 mg of (III_C-2) was obtained from 108 mg of (II_C-2) (yield 39%). 1H NMR (400 MHz, MeOH-d4) δ 3.88 (t, J = 2.8 Hz, 1H), 3.80 (t, J = 7.2 Hz, 2H), 3.61 (t, J = 9.6 Hz, 2H), 3.29 (dd, J = 9.6, 2.8 Hz, 3H), 2.91 (t, J = 9.6 Hz, 1H), 1.47 (q, J = 7.2 Hz, 2H), 0.80 - 0.62 (m, 1H), 0.41 - 0.30 (m, 2H), 0.07 - -0.10 (m, 2H).

[0267] 5-O-(9-Methoxynonyl)-myo-inositol (III_C-3): According to the general debenzylation procedure K, 27 mg of (III_C-3) was obtained from 127 mg of (II_C-3) (yield 50%). 1 1H NMR (400 MHz, MeOH-d4) δ 3.96 (t, J = 2.8 Hz, 1H), 3.80 (t, J = 7.0 Hz, 2H), 3.67 (d, J = 9.6 Hz, 2H), 3.40 (t, J = 6.8 Hz, 2H), 3.35 (dd, J = 9.6, 2.8 Hz, 2H), 2.97 (t, J = 9.6 Hz, 1H), 1.64 (t, J = 7.0 Hz, 3H), 1.57 (p, J = 6.8 Hz, 3H), 1.35 (br, 10H).

[0268] rac-1-O-Propyl-myo-inositol (III_D-1): 46 mg of (III_C-1) was obtained from 107 mg of (IX_D-1) according to the general debenzylation procedure K (yield 95%). 1 H NMR (400 MHz, MeOH-d4) δ 4.04 (t, J = 2.8 Hz, 1H), 3.59 (t, J = 9.6 Hz, 1H), 3.54 (dt, J = 9.2, 7.2 Hz, 1H), 3.53 (t, J = 9.6 Hz, 1H), 3.38 (dt, J = 9.2, 7.2 Hz, 1H), 3.24 (dd, J = 9.6, 2.8 Hz, 1H), 3.09 (t, J = 9.6 Hz, 1H), 3.01 (dd, J = 9.6, 2.8 Hz, 1H), 1.55 (h, J = 7.2 Hz, 2H), 0.85 (t, J = 7.2 Hz, 3H).

[0269] rac-4-O-(6-Amino-6-oxohexyl)-myo-inositol (III_A-22): 50 mg of (III_A-19) was obtained from 72 mg of (II_A-21) according to the general hydrolysis procedure S (yield 80%). 1 H NMR (400 MHz, MeOH-d4) δ 3.94 (t, J = 2.5 Hz, 1H), 3.82-3.77 (m, 2H), 3.61 (t, J = 9.5 Hz, 1H), 3.42-3.39 (m, 2H), 3.34-3.30 (m, 1H), 3.23-3.19 (m, 1H), 2.22 (t, J = 7.4 Hz, 2H), 1.68-1.61 (m, 4H), 1.47-1.39 (m, 2H).

[0270] 2-O-(5-(Benzyloxy)pentyl)-myo-inositol (III_B-7): 75 mg of (III_B-7) was obtained from 179 mg of (II_B-5) according to the general hydrolysis procedure F (yield 71%). HPLC-MS (Condition A): rt = 2.83 min; m / z: 357 [M+1] + , 379 [M+23] + .

[0249]

[0271] 2-O-(6,6,6-Trifluorohexyl)-myo-inositol (III_B-8): 54 mg of (III_B-8) was obtained from 85 mg of (VIII_B’-1) according to the general debenzylation procedure K (yield > 99%). HPLC-MS (Condition A): rt = 2.69 min; m / z: 319 [M+1] + 。

[0250]

[0272] 2-O-(6-Amino-6-oxohexyl)-myo-inositol (III-B-9): 45 mg of (III_B-9) was obtained from 75 mg of (VIII_B’-2) according to the general debenzylation procedure K (yield > 99%). 1 H NMR (400 MHz, MeOH-d4) δ 3.78 (t, J = 6.4, 1H), 3.76 (t, J = 6.4, 1H), 3.69 (q, J = 3.0 Hz, 1H), 3.59 (td, J = 10.0, 3.0 Hz, 2H), 3.39 (dt, J = 10.0, 3.0 Hz, 2H), 3.14 (td, J = 9.2, 3.6 Hz, 1H), 2.20 (t, J = 7.6 Hz, 2H), 1.67 - 1.57 (m, 4H), 1.47 - 1.39 (m, 2H).

[0273] 2-O-(2-Cyclopentylethyl)-myo-inositol (III_B-10): 120 mg of (III_B-10) was obtained from 200 mg of (VIII_B’-3) according to the general debenzylation procedure K (yield > 99%). HPLC-MS (Condition A): rt = 2.69 min; m / z: 277 [M+1] + 。

[0251]

[0274] 2-O-(2-Cyclopropylethyl)-myo-inositol (III_B-11): 150 mg of (III_B-11) was obtained from 261 mg of (VIII_B’-4) according to the general debenzylation procedure K (yield > 99%). 11H NMR (400 MHz, MeOH-d4) δ 3.84 (t, J = 6.9 Hz, 2H), 3.70 (t, J = 2.7 Hz, 1H), 3.58 (t, J = 9.5 Hz, 2H), 3.37 (dd, J = 9.5, 2.7 Hz, 2H), 3.12 (t, J = 9.2 Hz, 1H), 1.50 (q, J = 6.9 Hz, 2H), 0.81-0.69 (m, 1H), 0.43-0.39 (m, 2H), 0.07- 0.03 (m, 2H).

[0275] 2-O-(5-Aminopentyl)-myo-inositol (III_B-12): According to the general hydrolysis procedure F, 50 mg of (III_B-12) was obtained from 105 mg of (II_B-6) (yield 93%). 1 1H NMR (400 MHz, MeOH-d4) δ 3.79 (t, J = 6.2 Hz, 2H), 3.70 (t, J = 2.7 Hz, 1H), 3.57 (t, J = 9.2 Hz, 2H), 3.40 (dd, J = 10.0, 2.7 Hz, 2H), 3.15 (t, J = 9.2 Hz, 1H), 2.93 (t, J = 7.6 Hz, 2H), 1.74 - 1.61 (m, 4H), 1.53-1.45 (m, 2H).

[0276] 2-O-Prop-2-ynyl-myo-inositol (III_B-13): According to the general hydrolysis procedure F, 73 mg of (III_B-13) was obtained from 183 mg of (II_B-4) (yield 86%). 1 1H NMR (400 MHz, MeOH-d4) δ 4.49 (d, J = 2.6 Hz, 2H), 3.93 (t, J = 2.8 Hz, 1H), 3.57 (t, J = 9.6 Hz, 2H), 3.40 (dd, J = 10.0, 2.8 Hz, 2H), 3.13 (t, J = 9.2 Hz, 1H), 2.81 (t, J = 2.4 Hz, 1H).

[0277] 2-O-(5-(4-(Methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-myo-inositol (III_B-14): According to the general hydrolysis procedure F, 65 mg of (III_B-14) was obtained from 142 mg of (II_B-7) (yield 77%). HPLC-MS (Condition A): rt = 1.28 min; m / z: 362 [M+1] + 。

[0252]

[0278] 2-O-(5-Acetamidopentyl)-myo-inositol (III_B-15): According to the general amide formation procedure Q, 30 mg of (III_B-15) was obtained from 46 mg of (II_B-12) and 30 mg (1 equivalent) of 2,5-dioxopyrrolidin-1-yl acetate (yield 56%). HPLC-MS (Condition A): rt = 1.06 min; m / z: 308 [M+1] + 。

[0253]

[0279] 2-O-((1-(2-(Methoxycarbonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol (III_B-16): According to the general click reaction procedure L, 118 mg of (III_B-16) was obtained from 109 mg of (III_B-13) and 71 mg (1.1 equivalent) of (38) (68%). HPLC-MS (Condition A): rt = 0.97 min; m / z: 348 [M+1] + 。

[0254]

[0280] 5-O-(5-Methoxypentyl)-myo-inositol (III_C-4): According to the general debenzylation procedure K, 17 mg of (III_C-4) was obtained from 46 mg of (II_C-4) (yield >99%). 11H NMR (400 MHz, MeOH-d4) δ 3.94 (t, J = 2.8 Hz, 1H), 3.79 (t, J = 6.7 Hz, 2H), 3.66 (t, J = 9.5 Hz, 2H), 3.40 (t, J = 6.5 Hz, 2H), 3.36 - 3.32 (dd, J = 10.0, 2.8 Hz, 2H), 3.32 (s, 3H), 2.95 (t, J = 9.2 Hz, 1H), 1.68-1.56 (m, 4H), 1.47-1.40 (m, 2H).

[0281] 5-O-(6,6,6-Trifluorohexyl)-myo-inositol (III_C-5): According to the general debenzylation procedure K, 29 mg of (III_C-5) was obtained from 160 mg of (II_C-5) (yield 43%). 1 1H NMR (400 MHz, MeOH-d4) δ 3.94 (t, J = 2.8 Hz, 1H), 3.79 (t, J = 6.6 Hz, 2H), 3.66 (t, J = 9.6 Hz, 2H), 3.34 (dd, J = 10.0, 2.8 Hz, 2H), 2.95 (t, J = 9.2 Hz, 1H), 2.21-2.09 (m, 2H), 1.68- 1.56 (m, 4H), 1.52-1.46 (m, 2H).

[0282] 5-O-(5-(4-(Methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-myo-inositol (III_C-6): According to the general debenzylation procedure K, 15 mg of (III_C-6) was obtained from 102 mg of (II_C-6) (yield 33%). 11H NMR (400 MHz, MeOH-d4) δ 7.97 (s, 1H), 4.53 (s, 2H), 4.42 (t, J = 7.1 Hz, 2H), 3.94 (t, J = 2.8 Hz, 1H), 3.78 (t, J = 6.6 Hz, 2H), 3.65 (t, J = 9.5 Hz, 2H), 3.37 (s, 3H), 3.33 (dd, J = 10.0, 2.8 Hz, 2H), 2.94 (t, J = 9.2 Hz, 1H), 1.95 (p, J = 7.1 Hz, 2H), 1.66 (p, J = 6.6 Hz, 2H), 1.45 - 1.38 (m, 2H).

[0283] rac-1-O-(9-Methoxynonyl)-myo-inositol (III_D-2): 109 mg of (III_D-2) was obtained from 196 mg of (IX_D-2) according to the general debenzylation procedure K (yield > 99%). HPLC-MS (Condition A): rt = 2.89 min; m / z: 337 [M+1] + 。

[0255]

[0284] rac-1-O-(2-Cyclopropylethyl)-myo-inositol (III_D-3): 87 mg of (III_D-3) was obtained from 181 mg of (IX_D-3) according to the general debenzylation procedure K (yield > 99%). HPLC-MS (Condition A): rt = 1.06 min; m / z: 249 [M+1] + 。

[0256]

[0285] rac-1-O-(5-Acetamidopentyl)-myo-inositol (III_D-4): 57 mg of (III_D-4) was obtained from 107 mg of (IX_D-4) according to the general debenzylation procedure K (yield > 99%). 11H NMR (400 MHz, MeOH-d4) δ 4.13 (s, 1H), 3.70 - 3.60 (m, 3H), 3.51 (q, J = 7.1 Hz, 1H), 3.35 - 3.28 (m, 2H), 3 - 20 - 3.16 (m, 3H), 3.10 (d, J = 9.5 Hz, 1H), 1.95 (s, 3H), 1.69 - 1.60 (m, 2H), 1.58 - 1.49 (m, 2H), 1.47 - 1.39 (m, 2H).

[0286] rac-1-O-(6,6,6-Trifluorohexyl)-myo-inositol (III_D-5): 55 mg of (III_D-5) was obtained from 102 mg of (IX_D-5) according to the general debenzylation procedure K (yield >99%). HPLC-MS (Condition A): rt = 2.72 min; m / z: 319 [M+1] + , 341 [M+23] + .

[0257]

[0287] rac-1-O-(2-Cyclopentylethyl)-myo-inositol (III_D-6): 76 mg of (III_D-6) was obtained from 119 mg of (IX_D-6) according to the general debenzylation procedure K (yield 64%). HPLC-MS (Condition A): rt = 2.72 min; m / z: 277 [M+1] + , 299 [M+23] + .

[0258]

[0288] rac-1-O-((1-(2-(Methoxycarbonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol (III_D-7): 130 mg of (III_D-7) was obtained from 248 mg of (IX_D-10) according to the general debenzylation procedure K (yield 93%). HPLC-MS (Condition A): rt = 0.99 min; m / z: 348 [M+1] + .

[0259]

[0289] rac-1-O-(5-(4-(Methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-myo-inositol (III_D-8): 143 mg of (III_D-8) was obtained from 250 mg of (IX_D-8) according to the general debenzylation procedure K (yield > 99%). 1 H NMR (400 MHz, MeOH-d4) δ 8.04 (s, 1H), 4.57 (s, 2H), 4.46 (t, J = 7.0 Hz, 2H), 4.17 (t, J = 2.8 Hz, 1H), 3.74 - 3.65 (m, 3H), 3.54 (dt, J = 9.4, 6.5 Hz, 1H), 3.41 (s, 3H), 3.40 - 3.37 (m 1H), 3.24 (t, J = 9.2 Hz, 1H), 3.15 (dd, J = 10.0, 2.8 Hz, 1H), 1.98 (p, J = 7.2 Hz, 2H), 1.69 (p, J = 6.9 Hz, 2H), 1.48 - 1.41 (m, 2H). C.3. Intermediates IV_A, IV_B, IV_C, and IV_D

[0290] rac-1,2,3,5,6-Pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4-O-pentyl-myo-inositol (IV_A-1): 57.6 mg of (IV_A-1) was obtained from 76 mg of (III_A-1) according to the general phosphorylation procedure H (yield 16%). HPLC-MS (Condition A): rt = 4.15 min; m / z: 1161 [M+1] + 。

[0260]

[0291] rac-4-O-(5-(Benzyloxy)pentyl)-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_A-2): 30 mg of (IV_A-2) was obtained from 20 mg of (III_A-2) according to the general phosphorylation procedure H (yield 42%). HPLC-MS (Condition B): rt = 3.24 min; m / z: 1267 [M+1] + 。

[0261]

[0292] rac-4-O-(5-Methoxypentyl)-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_A-3): According to the general phosphorylation procedure H, 98 mg of (IV_A-3) was obtained from 45 mg of (III_A-3) (yield 51%). HPLC-MS (condition B): rt = 2.95 min; m / z: 1191 [M+1] + 。

[0262]

[0293] rac-4-O-(5-Methoxycarbonylpentyl)-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)myo-inositol (IV_A-4): According to the general phosphorylation procedure G, 23 mg of (IV_A-4) was obtained from 42 mg of (III_A-4) (yield 14%). HPLC-MS (condition B): rt = 2.99 min; m / z: 1219 [M+1] + 。

[0263]

[0294] rac-4-O-(2-(4-Acetylpiperazin-1-yl)ethyl)-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_A-5): According to the general phosphorylation procedure H, 29 mg of (IV_A-5) was obtained from 24 mg of (III_A-5) (yield 32%). HPLC-MS (condition B): rt = 2.37 min; m / z: 1245 [M+1] + 。

[0264]

[0295] 1,3,4,5,6-Pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-2-O-pentyl-myo-inositol (IV_B-1): According to the general phosphorylation procedure H, 399 mg of (IV_B-1) was obtained from 150 mg of (III_B-1) (yield 57%). HPLC-MS (Condition A): rt = 4.15 min; m / z: 1161 [M+1] + 。

[0265]

[0296] 2-O-(5-Methoxypentyl)-1,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_B-2): According to the general phosphorylation procedure H, 71 mg of (IV_B-2) was obtained from 84 mg of (III_B-2) (yield 19.9%). HPLC-MS (Condition A): rt = 3.99 min; m / z: 1191.6 [M+1] + 。

[0266]

[0297] 2-O-(9-Methoxynonyl)-1,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_B-3): According to the general phosphorylation procedure H, 110 mg of (IV_B-3) was obtained from 240 mg of (III_B-3) (yield 12.4%). HPLC-MS (Condition B): rt = 3.95 min; m / z: 1247 [M+1] + 、1264 [M+23] + 。

[0267]

[0298] 2-O-(19-Methoxynonadecyl)-1,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_B-4): According to the general phosphorylation procedure H, 80 mg of (IV_B-4) was obtained from 200 mg of (III_B-4) (yield 14%). HPLC-MS (Condition B): rt = 5.17 min; m / z: 1387 [M+1] + 。

[0268]

[0299] 2-O-(29-Methoxynonacosanoyl)-1,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_B-5): According to the general phosphorylation procedure H, 20 mg of (IV_B-5) was obtained from 75 mg of (III_B-5) (yield 11%). 31 P NMR (162 MHz, chloroform-d) δ -1.15, -4.17, -4.76.

[0300] rac-1,2,3,5,6-Pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4-O-(3-(p-tolyl)propyl)-myo-inositol (IV_A-6): According to the general phosphorylation procedure H, 44.6 mg of (IV_A-6) was obtained from 50 mg of (III_A-6) (yield 23%). 31 P NMR (162 MHz, chloroform-d) δ -0.71, -1.32, -1.89, -3.00, -4.16. HPLC-MS (condition A): rt = 4.46 min; m / z: 1223 [M+1] + 。

[0269]

[0301] rac-4-O-(4-Methylpentyl)-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_A-7): According to the general phosphorylation procedure H, 45 mg of (IV_A-7) was obtained from 50 mg of (III_A-7) (yield 20%). 31 P NMR (162 MHz, chloroform-d) δ -0.50, -1.20, -1.96, -3.05, -4.16. HPLC-MS (condition A): rt = 4.44 min; m / z: 1175 [M+1] + 。

[0270]

[0302] rac-1,2,3,5,6-Pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4-O-(6,6,6-trifluorohexyl)-myo-inositol (IV_A-8): According to the general phosphorylation procedure H, 48 mg of (IV_A-8) was obtained from 50 mg of (III_A-8) (yield 25%). 31 P NMR (162 MHz, chloroform-d) -0.67, -1.28, -1.85, -2.99, -4.10. HPLC-MS (Condition A): rt = 4.31 min; m / z: 1229 [M+1] + 。

[0271]

[0303] rac-4-O-(3-(4-Methoxyphenyl)propyl)-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_A-9): According to the general phosphorylation procedure H, 48 mg of (IV_A-9) was obtained from 50 mg of (III_A-9) (yield 25%). 31 P NMR (162 MHz, chloroform-d) δ -0.74, -1.33, -1.85, -3.00, -3.00, -4.15. HPLC-MS (Condition A): rt = 4.29 min; m / z: 1240 [M+1] + 。

[0272]

[0304] rac-1,2,3,5,6-Pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4-O-(3-(3-(trifluoromethyl)phenyl)propyl)-myo-inositol (IV_A-10): According to the general phosphorylation procedure H, 35 mg of (IV_A-10) was obtained from 50 mg of (III_A-10) (yield 20%). 31 P NMR (162 MHz, chloroform-d) δ -0.52, -1.24, -1.84, -3.01, -4.11. HPLC-MS (Condition A): rt = 4.51 min; 1277 m / z: [M+1] + 。

[0273]

[0305] rac-4-O-(2-Cyclopentylethyl)-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_A-11): According to the general phosphorylation procedure H, 33 mg of (IV_A-11) was obtained from 45 mg of (III_A-11) (yield 17%). 31 P NMR (162 MHz, chloroform-d) -0.59, -1.18, -1.93, -3.03, -4.15. HPLC-MS (Condition A): rt = 4.46 min; m / z: 1187 [M+1] + 。

[0274]

[0306] rac-4-O-(2-Cyclopropylethyl)-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_A-12): According to the general phosphorylation procedure H, 47 mg of (IV_A-12) was obtained from 52 mg of (III_A-12) (yield 19%). 31 P NMR (162 MHz, chloroform-d) δ -0.68, -1.24, -1.90, -3.00, -4.15. HPLC-MS (Condition A): rt = 4.15 min; m / z: 1159 [M+1] + 。

[0275]

[0307] rac-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4-O-(5-(1H-pyrazol-1-yl)pentyl)-myo-inositol (IV_A-13): According to the general phosphorylation procedure H, 100 mg of (IV_A-13) was obtained from 50 mg of (III_A-13) (yield 54%). 31 P NMR (162 MHz, chloroform-d) δ -0.72, -1.39, -1.88, -3.00, -4.13. HPLC-MS (Condition A): rt = 4.08 min; m / z: 1227 [M+1] + 。

[0276]

[0308] rac-4-O-(5-Acetamidopentyl)-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_A-14): According to the general phosphorylation procedure H, 14 mg of (IV_A-14) was obtained from 35 mg of (III_A-14) (yield 10%). 31 P NMR (162 MHz, chloroform-d) δ -0.75, -1.63, -1.78, -2.98, -4.04. HPLC-MS (Condition A): rt = 3.82 min; m / z: 1218 [M+1] + 。

[0277]

[0309] rac-4-O-(10-Methoxycarbonyldecyl)-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_A-15): According to the general phosphorylation procedure H, 7.5 mg of (IV_A-15) was obtained from 30 mg of (III_A-15) (yield 7%). 31 P NMR (162 MHz, chloroform-d) -0.51, -1.17, -1.92, -3.07, -4.18. HPLC-MS (Condition A): rt = 4.65 min; m / z: 1289 [M+1] + 。

[0278]

[0310] rac-4-O-(10-(Benzyloxy)decyl)-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_A-16): According to the general phosphorylation procedure H, 13 mg of (IV_A-16) was obtained from 19 mg of (III_A-16) (yield 22%). 31 P NMR (162 MHz, chloroform-d) δ -0.50, -1.14, -1.93, -3.07, -4.18. HPLC-MS (Condition A): rt = 5.11 min; m / z: 1337 [M+1] + 。

[0279]

[0311] rac-4-O-Methyl-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_A-17): According to the general phosphorylation procedure H, 10 mg of (IV_A-17) was obtained from 27 mg of (III_A-17) (yield 6%). 31 P NMR (162 MHz, chloroform-d) δ -0.83, -1.43, -1.80, -3.17, -4.20. HPLC-MS (Condition A): rt = 3.96 min; m / z: 1105 [M+1] + 。

[0280]

[0312] rac-4-O-(7-Methoxyheptyl)-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_A-18): According to the general phosphorylation procedure H, 32 mg of (IV_A-18) was obtained from 50 mg of (III_A-18) (yield 16%). 31 P NMR (162 MHz, chloroform-d) δ -0.54, -1.18, -1.92, -3.06, -4.17. HPLC-MS (Condition A): rt = 4.25 min; m / z: 1219 [M+1] + 。

[0281]

[0313] rac-1,2,3,5,6-Pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-4-O-propyl-myo-inositol (IV_A-19): According to the general phosphorylation procedure H, 20 mg of (IV_A-19) was obtained from 66 mg of (III_A-19) (yield 6%). 31 P NMR (162 MHz, chloroform-d) -0.59, -1.24, -1.92, -3.01, -4.14. HPLC-MS (Condition A): rt = 3.98 min; m / z: 1133 [M+1] + 。

[0282]

[0314] rac-4-O-(3-(4-(2-(Benzyloxycarbonyl)ethyl)-1H-1,2,3-triazol-1-yl)propyl)-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_A-20): According to the general phosphorylation procedure H, 14 mg of (IV_A-20) was obtained from 34 mg of (III_A-20) (yield 14%). 31 P NMR (162 MHz, chloroform-d) δ -0.63, -1.61 (d, J = 6.2 Hz), -2.97, -3.98. HPLC-MS (Condition A): rt = 4.16 min; m / z: 1363 [M+1] + 。

[0283]

[0315] rac-4-O-(6-(4-(Methoxycarbonyl)-1H-1,2,3-triazol-1-yl)hexyl)-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_A-21): According to the general phosphorylation procedure H, 15 mg of (IV_A-21) was obtained from 40 mg of (III_A-21) (yield 11%). 31 P NMR (162 MHz, chloroform-d) δ -0.95, -1.45, -1.78, -3.04, -4.12. HPLC-MS (Condition A): rt = 4.00 min; m / z: 1300 [M+1] + 。

[0284]

[0316] 1,2,3,4,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-5-O-propyl-myo-inositol (IV_C-1): According to the general phosphorylation procedure H, 10 mg of (IV_C-1) was obtained from 15 mg of (III_C-1) (yield 13%). 31 P NMR (162 MHz, chloroform-d) δ -0.16, -3.40, -3.90. HPLC-MS (Condition A): rt = 4.04 min; m / z: 1133 [M+1]+ .

[0285]

[0317] 5-O-(2-Cyclopropylethyl)-1,2,3,4,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_C-2): According to the general phosphorylation procedure H, 10 mg of (IV_C-2) was obtained from 15 mg of (III_C-2) (yield 14%). 31 P NMR (162 MHz, chloroform-d) δ -0.21, -3.36, -3.90. HPLC-MS (Condition A): rt = 4.17 min; m / z: 1160 [M+1] + .

[0286]

[0318] 5-O-(9-Methoxynonyl)-1,2,3,4,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_C-3): According to the general phosphorylation procedure H, 15 mg of (IV_C-3) was obtained from 27 mg of (III_C-3) (yield 15%). 31 P NMR (162 MHz, chloroform-d) δ -0.07, -3.35, -3.92. HPLC-MS (Condition A): rt = 4.55 min; m / z: 1248 [M+1] + .

[0287]

[0319] rac-2,3,4,5,6-Pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-1-O-propyl-myo-inositol (IV_D-1): According to the general phosphorylation procedure H, 53 mg of (IV_D-1) was obtained from 61 mg of (III_D-1) (yield 17%). 31 P NMR (162 MHz, chloroform-d) δ -1.76, -2.59, -3.97, -4.47, -4.69. HPLC-MS (Condition A): rt = 4.10 min; m / z: 1133 [M+1] + .

[0288]

[0320] rac-4-O-(6-Amino-6-oxohexyl)-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_A-22): According to the general phosphorylation procedure H, 6 mg of (IV_A-22) was obtained from 130 mg of (III_A-22) (yield 1%). 31 P NMR (162 MHz, chloroform-d) δ -1.64, -1.81, -2.31, -2.89, -4.09. HPLC-MS (Condition A): rt = 3.44 min; m / z: 1205 [M+1] + 。

[0289]

[0321] 1,3,4,5,6-Pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-2-O-prop-2-ynyl-myo-inositol (IV_B-6): According to the general phosphorylation procedure H, 10 mg of (IV_B-6) was obtained from 54 mg of (III_B-13) (yield 3.6%). 31 P NMR (162 MHz, chloroform-d) δ -2.03, -4.28, -4.89. HPLC-MS (Condition A): rt = 3.98 min; m / z: 1129 [M+1] + 。

[0290]

[0322] 2-O-(5-(Benzyloxy)pentyl)-1,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_B-7): According to the general phosphorylation procedure H, 75 mg of (IV_B-7) was obtained from 67 mg of (III_B-7) (yield 32%). 31 P NMR (162 MHz, chloroform-d) δ -1.06, -4.00, -4.63. HPLC-MS (Condition A): rt = 4.43 min; m / z: 1267 [M+1] + 。

[0291]

[0323] 2-O-(6,6,6-Trifluorohexyl)-1,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_B-8): According to the general phosphorylation procedure R, 56 mg of (IV_B-8) was obtained from 54 mg of (III_B-8) (yield 27%). 31 P NMR (162 MHz, chloroform-d) δ δ -0.76, -3.76, -4.57. HPLC-MS (Condition A): rt = 4.37 min; m / z: 1229 [M+1] + 。

[0292]

[0324] 2-O-(6-Amino-6-oxohexyl)-1,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_B-9): According to the general phosphorylation procedure R, 23 mg of (IV_B-9) was obtained from 46 mg of (III_B-9) (yield 14%). 31 P NMR (162 MHz, chloroform-d) δ -0.71, -4.15, -4.34. HPLC-MS (Condition A): rt = 3.77 min; m / z: 1204 [M+1] + 。

[0293]

[0325] 2-O-(2-Cyclopentylethyl)-1,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_B-10): According to the general phosphorylation procedure R, 124 mg of (IV_B-10) was obtained from 121 mg of (III_B-10) (yield 24%). 31 P NMR (162 MHz, chloroform-d) δ -1.09, -4.00, -4.64. HPLC-MS (Condition A): rt = 4.40 min; m / z: 1187 [M+1] + 。

[0294]

[0326] 2-O-(2-Cyclopropylethyl)-1,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_B-11): 85 mg of (IV_B-11) was obtained from 62 mg of (III_B-11) according to the general phosphorylation procedure H (yield 29%). 31 P NMR (162 MHz, chloroform-d) δ -1.30, -3.99, -4.70. HPLC-MS (Condition A): rt = 4.15 min; m / z: 1159 [M+1] + 。

[0295]

[0327] 2-O-(5-(4-(Methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-1,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_B-12): 25 mg of (IV_B-12) was obtained from 65 mg of (III_B-14) according to the general phosphorylation procedure G (yield 11%). 31 P NMR (162 MHz, chloroform-d) δ -0.64, -3.84, -4.44. HPLC-MS (Condition A): rt = 3.92 min; m / z: 1272 [M+1] + 。

[0296]

[0328] 2-O-(5-Acetamidopentyl)-1,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_B-13): 10 mg of (IV_B-13) was obtained from 30 mg of (III_B-15) according to the general phosphorylation procedure H (yield 8%). 31 P NMR (162 MHz, chloroform-d) δ -0.61, -4.30 (d, J = 3.6 Hz). HPLC-MS (Condition A): rt = 3.73 min; m / z: 1218 [M+1] + 。

[0297]

[0329] 2-O-((1-(2-(Methoxycarbonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-1,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_B-14): According to the general phosphorylation procedure G, 101 mg of (IV_B-14) was obtained from 118 mg of (III_B-16) (yield 24%). 31 P NMR (162 MHz, chloroform-d) δ -1.44, -4.02, -4.58. HPLC-MS (Condition A): rt = 3.84 min; m / z: 1258 [M+1] + 。

[0298]

[0330] 5-O-(5-Methoxypentyl)-1,2,3,4,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_C-4): According to the general phosphorylation procedure H, 6 mg of (IV_C-4) was obtained from 23 mg of (III_C-4) (yield 6%). 31 P NMR (162 MHz, chloroform-d) δ -0.06, -3.39, -3.90. HPLC-MS (Condition A): rt = 4.03 min; m / z: 1192 [M+1] + 。

[0299]

[0331] 5-O-(6,6,6-Trifluorohexyl)-1,2,3,4,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_C-5): According to the general phosphorylation procedure H, 10 mg of (IV_C-5) was obtained from 28 mg of (III_C-5) (yield 9%). 31 P NMR (162 MHz, chloroform-d) δ -0.11, -3.21, -3.83. HPLC-MS (Condition A): rt = 4.34 min; m / z: 1230 [M+1] + 。

[0300]

[0332] 5-O-(5-(4-(Methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-1,2,3,4,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_C-6): According to the general phosphorylation procedure H, 7 mg of (IV_C-6) was obtained from 15 mg of (III_C-6) (yield 13%). 31 P NMR (162 MHz, chloroform-d) δ -0.50, -2.93, -3.74. HPLC-MS (Condition A): rt = 3.84 min; m / z: 1273 [M+1] + 。

[0301]

[0333] rac-1-O-(9-Methoxynonyl)-2,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_D-2): According to the general phosphorylation procedure H, 100 mg of (IV_D-2) was obtained from 113 mg of (III_D-2) (yield 24%). 31 P NMR (162 MHz, chloroform-d) δ -1.97, -2.60, -4.01, -4.49, -4.61. HPLC-MS (Condition A): rt = 4.40 min; m / z: 1248 [M+1] + 。

[0302]

[0334] rac-1-O-(2-Cyclopropylethyl)-2,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_D-3): According to the general phosphorylation procedure H, 90 mg of (IV_D-3) was obtained from 96 mg of (III_D-3) (yield 20%). 31 P NMR (162 MHz, chloroform-d) δ -2.28, -2.56, -4.03, -4.49, -4.58. HPLC-MS (Condition A): rt = 4.08 min; m / z: 1160 [M+1] + 。

[0303]

[0335] rac-1-O-(5-Acetamidopentyl)-2,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_D-4): According to the general phosphorylation procedure G, 10 mg of (IV_D-4) was obtained from 59 mg of (III_D-4) (yield 4%). 31 P NMR (162 MHz, chloroform-d) δ -2.18, -2.69, -3.76, -4.30, -4.54. HPLC-MS (condition A): rt = 3.71 min; m / z: 1219 [M+1] + 。

[0304]

[0336] rac-1-O-(6,6,6-Trifluorohexyl)-2,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_D-5): According to the general phosphorylation procedure H, 25 mg of (IV_D-5) was obtained from 64 mg of (III_D-5) (yield 10%). 31 P NMR (162 MHz, chloroform-d) δ -1.90, -2.58, -3.97, -4.46, -4.64. HPLC-MS (condition A): rt = 4.28 min; m / z: 1230 [M+1] + 。

[0305]

[0337] rac-1-O-(2-Cyclopentylethyl)-2,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_D-6): According to the general phosphorylation procedure H, 25 mg of (IV_D-6) was obtained from 71 mg of (III_D-6) (yield 8%). 31 P NMR (162 MHz, chloroform-d) δ -1.94, -2.49, -4.12, -4.50, -4.71. HPLC-MS (condition A): rt = 4.35 min; m / z: 1188 [M+1] + 。

[0306]

[0338] rac-1-O-((1-(2-(Methoxycarbonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-2,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_D-7): According to the general phosphorylation procedure G, 104 mg of (IV_D-7) was obtained from 130 mg of (III_D-7) (yield 22%). 31 P NMR (162 MHz, chloroform-d) δ -2.38, -2.62, -3.63, -4.36, -4.50. HPLC-MS (Condition A): rt = 3.89 min; m / z: 1259 [M+1] + 。

[0307]

[0339] rac-1-O-(5-(4-(Methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-2,3,4,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (IV_D-8): According to the general phosphorylation procedure H, 10 mg of (IV_D-8) was obtained from 46 mg of (III_D-8) (yield 6%). 31 P NMR (162 MHz, chloroform-d) δ -2.06, -2.65, -3.84, -4.36, -4.59. HPLC-MS (Condition A): rt = 3.86 min; m / z: 1273 [M+1] + 。

[0308] C.4. Intermediates V_A, V_B, V_C, and V_D

[0340] rac-4-O-(3-Azidopropyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidine-myo-inositol (V_A-1): According to the general alkylation procedure A, 85 mg of (V_A-1) was obtained from 613 mg (2.1 eq) of (18) (19%). HPLC-MS (Condition B): rt = 3.15 min; m / z: 388 [M+1] + 。

[0309]

[0341] rac-4-O-(6-Azidohexyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylidene-myo-inositol (V_A-2): According to the general alkylation procedure A, 36 mg of (V_A-2) was obtained from 391 mg (2 equivalents) of (22) (13%). HPLC-MS (Condition B): rt = 4.83 min; m / z: 430 [M+1] + 。

[0310]

[0342] 2-O-(5-Azidopentyl)-4,6-bis-O-(4-methoxybenzyl)-1,3,5-O-methylidene-myo-inositol (V_B-1): According to the general alkylation procedure A, 225 mg of (V_B-1) was obtained from 236 mg of (3) and 311 mg (2 equivalents) of (37) (yield 76%). HPLC-MS (Condition A): rt = 4.55 min; m / z: 542 [M+1] + 。

[0311]

[0343] 5-O-(5-Azidopentyl)-1,2,3,4,6-penta-O-benzyl-myo-inositol (V_C-1): According to the general alkylation procedure A, 218 mg of (V_C-1) was obtained from 200 mg of (33) and 180 mg (2 equivalents) of (37) (yield 93%). HPLC-MS (Condition A): rt = 6.30 min; m / z: 765 [M+23] + 。

[0312]

[0344] rac-1-O-(5-Azidopentyl)-2,4,6-tri-O-benzyl-3,5-O-ethylidene-myo-inositol (V_D-1): According to the general alkylation procedure B, 351 mg of (V_D-1) was obtained from 285 mg of (34) and 254 mg (1.5 equivalents) of (37) (yield >99%). HPLC-MS (Condition A): rt = 5.55 min; m / z: 610 [M+23] + 。

[0313] C.5. Intermediate VI_A

[0345] rac-4-O-(3-azidopropyl)-myo-inositol (VI_A-1): According to the general hydrolysis procedure S, 110 mg of (VI_A-1) was obtained from 166 mg of (V_A-1) (97%). HPLC-MS (Condition A): rt = 2.59 min; m / z: 265 [M+1] + .

[0314]

[0346] rac-4-O-(6-azidohexyl)-myo-inositol (VI_A-2): According to the general hydrolysis procedure S, 160 mg of (VI_A-2) was obtained from 279 mg of (V_A-2) (81%). HPLC-MS (Condition A): rt = 2.59 min; m / z: 306 [M+1] + .

[0315] C.6. Intermediate VII_A

[0347] rac-4-O-(3-azidopropyl)-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (VII_A-1): According to the general phosphorylation procedure H, 15 mg of (VII_A-2) was obtained from 55 mg of (VI_A-1) (yield 6%). 31 P NMR (162 MHz, chloroform-d) δ -0.38, -1.11, -1.80, -3.06, -4.12. HPLC-MS (Condition A): rt = 4.11 min; m / z: 1174 [M+1] + .

[0316]

[0348] rac-4-O-(3-azidopropyl)-1,2,3,5,6-pentakis-O-(3-oxide-1,5-dihydrobenzo[e][1,3,2]dioxaphosphepin-3-yl)-myo-inositol (VII_A-2): According to the general phosphorylation procedure H, 44 mg of (VII_A-2) was obtained from 40 mg of (VI_A-1) (yield 28%). 31 P NMR (162 MHz, chloroform-d) δ -0.63, -1.25, -1.88, -3.02, -4.14. HPLC-MS (Condition A): rt = 4.31 min; m / z: 1216 [M+1]+ 。

[0317] C.7. Intermediate VIII_B and VIII-B’

[0349] 2-O-(19-Methoxynadecyl)-1,3,5-O-methylidene-myo-inositol (VIII_B-1): According to the general debenzylation procedure K, 337 mg of (VIII_B-1) was obtained from 504 mg of (II_B’-1) (yield 91%). 1 H NMR (400 MHz, chloroform-d) δ 5.50 (d, J = 1.3 Hz, 1H), 4.58 (t, J = 3.9 Hz, 2H), 4.32 (br, 2H), 4.27 (br, 1H), 3.82 (br, 1H), 3.62 (t, J = 6.8 Hz, 2H), 3.35 (t, J = 6.8 Hz, 2H), 3.31 (s, 3H), 1.67 (p, J = 7.2 Hz, 2H), 1.54 (p, J = 7.2 Hz, 2H), 1.38-1.18 (s, 50H).

[0350] 2-O-(29-Methoxynonacosyl)-1,3,5-O-methylidene-myo-inositol (VIII_B-2): According to the general debenzylation procedure K, 282 mg of (VIII_B-2) was obtained from 776 mg of (II_B’-2) (yield 46%). 1 H NMR (400 MHz, chloroform-d) δ 5.49 (d, J = 1.3 Hz, 1H), 4.57 (t, J = 4.0 Hz, 2H), 4.32 (dt, J = 4.7, 1.7 Hz, 2H), 4.26 (br, 1H), 3.82 (d, J = 1.7 Hz, 1H), 3.61 (t, J = 6.8 Hz, 2H), 3.35 (t, J = 6.8 Hz, 2H), 3.31 (s, 3H), 1.65 (q, J = 8.7, 7.0 Hz, 2H), 1.54 (p, J = 6.8 Hz, 2H), 1.38-1.18 (s, 59H).

[0351] 4,6-di-O-benzyl-2-O-(6,6,6-trifluorohexyl)-myo-inositol (VIII_B’-1): According to the general hydrolysis procedure S, 85 mg of (VIII_B’-1) was obtained from 90 mg of (II_B’-3) (yield 96%). HPLC-MS (Condition A): rt = 4.19 min; m / z: 521 [M+23] + 。

[0318]

[0352] 2-O-(6-amino-6-oxohexyl)-4,6-di-O-benzyl-myo-inositol (VIII_B’-2): According to the general hydrolysis procedure S, 68 mg of (VIII_B’-2) was obtained from 70 mg of (II_B’-4) (yield >99%). HPLC-MS (Condition A): rt = 3.19 min; m / z: 474 [M+1] + 。

[0319]

[0353] 4,6-di-O-benzyl-2-O-(2-cyclopentylethyl)-myo-inositol (VIII_B’-3): According to the general hydrolysis procedure S, 180 mg of (VIII_B’-3) was obtained from 185 mg of (II_B’-5) (yield >99%). HPLC-MS (Condition A): rt = 4.43 min; m / z: 457 [M+1] + 、479 [M+23] + 。

[0320]

[0354] 4,6-di-O-benzyl-2-O-(2-cyclopropylethyl)-myo-inositol (VIII_B’-4): According to the general hydrolysis procedure S, 230 mg of (VIII_B’-4) was obtained from 237 mg of (II_B’-6) (yield >99%). HPLC-MS (Condition A): rt = 4.43 min; m / z: 451 [M+23] + 。

[0321] C.8 Intermediate IX_D

[0355] rac-2,4,6-tri-O-benzyl-1-O-propyl-myo-inositol (IX_D-1): According to the general hydrolysis procedure S, 63 mg of (IX_D-1) was obtained from 68 mg of (II_D-1) (98%). HPLC-MS (Condition A): rt = 4.36 min; m / z: 511 [M+23] + .

[0322]

[0356] rac-2,4,6-tri-O-benzyl-1-O-(9-methoxynonyl)-myo-inositol (IX_D-2): According to the general hydrolysis procedure S, 198 mg of (IX_D-2) was obtained from 306 mg of (II_D-2) (68%). HPLC-MS (Condition A): rt = 5.29 min; m / z: 607 [M+1] + , 629 [M+23] + .

[0323]

[0357] rac-2,4,6-tri-O-benzyl-1-O-(2-cyclopropylethyl)-myo-inositol (IX_D-3): According to the general hydrolysis procedure S, 181 mg of (IX_D-3) was obtained from 255 mg of (II_D-3) (74%). HPLC-MS (Condition A): rt = 4.77 min; m / z: 519 [M+1] + .

[0324]

[0358] rac-1-O-(5-aminopentyl)-2,4,6-tri-O-benzyl-myo-inositol (IX_D-4): According to the general azide reduction procedure P, 198 mg of (IX_D-4) was obtained from 262 mg of (X_D-1) (79%). HPLC-MS (Condition A): rt = 3.16 min; m / z: 536 [M+1] + .

[0325]

[0359] rac-2,4,6-tri-O-benzyl-1-O-(6,6,6-trifluorohexyl)-myo-inositol (IX_D-5): According to the general hydrolysis procedure S, 102 mg of (IX_D-5) was obtained from 107 mg of (II_D-5) (>99%). HPLC-MS (Condition A): rt = 4.89 min; m / z: 589 [M+1] + .

[0360] rac-2,4,6-tri-O-benzyl-1-O-(2-cyclopentylethyl)-myo-inositol (IX_D-6): According to the general hydrolysis procedure S, 118 mg of (IX_D-6) was obtained from 124 mg of (II_D-6) (>99%). HPLC-MS (Condition A): rt = 5.28 min; m / z: 548 [M+1] + 。

[0326]

[0361] rac-1-O-(5-acetamidopentyl)-2,4,6-tri-O-benzyl-myo-inositol (IX_D-7): According to the general amide formation procedure Q, 107 mg of (IX_D-7) was obtained from 112 mg of (IX_D-4) and 36 mg (1.1 eq) of 2,5-dioxopyrrolidin-1-yl acetate (89%). HPLC-MS (Condition A): rt = 3.82 min; m / z: 579 [M+1] + 。

[0327]

[0362] rac-2,4,6-tri-O-benzyl-1-O-(5-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-myo-inositol (IX_D-8): According to the general click reaction procedure M, 254 mg of (IX_D-8) was obtained from 226 mg of (X_D-1) and 56 mg (2 eq) of 3-methoxyprop-1-yne (>99%). HPLC-MS (Condition A): rt = 4.01 min; m / z: 633 [M+1] + 。

[0328]

[0363] rac-2,4,6-tri-O-benzyl-2-O-prop-2-ynyl-myo-inositol (IX_D-9): According to the general hydrolysis procedure S, 120 mg of (IX_D-9) was obtained from 164 mg of (II_D-4) (77%). HPLC-MS (Condition A): rt = 4.24 min; m / z: 489 [M+1] + 。

[0329]

[0364] rac-2,4,6-tri-O-benzyl-1-O-((1-(2-(methoxycarbonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol (IX_D-10): According to the general click reaction procedure L, 234 mg of (IX_D-10) was obtained from 185 mg of (IX_D-9) and 54 mg (1.1 eq) of (38) (>99%). HPLC-MS (condition A): rt = 3.88 min; m / z: 618 [M+1] + 。

[0330] C.9 Intermediate X_D

[0365] rac-1-O-(5-azidopentyl)-2,4,6-tri-O-benzyl-myo-inositol (X_D-1): According to the general hydrolysis procedure S, 263 mg of (X_D-1) was obtained from 394 mg of (V_D-1) (70%). HPLC-MS (condition A): rt = 4.74 min; m / z: 585 [M+23] + 。

[0331] D. Compound Property Evaluation: Analytical Tests and Spectroscopic Tests D.1. NMR

[0366] The NMR spectra were recorded on an Agilent VNMRS-40 (at 400.10 MHz for 1 H and 162 MHz for 31 P). 1 In 1H-NMR, the chemical shifts were expressed in ppm relative to TMS and the coupling constants (J) in Hz. 31 In 31P NMR, no internal standard was used to recover the phosphorus NMR spectra. The usual internal standard is phosphoric acid, but 1 it was not used due to concerns that it would affect 1H-NMR.

[0332] D.2. HPLC-MS

[0367] Condition A: High-performance Liquid Chromatography (HPLC) 2795 Alliance Waters Aquity was connected to Detector DAD Agilent 1100 and Detector MS Waters ESI triple quadrupole Quattro micro, and a sample in 10 μL of MeOH was injected. Mass spectrometry (MS) was analyzed by FIA (flux injected analysis) connected to an LCT Premier Orthogonal Accelerated Time of Flight Mass Spectrometer, and data were obtained by electrospray ionization (ESI) in positive mode. The spectrum was scanned by value every 0.2 seconds between 50 and 1500 Da, and m / z was given to the peak (% of the base peak). Stationary phase: ZORBAX Extend-C18 3.5 μm 2.1×50 mm (T a 35 °C).

[0333]

Table 2

[0334]

Table 3

[0335]

[0368] Condition B: HPLC-MS was performed by High-Performance Liquid Chromatography Thermo Ultimate 3000SD (Thermo Scientific Dionex) connected to a photodiode array detector and a mass spectrometer LTQ XL ESI-ion trap (Thermo Scientific); 5 μL - 20 μL of sample MeOH was injected (c = 0.5 mg / mL). Mass spectrum data were analyzed by electrospray ionization in positive mode and negative mode, and m / z was given to the peak (% of the base peak). Stationary phase: ZORBAX Extend-C18 3.5 μm 2.1×50 mm (T a 35 °C).

[0336]

Table 4

[0337]

Table 5

[0338]

[0369] Condition C: Performed by High-Performance Liquid Chromatography Thermo Ultimate 3000SD (Thermo Scientific Dionex) connected with HPLC-MS to a photodiode array detector and a mass spectrometer LTQ XL ESI-ion trap (Thermo Scientific); 5 μL - 20 μL of sample MeOH was injected (c = 0.5 mg / mL). The mass spectrum data was analyzed by electrospray ionization in positive mode and negative mode, giving m / z to the peaks (% of the base peak). Stationary phase: Xbridge BEH Amide 2.5 μm 4.6×150 mm XP.

[0339]

Table 6

[0340]

Table 7

[0341]

[0370] Condition D: Performed by High-Performance Liquid Chromatography Thermo Ultimate 3000SD (Thermo Scientific Dionex) connected with a photodiode array detector and a mass spectrometer LTQ XL ESI-ion trap (Thermo Scientific); 5 μL - 20 μL of sample MeOH was injected (c = 0.5 mg / mL). The data of the mass spectrum was analyzed by electrospray ionization in positive mode and negative mode, giving m / z to the peak (% of the base peak). Stationary phase: ZORBAX Extend-C18 3.5 μm 2.1×50 mm (T a 35 °C).

[0342]

Table 8

[0343]

Table 9

[0344]

[0371] Condition E: Performed by High-Performance Liquid Chromatography Thermo Ultimate 3000SD (Thermo Scientific Dionex) connected with a photodiode array detector and a mass spectrometer LTQ XL ESI-ion trap (Thermo Scientific); 5 μL - 20 μL of sample water was injected (c = 0.5 mg / mL). The data of the mass spectrum was analyzed by electrospray ionization in positive mode and negative mode, giving m / z to the peak (% of the base peak). Stationary phase: Atlantis Premier BEH C18 AX 2.5 μm 2.1×100 mm, SN 1013130715504.

[0345]

Table 10

[0346]

Table 11

[0347]

[0372] Condition F: Performed by High-Performance Liquid Chromatography Thermo Ultimate 3000SD (Thermo Scientific Dionex) connected to a photodiode array detector and a mass spectrometer LTQ XL ESI-ion trap (Thermo Scientific); 5 μL to 20 μL of sample water was injected (c = 0.5 mg / mL). Mass spectrum data was analyzed by electrospray ionization in positive mode and negative mode, giving m / z to the peaks (% of the base peak). Stationary phase: CORTECS T3 2.7 μm 2.1×150 mm, SN 1353131615509.

[0348]

Table 12

[0349]

Table 13

Example

[0350] Compound 1 rac-4-O-pentyl-myo-inositol-1,2,3,5,6-pentakis(phosphate) decasodium salt

[0373] According to the general phosphate deprotection procedure I, 14.9 mg of Compound 1 (I_A-1) was obtained from 64 mg of (IV_A-1) (yield 31%). 11H NMR (400 MHz, D2O) δ 4.99 - 4.91 (m, 1H), 4.42 (q, J = 9.6 Hz, 1H), 4.15 - 3.95 (m, 3H), 3.88 - 3.81 (m, 1H), 3.79 - 3.71 (m, 2H), 3.64 (m, 3H), 1.65 (p, 7.2 Hz, 2H), 1.35 - 1.29 (m, 4H), 0.88 (m, 7.2 Hz, 3H). 31 31P NMR (162 MHz, D2O) δ 3.94, 3.26. HPLC - MS (Condition C): rt = 10.02 min; m / z: 797 [M + 1 + DEA] + , 870 [M + 1 + 2DEA] + .

[0351] Compound 2 rac - 4 - O - (5 - hydroxypentyl) - myo - inositol - 1,2,3,5,6 - pentakis(phosphate) decasodium salt

[0374] Following the general phosphate deprotection procedure I, 8.24 mg of Compound 2 (I_A - 2) was obtained from 30 mg of (IV_A - 2) (yield 39%). 1 1H NMR (400 MHz, D2O) δ 5.10 - 5.01 (m, 1H), 4.50 - 4.39 (m, 1H), 4.18 - 4.01 (m, 3H), 3.92 - 3.85 (m, 1H), 3.81 - 3.71 (m, 2H), 3.61 (t, J = 6.8 Hz, 2H), 1.70 - 1.63 (m, 2H), 1.62 - 1.55 (m, 2H), 1.45 - 1.38 (m, 2H). 31 31P NMR (162 MHz, D2O) δ 4.76, 2.86, 2.54, - 0.16. HPLC - MS (Condition C): rt = 10.36 min; m / z: 813 [M + 1 + DEA] + , 886 [M + 1 + 2DEA] + .

[0352] Compound 3 rac - 4 - O - (5 - methoxypentyl) - myo - inositol - 1,2,3,5,6 - pentakis(phosphate) decasodium salt

[0375] According to the general phosphate deprotection procedure I, 20.5 mg of compound 3 (I_A-3) was obtained from 97 mg of (IV_A-3) (yield 28%). 1 H NMR (400 MHz, D2O) δ 5.00-4.96 (m, 1H), 4.52-4.42 (m, 1H), 4.23-4.61 (m, 3H), 3.86-3.72 (m, 3H), 3.51 (t, J = 6.8 Hz, 2H), 3.35 (s, 3H), 1.70-1.60 (m, 4H), 1.41-1.34 (m, 2H). HPLC-MS (condition C): rt = 10.13 min; m / z: 827 [M+1+DEA] + , 900 [M+1+2DEA] + .

[0353] Compound 4 rac-4-O-(5-carboxypentyl)-myo-inositol-1,2,3,5,6-pentakis(phosphate) undecasodium salt

[0376] According to the general phosphate deprotection procedure J, 4.4 mg of compound 4 (I_A-4) was obtained from 23 mg of (IV_A-4) (yield 25%). 1 H NMR (400 MHz, D2O) δ: 5.08 (s, 1H), 5.51-4.43 (m, 1H), 4.25 - 3.97 (m, 3H), 3.86-3.72 (m, 4H), 2.20 (t, J = 7.6 Hz, 2H), 1.71-1.64 (m, 2H), 1.562-1.55 (m, 2H), 1.36-1-32 (m, 2H). HPLC-MS (condition C): rt = 10.46 min; m / z: 841 [M+1+DEA] + , 914 [M+1+2DEA] + .

[0354] Compound 5 rac-4-O-(2-(4-acetylpiperazin-1-yl)ethyl)-myo-inositol-1,2,3,5,6-pentakis(phosphate) decasodium salt

[0377] According to the general phosphate deprotection procedure I, 2.8 mg of compound 5 (I_A-5) was obtained from 31 mg of (IV_A-5) (yield 12%). 1 H NMR (400 MHz, D2O) δ 4.93-4.86 (m, 1H), 4.45 (q, J = 9.6Hz, 1H), 4.28-4.20 (m, 2H), 4.18-4.11(m, 4H), 4.06 (q, J = 9.6Hz, 2H), 4.01-3.88 (m, 2H), 3.88 (t, J = 9.6 Hz, 2H), 3.44-3.29 (m, 4H), 2.18 (s, 3H). HPLC-MS (condition C): rt = 10.28 min; m / z: 808 [M+1+DEA] + , 881 [M+1+2DEA] + , 954 [M+1+3DEA] + .

[0355] Compound 6 2-O-Pentyl-myo-inositol-1,3,4,5,6-pentakis(phosphate) decasodium salt

[0378] According to the general phosphate deprotection procedure I, 88.56 mg of compound 6 (I_B-1) was obtained from 325 mg of (IV_B-1) (yield 36%). 1 H NMR (400 MHz, D2O) δ 4.36 (m, 3H), 4.08 (q, J = 9.6 Hz, 1H), 4.00 (t, J = 9.6 Hz, 2H), 3.92 (t, J = 7.2 Hz, 2H), 1.63 (p, J = 7.2 Hz, 2H), 1.37-1.30 (m, 4H), 0.96-0.80 (m, 3H). 31 P NMR (162 MHz, D2O) δ 3.28, 2.32, 1.45. HPLC-MS (condition C): rt = 10.23 min; m / z: 724 [M+1] + , 797 [M+1+DEA] + , 870 [M+1+2DEA] + .

[0356] Compound 7 Sodium 2-O-(5-methoxypentyl)-myo-inositol-1,3,4,5,6-pentakis(phosphate) decahydrate

[0379] Following the general phosphate deprotection procedure I, 6.7 mg of compound 7 (I_B-2) was obtained from 71 mg of (IV_B-2) (yield 12.5%). 1 H NMR (400 MHz, D2O) δ 4.38 (q, J = 9.5 Hz, 2H), 4.20 (br, 1H), 4.13 - 4.05 (m, 3H), 3.90 (t, J = 7.2 Hz, 2H), 3.51 (t, J = 6.8 Hz, 2H), 3.52 (s, 3H), 1.67 (p, J = 7.2 Hz, 2H), 1.62 (p, J = 7.2 Hz, 2H), 1.40 (p, J = 7.2 Hz 2H). 31 P NMR (162 MHz, D2O) δ 1.66 (br), 1.23 (br). HPLC-MS (condition C): rt = 10.24 min; m / z: 827 [M + 1 + DEA] + , 900 [M + 1 + 2DEA] + 。

[0357] Compound 8 Sodium 2-O-(9-methoxynonyl)-myo-inositol-1,3,4,5,6-pentakis(phosphate) decahydrate

[0380] Following the general phosphate deprotection procedure I, 10 mg of compound 8 (I_B-3) was obtained from 114 mg of (IV_B-3) (yield 11.4%). 1 H NMR (400 MHz, D2O) δ 4.24 (q, J = 8.8 Hz, 2H), 4.02 (s, 1H), 3.95 (t, J = 9.7 Hz, 3H), 3.71 (t, J = 6.8 Hz, 2H), 3.33 (t, J = 6.8 Hz, 2H), 3.18 (s, 3H), 1.48 (t, J = 6.8 Hz, 2H), 1.42 (q, J = 6.8 Hz, 2H), 1.17 (m, 10H). 31P NMR (162 MHz, D2O) δ 1.45, 1.24, 0.71. HPLC-MS (Condition D): rt = 0.64 min; m / z: 737 [M+1] + , 810 [M+1+DEA] + , 883 [M+1+2DEA] + .

[0358] Compound 9 2-O-(19-Methoxynonadecyl)-myo-inositol-1,3,4,5,6-pentakis(phosphate) decasodium salt

[0381] According to the general phosphate deprotection procedure I, 13.5 mg of Compound 9 (I_B-4) was obtained from 35 mg of (IV_B-4) (yield 43%). 1 H NMR (400 MHz, D2O) δ 4.20 (q, J = 8.8 Hz, 2H), 4.08 (s, 1H), 3.97 - 3.83 (m, 3H), 3.73 (t, J = 7.5 Hz, 2H), 3.32 (t, J = 6.7 Hz, 2H), 3.18 (s, 3H), 1.50 - 1.39 (m, 4H), 1.12 (br, 30H). 31 P NMR (162 MHz, D2O) δ 2.29, 1.56, 1.37. HPLC-MS (Condition D): rt = 6.90 min; m / z: 1023 [M+1+2DEA] + , 1095 [M+1+3DEA] + .

[0359] Compound 10 2-O-(29-Methoxynonacosyl)-myo-inositol-1,3,4,5,6-pentakis(phosphate) decasodium salt

[0382] According to the general phosphate deprotection procedure I, 5 mg of Compound 10 (I_B-5) was obtained from 18 mg of (IV_B-5) (yield 34%). 11H NMR (400 MHz, D2O) δ 4.25 (q, J = 9.4 Hz, 2H), 4.03 - 3.92 (m, 4H), 3.72 - 3.66 (m, 2H), 3.32 (t, J = 6.7 Hz, 2H), 3.18 (s, 3H), 1.51 - 1.38 (m, 4H), 1.17 - 1.11 (m, 50H). 31 31P NMR (162 MHz, D2O) δ 1.47, 0.91, -0.25. Compound 11 rac - 4 - O-(3-(p - Tolyl)propyl)-myo - inositol - 1,2,3,5,6 - pentakis(phosphate) decasodium salt

[0383] According to the general phosphate deprotection procedure I, 10 mg of Compound 11 (I_A - 6) was obtained from 44 mg of (IV_A - 6) (yield 30%). 1 1H NMR (400 MHz, D2O) δ 7.19 (d, J = 7.8 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 4.43 - 3.83 (m, 2H), 3.81 - 3.66 (m, 2H), 2.59 (t, J = 8 Hz, 2H), 2.22 (s, 3H), 1.90 - 1.78 (m, 2H). HPLC - MS (Condition C): rt = 9.90 min; m / z: 713 [M + 1] + 、785 [M + 1 + DEA] + 、759 [M + 1 + 2DEA] + 、932 [M + 1 + 3DEA] + 。

[0360] Compound 12 rac - 4 - O-(4 - methylpentyl)-myo - inositol - 1,2,3,5,6 - pentakis(phosphate) decasodium salt

[0384] According to the general phosphate deprotection procedure I, 10.2 mg of compound 12 (I_A-7) was obtained from 47 mg of (IV_A-7) (yield 30%). δ 1H NMR (400 MHz, D2O) δ 4.57 - 3.85 (m, 6H), 3.71 - 3.60 (m, 2H), 1.63 - 1.52 (m, 2H), 1.52 - 1.43 (m, 1H), 1.13 - 1.07 (m, 2H), 0.79 (d, J = 6.6 Hz, 6H). HPLC-MS (condition E): rt = 10.13 min; m / z: 665 [M+1] + , 738 [M+1+DEA] + , 811 [M+1+2DEA] + , 884 [M+1+3DEA] + .

[0361] Compound 13 rac-4-O-(6,6,6-trifluorohexyl)-myo-inositol-1,2,3,5,6-pentakis(phosphate) decasodium salt

[0385] According to the general phosphate deprotection procedure I, 3.8 mg of compound 13 (I_A-... 1 H NMR (400 MHz, D2O) δ 4.58 - 3.86 (m, 6H), 3.78 - 3.59 (m, 2H), 2.17 - 2.05 (m, 2H), 1.60 (p, J = 7.6 Hz, 2H), 1.50 (p, J = 7.6 Hz, 2H), 1.35 (p, J = 7.6 Hz, 2H). HPLC-MS (condition C): rt = 10.49 min; m / z: 865 [M+1+2DEA] + .

[0362] Compound 14 rac-4-O-(3-(4-methoxyphenyl)propyl)-myo-inositol-1,2,3,5,6-pentakis(phosphate) decasodium salt

[0386] According to the general phosphate deprotection procedure I, 4.1 mg of compound 14 (I_A-9) was obtained from 48 mg of (IV_A-9) (yield 11%). 11H NMR (400 MHz, D2O) δ 7.23 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 4.46 - 3.80 (m, 6H), 3.79 - 3.68 (m, 2H), 2.58 (t, J = 8.0 Hz, 2H), 1.85 (p, J = 8.0 Hz, 2H). HPLC-MS (Condition C): rt = 10.11 min; m / z: 729 [M+1] + 、802 [M+1+DEA] + 、875 [M+1+2DEA] + 。

[0363] Compound 15 rac-4-O-(3-(3-(Trifluoromethyl)phenyl)propyl)-myo-inositol-1,2,3,5,6-pentakis(phosphate) decasodium salt

[0387] According to the general phosphate deprotection procedure I, 8.6 mg of compound 15 (I_A-10) was obtained from 35 mg of (IV_A-10) (yield 32%). 1 1H NMR (400 MHz, D2O) δ 7.59 (s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 4.50 - 3.89 (m, 5H), 3.87 - 3.72 (m, 3H), 2.71 (t, J = 8.0 Hz, 2H), 1.95 - 1.83 (m, 2H). HPLC-MS (Condition C): rt = 9.55 min; m / z: 767 [M+1] + 、840 [M+1+DEA] + 、913 [M+1+2DEA] + 。

[0364] Compound 16 rac-4-O-(2-Cyclopentylethyl)-myo-inositol-1,2,3,5,6-pentakis(phosphate) decasodium salt

[0388] According to the general phosphate deprotection procedure I, 6.6 mg of compound 16 (I_A-11) was obtained from 33 mg of (IV_A-11) (yield 26%). 1 H NMR (400 MHz, D2O) δ 4.49-3.81 (m, 6H), 3.79-3.61 (m, 2H), 1.73-1.64 (m, 2H), 1.63-1.55 (m, 2H), 1.52-1.45 (m, 2H), 1.43-1.36 (m, 2H), 1.22-1.16 (m, 1H), 1.14-099 (m, 2H). HPLC-MS (condition C): rt = 10.34 min; m / z: 677 [M+1] + , 823 [M+1+2DEA] + .

[0365] Compound 17 rac-4-O-(2-cyclopropylethyl)-myo-inositol-1,2,3,5,6-pentakis(phosphate) decasodium salt

[0389] According to the general phosphate deprotection procedure I, 9.5 mg of compound 17 (I_A-12) was obtained from 46 mg of (IV_A-12) (yield 27%). 1 H NMR (400 MHz, D2O) δ 4.55-3.84 (m, 6H), 3.77-3.71 (m, 2H), 1.44 (q, J = 7.3 Hz, 2H), 0.74-0.59 (m, 1H), 0.32-0.21 (m, 2H), 0.10--0.10 (m, 2H). HPLC-MS (condition C): rt = 10.77 min; m / z: 649 [M+1] + , 795 [M+1+2DEA] + .

[0366] Compound 18 rac-4-O-(5-(1H-pyrazol-1-yl)pentyl)-myo-inositol-1,2,3,5,6-pentakis(phosphate) decasodium salt

[0390] According to the general phosphate deprotection procedure I, 18.8 mg of compound 18 (I_A-13) was obtained from 100 mg of (IV_A-13) (yield 25%). 11H NMR (400 MHz, D2O) δ 7.60 (dd, J = 2.2, 0.8 Hz, 1H), 7.46 (dd, J = 2.2, 0.8 Hz, 1H), 6.24 (t, J = 2.2 Hz, 1H), 4.63 - 3.89 (m, 6H), 4.08 (t, J = 7.2 Hz, 2H), 3.73 - 3.56 (m, 2H), 1.76 (p, J = 7.2 Hz, 2H), 1.62 - 1.51 (m, 2H), 1.18 (p, J = 7.2 Hz, 2H). HPLC-MS (Condition C): rt = 10.13 min; m / z: 717 [M+1] + and 790 [M+1+DEA] + and 863 [M+1+2DEA] + .

[0367] Compound 19 rac-4-O-(5-Acetamidopentyl)-myo-inositol-1,2,3,5,6-pentakis(phosphate) decasodium salt

[0391] According to the general phosphate deprotection procedure I, 3.1 mg of compound 19 (I_A-14) was obtained from 14 mg of (IV_A-14) (yield 29%). 1 1H NMR (400 MHz, D2O) δ 4.55 - 3.84 (m, 6H), 3.70 - 3.47 (m, 2H), 3.09 (t, J = 6.8 Hz, 2H), 1.90 (s, 3H), 1.55 - 1.42 (m, 2H), 1.25 - 1.18 (m, 4H). HPLC-MS (Condition E): rt = 4.88 min; m / z: 781 [M+1+DEA] + and 854 [M+1+2DEA] + .

[0368] Compound 20 rac-4-O-(10-Carboxydecyl)-myo-inositol-1,2,3,5,6-pentakis(phosphate) undecasodium salt

[0392] According to the general phosphate deprotection procedure J, 3.4 mg of compound 20 (I_A-15) was obtained from 7.5 mg of (IV_A-15) (yield 59%).1 1H NMR (400 MHz, D2O) δ 4.58 - 3.76 (m, 6H), 3.78 - 3.58 (m, 2H), 2.08 (t, J = 7.6 Hz, 2H), 1.61 - 1.52 (m, 2H), 1.45 (t, J = 7.6 Hz, 2H), 1.21 (br, 12H). HPLC-MS (Condition E): rt = 5.20 min; m / z: 838 [M + 1 + DEA] + , 911 [M + 1 + 2DEA] + , 984 [M + 1 + 3DEA] + 。

[0369] Compound 21 rac-4-O-(10-Hydroxydecyl)-myo-inositol-1,2,3,5,6-pentakis(phosphate) decasodium salt

[0393] According to the general phosphate deprotection procedure I, 2.8 mg of compound 21 (I_A-16) was obtained from 12.9 mg of (IV_A-16) (yield 31%). 1 1H NMR (400 MHz, D2O) δ 4.49 - 3.74 (m, 6H), 3.72 - 3.63 (m, 2H), 3.51 (t, J = 6.8 Hz, 2H), 1.60 - 1.53 (m, 2H), 1.45 (t, J = 6.8 Hz, 2H), 1.22 (br, 12H). HPLC-MS (Condition F): rt = 6.27 min; m / z: 810 [M + 1 + DEA] + , 883 [M + 1 + 2DEA] + 。

[0370] Compound 22 rac-4-O-Methyl-myo-inositol-1,2,3,5,6-pentakis(phosphate) decasodium salt

[0394] According to the general phosphate deprotection procedure I, 0.6 mg of compound 22 (I_A-17) was obtained from 10 mg of (IV_A-17) (yield 8%). 11H NMR (400 MHz, D2O) δ 4.49 - 3.77 (m, 6H), 3.52 (s, 3H). HPLC-MS (Condition E): rt = 2.26 min; m / z: 668 [M+1+DEA] + 、741 [M+1+2DEA] + 、814 [M+1+3DEA] + 。

[0371] Compound 23 rac-4-O-(7-methoxyheptyl)-myo-inositol-1,2,3,5,6-pentakis(phosphate) decasodium salt

[0395] According to the general phosphate deprotection procedure I, 9.7 mg of compound 23 (I_A-18) was obtained from 30 mg of (IV_A-18) (yield 42%). 1 1H NMR (400 MHz, D2O) δ 4.45 - 3.79 (m, 5H), 3.77 - 3.60 (m, 3H), 3.40 (t, J = 6.8 Hz, 2H), 3.26 (s, 3H), 1.66 - 1.38 (m, 4H), 1.25 (br, 6H). HPLC-MS (Condition C): rt = 10.98 min; m / z: 855 [M+1+2DEA] + 。

[0372] Compound 24 rac-4-O-propyl-myo-inositol-1,2,3,5,6-pentakis(phosphate) decasodium salt

[0396] According to the general phosphate deprotection procedure I, 1.5 mg of compound 24 (I_A-19) was obtained from 20 mg of (IV_A-19) (yield 10%). 1 1H NMR (400 MHz, D2O) δ 4.40 - 3.60 (m, 8H), 1.60, -1 - 51 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H). HPLC-MS (Condition E): rt = 3.49 min; m / z: 696 [M+1+DEA] + 、769 [M+1+2DEA] + 、842 [M+1+3DEA] + 。

[0373] Compound 25 rac-4-O-(3-(4-(2-Carboxyethyl)-1H-1,2,3-triazol-1-yl)propyl)-myo-inositol-1,2,3,5,6-pentakis(phosphate) undecasodium salt

[0397] Following the general phosphate deprotection procedure J, 3.0 mg of Compound 25 (I_A-20) was obtained from 14 mg of (IV_A-20) (yield 29%). 1 H NMR (400 MHz, D2O) δ 7.81 (s, 1H), 4.53 - 4.44 (m, 2H), 4.39 - 3.60 (m, 8H), 2.84 (t, J = 8 Hz, 2H), 2.44 (t, J = 8 Hz, 2H), 2.16 - 2.05 (m, 2H). HPLC-MS (Condition E): rt = 4.73 min; m / z: 762 [M+1] + , 835 [M+1+DEA] + , 908 [M+1+2DEA] + , 981 [M+1+3DEA] + .

[0374] Compound 26 rac-4-O-(6-(4-(Carboxy)-1H-1,2,3-triazol-1-yl)hexyl)-myo-inositol-1,2,3,5,6-pentakis(phosphate) undecasodium salt

[0398] Following the general phosphate deprotection procedure J, 1.9 mg of Compound 26 (I_A-21) was obtained from 15 mg of (IV_A-21) (yield 16%). 1 H NMR (400 MHz, D2O) δ 8.13 (s, 1H), 4.35 (t, J = 7.2 Hz, 2H), 4.39 - 3.43 (m, 8H), 1.88 - 1.78 (m, 2H), 1.62 - 1.54 (m, 2H), 1.36 - 1.23 (m, 4H). HPLC-MS (Condition E): rt = 4.94 min; m / z: 849 [M+1+DEA] + , 922 [M+1+2DEA] + , 994 [M+1+3DEA] + .

[0375] Compound 27 rac-4-O-(3-aminopropyl)-myo-inositol-1,2,3,5,6-pentakis(phosphate) decasodium salt

[0399] According to the general phosphate deprotection procedure I, 1.9 mg of Compound 27 (I_A-22) was obtained from 15 mg of (IV_A-1) (yield 17%). 1 H NMR (400 MHz, D2O) δ 4.40 - 3.80 (m, 6H), 3.08 (t, J = 6.4 Hz, 2H), 1.94 - 1.88 (m, 2H). HPLC-MS (Condition E): rt = 1.63 min; m / z: 638 [M+1] + , 711 [M+1+DEA] + , 784 [M+1+2DEA] + .

[0376] Compound 28 rac-4-O-(6-aminohexyl)-myo-inositol-1,2,3,5,6-pentakis(phosphate) decasodium salt

[0400] According to the general phosphate deprotection procedure I, 15.6 mg of Compound 28 (I_A-23) was obtained from 44 mg of (IV_A-2) (yield 48%). 1 H NMR (400 MHz, D2O) δ 4.40 - 3.80 (m, 6H), 3.55 - 3.65 (m, 2H), 2.92 (dd, J = 7.6, 5.6 Hz, 2H), 1.70 - 1.40 (m, 4H), 1.28 - 1.13 (m, 4H). HPLC-MS (Condition C): rt = 9.23 min; m / z: 752 [M+1+DEA] + , 825 [M+1+2DEA] + .

[0377] Compound 29 5-O-propyl-myo-inositol-1,2,3,4,6-pentakis(phosphate) decasodium salt

[0401] According to the general phosphate deprotection procedure I, 3.3 mg of Compound 29 (I_C-1) was obtained from 10 mg of (IV_C-1) (yield 45%).1 1H NMR (400 MHz, D2O) δ 4.64 - 4.56 (m, 1H), 4.38 (q, J = 9.6 Hz, 2H), 4.02 - 3.93 (m, 2H), 3.71 (t, J = 7.4 Hz, 2H), 3.34 (t, J = 9.6 Hz, 1H), 1.58 (q, J = 7.4 Hz, 2H), 0.81 (t, J = 7.4 Hz, 3H). HPLC-MS (Condition E): rt = 3.41 min; m / z: 696 [M + 1 + DEA] + , 769 [M + 1 + 2DEA] + , 842 [M + 1 + 3DEA] + .

[0378] Compound 30 5 - O-(2 - cyclopropylethyl)-myo - inositol - 1,2,3,4,6 - pentakis(phosphate) decasodium salt

[0402] According to the general phosphate deprotection procedure I, 3.53 mg of compound 30 (I_C - 2) was obtained from 10 mg of (IV_C - 2) (yield 47%). 1 1H NMR (400 MHz, D2O) δ 4.36 (q, J = 9.6 Hz, 2H), 3.99 - 3.91 (m, 2H), 3.81 (t, J = 7.6 Hz, 2H), 3.65 - 3.55 (m, 1H), 3.36 - 3.26 (m, 1H), 1.47 (q, J = 7.6 Hz, 2H), 0.70 - 061 (m, 1H), 0.32 - 0.26 (m, 2H), 0.01 - -0.04 (m, 2H). HPLC-MS (Condition E): rt = 4.96 min; m / z: m / z: 722 [M + 1 + DEA] + , 795 [M + 1 + 2DEA] + , 868 [M + 1 + 3DEA] + .

[0379] Compound 31 5 - O-(9 - methoxynonyl)-myo - inositol - 1,2,3,4,6 - pentakis(phosphate) decasodium salt

[0403] According to the general phosphate deprotection procedure I, 6.7 mg of compound 31 (I_C-3) was obtained from 15 mg of (IV_C-3) (yield 58%). 1 H NMR (400 MHz, D2O) δ 4.54-4.46 (m, 2H), 4.44-4.15 (m, 3H), 3.84 (br, 1H), 3.66 (t, J = 7.6 Hz, 2H), 3.40 (t, J = 6.8 Hz, 2H), 3.26 (s, 3H), 1.63-1.53 (m, 2H), 1.53-1.43 (m, 2H), 1.23 (br, 10H). HPLC-MS (condition E): rt = 5.95 min; m / z: m / z: 810 [M+1+DEA] + , 883 [M+1+2DEA] + , 956 [M+1+3DEA] + .

[0380] Compound 32 rac-1-O-propyl-myo-inositol-2,3,4,5,6-pentakis(phosphate) decasodium salt

[0404] According to the general phosphate deprotection procedure I, 13.28 mg of compound 32 (I_D-1) was obtained from 53 mg of (IV_D-1) (yield 34%). 1 H NMR (400 MHz, D2O) δ 4.60-3.80 (m, 6H), 3.70-3.52 (m, 2H), 1.66-1.53 (m, 2H), 0.81 (t, J = 7.6 Hz, 3H). HPLC-MS (condition E): rt = 3.65 min; m / z: 696 [M+1+DEA] + , 769 [M+1+2DEA] + , 842 [M+1+3DEA] + .

[0381] Compound 33 rac-4-O-(6-amino-6-oxohexyl)-myo-inositol-1,2,3,5,6-pentakis(phosphate) decasodium salt

[0405] According to the general phosphate deprotection procedure I, 1.42 mg of compound 33 (I_A-24) was obtained from 6 mg of (IV_A-22) (yield 31%). 1 H NMR (400 MHz, D2O) δ 4.36 (q, J = 9.2 Hz, 1H), 4.06 (q, J = 9.2 Hz, 1H), 4.00 (d, J = 8.0 Hz, 1H), 3.94 (t, J = 9.2 Hz, 1H), 3.78 (q, J = 8.0 Hz, 1H), 3.72-3.67 (m, 1H) 3.67 (t, J = 6.8 Hz, 2H), 2.21 (t, J = 6.8 Hz, 1H), 1.58 (p, J = 6.8 Hz, 2H), 1.55 (p, J = 6.8 Hz, 2H), 1.32 (p, J = 6.8 Hz, 2H). HPLC-MS (condition E): rt = 2.25 min; m / z: 694 [M+1] + , 767 [M+1+DEA] + , 840 [M+1+2DEA] + .

[0382] Compound 34 2-O-Propyl-myo-inositol-1,3,4,5,6-pentakis(phosphate) decasodium salt

[0406] According to the general phosphate deprotection procedure I, 5 mg of compound 34 (I_B-6) was obtained from 30 mg of (IV_B-6) (yield 23%). 1 H NMR (400 MHz, D2O) δ 4.80-4.70 (m, 1H) 4.55-4.43 (m, 2H), 4.24 (brs, 1H), 4.22-4.13 (m, 2H), 3.84 (t, J = 7.2 Hz, 2H), 1.64 (q, J = 7.2 Hz, 2H), 0.94 (t, J = 7.2 Hz, 3H). HPLC-MS (condition E): rt = 4.85 min; m / z: 623 [M+1] + , 796 [M+1+DEA] + , 769 [M+1+2DEA] + .

[0383] Compound 35 Sodium 2-O-(5-acetamidopentyl)-myo-inositol-1,3,4,5,6-pentakis(phosphate) decahydrate

[0407] Following the general phosphate deprotection procedure I, 8 mg of compound 35 (I_B-7) was obtained from 12 mg of (IV_B-13) (yield 89%). 1 H NMR (400 MHz, D2O) δ 4.80 - 4.70 (m, 1H), 4.48 - 4.31 (m, 2H), 4.13 - 3.87 (m, 5H), 3.86 - 3.74 (m, 1H), 3.19 (t, J = 6.7 Hz, 2H), 1.99 (s, 3H), 1.72 - 1.61 (m, 2H), 1.56 (q, J = 7.6 Hz, 2H), 1.46 - 1.37 (m, 2H). HPLC-MS (condition E): rt = 4.97 min; m / z: 781 [M + 1 + DEA] + , 854 [M + 1 + 2DEA] + .

[0384] Compound 36 Sodium 2-O-(6,6,6-trifluorohexyl)-myo-inositol-1,3,4,5,6-pentakis(phosphate) decahydrate

[0408] Following the general phosphate deprotection procedure I, 8.5 mg of compound 36 (I_B-8) was obtained from 58 mg of (IV_B-8) (yield 20%). 1 H NMR (400 MHz, D2O) 4.80 - 4.70 (m, 1H), δ 4.45 - 4.30 (m, 2H), 4.15 - 3.86 (m, 4H), 3.86 - 3.70 (m, 1H), 2.32 - 2.08 (m, 2H), 1.67 (p, J = 7.6 Hz, 2H), 1.60 (p, J = 7.6 Hz, 2H), 1.47 (p, J = 7.6 Hz, 2H). 31 P NMR (162 MHz, D2O) δ 3.23, 2.24, 1.51. HPLC-MS (condition E): rt = 4.85 min; m / z: 719 [M + 1] + , 792 [M + 1 + DEA] +, 865 [M + 1 + 2DEA] + , 938 [M + 1 + 3DEA] + .

[0385] Compound 37 2-O-(6-amino-6-oxohexyl)-myo-inositol-1,3,4,5,6-pentakis(phosphate) decasodium salt

[0409] Following the general phosphate deprotection procedure I, 4.2 mg of Compound 37 (I_B-9) was obtained from 24 mg of (IV_B-9) (yield 24%). 1 H NMR (400 MHz, D2O) δ 4.73 - 4.83 (m, 1H), 4.43 - 4.31 (m, 2H), 4.15 - 3.99 (m, 3H), 3.96 (m, 2H), 2.31 (t, J = 7.6 Hz, 2H), 1.66 (p, J = 7.4 Hz, 4H), 1.48 - 1.42 (m, 2H). 31 P NMR (162 MHz, D2O) δ 2.96, 1.94, 1.39. HPLC-MS (Condition E): rt = 1.77 min; m / z: 694 [M + 1] + , 767 [M + 1 + DEA] + , 840 [M + 1 + 2DEA] + , 913 [M + 1 + 3DEA] + .

[0386] Compound 38 2-O-(2-cyclopentylethyl)-myo-inositol-1,3,4,5,6-pentakis(phosphate) decasodium salt

[0410] Following the general phosphate deprotection procedure I, 7.2 mg of Compound 38 (I_B-10) was obtained from 124 mg of (IV_B-10) (yield 7.7%). 11H NMR (400 MHz, D2O) δ 4.92 - 4.65 (m, 2H), 4.57 - 4.28 (m, 2H), 4.18 - 3.87 (m, 3H), 3.86 - 3.74 (m, 1H), 1.89 - 1.74 (m, 3H), 1.73 - 1.64 (m, 2H), 1.64 - 1.53 (m, 2H), 1.53 - 1.41 (m, 2H), 1.20 - 1.10 (m, 2H). HPLC-MS (Condition E): rt = 5.16 min; m / z: 677 [M+1] + and 750 [M+1+DEA] + and 823 [M+1+2DEA] + and 896 [M+1+3DEA] + .

[0387] Compound 39 2-O-(2-Cyclopropylethyl)-myo-inositol-1,3,4,5,6-pentakis(phosphate) decasodium salt

[0411] Following the general phosphate deprotection procedure I, 3.0 mg of Compound 39 (I_B-11) was obtained from 65 mg of (IV_B-11) (yield 4.7%). 1 1H NMR (400 MHz, D2O) δ 5.00 - 4.78 (m, 1H), 4.33 - 4.15 (m, 2H), 4.05 - 3.83 (m, 4H), 3.84 - 3.68 (m, 1H), 1.44 (q, J = 7.2 Hz, 2H), 0.77 - 0.60 (m, 1H), 0.38 - 0.25 (m, 2H), 0.07 - 0.08 (m, 2H). HPLC-MS (Condition E): rt = 1.94 min; m / z: 649 [M+1] + and 722 [M+1+DEA] + and 795 [M+1+2DEA] + and 868 [M+1+3DEA] + .

[0388] Compound 40 2-O-(5-Hydroxypentyl)-myo-inositol-1,3,4,5,6-pentakis(phosphate) decasodium salt

[0412] According to the general phosphate deprotection procedure I, 13.6 mg of compound 40 (I_B-12) was obtained from 73 mg of (IV_B-7) (yield 27%). 1 H NMR (400 MHz, D2O) δ 5.21-4.73 (m, 2H), 4.60-4.17 (m, 2H), 4.40 (q, J = 9.6 Hz, 1H), 4.08 (q, J = 9.6 Hz, 1H), 4.03-3.89 (m, 1H), 3.89 -3.70 (m, 1H), 3.63 (t, J = 6.5 Hz, 2H), 1.75-1.59 (m, 4H), 1.48-144 (m, 2H). HPLC-MS (condition E): rt = 4.85 min; m / z: 667 [M+1] + 。

[0389] Compound 41 2-O-(5-(4-(Methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-myo-inositol-1,3,4,5,6-pentakis(phosphate) decasodium

[0413] According to the general phosphate deprotection procedure I, 10.8 mg of compound 41 (I_B-13) was obtained from 25 mg of (IV_B-12) (yield 56%). 1 H NMR (400 MHz, D2O) δ 8.08 (s, 1H), 4.61 (s, 2H), 4.47 (t, J = 7.2 Hz, 2H), 4.47-4.28 (m, 3H), 4.17-3.87 (m, 4H), 3.39 (s, 3H), 1.97 (p, J = 7.7 Hz, 2H), 1.69 (p, J = 7.7 Hz, 2H), 1.45-1.33 (m, 2H). 31 P NMR (162 MHz, D2O) δ 3.65, 2.66, 1.67. HPLC-MS (condition E): rt = 5.33 min; m / z: 907 [M+1+2DEA] + 。

[0390] Compound 42 Sodium undecanoate 2-O-((1-(2-carboxyethyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol-1,3,4,5,6-pentakis(phosphate)

[0414] According to the general phosphate deprotection procedure J, 45 mg of compound 42 (I_B-14) was obtained from 100 mg of (IV_B-14) (yield 57%). 1 H NMR (400 MHz, D2O) δ 8.16 (s, 1H), 5.07 (s, 2H), δ 4.73-4.83 (m, 1H), 4.63 (t, J = 7.2 Hz, 3H), 4.32 (brs, 3H), 4.04 (brs, 2H), 2.81 (t, J = 7.2 Hz, 2H). HPLC-MS (condition E): rt = 1.16 min; m / z: 880 [M+1+2DEA] + , 953 [M+1+3DEA] + 。

[0391] Compound 43 Sodium decanoate 2-O-prop-2-ynyl-myo-inositol-1,3,4,5,6-pentakis(phosphate)

[0415] According to the general phosphate deprotection procedure T, 7.5 mg of compound 43 (I_B-15) was obtained from 25 mg of (IV_B-6) (yield 40%). 1 H NMR (400 MHz, D2O) δ 4.64 (s, 2H), 4.42-4.34 (m, 3H), 4.14-4.06 (m, 3H), 2.88 (t, J = 2.4 Hz, 1H). 31 P NMR (162 MHz, D2O) δ 2.89, 1.95, 1.43. HPLC-MS (condition E): rt = 3.20 min; m / z: 693 [M+1+DEA] + , 766 [M+1+2DEA] + 。

[0392] Compound 44 Sodium decanoate 5-O-(9-methoxypentyl)-myo-inositol-1,2,3,4,6-pentakis(phosphate)

[0416] Following the general phosphate deprotection procedure I, 1.7 mg of compound 44 (I_C-4) was obtained from 6 mg of (IV_C-4) (yield 37%). 1 H NMR (400 MHz, D2O) δ 4.64-4.45 (m, 1H), 4.43-4.35 (m, 1H), 4.32-4.16 (m, 1H), 4.023-3.87 (m, 2H), 3.77-3.70 (m, 2H), 3.66-3.55 (m, 1H), 3.42 (t, J = 6.8 Hz, 2H), 3.26 (s, 3H), 1.65-1.56 (m, 2H), 1.53 (iq, J = 6.8 Hz, 2H), 1.20-1.23 (m, 2H). 31 P NMR (162 MHz, D2O) δ 3.64, 3.23, 2.63. HPLC-MS (condition E): rt = 4.67 min; m / z: 826 [M+1+2DEA] + , 899 [M+1+3DEA] + .

[0393] Compound 45 5-O-(6,6,6-Trifluorohexyl)-myo-inositol-1,2,3,4,6-pentakis(phosphate) decasodium salt

[0417] Following the general phosphate deprotection procedure I, 1 mg of compound 45 (I_C-5) was obtained from 10 mg of (IV_C-5) (yield 13%). 1 H NMR (400 MHz, D2O) δ 4.58-4.16 (m, 3H), 4.02-3.90 (m, 2H), 3.80-3.71 (m, 2H), 3.39-3.22 (m, 1H), 2.23-2.02 (m, 2H), 1.67-1.56 (m, 2H), 1.51 (p, J = 7.4 Hz, 2H), 1.38-1.30 (m, 2H). HPLC-MS (condition E): rt = 6.12 min; m / z: 865 [M+1+2DEA] + , 938 [M+1+3DEA] + .

[0394] Compound 46 5-O-(5-(4-(Methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-myo-inositol-1,2,3,4,6-pentakis(phosphate) decasodium salt

[0418] According to the general phosphate deprotection procedure I, 2.5 mg of compound 45 (I_C-6) was obtained from 7 mg of (IV_C-6) (yield 46%). 1 H NMR (400 MHz, D2O) δ 7.99 (s, 1H), 4.53 (s, 2H), 4-50 - 4.35 (m, 1H), 4.37 (t, J = 7.0 Hz, 2H), 4.06 - 3.84 (m, 3H), 3.78 - 3.68 (m, 2H), 3.30 (s, 3H), 1.86 (t, J = 7.6 Hz, 2H), 1.69 - 1.58 (m, 2H), 1.33 - 1.14 (m, 4H). HPLC-MS (condition E): rt = 3.20 min; m / z: 762 [M+1] + 。

[0395] Compound 47 rac-1-O-(9-Methoxynonyl)-myo-inositol-2,3,4,5,6-pentakis(phosphate) decasodium salt

[0419] According to the general phosphate deprotection procedure I, 44 mg of compound 47 (I_D-2) was obtained from 100 mg of (IV_D-2) (yield 57%). 1 H NMR (400 MHz, D2O) δ 4.65 - 4.39 (m, 4H), 4.29 (d, J = 11.6 Hz, 1H), 4.18 - 3.94 (m, 1H), 3.85 - 3.73 (m, 1H), 3.72 - 3.65 (m, 1H), 3.47 (t, J = 6.6 Hz, 2H), 3.33 (s, 3H), 1.71 - 1.61 (m, 2H), 1.56 (p, J = 6.6 Hz, 2H), 1.30 (brs, 10H). HPLC-MS (condition E): rt = 5.45 min; m / z: 810 [M+1+DEA] + , 883 [M+1+2DEA] + 。

[0396] Compound 48 rac-1-O-(2-Cyclopropylethyl)-myo-inositol-2,3,4,5,6-pentakis(phosphate) decasodium salt

[0420] Following the general phosphate deprotection procedure I, 15.4 mg of Compound 48 (I_D-3) was obtained from 90 mg of (IV_D-3) (yield 23%). 1 H NMR (400 MHz, D2O) δ 4.64 - 4.32 (m, 5H), 4.22 - 4.09 (m, 1H), 3.78 - 3.65 (m, 2H), 1.49 - 1.41 (m, 2H), 0.72 - 0.59 (m, 1H), 0.34 - 0.27 (m, 2H), 0.04 - -0.04 (m, 2H). HPLC-MS (Condition E): rt = 4.92 min; m / z: 722 [M+1+DEA] + , 795 [M+1+2DEA] + , 868 [M+1+3DEA] + .

[0397] Compound 49 rac-1-O-(5-Acetamidopentyl)-myo-inositol-2,3,4,5,6-pentakis(phosphate) decasodium salt

[0421] Following the general phosphate deprotection procedure I, 1.7 mg of Compound 49 (I_D-4) was obtained from 10 mg of (IV_D-4) (yield 22%). 1 H NMR (400 MHz, D2O) δ 4.39 - 4.22 (m, 2H), 4.10 - 4.00 (m, 1H), 3.97 - 3.86 (m, 1H), 3.73 - 3.66 (m, 1H), 3.54 - 3.46 (m, 1H), 3.09 (t, J = 6.5 Hz, 2H), 1.90 (s, 3H), 1.62 - 1.52 (m, 2H), 1.49 - 1.41 (m, 2H), 1.37 - 1.29 (m, 2H). HPLC-MS (Condition E): rt = 3.10 min; m / z: 781 [M+1+DEA] + , 854 [M+1+2DEA] + , 926 [M+1+3DEA] + .

[0398] Compound 50 rac-1-O-(6,6,6-trifluorohexyl)-myo-inositol-2,3,4,5,6-pentakis(phosphate) decasodium salt (CSC-san17-016)

[0422] According to the general phosphate deprotection procedure I, 0.6 mg of Compound 50 (I_D-5) was obtained from 23 mg of (IV_D-5) (yield 3.4%). HPLC-MS (Condition E): rt = 6.83 min; m / z: 719 [M+1] + , 865 [M+1+2DEA] + .

[0399] Compound 51 rac-1-O-(2-cyclopentylethyl)-myo-inositol-2,3,4,5,6-pentakis(phosphate) decasodium salt

[0423] According to the general phosphate deprotection procedure I, 1.6 mg of Compound 51 (I_D-6) was obtained from 25 mg of (IV_D-6) (yield 8.5%). HPLC-MS (Condition E): rt = 6.35 min; m / z: 677 [M+1] + , 750 [M+1+DEA] + , 823 [M+1+2DEA] + , 896 [M+1+3DEA] + .

[0400] Compound 52 rac-1-O-(5-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-myo-inositol-2,3,4,5,6-pentakis(phosphate) decasodium salt

[0424] According to the general phosphate deprotection procedure I, 6.3 mg of Compound 52 (I_D-7) was obtained from 10 mg of (IV_D-8) (yield 82%). 11H NMR (400 MHz, D2O) δ 8.07 (s, 1H), 4.61 (s, 2H), 4.51 - 4.41 (m, 1H), 4.46 (t, J = 7.2 Hz, 2H), 4.36 - 4.24 (m, 1H), 4.16 - 3.88 (m, 1H), 3.84 - 3.52 (m, 3H), 3.39 (s, 3H), 2.00 - 1.92 (m, 2H), 1.87 - 1.61 (m, 2H), 1.48 - 1.26 (m, 2H). HPLC-MS (Condition E): rt = 5.19 min; m / z: 835 [M + 1 + DEA] + and 908 [M + 1 + 2DEA] + 。

[0401] Compound 53 rac-1-O-((1-(2-(Methoxycarbonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-myo-inositol-2,3,4,5,6-pentakis(phosphate) undecasodium salt

[0425] Following the general phosphate deprotection procedure J, 44.1 mg of Compound 53 (I_D-8) was obtained from 104 mg of (IV_D-7) (yield 55%). 1 1H NMR (400 MHz, D2O) δ 8.01 (s, 1H), 4.94 (d, J = 12.4 Hz, 1), 4.86 (d, J = 12.4 Hz, 1H), 4.63 - 4.57 (m, 3H), 4.51 - 4.33 (m, 2H), 4.31 - 4.08 (m, 3H), 4.02 - 3.78 (m, 1H), 2.73 (t, J = 7.1 Hz, 2H). HPLC-MS (Condition E): rt = 1.21 min; m / z: 880 [M + 1 + 2DEA] + and 953 [M + 1 + 3DEA] + 。

[0402] Pharmacological Assay A. In Vitro Inhibition of Calcium Phosphate Crystallization

[0426] The in vitro efficacy of the IP5-substituted compounds of the present invention (for example, Compounds 1 to 32) against the inhibition of calcium phosphate crystallization in human plasma samples was evaluated according to the spectroscopic evaluation already described in the art (Ferrer M et al., Sci Rep 2017;7:6858, doi:10.1038 / s41598-017-07203-x).

[0403]

[0427] A 96-well plate was used. Derivatives at concentrations increasing in the range of 0 to 100 μM were mixed with plasma (1 volume of the IP5-substituted compound of the present invention per 19 volumes of plasma). The plasma was then centrifuged at 10,000 g at room temperature, and then mixed with a mixture of 5 mM hydrogen phosphate and 41.67 mM calcium to obtain final concentrations of 1.5 mM phosphate and 12.5 mM calcium, respectively. All reagent solutions were filtered and adjusted to pH 7.4.

[0404]

[0428] The crystallization of calcium phosphate was spectroscopically monitored at room temperature for 30 minutes by measuring the increase in absorbance at 550 nm using a Biotek Powerwave XS Microplate spectrophotometer (BioTek Instruments, Inc., Winooski, VT, US). The plate was incubated at room temperature on an orbital shaker, and the absorbance was measured every 3 minutes.

[0405]

[0429] The crystallization of plasma was evaluated based on the measurement of the slope in the linear range between 6 and 24 minutes from the plot of the increase in absorbance against the logarithm of time. The efficacy of different myo-inositol phosphate derivatives in preventing the in vitro formation of calcium phosphate crystals was evaluated in human plasma samples using the slope obtained between 6 and 24 minutes. The inhibition of crystallization was measured by comparing the slope of the control sample (blank plasma) with that of the sample containing the inhibitor as shown below.

[0406]

[0430]

[0407]

Number

[0408]

[0431] Refer to Table 14.

[0409]

Table 14-1

[0410]

Table 14-2

[0411]

[0432] It is understood that the part of the mode for carrying out the invention rather than the part of the summary and abstract is intended to be used for explaining the claims. The part of the summary and abstract can show one or more but not all of the embodiments of the present invention considered by the inventor, and thus is not intended to limit the present invention and the appended claims in any way.

[0412]

[0433] The present invention has been described above using functional components that explain the implementation of specific functions and their relationships. The boundaries of these functional components are arbitrarily defined in this specification for the convenience of description. Other boundaries can be defined as long as the specific functions and their relationships are properly implemented.

[0413]

[0434] The foregoing description of specific embodiments enables others skilled in the art to readily modify and / or adapt such specific embodiments for various applications without undue experimentation and without departing from the basic concepts of the present invention. Thus, such adaptations and modifications are intended to be within the meaning and scope of equivalents of the disclosed embodiments based upon the teachings and guidance presented herein. The description and terminology herein is for the purpose of illustration and not of limitation, and it is understood that the terminology or phraseology herein will be interpreted by those of ordinary skill in the art in light of the teachings and guidance.

[0414]

[0435] The breadth and scope of the present invention should not be limited by any of the above-described examples, but should be defined only in accordance with the following claims and their equivalents.

Claims

1. General formula I: 【Chemistry 1】 Compounds of the same, their pharmaceutically acceptable salts, or combinations thereof (wherein the formula, (i) R １ , R ２ , R ３ , R ５ , and R ６ independently represent -OPO ３ H ２ , and R ４ is a substituent of formula II or formula III, or R １ , R ２ , R ３ , R ４ , and R ５ independently represent -OPO ３ H ２ , and R ６ is a substituent of formula II or formula III, 【Chemistry 2】 (ii) R １ , R ３ , R ４ , R ５ , and R ６ OPO operates independently. ３ H ２ Represents R ２ is a substituent of formula II or formula III, (iii) R １ , R ２ , R ３ , R ４ , and R ６ OPO operates independently. ３ H ２ Represents R ５ is a substituent of formula II or formula III, (iv)R ２ , R ３ , R ４ , R ５ , and R ６ OPO operates independently. ３ H ２ Represents R １ is a substituent of formula II, or R １ , R ２ , R ４ , R ５ , and R ６ OPO operates independently. ３ H ２ Represents R ３ is a substituent of formula II or formula III, For equation II, n is an integer from 1 to 30, and the terminal base X is -H, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO ２ R, -NHCONRR', halogen, -CF ３ The group is selected from the group consisting of alkyl, alkenyl, alkynyl, carbocyclic, and heterocyclic groups, where R and R' are H or alkyl groups, and for formula III, y and y' are integers from 0 to 10, Cy is a cyclic linker, and the terminal group Z is alkyl, -COR, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO ２ R, -NHCONRR', halogen, and -CF ３ Selected from the group consisting of (where R and R' are H or alkyl groups).

2. The compound according to claim 1, wherein the pharmaceutically acceptable salt is a sodium salt or a magnesium salt.

3. The compound according to claim 2, wherein the sodium salt is tetrasodium salt, pentasodium salt, hexasodium salt, heptasodium salt, octasodium salt, nonasodium salt, decanodium salt, or undecasodium salt.

4. The compound according to claim 1, wherein the compound is selected from the group consisting of compound 1 to compound 53 and any combination thereof.

5. The aforementioned compound has the following chemical structure: 【Transformation 3】 The compound according to claim 4, which is compound 1.

6. The aforementioned compound has the following chemical structure: 【Chemistry 4】 The compound according to claim 4, which is compound 2.

7. The aforementioned compound has the following chemical structure: 【Transformation 5】 The compound according to claim 3, which is compound 16.

8. A pharmaceutical composition comprising the compound described in claim 1 and at least one pharmaceutically acceptable excipient.

9. A pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is for use in a method of inhibiting the formation or growth of calcium salts / crystals in a subject that requires it, the method comprising the step of administering an effective amount of the pharmaceutical composition to the subject.

10. The pharmaceutical composition according to claim 9, wherein the calcium salt / crystal is calcium phosphate.

11. The pharmaceutical composition according to claim 10, wherein the calcium phosphate is hydroxyapatite.

12. A pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is for use in a method for treating or preventing a disease or disorder related to pathological crystallization in a subject in need thereof, the method comprising the step of administering an effective amount of the pharmaceutical composition to the subject.

13. A pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is for use in a method of inhibiting the progress of a crystallization process in a subject that requires such inhibition, the method comprising the step of administering an effective amount of the pharmaceutical composition to the subject.

14. The pharmaceutical composition according to any one of claims 9 to 13, wherein the subject is a human.

15. The pharmaceutical composition according to any one of claims 9 to 13, wherein the administration is local, enteral, or parenteral.

16. The pharmaceutical composition according to claim 15, wherein the parenteral administration is intravenous or subcutaneous.

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

18. A kit or product comprising at least one compound according to any one of claims 1 to 7, the pharmaceutical composition according to claim 8, or the compound according to claim 17.

19. A method for producing a compound of formula I according to any one of claims 1 to 7, comprising the use of at least one compound according to claim 17.

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