Ip4-4,6 substituted derivative compounds

Abstract

This invention provides substituted derivatives of IP4-4,6, their synthetic methods, and uses. In some embodiments, the IP4-4,6 derivatives are compounds of formula I, wherein R1, R3, R7, and R11 are OPO 32-, and R5 and R9 are selected from the group consisting of -O(alkyl)nX, -O(alkyl)yCy(alkyl2)yZ, -O(alkyl)yA(alkyl)y-Z', and their thiophosphate analogs. Methods for treating diseases and conditions (such as diseases and conditions related to pathological crystallization), pharmaceutical compositions and formulations, methods of use, articles, and kits are also provided.

Description

Technical Field

[0001] This invention relates to IP4-4,6 substituted derivative compounds, their synthesis methods, and their uses. Prior Technology

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

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

[0004] Several IP6 derivatives (e.g., having phosphate groups replaced by sulfate, thiosulfate, or water-soluble biopolymers such as polyethylene glycol (PEG)) have been described for use in treating diseases and conditions associated with pathological crystallization or other conditions such as bacterial infections. See, for example, WO2017098047 and WO2017098033. However, there is still a need in this field for novel and improved inositol phosphate derivatives (e.g., with varying degrees of crystallization inhibition, solubility, or degradation resistance) that can be used medically to treat pathological calcification and other conditions. Summary of the Invention

[0005] This invention discloses a compound of general formula I: Its pharmaceutically acceptable salt or combination thereof, wherein R1, R3, R7 and R11 independently represent OPO32-; R5 and R9 are substituents corresponding to the formula -O(alkyl)nX, wherein n is an integer between 1 and 20, wherein the terminal group X is selected from the group consisting of: -H, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', halogen, -CF3, carbocyclic (saturated or unsaturated) and heterocyclic (saturated or unsaturated), wherein R and R' are H or alkyl.

[0006] In some states, R1, R3, R7, and R11 independently represent OPO 3 2 -; R5 and R9 are substituents corresponding to the formula -O(alkyl) yCy(alkyl) yZ, where y is an integer between 0 and 10, where Cy is a cyclic linker, and where the terminal group Z is selected from the group consisting of: alkyl, -COR, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO 2R, -NHCONRR', halogen, and -CF 3, and where R and R' are H or alkyl.

[0007] In some states, R1, R3, R7, and R11 independently represent OPO 3 2 -; R5 and R9 are substituents corresponding to the formula -O(alkyl) yA(alkyl) y-Z', where y is an integer between 0 and 10, where A is a linker selected from the group consisting of -CONR-, -NHCOO-, -NHSO 2, -NHCONR-, -OCONR, and -NHCO-, where the terminal group Z' is selected from the group consisting of: -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO 2R, -NHCONRR', carbocyclic (saturated or unsaturated), heterocyclic (saturated or unsaturated), and where R and R' are H or alkyl.

[0008] In some states, at least one of R1, R3, R7 or R11 of the compound of formula I is a thiophosphate (-OPSO 2 2 -) group.

[0009] In some samples, the R5 and R9 substituents of compound I are the same. In other samples, the R5 and R9 substituents of compound I are different.

[0010] In some samples, the alkyl moiety in the R5 and R9 substituents includes at least one carbon double bond or carbon-dependent secondary bond, i.e., forming an alkenyl chain or an alkynyl chain, respectively. In some samples, the alkenyl chains in the R5 and R9 substituents are identical. In some samples, the alkenyl chains in the R5 and R9 substituents are different. In some samples, the alkynyl chains in the R5 and R9 substituents are identical. In some samples, the alkynyl chains in the R5 and R9 substituents are different. In some samples, the alkyl moiety in the R5 and R9 substituents includes at least one carbon double bond and at least one carbon-dependent secondary bond, thereby forming a combination of alkenyl and alkynyl chains. In some samples, the combination of alkenyl and alkynyl chains in the R5 and R9 substituents is identical. In some samples, the combination of alkenyl and alkynyl chains in the R5 and R9 substituents is different.

[0011] In some cases, the compounds of formula I are selected from the group consisting of compounds 1 to 53.

[0012] In some formulations, the pharmaceutically acceptable salt is the sodium salt. In some formulations, the sodium salt is a tetrasodium, pentasodium, hexasodium, heptasodium, octasodium, nonasodium, or decasodium salt. In some formulations, the sodium salt is a tetrasodium, pentasodium, hexasodium, heptasodium, or octasodium salt. In some formulations, the sodium salt is a hexasodium, octasodium, nonasodium, or decasodium salt.

[0013] The present invention also provides a pharmaceutical composition comprising a compound of formula I disclosed above and at least one pharmaceutically acceptable excipient.

[0014] Also provided is a method for inhibiting the formation or growth of calcium salts / crystals (e.g., calcium phosphate, hydroxyapatite (HAP)) in an individual in need, comprising administering to the individual an effective amount of a compound of formula I or a pharmaceutical composition disclosed herein.

[0015] In addition, the present invention provides a method for treating or preventing diseases or conditions related to pathological crystals in an individual of need, comprising administering to the individual an effective amount of a compound of formula I disclosed herein or a pharmaceutical composition.

[0016] A method for inhibiting the progression of crystallization in an individual in need is also provided, comprising administering to the individual an effective amount of a compound of formula I or a pharmaceutical composition disclosed herein.

[0017] The present invention also provides a method for restoring or increasing blood perfusion in an individual in need, comprising administering to the individual an effective amount of a compound of formula I disclosed herein or a pharmaceutical composition.

[0018] In some cases, the individual is human. In some cases, the administration is local, enteric, or non-enteric. In some cases, non-enteric administration is intravenous. In some cases, intravenous administration is performed by bolus injection or infusion.

[0019] The present invention also provides a kit or article comprising at least one compound of formula I or a pharmaceutical composition comprising a compound of formula I and instructions for administration according to any method disclosed herein. In some embodiments, the kit or article may also comprise at least one compound selected from the group of compounds listed in Table 1.

[0020] In some embodiments, the present invention further provides a method for manufacturing a compound of formula I (e.g., compound 1 to compound 53) comprising using at least one compound selected from the group of compounds listed in Table 1. Simple Explanation of the Diagram

[0021] [picture] [1] is a simplified schematic diagram illustrating the physiological and chemical mechanism by which the IP4-4,6 substituted derivative of the present invention inhibits hydroxyapatite (HAP) crystallization and is therefore applicable to the treatment of HAP-crystallization-mediated diseases.

[0022] [picture] [2A] and [picture] [2B] Presents representative structures of the IP4-4,6 substituted derivative family A (e.g., compounds 1 to 30 and compounds 52 to 53).

[0023] [picture] [3A] and [picture] [3B] presents a representative structure of the IP4-4,6 substituted derivative compound family B (e.g., compounds 31 to 44).

[0024] [picture] [4] They exhibit representative structures of the IP4-4,6 substituted derivative family C (e.g., compounds 45 to 49).

[0025] [picture] [5] The structures of the IP4-4,6-substituted derivative compound family D (e.g., compounds 50 to 51) are representative.

[0026] [picture] [6] is a schematic diagram of the synthesis process 1.

[0027] [picture] [7] is a schematic diagram of the synthesis process 2.

[0028] [picture] [8] is a schematic diagram of the synthesis process 3.

[0029] [picture] [9] is a schematic diagram of the synthesis process 4.

[0030] [picture]

[10] is a schematic diagram of the synthesis process 5. Implementation

[0031] This invention provides substituted derivatives of IP4-4,6, their synthetic methods, and their uses. In some samples, the substituted derivatives of IP4-4,6 are compounds of general formula I. Its pharmaceutically acceptable salts or combinations thereof, wherein R1, R3, R7, and R11 are OPO 3 2 - or OPSO 2 2 -, and R5 and R9 are the same. In some states, R5 and R9 are different. In some states, the IP4-4,6 derivative is a sodium salt. In some states, the IP4-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, octasodium, nonasodium, or decasodium salt. In some states, the IP4-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, or octasodium salt. In some states, the IP4-4,6 derivative is a hexasodium, octasodium, nonasodium, or decasodium salt. In some states, the IP4-4,6 derivative is an octasodium salt.

[0032] It also provides methods for treating diseases and conditions (such as diseases and conditions related to pathological crystallization), pharmaceutical compositions and formulations, methods of use, products and kits.

[0033] To make this invention more readily understood, certain terms are first defined below. As used in this application, unless otherwise expressly provided herein, each of the following terms shall have the meaning described below. Other definitions are set forth throughout this application. [, I. , ] [, definition , ] [, , ]

[0034] This invention includes a state in which exactly one member of a group is present, used in, or otherwise associated with a given product or method. This invention also includes a state in which more than one or all members of a group are present, used in, or otherwise associated with a given product or method.

[0035] 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 relating to this invention. 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 general dictionaries for those skilled in the art regarding many terms used in this invention.

[0036] Units, prefixes, and symbols are expressed in their internationally recognized form according to the International System of Units (SI). A numerical range includes the numerical value that defines the range. In describing a range of values, it should be understood, and specifically disclosed, that each intermediate integer value between the upper and lower limits of that range and its fractions, as well as the sub-ranges between those values. The upper and lower limits of any range may be independently included in or excluded from that range, and ranges including any limit value, an infinite value, or both limit values ​​are also covered within this invention.

[0037] Where values ​​are explicitly listed, it should be understood that values ​​of approximately the same quantity or amount as those listed are also within the scope of this invention. Where combinations are disclosed, each sub-combination of the elements in that combination is also specifically disclosed and is within the scope of this invention. Conversely, where different elements or groups of elements are disclosed independently, their combinations are also disclosed. Where any element of the invention is disclosed to have a plurality of alternatives, examples of that invention are also disclosed herein, wherein each alternative is excluded individually or in any combination with other alternatives; more than one element of the invention may have such exclusions, and all combinations of elements having such exclusions are disclosed herein.

[0038] Approximately: As used herein, “approximately” refers to a value or composition within an acceptable range of error for a particular value or composition, as determined by someone generally skilled in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, “approximately” may mean within 1 or more than 1 standard deviation, according to practice in this art. Alternatively, “approximately” may mean a range of up to 20%. Furthermore, especially in the context of biological systems or methods, these terms may mean a value of up to an order of magnitude or up to 5 times.

[0039] When a specific value or composition is provided in this application and the claims, unless otherwise stated, the meaning of "about" shall be assumed to be within an acceptable margin of error for the specific value or composition. When the term "about" is used in conjunction with a numerical range, its range is adjusted by extending the boundary of the value upwards or downwards. Thus, "about 10 to 20" means "about 10 to about 20". Generally, the term "about" may modify a numerical value that is higher or lower than the value, for example, by about 10% (higher or lower).

[0040] And / or: When used herein, “and / or” means a particular invention in which each of two specified features or components has or does not have the other. Therefore, the term “and / or” as used in phrases such as “A and / or B” herein is intended to include “A and B”, “A or B”, “A” (alone) and “B” (alone). Similarly, the term “and / or” as used in phrases such as “A, B and / or C” is intended to cover each of the following states: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone) and C (alone).

[0041] Approximately: As used herein, the term "approximately" when applied to one or more values ​​of interest means that the value is similar to the reference value. In some cases, unless otherwise stated or otherwise obvious from the context (unless such a value would exceed 100% of the possible value), the term "approximately" means a range of values ​​within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in any direction (greater than or less than) of the reference value.

[0042] Includes: It should be understood that whenever a state is described in this document using the language “includes”, similar states described using the terms “consisting of” and / or “substantially consisting of” are also provided.

[0043] Compound: As used herein, the term "compound" is intended to include any and all free bases, isomers, and isotopes of the described structure. As used herein, the term "isomer" means any geometric isomer, tautomer, zwitterion, stereoisomer, mirror-image isomer, or non-mirror-image isomer of the compound. A compound may include one or more antipodal centers and / or double bonds, and therefore may exist as stereoisomers, such as double bond isomers (i.e., geometric E / Z isomers) or non-mirror-image isomers (e.g., mirror-image isomers (i.e., (+) or (-))) or cis / trans isomers). This invention covers any and all isomers of the compounds described herein, including stereoisomeric pure forms (e.g., geometrically pure, mirror-image isomeric pure, or non-mirror-image isomeric pure) and mixtures of mirror-image and stereoisomers (e.g., racemic mixtures). Methods for resolving mixtures of mirror-image and stereoisomers of compounds into their mirror-image or stereoisomeric components are well known. The compounds, salts, or complexes of this invention can be prepared by combining with solvents or water molecules to form solvates and hydrates using conventional methods. In some embodiments, the term "compound" is used to refer to the IP4-4,6 substituted derivatives of this invention.

[0044] Effective Amount: As used herein, the term "effective amount" of a therapeutic agent is, in relation to (i) the IP4-4,6-substituted derivatives of the present invention, (ii) any dosage form, pharmaceutical composition, or formulation disclosed herein comprising at least one IP4-4,6-substituted derivative of the present invention, or (iii) a combination of the IP4-4,6-substituted derivative of the present invention with one or more additional therapeutic agents, an amount sufficient to achieve a beneficial or desired outcome. In some cases, a beneficial or desired outcome is, for example, a clinical outcome, and therefore "effective amount" depends on the context in which it is applied. The term "effective amount" may be used interchangeably with "effective dose," "therapeutic effective amount," or "therapeutic effective dose."

[0045] The term "effective amount" is related to the specific use of the IP4-4,6-substituted derivative. For example, when the IP4-4,6-substituted derivative is used to inhibit the formation or growth of calcium salts / crystals (e.g., calcium phosphate, HAP), the effective amount will be the amount of IP4-4,6-substituted derivative that achieves the desired effect (e.g., reducing HAP crystallization / formation in serum or plasma).

[0046] Enteral administration: As used herein, the term "enteral administration" and related terms "enteral" refer to any pharmaceutical composition containing or containing the IP4-4,6 substituted derivatives of the present invention administered via the gastrointestinal tract. Enteral administration includes (but is not limited to) oral, sublingual, and rectal routes.

[0047] Prevention: As used herein, the term "prevention" refers to measures taken to maintain health and to prevent or delay the onset of a disease or condition or to alleviate the degree and / or severity of its symptoms. Therefore, the preventive use of the therapeutic agents disclosed herein, such as (i) the IP4-4,6-substituted derivatives of the present invention, or (ii) combinations thereof, or (iii) any dosage form comprising at least one IP4-4,6-substituted derivative of the present invention, or (iv) any formulation comprising at least one IP4-4,6-substituted derivative of the present invention, or (v) a combination of the IP4-4,6-substituted derivative of the present invention with one or more additional therapeutic agents, corresponds to an amount sufficient to achieve a beneficial or desired outcome.

[0048] Range: As stated herein, unless otherwise specified, any concentration range, percentage range, ratio range or integer range shall be understood to include any integer value within the range and (where appropriate) its fraction (such as one-tenth and one-hundredth of an integer).

[0049] The IP4-4,6 substituted derivatives of the present invention: as used herein, the term "IP4-4,6 substituted derivatives of the present invention" and its grammatical variations refer to compounds of formula I: Wherein R1, R3, R7, and R11 are OPO 3 2 - or OPSO 2 2 -, and R5 and R9 may be the same or different, and wherein the substituents of R5 and R9 are those of the compound families A, B, C, and D disclosed in detail below and their salts (e.g., their pharmaceutically acceptable salts). In some embodiments, the term IP4-4,6-substituted derivatives of the present invention covers compounds 1 to 53, any salts thereof (e.g., sodium salts), and any combination thereof. In some embodiments, the term IP4-4,6-substituted derivatives of the present invention covers compounds of formula I, which are intermediates in the synthesis of compounds 1 to 53, such as compounds selected from the group consisting of compounds listed in Table 1, any salts thereof (e.g., sodium salts), and any combination thereof. In some embodiments, the term IP4-4,6 of the present invention, when substituted derivatives, encompass compounds of formula I, which are compounds 1 to 53 and compounds selected from the group consisting of compounds listed in Table 1, any salts thereof (e.g., sodium salts) thereof, and any combination thereof.

[0050] The group consisting of compounds 1 to 53: In the context of this invention, "the group consisting of compounds 1 to 53" refers to the group of compounds including compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, and 53. In some embodiments, the group consisting of compounds 1 to 53 also includes combinations thereof. In some states, the combination of compounds in the group consisting of compounds 1 to 53 may include 2, 3, 4, 5, 6, 7, 8, 9, 10 or more compounds from the group consisting of compounds 1 to 53.

[0051] The group consisting of compounds listed in Table 1: In the context of this invention, reference to "the group consisting of compounds listed in Table 1" refers to the group of intermediate compounds used for, for example, the synthesis of substituted derivatives of IP4-4,6 of this invention (e.g., compounds selected from the group consisting of compounds 1 to 53), namely intermediates II-1 to II-27, intermediates III-1 to III-47, intermediates IV-1 to IV-48, intermediates VI'-1 to IV'-2, intermediates V-1, intermediates VI-1, intermediates VII-1 to VII-2, intermediates VIII-1 to VIII-5, intermediates IX-1 to IX-5, intermediates X-1 to X-3, intermediates XI-1 to XI-2, intermediates XII-1 to XII-2, and intermediates XIII-1 to XIII-3. In some cases, the group consisting of compounds listed in Table 1 may also include combinations thereof. In some cases, the combination of compounds in the group consisting of the compounds listed in Table 1 may include 2, 3, 4, 5, 6, 7, 8, 9, 10 or more compounds from the group consisting of the compounds listed in Table 1.

[0052] Non-enteric administration: As used herein, the term "non-enteric administration" and related terms "non-enteric" refer to administration of the substituted derivatives of IP4-4,6 of the present invention characterized by invasiveness into individual body tissue, and administration of the derivatives via a wound in the tissue. Non-enteric administration includes (but is not limited to) administration of the substituted derivatives of IP4-4,6 of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53) or pharmaceutical compositions containing the derivatives by means of application of the derivatives or compositions via, for example, a surgical incision or a non-surgical wound penetrating tissue. Specifically, non-enteric administration includes (but is not limited to) epidural, intra-arterial, intradermal, intrathecal, intramuscular, intraperitoneal, intrasternal injection, intravascular, intravenous, intravenous infusion, spinal, subcutaneous, and subcutaneous reservoir administration routes.

[0053] Individual: The term "subject," "individual," "animal," "patient," or "mammal" means any individual requiring diagnosis, prognosis, or treatment, especially a mammalian individual. Mammal individuals include (but are not limited to) humans, livestock, farm animals, zoo animals, joeys, pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, and dairy cows; primates such as apes, monkeys, orangutans, and chimpanzees; canines such as dogs and wolves; felines such as cats, lions, and tigers; equines such as horses, donkeys, and zebras; bears; edible animals such as dairy cows, pigs, and sheep; ungulates such as deer and giraffes; and rodents such as mice, rats, hamsters, and guinea pigs. In some categories, the mammal is a human individual. In other categories, the individual is a human patient. In a specific category, the individual is a human patient who has developed pathological crystals or is at risk of developing pathological crystals.

[0054] In essence: As used herein, the term "in essence" refers to a qualitative condition that demonstrates all or nearly all the limits or extent of the feature or characteristic of interest. Those skilled in biotechnology will understand that biological and chemical phenomena rarely (if ever) proceed completely and / or continue to achieve or avoid absolute results. Therefore, the term "in essence" is used herein to capture the inherent lack of completeness in many biological and chemical phenomena.

[0055] Therapeutic agents: As used herein, the term "therapeutic agent" is used broadly to include compositions comprising the IP4-4,6-substituted derivatives of the present invention that can provide significant therapeutic benefits to individuals in need. In some cases, the individuals in need are those who suffer from or are at risk of developing a disease or condition associated with pathological crystals (e.g., calcium phosphate or HAP crystals). Therefore, generally, a therapeutic agent according to the present invention can be the IP4-4,6-substituted derivative of the present invention, alone or in combination with one or more additional therapeutic agents, administered in an amount sufficient to achieve a beneficial or desired outcome.

[0056] The term therapeutic agent also encompasses preventive, diagnostic, or imaging agents comprising the substituted derivatives of IP4-4,6 of the present invention, wherein the therapeutic agent is administered (i.e., topically, enterically, or non-enterically). The therapeutic agents of the present invention include agents that inhibit the formation or growth of calcium salts / crystals (e.g., calcium phosphate, HAP) and / or can improve and / or prevent any symptoms associated with pathological crystallization.

[0057] Local administration: As used herein, the term "local administration" and the related term "local" refer to any administration of the substituted derivatives of IP4-4,6 of the present invention or pharmaceutical compositions comprising such derivatives, which is accomplished by applying the derivative or composition to a specific site on or within the body (such as the skin or mucous membrane). Local administration includes (but is not limited to) routes of administration such as the ear, skin, nose, percutaneous, urethra, vagina, and urethral.

[0058] Treatment (Treatment, therapy): As used herein, the term “treatment” means the partial or complete relief, mitigation, improvement, reduction, delay of the onset of a disease, inhibition of its worsening, reduction of its severity, reduction of the incidence of one or more of its symptoms or features, or any combination thereof.

[0059] Therapies comprising the IP4-4,6 substituted derivatives of the present invention may be administered to individuals who do not present with symptoms of disease, condition and / or illness, and / or individuals who present only with early symptoms of disease, condition and / or illness, for purposes such as (i) reducing the risk of developing lesions associated with disease, condition and / or illness, (ii) delaying the onset of disease, condition and / or illness or lesions associated with such disease, condition and / or illness, or (iii) alleviating the symptoms and / or sequelae of disease, condition and / or illness or lesions associated with such disease, condition and / or illness.

[0060] Therefore, in general, the term "treatment" refers to the effect of counteracting the result of a disease or pathological condition of concern to an individual, including (i) suppressing the disease or pathological condition, in other words, slowing or stopping its development or worsening; (ii) alleviating the disease or pathological condition, in other words, causing the disease or pathological condition or its symptoms to subside; (iii) stabilizing the disease or pathological condition; and (iv) any combination thereof.

[0061] ug, uM, uL: As used in this article, the terms “ug”, “uM” and “uL” can be used interchangeably with “μg”, ​​“μM” and “μL”, respectively. [, II. , ] [, IP4 , ] [, - , ] [, 4 , ] [,, , ] [, 6 , ] [, Substituted derivatives , ] [, , ]

[0062] This invention provides substituted derivatives of IP4-4,6, their synthetic methods, and their uses. In some samples, the substituted derivatives of IP4-4,6 are compounds of general formula I. R1, R3, R7, and R11 independently represent OPO 3 2 - or OPSO 2 2 -, and R5 and R9 are substituents. In some samples, R5 and R9 are the same substituent. In some samples, R5 and R9 are different substituents. In some samples, the IP4-4,6 substituted derivatives of the present invention are acceptable salts of compounds of formula I (e.g., pharmaceutically acceptable salts) or combinations thereof.

[0063] In some states, the positive charge of the ions cannot compensate for all the negative charge in the IP4-4,6 derivatives of the present invention. Therefore, the IP4-4,6 derivatives of the present invention can be, for example, tetraionic salts (e.g., tetrasodium salts), pentaionic salts (e.g., pentasodium salts), hexaionic salts (e.g., hexasodium salts), heptaionic salts (e.g., heptasodium salts), octaionic salts (e.g., octasodium salts), nonaionic salts (e.g., nonasodium salts), or decaionic salts (e.g., decasodium salts). In some states, the presence of additional negatively charged groups in the substituted IP4-4,6 derivatives can lead to the formation of complexes with additional ions. In some states, the IP4-4,6 derivatives of the present invention are sodium salts. In some states, the IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts, octasodium salts, nonasodium salts, or decasodium salts. In some states, the IP4-4,6 derivatives are tetrasodium salts, pentasodium salts, hexasodium salts, heptasodium salts, or octasodium salts. In some forms, the IP4-4,6 derivatives are hexasodium, octasodium, nonasodium, or decasodium salts. Formula I and the others presented in this invention are intended to cover any isomers of the compounds thereby covered.

[0064] In the context of this invention, the term "alkenyl" or "alkenyl chain" refers to a substituted or unsubstituted straight-chain or branched alkyl chain (e.g., containing between 2 and 10 carbon atoms) containing one or more double bonds. Examples particularly include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, and 1,3-butadienyl.

[0065] In the context of this invention, the term "alkyl" or "alkyl chain" refers to a saturated hydrocarbon moiety, which can be straight-chain, branched-chain, cyclic, or cyclic saturated hydrocarbon moiety having straight-chain or branched side chains. The term alkyl includes partially unsaturated hydrocarbons, such as propenyl. Examples are methyl, ethyl, n-butyl or isobutyl, n-hexyl or cyclohexyl. The term alkyl can be extended to alkyl groups linked or bridged by heteroatoms. In the context of this invention, heteroatoms are nitrogen (N), sulfur (S), oxygen (O), and halogens.

[0066] In the context of this invention, the term "alkynyl" or "alkynyl chain" refers to a substituted or unsubstituted straight or branched alkyl chain (e.g., containing between 2 and 10 carbon atoms) containing one or more linkages. Examples particularly include ethynyl, propynyl, 1-butynyl, and 3-butynyl.

[0067] "Amine functional group" or "amine group" is a functional group NRR', wherein R and R' are independently selected, for example, from hydrogen (-H) and alkyl groups, such as C1-Cn alkyl groups, where n is an integer between 0 and 20.

[0068] The "hydroxyl functional group" or "hydroxyl group" is OH.

[0069] The "carboxylic acid functional group" or "carboxylic acid group" is COOH or its anion COO-.

[0070] "Carboxylic acid amine" is CONRR' or NCOR, where R and R' are independently selected, for example, from hydrogen (-H) and alkyl, such as C1-Cn alkyl, where n is an integer between 0 and 20.

[0071] "Carbon ring" refers to a 3- to 10-membered carbon ring, which may be saturated, partially unsaturated, or aromatic and is bonded to the rest of the molecule by any available carbon atom. The term includes carbon rings substituted with one or more heteroatoms (e.g., N, O, halogen atoms).

[0072] "Heterocycle" refers to a 3- to 10-membered ring containing at least one heteroatom selected from N, O, and S, which may be saturated, partially unsaturated, or aromatic and is bonded to the rest of the molecule via any available C or N atom. The term includes heterocycles substituted with one or more halogen atoms.

[0073] Examples of carbocyclic and heterocyclic compounds include, in particular, phenyl, naphthyl, thiophene, furanyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyridyl, pyrimidinyl, pyridyl, pyridyl, benzimidazolyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, benzothiophene, benzothiazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azacyclobutyl, and azapropylidinyl.

[0074] The "halogen" group refers to fluorine, chlorine, bromine, or iodine.

[0075] In the context of this invention, the term "OPO 3 2 -" also does not explicitly refer to OPO 3H - and OPO 3H 2.

[0076] In some samples, the methods disclosed in US9612250 can be used to detect and / or quantify the IP4-4,6 substituted derivatives of the present invention or the intermediate compounds disclosed herein. See also US8377909, US8778912 and US20070066574.

[0077] The IP4-4,6 substituted derivatives of this invention can exist in any form commonly used in pharmaceutical technology. Specific forms include (but are not limited to) sodium salts, magnesium salts, potassium salts, ammonium salts, free acids, or mixtures of the foregoing forms. Other pharmaceutically acceptable salts are known to those skilled in the art and can be obtained by the methods described above (Haynes M et al., J. Pharmaceutical Sci. 2005; 94:2111-2120).

[0078] In some states, R1, R3, R7, and R11 independently represent phosphate esters (-OPO 3 2 -) and R5 / R9 correspond to the formula -O(alkyl) nX (i.e., R5 / R9 is an alkyl chain with or without branches), where n is an integer between 1 and 20, and the terminal group X is selected from the group consisting of: -H, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO 2R, -NHCONRR', halogen, -CF 3, carbocyclic (saturated or unsaturated), and heterocyclic (saturated or unsaturated), and where R and R' are H or alkyl. Throughout this invention, this family of substituted derivatives of IP4-4,6 is designated as [family] [A].

[0079] In some forms, R1, R3, R7, and R11 independently represent phosphate esters (-OPO 3 2 -) and R5 / R9 corresponds to the formula -O(alkyl) yCy(alkyl) yZ (i.e., R5 / R9 comprises two alkyl chains connected by a cyclic linker inserted between two alkyl chains), wherein each alkyl chain comprises y carbon (e.g., CH 2) units, where y is an integer between 0 and 10, and the terminal alkyl chain comprises a terminal group Z selected from the group consisting of: alkyl, -COR, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO 2R, -NHCONRR', halogen, and -CF 3, wherein R and R' are H or alkyl. Throughout this invention, IP4-4,6 are designated as this family of substituted derivatives. [family] [B].

[0080] In some states, R1, R3, R7, and R11 independently represent phosphate esters (-OPO 3 2 -) and R5 / R9 correspond to the formula -O(alkyl) yA(alkyl) yZ' (i.e., two alkyl chains connected by a linker A inserted between two alkyl chains), wherein each alkyl chain contains y carbon (e.g., CH 2) units, where y is an integer between 0 and 10, wherein the linker A is selected from the group consisting of: -CONR-, -NHCOO-, -NHSO 2-, -NHCONR-, -NHCO-, and -OCONR-, wherein the terminal alkyl chain contains a terminal group Z' selected from the group consisting of: -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO 2R, -NHCONRR', a carbocyclic (saturated or unsaturated), a heterocyclic (saturated or unsaturated), and wherein R and R' are H or alkyl. Throughout this invention, IP4-4,6 is designated as a family of substituted derivatives. [family] [C].

[0081] In some embodiments, the substituted derivatives of IP4-4,6 of family D are analogs of compounds from families A, B, or C, wherein at least one of R1, R3, R7, or R11 is a thiophosphate (-OPSO₂). Throughout this invention, this family of substituted derivatives of IP4-4,6 is designated as [family] [D]

[0082] Among some states of the substituted IP4-4,6 derivatives of family D, one of R1, R3, R7, or R11 from compounds of families A, B, or C is a thiophosphate (-OPSO 2 2 -). Among some states of the substituted IP4-4,6 derivatives of family D, two of R1, R3, R7, or R11 from compounds of families A, B, or C are thiophosphates (-OPSO 2 2 -). Among some states of the substituted IP4-4,6 derivatives of family D, three of R1, R3, R7, or R11 from compounds of families A, B, or C are thiophosphates (-OPSO 2 2 -). In some forms of IP4-4,6 substituted derivatives of family D, R1, R3, R7, or R11 from compounds of families A, B, or C are thiophosphates (-OPSO2-).

[0083] In some states of the substituted IP4-4,6 derivatives of family D, the family D compound contains a thiophosphate (-OPSO 2 2 -) only at position R1. In some states of the substituted IP4-4,6 derivatives of family D, the family D compound contains a thiophosphate (-OPSO 2 2 -) only at position R3. In some states of the substituted IP4-4,6 derivatives of family D, the family D compound contains a thiophosphate (-OPSO 2 2 -) only at position R7. In some states of the substituted IP4-4,6 derivatives of family D, the family D compound contains a thiophosphate (-OPSO 2 2 -) only at position R11. In some states of the substituted IP4-4,6 derivatives of family D, the family D compound contains a thiophosphate (-OPSO 2 2 -) at positions R1, R3, R7, and R11. In some forms of the substituted IP4-4,6 derivatives of family D, the family D compounds contain thiophosphates (-OPSO 2 2 -) at positions R1 and R3. In some forms of the substituted IP4-4,6 derivatives of family D, the family D compounds contain thiophosphates (-OPSO 2 2 -) at positions R1 and R7. In some forms of the substituted IP4-4,6 derivatives of family D, the family D compounds contain thiophosphates (-OPSO 2 2 -) at positions R1 and R11. In some forms of the substituted IP4-4,6 derivatives of family D, the family D compounds contain thiophosphates (-OPSO 2 2 -) at positions R3 and R7. In some forms of the substituted IP4-4,6 derivatives of family D, the family D compounds contain thiophosphates (-OPSO 2 2 -) at positions R3 and R11. In some forms of the substituted IP4-4,6 derivatives of family D, the family D compounds contain thiophosphates (-OPSO 2 2 -) at positions R7 and R11. (This text is repeated four times in the original.) Among some substituted derivatives of family D, IP4-4,6, family D compounds contain thiophosphates (-OPSO2-) at positions R1, R7, and R11.

[0084] In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise IP4-4,6 substituted derivatives of family A, family B, family C, family D, or combinations thereof.

[0085] In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise IP4-4,6 substituted derivatives from family A. In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise IP4-4,6 substituted derivatives from family B. In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise IP4-4,6 substituted derivatives from family C. In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise IP4-4,6 substituted derivatives from family D.

[0086] In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of IP4-4,6 substituted derivatives selected from the group consisting of compounds 1 to 53 and combinations thereof. In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of IP4-4,6 substituted derivatives selected from the group consisting of compounds 1 to 30 and combinations thereof. In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of IP4-4,6 substituted derivatives selected from the group consisting of compounds 31 to 44 and combinations thereof. In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of IP4-4,6 substituted derivatives selected from the group consisting of compounds 45 to 49 and combinations thereof. In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of IP4-4,6 substituted derivatives selected from the group consisting of compounds 50 to 51 and combinations thereof. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 1. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 2. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 3. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 4. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 5. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 6. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 7. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 8. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 9. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 10. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 11. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 12. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 13. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 14. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 15. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 16. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 17. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 18.In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 19. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 20. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 21. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 22. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 23. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 24. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 25. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 26. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 27. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 28. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 29. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 30. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 31. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 32. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 33. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 34. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 35. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 36. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 37. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 38. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 39. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 40. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 41. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 42. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 43. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 44. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 45.In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 46. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 47. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 48. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 49. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 50. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 51. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 52. In some samples, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 53.

[0087] In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of an analog of compound 1, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 2 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO 2 2 -). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 3 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 4 analogs, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 5 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-).In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of an analog of compound 6, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 7 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 8 analogs, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 9 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 10 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-).In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of an analog of compound 11, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 12 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 13 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 14 analogs, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 15 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-).In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 16 analogs, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 17 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 18 analogs, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 19 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 20 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-).In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of an analog of compound 21, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO 2 2 -). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 22 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO 2 2 -). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 23 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO 2 2 -). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 24 analogs, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO 2 2 -). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 25 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-).In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 26 analogs, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO 2 2 -). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 27 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO 2 2 -). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 28 analogs, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 29 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO 2 2 -). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 30 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-).In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 31 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 32 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 33 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-). In some embodiments, the IP4-4,6 substituted derivatives of the present invention comprise or consist of compound 34 analogs, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 35 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-).In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 36 analogs, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 37 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 38 analogs, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 39 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 40 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-).In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of an analog of compound 41, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 42 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 43 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 44 analogs, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 45 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-).In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 46 analogs, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 47 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 48 analogs, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 49 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compound 50 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-).In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of an analog of compound 51, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO22-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 52 analogues, wherein R1, R3, R7 or R11; R1, R3, R7 and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3 and R7; R1, R3 and R11; R3, R7 and R11; or R1, R7 and R11 are thiophosphates (-OPSO2-). In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds 53 analogues, wherein R1, R3, R7, or R11; R1, R3, R7, and R11; R1 and R3; R1 and R7; R1 and R11; R3 and R7; R3 and R11; R7 and R11; R1, R3, and R7; R1, R3, and R11; R3, R7, and R11; or R1, R7, and R11 are thiophosphates (-OPSO2-).

[0088] In some samples, the alkyl moiety in the R5 and R9 substituents of the IP4-4,6 substituted derivatives of the present invention includes at least one carbon double bond or carbon-dependent secondary bond, i.e., forming alkenyl or alkynyl chains respectively. In some samples, the alkenyl chains in the R5 and R9 substituents are the same. In some samples, the alkenyl chains in the R5 and R9 substituents are different. In some samples, the alkynyl chains in the R5 and R9 substituents are the same. In some samples, the alkynyl chains in the R5 and R9 substituents are different. In some samples, the alkyl moiety in the R5 and R9 substituents includes at least one carbon double bond and at least one carbon-dependent secondary bond, thereby forming a combination of alkenyl and alkynyl chains. In some samples, the combination of alkenyl and alkynyl chains in the R5 and R9 substituents is the same. In some samples, the combination of alkenyl and alkynyl chains in the R5 and R9 substituents is different. In some forms, the alkyl moiety of the R5 or R9 substituent comprising at least one carbon double bond or carbon-dependent bond is included in the substituted derivatives of the present invention IP4-4,6, which are Family A compounds. In some forms, Family A compounds comprising at least one carbon double bond or carbon-dependent bond are compounds 1 to 30 and compound 52.

[0089] In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds of the following formula: Where n is an integer between 1 and 20, the alkyl group is CH₂ and X is -H. In some samples, 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 samples, the IP₄-4,6 derivative is a sodium salt. In some samples, the IP₄-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP₄-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, or octasodium salt. In some samples, the IP₄-4,6 derivative is a hexasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP₄-4,6 derivative is an octasodium salt. In some samples, n is 5, the alkyl group is CH₂ and X is -H (Compound 1). In some samples, n is 10, the alkyl group is CH2 and X is -H (compound 2). In some samples, n is 14, the alkyl group is CH2 and X is -H (compound 3). In some samples, n is 3, the alkyl group is CH2 and X is -H (compound 4). In some samples, n is 7, the alkyl group is CH2 and X is -H (compound 5).

[0090] In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds of the following formula: Where n is an integer between 1 and 20, the alkyl group is CH2, and the X series is selected from the group consisting of -OH and -OMe. In some samples, the IP4-4,6 derivative is a sodium salt. In some samples, the IP4-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP4-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, or octasodium salt. In some samples, the IP4-4,6 derivative is a hexasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP4-4,6 derivative is an octasodium salt. In some samples, 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 samples, n is 5, the alkyl group is CH₂ and X is -OH (compound 6). In some samples, n is 10, the alkyl group is CH₂ and X is -OH (compound 7). In some samples, n is 14, the alkyl group is CH₂ and X is -OH (compound 8). In some samples, n is 5, the alkyl group is CH₂ and X is -OMe (compound 9). In some samples, n is 3, the alkyl group is CH₂ and X is -OMe (compound 10). In some samples, n is 7, the alkyl group is CH₂ and X is -OMe (compound 11). In some samples, n is 9, the alkyl group is CH₂ and X is -OMe (compound 12). In some samples, n is 19, the alkyl group is CH₂ and X is -OMe (compound 20).

[0091] In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds of the following formula: Where n is an integer between 1 and 20, the alkyl group is CH₂, and X is an amino group. In some samples, 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 samples, the IP₄-4,6 derivative is a sodium salt. In some samples, the IP₄-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP₄-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, or octasodium salt. In some samples, the IP₄-4,6 derivative is a hexasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP₄-4,6 derivative is a hexasodium salt. In some samples, n is 3, the alkyl group is CH2 and X is -NH2 (compound 13). In some samples, n is 5, the alkyl group is CH2 and X is -NH2 (compound 14). In some samples, n is 10, the alkyl group is CH2 and X is -NH2 (compound 15).

[0092] In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds of the following formula: Where n is an integer between 1 and 20, the alkyl group is CH₂, and X is pyrazole or triazole. In some samples, 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 samples, the IP₄-4,6 derivative is a sodium salt. In some samples, the IP₄-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP₄-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, or octasodium salt. In some samples, the IP₄-4,6 derivative is a hexasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP₄-4,6 derivative is an octasodium salt. In some samples, n is 5, the alkyl group is CH2, and X is pyrazole (compound 16). In some samples, n is 5, the alkyl group is CH2, and X is triazole (compound 17).

[0093] In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds of the following formula: Where n is an integer between 1 and 20, the alkyl group is CH₂, and X is -COOH. In some samples, 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 samples, the IP₄-4,6 derivative is a sodium salt. In some samples, the IP₄-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP₄-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, or octasodium salt. In some samples, the IP₄-4,6 derivative is a hexasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP₄-4,6 derivative is an octasodium or decasodium salt. In some samples, n is 5, the alkyl group is CH2 and X is -COOH (compound 18). In some samples, n is 10, the alkyl group is CH2 and X is -COOH (compound 19). In some samples, n is 3, the alkyl group is CH2 and X is -COOH (compound 52).

[0094] In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds of the following formula: Where n is an integer between 1 and 20, the alkyl group is CH2, and X is -CONRR', -NHCOR, -NHCOOR, -NHCONRR', or -CF3. In some samples, 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 samples, the IP4-4,6 derivative is a sodium salt. In some samples, the IP4-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP4-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, or octasodium salt. In some samples, the IP4-4,6 derivative is a hexasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP4-4,6 derivative is an octasodium salt. In some samples, n is 3, the alkyl group is CH2, and X is -CF3 (Compound 22). In some samples, n is 5, the alkyl group is CH2, and X is -CF3 (Compound 23). In some samples, n is 3, the alkyl group is CH2, and X is -NHCOOMe (Compound 24). In some samples, n is 5, the alkyl group is CH2, and X is -NHCOOMe (Compound 25). In some samples, n is 3, the alkyl group is CH2, and X is -CONH2 (Compound 26). In some samples, n is 5, the alkyl group is CH2, and X is -NHCOMe (Compound 27). In some samples, n is 5, the alkyl group is CH2, and X is -NHCONHPr (Compound 30).

[0095] In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds of the following formula: Where n is an integer between 1 and 20, the alkyl group is CH₂, and X is cyclopropane or cyclopentane. In some samples, 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 samples, the IP₄-4,6 derivative is a sodium salt. In some samples, the IP₄-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP₄-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, or octasodium salt. In some samples, the IP₄-4,6 derivative is a hexasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP₄-4,6 derivative is an octasodium salt. In some samples, n is 2, the alkyl group is CH2, and X is cyclopropane (compound 28). In some samples, n is 2, the alkyl group is CH2, and X is cyclopentane (compound 29).

[0096] In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds of the following formula: Where n is an integer between 1 and 20, the alkyl group is a branched chain, and X is -H. In some samples, 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 samples, the IP4-4,6 derivative is a sodium salt. In some samples, the IP4-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP4-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, or octasodium salt. In some samples, the IP4-4,6 derivative is a hexasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP4-4,6 derivative is an octasodium salt. In some samples, the substituted derivatives of the IP4-4,6 of the present invention contain, as follows: [picture] The compound 21 shown in [2B] or composed of it.

[0097] In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds of the following formula: Where n is an integer between 1 and 20, the alkyl group is an alkynyl chain, and X is -H. In some samples, 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 samples, the IP4-4,6 derivative is a sodium salt. In some samples, the IP4-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP4-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, or octasodium salt. In some samples, the IP4-4,6 derivative is a hexasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP4-4,6 derivative is an octasodium salt. In some samples, the substituted derivatives of the IP4-4,6 of the present invention comprise, as follows: [picture] The compound 53 shown in [2B] or composed of it.

[0098] In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds of the following formula: Where y and y' are integers between 0 and 10, the alkyl group is CH2, the Cy series is selected from the group consisting of piperazine, triazole-1, and triazole-2, and the Z series is selected from the group consisting of -COOH, -OMe, and -COCH3. See also [picture] [3A]. In some samples, the IP4-4,6 derivative is a sodium salt. In some samples, the IP4-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP4-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, or octasodium salt. In some samples, the IP4-4,6 derivative is a hexasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP4-4,6 derivative is an octasodium or nonasodium salt. In some samples, y or y' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some samples, y is 1, y' is 2, the alkyl group is CH 2, Cy is triazole-2, and Z is -COOH (compound 31). In some samples, y is 1, y' is 3, the alkyl group is CH 2, Cy is triazole-2, and Z is -OMe (compound 32). In some samples, y is 1, y' is 6, the alkyl group is CH 2, Cy is triazole-2, and Z is -OMe (compound 33). In some samples, y is 2, y' is 0, the alkyl group is CH 2, Cy is piperazine, and Z is -COCH 3 (compound 34). In some samples, y is 3, y' is 2, the alkyl group is CH 2, Cy is triazole-1, and Z is -COOH (compound 35). In some samples, y is 3, y' is 1, the alkyl group is CH 2, Cy is triazole-1, and Z is -OMe (compound 36). In some samples, y is 4, y' is 1, the alkyl group is CH 2, Cy is triazole-1, and Z is -OMe (compound 37). In some samples, y is 5, y' is 1, the alkyl group is CH 2, Cy is triazole-1, and Z is -OMe (compound 38). In some samples, y is 6, y' is 1, the alkyl group is CH 2, Cy is triazole-1, and Z is -OMe (compound 39). In some samples, y is 6, y' is 0, the alkyl group is CH 2, Cy is triazole-1, and Z is -COOH (compound 40). In some samples, y is 6, y' is 1 / 0, the alkyl group is CH 2, Cy is triazole-1, and Z is -OMe / -COOH (compound 41).

[0099] In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds of the following formula: Where y and y' are integers between 0 and 10, the alkyl group is CH2, the Cy series is selected from the group consisting of 1,3-substituted phenyl and 1,4-substituted phenyl groups, and the Z series is selected from the group consisting of -Me, -OMe, and -CF3. See also [picture] [3B]. In some samples, the IP4-4,6 derivative is a sodium salt. In some samples, the IP4-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP4-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, or octasodium salt. In some samples, the IP4-4,6 derivative is a hexasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP4-4,6 derivative is an octasodium salt. In some samples, y or y' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some samples, y is 3, y' is 0, the alkyl group is CH2, Cy is a 1,4-substituted phenyl group, and Z is -Me (compound 42). In some states, y is 3, y' is 0, the alkyl group is CH 2, Cy is a 1,4-substituted phenyl group, and Z is -OMe (compound 43). In some states, y is 3, y' is 0, the alkyl group is CH 2, Cy is a 1,3-substituted phenyl group, and Z is -CF 3 (compound 44).

[0100] In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds of the following formula: Where y and y' are integers between 0 and 10, the alkyl group is CH2, the A series is selected from the group consisting of -NHCO and -NHCONH, and the Z series is selected from the group consisting of -COOH, phenyl, cyclopentyl, and thiophene. In some states, the IP4-4,6 derivative is a sodium salt. In some states, the IP4-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, octasodium, nonasodium, or decasodium salt. In some states, the IP4-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, or octasodium salt. In some states, the IP4-4,6 derivative is a hexasodium, octasodium, nonasodium, or decasodium salt. In some states, the IP4-4,6 derivative is an octasodium or decasodium salt. In some states, y or y' is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some samples, y is 3, y' is 3, the alkyl group is CH2, A is -NHCO, and Z is -COOH (Compound 45). In some samples, y is 3, y' is 0, the alkyl group is CH2, A is -NHCONH, and Z is phenyl (Compound 46). In some samples, y is 3, y' is 0, the alkyl group is CH2, A is -NHCONH, and Z is cyclopentyl (Compound 47). In some samples, y is 5, y' is 0, the alkyl group is CH2, A is -NHCO, and Z is phenyl (Compound 48). In some samples, y is 5, y' is 0, the alkyl group is CH2, A is -NHCO, and Z is thiophene (Compound 49).

[0101] In some embodiments, the substituted derivatives of IP4-4,6 of the present invention comprise or consist of compounds of the following formula: Where n is an integer between 1 and 20, the alkyl group is CH2, and the X series is selected from the group consisting of -H and -OMe. In some samples, 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 samples, the IP4-4,6 derivative is a sodium salt. In some samples, the IP4-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP4-4,6 derivative is a tetrasodium, pentasodium, hexasodium, heptasodium, or octasodium salt. In some samples, the IP4-4,6 derivative is a hexasodium, octasodium, nonasodium, or decasodium salt. In some samples, the IP4-4,6 derivative is an octasodium salt. In some samples, n is 5, the alkyl group is CH2, and X is -H (compound 50). In some samples, n is 5, the alkyl group is CH2, and X is -OMe (compound 51).

[0102] The IP4-4,6 derivatives of this invention are disclosed in the form of inositol. However, this invention is also intended to cover all other isomers of the inositol architecture, such as squalinositol, mucosal inositol, 1D-palmophysitol, 1L-palmophysitol, neo-inositol, isoisitol, epi-inositol, and cis-inositol counterparts of the IP4-4,6 derivatives of this invention.

[0103] This invention also provides chemical intermediates suitable for preparing the IP4-4,6 substituted derivatives of this invention (e.g., compounds 1 to 53). In some cases, such intermediates are compounds listed in Table 1. The intermediates disclosed herein can be converted into the IP4-4,6 substituted derivatives of this invention by using the procedures described herein. Therefore, this invention provides a method for preparing the IP4-4,6 substituted derivatives of this invention (e.g., compounds selected from the group consisting of compounds 1 to 53), comprising using an intermediate compound selected from the group consisting of compounds listed in Table 1. This invention also provides a method for preparing the intermediates disclosed herein. Therefore, this invention provides a method for preparing intermediate compounds selected from the group consisting of compounds listed in Table 1 for the production of the IP4-4,6 substituted derivatives of this invention (e.g., compounds selected from the group consisting of compounds 1 to 53). [, surface , ] [, 1 , ] [, , ] [, intermediate , ] [, , ] Mode intermediate II-1 4,6-O-bis(5-(benzooxy)pentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methiminositol II-2 4,6-O-bis(10-(benzooxy)decyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methiminositol II-3 4,6-O-bis(14-(benzooxy)tetradecyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methiminositol II-4 2-O-Tributyldimethylsilyl-4,6-O-bis(3-methoxypropyl)-1,3,5-O-methimoxyinositol II-5 2-O-Tributyldimethylsilyl-4,6-O-bis(5-methoxypentyl)-1,3,5-O-methimoxyinositol II-6 2-O-Tributyldimethylsilyl-4,6-O-bis(9-methoxynonyl)-1,3,5-O-methimoxyinositol II-7 2-O-Tributyldimethylsilyl-4,6-O-bis(7-methoxyheptyl)-1,3,5-O-methimoxyinositol II-8 2-O-Tributyldimethylsilyl-1,3,5-O-methimide-4,6-O-dipropyl-inositol II-9 2-O-Tributyldimethylsilyl-1,3,5-O-methimide-4,6-O-dipentyl-inositol II-10 2-O-Tributyldimethylsilyl-4,6-O-diheptyl-1,3,5-O-methiminositol II-11 2-O-Tributyldimethylsilyl-4,6-O-decyl-1,3,5-O-methiminositol II-12 2-O-Tributyldimethylsilyl-1,3,5-O-methimide-4,6-O-di(tetradecyl)-inositol II-13 2-O-Tributyldimethylsilyl-4,6-O-bis(5-ethoxycarbonylpentyl)-1,3,5-O-methimoxyinositol II-14 2-O-Tributyldimethylsilyl-4,6-O-bis(10-ethoxycarbonyldecyl)-1,3,5-O-methimyl-inositol II-15 2-O-Tributyldimethylsilyl-1,3,5-O-methimide-4,6-O-bis(5-(1H-pyrazol-1-yl)pentyl)-inositol II-16 2-O-Tributyldimethylsilyl-1,3,5-O-methimide-4,6-O-bis(5-(1H-1,2,4-triazol-1-yl)pentyl)-inositol II-17 4,6-O-bis(2-(4-acetylopyr-1-yl)ethyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methiminositol II-18 2-O-Tributyldimethylsilyl-1,3,5-O-methimide-4,6-O-bis(4,4,4-trifluorobutyl)-inositol II-19 2-O-Tributyldimethylsilyl-1,3,5-O-methimide-4,6-O-bis(6,6,6-trifluorohexyl)-inositol II-20 2-O-Tributyldimethylsilyl-1,3,5-O-methimide-4,6-O-bis(4-methylpentyl)-inositol II-21 2-O-Tributyldimethylsilyl-4,6-O-bis(19-methoxy-nonadenylon-10-yn-1-yl)-1,3,5-O-methimyl-inositol II-22 2-O-Tributyldimethylsilyl-4,6-O-bis(2-cyclopropylethyl)-1,3,5-O-methiminositol II-23 2-O-Tributyldimethylsilyl-4,6-O-bis(2-cyclopentylethyl)-1,3,5-O-methiminositol II-24 2-O-Tributyldimethylsilyl-4,6-O-bis(3-(4-methoxyphenyl)propyl)-1,3,5-O-methimoxy-inositol II-25 2-O-Tributyldimethylsilyl-1,3,5-O-methimide-4,6-O-bis(3-(3-(trifluoromethyl)phenyl)propyl)-inositol II-26 2-O-Tributyldimethylsilyl-1,3,5-O-methimide-4,6-O-bis(3-(p-tolyl)propyl)-inositol II-27 2-O-Tributyldimethylsilyl-4,6-O-bis(3-methoxycarbonylpropenyl)-1,3,5-O-methimide-inositol III-1 4,6-O-bis(5-(benzooxy)pentyl)-inositol III-2 4,6-O-bis(5-methoxypentyl)-inositol III-3 4,6-O-bis(10-(benzooxy)decyl)-inositol III-4 4,6-O-bis(14-(benzooxy)tetradecyl)-inositol III-5 4,6-O-bis(5-ethoxycarbonylpentyl)-inositol III-6 4,6-O-bis(10-ethoxycarbonyldecyl)-inositol III-7 4,6-O-bis(2-cyclopropylethyl)-inositol III-8 4,6-O-bis(2-cyclopentylethyl)-inositol III-9 4,6-O-bis(5-(1H-pyrazol-1-yl)pentyl)-inositol III-10 4,6-O-bis(5-(1H-1,2,4-triazol-1-yl)pentyl)-inositol III-11 4,6-O-bis(2-(4-acetylopano-1-yl)ethyl)-inositol III-12 4,6-O-bis(3-methoxypropyl)-inositol III-13 4,6-O-bis(7-methoxyheptyl)-inositol III-14 4,6-O-bis(9-methoxynonyl)-inositol III-15 4,6-O-dipropyl-inositol III-16 4,6-O-dipentyl-inositol III-17 4,6-O-diheptyl-inositol III-18 4,6-O-didecyl-inositol III-19 4,6-O-Di(tetradecyl)-inositol III-20 4,6-O-bis((1-(2-(benzyloxycarbonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-inositol III-21 4,6-O-bis(3-(4-(2-(benzyloxycarbonyl)ethyl)-1H-1,2,3-triazol-1-yl)propyl)-inositol III-22 4,6-O-bis(3-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)propyl)-inositol III-23 4,6-O-bis(4-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)butyl)-inositol III-24 4,6-O-bis(5-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-inositol III-25 4,6-O-bis(6-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)hexyl)-inositol III-26 4,6-O-bis(1-(3-(methoxypropyl)-1H-1,2,3-triazol-4-yl)methyl)-inositol III-27 4,6-O-bis((1-(6-methoxyhexyl)-1H-1,2,3-triazol-4-yl)methyl)-inositol III-28 4,6-O-bis((3-(4-ethyloxycarbonylbutyramine)propyl))-inositol III-29 4,6-O-bis(3-(4-methoxyphenyl)propyl)-inositol III-30 4,6-O-bis(3-(3-(trifluoromethyl)phenyl)propyl)-inositol III-31 4,6-O-bis(3-(p-Tolyl)propyl)-inositol III-32 4,6-O-bis(4,4,4-trifluorobutyl)-inositol III-33 4,6-O-bis(6,6,6-trifluorohexyl)-inositol III-34 4,6-O-bis(4-methylpentyl)-inositol III-35 4,6-O-bis(19-methoxy-19-naphthyl-1-yl)-inositol III-36 4,6-O-bis(3-(3-phenylureo)propyl)-inositol III-37 4,6-O-bis(3-(3-cyclopentylureido)propyl)-inositol III-38 4,6-O-bis(3-((methoxycarbonyl)amino)propyl)-inositol III-39 4,6-O-bis(5-acetaminophenopentyl)-inositol III-40 4,6-O-bis(5-benzoylaminopentyl)-inositol III-41 4,6-O-bis(5-(thiophene-2-methamido)pentyl)-inositol III-42 4,6-O-(6-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)hexyl)-inositol III-43 4-O-(6-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)hexyl)-6-O-(6-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)hexyl)-inositol III-44 4,6-O-bis(4-amino-4-sideoxybutyl)-inositol III-45 4,6-O-bis(5-(3-propylureo)pentyl)-inositol III-46 4,6-O-bis(5-((methoxycarbonyl)amino)pentyl)-inositol III-47 4,6-O-bis(3-methoxycarbonylpropyl)-inositol IV-1 4,6-O-bis(10-(benzyloxy)decyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-2 4,6-O-bis(14-(benzyloxy)tetradecyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-3 4,6-O-bis(3-methoxypropyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-4 4,6-O-bis(5-methoxypentyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-5 4,6-O-bis(7-methoxyheptyl)-1,2,3,5-O-tetra(3-oxo-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-6 4,6-O-bis(7-methoxynonyl)-1,2,3,5-O-tetra(3-oxo-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-7 1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-heptane-3-yl)-4,6-O-dipropyl-inositol IV-8 1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-heptane-3-yl)-4,6-O-dipentyl-inositol IV-9 4,6-O-diheptyl-1,2,3,5-O-tetra(3-oxo-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-10 4,6-O-decyl-1,2,3,5-O-tetra(3-oxo-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-11 1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazenecycloheptane-3-yl)-4,6-O-di(tetradecyl)-inositol IV-12 4,6-O-bis(5-ethoxycarbonylpentyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-13 4,6-O-bis(10-ethoxycarbonyldecyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-14 1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazine-heptane-3-yl)-4,6-O-bis(5-(1H-pyrazol-1-yl)pentyl)-inositol IV-15 1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazine-heptane-3-yl)-4,6-O-bis(5-(1H-1,2,4-triazol-1-yl)pentyl)-inositol IV-16 4,6-O-bis((1-(2-(benzyloxycarbonyl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazenecycloheptane-3-yl)-inositol IV-17 4,6-O-bis((1-(3-methoxypropyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazine-3-yl)-inositol IV-18 4,6-O-bis((1-(6-methoxyhexyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazanheptan-3-yl)-inositol IV-19 4,6-O-bis(3-(4-(2-(benzyloxycarbonyl)ethyl)-1H-1,2,3-triazol-1-yl)propyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazenecycloheptane-3-yl)-inositol IV-20 4,6-O-bis(3-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)propyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazine-3-yl)-inositol IV-21 4,6-O-bis(4-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)butyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazine-3-yl)-inositol IV-22 4,6-O-bis(5-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)pentyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazenecycloheptane-3-yl)-inositol IV-23 4,6-O-bis(6-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)hexyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazenecycloheptane-3-yl)-inositol IV-24 4,6-O-bis(2-(4-acetylopyr-1-yl)ethyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazine-3-yl)-inositol IV-25 4,6-O-bis((3-(4-ethyloxycarbonylbutyramine)propyl))-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazane-3-yl)-inositol IV-26 4,6-O-bis(5-(benzyloxy)pentyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-27 4,6-O-bis(2-cyclopropylethyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphatane-3-yl)-inositol IV-28 4,6-O-bis(2-cyclopentylethyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphatane-3-yl)-inositol IV-29 4,6-O-bis(3-(4-methoxyphenyl)propyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-30 1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazenecycloheptane-3-yl)-4,6-O-bis(3-(3-(trifluoromethyl)phenyl)propyl)-inositol IV-31 1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazine-heptane-3-yl)-4,6-O-bis(3-(p-tolyl)propyl)-inositol IV-32 1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazine-heptane-3-yl)-4,6-O-bis(4,4,4-trifluorobutyl)-inositol IV-33 1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazine-heptane-3-yl)-4,6-O-bis(6,6,6-trifluorohexyl)-inositol IV-34 4,6-O-bis(4-methylpentyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-35 4,6-O-bis(19-methoxy-19-naphthyl-1-yl)-1,2,3,5-O-tetra(3-oxo-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazenecycloheptane-3-yl)-inositol IV-36 1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazine-heptane-3-yl)-4,6-O-bis(3-(3-phenylureo)propyl)-inositol IV-37 4,6-O-bis(3-(3-cyclopentylureido)propyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazonyl-3-yl)-inositol IV-38 4,6-O-bis(3-((methoxycarbonyl)amino)propyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-39 4,6-O-bis(5-acetaminopentyl)-1,2,3,5-O-tetra(3-oxo-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-40 4,6-O-bis(5-benzylaminopentyl)-1,2,3,5-O-tetra(3-oxo-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-41 1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazenecycloheptane-3-yl)-4,6-O-bis(5-(thiophene-2-methamido)pentyl)-inositol IV-42 4,6-O-(6-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)hexyl)-1,2,3,5-O-tetra(3-oxo-ion-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-43 4-O-(6-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)hexyl)-6-O-(6-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)hexyl)-1,2,3,5-O-tetra(3-oxo-ion-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-44 4,6-O-bis(4-amino-4-sideoxybutyl)-1,2,3,5-O-tetra(3-oxo-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-45 1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazine-heptane-3-yl)-4,6-O-bis(5-(3-propylureo)pentyl)-inositol IV-46 4,6-O-bis(5-((methoxycarbonyl)amino)pentyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-47 4,6-O-bis(3-methoxycarbonylpropyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV-48 4,6-O-dipropynyl-1,2,3,5-O-tetra(3-oxo-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV'-1 4,6-O-dipentyl-1,2,3,5-O-tetra(3-thio-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol IV'-2 4,6-O-bis(5-methoxypentyl)-1,2,3,5-O-tetra(3-thio-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol V-1 2-O-Tributyldimethylsilyl-1,3,5-O-methimide-4,6-O-dipropynyl-inositol VI-1 4,6-O-dipropynyl-inositol VII-1 4,6-O-bis((1-(3-(toluenesulfonoxy)propyl)-1H-1,2,3-triazol-4-yl)methyl)-inositol VII-2 4,6-O-bis((1-(6-(toluenesulfonoxy)hexyl)-1H-1,2,3-triazol-4-yl)methyl)-inositol VIII-1 4,6-O-bis(3-azidopropyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methiminositol VIII-2 4,6-O-bis(5-azidopentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methiminositol VIII-3 4,6-O-bis(10-azidodecyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methiminositol VIII-4 4,6-O-bis(4-azidobutyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methiminositol VIII-5 4,6-O-bis(6-azidohexyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methiminositol IX-1 4,6-O-bis(4-azidobutyl)-inositol IX-2 4,6-O-bis(6-azidohexyl)-inositol IX-3 4,6-O-bis(3-azidopropyl)-inositol IX-4 4,6-O-bis(5-azidopentyl)-inositol IX-5 4,6-O-bis(10-azidodecyl)-inositol X-1 4,6-O-bis(3-azidopropyl)-1,2,3,5-O-tetra(3-oxo-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol X-2 4,6-O-bis(5-azidopentyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol X-3 4,6-O-bis(10-azidodecyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazene-3-yl)-inositol XI-1 4,6-O-bis(3-aminopropyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methiminositol XI-2 4,6-O-bis(5-aminopentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methiminositol XII-1 4,6-O-bis(3-aminopropyl)-inositol·2TFA XII-2 4,6-O-bis(5-aminopentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methiminositol XIII-1 4,6-O-bis(5-acetaminopentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methiminositol XIII-2 4,6-O-bis(5-benzoylaminopentyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methiminositol XIII-3 2-O-Tributyldimethylsilyl-4,6-O-bis(5-((methoxycarbonyl)amino)pentyl)-1,3,5-O-methimide-inositol

[0104] The IP4-4,6-substituted derivatives of the present invention and the intermediates used to synthesize them can be synthesized using the methods described herein and other methods known in the field of organic chemistry. In some embodiments, these methods include (but are not limited to) the general procedures shown in synthetic procedures 1, 2, 3, and 4 described herein. Therefore, in some embodiments, the present invention provides a method for manufacturing the IP4-4,6-substituted derivatives of the present invention, comprising applying synthetic procedure 1 disclosed below. In some embodiments, the present invention provides a method for manufacturing the IP4-4,6-substituted derivatives of the present invention, comprising applying synthetic procedure 2 disclosed below. In some embodiments, the present invention provides a method for manufacturing the IP4-4,6-substituted derivatives of the present invention, comprising applying synthetic procedure 3 disclosed below. In some embodiments, the present invention provides a method for manufacturing the IP4-4,6-substituted derivatives of the present invention, comprising applying synthetic procedure 4 disclosed below.

[0105] In some embodiments, the present invention provides a method for manufacturing intermediates for synthesizing the IP4-4,6 substituted derivatives of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53), comprising applying the synthetic process 1 disclosed below. In some embodiments, the present invention provides a method for manufacturing intermediates for synthesizing the IP4-4,6 substituted derivatives of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53), comprising applying the synthetic process 2 disclosed below. In some embodiments, the present invention provides a method for manufacturing intermediates for synthesizing the IP4-4,6 substituted derivatives of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53), comprising applying the synthetic process 3 disclosed below. In some embodiments, the present invention provides a method for manufacturing intermediates for synthesizing the IP4-4,6 substituted derivatives of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53), comprising applying the synthetic process 4 disclosed below.

[0106] [process] [1]: The IP4-4,6 substituted derivatives of the present invention can be obtained by, for example, descaling... [IV] Intermediates (e.g., intermediates IV-1 to IV-48) and formula [IV] ['] It is obtained by protecting the intermediate (e.g., intermediates IV'-1 to IV'-2). See process 1, [picture] [6]. In each case, the "protecting group" or PG may be (but is not limited to) benzyl, benzyl acetopropionate, tributyl, o-xylyl (e.g., by combining two PGs into the same phosphate ester), 9-pyroxymethyl, cyanoethyl, and other suitable protecting groups. [IV] Intermediates (e.g., intermediates IV-1 to IV-48) can be made, for example, by means of a procedure described in the literature. [III] Phosphorylation of intermediates, for example by reaction with an aminophosphite derivative followed by oxidation with an oxidizing agent (e.g., m-CPBA, H₂O₂, tBuOOH). [IV] ['] Intermediates (e.g., intermediates IV'-1 to IV'-2) can be made, for example, by means of the procedure described in this art. [III] This is achieved through intermediate thiophosphorylation, for example by reacting with an aminophosphite derivative followed by thiooxidation with sulfur. Meanwhile, formula... [III] Intermediates (e.g., intermediates III-1 to III-47) can be, for example, by reacting them in an acidic medium. [II] Obtained by hydrolysis of intermediates (e.g., intermediates II-1 to II-27). Finally, [II] Intermediates (e.g., intermediates II-1 to II-27) can be, for example, alkylated by an alkylating agent. [(] [2] [)] is obtained by alkylation. This has been previously described in the literature. [(] [2] Preparation of [] (Martin S et al., J. Org. Chem. 1994; 59: 4805; Kardivel M, Org. & Biomolecular Chem. 2008; 6(11):1966-72). The "leaving group" or LG can be (but is not limited to) chloride, bromide, iodide, toluenesulfonyl (Ts) or methanesulfonyl (Ms).

[0107] [process] [2]: As an alternative to process 1, for example when R5 and R9 contain substituted 1,2,3-triazole, formula [I] The compound (i.e., the IP4-4,6 substituted derivative of the present invention) can be obtained by following process 2. [(] [picture] [7] The alternative methods described in [)] are used to obtain it. In this way, the formula [III] Intermediates (e.g., intermediates III-20, III-26, and III-27) can, for example, be activated via a click response, by using a formula [VI] Obtained using an intermediate (e.g., intermediate VI-1) and an alkyl reagent as starting materials. [VI] [](For example, intermediate VI-1) can be achieved by alkylating and hydrolyzing intermediate 2 with appropriate reagents.

[0108] [process] [3]: As an alternative to processes 1 and 2, for example when R5 and R9 contain substituted 1,2,3-triazole, formula [I] The compound (i.e., the IP4-4,6 substituted derivative of the present invention) can be obtained by following process 3. [(] [picture] [8] The alternative approach described in [)] is used to obtain it. In this case, formula [III] Intermediates (e.g., intermediates III-21 to III-25, III-42 and III-43) can be, for example, via a click-through response, by using a formula [IX] Intermediates (e.g., intermediates IX-1 to IX-5) and alkynyl click reagents were used as starting materials. [IX] This can be achieved by alkylating and hydrolyzing compound 2 using an azide alkylating agent. As an alternative to process 1, when R5 and R9 contain amine groups, the compound of formula I (i.e., the substituted derivatives of IP4-4,6 of this invention) can be produced as in process 3. [(] [picture] [8] The intermediate IX is obtained as shown in [ ] . Therefore, intermediate IX (e.g., intermediates IX-1 to IX-5) can be phosphorylated to obtain intermediate IX. [X] (e.g., intermediates X-1 to X3), and subsequently intermediates [X] can be deprotected to obtain the formula [I] Compound.

[0109] [process] [4]: As an alternative to process 1, when R5 and R9 contain substituted amides, sulfonamides, carbamates or ureas, the intermediate... [III] (e.g., intermediates III-28, III-36 to III-41, and III-44 to III-46) can be as follows [picture] The intermediate is obtained as shown in [9]. [III] (For example, intermediates III-28, III-36 to III-41 and III-44 to III-46) can be derived from intermediates [VIII] [] (e.g., VIII-1 to VIII-5) are reduced by azide (e.g., intermediates XI-1 to XI-2), followed by removal of the protecting group (e.g., intermediate XII-1) and finally by intermediate [XII] The reaction of [ ] (e.g., intermediate XII-1) with a suitable reagent to form amide / sulfonamide / urea or carbamate is achieved. Alternatively, the reaction order can be changed, starting with the intermediate. [XIII] (e.g., intermediates XIII-1 to XIII-3) yields amides / sulfonamides / ureas or carbamates, and subsequently, by hydrolysis, yields intermediates. [III].

[0110] Any alkylating agent or clicker (including azides or alkynyl groups) and reagents for the formation of amides, sulfonamides, ureas, or carbamates are commercially available or can be obtained using reactions well known in the field of organic chemistry. In some cases, the method includes (but is not limited to) process 5. [(] [picture]

[10] The general procedure shown in [)].

[0111] Representative IP4-4,6 substituted derivatives of this invention (e.g., compounds selected from the group consisting of compounds 1 to 53) are presented herein, and all of them are inositol configurations. However, it should be understood that any exemplary IP4-4,6 substituted derivatives of this invention in an inositol configuration are not limited to the representative configurations shown. Thus, by way of example, compounds 1 to 53 and the intermediates presented herein will also encompass corresponding equivalents in the configurations of squalinositol, mucosa inositol, 1D-palmophysitol, 1L-palmophysitol, neo-inositol, isoisitol, epi-inositol, and cis-inositol. The most stable configuration of the inositol isomers is the chair configuration, which shifts the largest number of hydroxyl groups to the equatorial position, where they are furthest apart from each other. In this configuration, the natural inositol isomer has a structure in which five of the six hydroxyl groups (first, third, fourth, fifth, and sixth) are in the equatorial position, while the second hydroxyl group is axial.

[0112] The present invention also provides a method for manufacturing a medicament for treating pathological crystals, comprising using an intermediate compound selected from the group of compounds listed in Table 1. Compounds of Formula I suitable as medicaments (e.g., selected from the group of compounds 1 to 53) are also provided. The use of compounds of Formula I (e.g., selected from the group of compounds 1 to 53) in the manufacture of medicaments for the prevention or treatment of diseases associated with pathological crystals is also provided. [, III. , ] [, Pharmaceutical Composition , ] [, , ]

[0113] The present invention also provides pharmaceutical compositions for methods of preventing and / or treating the diseases and conditions disclosed herein (e.g., pathological calcification), wherein the pharmaceutical composition comprises at least one IP4-4,6-substituted derivative of the present invention (e.g., a compound selected from the group consisting of compounds 1 to 53). In some embodiments, the pharmaceutical composition comprises, alone or in combination with one or more pharmaceutically acceptable excipients or carriers, an IP4-4,6-substituted derivative of the present invention (e.g., a compound selected from the group consisting of compounds 1 to 53).

[0114] As used herein, the term "excipient" refers to a substance that facilitates the absorption of a pharmaceutical composition component, stabilizes or activates such components, or contributes to the preparation of the composition. Therefore, examples of excipients used in non-enteric formulations include (but are not limited to) antimicrobial agents (e.g., benzalkonium chloride, m-cresol, thimerosal), cosolvents (e.g., ethanol), buffers, tensioning agents (e.g., NaCl), and pH adjusting factors (e.g., carbonate, citrate, phosphate solutions).

[0115] Similar to excipients, a "pharmaceutically acceptable mediator" is a substance in a composition used to dilute any of its components to a predetermined volume or weight (e.g., 0.9% (w / v) aqueous NaCl solution). A pharmaceutically acceptable mediator is an inert substance or a substance having a similar effect to any component of a pharmaceutical composition comprising the present invention. The mediator functions to allow for the incorporation of other components, to allow for better administration and dosing, or to provide consistency and form to the composition.

[0116] The pharmaceutical composition may contain about 1% to about 95% of the active ingredient. In some embodiments, for example, the pharmaceutical composition of the present invention may contain about 20% to about 90% of the active ingredient (i.e., the IP4-4,6 substituted derivative of the present invention alone or in combination with one or more other therapeutic agents).

[0117] Formulas suitable for non-enteric administration of pharmaceutical compositions contain an active ingredient, such as the IP4-4,6-substituted derivatives of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53), in combination with a pharmaceutically acceptable carrier (such as sterile water or sterile isotropic saline (e.g., 0.9% (w / v) NaCl aqueous solution)). Such formulas can be prepared, packaged, or sold in forms suitable for bolus or continuous administration. Injectable formulas can be prepared, packaged, or sold in unit dosage forms, such as in ampoules or in multi-dose containers containing preservatives. Formulas for non-enteric administration include (but are not limited to) suspensions, solutions, emulsions in oily or aqueous media, pastes, and implantable sustained-release or biodegradable formulas. Such formulas may further contain one or more additional ingredients, including (but not limited to) suspending agents, stabilizers, or dispersants.

[0118] In some formulations intended for non-enteral administration, the active ingredient (e.g., the IP4-4,6 substituted derivatives of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53)) is provided in a dry (i.e., powder or granule) form for reconstitution with a suitable medium (e.g., sterile, pyrogen-free water), followed by non-enteral administration of the reconstituted composition.

[0119] Pharmaceutical compositions can be prepared, packaged, or sold as sterile, injectable aqueous or oily suspensions or solutions. These suspensions or solutions can be formulated according to known techniques and may contain additional ingredients, such as dispersants, wetting agents, or suspending agents as described herein, in addition to the active ingredient (e.g., inositol phosphophosphate of this invention). Such sterile injectable formulations can be prepared using non-enteric-acceptable, non-toxic diluents or solvents (such as water or 1,3-butanediol). Other acceptable diluents and solvents include (but are not limited to) Ringer's solution, isotonic sodium chloride solution, and non-volatile oils, such as synthetic monoglycerides or diglycerides.

[0120] Other suitable dosable and reconstituteable formulations include those comprising active ingredients in microcrystalline form, liposome formulations, or as components of biodegradable polymer systems. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials, such as emulsions, ion exchange resins, slightly soluble polymers, or slightly soluble salts. Compositions and methods for preparing formulations of the IP4-4,6 substituted derivatives of the present invention (including controlled- or sustained-release formulations containing such active agents) are described in this 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, WO2003035 040, WO2003035029, WO2003035177, WO2003035039, WO2002096404, WO2002032416, WO2001097783, WO2001056544, WO2001032217, WO1998055107, WO1998011879, WO1997047285, WO1993018755 and WO1990011757.

[0121] The pharmaceutical preparations according to the present invention are manufactured by methods known in this art, particularly by conventional mixing, coating, granulation, dissolving or freeze-drying.

[0122] The present invention also provides compounds or combinations of compounds or pharmaceutical formulations that conform to any of the above embodiments according to the invention, conform to the broadest definition given, or as specified in any of the above embodiments, for use as pharmaceutical preparations.

[0123] The present invention also provides compounds or combinations of compounds or pharmaceutical formulations according to any one or more embodiments of the invention, conforming to the broadest definition given, or as specified in any of the foregoing embodiments, for the treatment and / or prevention of the diseases or conditions disclosed herein.

[0124] The present invention also provides compounds or combinations of compounds or pharmaceutical formulations according to any one or more embodiments of the invention, conforming to the broadest definition given, or as specified in any of the above embodiments, for use in the manufacture of medicaments for the prevention and / or treatment of the diseases or conditions disclosed herein. [, IV. , ] [, , ] [, Products and sets , ] [, , ]

[0125] The present invention also provides articles and kits. Such articles and kits may comprise containers (e.g., boxes) containing one or more vials containing a formulation comprising one or more of the substituted derivatives of IP4-4,6 of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53) and / or a solvent used for its medical administration or other purposes according to the methods disclosed herein.

[0126] The kits or articles provided according to the present invention may also include a manual or instruction manual describing the medical administration methods and dosages disclosed herein, or the use of the IP4-4,6 substituted derivatives of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53) according to the methods disclosed herein. In some embodiments, the kits or articles may include multiple vials, each containing a single dose. In other embodiments, the kits or articles may include one or more vials, each containing more than one dose.

[0127] In some formulations, the article is a bag containing a solution of the substituted derivatives of IP4-4,6 of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53). In other formulations, the article is a bottle (e.g., a glass or plastic bottle) containing a solution of the substituted derivatives of IP4-4,6 of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53). In some formulations, the article is a bag containing the substituted derivatives of IP4-4,6 of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53) in powder form, which is used for reconstitution in a suitable solvent. In some formulations, the article is a bottle (e.g., a glass or plastic bottle) containing the substituted derivatives of IP4-4,6 of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53) in powder form, which is used for reconstitution in a suitable solvent.

[0128] The kit and articles thereof may include, according to the instructions, administration of IP4-4,6 of the present invention, substituted derivatives (e.g., compounds selected from the group consisting of compounds 1 to 53) one or more times according to the methods and dosages disclosed herein.

[0129] Instructions included in kits and articles may be attached to packaging materials or included as pharmaceutical instructions. While instructions are typically written or printed materials, they are not limited to these. This encompasses any media capable of storing such instructions and communicating them to the end user. Such media include (but are not limited to) electronic storage media (e.g., magnetic disks, magnetic tapes, cassettes, chips), optical media (e.g., CD-ROMs), and similar media. As used herein, the term "instructions" may include the address of the internet site providing the instructions. [, V. , ] [, Mode , ] [, I , ] [, Of , ] [, IP4 , ] [, - , ] [, 4 , ] [, , , ] [, 6 , ] [, Uses of substituted derivatives , ] [, , ]

[0130] This invention provides methods for treating diseases and conditions using the IP4-4,6 substituted derivatives of this invention (e.g., compounds selected from the group consisting of compounds 1 to 53). In some embodiments, the medical use disclosed herein refers to the ability of the IP4-4,6 substituted derivatives of this invention (e.g., compounds selected from the group consisting of compounds 1 to 53) to (i) inhibit the formation or growth of calcium salts / crystals (e.g., calcium phosphate, HAP) and / or (ii) restore or increase blood perfusion in an individual in need, comprising administering to that individual an effective amount of a compound of formula I disclosed herein or a pharmaceutical composition. Therefore, the IP4-4,6 substituted derivatives of this invention (e.g., compounds selected from the group consisting of compounds 1 to 53) can be used to treat and prevent diseases and conditions associated with pathological crystallization. See also [picture] [1].

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

[0132] The present invention also provides a method for manufacturing a pharmaceutical agent for treating pathological crystals, comprising using an intermediate compound selected from the group consisting of compounds listed in Table 1. A compound selected from the group consisting of compounds 1 to 53 is also provided for treating pathological crystals and / or their effects on an individual in need.

[0133] In some embodiments, the substituted derivatives of IP4-4,6 of the present invention (e.g., compounds selected from the group consisting of compounds 1 to 53) may be administered locally, enterically or non-enterically. [, A. , ] [, Synthetic protected inositol agents, alkylating agents or clickers, and activated acids , ] [, , ] [, A.1. , ] [, Synthetic protected inositol agents , ] [,( , ] [, 1 , ] [, ) , ] [, and , ] [, ( , ] [, 2 , ] [, ) , ]

[0134] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [1] [)]: [(] [1] The synthesis of [)] has been previously described in the literature (Martin S et al., J. Org. Chem. 1994; 59(17):4805-4820).

[0135] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [2] [)]: [(] [2] The synthesis of [)] has been previously described in the literature (Kadirvel M et al., Org. Biomol. Chem. 2008; 6 (11):1966-1972). [, A.2. , ] [, Synthesis of alkylating agents or clickers , ] [, , ]

[0136] [((()]

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

[0137] [((()]

[14] [-] [Bromide Tetradecyl] [)] [Oxygen group] [)] [methyl] [)] [benzene] [(] [5] [)] [:] [(] [5] The synthesis of [)] has been previously described in the literature (Hitosugi S et al., Organic Letters 2014; 16(3):844-847).

[0138] [1] [-] [bromine] [-] [7] [-] [Methoxy] [Heptane] [(] [6] [)] A mixture of 1,7-dibromoheptane (3.27 mL, 19.38 mmol) and 5N sodium methoxide (3.88 mL, 19.38 mmol) was stirred at 40 °C for 4 hours. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by rapid chromatography (silicone, hexane:ethyl acetate 10:1) to give 1.4 g. [(] [6] [)](34.5%). 1H NMR (400 MHz, chloroform-d) δ 3.40 (t, J= 6.9 Hz, 2H), 3.36 (t, J= 6.6 Hz, 2H), 3.33 (s, 3H), 1.89-1.82 (m, 2H), 1.60-1.53 ​​(m, 2H), 1.47-1.40 (m, 2H), 1.39-1.32 (m, 4H).

[0139] [4] [-] [methyl] [Benzenesulfonic acid] [9] [-] [Methoxynonyl ester] [(] [7] [)]

[0140] Step 1: 9-Methoxynon-1-ol [(] [3] [)] A mixture of 9-bromonon-1-ol (0.5 g, 2.24 mmol) and 4 N sodium methoxide (25 mL, 100 mmol) was stirred at 40 °C for 18 hours. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by rapid chromatography (silicone, hexane:EtOAc 4:1) to give 324 mg. [(] [3] [)](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).

[0141] Step 2: 4-Methylbenzenesulfonic acid 9-methoxynonyl ester [(] [7] [)] [:]Towards [(] [3] [ ] (1.5 g, 8.61 mmol) was added to a solution of dichloromethane (DCM, 28.7 mL) with triethylamine (TEA) (1.80 mL, 12.91 mmol) and toluenesulfonic acid chloride (Ts-Cl, 2.13 g, 11.19 mmol). The reaction mixture was stirred at room temperature for 24 hours, then quenched with water and washed with brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (silicone, hexane:EtOAc 4:1) to give 2.15 g. [(] [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).

[0142] [4] [-] [Methylbenzenesulfonic acid] [3] [-] [Azide Propyl] [(] [8] [)] At 0 °C, TEA (2.07 mL, 14.84 mmol) and Ts-Cl (2.26 g, 11.87 mmol) were added to a solution of 3-azidopropane-1-ol (1 g, 9.89 mmol) in DCM (0.2 M). The reaction mixture was stirred at room temperature for 24 hours, then quenched with water and washed with brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (silicone, hexane:EtOAc 4:1) to give 1.27 g. [(] [8] [)](50%). 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).

[0143] [4] [-] [Methylbenzenesulfonic acid] [5] [-] [Azide-pentyl ester] [(]

[10] [)]

[0144] Step 1: 5-Azide-1-pentane-1-ol [(] [9] [)] A solution of 5-bromopentan-1-ol (0.10 mL, 0.89 mmol) and sodium azide (63 mg, 0.98 mmol) in dimethylformamide (DMF, 0.2 M) was stirred at 80 °C for 18 hours. The reaction mixture was then quenched with water / EtOAc and washed with brine (3 times). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum to give 57 mg. [(] [9] [)](50%). 1H NMR (400 MHz, chloroform-d) δ 3.63 (t, J= 6.8 Hz, 2H), 3.26 (t, J= 6.8 Hz, 2H), 1.61 (p, J= 7.2 Hz, 2H), 1.58 (p, J= 6.8 Hz, 2H), 1.52-1.36 (m, 2H).

[0145] Step 2: 5-Azide-pentyl 4-methylbenzenesulfonic acid [(]

[10] [)]: At 0℃, towards [(] [9] [ )] (54 mg, 0.42 mmol) was added to a solution of DCM (0.2 M) with TEA (87 µL, 0.63 mmol) and Ts-Cl (80 mg, 0.42 mmol). The reaction mixture was stirred at room temperature for 60 hours, followed by quenching with water / DCM and washing with brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum to give 92 mg [(]

[10] [)](78%). HPLC-MS (condition A): rt= 3.00 min; m / z: 284 [M+1]+.

[0146] [4] [-] [Methylbenzenesulfonic acid]

[10] [-] [azidodecyl] [ester] [(]

[12] [)]

[0147] Step 1: 10-Azide-1-Decanol [(]

[11] [)] A solution of 10-bromo-1-decyl alcohol (0.42 mL, 2.11 mmol) and sodium azide (151 mg, 2.32 mmol) in DMF (0.2 M) was stirred at 80 °C for 18 hours. The reaction mixture was then quenched with water / EtOAc and washed with brine (3 times). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum to give 388 mg. [(]

[11] [)](92%). 1H NMR (400 MHz, chloroform-d) δ 3.64 (t, J= 6.8 Hz, 2H), 3.25 (t, J= 6.8 Hz, 2H), 1.59 (p, J=6.8 Hz, 2H), 1.56 (p, J= 6.8 Hz, 2H), 1.44-1.19 (m, 12H).

[0148] Step 2: 10-Azide-decyl 4-methylbenzenesulfonic acid [(]

[12] [)]: At 0℃, towards [(]

[11] [ )] (388 mg, 1.95 mmol) was added to a solution of TEA (407 µL, 2.92 mmol) and Ts-Cl (371 mg, 1.95 mmol) in DCM (0.2 M). The reaction mixture was stirred at room temperature for 60 hours, then quenched with water / DCM and washed with brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (silicone, hexane:EtOAc 1:1) to give 234 mg [(]

[12] [)](34%). 1H NMR (400 MHz, chloroform-d) δ 7.79 (d, J= 8.1 Hz, 2H), 7.34 (d, J= 8.1 Hz, 2H), 4.02 (t, J= 6.4 Hz, 2H), 3.25 (t, J= 6.8 Hz, 2H), 2.45 (s, 3H), 1.63 (p, J= 6.4 Hz, 2H), 1.59 (p, = 6.8 Hz, 2H), 1.35- 1.15 (m, 12H).

[0149] [1] [-(] [5] [-] [Bromopentyl] [)-] [1, H , ] [-] [Pyrazole] [(]

[13] [)]: 1,5-Dibromopentane (1.56 mL, 11.49 mmol) was added to a mixture of 1 H-pyrazole (0.78 g, 11.49 mmol) and Cs₂CO₃ (3.74 mg, 11.49 mmol) in ACN (57 mL). The mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by rapid chromatography (silicone, hexane:EtOAc 1:1) to give 1.1 g. [(]

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

[0150] [1] [-(] [5] [-] [Bromopentyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [4] [-] [three] [azole] [(]

[14] [)]: 1,5-Dibromopentane (1.56 mL, 11.49 mmol) was added to a mixture of 1 H-1,2,4-triazole (0.79 g, 11.50 mmol) and Cs₂CO₃ (3.74 mg, 11.50 mmol) in ACN (57 mL). The mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by rapid chromatography (silicone, hexane:EtOAc (1:5)) to give 0.55 g [(]

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

[0151] [3] [-] [Benzyl azidopropionate] [(]

[15] [)] [:] A solution of 3-azidopropionic acid (1.62 mL, 17.38 mmol) in DMF (1 M) was added to (bromomethyl)benzene (4.1 mL, 34.8 mmol), followed by dropwise addition of TEA (7.3 mL, 52.1 mmol). After stirring at room temperature for 1 day, the mixture was concentrated, diluted with EtOAc, washed with Na₂CO₃ (1 time), water (3 times), and brine (1 time), dried over Na₂SO₄, and filtered. The solvent was removed under vacuum to give 2.90 g. [(]

[15] [)](81%). 1H NMR (400 MHz, chloroform-d) δ 7.46-7.29 (m, 5H), 5.17 (s, 2H), 3.60 (t, J= 6.5 Hz, 2H), 2.63 (t, J= 6.5 Hz, 2H).

[0152] [4] [-] [Methylbenzenesulfonic acid] [6] [-] [Azide Hexyl Ester] [(]

[17] [)]

[0153] Step 1: 6-Azide-1-Hexyl alcohol [(]

[16] [)]: A solution of 6-bromohexane-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 hours. Subsequently, the reaction mixture was quenched with water / EtOAc and washed with brine (3 times). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum to give 470 mg [(]

[16] [)](>99%). 1H NMR (400 MHz, chloroform-d) δ 3.65 (t, J= 6.8 Hz, 2H), 3.27 (t, J= 6.8 Hz, 2H), 1.70-1.56 (m, 4H), 1.40 (m, 4H).

[0154] Step 2: 6-Azide-hexyl 4-methylbenzenesulfonic acid [(]

[17] [)] [:] At 0°C, p-Ts-Cl (720 mg, 3.78 mmol) was added to... [(]

[16] [ )] (515 mg, 3.60 mmol) and TEA (1.5 mL, 10.79 mmol) were added to anhydrous DCM (0.6 M). The reaction mixture was stirred overnight at room temperature. It was diluted with EtOAc and washed with 10% NaHSO4 aqueous solution. The aqueous phase was extracted with EtOAc (3 times). The combined layers were washed with saturated NaHCO3 aqueous solution and dried over anhydrous Na2SO4. The solvent was removed under vacuum and the residue was purified by rapid chromatography (silicone:EtOAc 6:1) to give 666 mg [(]

[17] [)](62%). 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).

[0155] [4] [-] [Methylbenzenesulfonic acid] [4] [-] [Azide Butyl Ester] [(]

[19] [)]

[0156] Step 1: 4-Azidebut-1-ol [(]

[18] [)]: A solution of 4-bromobut-1-ol (298 µL, 3.27 mmol) and sodium azide (850 mg, 13.08 mmol) in DMF (0.8 M) was stirred at 80 °C for 18 hours. Subsequently, the reaction mixture was quenched with water / EtOAc and washed with brine (3 times). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum to give 213 mg [(]

[18] [)](56%). 1H NMR (400 MHz, chloroform-d) δ 3.69 (t, J= 5.9 Hz, 2H), 3.33 (t, J= 6.4 Hz, 2H), 1.76-1.59 (m, 4H).

[0157] Step 2: 4-Toluenesulfonic acid 4-azidobutyl ester [(]

[19] [)]: At 0℃, Ts-Cl (370 mg, 1.94 mmol) was added to [(]

[18] [ )] (213 mg, 1.85 mmol) and TEA (774 µL, 5.55 mmol) were added to anhydrous DCM (0.6 M). The reaction mixture was stirred overnight at room temperature. It was diluted with EtOAc and washed with 10% NaHCO3 aqueous solution. The aqueous phase was extracted with EtOAc (3 times). The combined layers were dried over anhydrous Na2SO4. The solvent was removed under vacuum and the residue was purified by rapid chromatography (silicone, hexane:EtOAc 6:1) to give 271 mg [(]

[19] [)](54%). 1H NMR (400 MHz, chloroform-d) δ 7.79 (d, J= 8 Hz, 2H), 7.36 (d, J= 8 Hz, 2H), 4.06 (td, J= 6.1, 0.8 Hz, 2H), 3.26 (t, J= 6.6 Hz, 2H), 2.46 (s, 3H), 1.81-1.68 (m, 2H), 1.68-1.60 (m, 2H).

[0158] [1] [-(] [4] [-(] [2] [-] [Chloroethyl] [)] [Pipeline] [𠯤] [-] [1] [-] [base] [)] [Ethylene ketone] [(]

[20] [)] At 0°C, TEA (2.1 mL, 15.15 mmol) and Ts-Cl (2.31 g, 12.12 mmol) were added to a solution of 1-(4-(2-hydroxyethyl)piperazine-1-yl)acetone (1.74 g, 10.10 mmol) in DCM (0.2 M). The reaction mixture was stirred at room temperature for 72 hours and concentrated under vacuum. The residue was purified by rapid chromatography (silicone, DCM:MeOH 95:5) to give 1.28 g. [(]

[20] [)](66%). HPLC-MS (condition A): rt= 0.24 min; m / z: 191, 193 [M, M+2] +. []

[0159] [4] [-] [Methylbenzenesulfonic acid] [2] [-] Cyclopropyl ethyl ester [(] [twenty one] [)] TEA (7.10 mL, 50.9 mmol) and Ts-Cl (7.77 g, 40.8 mmol) were added to a solution of 2-cyclopropylethanol (3 mL, 34.0 mmol) in DCM (85 mL), and the mixture was stirred for 18 hours. Water was added to the reaction mixture and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silicone column chromatography (hexane-EtOAc, 4:1) to yield 6.23 g (76%) of TEA. [(] [twenty one] [)] [. ] 1H 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).

[0160] [4] [-] [Methylbenzenesulfonic acid] [2] [-] Cyclopentyl ethyl ester [(] [twenty two] [)] TEA (1.83 mL, 13.1 mmol) and Ts-Cl (2.00 g, 10.5 mmol) were added to a solution of 2-cyclopentylethanol (1.09 mL, 8.76 mmol) in DCM (22 mL), and the mixture was stirred for 18 hours. Water was added to the reaction mixture and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silicone column chromatography (hexane-EtOAc, 4:1) to yield 1.53 g (65%) of TEA. [(] [twenty two] [)]. 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). []

[0161] [4] [-] [Methylbenzenesulfonic acid] [3] [-(] [4] [-] [Methoxyphenyl] [)] [C] [ester] [(] [twenty three] [)]: TEA (1.26 mL, 9.02 mmol) and Ts-Cl (1.38 g, 7.22 mmol) were added to a solution of 3-(4-methoxyphenyl)prop-1-ol (0.96 mL, 6.02 mmol) in DCM (15 mL), and the resulting mixture was stirred for 18 hours. Water was added to the reaction mixture and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silicone column chromatography (hexane-EtOAc, 4:1) to produce 1.59 g (82%) of […]. [(] [twenty three] [)]. 1H NMR (400 MHz, chloroform-d) δ 7.81 (d, J= 8 Hz, 2H), 7.37 (d, J= 8 Hz, 2H), 7.00 (d, J= 8.6 Hz, 2H), 6.80 (d, J= 8.6 Hz, 2H), 4.04 (t, J= 6 Hz, 2H), 3.80 (s, 3H), 2.61 (dd, J= 8.2, 6.8 Hz, 2H), 2.48 (s, 3H), 2.03-1.86 (ddt, J= 8.2, 6.8, 6 Hz, 2H). []

[0162] [4] [-] [Methylbenzenesulfonic acid] [3] [-(] [3] [-(] [Trifluoromethyl] [)] [Phenyl] [)] [C] [ester] [(] [twenty four] [)]: TEA (1.02 mL, 7.35 mmol) and Ts-Cl (1.12 g, 5.88 mmol) were added to a solution of 3-(3-(trifluoromethyl)phenyl)prop-1-ol (0.91 mL, 4.90 mmol) in DCM (12 mL), and the resulting mixture was stirred for 18 hours. Water was added to the reaction mixture and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silicone column chromatography (hexane-EtOAc, 4:1) to yield 1.53 g (87%) of [the product]. [(] [twenty four] [)]. 1H NMR (400 MHz, chloroform-d) δ 7.63 (d, J= 8.5 Hz, 2H), 7.28 (d, J= 7.8 Hz, 1H), 7.21-7.16 (m. 2H), 7.19 (d, J= 8.5 Hz, 2H), 7.12 (, J= 7.8 Hz, 1H), 3.88 (t, J= 6.2 Hz, 2H), 2.56 (dd, 8.0, 7.6Hz, 2H), 2.29 (s, 3H), 1.81 (ddt, J= 8.0, 7.6, 6.2 Hz, 2H). []

[0163] [4] [-] [Methylbenzenesulfonic acid] [3] [-(] [right] [Toluyl] [)] [C] [ester] [(]

[25] [)]: TEA (1.39 mL, 9.99 mmol) and Ts-Cl (1.52 g, 7.99 mmol) were added to a solution of 3-(p-tolyl)prop-1-ol (1 g, 6.66 mmol) in DCM (17 mL), and the resulting mixture was stirred for 18 hours. Water was added to the reaction mixture and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silicone column chromatography (hexane-EtOAc, 4:1) to yield 1.85 g (87%) of [the product]. [(]

[25] [)]. 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). []

[0164] [4] [-] [Methylbenzenesulfonic acid]

[19] [-] [Methoxy-19] [-]

[10] [-] [Alkyne] [-] [1] [-] [base] [ester] [(]

[31] [)] []

[0165] Step 1: 2-((9-bromononyl)oxy)tetrahydro-2H-piperanan [(]

[26] [)]: p-TSA (105 mg, 0.55 mmol) was added to a solution of 9-bromonon-1-ol (6.17 g, 27.6 mmol) and 2,3-dihydro-2H-piperanol (3.78 mL, 23 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with 1 N Na₂CO₃, extracted twice with diethyl ether, dried over Na₂SO₄, filtered, and the solvent was removed under vacuum. The filtrate was concentrated and purified by column chromatography (0 to 5% EtOAc / Hex) to yield 6.31 g (74%) of p-TSA. [(]

[26] [)] [. ] 1H NMR (400 MHz, chloroform-d) δ 4.56 (dd, J= 4.3, 2.7 Hz, 1H), 3.85 (td, J= 7.5, 3.8 Hz, 1H), 3.71 (dt, J= 9.6, 6.9 Hz, 1H), 3.52-3.32 (m, 4H), 1.88-1.24 (m, 20H).

[0166] Step 2: Dec-9-yne-1-yl mesylate [(]

[27] [)]: At 0 °C under a nitrogen atmosphere, TEA (3.52 mL, 25.3 mmol) and methanesulfonyl chloride (1.97 mL, 25.3 mmol) were added dropwise to a stirred solution of deca-9-yn-1-ol (3.45 mL, 19.5 mmol) in THF (56 mL). The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated; water was added to the reaction mixture and subsequently extracted with DCM. The organic layer was dried over Na₂SO₄, filtered, and evaporated under reduced pressure to obtain 4.45 g (98%) of [the product]. [(]

[27] [)]. HPLC-MS (condition A): rt = 3.58 min.

[0167] Step 3: 10-Methoxydec-1-Alkyne [(]

[28] [)]: Add to a stirred solution of 5 M sodium methoxide in MeOH [(]

[27] [)](4.45 g, 19.1 mmol) was stirred at 45 °C for 18 hours. The suspension was then dissolved in water and extracted twice with Et₂O. The organic layer was dried over Na₂SO₄ and evaporated to dryness. The crude product was purified by column chromatography (5% EtOAc / Hex) to obtain [(]

[28] [)](2.58 g, 80%). ¹H NMR (400 MHz, chloroform-d) δ 3.34 (t, J = 5.2 Hz, 2H), 3.31 (s, 3H), 2.16 (td, J = 7.2, 2.1 Hz, 2H), 1.91 (t, J = 3.2 Hz, 1H), 1.53–1.48 (m, 4H), 1.40–1.27 (m, 8H).

[0168] Step 4: 2-((19-methoxy-10-yn-1-yl)oxy)tetrahydro-2H-piperanan [(]

[29] [)]: Cooled at -40℃ [(]

[28] [4 g, 23.8 mmol] was slowly added to a solution of n-BuLi (15.5 mL, 24.8 mmol) in 30 mL THF and 25 mL HMPA, followed by stirring at the same temperature for 30 minutes, and then stirring for another 30 minutes at 0°C. After cooling to -20°C, [the solution was then slowly added]. [(]

[26] [)] (6.09 g, 19.81 mmol) was dissolved in 25 mL of HMPA. The mixture was stirred at the same temperature for 10 minutes, then the temperature was raised to room temperature. Stirring was continued at the same temperature for 18 hours. Under ice-cooling (at 4 °C), 10% HCl aqueous solution was added, and the mixture was extracted (3 times) with tBuMeO. The ether layer was washed with saturated brine and further dried over anhydrous MgSO4. After filtration, the solvent was distilled off under reduced pressure to give a yellow oil. The residue was purified by column chromatography using EtOAc / Hex (1:20) to obtain... [(]

[29] [)](2.36 g, 30%). 1H NMR (400 MHz, chloroform-d) δ 4.55 (dd, J= 4.4, 2.8 Hz, 1H), 3.86-3.74 (m, 1H) 3.70 (dt, J= 9.6, 6.8 Hz, 1H), 3.52-3.46 (m, 1H), 3.39-3.33 (m, 3H), 3.31 (s, 3H), 2.11 (td, J= 7.2, 2.1 Hz, 2H), 1.86-1.78 (m, 1H), 1.74-1.65 (m, 1H), 1.53-1.26 (m, 31H), 0.86-0.83 (m, 1H).

[0169] Step 5: 19-Methoxy-10-Alkyne-1-ol [(]

[30] [)]:Towards [(]

[29] p-TSA (68 mg, 0.36 mmol) was added fractionally to a solution of [ ] (2.36 g, 6 mmol) in MeOH (10 mL). The solution was stirred at 60 °C for 16 hours and then concentrated under vacuum. The residue was dissolved in a saturated aqueous solution of NaHCO3 and extracted (tBuMeO) twice. The combined organic extracts were washed with brine and dried over Na2SO4. No further purification was required, yielding 1.32 g (71%). [(]

[30] [)] [。 ] 1H NMR (400 MHz, chloroform-d) δ 3.62 (t, J = 6.6 Hz, 2H), 3.34 (t, J = 6.7 Hz, 2H), 3.31 (s, 3H), 2.15-2.09 (m, 4H), 1.54 (m, 6H), 1.50-1.40 (m, 5H), 1.40-1.22 (m, 16H).

[0170] Step 6: 4-Methylbenzenesulfonic acid 19-methoxy-10-acetyl-1-yl ester [(]

[31] [)]:Towards [(]

[30] [)] (1.32 g, 4.25 mmol) was added to a solution of Ts-Cl (973 mg, 5.10 mmol) and 5 M NaOH (1.020 mL, 5.10 mmol) in 8.5 mL of THF, and the mixture was stirred for 18 hours. Water was added to the reaction mixture and the mixture was extracted twice with tBuMeO. The combined organic layers were washed with water and brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane-EtOAc, 6:1) to yield 1.69 g (86%) of [ ]. [(]

[31] [)]. 1H NMR (400 MHz, chloroform-d) δ 7.65 (d, J= 8.2 Hz, 2H), 7.20 (d, J= 8.2 Hz, 2H), 3.87 (t, J= 6.5 Hz, 2H), 3.22 (t, J= 6.7 Hz, 2H), 3.18 (s, 3H), 2.31 (s, 3H), 2.00-1.96 (m, 4H), 1.52-1.45 (m, 2H), 1.44-1.38 (m, 2H), 1.34-1.27 (m, 4H), 1.27-1.05 (m, 18H). [] [, A.3. , ] [, Activated acid synthesis , ]

[0171] [Benzyl glutarate] [(] [2] [,] [5] [-] [Di-side oxygen pyrrolidine] [-] [1] [-] [base] [)] [ester] [(]

[32] [)]: TEA (357 µL, 2.56 mmol) was added to a solution of 5-(benzyloxy)-5-t-oxyvalerate (285 mg, 1.28 mmol) and (2,5-dit-oxypyrrolidin-1-yl) carbonate (600 mg, 2.34 mmol) in DCM (0.05 M). The reaction mixture was stirred at room temperature for 24 hours, then quenched with water and washed with brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (silicone, hexane:EtOAc 1:1) to give 254 mg [(]

[32] [)](64%). HPLC-MS (condition B): rt=2.55 min; m / z: 320 [M+1] +, 342 [M+23] +.

[0172] [thiophene] [-] [2] [-] [First] [acid] [2] [,] [5] [-] [Di-side oxygen pyrrolidine] [-] [1] [-] [Base ester] [(]

[33] [)]: TEA (653 μL, 4.68 mmol) was added to a solution of thiophene-2-carboxylic acid (300 mg, 2.34 mmol) and di(N-succinimino) carbonate (600 mg, 2.34 mmol) in DCM (4 mL). The mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture and the mixture was extracted with DCM (twice). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was used without further purification. ¹H NMR (400 MHz, chloroform-d) δ 8.06 (dd, J = 4.8, 0.8 Hz, 1H), 7.80 (dd, J = 4.8, 0.8 Hz, 1H), 7.23 (dd, J = 4.8 Hz, 1H), 2.88 (br, 4H). [] [, B. , ] [, General Program , ] [, , ] [, B.1. , ] [, Alkylation process , ] [, , ]

[0173] Program A: At 0℃ [(] [2] [ ] (1 equivalent) of NaH (2.15 equivalents) was added to a solution in DMF (0.2 M). When the addition was complete, the mixture was stirred at room temperature for 5 minutes. Finally, an 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 under vacuum. The residue was purified by rapid chromatography (silicone) to obtain the pure compound. []

[0174] Program B: At 0℃ [(] [2] LiH was added (1 equivalent) to a solution in DMF (0.2 M). After the addition was complete, the mixture was stirred for 5 minutes at room temperature. Finally, an alkylating agent was added. Depending on the alkylating agent, the reaction mixture was stirred for different times at different temperatures, followed by quenching with water and extraction with EtOAc. The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (silicone) to obtain the pure compound. [] [, B.2. Hydrolysis process [, , ]

[0175] Program C: [Transfer intermediate materials] [(] [II] [)]、 [(] [V] [)]、 [(] [VIII] [)]、 [(] [XI] [)]or [(] [XIII] [)] (1 equivalent) was dissolved in a mixture of methanol / water / DCM / trifluoroacetic acid (3:1:1:1, 0.1 M), and the solution was stirred overnight at room temperature. Finally, the solvent and excess TFA were removed under vacuum to obtain the desired compound. []

[0176] Program D: intermediate items [(] [II] [)]、 [(] [V] [)]、 [(] [VIII] [)]、 [(] [XI] [)]or [(] [XIII] [ ] (1 equivalent) was dissolved in a mixture of methanol / water / DCM / trifluoroacetic acid (3:1:1:1, 0.1 M), and the solution was stirred overnight at room temperature. Subsequently, the solvent and excess TFA were removed under vacuum. Finally, the residue was dissolved in methanol (MeOH), treated with IRA-400 resin until the pH was alkaline, filtered, and the solvent was removed under vacuum to obtain the desired compound. []

[0177] Program E: To the intermediate [(] [II] [)]、 [(] [V] [)]、 [(] [VIII] [)]、 [(] [XI] [)]or [(] [XIII] [)](1 equivalent) of a solution of TBAF in THF (c=0.1 M) was added to a solution of 0.1 M TBAF in THF (1.2 equivalent). The reaction mixture was stirred at room temperature for 18 hours, quenched with water, and extracted with EtOAc. The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was dissolved in a mixture of MeOH / water / DCM / TFA (3:1:1:1, 0.1 M) and the solution was stirred overnight at room temperature. Subsequently, the solvent and excess TFA were removed under vacuum. Finally, the residue was dissolved in methanol (MeOH), treated with IRA-400 resin until the pH was alkaline, filtered, and the solvent was removed under vacuum to obtain the desired compound. []

[0178] Program F: intermediate [(] [II] [)]、 [(] [V] [)]、 [(] [VIII] [)]、 [(] [XI] [)]or [(] [XIII] [)] (1 equivalent) was dissolved in a mixture of DCM / TFA (4:1, 0.14 M) and the solution was stirred at room temperature for 1 hour. Subsequently, water (final concentration 0.1 M) was added and the reaction mixture was stirred at room temperature for 18 hours. Finally, the layers were separated and the water layer was concentrated under vacuum to obtain the desired compound. []

[0179] Program S: intermediate [(] [II] [)]、 [(] [V] [)]、 [(] [VIII] [)]、 [(] [XI] [)]or [(] [XIII] [)] (1 equivalent) was dissolved in a mixture of MeOH / HCl 1N (10:1, 0.1 M), and the solution was stirred overnight at 60°C. Finally, the solvent and excess HCl were removed under vacuum to obtain the desired compound. [] [, B.3. , ] [, Click the reaction program , ] [, , ]

[0180] Program K: To the intermediate [(] [VI] A suspension of [ )] (1 equivalent) and CuI (0.03 equivalent) in DCM (0.1 M) was supplemented with a solution of azide reagent (2 equivalents), DIPEA (0.07 equivalents), and AcOH (0.07 equivalents) in DCM / MeOH (1 M). The reaction mixture was stirred at 35 °C for 20 hours under an inert atmosphere and then concentrated under vacuum to obtain the desired compound.

[0181] Program L: To the intermediate [(] [VI] A solution of [ )] (1 equivalent), CuSO₄·5H₂O (0.4 equivalent), and sodium ascorbate (0.6 equivalent) in water (0.07 M) was mixed with a solution of azide reagent (2 equivalents) in THF (0.35 M). The reaction mixture was stirred for 20 hours at room temperature under an inert atmosphere, filtered through diatomaceous earth, and concentrated under vacuum. The residue was treated with water / DCM. Subsequently, the organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the desired compound.

[0182] Program M: To the intermediate [(] [IX] A solution of [ )] (1 equivalent), CuSO₄·5H₂O (0.4 equivalent), and sodium ascorbate (0.6 equivalent) in mixed water (0.07 M) was mixed with an alkynyl reagent (2 equivalents) in THF (0.35 M). The reaction mixture was stirred for 24 hours at room temperature under an inert atmosphere, filtered through diatomaceous earth, and concentrated under vacuum. The residue was dissolved in MeOH, treated with IRA-400 resin until the pH was alkaline, filtered, and the solvent was removed under vacuum to obtain the desired compound. [, B.4. , ] [, Group conversion procedure , ]

[0183] Program N: intermediate [(] [VII] A mixture of [ )] (1 equivalent) and 25% sodium methoxide (3 equivalents) in MeOH (0.1 M) was stirred at 40°C for 18 hours. The reaction mixture was diluted in water / DCM, the organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain the desired compound. [, B.5. , ] [, azide reduction program , ] [, , ]

[0184] Program Q: To the intermediate ( [VIII] [ ] (1 equivalent) of DIPEA (3 equivalents) and PPh 3 (2.6 equivalents) were added to a solution of a mixture of THF / water (9:1, 0.08 M). 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 Na 2SO 4, filtered, and concentrated under vacuum to obtain the desired compound. [, B.6. , ] [, Acrylamine formation process , ] [, , ]

[0185] Program P: To the intermediate ( [XI] [)]or( [XII] [)](1 equivalent) of TEA (4 equivalents) and activating acid (2 equivalents) were added to a solution in DMF (0.1 M). The reaction mixture was stirred at room temperature for 4 hours and concentrated under vacuum. The residue was dissolved in MeOH, treated with IRA-400 resin until the pH was alkaline, filtered, and the solvent was removed under vacuum. Finally, the residue was purified by rapid chromatography (silicone) to obtain the pure compound. [, B.7. , ] [, Urea formation process , ]

[0186] Program H: Transform the intermediate ( [XI] [)]or( [XII] [)] (1 equivalent) was dissolved in MeOH and treated with IRA-400 resin until the pH was alkaline. The mixture was filtered and the solvent was removed under vacuum. The residue was dissolved in EtOH (0.1 M) and an isocyanate reagent (2 equivalents) was added. The reaction mixture was stirred at 60 °C for 24 hours and concentrated under vacuum to give the pure compound. [, B.8. , ] [, Carbamate Formation Procedure , ] [, , ]

[0187] Program V: will use the intermediate ( [XI] [)]or( [XII] [ ] (1 equivalent) was dissolved in MeOH and treated with IRA-400 resin until the pH was alkaline. The solution was then filtered and the solvent removed under vacuum. The residue was dissolved in MeOH (1 M) and dimethyl carbonate (40 equivalents), and tetrabutylammonium bromide (0.1 equivalents) and L-proline (0.1 equivalents) were added. The reaction mixture was stirred at 60°C for 48 hours and concentrated. The residue was treated with water and DCM, and the aqueous layer was concentrated under vacuum. The residue was dissolved in MeOH and treated with DOWEX resin until the pH was acidic. The solution was then filtered and the solvent removed under vacuum to give the desired compound. [, B.9. , ] [, Phosphorylation or thiophosphorylation procedure , ] [, , ]

[0188] Program G: intermediate [(] [III] [)] [、] [(] [VI] [-] [1] [)]or [(] [IX] [ ] (1 equivalent) was dissolved in DCM (0.02 M) and a solution of tetrazolium in ACN (0.43 M) (10 to 14.4 equivalents) was added. The mixture was stirred at room temperature for 30 minutes. Subsequently, N,N-diethyl-1,5-dihydrobenzo[e][1,3,2]-dioxaphosphazenecycloheptan-3-amine (5 to 7.2 equivalents) was added and the mixture was stirred at room temperature overnight. Finally, the reaction mixture was cooled at 0°C and a solution of tributyl hydroperoxide in hexane (5.5 M) (15 to 19.2 equivalents) was added. The solution was allowed to reach room temperature and stirred for 1 hour. The mixture was washed with dilute sodium sulfite and extracted with DCM. The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (silicone) or by crystallization to obtain the pure compound.

[0189] Program T: Transmit intermediates [(] [III] [)]or [(] [IX] [ )] (1 equivalent) was dissolved in DCM (0.02 M) and a solution of tetrazolium in ACN (0.43 M) (10 to 14.4 equivalents) was added. The mixture was stirred at room temperature for 30 minutes. Subsequently, N,N-diethyl-1,5-dihydrobenzo[e][1,3,2]-dioxaphosphazenecycloheptane-3-amine (5 to 7.2 equivalents) was added and the mixture was stirred at room temperature overnight. Finally, pyridine (40 equivalents) and sulfur (40 equivalents) were added and the solution was stirred at room temperature for 24 hours. The mixture was washed with dilute sodium sulfite and extracted with DCM. The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (silicone) or by crystallization to obtain the pure compound. [, B.10. , ] [, Phosphate or thiophosphate removal protecting group procedure , ] [, , ]

[0190] Procedure I: Phosphorylating compounds [(] [IV] [)]or [(] [X] [)] was dissolved in a mixture of THF / MeOH / water (3:1:1, 0.01 M), followed by the addition of excess palladium hydroxide / carbon. The mixture was placed under a hydrogen atmosphere and stirred at room temperature for 2 days. The mixture was then purged with nitrogen, filtered, and concentrated. The pH of the compound was adjusted to 9 to 10 by adding dilute NaOH aqueous solution (1 N), and the residue was purified by dissociation with water in a dextran gel column (PD-10, G-25-M). All dissociated fractions were lyophilized and analyzed by 1H-RMN. The fraction containing the product was further purified by dissociation with water in a reversed-phase filter cartridge (Sep-Pack® C18 cartridge, 1 g, Waters Corp., Milford, MA, USA). All dissociated fractions were lyophilized and analyzed by 1H-RMN.

[0191] Program J: Phosphorylation of compounds [(] [IV] [)]or [(] [X] [)] was dissolved in a mixture of THF / MeOH / water (3:1:1, 0.01 M), followed by the addition of excess palladium hydroxide / carbon. The mixture was placed under a hydrogen atmosphere and stirred at room temperature for 2 days. The mixture was then purged with nitrogen, filtered, and concentrated. The pH of the compound was adjusted to 10 by adding dilute NaOH aqueous solution (1 N), and the solution was stirred for 24 to 48 hours. Finally, the solution was purified by dissociation with water on a dextran gel column (PD-10, G-25-M). All dissociated fractions were lyophilized and analyzed by 1H-RMN. The fraction containing the product was further purified by dissociation with water in a reversed-phase filter cartridge (Sep-Pack® C18 cartridge, 1 g, Waters Corp., Milford, MA, USA). All dissociated fractions were lyophilized and analyzed by 1H-RMN.

[0192] Program U: Treatment of phosphorylated or thiophosphorylated compounds with thiophenol (40 equivalents) and m-cresol (40 equivalents) in TFA (0.045 M). [(] [IV] [)] [、] [(] [IV] [')]or [(] [X] [)] [。] Subsequently, TBMSBr (40 equivalents) was slowly added and the mixture was stirred at room temperature for 4 hours, quenched with water, and extracted with DCM (3 times). The aqueous layer was concentrated under vacuum. The pH of the residue was adjusted to 9 to 10 by adding water and dilute NaOH aqueous solution (1 N), and the residue was purified by dissociation with water on a dextran gel column (PD-10, G-25-M). All dissociated fractions were lyophilized and analyzed by 1H-RMN. The fraction containing the product was further purified by dissociation with water in a reversed-phase filter cartridge (Sep-Pack® C18 cartridge, 1 g, Waters Corp., Milford, MA, USA). All dissociated fractions were lyophilized and analyzed by 1H-RMN. [] [, C , ] [, . , ] [, Synthetic intermediates , ] [, II , ] [, - , ] [, XIII , ] [, C.1. , ] [, intermediate , ] [, II , ]

[0193] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-(] [Benzyloxy] [)] [Pentyl] [)-] [2] [-] [, O , ] [-] [Tri-butyldimethyl] [Silyl group] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [II] [-] [1] [)]: 202 mg of alkylation product was obtained from 1.04 mL (3 equivalents) (((5-bromopentyl)oxy)methyl)benzene according to general alkylation procedure A. [(] [II] [-] [1] [)](18.3%). HPLC-MS (condition A): rt=6.30 min; m / z: 657 [M+1]+, 679 [M+23]+.

[0194] [4] [,] [6] [-] [, O , ] [-] [pair] [(]

[10] [-(] [Benzyloxy] [)] [Guiji] [)-] [2] [-] [, O , ] [-] [Tri-butyldimethyl] [Silyl group] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [II] [-] [2] [)]: According to general alkylation procedure A, 408 mg (2 equivalents, in 2 mL DMF) was produced. [(] [4] [)] [,] 75 mg was obtained [(] [II] [-] [2] [)](16%). 1H NMR (400 MHz, chloroform-d) δ 7.39-7.25 (m, 10H), 5.53 (d, J= 1.2 Hz, 1H), 4.50 (s, 4H), 4.36 (dt, J= 3.6, 1.6 Hz, 1H), 4.25 (q, J= 1.6 Hz, 1H), 4.16 (t, J= 3.6 Hz, 2H), 4.10 (dt, J= 3.6, 1.6 Hz, 2H), 3.53 (dt, J= 8.8, 6.4 Hz, 2H), 3.46 (t, J= 6.8 Hz, 4H), 3.50 (dt, J= 8.8, 6.4 Hz, 2H), 1.61 (p, J= 6.8 Hz, 4H), 1.54-1.48 (m, 4H), 1.44-1.16 (m, 24H), 0.94 (s, 9H), 0.14 (s, 6H).

[0195] [4] [,] [6] [-] [, O , ] [-] [pair] [(]

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

[0196] [2] [-] [, O , ] [-] [Tributyldimethylsilicon] [alkyl] [base] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-] [Methoxypropyl] [)-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [II] [-] [4] [)]: According to general alkylation procedure A, 232 mg of 1-bromo-3-methoxypropane was obtained from 0.55 mL (5 equivalents) of 1-bromo-3-methoxypropane. [(] [II] [-] [4] [)](52%). HPLC-MS (condition A): rt=4.58 min; m / z: 449 [M+1] +, 471 [M+23] +.

[0197] [2] [-] [, O , ] [-] [Tributyldimethylsilicon] [alkyl] [base] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-] [Methoxypentyl] [)-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [II] [-] [5] [)]: According to general alkylation procedure A, 21 mg of 1-bromo-5-methoxypentane was obtained from 241 mg (2.2 equivalents, in 3 mL DMF). [(] [II] [-] [5] [)](7%). HPLC-MS (condition B): rt= 3.80 min; m / z: 505 [M+1] +, 527 [M+23] +.

[0198] [2] [-] [, O , ] [-] [Tributyldimethylsilicon] [alkyl] [base] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [9] [-] [Methoxynonyl] [)-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [II] [-] [6] [)]: According to the general alkylation procedure A, 803 mg (2.5 equivalents, in 1.2 mL DMF) [(] [7] [)] [,] 194 mg was obtained [(] [II] [-] [6] [)](32%). 1H NMR (400 MHz, chloroform-d) δ 5.53 (d, J= 1.2 Hz, 1H), 4.36 (tt, J= 3.2, 1.6 Hz, 1H), 4.24 (dd, J= 3.2, 2,4 Hz, 1H), 4.16 (t, J= 3.6 Hz, 2H), 4.10 (dt, J= 4, 1.6 Hz, 2H), 3.53 (dt, J= 8.8, 6.4 Hz, 2H), 3.44 (dt, J= 8.8, 6.4 Hz, 2H), 3.36 (t, J= 6.4 Hz, 4H), 3.33 (s, 6H), 1.59-1.48 (m, 8H), 1.35-1.26 (m, 20H), 0.94 (s, 9H), 0.14 (s, 6H).

[0199] [2] [-] [, O , ] [-] [Tributyldimethylsilicon] [alkyl] [base] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [7] [-] [Methoxyheptyl] [)-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [II] [-] [7] [)]: According to the general alkylation procedure A, 780 mg (2.5 equivalents, in 1.5 mL DMF) [(] [6] [)], obtained 398 mg [(] [II] [-] [7] [)](47.6%). HPLC-MS (condition A); rt=6.11 min; m / z: 561 [M+1] +, 583 [M+23] +.

[0200] [2] [-] [, O , ] [-] [Tributyldimethylsilicon] [alkyl] [base] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [4] [,] [6] [-] [, O , ] [-] [Dipropyl] [-] [Inositol] [(] [II] [-] [8] [)]: According to general alkylation procedure A, 79.14 mg of 1-iodopropane was obtained from 481 µL (5 equivalents). [(] [II] [-] [8] [)](twenty one%). 1H NMR (400 MHz, chloroform-d) δ 5.52 (d, J= 1.4 Hz, 1H), 4.37 (h, J= 1.6 Hz, 1H), 4.26 (q, J= 1.6 Hz, 1H), 4.16 (t, J= 4 Hz, 2H), 4.11 (dt, J= 4, 1.6 Hz, 2H), 3.51 (dt, J= 8.8, 6.8 Hz, 2H), 3.41 (dt, J= 8.8, 6.8 Hz, 3H), 1.55 (h, J= 6.8 Hz, 4H), 0.93 (s, 9H), 0.90 (t, J= 6.8 Hz, 6H), 0.13 (s, 6H).

[0201] [2] [-] [,O , ] [-] [Tributyldimethylsilicon] [alkyl] [base] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [4] [,] [6] [-] [, O , ] [-] [Dipentyl] [-] [Inositol] [(] [II] [-] [9] [)]: According to general alkylation procedure A, 255 mg of 1-bromopentane was obtained from 377 µL (3 equivalents). [(] [II] [-] [9] [)](58%). HPLC-MS (condition A): rt= 6.38 min; m / z: 445 [M+1]+.

[0202] [2] [-] [, O , ] [-] [Tributyldimethylsilicon] [alkyl] [base] [-] [4] [,] [6] [-] [, O , ] [-] [Second Gengji] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [II] [-]

[10] [)]: According to general alkylation procedure A, 250 mg of 1-bromoheptane was obtained from 560 µL (5 equivalents) of 1-bromoheptane. [(] [II] [-]

[10] [)](70%). 1H NMR (400 MHz, chloroform-d) δ 5.53 (d, J= 1.2 Hz, 1H), 4.36 (h, J= 1.6 Hz, 1H), 4.25 (d, J= 1.6 Hz, 1H), 4.16 (t, J= 4 Hz, 2H), 4.11 (dt, J= 4, 1.6 Hz, 2H), 3.54 (dt, J= 8.8, 6.4 Hz, 2H), 3.44 (dt, J= 8.8, 6.4 Hz, 2H), 1.57-1.49 (m, 4H), 1.37-1.17 (m, 16H), 0.94 (s, 9H), 0.88 (t, J= 6.8 Hz, 6H), 0.14 (s, 6H).

[0203] [2] [-] [, O , ] [-] [Tributyldimethylsilicon] [alkyl] [base] [-] [4] [,] [6] [-] [, O , ] [-] [Dioctyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [II] [-]

[11] [)]: According to general alkylation procedure A, 272.6 mg of 1-bromodecane was obtained from 511 µL (3 equivalents). [(] [II] [-]

[11] [)](57%). 1H NMR (400 MHz, chloroform-d) δ 5.53 (d, J= 1.2 Hz, 1H), 4.37 (h, J=1.6 Hz, 1H), 4.25 (q, J= 1.6 Hz, 1H), 4.16 (t, J= 4 Hz, 2H), 4.11 (dt, J= 4.0, 1.6 Hz, 2H), 3.54 (dt, J= 8.8, 6.4 Hz, 2H), 3.44 (dt, J= 8.8, 6.4 Hz, 2H), 1.55-1.50 (m, 4H), 1.37-1.22 (m, 28H), 0.94 (s, 9H), 0.88 (t, J= 7.2 Hz 6H), 0.14 (s, 6H).

[0204] [2] [-] [, O , ] [-] [Tributyldimethylsilicon] [alkyl] [base] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [4] [,] [6] [-] [, O , ] [-] [two] [(] [Tetradecyl] [)-] [Inositol] [(] [II] [-]

[12] [)]: According to general alkylation procedure A, 350 mg of 1-bromotetradecane was obtained from 670 µL (3 equivalents) of 1-bromotetradecane. [(] [II] [-]

[12] [)](61%). 1H NMR (400 MHz, chloroform-d) δ 5.53 (d, J= 1.6 Hz, 1H), 4.36 (h, J= 1.6 Hz, 1H), 4.25 (q, J= 1.6 Hz, 1H), 4.16 (t, J= 4 Hz, 2H), 4.11 (dt, J= 4, 1.6 Hz, 2H), 3.54 (dt, J= 8.8, 6.4 Hz, 2H), 3.44 (dt, J= 8.8, 6.4 Hz, 2H), 1.60-1.45 (m, 4H), 1.32-126 (m, 44H), 0.94 (s, 9H), 0.88 (t, J= 6.8, 6H), 0.14 (s, 6H).

[0205] [2] [-] [, O , ] [-] [Tributyldimethylsilicon] [alkyl] [base] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-] [ethoxycarbonyl] [Pentyl] [)-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [II] [-]

[13] [)]: 90 mg of ethyl 6-bromohexanoate was obtained from 351 µL of ethyl 6-bromohexanoate (3 equivalents) according to general alkylation procedure A. [(] [II] [-]

[13] [)](23%). HPLC-MS (condition A): rt=5.46 min; m / z: 589 [M+1] +, 611 [M+23] +.

[0206] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(]

[10] [-] [ethoxycarbonyldecyl] [)-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [II] [-]

[14] [)]: According to general alkylation procedure A, 169 mg of ethyl 11-bromoundecanoate (2.5 equivalents) was obtained from 455 µL of ethyl 11-bromoundecanoate. [(] [II] [-]

[14] [)](34%). 1H NMR (400 MHz, chloroform-d) δ 5.50 (d, J= 1.6 Hz, 1H), 4.34 (h, J= 1.6 Hz, 1H), 4.23 (q, J= 1.6 Hz, 1H), 4.15-4.07 (m, 8H), 3.52 (dt, J= 8.8, 6.4 Hz, 2H), 3.42 (dt, J= 8.8, 6.4 Hz, 2H), 2.26 (t, J= 7.2 Hz, 4H), 1.59 (p, J= 7.2 Hz, 4H), 1.50 (p, J= 6.4 Hz, 4H), 1.37-1.17 (m, 30H), 0.92 (s, 9H), 0.12 (s, 6H).

[0207] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-(] [1, H , ] [-] [Pyrazole] [-] [1] [-] [base] [)] [Pentyl] [)-] [Inositol] [(] [II] [-]

[15] [)]: According to general alkylation procedure A, from 450 mg [(]

[12] [)], obtained 101 mg [(] [II] [-]

[15] [)](12%). HPLC-MS (condition A): rt=4.56 min; m / z: 578 M+1] +.

[0208] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-(] [1,H , ] [-] [1] [,] [2] [,] [4] [-] [Triazole] [-] [1] [-] [base] [)] [Pentyl] [)-] [Inositol] [(] [II] [-]

[16] [)]: According to the general alkylation procedure A, from 500 mg [(]

[14] [)], obtained 60 mg [(] [II] [-]

[16] [)](6%). HPLC-MS (condition A): rt=3.70 min; m / z: 579 [M+1]+.

[0209] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [2] [-(] [4] [-] [Acetylpyridinium] [𠯤] [-] [1] [-] [base] [)] [Ethyl] [)-] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [II] [-]

[17] [)]

[0210] Step 1: Racemic-4-O-(2-(4-acetylopyr-1-yl)ethyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylene-inositol [(]

[34] [)] [:]According to the general alkylation procedure A, from 700 mg [(]

[20] [)](2.5 equivalents, in 7.3 mL DMF), yielded 460 mg [(]

[34] [)](68%). HPLC-MS (condition A): rt=1.90 min; m / z: 459 [M+1]+.

[0211] Step 2: 4,6-O-bis(2-(4-acetylopyr-1-yl)ethyl)-2-O-tert-butyldimethylsilyl-1,3,5-O-methylene-inositol [(] [II] [-]

[17] [)]: At 0℃ towards [(]

[34] [ )] (279 mg, 0.61 mmol) was added to a solution of NaH (55.7 mg, 1.39 mmol) in DMF (0.2 M). When the addition was complete, the mixture was stirred at room temperature for 5 minutes. Finally, [ ] was added. [(]

[20] [ )] (309 mg, 1.62 mmol) was dissolved in DMF (3.2 mL). The reactants were heated at 90 °C, stirred overnight, and concentrated under vacuum. The residue was purified by rapid chromatography (silicone, DCM:MeOH 95:5, 1% NH3) to obtain 89 mg [(] [II] [-]

[17] [)](22%). HPLC-MS (condition A): rt=1.56 min; m / z: 613 [M+1]+.

[0212] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [4] [,] [4] [,] [4] [-] [Trifluorobutyl] [)-] [Inositol] [(] [II] [-]

[18] [)]: According to the general alkylation procedure B, 3.61 g of 4-bromo-1,1,1-trifluorobutane was obtained from 4.2 mL (3 equivalents) of 4-bromo-1,1,1-trifluorobutane and 934 mg (10 equivalents) of LiH. [(] [II] [-]

[18] [)](60% yield). HPLC-MS (condition A): rt=5.23 min; m / z: 525 [M+1]+.

[0213] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [6] [,] [6] [,] [6] [-] [Trifluorohexyl] [)-] [Inositol] [(] [II] [-]

[19] [)]: According to general alkylation procedure B, 594 mg of 6-bromo-1,1,1-trifluorohexane was obtained from 1.16 g (2.5 equivalents) of 6-bromo-1,1,1-trifluorohexane and 43 mg (2.5 equivalents) of LiH. [(] [II] [-]

[19] [)](48%). HPLC-MS (condition A): rt=6.87 min; m / z: 573 [M+1] +, 595 [M+23] +.

[0214] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [4] [-] [Methylpentyl] [)-] [Inositol] [(] [II] [-]

[20] [)]: According to the general alkylation procedure B, 273 mg of 1-bromo-4-methylpentane and 58 mg of LiH were used to obtain 273 mg of alkylation solution. [(] [II] [-]

[20] [)](20%). HPLC-MS (condition A): rt=5.77 min; m / z: 581 [M+1]+. [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(]

[19] [-] [Methoxy] [nineteen] [-]

[10] [-] [Alkyne] [-] [1] [-] [base] [)-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [II] [-] [twenty one] [)]: According to the general alkylation procedure A, from 2.93 g (2.5 equivalents) [(]

[31] [)], yielding 1.236 g [(] [II] [-] [twenty one] [)](55%). 1H NMR (400 MHz, chloroform-d) δ 5.53 (d, J= 1.3 Hz, 1H), 4.36 (tt, J= 3.6, 1.6 Hz, 1H), 4.25 (q, J= 1.6 Hz, 1H), 4.16 (t, J= 3.6 Hz, 2H), 4.11-4.09 (m, 2H), 3.53 (dt, J= 8.8, 6.4 Hz, 2H), 3.44 (dt, J= 8.8, 6.4 Hz, 2H), 3.36 (t, J= 6.8 Hz, 4H), 3.33 (s, 6H), 2.19-2.07 (m, 8H), 1.55-1.43 (m, 14H), 1.38-1.26 (m, 38H), 0.94 (s, 9H), 0.14 (s, 6H). []

[0215] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [2] [-] [ring] [Propylethyl] [)-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [II] [-] [twenty two] [)]: According to the general alkylation procedure B, from 6.24 g (2.2 equivalents) [(] [twenty one] [)] and 213 mg (2.2 equivalents) of LiH were used to obtain 3.1 g [(] [II] [-] [twenty two] [)](59.6%). HPLC-MS (condition A): rt=5.94 min; 441 [M+1] +, 563 [M+23] +.

[0216] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [2] [-] [Cyclopentylethyl] [)-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [II] [-] [twenty three] [)]: According to the general alkylation procedure B, from 1.53 g (2.5 equivalents) [(] [twenty two] [)] and 43 mg (2.5 equivalents) of LiH yielded 267 mg [(] [II] [-] [twenty three] [)](23.5%). HPLC-MS (condition A): rt= 7.22 min; 497 [M+1] +, 519 [M+23] +.

[0217] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-(] [4] [-] [Methoxyphenyl] [)] [Propyl] [)-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [II] [-] [twenty four] [)]: According to the general alkylation procedure B, from 1.59 g (2.5 equivalents) [(] [twenty three] [)] and 41 mg (2.5 equivalents) of LiH, yielding 60 mg [(] [II] [-] [twenty four] [)](5%). HPLC-MS (condition A): rt=5.80 min; 601.5 [M+1] +, 623.5 [M+23] +.

[0218] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-(] [3] [-(] [Trifluoromethyl] [)] [Phenyl] [)] [Propyl] [)-] [Inositol] [(] [II] [-]

[25] [)]: According to the general alkylation procedure B, from 1.53 g (2.5 equivalents) [(] [twenty four] [)] and 35 mg (2.5 equivalents) of LiH, yielding 35 mg [(] [II] [-]

[25] [)](3%). HPLC-MS (condition A): rt=6.19 min; 677.4 [M+1]+, 699.4 [M+23]+.

[0219] [2] [-] [, O , ] [-] [Level 3] [Butyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-(] [right] [Toluyl] [)] [Propyl] [)-] [Inositol] [(] [II] [-]

[26] [)]: According to the general alkylation procedure B, from 1.85 g (2.5 equivalents) [(]

[25] [)] and 50 mg (2.5 equivalents) of LiH yielded 261 mg [(] [II] [-]

[26] [)](19%). HPLC-MS (condition A): rt= 6.45 min; 569.4 [M+1] +, 591.4 [M+23] +.

[0220] [2] [-] [, O , ] [-] [Level 3] [Butyldimethylsilyl] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-] [Methoxy] [Carbonylpropyl] [)-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [II] [-]

[27] [)]: According to the general alkylation procedure B, 264 mg of methyl 4-bromobutyrate was obtained from 2.65 mL (6 equivalents) of methyl 4-bromobutyrate and 288 mg (10 equivalents) of LiH. [(] [II] [-]

[27] [)](15%). HPLC-MS (condition A): rt=4.52 min; 505 [M+1]+. [] [, C.2. , ] [, intermediate , ] [, III , ] [, , ]

[0221] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-(] [Benzyloxy] [)] [Pentyl] [)-] [Inositol] [(] [III] [-] [1] [)]: According to the general hydrolysis procedure C, from 202 mg... [(] [II] [-] [1] [)], obtained 163 mg [(] [III] [-] [1] [)](>99%). HPLC-MS (condition A): rt=3.59 min; m / z: 533 [M+1]+. []

[0222] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-] [Methoxypentyl] [)-] [Inositol] [(] [III] [-] [2] [)] [:]According to the general hydrolysis procedure C, from 510 mg... [(] [II] [-] [5] [)], obtained 348 mg [(] [III] [-] [2] [)](>99%). HPLC-MS (condition A): rt=2.69 min; m / z: 381 [M+1] +, 403 [M+23] +. []

[0223] [4] [,] [6] [-] [, O , ] [-] [pair] [(]

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

[0224] [4] [,] [6] [-] [, O , ] [-] [pair] [(]

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

[0225] [4] [,] [6] [-] [, O, ] [-] [pair] [(] [5] [-] [ethoxycarbonyl] [Pentyl] [)-] [Inositol] [(] [III] [-] [5] [)] [:]According to the general hydrolysis procedure D, from 114 mg... [(] [II] [-]

[13] [)], yielding 87.7 mg [(] [III] [-] [5] [)](>99%). HPLC-MS (condition A): rt= 2.95 min; m / z: 465 [M+1]+. []

[0226] [4] [,] [6] [-] [, O , ] [-] [pair] [(]

[10] [-] [ethoxycarbonyldecyl] [)-] [Inositol] [(] [III] [-] [6] [)]: According to the general hydrolysis procedure D, from 166 mg of [(] [II] [-]

[14] [)], obtained 129 mg [(] [III] [-] [6] [)](94%). HPLC-MS (condition A): rt=4.47 min; m / z: 605 [M+1]+. []

[0227] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [2] [-] [Cyclopropylethyl] [)-] [Inositol] [(] [III] [-] [7] [)]: According to the general hydrolysis procedure S, from 3.10 g [(] [II] [-] [twenty two] [)], yielding 2.23 g [(] [III] [-] [7] [)](100%). HPLC-MS (condition A): rt=2.82 min; m / z: 317 [M+1] +, 339 [M+23] +.

[0228] 4,6-O-bis(2-cyclopentylethyl)-inositol (III-8): 267 mg was obtained according to the general hydrolysis procedure S. [(] [II] [-] [twenty three] [)], obtained 201 mg [(] [III] [-] [8] [)](>99%). HPLC-MS (condition A): rt=3.50 min; m / z: 373 [M+1] +, 395 [M+23] +.

[0229] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-(] [1, H , ] [-] [Pyrazole] [-] [1] [-] [base] [)] [Pentyl] [)-] [Inositol] [(] [III] [-] [9] [)]: According to the general hydrolysis procedure D, from 90 mg of [(] [II] [-]

[15] [)], obtained 67 mg [(] [III] [-] [9] [)](95%). HPLC-MS (condition A): rt=2.79 min; m / z: 453 [M+1]+. []

[0230] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-(] [1, H , ] [-] [1] [,] [2] [,] [4] [-] [Triazole] [-] [1] [-] [base] [)] [Pentyl] [)-] [Inositol] [(] [III] [-]

[10] [)]: According to the general hydrolysis procedure D, from 19 mg [(] [II] [-]

[16] [)], obtained 15 mg [(] [III] [-]

[10] [)](>99%). HPLC-MS (condition A): rt=2.29 min; m / z: 455 [M+1]+. []

[0231] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [2] [-(] [4] [-] [Acetylpyridinium] [𠯤] [-] [1] [-] [base] [)] [Ethyl] [)] [-] [Inositol] [(] [III] [-]

[11] [)]: According to the general hydrolysis procedure C, from 45 mg [(] [II] [-]

[17] [)], obtained 36 mg [(] [III] [-]

[11] [)](>99%). HPLC-MS (condition B): rt=0.23 min; m / z: 489 [M+1] +, 511 [M+23] +. []

[0232] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-] [Methoxypropyl] [)-] [Inositol] [(] [III] [-]

[12] [)]: According to the general hydrolysis procedure E, from 232 mg of [(] [II] [-] [4] [)], obtained 23 mg [(] [III] [-]

[12] [)](13%). HPLC-MS (condition A): rt=1.83 min; m / z: 325 [M+1]+. []

[0233] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [7] [-] [Methoxyheptyl] [)-] [Inositol] [(] [III] [-]

[13] [)]: According to the general hydrolysis procedure E, from 389 mg [(] [II] [-] [7] [)], obtained 321 mg [(] [III] [-]

[13] [)](>99%). HPLC-MS (condition A): rt=3.14 min; m / z: 437[M+1]+. []

[0234] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [9] [-] [Methoxynonyl] [)-] [Inositol] [(] [III] [-]

[14] [)]: According to the general hydrolysis procedure E, from 194 mg of [(] [II] [-] [6] [)], obtained 156 mg [(] [III] [-]

[14] [)](>99%). HPLC-MS (condition A): rt=3.76 min; m / z: 493 [M+1] +, 515 [M+23] +. []

[0235] [4] [,] [6] [-] [, O , ] [-] [Dipropyl] [-] [Inositol] [(] [III] [-]

[15] [)]: According to the general hydrolysis procedure E, from 79 mg of [(] [II] [-] [8] [)], yielding 26.3 mg [(] [III] [-]

[15] [)](49%). HPLC-MS (condition A): rt=1.85 min; m / z: 265 [M+1] +, 287 [M+23] +. []

[0236] [4] [,] [6] [-] [, O , ] [-] [Dipentyl] [-] [Inositol] [(] [III] [-]

[16] [)]: According to the general hydrolysis procedure E, from 255 mg... [(] [II] [-] [9] [)], obtained 107 mg [(] [III] [-]

[16] [)](59%). HPLC-MS (condition A): rt= 3.00 min; m / z: 321 [M+1]+. []

[0237] [4] [,] [6] [-] [, O , ] [-] [Second Gengji] [-] [Inositol] [(] [III] [-]

[17] [)]: According to the general hydrolysis procedure E, from 250 mg... [(] [II] [-]

[10] [)], obtained 149 mg [(] [III] [-]

[17] [)](77%). HPLC-MS (condition A): rt= 3.89 min; m / z: 377 [M+1] +, 399 [M+23] +. []

[0238] [4] [,] [6] [-] [, O , ] [-] [Dioctyl] [-] [Inositol] [(] [III] [-]

[18] [)]: According to the general hydrolysis procedure E, from 272 mg of [(] [II] [-]

[11] [)], obtained 185 mg [(] [III] [-]

[18] [)](84%). HPLC-MS (condition A): rt= 5.36 min; m / z: 461 [M+1]+. []

[0239] [4] [,] [6] [-] [,O , ] [-] [two] [(] [Tetradecyl] [)-] [Inositol] [(] [III] [-]

[19] [)]: According to the general hydrolysis procedure E, from 360 mg of [(] [II] [-]

[12] [)], obtained 212 mg [(] [III] [-]

[19] [)](69%). 1H NMR (400 MHz, chloroform-d) δ 4.19-4.12 (m, 1H), 3.83 (dt, J= 9.2, 6.8 Hz, 2H), 3.65 (dt, J= 9.2, 6.8 Hz, 2H), 3.52-3.44 (m, 4H), 3.43-3.36 (m, 1H), 1.59 (p, J= 6.8 Hz, 4H), 1.33-1.25 (m, 44H), 0.88 (t, J= 6.8 Hz, 6H). []

[0240] [4] [,] [6] [-] [, O , ] [-] [pair] [(()] [1] [-(] [2] [-(] [Benzyloxycarbonyl] [)] [Ethyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [4] [-] [base] [)] [methyl] [)-] [Inositol] [(] [III] [-]

[20] [)]: According to the general click-response procedure K, 615 mg of [(]

[15] [)], obtained 983 mg [(] [III] [-]

[20] [)](98%). HPLC-MS (condition A): rt=3.18 min; m / z: 667 [M+1]+. []

[0241] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-(] [4] [-(] [2] [-(] [Benzyloxycarbonyl] [)] [Ethyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Propyl] [)-] [Inositol] [(] [III] [-] [twenty one] [)]: According to the general click-response procedure M, 70 mg of [(] [IX] [-] [3] [)] and 76 mg of pentyl-4-ynylbenzyl ester, yielding 98 mg [(] [III] [-] [twenty one] [)](67%). Under these conditions, rapid chromatography was used. HPLC-MS (condition B): rt=2.37 min; m / z: 723 [M+1] + []

[0242] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-(] [4] [-(] [Methoxymethyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Propyl] [)-] [Inositol] [(] [III] [-] [twenty two] [)]: According to the general click-response procedure M, 41 mg of [(] [IX] [-] [3] [)] and 19 µL of 3-methoxyprop-1-yne were used to obtain 35 mg [(] [III] [-] [twenty two] [)](61%). HPLC-MS (condition A): rt=2.32 min; m / z: 487 [M+1] + []

[0243] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [4] [-(] [4] [-(] [Methoxymethyl] [)-] [1,H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Dilki] [)-] [Inositol] [(] [III] [-] [twenty three] [)]: According to the general click-response procedure M, 43 mg of [(] [IX] [-] [1] [)] and 19 µL of 3-methoxyprop-1-yne were used to obtain 13 mg [(] [III] [-] [twenty three] [)](22%). HPLC-MS (condition A): rt=2.40 min; m / z: 515 [M+1] + []

[0244] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-(] [4] [-(] [Methoxymethyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Pentyl] [)-] [Inositol] [(] [III] [-] [twenty four] [)]: According to the general click-response procedure M, 58 mg of... [(] [IX] [-] [4] [)] and 12 µL of 3-methoxyprop-1-yne were used to obtain 50 mg [(] [III] [-] [twenty four] [)](64%). HPLC-MS (condition A): rt=2.48 min; m / z: 543 [M+1] + []

[0245] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [6] [-(] [4] [-(] [Methoxymethyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Jiji] [)-] [Inositol] [(] [III] [-]

[25] [)]: According to the general click-response procedure M, from 2 g of [(] [IX] [-] [2] [)] and 1.16 mL of 3-methoxyprop-1-yne were used to obtain 321 mg. [(] [III] [-]

[25] [)](12%). HPLC-MS (condition A): rt=2.65 min; m / z: 571 [M+1]+. Two other compounds were isolated in this reaction: 278 mg of 4,6-O-(6-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)hexyl)-inositol ( [III] [-]

[42] , 10%) and 454 mg of 4-O-(6-(4-(methoxycarbonyl)-1H-1,2,3-triazol-1-yl)hexyl)-6-O- [(]6-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)hexyl)-inositol( [III] [-]

[43] ,17%). [III] [-]

[42] :HPLC-MS (condition A): rt=2.78 min; m / z: 599 [M+1]. [III] [-]

[43] :HPLC-MS (condition A): rt=2.70 min; m / z: 585 [M+1]. []

[0246] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [1] [-(] [3] [-(] [Methoxypropyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [4] [-] [base] [)] [methyl] [)-] [Inositol] [(] [III] [-]

[26] [)]: According to the general group conversion procedure N, from 110 mg of [(] [VII] [-] [1] [)], obtained 38 mg [(] [III] [-]

[26] [)](54%). HPLC-MS (condition A): rt=2.42 min; m / z: 487 [M+1] + []

[0247] [4] [,] [6] [-] [, O , ] [-] [pair] [(()] [1] [-(] [6] [-] [Methoxyhexyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [4] [-] [base] [)] [methyl] [)-] [Inositol] [(] [III] [-]

[27] [)]: According to the general group conversion procedure N, from 160 mg of [(] [VII] [-] [2] [)], obtained 59 mg [(] [III] [-]

[27] [)](55%). HPLC-MS (condition A): rt=2.88 min; m / z: 571 [M+1] + []

[0248] [4] [,] [6] [-] [, O , ] [-] [pair] [(()] [3] [-(] [4] [-] [Ethyloxycarbonylbutyramine] [)] [Propyl] [)] [)-] [Inositol] [(] [III] [-]

[28] [)]: According to the general amide formation procedure P, from 160 mg [(] [XII] [-] [1] [)] and 196 mg [(]

[32] [)], obtained 57 mg [(] [III] [-]

[28] [)](34%). HPLC-MS (condition B): rt=1.45 min; m / z: 551 [M+1] +, 573 [M+23] +. []

[0249] [4] [,] [6] [-] [,O , ] [-] [pair] [(] [3] [-(] [4] [-] [Methoxyphenyl] [)] [Propyl] [)] [-] [Inositol] [(] [III] [-]

[29] [)]: According to the general hydrolysis procedure S, from 60 mg of [(] [II] [-] [twenty four] [)], obtained 47 mg [(] [III] [-]

[29] [)](>99%). HPLC-MS (condition A): rt=3.31 min; m / z: 477 [M+1]+.

[0250] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-(] [3] [-(] [Trifluoromethyl] [)] [Phenyl] [)] [Propyl] [)-] [Inositol] [(] [III] [-]

[30] [)]: According to the general hydrolysis procedure S, from 262 mg of [(] [II] [-]

[25] [)], obtained 212 mg [(] [III] [-]

[30] [)](84%). HPLC-MS (condition A): rt=3.88 min; m / z: 553 [M+1] +, 575 [M+23] +. []

[0251] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-(] [right] [Toluyl] [)] [Propyl] [)] [-] [Inositol] [(] [III] [-]

[31] [)]: According to the general hydrolysis procedure S, from 85 mg of [(] [II] [-]

[26] [)], obtained 57 mg [(] [III] [-]

[31] [)](85%). HPLC-MS (condition A): rt=3.88 min; m / z: 445 [M+1] +, 467 [M+23] +.

[0252] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [4] [,] [4] [,] [4] [-] [Trifluorobutyl] [)-] [Inositol] [(] [III] [-]

[32] [)]: According to the general hydrolysis procedure S, from 3.61 g of [(] [II] [-]

[18] [)], yielded 2.73 g [(] [III] [-]

[32] [)](99%). HPLC-MS (condition A): rt=3.01 min; m / z: 401 [M+1] +, 423 [M+23] +.

[0253] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [6] [,] [6] [,] [6] [-] [Trifluorohexyl] [)-] [Inositol] [(] [III] [-]

[33] [)]: According to the general hydrolysis procedure S, from 594 mg [(] [II] [-]

[19] [)], obtained 457 mg [(] [III] [-]

[33] [)](98%). HPLC-MS (condition A): rt=3.40 min; m / z: 457 [M+1]+.

[0254] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [4] [-] [Methylpentyl] [)-] [Inositol] [(] [III] [-]

[34] [)]: According to the general hydrolysis procedure S, from 273 mg of [(] [II] [-]

[20] [)], obtained 193 mg [(] [III] [-]

[34] [)](96%). HPLC-MS (condition A): rt=3.40 min; m / z: 349 [M+1]+.

[0255] [4] [,] [6] [-] [, O , ] [-] [pair] [(]

[19] [-] [Methoxy] [nineteen] [-]

[10] [-] [Alkyne] [-] [1] [-] [base] [)-] [Inositol] [(] [III] [-]

[35] [)]: According to the general hydrolysis procedure S, from 1.2 g of [(] [II] [-] [twenty one] [)], yielding 1.03 g [(] [III] [-]

[35] [)](>99%). HPLC-MS (condition A): rt=7.18 min; m / z: 765.6 [M+1] +, 787.7 [M+23] +.

[0256] [4] [,] [6] [-] [,O , ] [-] [pair] [(] [3] [-(] [3] [-] [Phenylurea] [)] [Propyl] [)] [-] [Inositol] [(] [III] [-]

[36] [)]: According to the general urea formation procedure H, from 89 mg [(] [XII] [-] [1] [)] and 39 uL of phenyl isocyanate were used to obtain 90 mg [(] [III] [-]

[36] [)](>99%). HPLC-MS (condition A): rt=2.70 min; m / z: 533 [M+1]+.

[0257] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-(] [3] [-] [Cyclopentyl] [Urea] [)] [Propyl] [)] [-] [Inositol] [(] [III] [-]

[37] [)]: According to the general urea formation procedure H, from 89 mg [(] [XII] [-] [1] [)] and 40.2 μL of isocyanate-cyclopentane yielded 80 mg [(] [III] [-]

[37] [)](91%). HPLC-MS (condition A): rt=2.79 min; m / z: 517 [M+1]+.

[0258] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-((] [Methoxycarbonyl] [)] [Amine] [)] [Propyl] [)] [-] [Inositol] [(] [III] [-]

[38] [)]: According to the general carbamate formation procedure V, from 74 mg [(] [XII] [-] [1] [)], obtained 7 mg [(] [III] [-]

[38] [)](12%). HPLC-MS (condition B): rt=0.25 min; m / z: 411 [M+1] +, 433 [M+23] +. []

[0259] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-] [Acetaminopentyl] [)-] [Inositol] [(] [III] [-]

[39] [)]: According to the general hydrolysis procedure S, from 93 mg of [(] [XIII] [-] [1] [)], obtained 52 mg [(] [III] [-]

[39] [)](72%). HPLC-MS (condition B): rt=0.25 min; m / z: 435 [M+1] +, 457 [M+23] +. []

[0260] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-] [Benzylaminopentyl] [)-] [Inositol] [(] [III] [-]

[40] [)]: According to the general hydrolysis procedure S, from 43 mg of [(] [XIII] [-] [2] [)], obtained 35 mg [(] [III] [-]

[40] [)](>99%). HPLC-MS (condition A): rt=2.92 min; m / z: 559 [M+1]+. []

[0261] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-(] [thiophene] [-] [2] [-] [Cremate] [)] [Pentyl] [)-] [Inositol] [(] [III] [-]

[41] [)]: According to the general acetamide formation procedure P, from 121 mg [(] [XII] [-] [2] [)] and 129 mg [(]

[33] [)], obtained 158 mg [(] [III] [-]

[41] [)](97%). HPLC-MS (condition B): rt=2.14 min; m / z: 571 [M+1]+. []

[0262] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [4] [-] [Amine] [-] [4] [-] [Side-oxybutyl] [)-] [Inositol] [(] [III] [-]

[44] [)]: 185 mg [(] [III] [-]

[47] [)] was dissolved in 1 mL of ammonia water (37% aqueous solution) and the solution was stirred at 60°C for 24 hours. Subsequently, the solution was concentrated under vacuum to obtain 98 mg. [(] [III] [-]

[44] [)](57%). HPLC-MS (condition A): rt=2.44 min; m / z: 381 [M+1] +, 403 [M+23] +. []

[0263] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-(] [3] [-] [Propyl] [Urea] [)] [Pentyl] [)-] [Inositol] [(] [III] [-]

[45] [)]: According to the general urea formation procedure H, from 89 mg [(] [XII] [-] [1] [)] and 50 μL of 1-isocyanopropane were used to obtain 120 mg [(] [III] [-]

[45] [)](91%). HPLC-MS (condition A): rt=2.72 min; m / z: 521 [M+1] +. []

[0264] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-((] [Methoxycarbonyl] [)] [Amine] [)] [Pentyl] [)-] [Inositol] [(] [III] [-]

[46] [)]: According to the general hydrolysis procedure S, from 54 mg of [(] [XIII] [-] [3] [)], obtained 43 mg [(] [III] [-]

[46] [)](>99%). HPLC-MS (condition A): rt=2.62 min; m / z: 467 [M+1] +, 490 [M+23] +. []

[0265] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-] [Methoxycarbonylpropyl] [)-] [Inositol] [(] [III] [-]

[47] [)]: According to the general hydrolysis procedure S, from 274 mg of [(] [II] [-]

[27] [)], obtained 200 mg [(] [III] [-]

[47] [)](97%). 1H NMR (400 MHz, methanol-d 4) δ 3.79 (br, 1H), 3.74-3.60 (m, 4H), 3.31-3.25 (m, 4H), 3.22 (s, 6H), 2.26-2.19 (m, 4H), 1.76 (p, J= 6.8 Hz, 4H). [] [, C.3. , ] [Intermediate substance] [IV] [and] [IV] ['] [, , ]

[0266] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-(] [Benzyloxy] [)] [Pentyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] (IV-26): Administered in doses of 164 mg according to the universal phosphorylation schedule G. [(] [III] [-] [1] [)], obtained 173 mg [(] [IV] [-]

[26] [)](44.6%). HPLC-MS (condition A): rt=4.85 min; m / z: 1261 [M+1] +. []

[0267] [4] [,] [6] [-] [, O , ] [-] [pair] [(]

[10] [-(] [Benzyloxy] [)] [Guiji] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-] [1] [)]: According to the general phosphorylation schedule G, from 50 mg... [(] [III] [-] [3] [)], obtained 50 mg [(] [IV] [-] [1] [)](48%). HPLC-MS (condition B): rt=4.21 min; m / z: 1401 [M+1] +. []

[0268] [4] [,] [6] [-] [, O , ] [-] [pair] [(]

[14] [-(] [Benzyloxy] [)] [Tetradecyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-] [2] [)]: According to the general phosphorylation program G, from 16 mg [(] [III] [-] [4] [)], obtained 8 mg [(] [IV] [-] [2] [)](26%). []

[0269] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-] [Methoxypropyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-] [3] [)]: According to the general phosphorylation schedule G, from 37 mg [(] [III] [-]

[12] [)], obtained 25 mg [(] [IV] [-] [3] [)](21%). HPLC-MS (condition A): rt=3.78 min; m / z: 1053 [M+1] +. []

[0270] 4,6-O-bis(5-methoxypentyl)-1,2,3,5-O-tetra(3-oxo-iono-1,5-dihydrobenzo[e][1,3,2]dioxaphosphazenecycloheptane-3-yl)-inositol (IV-4): 444 mg of [the product is used according to the general phosphorylation procedure G]. [(] [III] [-] [2] [)], obtained 326 mg [(] [IV] [-] [4] [)](25%). HPLC-MS (condition A): rt=4.03 min; m / z: 1109 [M+1] +. []

[0271] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [7] [-] [Methoxyheptyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-] [5] [)]: According to the general phosphorylation schedule G, 365 mg of [(] [III] [-]

[13] [)], obtained 191 mg [(] [IV] [-] [5] [)](19.6%). HPLC-MS (condition A): rt=4.49 min; m / z: 1165 [M+1]+. []

[0272] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [7] [-] [Methoxy] [Renji] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-] [6] [)]: According to the general phosphorylation program G, from 219 mg [(] [III] [-]

[14] [)], obtained 71 mg [(] [IV] [-] [6] [)](13.1%). HPLC-MS (condition A): rt=4.98 min; m / z: 1221.6 [M+1]+. []

[0273] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e, ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [4] [,] [6] [-] [, O , ] [-] [Dipropyl] [, - , ] [Inositol] [(] [IV] [-] [7] [)]: According to the general phosphorylation schedule G, from 26.3 mg [(] [III] [-]

[15] [)], obtained 24 mg [(] [IV] [-] [7] [)](24%). HPLC-MS (condition A): rt=3.99 min; m / z: 993 [M+1]+. []

[0274] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [4] [,] [6] [-] [, O , ] [-] [Dipentyl] [-] [Inositol] [(] [IV] [-] [8] [)]: According to the general phosphorylation schedule G, from 105 mg... [(] [III] [-]

[16] [)], obtained 143 mg [(] [IV] [-] [8] [)](42%). HPLC-MS (condition A): rt=4.39 min; m / z: 1049[M+1]+. []

[0275] [4] [,] [6] [-] [, O , ] [-] [Second Gengji] [-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-] [9] [)]: According to the general phosphorylation schedule G, 150 mg of... [(] [III] [-]

[17] [)], obtained 244 mg [(] [IV] [-] [9] [)](55%). HPLC-MS (condition A): rt=5.04 min; m / z: 1105[M+1]+. []

[0276] [4] [,] [6] [-] [, O , ] [-] [Dioctyl] [-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[10] [)]: According to the general phosphorylation schedule G, from 180 mg... [(] [III] [-]

[18] [)], obtained 64 mg [(] [IV] [-]

[10] [)](14%). 1H NMR (400 MHz, chloroform-d) δ 7.35-7.09 (m, 16H), 5.41-4.97 (m, 17H), 4.43 (t, J= 8.8 Hz, 2H), 4.37 (dt, J= 11.2, 4.8 Hz, 1H), 3.81 (t, J= 8.8 Hz, 2H), 3.64 (t, J= 7.2 Hz, 4H), 1.54 (p, J= 7.2 Hz, 4H), 1.25-1.11 (m, 28H), 0.79 (t, J= 7.2 Hz, 6H). []

[0277] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [4] [,] [6] [-] [, O , ] [-] [two] [(] [Tetradecyl] [)-] [Inositol] [(] [IV] [-]

[11] [)]: According to the general phosphorylation schedule G, from 134 mg... [(] [III] [-]

[19] [)], obtained 193 mg [(] [IV] [-]

[11] [)](63%). HPLC-MS (condition B): rt=5.25 min; m / z: 1301 [M+1] +. []

[0278] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-] [Ethoxy] [Carbonylpentyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[12] [)]: According to the general phosphorylation schedule G, from 90 mg... [(] [III] [-] [5] [)], yielding 35.5 mg [(] [IV] [-]

[12] [)](15%). HPLC-MS (condition A): rt=4.31 min; m / z: 1193 [M+1]+. []

[0279] [4] [,] [6] [-] [, O , ] [-] [pair] [(]

[10] [-] [ethoxycarbonyldecyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[13] [)]: According to the general phosphorylation schedule G, from 129 mg... [(] [III] [-] [6] [)], obtained 161 mg [(] [IV] [-]

[13] [)](57%). HPLC-MS (condition A): rt=5.38 min; m / z: 1333 [M+1] +. []

[0280] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [,e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-(] [1, H , ] [-] [Pyrazole] [-] [1] [-] [base] [)] [Pentyl] [)-] [Inositol] [(] [IV] [-]

[14] [)]: According to the general phosphorylation schedule G, 70 mg of... [(] [III] [-] [9] [)], obtained 26 mg [(] [IV] [-]

[14] [)](14%). HPLC-MS (condition A): rt=3.89 min; m / z: 1182 [M+1] +. []

[0281] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-(] [1, H , ] [-] [1] [,] [2] [,] [4] [-] [Triazole] [-] [1] [-] [base] [)] [Pentyl] [)-] [Inositol] [(] [IV] [-]

[15] [)]: According to the general phosphorylation schedule G, from 19 mg... [(] [III] [-]

[10] [)], yielding 8.8 mg [(] [IV] [-]

[15] [)]. HPLC-MS (condition A): rt = 3.46 min; m / z: 1184 [M+1] +. []

[0282] [4] [,] [6] [-] [, O , ] [-] [pair] [(()] [1] [-(] [2] [-(] [Benzyloxycarbonyl] [)] [Ethyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [4] [-] [base] [)] [methyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[16] [)]: According to the general phosphorylation schedule G, from 423 mg [(] [III] [-]

[20] [)], obtained 445 mg [(] [IV] [-]

[16] [)](50%). HPLC-MS (condition A): rt=4.16 min; m / z: 1395[M+1]+. []

[0283] [4] [,] [6] [-] [, O , ] [-] [pair] [(()] [1] [-(] [3] [-] [Methoxypropyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [4] [-] [base] [)] [methyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[17] [)]: According to the general phosphorylation schedule G, from 62 mg... [(] [III] [-]

[26] [)], obtained 64 mg [(] [IV] [-]

[17] [)](41%). HPLC-MS (condition A): rt=3.64 min; m / z: 1215 [M+1] +. []

[0284] [4] [,] [6] [-] [, O , ] [-] [pair] [(()] [1] [-(] [6] [-] [Methoxyhexyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [4] [-] [base] [)] [methyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[18] [)]: According to the general phosphorylation schedule G, from 59 mg [(] [III] [-]

[27] [)], obtained 15 mg [(] [IV] [-]

[18] [)](11%). HPLC-MS (condition A): rt=3.95 min; m / z: 1299 [M+1] +. []

[0285] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-(] [4] [-(] [2] [-(] [Benzyloxycarbonyl] [)] [Ethyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Propyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[19] [)]: According to the general phosphorylation program G, from 100 mg... [(] [III] [-] [twenty one] [)], obtained 86 mg [(] [IV] [-]

[19] [)](43%). HPLC-MS (condition B): rt=3.18 min; m / z: 1451 [M+1]+. []

[0286] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-(] [4] [-(] [Methoxymethyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Propyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[20] [)]: According to the general phosphorylation schedule G, from 40 mg... [(] [III] [-] [twenty two] [)], yielded 7.2 mg [(] [IV] [-]

[20] [)](7%). HPLC-MS (condition A): rt=3.48 min; m / z: 1215 [M+1]+. []

[0287] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [4] [-(] [4] [-(] [Methoxymethyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Dilki] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzo[]] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxophosphorus heterocyclic heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-] [twenty one] [)]: According to the general phosphorylation schedule G, from 20 mg... [(] [III] [-] [twenty three] [)], obtained 11 mg [(] [IV] [-] [twenty one] [)](23%). HPLC-MS (condition A): rt=3.53 min; m / z: 1243 [M+1] +. []

[0288] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-(] [4] [-(] [Methoxymethyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Pentyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-] [twenty two] [)]: According to the general phosphorylation schedule G, from 54 mg [(] [III] [-] [twenty four] [)], yielding 9.7 mg [(] [IV] [-] [twenty two] [)](8%). HPLC-MS (condition A): rt=3.59 min; m / z: 1271 [M+1]+. []

[0289] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [6] [-(] [4] [-(] [Methoxymethyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Jiji] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-] [twenty three] [)]: According to the general phosphorylation schedule G, 85 mg of [(] [III] [-]

[25] [)], yielding 35.5 mg [(] [IV] [-] [twenty three] [)](18%). HPLC-MS (condition A): rt=3.66 min; m / z: 1299 [M+1] +. []

[0290] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [2] [-(] [4] [-] [Acetylpyridinium] [𠯤] [-] [1] [-] [base] [)] [Ethyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-] [twenty four] [)]: According to the general phosphorylation program G, 81.5 mg of [(] [III] [-]

[11] [)], obtained 16 mg [(] [IV] [-] [twenty four] [)](8%). HPLC-MS (condition B): rt=1.92 min; m / z: 1217 [M+1]+. []

[0291] [4] [,] [6] [-] [, O , ] [-] [pair] [(()] [3] [-(] [4] [-] [Ethyloxycarbonyl] [Butylated] [)] [Propyl] [))-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[25] [)]: According to the general phosphorylation schedule G, from 57 mg... [(] [III] [-]

[28] [)], obtained 28 mg [(] [IV] [-]

[25] [)](21%). HPLC-MS (condition A): rt=2.66 min; m / z: 1279 [M+1] +. []

[0292] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [2] [-] [Cyclopropylethyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[27] [)]: According to the general phosphorylation program G, from 2.3 g of [(] [III] [-] [7] [)], obtained 3 g [(] [IV] [-]

[27] [)](39%). HPLC-MS (condition A): rt=4.30 min; m / z: 1045 [M+1]+.

[0293] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [2] [-] [Cyclopentylethyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[28] [)]: According to the general phosphorylation schedule G, from 200 mg... [(] [III] [-] [8] [)], obtained 164 mg [(] [IV] [-]

[28] [)](28%). HPLC-MS (condition A): rt=4.74 min; m / z: 1101 [M+1] +.

[0294] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-(] [4] [-] [Methoxyphenyl] [)] [Propyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[29] [)]: According to the general phosphorylation schedule G, from 60 mg [(] [III] [-]

[29] [)], obtained 36 mg [(] [IV] [-]

[29] [)](24%). HPLC-MS (condition A): rt=4.20 min; m / z: 1206 [M+1]+.

[0295] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-(] [3] [-(] [Trifluoromethyl] [)] [Phenyl] [)] [Propyl] [)-] [Inositol] [(] [IV] [-]

[30] [)]: According to the general phosphorylation schedule G, from 214 mg [(] [III] [-]

[30] [)], obtained 64 mg [(] [IV] [-]

[30] [)](13%). HPLC-MS (condition A): rt=4.83 min; m / z: 1281 [M+1] +.

[0296] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-(] [right] [Toluyl] [)] [Propyl] [)-] [Inositol] [(] [IV] [-]

[31] [)]: According to the general phosphorylation program G, from 54.7 mg [(] [III] [-]

[31] [)], yielding 19.1 mg [(] [IV] [-]

[31] [)](13%). HPLC-MS (condition A): rt=4.76 min; m / z: 1274 [M+1]+.

[0297] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [4] [,] [6] [-] [, O, ] [-] [pair] [(] [4] [,] [4] [,] [4] [-] [Trifluorobutyl] [)-] [Inositol] [(] [IV] [-]

[32] [)]: According to the general phosphorylation program G, from 1.62 g of [(] [III] [-]

[32] [)], yielding 2.34 g [(] [IV] [-]

[32] [)](51%). HPLC-MS (condition A): rt=4.29 min; m / z: 1129 [M+1] +.

[0298] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [6] [,] [6] [,] [6] [-] [Trifluorohexyl] [)-] [Inositol] [(] [IV] [-]

[33] [)]: According to the general phosphorylation schedule G, 457 mg of [(] [III] [-]

[33] [)], obtained 414 mg [(] [IV] [-]

[33] [)](35%). HPLC-MS (condition A): rt=4.53 min; m / z: 1185 [M+1] +.

[0299] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [4] [-] [Methylpentyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[34] [)]: According to the general phosphorylation schedule G, 457 mg of [(] [III] [-]

[34] [)], obtained 168 mg [(] [IV] [-]

[34] [)](12%). HPLC-MS (condition A): rt=4.568 min; m / z:1077 [M+1]+.

[0300] [4] [,] [6] [-] [, O , ] [-] [pair] [(]

[19] [-] [Methoxy] [nineteen] [-]

[10] [-] [Alkyne] [-] [1] [-] [base] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[35] [)]: According to the general phosphorylation program G, from 1.03 g of [(] [III] [-]

[35] [)], obtained 939 mg [(] [IV] [-]

[35] [)](45%). HPLC-MS (condition A): rt=7.19 min; m / z: 1494 [M+1]+.

[0301] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-(] [3] [-] [Phenylurea] [)] [Propyl] [)-] [Inositol] [(] [IV] [-]

[36] [)]: According to the general phosphorylation schedule G, from 96 mg... [(] [III] [-]

[36] [)], obtained 187 mg [(] [IV] [-]

[36] [)](82%). HPLC-MS (condition A): rt=4.02 min; m / z: 1262 [M+1] +.

[0302] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-(] [3] [-] [Cyclopentyl] [Urea] [)] [Propyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[37] [)]: According to the general phosphorylation schedule G, from 80 mg [(] [III] [-]

[37] [)], obtained 181 mg [(] [IV] [-]

[37] [)](94%). HPLC-MS (condition A): rt=3.83 min; m / z: 1245 [M+1]+.

[0303] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-((] [Methoxycarbonyl] [)] [Amine] [)] [Propyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[38] [)]: According to the general phosphorylation schedule G, from 10 mg... [(] [III] [-]

[38] [)], obtained 3 mg [(] [IV] [-]

[38] [)](11%). HPLC-MS (condition B): rt=2.90 min; m / z: 1139 [M+1] +.

[0304] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-] [Acetamino] [Pentyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[39] [)]: According to the general phosphorylation schedule G, from 52 mg... [(] [III] [-]

[39] [)], obtained 110 mg [(] [IV] [-]

[39] [)](79%). HPLC-MS (condition B): rt=2.69 min; m / z: 1163 [M+1]+. []

[0305] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-] [Benzylaminopentyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[40] [)]: According to the general phosphorylation schedule G, from 39 mg... [(] [III] [-]

[40] [)], obtained 38 mg [(] [IV] [-]

[40] [)](42%). HPLC-MS (condition A): rt=4.04 min; m / z: 1288 [M+1] +. []

[0306] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-(] [thiophene] [-] [2] [-] [Cremate] [)] [Pentyl] [)-] [Inositol] [(] [IV] [-]

[41] [)]: According to the general phosphorylation program G, 158 mg of [(] [III] [-]

[41] [)], obtained 196 mg [(] [IV] [-]

[41] [)](54%). HPLC-MS (condition B): rt=3.13 min; m / z: 1299 [M+1] +. []

[0307] [4] [,] [6] [-] [, O , ] [-(] [6] [-(] [4] [-(] [Methoxycarbonyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Jiji] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzo[]] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxophosphorus heterocyclic heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[42] [)]: According to the general phosphorylation program G, 278 mg of ( [III] [-]

[42] [)], obtained 34 mg [(] [IV] [-]

[42] [)](5.5%). HPLC-MS (condition A): rt=3.86 min; m / z: 1327 [M+1]+. []

[0308] [4] [-] [, O , ] [-(] [6] [-(] [4] [-(] [Methoxycarbonyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Jiji] [)-] [6] [-] [, O , ] [, - , ] [(] [6] [-(] [4] [-(] [Methoxymethyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Jiji] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzo[]] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxophosphorus heterocyclic heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[43] [)]: According to the general phosphorylation program G, 454 mg of ( [III] [-]

[43] [)], obtained 101 mg [(] [IV] [-]

[43] [)](10%). HPLC-MS (condition A): rt=3.76 min; m / z: 1313 [M+1] +. []

[0309] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [4] [-] [Amine] [-] [4] [-] [Side-oxybutyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[44] [)]: According to the general phosphorylation program G, from 97.5 mg [(] [III] [-]

[44] [)], obtained 179 mg [(] [IV] [-]

[44] [)](59%). HPLC-MS (condition A): rt=3.29 min; m / z:1079.5 [M+1]+. []

[0310] [1] [,] [2] [,] [3] [,] [5] [-] [, O, ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-(] [3] [-] [Propylurea] [)] [Pentyl] [)-] [Inositol] [(] [IV] [-]

[45] [)]: According to the general phosphorylation schedule G, from 120 mg... [(] [III] [-]

[45] [)], obtained 210 mg [(] [IV] [-]

[45] [)](73%). HPLC-MS (condition A): rt=3.73 min; m / z: 1250.5 [M+1] +. []

[0311] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-((] [Methoxycarbonyl] [)] [Amine] [)] [Pentyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[46] [)]: According to the general phosphorylation schedule G, from 50 mg... [(] [III] [-]

[46] [)], obtained 64 mg [(] [IV] [-]

[46] [)](50%). HPLC-MS (condition A): rt=3.86 min; m / z: 1195 [M+1]+. []

[0312] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-] [Methoxycarbonylpropyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [e] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[47] [)]: According to the general phosphorylation schedule G, 70 mg of... [(] [III] [-]

[47] [)], obtained 40 mg [(] [IV] [-]

[47] [)](19%). HPLC-MS (condition A): rt= 3.77 min; m / z: 1109 [M+1] +. []

[0313] [4] [,] [6] [-] [, O , ] [-] [two] [Propynyl] [-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] [-]

[48] [)]: According to the general phosphorylation program G, from 3.92 g of [(] [VI] [-] [1] [)], yielded 4.69 g [(] [IV] [-]

[48] [)](32%). HPLC-MS (condition A): rt= 3.69 min; m / z: 985 [M+1]+. []

[0314] [4] [,] [6] [-] [, O , ] [-] [Dipentyl] [-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Sulfide group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [e] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] ['-] [1] [)]: According to the general thiophosphorylation procedure T, from 64 mg of ( [III] [-]

[16] [)], obtained 28 mg [(] [IV] ['-] [1] [)](13%). HPLC-MS (condition A): rt=5.94 min; m / z: 1113 [M+1] +.

[0315] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-] [Methoxypentyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Sulfide group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [e] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [IV] ['-] [2] [)]: According to the general thiophosphorylation procedure T, from 76 mg [(] [III] [-] [2] [)], obtained 70 mg [(] [IV] ['-] [2] [)](30%). HPLC-MS (condition A): rt=5.49 min; m / z: 1173 [M+1]+. [, C.4. , ] [, intermediate , ] [, V , ] [, , ]

[0316] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [4] [,] [6] [-] [, O , ] [-] [Dipropynyl] [-] [Inositol] [(] [V] [-] [1] [)]: According to general alkylation procedure A, 1.2 g of toluene (2.1 equivalents, 80%) containing 3-bromoprop-1-yne was obtained from 1.0 mL. [(] [V] [-] [1] [)](>99%). HPLC-MS (condition A): rt=4.36 min; m / z: 381 [M+1]+. [] [, C.5. , ] [, intermediate , ] [, VI , ] [, , ]

[0317] [4] [,] [6] [-] [, O , ] [-] [Dipropynyl] [-] [Inositol] [(] [VI] [-] [1] [)]: According to the general hydrolysis procedure D, from 1.2 g of [(] [V] [-] [1] [)], obtained 740 mg [(] [VI] [-] [1] [)](92%). 1H NMR (400 MHz, methanol-d 4) δ 4.48 (d, J= 2.4 Hz, 4H), 3.89 (t, J= 2.8 Hz, 1H), 3.56 (t, J= 9.6 Hz, 2H), 3.39 (dd, J= 9.6, 2.8 Hz, 2H), 3.33 (d, J= 9.6 Hz, 1H), 2.80 (t, J= 2.4 Hz, 2H). [] [, C.6. , ] [, intermediate , ] [, VII , ] [, , ]

[0318] [4] [,] [6] [-] [, O , ] [-] [pair] [(()] [1] [-(] [3] [-(] [Toluenesulfonyloxy] [)] [Propyl] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [4] [-] [base] [)] [methyl] [)-] [Inositol] [(] [VII] [-] [1] [)]: According to the general click-response procedure L, starting with 100 mg... [(] [8] [)], obtained 110 mg [(] [VII] [-] [1] [)](73%). HPLC-MS (condition A): rt=3.30 min; m / z: 767 [M+1]+. []

[0319] [4] [,] [6] [-] [, O , ] [-] [pair] [(()] [1] [-(] [6] [-(] [Toluenesulfonyloxy] [)] [Jiji] [)-] [1, H , ] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [4] [-] [base] [)] [methyl] [)-] [Inositol] [(] [VII] [-] [2] [)]: According to the general click-response procedure L, 116 mg of [(]

[17] [)], obtained 162 mg [(] [VII] [-] [2] [)](98%). HPLC-MS (condition A): rt=3.71 min. [] [, C.7. , ] [, intermediate , ] [, VIII , ] [, , ]

[0320] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-] [Azidepropyl] [)-] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [VIII] [-] [1] [)]: According to the general alkylation procedure A, 1.27 g (2.1 equivalents in 5.9 mL DMF) of [(] [8] [)], obtained 249 mg [(] [VIII] [-] [1] [)](22%). HPLC-MS (condition A): rt=5.12 min; m / z: 471 [M+1]+. []

[0321] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-] [azidopentyl] [)-] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [VIII] [-] [2] [)]: According to the general alkylation procedure A, 2 g (2.1 equivalents in 8.4 mL DMF) of [(]

[10] [)], obtained 900 mg [(] [VIII] [-] [2] [)](51%). HPLC-MS (condition A): rt=5.62 min; m / z: 527 [M+1] +, 549 [M+23] +. []

[0322] [4] [,] [6] [-] [, O , ] [-] [pair] [(]

[10] [-] [azidodecyl] [)-] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [VIII] [-] [3] [)]: According to the general alkylation procedure A, 234 mg (in 2 mL DMF, 2.05 equivalents) of [(]

[12] [)], yielding 57.5 mg [(] [VIII] [-] [3] [)](27%). 1H NMR (400 MHz, chloroform-d) δ 5.52 (d, J= 1.6 Hz, 1H), 4.36 (h, J= 1.6 Hz, 1H), 4.24 (q, J= 1.6 Hz, 1H), 4.16 (t, J= 4 Hz, 2H), 4.10 (dt, , 1.57-1.46 (m, 4H), 1.38-1.26 (m, 24H), 0.94 (s, 9H), 0.14 (s, 6H). []

[0323] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [4] [-] [azidobutyl] [)-] [2] [-] [, O, ] [-] [Tributyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [VIII] [-] [4] [)]: According to the general alkylation procedure A, 245 mg (2 equivalents, in 1.2 mL DMF) [(]

[19] [)], obtained 17 mg [(] [VIII] [-] [4] [)](7%). HPLC-MS (condition A): rt=5.33 min; m / z: 499 [M+1] +, 521 [M+1] +. []

[0324] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [6] [-] [azidohexyl] [)-] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [VIII] [-] [5] [)]: According to the general alkylation procedure A, 200 mg (2 equivalents, in 1.6 mL DMF) [(]

[17] [)], obtained 74 mg [(] [VIII] [-] [5] [)](20%). HPLC-MS (condition A): rt=5.97 min; m / z: 555 [M+1] +, 577 [M+1] +. [] [, C.8. , ] [, intermediate , ] [, IX , ] [, , ]

[0325] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [4] [-] [azidobutyl] [)-] [Inositol] [(] [IX] [-] [1] [)]: Based on the general hydrolysis procedure C with slight modifications (water treatment), from 16.7 mg [(] [VIII] [-] [4] [)], obtained 8 mg [(] [IX] [-] [1] [)](64%). HPLC-MS (condition A): rt=2.76 min; m / z: 375 [M+1] +, 397 [M+23] +. []

[0326] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [6] [-] [azidohexyl] [)-] [Inositol] [(] [IX] [-] [2] [)]: Based on the general hydrolysis procedure C with slight modifications (water treatment), from 74.7 mg [(] [VIII] [-] [5] [)], obtained 40 mg [(] [IX] [-] [2] [)](69%). HPLC-MS (condition A): rt=3.29 min; m / z: 431 [M+1] +, 453 [M+23] +. []

[0327] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-] [Azidepropyl] [)-] [Inositol] [(] [IX] [-] [3] [)]: According to the general hydrolysis procedure E, from 250 mg... [(] [VIII] [-] [1] [)], obtained 174 mg [(] [IX] [-] [3] [)](94%). HPLC-MS (condition A): rt=2.45 min; m / z: 347 [M+1]+, 369 [M+23]+. []

[0328] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-] [azidopentyl] [)-] [Inositol] [(] [IX] [-] [4] [)]: According to the general hydrolysis procedure D, from 8.9 mg [(] [VIII] [-] [2] [)], yielding 6.8 mg [(] [IX] [-] [4] [)](>99%). HPLC-MS (condition A): rt=3.06 min; m / z: 403 [M+1] +, 425 [M+23] +.

[0329] [4] [,] [6] [-] [, O , ] [-] [pair] [(]

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

[0330] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-] [Azidepropyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [X] [-] [1] [)]: According to the general phosphorylation schedule G, from 305 mg... [(] [IX] [-] [3] [)], obtained 148 mg [(] [X] [-] [1] [)](16%). HPLC-MS (condition A): rt=4.01 min; m / z: 1075 [M+1]+. []

[0331] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-] [azidopentyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [X] [-] [2] [)]: According to the general phosphorylation schedule G, from 300 mg... [(] [IX] [-] [4] [)], obtained 530 mg [(] [X] [-] [2] [)](63%). HPLC-MS (condition A): rt=4.32 min; m / z: 1131 [M+1]+. []

[0332] [4] [,] [6] [-] [, O , ] [-] [pair] [(]

[10] [-] [azidodecyl] [)-] [1] [,] [2] [,] [3] [,] [5] [-] [, O , ] [-] [IV] [(] [3] [-] [Oxygen ion group] [-] [1] [,] [5] [-] [Dihydrobenzox] [[] [, e , ] [][] [1] [,] [3] [,] [2] []] [Dioxaphosphonium heptane] [-] [3] [-] [base] [)-] [Inositol] [(] [X] [-] [3] [)]: According to the general phosphorylation program G, from 100 mg... [(] [IX] [-] [5] [)], obtained 63 mg [(] [X] [-] [3] [)](27%). HPLC-MS (condition B): rt=3.86 min; m / z: 1271 [M+1] +. [] [, C.10. , ] [, intermediate , ] [, XI , ] [, , ]

[0333] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-] [aminopropyl] [)-] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [XI] [-] [1] [)]: According to the general azide reduction procedure Q, from 144 mg... [(] [VIII] [-] [1] [)], to obtain sufficiently pure [(] [XI] [-] [1] [)], can be used without purification. HPLC-MS (condition B): rt=2.43 min; m / z: 419 [M+1] +, 441 [M+23] +. []

[0334] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-] [Aminopentyl] [)-] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [XI] [-] [2] [)]: According to the general azide reduction procedure Q, from 2.5 g of [(] [VIII] [-] [2] [)], after column purification, 1.4 g was obtained. [(] [XI] [-] [2] [)](62%). HPLC-MS (condition A): rt=2.73 min; m / z: 475 [M+1] +, 493 [M+23] +. [] [, C.11. , ] [, intermediate , ] [, XII , ] [, , ]

[0335] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [3] [-] [aminopropyl] [)-] [Inositol] [·] [2TFA] [] [(] [XII] [-] [1] [)]: Based on the slightly modified (water treatment) general hydrolysis procedure C, from 128 mg [(] [XI] [-] [1] [)], obtained 160 mg [(] [XII] [-] [1] [)](>99%). HPLC-MS (condition B): rt=0.24 min; m / z: 295 [M+1] +.

[0336] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-] [Aminopentyl] [)-] [Inositol] [·] [2HCl] [(] [XII] [-] [2] [)]: According to the general hydrolysis procedure S, from 1.13 g of [(] [XI] [-] [2] [)], obtained 447 mg [(] [XII] [-] [2] [)](54%). HPLC-MS (condition B): rt=0.25 min; m / z: 351 [M+1] +. [, C.12. , ] [, intermediate , ] [, XIII , ] [, , ]

[0337] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-] [Acetamino] [Pentyl] [)-] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [XIII] [-] [1] [)]: According to the general amide formation procedure P, from 115 mg [(] [XI] [-] [2] [)] and 38 μL of acetyl chloride were added to obtain 93 mg [(] [XIII] [-] [1] [)](69%). HPLC-MS (condition A): rt=3.67 min; m / z: 559 [M+1]+. []

[0338] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-] [Benzylaminopentyl] [)-] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [, - , ] [Inositol] [(] [XIII] [-] [2] [)]: According to the general amide formation procedure P, from 125 mg [(] [XI] [-] [2] [)] and 67 μL of benzoyl chloride, yielding 57 mg [(] [XIII] [-] [2] [)](32%). HPLC-MS (condition B): rt=3.56 min; m / z: 683 [M+1] +. []

[0339] [2] [-] [, O , ] [-] [Tributyldimethylsilyl] [-] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-((] [Methoxycarbonyl] [)] [Amine] [)] [Pentyl] [)-] [1] [,] [3] [,] [5] [-] [, O , ] [-] [Methionine] [-] [Inositol] [(] [XIII] [-] [3] [)]: According to the general carbamate formation procedure V, from 127 mg [(] [XI] [-] [2] [)], obtained 54 mg [(] [XIII] [-] [3] [)](38%). HPLC-MS (condition A): rt=4.31 min; m / z: 591 [M+1]+. [, D. , ] [, Compound characterization: analysis and spectroscopic testing , ] [, , ] [, D1. NMR , ]

[0340] NMR spectra were recorded on an Agilent VNMRS-400 (400.10 MHz for 1H and 162 MHz for 31P). In 1H NMR, chemical shifts are expressed in ppm relative to TMS, and coupling constants (J) are expressed in Hz. In 31P NMR, phosphorus NMR spectra were collected without an internal standard. Phosphoric acid is commonly used as an internal standard, but it is not used due to concerns that it would affect 1H NMR. [] [, D.2. HPLC-MS , ]

[0341] Condition A: A 2795 Alliance Waters Aquity HPLC system was coupled with an Agilent 1100 DAD detector and a Waters ESI triple cuadrupolo Quattro micro detector. 10 μL of MeOH containing the sample was injected. Flux injection mass spectrometry (FIA) was used to analyze the mass spectrometry (MS) via an LCT Premier orthogonal accelerated time-of-flight mass spectrometer, acquiring data in positive mode via electrospray ionization (ESI). The spectrum was scanned between 50 and 1500 Da, with values ​​taken every 0.2 seconds, and peaks are shown as m / z (%) of the base peak. Stationary phase: ZORBAX extension-C18 3.5 µm 2.1 × 50 mm (Ta 35℃). [surface] [3]: Condition A, moving phase [] [Moving Phase] [A] [Moving Phase] [B] 1 Water + 0.05% formic acid Acetonitrile + 0.05% formic acid [surface] [4]: Condition A, gradient [time] [(] [minute] [)] [Flow rate] [(mL)] [ / min] [)] [A (%)] [B (%)] [curve] 1 0.0 0.50 95.0 5.0 5 2 0.50 0.50 95.0 5.0 5 3 5.50 0.50 0.0 100.0 5 4 7.50 0.50 0.0 100.0 5

[0342] Condition B: HPLC-MS was performed using a Thermo Ultimate 3000SD (Thermo Scientific Dionex) high-performance liquid chromatography system coupled to a photodiode array detector and an LTQ XL ESI-ion trap (Thermo Scientific); 5 μL–20 μL of sample MeOH (c = 0.5 mg / mL) was injected. Mass spectrometry data were analyzed by electrospray ionization in both positive and negative modes, and peaks are shown as m / z (%) of the base peak. Stationary phase: ZORBAX extension-C18 3.5 µm 2.1 × 50 mm (Ta 35℃). [surface] [5]: Condition B, moving phase [] [Moving Phase] [A] [Moving Phase] [B] 1 Water + 0.05% formic acid Acetonitrile + 0.05% formic acid [surface] [6]: Condition B, gradient [time] [(] [minute] [)] [Flow rate] [(mL)] [ / min] [)] [A (%)] [B (%)] [curve] 1 0.0 0.50 95.0 5.0 5 2 0.50 0.50 95.0 5.0 5 3 5.50 0.50 0.0 100.0 5 4 7.50 0.50 0.0 100.0 5

[0343] Condition C: HPLC-MS was performed using a Thermo Ultimate 3000SD (Thermo Scientific Dionex) high-performance liquid chromatography system coupled to a photodiode array detector and an LTQ XL ESI-ion trap (Thermo Scientific); 5 μL–20 μL of sample MeOH (c = 0.5 mg / mL) was injected. Mass spectrometry data were analyzed in both positive and negative modes by electrospray ionization, and peaks are shown as m / z (%) of the base peak. Stationary phase: Xbridge BEH acetylamine 2.5 µm 4.6 x 150 mm XP. [surface] [7]: Condition C, moving phase [] [Moving Phase] [A] [Moving Phase] [B] 1 H 2O + 0.1% DEA + 40 mM AcONH 4 AcN [surface] [8]: Condition C, gradient [time] [(] [minute] [)] [Flow rate] [(mL)] [ / min] [)] [A] [(%) [B] [(%) [curve] 1 0.0 1.0 5.0 95.0 5 2 10.00 1.0 60.0 40.0 5 3 15.00 1.0 60.0 40.0 5

[0344] Condition D: HPLC-MS was performed using a Thermo Ultimate 3000SD (Thermo Scientific Dionex) high-performance liquid chromatography system coupled to a photodiode array detector and an LTQ XL ESI-ion trap (Thermo Scientific); 5 μL–20 μL of sample MeOH (c = 0.5 mg / mL) was injected. Mass spectrometry data were analyzed by electrospray ionization in both positive and negative modes, and peaks are shown as m / z (%) of the base peak. Stationary phase: ZORBAX extension-C18 3.5 µm 2.1 × 50 mm (Ta 35℃). [surface] [9]: Condition D, moving phase [] [Moving Phase] [A] [Moving Phase] [B] 1 H 2O + 0.1% DEA + 40 mM AcONH 4 AcN [surface]

[10] : Condition D, gradient [time] [(] [minute] [)] [Flow rate] [(mL)] [ / min] [)] [A] [(%) [B] [(%) [curve] 1 0.0 0.90 99.0 1.0 5 2 5.00 0.90 99.0 1.0 5 3 7.00 0.90 0.0 100.0 5 4 10.00 0.90 0.0 100.0 5

[0345] Condition E: HPLC-MS was performed using a Thermo Ultimate 3000SD (Thermo Scientific Dionex) high-performance liquid chromatography system coupled to a photodiode array detector and an LTQ XL ESI-ion trap (Thermo Scientific); 5 μL–20 μL of sample MeOH (c = 0.5 mg / mL) was injected. Mass spectrometry data were analyzed by electrospray ionization in both positive and negative modes, and peaks are shown as m / z (%) of the base peak. Stationary phase: ZORBAX extension-C18 3.5 µm 2.1 × 50 mm (Ta 30℃). [surface]

[11] : Condition E, moving phase [] [Moving Phase] [A] [Moving Phase] [B] 1 0.1% NH4OH (30%) / water 0.1% NH4OH (30%) / ACN [surface]

[12] : Condition E, gradient [time] [(] [minute] [)] [Flow rate] [(mL)] [ / min] [)] [A] [(%) [B] [(%) [curve] 1 0.0 0.60 95.0 5.0 5 2 5.00 0.60 95.0 5.0 5 3 7.00 0.60 0.0 100.0 5 4 10.00 0.60 0.0 100.0 5 [Example] [1] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [5] [-] [Hydroxypentyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound] [6] [)] []

[0346] According to the general phosphate ester deprotection procedure I, starting from 100 mg... [(] [IV] [-]

[26] [)] 38 mg was obtained [Compound] [6](56.5%). 1H NMR (400 MHz, D 2O) δ 4.87-4.80 (m, 1H), 4.55-4-15 (m, 3H), 4.10-3.80 (m, 2H), 3.81-3.71 (m, 4H), 3.45 (t, J= 6.6 Hz, 4H), 1.66-1.55 (m, 8H), 1.40 (p, J= 7.2 Hz, 4H). 31P NMR (162 MHz, D 2O) δ 4.85, 4.41, 4.21. HPLC-MS (condition C): rt = 10.06 min; m / z: 673 [M+1] +, 746 [M+1+DEA] +, 819 [M+1+2DEA] +. [Example] [2] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(]

[10] [-] [Hydroxydecyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound] [7] [)] []

[0347] According to the general phosphate ester deprotection procedure I, starting from 50 mg... [(] [IV] [-] [1] [)] 3.15 mg was obtained. [Compound] [7](10.9%). ¹H NMR (400 MHz, D₂O) δ 5.08–5.01 (m, 1H), 4.10–4.02 (m, 3H), 3.81–3.75 (m, 6H), 3.60 (t, J = 6.6 Hz, 4H), 1.66–1.60 (m, 4H), 1.56–1.52 (m, 4H), 1.30 (br, 24H). ³¹P NMR (162 MHz, D₂O) δ 1.57, -0.15, -1.08. HPLC-MS (condition C): rt = 6.89 min; m / z: 813 [M+1] +, 886 [M+1+DEA] +, 959 [M+1+2DEA] +. [Example] [3] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(]

[14] [-] [Hydroxytetradecyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound] [8] [)]

[0348] According to the general phosphate ester deprotection procedure I, starting from 8.3 mg [(] [IV] [-] [2] [)] 0.6 mg was obtained. [Compound] [8](8%). ¹H NMR (400 MHz, D₂O) δ 4.25–3.71 (m, 3H), 3.69–3.50 (m, 6H), 3.44 (t, J = 6.7 Hz, 4H), 1.54–1.29 (m, 8H), 1.15 (m, 40H). HPLC-MS (condition D): rt = 6.8 min; m / z: 998 [M⁺¹ + DEA]⁺, 1071 [M⁺¹ + 2DEA]⁺. [] [Example] [4] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [3] [-] [Methoxypropyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[10] [)] []

[0349] According to the general phosphate deprotection procedure I, starting from 23 mg... [(] [IV] [-] [3] [)] 17.7 mg was obtained. [Compound]

[10] [](99%). 1H NMR (400 MHz, D 2O) δ 4.35 (br, 4H), 4.14 (br, 2H), 3.82-3.73 (m, 4H), 3.59 (t, J= 6.7 Hz, 4H), 3.36 (s, 6H), 1.90 (q, J= 6.7, Hz, 4H). 31P NMR (162 MHz, D 2O) δ 3.90 (br). HPLC-MS (condition C): rt=9.96 min; m / z: 718 [M+1+DEA]+, 791 [M+1+2DEA]+. [Example] [5] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [5] [-] [Methoxypentyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound] [9] [)] []

[0350] According to the general phosphate ester deprotection procedure I, starting from 326 mg [(] [IV] [-] [4] [)] 193 mg was obtained [Compound] [9] [](75%). 1H NMR (400 MHz, D 2O) δ 4.47-4.36 (m, 3H), 4.31-4.21 (br, 1H) 4.20-4.13 (br, 2H), 3.74-3.66 (m, 4H), 3.50 (t, J= 6.8 Hz, 4H), 3.35 (s, 6H), 1.66-154 (m, 8H), 1.38 (p, J= 7.6 Hz, 4H). 31P NMR (162 MHz, D 2O) δ 7.46 (br), 6.71 (br). HPLC-MS (condition C): rt = 9.59 min; m / z: 774 [M+1+DEA] +, 847 [M+1+2DEA] +. [Example] [6] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [7] [-] [Methoxyheptyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[11] [)] []

[0351] According to the general phosphate deprotection procedure I, starting from 169.5 mg [(] [IV] [-] [5] [)] 29.8 mg was obtained. [Compound]

[11] (22%). 1H NMR (400 MHz, D 2O) δ 4.96 (d, J= 10.6 Hz, 1H), 4.07 (t, J= 9.2 Hz, 3H), 3.82-3.70 (m, 6H), 3.49 (t, J= 6.8 Hz, 4H), 3.34 (s, 6H), 1.63 (q, J= 7 Hz, 4H), 1.59 (q, J= 6.8 Hz, 4H), 1.18 (d, J= 4.5 Hz, 12H). 31P NMR (162 MHz, D 2O) δ 1.92, -0.04, -1.03. HPLC-MS (condition C): rt = 8.95 min; m / z: 757 [M+1] +, 830 [M+1+DEA] +, 903 [M+1+2DEA] +. [Example] [7] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [9] [-] [Methoxynonyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[12] [)]

[0352] According to the general phosphate ester deprotection procedure I, starting from 67 mg... [(] [IV] [-] [6] [)] 7.65 mg was obtained. [Compound]

[12] [14% yield]. ¹H NMR (400 MHz, D₂O) δ 4.95 (d, J = 9.8 Hz, 1H), 4.11–4.02 (m, 3H), 3.89–3.71 (m, 6H), 3.49 (t, J = 6.8 Hz, 4H), 3.18 (s, 6H), 1.65–1.55 (m, 8H), 1.31 (br, 20H). ³¹P NMR (162 MHz, D₂O) δ 0.84, -0.36, -1.12. HPLC-MS (condition C): rt = 8.52 min; m / z: 813 [M+1] +, 886 [M+1+DEA] +, 959 [M+1+2DEA] +. [Example] [8] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [Dipropyl] [-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound] [4] [)] []

[0353] According to the general phosphate deprotection procedure I, starting from 24 mg... [(] [IV] [-] [7] [)] 3.8 mg was obtained. [Compound] [4](20%). ¹H NMR (400 MHz, D₂O) δ 4.96 (d, J = 10.6 Hz, 1H), 4.20–3.96 (m, 3H), 3.75 (t, J = 7.2 Hz, 4H), 3.75–371 (m, 2H), 1.63 (sextet, J = 7.2 Hz, 4H), 0.90 (t, J = 7.2 Hz, 6H). ³¹P NMR (162 MHz, D₂O) δ 1.32, -0.26, -1.18. HPLC-MS (condition C): rt = 10.09 min; m / z: 731 [M+1+2DEA]⁺. [Example] [9] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [Dipentyl] [-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound] [1] [)] []

[0354] According to the general phosphate ester deprotection procedure I, starting from 143 mg [(] [IV] [-] [8] [)] Obtained 92 mg [Compound] [1](83%). ¹H NMR (400 MHz, D₂O) δ 5.01–4.91 (m, 1H), 4.10–4.00 (m, 3H), 3.84–3.72 (m, 6H), 1.63 (p, J = 7.2 Hz, 4H), 1.36–1.27 (m, 8H), 0.88 (p, J = 7.2 Hz, 6H). ³¹P NMR (162 MHz, D₂O) δ 1.32, -0.31, -1.13. HPLC-MS (condition D): rt = 6.16 min; m / z: 714 [M+1] +, 787 [M+1+DEA] +, 860 [M+1+2DEA] +. [Example]

[10] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [Second Gengji] [-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound] [5] [)] []

[0355] According to the general phosphate ester deprotection procedure I, starting from 244 mg [(] [IV] [-] [9] [)] 7.8 mg was obtained. [Compound] [5] [](4%). 1H NMR (400 MHz, D 2O) δ 4.10-4.03 (s, 3H), 3.81-3.71 (m, 6H), 1.68-1.59 (m, 4H), 1.41-1.18 (m, 16H), 0.87 (t, J= 7.2 Hz, 6H). 31P NMR (162 MHz, D 2O) δ 1.96, 0.08, -0.89. HPLC-MS (condition C): rt=8.46 min; m / z: 843 [M+1+DEA]+, 916 [M+1+2DEA]+. [Example]

[11] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [Dioctyl] [-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound] [2] [)] []

[0356] According to the general phosphate deprotection procedure I, starting from 63 mg... [(] [IV] [-]

[10] [)] 1.6 mg was obtained. [Compound] [2] [](4%). 1H NMR (400 MHz, D 2O) δ 5.02 (d, J= 8 Hz, 1H), 4.15-3.95 (m, 3H), 3.85-3.70 (m, 6H), 1.67-1.60 (m, 4H), 1.35-1.24 (m, 28H), 0.86 (t, J= 6.8 Hz, 6H). HPLC-MS (condition D): rt=6.89 min; m / z: 781 [M+1] +, 854 [M+1+DEA] +, 927 [M+1+2DEA] +, 1000 [M+1+2DEA] +. [Example]

[12] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [two] [(] [Tetradecyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound] [3] [)] []

[0357] According to the general phosphate ester deprotection procedure I, starting from 1.5 g [(] [IV] [-]

[11] [)] 656 mg was obtained. [Compound] [3](66.5%). 1H NMR (400 MHz, D 2O) δ 4.96 (d, J= 8.8 Hz, 1H), 4.14-4.02 (m, 3H), 3.84-3.67 (m, 6H), 1.70-1.58 (m, 4H), 1.34-1.26 (m, 44H), 0.86 (t, J= 6.8 Hz, 6H). 31P NMR (162 MHz, D 2O) δ 4.01, 3.39, 3.02. HPLC-MS (condition D): 966 [M+1] +, 1039 [M+1+DEA] +, 1111 [M+1+2DEA] +. [Example]

[13] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [3] [-] [aminopropyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[13] [)] []

[0358] According to the general phosphate ester deprotection procedure I, starting from 45.6 mg [(] [X] [-] [1] [)] 5.6 mg was obtained. [Compound]

[13] (16.7%). HPLC-MS (condition C): rt = 10.73 min; m / z: 615 [M+1] +, 688 [M+1+DEA] +. [Example]

[14] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [5] [-] [Aminopentyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[14] [)] []

[0359] According to the general phosphate ester deprotection procedure I, starting from 145 mg... [(] [X] [-] [2] [)] 11.3 mg was obtained. [Compound]

[14] (10%). ¹H NMR (400 MHz, D₂O) δ 4.95 (s, ¹H), 4.07–4.05 (m, 3H), 3.94 (m, 2H), 3.84–3.70 (m, 7H), 3.02 (t, J = 6.7 Hz, 2H), 1.79–1.47 (m, 12H). ³¹P NMR (162 MHz, D₂O) δ 1.86, 0.46, 0.15. HPLC-MS (condition C): rt = 10.77 min; m / z: 671 [M+1]⁺, 744 [M+1+DEA]⁺. [Example]

[15] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(]

[10] [-] [Aminodecyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[15] [)] []

[0360] According to the general phosphate ester deprotection procedure I, starting from 57.5 mg [(] [X] [-] [3] [)] 0.8 mg was obtained. [Compound]

[15] (2%). 1H NMR (400 MHz, D 2O) δ 4.95 (d, J= 10.3 Hz, 1H), 4.06 (t, J= 9.2 Hz, 3H), 3.89-3.67 (m, 7H), 3.59 (t, J= 6.8 Hz, 1H), 2.99 (t, J= 7.4 Hz, 2H), 1.76-1.57 (m, 8H), 1.45-1.19 (m, 24H). 31P NMR (162 MHz, D 2O) δ 2.04, -0.05, -1.00. HPLC-MS (condition D): rt = 6.48 min; m / z: 811 [M+1] +, 884 [M+1+DEA] +, 958 [M+1+2DEA] +. [Example]

[16] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [5] [-(] [1H] [-] [Pyrazole] [-] [1] [-] [base] [)] [Pentyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[16] [)] []

[0361] According to the general phosphate ester deprotection procedure I, starting from 36.6 mg [(] [IV] [-]

[14] [)] 8.5 mg was obtained. [Compound]

[16] [](29%). 1H NMR (400 MHz, D 2O) δ 7.64 (d, J= 2.4 Hz, 2H), 7.52 (br, 2H), 6.31 (t, J= 2.4 Hz, 2H), 4.42 (m, 3H), 4.28-4.14 (m, 3H), 4.13 (t, J= 7 Hz, 4H), 3.66 (m, 4H), 1.82 (p, J= 7.0 Hz, 4H), 1.67-1.49 (m, 4H), 1.42-1.18 (m, 4H). 31P NMR (162 MHz, D 2O) δ4.91, 4.21. HPLC-MS (condition C): rt = 9.20 min; m / z: 773 [M+1] +, 846 [M+1+DEA] +, 919 [M+1+2DEA] +. [Example]

[17] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [5] [-(] [1H] [-] [1] [,] [2] [,] [4] [-] [Triazole] [-] [1] [-] [base] [)] [Pentyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[17] [)] []

[0362] According to the general phosphate deprotection procedure I, starting from 8.8 mg [(] [IV] [-]

[15] [)] 5.2 mg was obtained. [Compound]

[17] [](74%). 1H NMR (400 MHz, D 2O) δ 8.46-8.45 (m, 2H), 8.03-8.01 (m, 2H), 4.32 - 4.23 (m, 5H), 4.12-3.88 (m, 3H), 3.85-3.55 (m, 6H), 1.89 (m, 4H), 1.75-1.53 ​​(m, 4H), 1.31 (p, J= 7.4 Hz, 4H). HPLC-MS (condition C): rt=9.86 min; m / z: 776 [M+1] +, 849 [M+1+DEA] +, 922 [M+1+2DEA] +. [Example]

[18] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(()] [1] [-(] [2] [-] [Carboxyethyl] [)-] [1H] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [4] [-] [base] [)] [methyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Decasodium salt] [(] [Compound]

[31] [)]

[0363] According to the universal phosphate ester deprotection program I, starting from 315 mg [(] [IV] [-]

[16] [)] 72 mg was obtained [Compound]

[31] (39%). 1H NMR (400 MHz, D 2O) δ 8.22 (s, 2H), 5.08 (d, J= 11.6 Hz, 2H), 5.10-4.97 (m, 1H), 4.99 (d, J= 11.6 Hz, 2H), 4.70 (t, J= 7.2 Hz, 4H), 4.26-4.18 (m, 3H), 3.99 (t, J= 9.5 Hz, 2H), 2.88 (t, J= 7.2 Hz, 4H). 31P NMR (162 MHz, D 2O) δ 1.57, 0.29, -1.00. HPLC-MS (condition C): rt = 10.62 min; m / z: 807 [M+1] +, 880 [M+1+DEA] +, 953 [M+1+2DEA] +. [] [Example]

[19] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(()] [1] [-(] [3] [-] [Methoxypropyl] [)-] [1H] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [4] [-] [base] [)] [methyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[32] [)]

[0364] According to the general phosphate ester deprotection procedure I, starting from 64 mg [(] [IV] [-]

[17] [)] 22 mg was obtained [Compound]

[32] (43%). ¹H NMR (400 MHz, D₂O) δ 8.40–7.75 (br, 2H), 5.06–4.80 (m, 5H), 4.55–4.44 (m, 4H), 4.40–3.82 (m, 5H), 3.43 (q, J = 6.2 Hz, 4H), 3.32 (s, 6H), 2.12–2.10 (m, 4H). HPLC-MS (condition C): rt = 9.56 min; m / z: 880 [M⁺¹⁺DEA]⁺. [Example]

[20] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(()] [1] [-(] [6] [-] [Methoxyhexyl] [)-] [1H] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [4] [-] [base] [)] [methyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[33] [)] []

[0365] According to the general phosphate deprotection procedure I, starting from 15 mg... [(] [IV] [-]

[18] [)] 1.8 mg was obtained. [Compound]

[33] [](15%). 1H NMR (400 MHz, D 2O) δ 8.08 (s, 2H), 4.87 (d, J= 11.6 Hz, 2H), 4.85-4.75 (m, 1H), 4.81 (d, J= 11.6 Hz, 2H), 4.27 (t, J= 7 Hz, 4H), 4.07-3.90 (m, 3H), 3.83-3.73 (m, 2H), 3.30 (t, J= 6.8 Hz, 4H), 3.17 (s, 6H), 1.76 (p, J= 7 Hz, 4H), 1.40 (p, J= 6.8 Hz, 4H), 1.17 (m, 8H). HPLC-MS (condition C): rt = 8.83 min; m / z: 891 [M+1] +, 964 [M+1+DEA] +, 1037 [M+1+2DEA] +. [Example] [twenty one] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [3] [-(] [4] [-(] [Methoxymethyl] [)-] [1H] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Propyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[36] [)] []

[0366] According to the general phosphate deprotection procedure I, starting from 7.2 mg... [(] [IV] [-]

[20] [)] 1.7 mg was obtained. [Compound]

[36] (28%). ¹H NMR (400 MHz, D₂O) δ 8.21 (s, 2H), 5.20 (br, 1H), 4.90–4.61 (m, 4H), 4.61 (s, 4H), 4.20–3.92 (m, 5H), 3.83–3.70 (m, 4H), 3.39 (s, 6H), 2.27–2.18 (m, 4H). HPLC-MS (condition C): rt = 9.73 min; m / z: 880 [M⁺¹⁺DEA]⁺. [Example] [twenty two] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [4] [-(] [4] [-(] [Methoxymethyl] [)-] [1H] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Dilki] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[37] [)] []

[0367] According to the general phosphate ester deprotection program I, starting from 11 mg [(] [IV] [-] [twenty one] [)] 1.2 mg was obtained. [Compound]

[37] (13%). ¹H NMR (400 MHz, D₂O) δ 8.08 (s, 2H), 5.20 (br, 1H), 4.61 (s, 4H), 4.55–4.38 (m, 4H), 4.10–3.85 (m, 5H), 3.83–3.70 (m, 4H), 3.39 (s, 6H), 2.05–1.91 (m, 4H), 1.49–1.70 (m, 4H). HPLC-MS (condition C): rt = 9.59 min; m / z: 835 [M+1]⁺, 908 [M+1+DEA]⁺. [Example] [twenty three] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [5] [-(] [4] [-(] [Methoxymethyl] [)-] [1H] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Pentyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[38] [)] []

[0368] According to the general phosphate deprotection procedure I, starting from 11 mg... [(] [IV] [-] [twenty two] [)] 1.4 mg was obtained. [Compound]

[38] (16%). ¹H NMR (400 MHz, D₂O) δ 8.07 (s, 2H), 5.05 (br, 1H), 4.61 (s, 4H), 4.45 (t, J = 7.6 Hz, 4H), 4.03 (m, 3H), 3.80–3.70 (m, 6H), 3.39 (s, 6H), 1.93 (p, J = 7.6 Hz, 4H), 1.67 (p, J = 7.6 Hz, 4H), 1.34 (p, J = 7.6 Hz, 4H). HPLC-MS (condition C): rt = 9.53 min; m / z: 936 [M⁺¹⁺DEA]⁺. [Example] [twenty four] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [6] [-(] [4] [-(] [Methoxymethyl] [)-] [1H] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Jiji] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[39] [)] []

[0369] According to the general phosphate ester deprotection procedure I, starting from 35.5 mg [(] [IV] [-] [twenty three] [)] Obtained 10 mg [Compound]

[39] (34%). ¹H NMR (400 MHz, D₂O) δ 8.04 (s, 2H), 5.30–5.10 (br, 1H), 4.60 (s, 4H), 4.43 (t, J = 7.1 Hz, 4H), 4.15–3.97 (m, 3H), 3.83–3.68 (m, 6H), 3.39 (s, 6H), 1.96–1.86 (m, 4H), 1.67–1.57 (m, 4H), 1.41–1.24 (m, 8H). HPLC-MS (condition C): rt = 9.24 min; m / z: 964 [M⁺¹⁺DEA]⁺. [Example]

[25] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [2] [-(] [4] [-] [Acetylpyridinium] [𠯤] [-] [1] [-] [base] [)] [Ethyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[34] [)] []

[0370] According to the general phosphate deprotection procedure I, starting from 16 mg... [(] [IV] [-] [twenty four] [)] 6.2 mg was obtained. [Compound]

[34] [](48%). 1H NMR (400 MHz, D 2O) δ 5.10-5.03 (m, 1H), 4.35-4.25 (m, 3H), 4.11-3.85 (m, 12H), 3.65-3.55 (m, 6H), 3.33-3.14 (m, 8H), 2.18 (s, 6H). 31P NMR (162 MHz, D 2O) δ 1.32, 0.86, 0.70, 0.24. HPLC-MS (condition C): rt=10.26 min; m / z: 882 [M+1+DEA]+. [Example]

[26] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(()] [3] [-(] [4] [-] [Carboxybutyramine] [)] [Propyl] [))-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Decasodium salt] [(] [Compound]

[45] [)] []

[0371] According to the general phosphate deprotection procedure I, starting from 28 mg... [(] [IV] [-]

[25] [)] 4.4 mg was obtained. [Compound]

[45] (19%). ¹H NMR (400 MHz, D₂O) δ 5.29–4.90 (br, ¹H), 4.18–3.92 (m, ³H), 3.89–3.77 (m, 4H), 3.73–360 (m, 2H), 3.37–3.22 (m, 4H), 2.29–2.17 (m, 8H), 1.87–1.70 (m, 8H). HPLC-MS (condition C): rt = 10.18 min; m / z: 916 [M⁺¹+DEA]⁺, 989 [M⁺¹+²DEA]⁺. [Example]

[27] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [5] [-] [Carboxypentyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Decasodium salt] [(] [Compound]

[18] [)] []

[0372] According to the general phosphate ester deprotection procedure J, starting from 35.5 mg [(] [IV] [-]

[12] [)] 6.8 mg was obtained. [Compound]

[18] (23%). 1H NMR (400 MHz, D 2O) δ 4.31-4.24 (m, 3H), 4.12-4.08 (m, 1H), 4.01 (br, 2H), 3.58 (dt, J= 7.6, 7.2 Hz, 2H), 3.51 (dt, J= 7.6, 7.2 Hz, 2H), 2.03 (t, J= 7.6, 4H), 1.47 (p, J= 7.2 Hz, 4H), 1.42 (p, J= 7.6 Hz, 4H), 1.30-1.11 (m, 4H). 31P NMR (162 MHz, D 2O) δ 4.86, 4.21. HPLC-MS (condition C): rt = 10.37 min; m / z: 802 [M+1] +, 875 [M+1+DEA] +, 948 [M+1+2DEA] +. [Example]

[28] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(]

[10] [-] [Carboxydecyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Decasodium salt] [(] [Compound]

[19] [)] []

[0373] According to the general phosphate ester deprotection procedure J, starting from 187 mg... [(] [IV] [-]

[13] [)] 34.6 mg was obtained. [Compound]

[19] (22.6%). 1H NMR (400 MHz, D 2O) δ: 4.49 (d, J= 12.4 Hz, 1H), 4.42 (br, 1H), 4.40 (br, 1H), 4.25 (d, J= 12.4 Hz, 1H), 4.19 (s, 2H), 3.77-3.58 (m, 4H), 2.16 (t, J= 7.6 Hz, 4H), 1.66-1.49 (m, 8H), 1.36-1.25 (m, 24H). 31P NMR (162 MHz, D 2O) δ: 4.79, 4.12, 4.00. HPLC-MS (condition D): rt = 6.26 min; m / z: 942 [M+1] +, 1015 [M+1+DEA] +, 1088 [M+1+2DEA] +. [Example]

[29] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [3] [-(] [4] [-(] [2] [-] [Carboxyethyl] [)-] [1H] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Propyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Decasodium salt] [(] [Compound]

[35] [)] []

[0374] According to the general phosphate ester deprotection procedure J, starting from 74 mg [(] [IV] [-]

[19] [)] 11.8 mg was obtained. [Compound]

[35] (21%). ¹H NMR (400 MHz, D₂O) δ 7.89 (s, 2H), 5.28 (br, 1H), 4.66–4.49 (m, 4H), 4.24–3.86 (m, 5H), 3.85–3.55 (m, 4H), 2.94 (t, J = 7.8 Hz, 4H), 2.54 (t, J = 7.8 Hz, 4H), 2.24–2.15 (m, 4H). ³¹P NMR (162 MHz, D₂O) δ 1.94, 0.53. HPLC-MS (condition C): rt = 10.17 min; m / z: 936 [M⁺¹ + DEA]⁺, 1009 [M⁺¹ + 2DEA]⁺. [Example]

[30] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [2] [-] [Cyclopropylethyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[28] [)]

[0375] According to the general phosphate ester deprotection procedure I, starting from 1.34 g [(] [IV] [-]

[27] [)] 710 mg was obtained [Compound]

[28] (68%). ¹H NMR (400 MHz, D₂O) δ 4.51–4.20 (br, 2H), 4.10–3.91 (br, 2H), 3.85–3.63 (br, 5H), 1.46–1.41 (m, 4H), 0.72–0.63 (m, 2H), 0.35–0.31 (m, 4H), 0.00 (q, J = 4.7 Hz, 4H). ³¹P NMR (162 MHz, D₂O) δ 3.79–(-0.54) (br). HPLC-MS (condition C): rt = 9.51 min; m / z: 637 [M+1] +, 710 [M+1+DEA] +, 783 [M+1+2DEA] +. [Example]

[31] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [2] [-] [Cyclopentylethyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[29] [)]

[0376] According to the general phosphate ester deprotection procedure I, starting from 164 mg [(] [IV] [-]

[28] [)] 22 mg was obtained [Compound]

[29] (17%). ¹H NMR (400 MHz, D₂O) δ 4.39–4.19 (br, 3H), 4.11–3.95 (br, 2H), 3.65 (q, J = 8 Hz, 2H), 3.59 (q, J = 8 Hz, 2H), 1.76–1.59 (m, 6H), 1.56–1.29 (m, 12H), 1.03–0.97 (m, 4H). ³¹P NMR (162 MHz, D₂O) δ 4.99–3.20 (br). HPLC-MS (condition C): rt = 8.76 min; m / z: 693 [M+1] +, 766 [M+1+DEA] +, 839 [M+1+2DEA] +. [Example]

[32] [] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [3] [-(] [4] [-] [Methoxyphenyl] [)] [Propyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[43] [)] []

[0377] According to the general phosphate ester deprotection procedure I, starting from 36 mg [(] [IV] [-]

[29] [)] 10.8 mg was obtained. [Compound]

[43] (37%). 1H NMR (400 MHz, D 2O) δ 7.02 (d, J= 8.4 Hz, 4H), 6.72 (d, J= 8.4 Hz, 4H), 4.41-4.18 (m, 4H), 4.11 (br, 2H), 3.66 (s, 6H), 3.64 (t, J= 7.2 Hz, 4H), 2.47 (t, J= 8.0 Hz, 4H), 1.78-1.63 (m, 4H). 31P NMR (162 MHz, D 2O) δ 4.29-3.86 (br). HPLC-MS (condition C): rt = 8.55 min; m / z: 797 [M+1] +, 870 [M+1+DEA] +, 943 [M+1+2DEA] +. [Example]

[33] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [3] [-(] [3] [-(] [Trifluoromethyl] [)] [Phenyl] [)] [Propyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[44] [)]

[0378] According to the general phosphate ester deprotection procedure I, starting from 64 mg [(] [IV] [-]

[30] [)] 11.9 mg was obtained. [Compound]

[44] (23%). ¹H NMR (400 MHz, D₂O) δ 7.42–7.25 (m, 8H), 4.30–4.06 (m, 5H), 3.69 (s, 4H), 2.62 (t, J = 8.1 Hz, 4H), 1.87–1.70 (m, 4H). ³¹P NMR (162 MHz, D₂O) δ 5.09–2.92 (br). HPLC-MS (condition C): rt = 7.84 min; m / z: 873 [M+1] +, 946 [M+1+DEA] +, 1019 [M+1+2DEA] +. [Example]

[34] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [3] [-(] [p-Toluyl] [)] [Propyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[42] [)]

[0379] According to the general phosphate ester deprotection procedure I, starting from 19 mg [(] [IV] [-]

[31] [)] 1.1 mg was obtained. [Compound]

[42] (7%). ¹H NMR (400 MHz, D₂O) δ 7.13 (d, J = 7.4 Hz, 4H), 7.08 (d, J = 7.4 Hz, 4H), 4.02–3.90 (br, 3H), 3.81–3.70 (br, 4H), 3.66–3.57 (br, 2H), 2.57–2.53 (m, 4H), 2.18 (s, 6H), 1.84–1.77 (m, 4H). HPLC-MS (condition C): rt = 8.35 min; m / z: 911 [M+1+2DEA]⁺. [Example]

[35] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [4] [,] [4] [,] [4] [-] [Trifluorobutyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound] [twenty two] [)]

[0380] According to the general phosphate ester deprotection procedure I, starting from 2.32 g [(] [IV] [-]

[32] [)] Obtained 820 mg [Compound] [twenty two] [](44%). 1H NMR (400 MHz, D 2O) δ 4.84 (d, J= 10.6 Hz, 1H), 3.97-3.90 (m, 3H), 3.74 (t, J= 6.5 Hz, 4H), 3.60 (t, J= 9.6 Hz, 2H), 2.28-2.15 (m, 4H), 1.79-1.72 (m, 4H). 31P NMR (162 MHz, D 2O) δ 1.69, 0.17, -0.92. HPLC-MS (condition C): rt=8.86 min; m / z: 721 [M+1] +, 794 [M+1+DEA] +, 867 [M+1+2DEA] +. [Example]

[36] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [6] [,] [6] [,] [6] [-] [Trifluorohexyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound] [twenty three] [)]

[0381] According to the general phosphate ester deprotection procedure I, starting from 248 mg [(] [IV] [-]

[33] [)] 45 mg was obtained [Compound]

[23] (22%). ¹H NMR (400 MHz, D₂O) δ 4.40–3.78 (m, 5H), 3.69–3.56 (m, 4H), 2.13–2.01 (m, 4H), 1.57–1.43 (m, 8H), 1.35–1.28 (m, 4H). HPLC-MS (condition C): rt = 8.27 min; m / z: 923 [M+1+2DEA]⁺. [Example]

[37] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [4] [-] [Methylpentyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound] [twenty one] [)]

[0382] According to the general phosphate ester deprotection procedure I, starting from 167 mg [(] [IV] [-]

[34] [)] 4.6 mg was obtained. [Compound]

[21] (3.5%). ¹H NMR (400 MHz, D₂O) δ 4.44–4.34 (m, 2H), 4.25–4.19 (m, 2H), 3.91–3.80 (m, 1H), 3.72–3.50 (m, 4H), 1.68–1.39 (m, 6H), 1.19–1.04 (m, 4H), 0.76 (d, J = 6.6 Hz, 12H). HPLC-MS (condition C): rt = 8.74 min; m / z: 742 [M⁺¹ + DEA]⁺, 815 [M⁺¹ + 2DEA]⁺. [Example]

[38] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(]

[19] [-] [Methoxy-19] [-]

[10] [-] [Alkyne] [-] [1] [-] [base] [))-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[20] [)] []

[0383] According to the general phosphate ester deprotection procedure I, starting from 410 mg [(] [III] [-]

[35] [)] 4.3 mg was obtained. [Compound]

[20] (1.3%). 1H NMR (400 MHz, D 2O) δ 4.50-4.26 (m, 3H), 4.19-4.02 (m, 2H), 3.70-3.47 (m, 4H), 3.38-3.26 (m, 4H), 3.22 (s, 6H), 1.49-1.41 (m, 8H), 1.25-1.16 (m, 60H). 31P NMR (162 MHz, D 2O) δ 4.04 (bs), 3.73 (bs). [Example]

[39] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [3] [-(] [3] [-] [Phenylurea] [)] [Propyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[46] [)]

[0384] According to the general phosphate ester deprotection procedure I, starting from 187 mg [(] [IV] [-]

[36] [)] 6.5 mg was obtained. [Compound]

[46] (4.3%). ¹H NMR (400 MHz, D₂O) δ 7.27–7.20 (m, 8H), 6.98–6.91 (s, 2H), 4.96–4.78 (m, 1H), 4.03–3.83 (m, 3H), 3.82–3.67 (m, 4H), 3.64–3.45 (m, 2H), 3.27–3.07 (m, 4H), 1.72–1.61 (bs, 4H). HPLC-MS (condition C): rt = 8.73 min; m / z: 926 [M⁺¹+DEA]⁺, 999 [M⁺¹+2DEA]⁺. [Example]

[40] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [3] [-(] [3] [-] [Cyclopentylurea] [)] [Propyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[47] [)]

[0385] According to the general phosphate deprotection procedure I, starting from 181 mg... [(] [IV] [-]

[37] [)] 26 mg was obtained [Compound]

[47] (17.6%). ¹H NMR (400 MHz, D₂O) δ δ 4.87–4.73 (bs, ¹H), 3.78–3.64 (m, 5H), 3.62–3.52 (m, 2H), 3.14–3.02 (m, 4H), 1.80–1.71 (m, 4H), 1.65–1.59 (m, 4H), 1.58–1.51 (m, 4H), 1.46–1.39 (m, 4H), 1.32–1.24 (m, 4H). HPLC-MS (condition C): rt = 8.98 min; m / z: 837 [M+1] +, 910 [M+1+DEA] +, 983 [M+1+2DEA] +. [Example]

[41] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [3] [-((] [Methoxycarbonyl] [)] [Amine] [)] [Propyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound] [twenty four] [)]

[0386] According to the general phosphate deprotection procedure I, starting from 5 mg [(] [IV] [-]

[38] [)] 1.7 mg was obtained. [Compound]

[24] (42%). ¹H NMR (400 MHz, D₂O) δ 3.94–3.40 (m, 10H), 3.52 (s, 6H), 3.11 (m, 4H), 1.67 (m, 4H). HPLC-MS (condition C): rt = 9.69 min; m / z: 804 [M⁺¹ + DEA]⁺, 877 [M⁺¹ + 2DEA]⁺. [Example]

[42] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [5] [-] [Acetamino] [Pentyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[27] [)] []

[0387] According to the general phosphate ester deprotection procedure I, starting from 110 mg [(] [IV] [-]

[39] [)] 4.7 mg was obtained. [Compound]

[27] (5%). ¹H NMR (400 MHz, D₂O) δ 4.05–3.83 (m, 3H), 3.78–3.43 (m, 7H), 3.05 (t, J = 27.7, 6.7 Hz, 4H), 1.86 (s, 6H), 1.58–1.47 (m, 4H), 1.46–1.38 (m, 4H), 1.34–1.18 (m, 4H). HPLC-MS (condition C): rt = 9.71 min; m / z: 828 [M⁺¹ + DEA]⁺, 901 [M⁺¹ + 2DEA]⁺. [] [Example]

[43] [] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [5] [-] [Benzoylamine] [Pentyl] [)] [-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[48] [)] []

[0388] According to the general phosphate ester deprotection procedure I, starting from 43 mg [(] [IV] [-]

[40] [)] 15 mg was obtained [Compound]

[48] (43%). ¹H NMR (400 MHz, D₂O) δ 7.61–7.55 (m, 4H), 7.47–7.29 (m, 6H), 4.40–4.18 (m, 3H), 4.08–3.88 (m, 2H), 3.61–3.55 (m, 5H), 3.17 (t, J = 7 Hz, 4H), 1.56–1.41 (m, 8H), 1.33–1.23 (m, 4H). HPLC-MS (condition C): rt = 8.73 min; m / z: 879 [M+1] +, 952 [M+1+DEA] +, 1025 [M+1+2DEA] +. [] [Example]

[44] [Synthesis and Characterization] [4] [,] [6] [-] [, O , ] [-] [pair] [(] [5] [-(] [thiophene] [-] [2] [-] [Cremate] [)] [Pentyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[49] [)]

[0389] According to the universal phosphate ester deprotection procedure U, starting from 196 mg [(] [IV] [-]

[41] [)] 19 mg was obtained [Compound]

[49] (12%). ¹H NMR (400 MHz, D₂O) δ 7.68–7.37 (m, 4H), 7.15–6.84 (m, 2H), 4.48–4.03 (m, 5H), 3.56 (t, J = 8.2, 6.7 Hz, 4H), 3.19–3.12 (m, 4H), 1.50–1.37 (m, 8H), 1.25–1.19 (m, 4H). HPLC-MS (condition C): rt = 8.85 min; m / z: 964 [M⁺¹ + DEA]⁺, 1037 [M⁺¹ + 2DEA]⁺. [] [Example]

[45] [] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-(] [6] [-(] [4] [-] [carboxyl] [-] [1H] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Jiji] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Decasodium salt] [(] [Compound]

[40] [)] []

[0390] According to the general phosphate ester deprotection procedure J, starting from 34 mg [(] [IV] [-]

[42] [)] 9.3 mg was obtained. [Compound]

[40] (33%). ¹H NMR (400 MHz, D₂O) δ 8.08 (s, 2H), 4.32–4.22 (m, 8H), 4.10–3.96 (m, 2H), 3.65–3.54 (m, 4H), 1.76 (p, J = 7.5 Hz, 4H), 1.54–1.39 (m, 4H), 1.29–1.15 (m, 8H). ³¹P NMR (162 MHz, D₂O) δ 4.81–3.21 (bs). HPLC-MS (condition C): rt = 10.27 min; m / z: 964 [M⁺¹+DEA]⁺, 1037 [M⁺¹+²DEA]⁺. [Example]

[46] [] [Synthesis and Characterization] [4] [-] [O] [-(] [6] [-(] [4] [-] [carboxyl] [-] [1H] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Jiji] [)-] [6] [-] [O] [-(] [6] [-(] [4] [-(] [Methoxymethyl] [)-] [1H] [-] [1] [,] [2] [,] [3] [-] [Triazole] [-] [1] [-] [base] [)] [Jiji] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Nine-sodium salt] [(] [Compound]

[41] [)] []

[0391] According to the general phosphate ester deprotection procedure J, starting from 101 mg... [(] [IV] [-]

[43] [)] 35 mg was obtained [Compound]

[41] (42%). 1H NMR (400 MHz, D 2O) δ 8.05 (s, 1H), 7.86 (s, 1H), 4.42 (s, 2H), 4.37-4.16 (m, 7H), 4.13-4.08 (m, 1H), 4.05 (s, 2H), 3.62-3.50 (m, 4H), 3.22 (s, 3H), 1.83-1.64 (m, 4H), 1.56-1.33 (m, 4H), 1.29-1.19 (m, 4H), 1.18-1.08 (m, 4H). 31P NMR (162 MHz, D 2O) δ 4.83, 4.18, 4.10. HPLC-MS (condition C): rt = 9.65 min; m / z: 891 [M+1] +, 964 [M+1+DEA] +, 1037 [M+1+2DEA] +. [Example]

[47] [] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [4] [-] [Amine] [-] [4] [-] [Side-oxybutyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[26] [)] []

[0392] According to the general phosphate deprotection procedure I, starting from 168 mg... [(] [IV] [-]

[44] [)] Obtain mg [Compound]

[26] (25%). ¹H NMR (400 MHz, D₂O) δ 4.17–3.39 (m, 10H), 2.48–2.17 (m, 3H), 2.16–2.03 (m, 1H), 1.77 (p, J = 6.8 Hz, 4H). HPLC-MS (condition C): rt = 10.47 min; m / z: 744 [M⁺¹ + DEA]⁺, 817 [M⁺¹ + 2DEA]⁺ [Example]

[48] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [5] [-(] [3] [-] [Propionyl] [)] [Pentyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[30] [)] []

[0393] According to the general phosphate ester deprotection procedure I, starting from 210 mg [(] [IV] [-]

[45] [)] Obtained 100 mg [Compound]

[30] (58%). ¹H NMR (400 MHz, D₂O) δ 4.41–3.90 (m, 6H), 3.60 (t, J = 6.5 Hz, 4H), 3.04–2.85 (m, 8H), 1.61–1.18 (m, 16H), 0.75 (t, J = 7.4 Hz, 6H). HPLC-MS (condition C): rt = 9.20 min; m / z: 841 [M+1]⁺, 914 [M+1+DEA]⁺. [Example]

[49] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [5] [-((] [Methoxycarbonyl] [)] [Amine] [)] [Pentyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[25] [)]

[0394] According to the general phosphate ester deprotection procedure I, starting from 60 mg... [(] [IV] [-]

[46] [)] 25 mg was obtained [Compound]

[25] (61% yield). ¹H NMR (400 MHz, D₂O) δ 4.37–3.82 (m, 6H), 3.64 (m, 4H), 3.52 (s, 6H), 3.00 (t, J = 7.1 Hz, 4H), 1.64–1.46 (m, 4H), 1.45–1.33 (m, 4H), 1.33–1.17 (m, 4H). HPLC-MS (condition C): rt = 9.33 min; m / z: 787 [M+1] +, 860 [M+1+DEA] +, 932 [M+1+2DEA] +. [Example]

[50] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [Dipentyl] [-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Thiophosphates] [)] [Octasodium salt] [(] [Compound]

[50] [)] []

[0395] According to the universal phosphate ester deprotection procedure U, starting from 97 mg [(] [IV] ['-] [1] [)] 2.2 mg was obtained. [Compound]

[50] (3%). ¹H NMR (400 MHz, D₂O) 4.63–4.55 (m, 2H), 4.52–4.44 (m, 2H), 4.34–4.28 (m, 2H), 3.67 (t, J = 7.0 Hz, 4H), 1.59–1.48 (m, 4H), 1.27–1.18 (m, 8H), 0.77 (t, J = 6.8 Hz, 6H). HPLC-MS (condition C): rt = 9.36 min; m / z: 850 [M+1+2DEA] +, 923 [M+1+3DEA] +. [Example]

[51] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [5] [-] [Methoxypentyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Thiophosphates] [)] [Octasodium salt] [(] [Compound]

[51] [)] []

[0396] According to the universal phosphate ester deprotection procedure U, starting from 54 mg [(] [IV] ['-] [2] [)] 2.2 mg was obtained. [Compound]

[51] (5%). ¹H NMR (400 MHz, D₂O) δ 4.65–4.25 (m, 6H), 3.68 (m, 4H), 3.39 (t, J = 6.8 Hz, 4H), 3.23 (s, 6H), 1.60–1.47 (m, 8H), 1.30 (m, 4H). ³¹P NMR (162 MHz, D₂O) δ 45.82, 45.22, 44.23. HPLC-MS (condition C): rt = 9.89 min; m / z: 910 [M⁺¹ + 2DEA]⁺, 983 [M⁺¹ + 3DEA]⁺. [Example]

[52] [Synthesis and Characterization] [4] [,] [6] [-] [O] [-] [pair] [(] [3] [-] [Carboxypropyl] [)-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Decasodium salt] [(] [Compound]

[52] [)] []

[0397] According to the general phosphate ester deprotection procedure J, starting from 40 mg... [(] [IV] [-]

[47] [)] 11 mg was obtained [Compound]

[52] [](34%). 1H NMR (400 MHz, D 2O) δ 4.31-4.24 (m, 3H), 4.12-4.08 (m, 1H), 4.01 (br, 2H), 3.58 (m, 4H), 2.11 (m, 4H), 1.72 (m, 4H). HPLC-MS (condition C): rt = 10.73 min; m / z: 746 [M+1+1DEA]+, 819 [M+1+2DEA]+. [Example]

[53] [Synthesis and Characterization] [4] [,] [6] [-] [, O , ] [-] [Dipropynyl] [-] [Inositol] [-] [1] [,] [2] [,] [3] [,] [5] [-] [IV] [(] [Phosphate ester] [)] [Octasodium salt] [(] [Compound]

[53] [)] []

[0398] According to the universal phosphate ester deprotection procedure U, starting from 50 mg [(] [IV] [-]

[48] [)] Obtained 10 mg [Compound]

[53] (35%). ¹H NMR (400 MHz, D₂O) δ 4.89–4.81 (m, ¹H), 4.43 (d, J = 1.9 Hz, 4H), 4.11–3.87 (m, 3H), 3.79–3.60 (m, 2H), 2.77 (t, J = 1.9 Hz, 2H). ³¹P NMR (162 MHz, D₂O) δ 1.22, 0.47, -0.86. HPLC-MS (condition C): rt = 10.70 min; m / z: 724 [M⁺¹²DEA]⁺, 797 [M⁺¹³DEA]⁺. [Pharmacological Analysis] [] [, A. , ] [, In vitro inhibition of calcium phosphate crystallization , ] [, , ]

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

[0400] A 96-well plate was used. Increasing concentrations of the derivative in the range of 0-100 µM were added to plasma (one volume of the IP4-4,6 substituted derivative of this invention was added to every 19 volumes of plasma). The plasma was then centrifuged at 10,000 g at room temperature and subsequently mixed with a mixture of 5 mM hydrogen phosphate and 41.67 mM calcium to achieve final concentrations of 1.5 mM phosphate and 12.5 mM calcium, respectively. All reagent solutions were filtered and the pH adjusted to 7.4.

[0401] The increase in absorbance at 550 nm was measured using a Biotek Powerwave XS microdisk spectrophotometer (BioTek Instruments, Inc., Winooski, VT, US) to monitor calcium phosphate crystallization at room temperature for 30 minutes. Absorbance was measured every 3 minutes in a culture dish on a fixed-track oscillator at room temperature.

[0402] Plasma crystallization was assessed based on the slope measurements within a linear range between 6 and 24 minutes, using a curve of absorbance increment versus logarithm of time. The efficacy of different inositol phosphate derivatives in preventing calcium phosphate crystal formation in vitro was evaluated using human plasma samples, utilizing the slopes obtained between 6 and 24 minutes. Crystallization inhibition was measured by comparing the slopes of control samples (blank plasma) with those of samples containing inhibitors, as shown below.

[0403]

[0404] See Table 13. Table 13 compound family Example Relative effectiveness 6 A 1 +++ 7 A 2 + 10 A 4 +++ 9 A 5 +++ 11 A 6 + 12 A 7 + 4 A 8 +++ 1 A 9 +++ 5 A 10 +++ 2 A 11 + 3 A 12 +++ 13 A 13 ++ 14 A 14 +++ 15 A 15 + 16 A 16 +++ 17 A 17 + 31 B 18 +++ 32 B 19 +++ 33 B 20 ++ 36 B 21 ++ 37 B 22 ++ 38 B 23 +++ 39 B 24 +++ 34 B 25 ++ 45 C 26 +++ 18 A 27 +++ 19 A 28 + 35 B 29 +++ 28 A 30 +++ 29 A 31 +++ 43 B 32 ++ 44 B 33 + 22 A 35 +++ 23 A 36 + 21 A 37 + 20 A 38 +++ 46 C 39 ++ 47 C 40 +++ 24 A 41 + 27 A 42 +++ 48 C 43 + 49 C 44 ++ 40 B 45 +++ 41 B 46 +++ 26 C 47 +++ 30 A 48 +++ 25 C 49 +++ 50 D 50 + 51 D 51 + 52 A 52 +++ 53 A 53 +++ Symbol: +++ - EC50 ≤ 5 µM ++ - 5 µM < EC 50≤ 10 µM + - EC 50>10 µM [, B. , ] [, In vivo effects on calcification and blood perfusion , ] [, , ]

[0405] The effects of compounds 1, 6, 9, 14, 18, 31, and 39 on blood perfusion and tissue calcification following the initiation of limb ischemia were tested in a rat model for 5 consecutive days. Limb ischemia was induced in all groups from day 1 to day 3, except for the sham treatment group, which did not receive induced ischemia. Animals were administered placebo and active agent formulations from day 1 to day 5. Observations were obtained at several time points during treatment from day 0 to day 5. All animals were weighed daily prior to treatment.

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

[0407] Group 1 - Control Group (Sham Treatment Group)

[0408] Group 2 - Physiological saline solution

[0409] Group 3 - Compound 1

[0410] Group 4 - Compound 6

[0411] Group 5 - Compound 9

[0412] Group 6 - Compound 14

[0413] Group 7 - Compound 18

[0414] Group 8 - Compound 31

[0415] Group 9 - Compound 39

[0416] Limb ischemia was induced in rats from groups 2 to 9 by subcutaneous administration of a saline solution (2 mL / kg) containing 150,000 IU / kg vitamin D3 (cholecalciferol, Duphafral D 31000; Zoetis Inc., Parsippany, NJ, US) daily from day 1 to day 3. Rats in group 1 were not given vitamin D3.

[0417] Rats in groups 1 and 2 were administered 2 mL / kg of saline solution subcutaneously from day 1 to day 5. Rats in groups 3 to 9 were administered 2 mL / kg of saline solution subcutaneously from day 1 to day 5, containing 30 mg / kg of compounds 1, 6, 9, 14, 18, 31 and 39, respectively.

[0418] All groups underwent limb function and ischemia assessment at D0 and D5 using a PeriCam PSI Normal Resolution (Perimed AB, Järfälla, SE) laser Doppler perfusion imaging system. Perfusion differences and perfusion ratios were calculated by comparing baseline and D0 or D5 readings across groups. Additionally, the blood perfusion ratios of each treatment group (i.e., groups 2 through 9) and the sham treatment group were calculated. See Table 14.

[0419] All rats in groups 1 through 9 were sacrificed 30 minutes after administration on day 5 to determine their baseline calcium levels. Animals were anesthetized by inhalation of isoflurane. The entire aorta, carotid artery, femoral artery, heart, and right kidney were collected for calcium content determination. Tissues were lyophilized for 48 to 72 hours and weighed. The lyophilized tissues were then digested in a dry incubator at 180°C for 2 to 4 hours using a 1:1 HNO3:HClO4 mixture. The digested tissues were then diluted with ultrapure MilliQ® water (MilliporeSigma (Merck KGaA), Burlington, MA, US) to a final volume of 5 mL (for the femoral and carotid arteries) and 10 mL (for the heart, kidney, and aorta). Calcium content was quantified by inductively coupled plasma optical emission spectrometry (ICP-OES) using an Optima 7300 DV ICP-OES system spectrometer (PerkinElmer, Inc., Waltham, MA, US) according to the manufacturer's instructions. The mean blood perfusion recovery rate was also calculated compared to the mediator and sham treatment groups. See Table 14. The recovery rate in the sham treatment group was 100%. The blood perfusion recovery rate was calculated using the following equation: 100 - ((BP sham treatment group - BP new drug) / (BP sham treatment group - BP mediator) * 100). [surface]

[14] [] [] Calcification inhibition (%) 1 1 6 9 14 18 31 39 aorta Higher than Higher than Below Below Below Higher than Higher than Carotid artery Below Below Below Below Below Below Below femoral artery Higher than Higher than Higher than Higher than Below Higher than Higher than heart Higher than Higher than Higher than Higher than Higher than Higher than Higher than kidney Higher than Higher than Higher than Higher than Higher than Higher than Higher than BP recovery rate (%) 2 Below Higher than Higher than Higher than Higher than Higher than Higher than 1. Average inhibition percentage is higher or lower than 25% for calcification inhibition. 2. Average blood perfusion recovery rate is higher or lower than 25%. ***

[0420] It should be understood that the Description of Embodiments section, rather than the Summary and Invention section, is intended to interpret the scope of the claims. The Summary and Invention section may describe one or more, but not all, exemplary embodiments of the invention as contemplated by the inventors, and therefore is not intended to limit the invention and the scope of the appended claims in any way.

[0421] The invention has been described above using functional architecture blocks that illustrate the implementation of specific functions and their relationships. For ease of description, the boundaries of these functional architecture blocks have been arbitrarily defined herein. Alternative boundaries can be defined as long as the specified functions and their relationships are properly performed.

[0422] The foregoing description of specific embodiments will thus fully reveal the general nature of the invention: without ...

Claims

1. A compound of general formula I or a pharmaceutically acceptable salt thereof or a combination thereof, wherein R1, R3, R7 and R11 independently represent -OPO32- or -OPSO22-; R5 and R9 are substituents, each corresponding to the formula -O(alkyl)nX, corresponding to the following general formula: or, wherein n is an integer between 2 and 20, wherein the terminal group X is selected from the group consisting of: -H, -OR, -NRR', -COOR, -CONRR', -NHCOR, -NHCOOR, -OCONR, -NHSO2R, -NHCONRR', halogen, -CF3, carbocyclic (saturated or unsaturated) and heterocyclic (saturated or unsaturated), and wherein R and R' are H or alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof or a combination thereof, wherein R5 and R9 are the same substituents.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a combination thereof, wherein the pharmaceutically acceptable salt is a sodium salt.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof or a combination thereof, wherein the sodium salt is a tetrasodium, pentasodium, hexasodium, heptasodium, octasodium, nonasodium or decasodium salt.

5. The compound of claim 3 or a pharmaceutically acceptable salt thereof or a combination thereof, wherein the sodium salt is a tetrasodium, pentasodium, hexasodium, heptasodium or octasodium salt.

6. The compound of claim 3 or a pharmaceutically acceptable salt thereof or a combination thereof, wherein the sodium salt is a hexasodium salt, octasodium salt, nonasodium salt or decasodium salt.

7. The compound of claim 3 or a pharmaceutically acceptable salt thereof or a combination thereof, wherein the sodium salt is an octasodium salt or a nonasodium salt.

8. A compound of claim 1 or a pharmaceutically acceptable salt thereof or a combination thereof, wherein the compound is selected from the group consisting of compounds 1 to 20, compounds 22 to 30 and compounds 50 to 52, and any combination thereof, wherein the selected compound is characterized by having the general formula of claim 1 and the following definitions of substituents: .

9. A compound of claim 1 or a pharmaceutically acceptable salt thereof or a combination thereof, wherein the compound is selected from the group consisting of compounds characterized by having the general formula of claim 1 and the following definitions of substituents: .

10. The compound of claim 1 or its pharmaceutically acceptable salt or combination thereof is selected from the group consisting of: .

11. The compound of claim 1 or its pharmaceutically acceptable salt or combination thereof is selected from the group consisting of: .

12. A pharmaceutical composition comprising a compound of any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, or a combination thereof, and at least one pharmaceutically acceptable excipient.

13. Use of a compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof or a combination thereof, or a pharmaceutical composition of claim 12, for the preparation of a medicament for inhibiting the formation or growth of calcium salts / crystals in an individual of need.

14. As claimed in claim 13, wherein the calcium salt / crystal is calcium phosphate.

15. As claimed in claim 14, wherein the calcium phosphate is hydroxyapatite.

16. Use of a compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof or a combination thereof, or a pharmaceutical composition of claim 12, for the preparation of a medicament for the treatment or prevention of a disease or condition associated with pathological crystallization in an individual in need.

17. Use of a compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof or a combination thereof, or a pharmaceutical composition of claim 12, for the preparation of a medicament for inhibiting the progression of crystallization in an individual in need.

18. Use of a compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof or a combination thereof, or a pharmaceutical composition of claim 12, for the preparation of a medicament for restoring or increasing blood perfusion in an individual in need.

19. The use of any of claims 13 to 18, wherein the individual is a human being.

20. The use of any of claims 13 to 18, wherein the drug is administered topically, enterically or non-enterically.

21. The use of any of claims 13 to 18, wherein the drug is administered intravenously or subcutaneously.

22. A compound selected from the group consisting of the following intermediate compounds: .

23. A kit or article comprising at least one compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or a combination thereof, a pharmaceutical composition of claim 12 or a compound of claim 22.

24. A method for preparing a compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof or a combination thereof, comprising using at least one compound of claim 22.

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