Pyridoxal-5-phosphate (P5P) analogues

Abstract

Disclosed is a compound represented by formula (I), its stereoisomers, its salts, hydrates, solvates, isotopes or crystalline forms thereof, wherein X, R 1 , R 2 , R 3 , R 4 and R 5 As disclosed herein, processes for their preparation, compositions containing such compounds, methods for the medical treatment or prevention of diseases with such compounds, and uses thereof are also disclosed. [Formula 1] The compound of TIFF2025500913000110.tif37170 is a pyridoxal-5-phosphate (P5P) analogue and can act as a prodrug.

Description

[Technical field]

[0001] This specification relates to pyridoxal-5-phosphate (P5P) analogs, processes for their preparation, compositions containing pyridoxal-5-phosphate (P5P) analogs, methods of medical treatment containing pyridoxal-5-phosphate (P5P) analogs, and uses thereof. [Background technology]

[0002] Vitamin B6 is necessary for the normal functioning of the human body. Deficiency of this vitamin leads to dysfunction and disease (Stach, et al. (2021) Vitamin B6 in Health and Disease. Nutrients, 13, 3229, incorporated herein by reference). Vitamin B6 is not a single molecule, but rather a family of related molecules - vitamers. These molecules include pyridoxal, pyridoxamine, pyridoxine and their respective 5'-monophosphorylated forms. The human body cannot synthesize these molecules de novo, and therefore some of the B6 form must be obtained through dietary intake. Once in the human physiological system, the various vitamers can be interconverted (Figure 1; Stach et al. (2021)).

[0003] Pyridoxal-5-phosphate (P5P) is the physiologically important form of vitamin B6. In this form, vitamin B6 is a cofactor in over 150 biochemical reactions (Stach et al. (2021)). Therefore, manipulating the amount of P5P in the body can affect health and reduce disease. However, due to the fact that this form is phosphorylated and therefore charged at physiological pH, it cannot easily cross biological membranes (Alghamdi, et al. (2021) Phenotypic and molecular spectrum of pyridoxamine-5'-phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine-5'-phosphate oxidase deficiency. Clin Genet 99, 99-110, incorporated herein by reference). Thus, P5P has poor oral bioavailability with limited ability to be absorbed across the gastrointestinal membrane (Vrolijk et al., (2020) Inter-individual differences in pharmacokinetics of vitamin B6: A possible explanation of different sensitivity to its neuropathic effects. PharmaNutrition 12, 1-7, incorporated herein by reference). To circumvent this problem, two approaches have been used: in the first approach vitamin B6 is given orally as pyridoxine, which is better absorbed. The body then converts some of the pyridoxine to P5P over time (Vrolijk et al., 2020; Coburn et al., (1991) Response of vitamin B-6 content of muscle to changes in vitamin B-6 intake in men. Am J Clin Nutr 53, 1436-42, all incorporated herein by reference).Unfortunately, oral pyridoxine (unlike oral P5P) leads to increased plasma levels of pyridoxine, which have shown evidence of neurotoxicity (Vrolijk et al., (2017) The vitamin B6 paradox: Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function. Toxicol In Vitro 44, 206-212; and Hadstein (2021) Vitamin B-6-Induced Neuropathy: Exploring the Mechanisms of Pyridoxine Toxicity. Adv Nutr 12, 1911-1929, all incorporated herein by reference). In the second approach, large amounts of P5P are given orally to achieve therapeutic levels in biological systems (Gibaud et al., et al. (2021) West Syndrome Is an Exceptional Presentation of Pyridoxine-and Pyridoxal Phosphate-Dependent Epilepsy: Data From a French Cohort and Review of the Literature. Front Pediatr 9, 621200; and Sudarsanam et al., (2014) Cirrhosis associated with pyridoxal 5'-phosphate treatment of pyridoxamine 5'-phosphate oxidase deficiency. JIMD Rep 17, 67-70, all of which are incorporated herein by reference).Unfortunately, this can cause gastrointestinal problems and may contribute to liver toxicity (Sudarsanam et al., (2014); Alghamdi et al., (2021) Phenotypic and molecular spectrum of pyridoxamine-5'-phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine-5'-phosphate oxidase deficiency. Clin Genet 99, 99-110, all of which are incorporated herein by reference).

[0004] ProTide technology was developed by Chris McGuigan at Cardiff University in the early 1990s as a method for delivering phosphorylated nucleosides (nucleotides) into cells. This technology has been used primarily to deliver monophosphorylated antivirals to cells (Mehellou et al., (2018) The ProTide Prodrug Technology: From the Concept to the Clinic. J Med Chem 61, 2211-2226; Thornton et al., (2016) Nucleoside Phosphate and Phosphonate Prodrug Clinical Candidates. J Med Chem 59, 10400-10410; Markovic et al., (2020) Prodrugs for Improved Drug Delivery: Lessons Learned from Recently Developed and Marketed Products. Pharmaceutics 12, 1031, all of which are incorporated herein by reference), and to improve the oral bioavailability of some of these same agents (such as sovosbuvir). Schwarz et al. (Schwarz et al., (2020) A Phosphoramidate Strategy Enables Membrane Permeability of a Non-nucleotide Inhibitor of the Prolyl Isomerase Pin1. ACS Med. Chem. Lett. 11, 1704-1711, incorporated herein by reference) discloses the membrane permeability of a non-nucleotide inhibitor of the prolyl isomerase Pin1.

[0005] The basic premise of the ProTide technology is the use of various chemical groups to mask the charge present on the phosphate group at physiological pH. These groups are specialized in that one group is an amino acid ester and the other is a chemically good leaving group, usually an aryl group. The resulting phosphoramidate created by the amino acid ester group provides stability to the molecule while the ester moiety is a substrate for the action of the enzyme esterase. It is the cleavage of this ester that initiates a series of chemical rearrangements that ultimately release the drug of interest (Figure 2; taken from Schwarz et al., (2020) A Phosphoramidate Strategy Enables Membrane Permeability of a Non-nucleotide Inhibitor of the Prolyl Isomerase Pin1. ACS Med. Chem. Lett. 11, 1704-1711, incorporated herein by reference). This release of the drug can occur in plasma or intracellularly.

[0006] There is a need in the art to develop analogs of vitamin B6 (P5P) with improved bioavailability that can more easily enter the biological system, because such analogs may be useful for treating disease and maintaining health. Such analogs could potentially allow the use of neurotoxic pyridoxine forms to be discontinued, and avoid the use of large oral doses of P5P. In addition, there is a need in the art for processes for the preparation of such P5P analogs. There is also a need in the art for compositions containing such P5P analogs. There is also a need in the art for the use of such P5P analogs for the treatment of disease, or for methods of medically treating disease by administering such P5P analogs. Summary of the Invention [Means for solving the problem]

[0007] The present disclosure relates to prodrugs of pyridoxal-5-phosphate (P5P) and prodrugs of analogs of P5P. In addition, the present disclosure relates to compounds of formula (I), including pharma- ceutically acceptable salts, hydrates, solvates, stereoisomers thereof, and pharmaceutical compositions of these compounds, which may be useful for prophylactic and therapeutic uses in human and veterinary medicine. Another aspect is an isotopically labeled compound of any of the formulae depicted herein. Such compounds contain one or more isotopic atoms (e.g., 1,2-diaminophenyl-2,4-diphenyl-1,4-di ... 3 H, 2 H, 14 C. 13 C. 18 F, 32 P). Such compounds may be useful for drug metabolism studies and for diagnostic, as well as therapeutic applications.

[0008] In a first aspect, the present specification relates to compounds represented by Formula I, their stereoisomers, salts, hydrates, solvates, isotopes or crystalline forms thereof. [ka] In the formula, X, R 1 , R 2 , R 3 , R 4 and R 5 is as described herein.

[0009] In a second aspect, the present disclosure relates to a process for the preparation of a compound of formula I, its stereoisomers, its salts, hydrates, solvates, isotopes or crystalline forms. [ka] The process includes reacting a compound of formula II with a compound of formula III in the presence of a base to form a compound of formula I. [ka] In the formula, X, LG, R 1 , R 2 , R 3 , R4 and R 5 is as described herein.

[0010] In a third aspect, the present disclosure relates to a composition comprising: A carrier, diluent or excipient; The present invention includes compounds represented by Formula I, their stereoisomers, salts, hydrates, solvates, isotopes or crystal forms thereof. [ka] In the formula, X, R 1 , R 2 , R 3 , R 4 and R 5 is as described herein.

[0011] In a fourth aspect, the present disclosure relates to the use of a compound represented by formula I, its stereoisomers, its salts, hydrates, solvates, isotopes or crystalline forms thereof, for the treatment or prevention of a disease. [ka] In the formula, X, R 1 , R 2 , R 3 , R 4 and R 5 is as described herein.

[0012] In a fifth aspect, the present invention relates to a method for the medical treatment or prevention of a disease, comprising administering to a subject in need thereof a compound represented by formula I, its stereoisomer, its salt, hydrate, solvate, isotope or crystalline form. [ka] In the formula, X, R 1 , R 2 , R 3 , R 4 and R 5 is as described herein.

[0013] Reference is now made, by way of example, to the accompanying drawings, which illustrate exemplary embodiments of the present application. [Brief description of the drawings]

[0014] [Figure 1] Once in the human physiological system, it exhibits a variety of vitamers that can be interconverted. [Diagram 2] FIG. 1 shows a schematic representation of the ability of phosphoramidates to enter the cytosol. [Figure 3(1)] Figure 2 shows the results of maximum tolerability of the test substance in rats under four different doses under single administration via PO route. [Figure 3 (2)] Figure 2 shows the results of maximum tolerability of the test substance in rats under four different doses under single administration via PO route. [Figure 3 (3)] Figure 2 shows the results of maximum tolerability of the test substance in rats under four different doses under single administration via PO route. [Figure 3 (4)] Figure 2 shows the results of maximum tolerability of the test substance in rats under four different doses under single administration via PO route. [Figure 4] A dose-dependent increase in plasma P5P levels was observed upon administration of the compound of formula 16i, confirming the efficacy of the prodrug. [Figure 5(1)] 1 shows the pharmacokinetic linearity results of the compound of formula 16 under multiple dosing. [Figure 5 (2)] 1 shows the pharmacokinetic linearity results of the compound of formula 16 under multiple dosing. [Figure 6(1)] 1 shows the differences in the pharmacokinetic profiles of prodrug 16 (given IV) compared to PLP given IV. [Figure 6 (2)] 1 shows the differences in the pharmacokinetic profiles of prodrug 16 (given IV) compared to PLP given IV. [Figure 7(1)] 1 shows the improved ability of prodrug 16 (given PO) to increase plasma PLP compared to PLP itself. [Figure 7(2)]1 shows the improved ability of prodrug 16 (given PO) to increase plasma PLP compared to PLP itself. [Figure 8] Individual rat data are shown demonstrating the difference in PLP levels when PLP is administered orally compared to PLP using the protide prodrug. Mean data are also shown. [Figure 9(1)] The effects of the different prodrugs 16v(a&b) administered intravenously at 1 mg / kg are compared with 16(c&d). [Figure 9 (2)] The effects of the different prodrugs 16v(a&b) administered intravenously at 1 mg / kg are compared with 16(c&d). [Figure 10(1)] The effects of the different prodrugs 16v (a and b) administered orally at 10 mg / kg are compared with 16 (c and d). [Figure 10(2)] The effects of the different prodrugs 16v (a and b) administered orally at 10 mg / kg are compared with 16 (c and d). [Figure 11(1)] The results of the mean plasma concentrations at 1 mg / kg and 10 mg / kg of PL, P5P and a compound not encompassed by Formula I are shown. [Figure 11 (2)] The results of the mean plasma concentrations at 1 mg / kg and 10 mg / kg of PL, P5P and a compound not encompassed by Formula I are shown. [Figure 12(1)] The results of the mean plasma concentrations of PL, P5P and the compound of formula 16vi at 1 mg / kg and 10 mg / kg are shown. [Figure 12 (2)] The results of the mean plasma concentrations of PL, P5P and the compound of formula 16vi at 1 mg / kg and 10 mg / kg are shown. [Figure 13(1)] The results of mean plasma concentrations of PL, P5P and formulae 16i (single isomer; a&b), 16ii (single isomer; c&d), and 16 (racemic, two samples; e&h) are shown. [Figure 13(2)] The results of mean plasma concentrations of PL, P5P and formulae 16i (single isomer; a&b), 16ii (single isomer; c&d), and 16 (racemic, two samples; e&h) are shown. [Figure 13(3)] The results of mean plasma concentrations of PL, P5P and formulae 16i (single isomer; a&b), 16ii (single isomer; c&d), and 16 (racemic, two samples; e&h) are shown. [Figure 13(4)] The results of mean plasma concentrations of PL, P5P and formulae 16i (single isomer; a&b), 16ii (single isomer; c&d), and 16 (racemic, two samples; e&h) are shown. [Figure 14(1)] Results are shown for the mean plasma concentrations at the phosphorus center of PL, P5P, and compounds S-isomer (16i) and R-isomer (16ii), with results shown for both IV and PO administration. [Figure 14(2)] Results are shown for the mean plasma concentrations at the phosphorus center of PL, P5P, and compounds S-isomer (16i) and R-isomer (16ii), with results shown for both IV and PO administration. [Figure 14(3)] Results are shown for the mean plasma concentrations at the phosphorus center of PL, P5P, and compounds S-isomer (16i) and R-isomer (16ii), with results shown for both IV and PO administration. [Figure 14(4)] Results are shown for the mean plasma concentrations at the phosphorus center of PL, P5P, and compounds S-isomer (16i) and R-isomer (16ii), with results shown for both IV and PO administration. [Figure 15(1)] The results of the mean plasma concentrations of PL, P5P and compounds S-isomer (16i) and R-isomer (16ii) and 16 (racemate) are shown. [Figure 15(2)] The results of the mean plasma concentrations of PL, P5P and compounds S-isomer (16i) and R-isomer (16ii) and 16 (racemate) are shown. [Figure 15(3)] The results of the mean plasma concentrations of PL, P5P and compounds S-isomer (16i) and R-isomer (16ii) and 16 (racemate) are shown. [Figure 16(1)] The results of the mean plasma concentrations of PL, P5P and PLP prodrug 16iii (racemate with D amino acid) at 1 mg / kg (IV administration, a&b) and at 10 mg / kg (PO administration-c&d) are shown. [Figure 16(2)]The results of the mean plasma concentrations of PL, P5P and PLP prodrug 16iii (racemate with D amino acid) at 1 mg / kg (IV administration, a&b) and at 10 mg / kg (PO administration-c&d) are shown. [Figure 17(1)] 1 shows the results of mean plasma concentrations of PL, P5P and PLP prodrug 16iii (racemate with D amino acids) compared to 16 (racemate) at 10 mg / kg via PO administration. [Figure 17(2)] 1 shows the results of mean plasma concentrations of PL, P5P and PLP prodrug 16iii (racemate with D amino acids) compared to 16 (racemate) at 10 mg / kg via PO administration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Similar reference numbers may be used in different figures to indicate similar components in different figures.

[0016] This specification includes headings and subheadings solely to aid in the review and understanding of the specification, and the disclosure under any heading or subheading is not limited to any particular section of the specification, but rather should be considered in light of the entire disclosure of the specification.

[0017] compound In an aspect, the present specification relates to compounds represented by Formula I, their stereoisomers, salts, hydrates, solvates, isotopes, or crystalline forms thereof. [ka] During the ceremony, X is NH or N; R 1 is H or C with one or more heteroatoms 1~15 is a substituent, R 2 is H or C with one or more heteroatoms 1~15 or when X is N, R 2 and N is C having one or more heteroatoms 2~15forming a ring structure with the atoms, R 3 is H or C with one or more heteroatoms 1~15 is a substituent, R 4 teeth [ka] where: [ka] is a single bond or a double bond, Where: [ka] is a single bond, A is NH2, NH-PG N , [ka] , O-H, O-P-G 01 where PG N is the protecting group attached to the nitrogen, PG 01 is the first protecting group attached to the oxygen, [ka] If is a double bond, A is O, R 5 H or PG 02 where PG 02 is a second protecting group attached to the oxygen, or PG 01 and P.G. 02 together form a diol protecting group.

[0018] The term "stereoisomer" as used herein is not particularly limited and is known to those skilled in the art. Stereoisomers, stereoisomerism, or spatial isomerism are isomeric forms in which molecules have the same molecular formula and order of bonded atoms (configuration), but the three-dimensional orientation of those atoms in space is different. Enantiomers and diastereomers are two types of stereoisomers. Enantiomers, also known as optical isomers, are two stereoisomers that are related to each other by reflection, and they are non-superimposable mirror images. Diastereomers are stereoisomers that are not related by reflection operations. They are not mirror images of each other. In stereochemistry, a stereocenter of a molecule is an atom, axis, or plane that is the focus of stereoisomerism, i.e., if at least three different groups are attached to the stereocenter, the exchange of any two different groups will create a new stereoisomer.

[0019] The compounds disclosed herein have multiple stereocenters, including P (phosphorus), which can be a chiral center, with the corresponding Cahn-Ingold-Prelog designation of "R" or "S" with the generally accepted unambiguous meaning. It is believed that the compounds of formula I may be racemic, stereochemically pure, or may have one stereoisomer, primarily due to the chirality at phosphorus. Applicants contemplate the use of racemates and / or resolved enantiomers.

[0020] The present application is not particularly limited and includes all possible stereoisomers, including not only racemates but also individual enantiomers and / or diastereomers. If a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by elucidation of the final product or any convenient intermediate. Elucidation of the final product, intermediate, or starting material can be effected by any suitable method known in the art (see, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley 30 lnterscience, 1994,), which is incorporated herein by reference).

[0021] The term "salt" disclosed herein is not particularly limited and should be known or can be determined by those skilled in the art. The salt of the compound of formula I formed can be used according to the application, including pharmaceutically acceptable salts. The "pharmaceutically acceptable salt" form of the compound of formula I can also impart desirable pharmacokinetic properties to the compound that were not initially present in the non-salt form, and can further favorably affect the pharmacodynamics of the compound of formula I with respect to its therapeutic activity in the body. The phrase "pharmaceutically acceptable salt" of a compound as used herein refers to a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include, for example, but are not limited to, (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or acid addition salts formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, salicylic acid, muconic acid, and the like; or (2) base addition salts formed with the conjugate base of any of the inorganic acids listed above (wherein the conjugate base is Na + , K + , Mg 2+ , Ca 2+ , and N.H. g R' 4-g + wherein R' is C 1~3 alkyl, and g is a number selected from 0, 1, 2, 3, or 4. It should be understood that all references to pharma- ceutically acceptable salts include the solvent addition forms (solvates) or crystal forms (polymorphs) described herein of the same acid addition salt.

[0022] The term "hydrate" used herein is not particularly limited and is known to those skilled in the art. In general, hydrates are substances that contain water or its constituent elements and can be formed by the addition of water. In addition, the compound of formula I can form crystals that can incorporate water into the crystal structure (water of crystallization) without chemically changing the compound. It should be understood that the formation of hydrates is common for many active ingredients. Many manufacturing processes provide the opportunity to form hydrates, and the state of hydrates can change with the humidity of the environment and time. The state of hydrate of a pharmaceutical active ingredient can significantly affect its solubility and dissolution rate, and therefore its bioavailability.

[0023] The term "solvate" used herein is not particularly limited and is understood by those skilled in the art. Solvates are similar to hydrates, but instead of water, solvent is present. In a broad sense, solvates are aggregates that consist of solute ions or molecules with one or more solvent molecules. This specification encompasses the solvates and hydrates of the compounds disclosed herein.

[0024] The term "isotope" as used herein is not particularly limited and is known to those skilled in the art. Isotopes are two or more types of atoms that have the same atomic number (the number of protons in their nuclei) and position in the periodic table (and therefore belong to the same chemical element) and differ in the number of neutrons in their nuclei, and therefore in the number of nucleons (mass numbers). The present specification encompasses compounds disclosed herein with various numbers and types of isotopes. For example, but not limited to, a compound of formula I can have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more isotopes present. In addition, for example, but not limited to, a compound of formula I can have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more isotopes present. 1 H 2 D or 3 It has been replaced by T. 12 C is 13 C or 14 has been replaced by C, and / or 31 P 32 P or 33This includes compounds where the compound is replaced with P. In the preparation of isotopes, appropriate starting materials or intermediates that are isotopically enriched and have the desired isotope can be used.

[0025] As used herein, the term "crystalline form" is not particularly limited and is understood to be within the meaning of those skilled in the art. A crystal or crystalline form is a solid material whose components (such as atoms, molecules, or ions) are arranged in a highly ordered microscopic structure forming a crystal lattice that extends in all directions.

[0026] "C 1~15 The terms "substituents" and the like are not particularly limited and are understood to be within the skill of one of ordinary skill in the art. 1~15 Substituents refer to organic moieties having 1-15 carbon atoms, such as, but not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, cycloheteroalkyl, alkylaryl, alkylheteroaryl, and the like, which may have one or more heteroatoms. In one embodiment, for example and without limitation, the number of carbon atoms present can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, including ranges based on any combination of the numbers of carbon atoms described herein.

[0027] In one embodiment, for example and without limitation, R in a compound of formula I 1 is H or C with one or more heteroatoms 1~15 In a second embodiment, for example and without limitation, R 1 is an organic moiety having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 carbon atoms, including ranges based on any combination of the numbers of carbon atoms described herein (such as, but not limited to, C 1~15 , C 1~10 , C 1~7 , C 3~15 , C 3~10 , C 3~7 , C 5~15 , C 5~10, C 5~7 In a third embodiment, for example and without limitation, R 1 -C6H5, -C6H4Cl, -C6H3BrF, -C6H3Cl2, -C6D5, -C7H7, -C7H4OF3, -C7H7O, -C9H9, -C 10 H 11 Or -C 10 It's H7.

[0028] In one embodiment, for example and without limitation, R in a compound of formula I 2 is H or C with one or more heteroatoms 1~15 or when X is N, R 2 and N are C having one or more heteroatoms 3~15 In a second embodiment, for example and without limitation, R 2 and N do not form a cyclic structure, R 2 is an organic moiety having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 carbon atoms, including ranges based on any combination of the numbers of carbon atoms described herein (such as, but not limited to, C 1~15 , C 1~10 , C 1~7 , C 3~15 , C 3~10 , C 3~7 , C 5~15 , C 5~10 , C 5~7 In a third embodiment, for example and without limitation, R 2 When and N form a cyclic structure, R in the compound of formula I 2 is an organic moiety having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 carbon atoms, including ranges based on any combination of the number of carbon atoms described herein (such as, but not limited to, C 3~15 , C 3~10 , C 3~7 , C 3~15 , C 5~10 , C 5~7, C 6~15 , C 6~10 , C 6~7 In a fourth embodiment, for example and without limitation, R 2 -H, -D, -CH3, -C2H2F3, -CH2CH2CH2-, -C4H9, -C5H9, -C6H5, -C7H7, -C7H7O, -C 14 H 12 O or -C 14 H 16 It is NO2.

[0029] In one embodiment, for example and without limitation, R in a compound of formula I 3 is H or C with one or more heteroatoms 1~15 In a second embodiment, for example and without limitation, R 3 is an organic moiety having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 carbon atoms, including ranges based on any combination of the numbers of carbon atoms described herein (such as, but not limited to, C 1~15 , C 1~10 , C 1~7 , C 3~15 , C 3~10 , C 3~7 , C 5~15 , C 5~10 , C 5~7 In a third embodiment, for example and without limitation, R 3 -CH3, -C3H7, -C3HD6, -C3D7, -C5H9, -C6H4Cl, -C6H7, -C6H 11 , -CH 12 N, -CH 13 , -C7H7, -C 10 H7 or -C 10 H 11 It is.

[0030] The term "heteroatom" as used herein is not particularly limited and is understood to be within the skill of the art. Heteroatoms include any atom that is not carbon or hydrogen. This term is generally used to more specifically refer to a non-carbon atom that replaces a carbon in the backbone of a molecular structure. In one embodiment, for example and without limitation, the heteroatom is nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), chlorine (Cl), bromine (Br), iodine (I), or any combination thereof.

[0031] "C with one or more heteroatoms 1~15 The term "substituents" and other similar terms will be apparent to one of ordinary skill in the art. In view of the above, this term includes, for example, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, cycloheteroalkyl, alkylaryl, alkylheteroaryl, and the like, having one or more nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), chlorine (Cl), bromine (Br), iodine (I), or any combination thereof.

[0032] The term "alkyl" as used herein is not particularly limited and is understood to be within the skill of the art. The term "alkyl" includes unbranched or branched chain saturated hydrocarbon residues containing 1 to 15 carbon atoms. 1~M The term "alkyl" refers to an alkyl group containing 1 to M carbon atoms, where M is an integer having the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. For example, "C 1~4The term "alkyl" refers to an alkyl group containing 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and the like. The terms (aryl)alkyl or (heteroaryl)alkyl refer to an alkyl group that is optionally substituted with an aryl or heteroaryl group, respectively. Embodiments of alkyl groups having one or more heteroatoms can include, but are not limited to, -OCH3, -OCH2CH2CH3, -CH2CHClCH3, -CH2CH2CH2NH2, and the like.

[0033] The term "alkenyl" as used herein is not particularly limited and is understood to be within the skill of the art. The term "alkenyl" includes unbranched or branched chain hydrocarbon residues containing 1 to 15 carbon atoms having one or more olefinic double bonds. 1~N The term "alkyl" refers to an alkenyl containing 1 to N carbon atoms, where N is an integer having the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. For example, "C 2~4 The term "alkenyl" refers to an alkenyl moiety containing 2-4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl (allyl) or 2-butenyl (crotyl). The terms (aryl)alkenyl or (heteroaryl)alkenyl refer to an alkenyl group optionally substituted with an aryl or heteroaryl group, respectively. Examples of alkenyl groups having one or more heteroatoms include, but are not limited to, -OCH2CH=CH2, -CH2CCl=CH2, -CH2CH=CHCH2NH2, and the like.

[0034] The term "alkynyl" as used herein is not particularly limited and is understood to be within the skill of the art. The term "alkynyl" includes unbranched or branched chain hydrocarbon residues containing 1 to 15 carbon atoms having one or more triple bonds. 2~N The term "alkynyl" refers to an alkynyl group containing 2 to N carbon atoms, where N is an integer having the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. For example, "C 2~4 The term "alkynyl" refers to an alkynyl moiety containing from 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, or 3-butynyl.

[0035] The term "cycloalkyl" as used herein is not particularly limited and is understood to be within the skill of one of ordinary skill in the art. The term "cycloalkyl" refers to a saturated carbocyclic ring having 3 to 8 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. As used herein, "cycloalkyl" refers to a saturated carbocyclic ring having 3 to 8 carbon atoms. 3~7 The term "cycloalkyl" refers to cycloalkyls having 3 to 7 carbons in the carbocyclic ring. Additionally, terms such as "cycloalkylalkyl," "cycloalkylalkenyl," or "cycloalkylalkynyl" refer to cycloalkyls with an alkyl, alkenyl, or alkynyl substituent.

[0036] The term "aryl" as used herein is not particularly limited and is known to those skilled in the art. The term "aryl" as used herein and unless otherwise specified refers to substituted or unsubstituted phenyl (Ph), biphenyl, or naphthyl. The aryl group may be substituted with one or more moieties, including, but not limited to, hydroxyl, F, Cl, Br, I, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, and phosphonate, either unprotected or protected as required, as known to those skilled in the art, as taught, for example, in TW Greene and PG M Huts, "Protective Groups in Organic Synthesis," 3rd ed., John Wiley & Sons, 1999 (hereby incorporated by reference).

[0037] The terms "alkaryl" or "alkylaryl" as used herein are not particularly limited and are intended to be understood by one of ordinary skill in the art. The terms "alkaryl" or "alkylaryl" refer to an alkyl group with an aryl substituent, such as benzyl. The terms "aralkyl" or "arylalkyl" refer to an aryl group with an alkyl substituent.

[0038] The term "heterocycle" as used herein is not particularly limited and is understood to be known to those skilled in the art. The term "heterocycle" refers to an unsubstituted or substituted heterocycle containing carbon, hydrogen and at least one of N, O, and S, where C and N can be trivalent or tetravalent, i.e., sp 2 or sp 3 Examples of heterocycles include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, imidazole, oxazole, piperazine, and the like.

[0039] The term "heteroaryl" as used herein is not particularly limited and is understood to be within the skill of the art. "Heteroaryl" refers to an aryl group having at least one of N, O, and S. Examples of heteroaryl include, but are not limited to, furan, oxazole, thiophene, 1,2,3-triazole, 1,2,4-triazine, 1,2,4-triazole, 1,2,5-thiadiazole 1,1-dioxide, 1,2,5-thiadiazole 1-oxide, 1,2,5-thiadiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3,5-triazine, imidazole, isothiazole, isoxazole, pyrazole, pyridazine, pyridine, etc.

[0040] The term "PG" refers to a protecting group. The protecting groups used in the compounds disclosed herein are not particularly limited and are known or can be determined by those skilled in the art. Protecting groups are introduced into molecules by chemically modifying functional groups to obtain chemical selectivity in subsequent chemical reactions.

[0041] As used herein, "PG N The term "protective group" refers to a protecting group attached to a nitrogen, for example, an amine protecting group. The amine protecting groups disclosed herein are not particularly limited and are known to those of skill in the art. Non-limiting examples of amine protecting groups include fluorenylmethoxycarbonyl protecting group (Fmoc), tert-butoxycarbonyl (BOC), carbobenzyloxy (Cbz), trifluoroacetamide, phthalimide, trityl (Tr), monomethoxytrityl (MMT), dimethoxytrityl (DMT), or benzylideneamine.

[0042] As used herein, "PG O " refers to a protecting group attached to an oxygen, e.g., an alcohol protecting group, while "PG O1 " refers to the first protecting group attached to the oxygen, and "PG O2 " refers to the second protecting group attached to the oxygen.O1 " and "PG O2 The choice of "PG O1 " and "PG O2 " may be the same or different. The alcohol protecting groups disclosed herein are not particularly limited and are known to those skilled in the art. Non-limiting examples of alcohol protecting groups include benzyl (Bn), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl (Piv), or benzyl (Bz), trityl (Tr), monomethoxytrityl (MMT), dimethoxytrityl (DMT). In addition, "PG O1 " and "PG O2 " together may be used to protect diols, for example, but not limited to: [ka] Form.

[0043] The term "prodrug" as used herein is not particularly limited and is known to those skilled in the art. A prodrug is a compound that undergoes biotransformation before it exhibits a pharmacological effect. A prodrug is a compound that is metabolized (i.e., transformed in the body) into a pharmacologically active drug after ingestion. Instead of administering a drug directly, the corresponding prodrug can be used to improve the way the drug is absorbed, distributed, metabolized, and excreted (ADME). Prodrugs are often designed to improve bioavailability when the drug itself is poorly absorbed from the gastrointestinal tract. Prodrugs can be used to improve the way the drug selectively interacts with cells or processes that are not the intended target. This reduces the adverse or unintended effects of the drug. The compounds of formula I disclosed herein are analogs of P5P that can be prodrugs for the treatment or prevention of diseases associated with P5P. Studies described herein have shown that compounds of formula I can be used to show improved bioavailability of P5P and therefore can function as potential prodrugs.

[0044] Using the methods disclosed herein, numerous compounds have been prepared that are encompassed by the compounds of Formula I. Embodiments of pyridoxamine prodrugs that are encompassed by the compounds of Formula I are shown in Table 1.

[0045] Table 1: Pyridoxamine Prodrug Embodiments [ka] Pyridoxamine Prodrug 14

[0046] [Table 1]

[0047] [Table 2]

[0048] Embodiments of pyridoxine prodrugs encompassed by compounds of Formula I are shown in Table 2.

[0049] Table 2: Pyridoxine Prodrug Embodiments [ka] Pyridoxine Prodrug 15

[0050] [Table 3]

[0051] [Table 4]

[0052] [Table 5]

[0053] [Table 6]

[0054] Embodiments of pyridoxal prodrugs encompassed by compounds of Formula I are shown in Table 3.

[0055] Table 3: Pyridoxal Prodrug Embodiments [ka] Pyridoxal Prodrug 16

[0056] [Table 7]

[0057] [Table 8]

[0058] [Table 9]

[0059] [Table 10]

[0060] [Table 11]

[0061] Process for preparation In an aspect, the present disclosure relates to processes for the preparation of a compound of formula I, its stereoisomers, its salts, hydrates, solvates, isotopes, or crystalline forms. [ka] The process includes reacting a compound of formula II with a compound of formula III in the presence of a base to form a compound of formula I. [ka] In the formula, X, R 1 , R 2 , R 3 , R 4 and R 5 is as described herein.

[0062] The base used to carry out the reaction is not particularly limited and should be known to those skilled in the art or can be determined by those skilled in the art. In one embodiment, for example and without limitation, the base is an organic base. In another embodiment, for example and without limitation, the base is diisopropylamine (DIPEA), pyridine, dimethylamine, imidazole, benzimidazole, etc.

[0063] The reaction can be carried out in the presence of a solvent. The solvent used is not particularly limited and is assumed to be known to those skilled in the art or can be determined by those skilled in the art. The selected solvent should avoid reacting with the compounds of formula II and III. In one embodiment, for example and without limitation, the solvent is an organic solvent. In another embodiment, for example and without limitation, the solvent can be a polar or non-polar solvent. In a further embodiment, for example and without limitation, the solvent can be an aprotic solvent. In yet a further embodiment, for example and without limitation, the solvent is dichloromethane, acetone, acetonitrile, dimethylformamide, ethyl acetate, dimethylsulfoxide, pyridine or tetrahydrofuran (THF).

[0064] Based on the disclosure herein, the compounds of the present application can be synthesized in a variety of ways using commercially available starting materials, compounds known in the literature, or from intermediates that are easily prepared. By utilizing standard synthetic methods and procedures, those skilled in the art of synthesis can successfully prepare the compounds of the present application. Standard synthetic methods and procedures for preparing organic molecules, as well as functional group transformations and manipulations, can be obtained from relevant literature in the field or from standard textbooks. There are many examples of textbooks on this subject, and Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley&Sons: New York, 2001; and Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley&15 Sons: New York, 1999 are good examples (all of which are incorporated herein by reference).

[0065] Suitable synthetic routes are shown in general schemes 1 and 2 to illustrate the general procedures for the preparation of the compounds of the present application. These schemes generally provide the desired final compounds, although in certain instances it may be desirable to further convert the compounds to pharma-ceutically acceptable salts, esters, carbonates, carbamates, or imines. The present application includes both possible stereoisomers (unless specified during synthesis), and includes not only racemates but also individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by elucidation of the final product or any convenient intermediate. Elucidation of the final product, intermediate, or starting material can be effected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley 30 lnterscience, 1994), which is incorporated herein by reference.

[0066] Description of General Scheme 1: Dichlorophosphate species 1 is reacted with a salt of amine 2 (HCl or TFA) in the presence of base to form species 3, which is not isolated. To the reaction mixture, 4-nitrophenol and additional base are added. The mixture is then stirred to form compound 5. After purification of compound 5, it is reacted with compound 6 in the presence of base to give compound 7. The purified compound 7 is deprotected to give compound 8, which is then oxidized to give compound 9. [ka]

[0067] The compounds of formulas 7, 8 and 9 shown above in Scheme 1 represent embodiments of compounds of structural formula I as described herein. The compounds of formula 6 shown above in Scheme I represent embodiments of compounds of structural formula II as described herein. The compounds of formulas 3 and 5 shown above in Scheme 1 represent embodiments of compounds of structural formula III or V (as described herein), depending on the substituents present. The compounds of formula 1 shown above in Scheme 1 represent embodiments of compounds of structural formula VI as described herein. The compounds of formula 2 shown above in Scheme 1 represent embodiments of compounds of structural formula VII as described herein. The compounds of formula 4 shown above in Scheme 1 represent embodiments of compounds of structural formula IV as described herein. Additionally, those disclosed in Scheme 1 are exemplary, non-limiting embodiments of compounds of structural formula IV. Also, in Scheme 1, the substituent R 1 , R 2 , R 3 , R 4 , R 5 and R 6 An exemplary, non-limiting embodiment of is also shown.

[0068] Description of General Scheme 2: Protected alcohol 11 is reacted with species 5 in the presence of base and MgCl2 to give compound 12. The protecting group is then removed to give 13. Using these general schemes 1 and 2, several preferred embodiments of the present application have been prepared that relate to compounds having one of the following structures or that are one of the following compounds: [ka]

[0069] Compounds of formula 11, shown above in Scheme 2, represent embodiments of compounds of formula II, as described herein. Compounds of formula 5, shown above in Scheme 2, represent embodiments of compounds of formula III or V, as described herein. Compounds of formulas 12 and 13, shown above in Scheme 2, represent embodiments of compounds of formula I, as described herein.

[0070] A number of compounds have been prepared based on the present specification and the general process described in Schemes 1 and 2. Compounds of Formula I that have been prepared and tested were greater than 95% pure by HPLC analysis.

[0071] Dosage, Administration and Use In a third aspect, the present disclosure relates to a composition comprising: A carrier, diluent or excipient; The present invention includes compounds represented by Formula I, their stereoisomers, salts, hydrates, solvates, isotopes or crystal forms thereof. [ka] In the formula, X, R 1 , R 2 , R 3 , R 4 and R 5 is as described herein.

[0072] The route of administration of the composition (or pharmaceutical composition) is not particularly limited and may be known or determined by those skilled in the art. In one embodiment, for example and without limitation, the composition may be formulated for enteral or parenteral route of administration.

[0073] In one embodiment, for example, but not limited to, the compounds disclosed herein may be formulated in a wide variety of oral administration forms and carriers.Oral administration may be in the form of tablets, coated tablets, hard and soft gelatin capsules, solutions, emulsions, syrups, or suspensions.The compounds of formula I as disclosed herein may be effective when administered by suppository administration, among other routes of administration.The most convenient method of administration is generally oral, using a convenient daily administration regimen that can be adjusted according to the severity of the disease and the patient's response to dosing.

[0074] The compound(s) disclosed herein, as well as their pharma- ceutically acceptable salts, may be placed in the form of pharmaceutical compositions and unit dosage forms together with one or more conventional excipients, carriers, or diluents. The pharmaceutical compositions and unit dosage forms may be composed of conventional ingredients in conventional proportions, with or without additional active compounds, and the unit dosage forms may contain any suitable effective amount of the active ingredient consistent with the intended daily dosage range to be used. The pharmaceutical compositions may be used as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids, such as suspensions, emulsions, or filled capsules for oral use, or in the form of suppositories for rectal or vaginal administration. A typical preparation will contain about 5% to about 95% (w / w) of the active compound(s). The term "preparation" or "dosage form" is intended to include both solid and liquid formulations of the active compound, and one skilled in the art will understand that the active ingredient may be present in different preparations depending on the desired dose and pharmacokinetic parameters.

[0075] The term "excipient" used herein is not particularly limited and is known to those skilled in the art. This term refers to a compound that is used to prepare pharmaceutical compositions and is generally safe, non-toxic, and not biologically undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. The compounds disclosed herein can be administered alone, but will generally be administered in combination with one or more suitable pharmaceutical excipients, diluents, or carriers selected with respect to the intended route of administration and standard pharmaceutical practice.

[0076] The term "pharmaceutically acceptable salts" is explained herein above.

[0077] Solid form preparations include powders, tablets, pills, capsules, suppositories, and dispersible granules. A solid carrier can be one or more substances that can also act as diluents, flavorings, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. In powders, the carrier is generally a finely divided solid that is mixed with the finely divided active ingredient. In tablets, the active ingredient is generally mixed with a carrier having the necessary binding capacity in a suitable ratio and compacted into the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like. Solid form preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0078] Liquid preparations are also suitable for oral administration, including liquid preparations including emulsions, syrups, elixirs, and aqueous suspensions. These also include solid form preparations that are intended to be converted to liquid form preparations shortly after use. Emulsions may be prepared in solution, for example, in aqueous propylene glycol, or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous suspensions can be prepared by dispersing finely divided active ingredients in water using viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0079] The compound of formula I as disclosed herein can be formulated for administration as suppository.A low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously, for example by stirring.The molten homogeneous mixture is then poured into conveniently sized molds, cooled, and solidified.

[0080] The compounds of formula I as disclosed herein may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams, or sprays containing such carriers in addition to the active ingredient will be known to those skilled in the art or can be determined by those skilled in the art based on the requirements of the particular application and as needed.

[0081] Suitable formulations with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by EW Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania, which is incorporated herein by reference. Compounds of formula I as disclosed herein can also be encapsulated in liposomes, such as those disclosed in U.S. Patent Nos. 6,180,134, 5,192,549, 5,376,380, 6,060,080, and 6,132,763, each of which is incorporated herein by reference. A skilled formulation scientist can modify the formulation within the teachings of this specification to provide a number of formulations for a specific administration route without destabilizing the compositions disclosed herein or impairing their therapeutic activity.

[0082] Modifications of the compounds of formula I as disclosed herein to render them more soluble in water or other vehicles, for example, but not limited to, minor modifications (e.g., salt formulations), can be readily accomplished and are well within the skill of, or can be determined by, one of ordinary skill in the art. Also, it is well within the skill of, one of ordinary skill in the art to modify the route of administration and dosing regimen of a particular compound to manage the pharmacokinetics of the compound for maximum beneficial effect in the patient.

[0083] In a fourth aspect, the present disclosure relates to the use of a compound represented by formula I, its stereoisomers, its salts, hydrates, solvates, isotopes or crystalline forms for the treatment or prevention of a disease. [ka] In the formula, X, R 1 , R 2 , R 3 , R 4 and R 5 is as described herein.

[0084] In a further aspect, the present specification also relates to the use of a compound represented by Formula I (as provided herein), its stereoisomer, its salt, hydrate, solvate, isotope or crystalline form in the preparation of a medicament for the treatment or prevention of a disease.

[0085] The term "medicament" as used herein is not particularly limited and is understood to be known to those skilled in the art. The term refers to a substance used in a method of treatment and / or prevention of a subject in need thereof, including, but not limited to, compositions, formulations, dosage forms, etc., containing a compound of formula I. The use of the compound in the manufacture of a medicament for the treatment of any of the conditions represented by formula I or disclosed herein is contemplated.

[0086] As mentioned above, the compounds of formula I as disclosed herein can function as prodrugs and have been shown to release the active form of pyridoxal 5-phosphate (P5P) both in vivo and in vitro. In addition, these prodrugs have been shown to improve the bioavailability of P5P (see dosing data). Furthermore, the compounds of formula I as disclosed herein can be used to treat several P5P-related conditions and fulfill all the roles that P5P is known to play.

[0087] Exemplary roles that can be played by the disclosed prodrug compounds (compounds of Formula I as disclosed herein) include being a cofactor for several enzymatic reactions, including, but not limited to, histamine, serotonin, and GABA (gama-aminobutyric acid).

[0088] In one embodiment, the present disclosure provides prodrug compounds that can be used to treat epileptic seizures in patients with known PNPO deficiency, as well as other clinical or biochemical features associated with disorders of vitamin B6 metabolism, including, but not limited to, congenital hypophosphatasia, P5P binding protein (PLPBP) deficiency, pyridoxine-dependent epilepsy, hyperprolinemia type II, and molybdenum cofactor deficiency.

[0089] In another embodiment, the present disclosure provides prodrug compounds that can be used to treat movement disorders including, but not limited to, dystonia, homocystinuria (dystonia, parkinsonism), carpal tunnel syndrome, Tourette's syndrome, and tardive dyskinesia.

[0090] In further embodiments, the present disclosure provides prodrug compounds that can be used in the treatment of clinical or biochemical problems associated with B6 deficiency, including, but not limited to, cardiovascular disease, ischemic heart disease, blood pressure, type 2 diabetes, immune or chronic inflammation, pneumonia, depression / anxiety, or cancer.

[0091] A list of potential therapeutic applications of the compounds of formula I disclosed herein related to B6 metabolic disorders is provided in Table 4 below.

[0092] [Table 12]

[0093] [Table 13]

[0094] A list of potential therapeutic applications of the compounds of formula I disclosed herein relating to B6 deficiency is provided in Table 5 below.

[0095] [Table 14]

[0096] In a fifth aspect, the present disclosure relates to a method for the medical treatment or prevention of a disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula I, its stereoisomer, its salt, hydrate, solvate, isotope or crystalline form. [ka] In the formula, X, R 1 , R 2 , R 3 , R 4 and R 5 is as described herein.

[0097] A subject in need thereof is intended to be a subject having any condition as disclosed herein.

[0098] The term "subject" as used herein is not particularly limited and is understood to be within the skill of the art. The term refers to mammals, including but not limited to cows, pigs, sheep, chickens, turkeys, buffalo, llamas, ostriches, dogs, cats, and humans. In one embodiment, for example and without limitation, the subject is a human.

[0099] The term "therapeutically effective amount" as used herein is not particularly limited and is known to those skilled in the art. This term means the amount necessary to reduce the symptoms of the disease in an individual. The dose is adjusted to the individual requirements in each particular case. The dosage can vary within wide limits depending on a number of factors, such as the severity of the disease being treated, the age and general health of the patient, other medicines with which the patient is being treated, the route and form of administration, as well as the preferences and experience of the physician involved. For oral administration, a daily dosage of about 0.1 to about 10 g (including all values ​​therebetween), for example, 0.25, 0.5, 0.75, I5 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, and 9.5 per day may be appropriate. In one embodiment, for example and without limitation, the daily dosage is about 0.5 to about 7.5 g per day, more preferably 1.5 to about 6.0 g per day. Those skilled in the art will be able to ascertain a therapeutically effective amount of a compound of formula I as disclosed herein for a given disease and patient in the treatment of the diseases described herein without undue experimentation and relying on personal knowledge, experience, and the disclosure of this application.

[0100] Therapeutic efficacy can be confirmed from tests of liver function including, but not limited to, protein levels such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, [gamma]-glutamyl transpeptidase, etc.), bilirubin synthesis, cholesterol synthesis, and bile acid synthesis; carbohydrate metabolism, amino acid and ammonia metabolism.

[0101] Biological assays Single Ascending Dose Study To assess the maximum tolerability of the P5P analog (compound of formula 16i) in rats at four different doses under one single administration via the oral (PO-oral) route, a single ascending dose study was performed to provide information on the linearity of the pharmacokinetics (PK) at multiple doses (Example 97: P5P Analog 16i: Single Ascending Dose Study).

[0102] To determine the effect of administered Formula 16i compounds on pyridoxine (PL) and P5P (PLP) levels, the basal levels of both PL and P5P were subtracted from the measured concentrations. Baseline subtraction was accomplished by subtracting the pre-dose concentration of either PL or P5P from subsequent values ​​over time.

[0103] A clear dose-dependent increase in plasma PL and P5P concentrations was observed, confirming the efficacy of compound of formula 16i. Increasing the dose of compound of formula 16i resulted in more P5P in plasma.

[0104] Based on the results obtained (see Figures 3-5), the efficacy of the compound of formula 16i was confirmed, since there was a clear dose-dependent increase in plasma PL and PLP concentrations. In this study, the MTD (maximum tolerated dose) was not determined, since animals in the highest dose group (300 mg / kg) did not show any toxicity signs (despite high plasma levels of PL and PLP). The compound of formula 16i showed dose linearity up to 300 mg / kg for plasma PL and PLP. Linearity was seen for both peak concentration (Cmax) and exposure (AUC). This allows prediction of plasma levels for repeated dosing.

[0105] In addition, the compound of formula 16i was safe at the given tested doses over a 24 hour period with no clinical signs observed. 1 / 2An increase in was noted for PL and PLP as dose increased. This may indicate that the clearance mechanisms are slowing / saturating with increasing dose and need to be monitored. It is also possible that a second source is adding PL and PLP to the plasma. The lack of dose linearity with the prodrugs may be due to instability of the prodrugs during the analysis.

[0106] Pharmacokinetic study 1 Pharmacokinetic study 1 was performed to determine whether P5P analog 16i can be converted to P5P and increase plasma P5P, whether P5P analog 16i is orally bioavailable, and to compare the ability of PO P5P analog 16i and PO P5P to increase plasma P5P (see Example 98: P5P Analog 16i: Pharmacokinetic Study 1).

[0107] To determine the effect of administered P5P analog 16i on pyridoxine (PL) and P5P (PLP) levels, the basal levels of both PL and P5P were subtracted from the measured concentrations. Baseline subtraction was accomplished by subtracting the pre-dose concentration of either PL or P5P from subsequent values ​​over time.

[0108] When administered IV, P5P analog 16i was converted to P5P, the half-life of which was greater than when P5P was administered IV. Furthermore, IV administration of P5P analog 16i was shown to result in elevated levels of P5P in plasma, confirming that P5P analog 16i was being converted to the desired product.

[0109] Based on the results obtained (see Figures 6-8), when administered orally, P5P analog 16i was able to cross the gastrointestinal wall (orally bioavailable) and was detectable in the circulatory system. Elevated plasma levels of P5P were detected after oral administration of P5P analog 16i. This elevated P5P had a half-life of approximately 7 hours. Oral administration of P5P by itself did not result in detectable P5P in plasma over a 24 hour period. This indicates that the oral bioavailability of P5P is 0%. The calculated oral bioavailability of P5P from administration of P5P analog 16i was 43%.

[0110] Pharmacokinetic study 2 Pharmacokinetic study 2 was performed to evaluate the effects of P5P analog 16v in comparison to P5P analog 16i (Example 99: P5P analog 16i: Pharmacokinetic study 2).

[0111] To determine the effect of administered P5P analogs 16i and 16v on pyridoxine (PL) and P5P levels, the basal levels of both PL and P5P were subtracted from the measured concentrations. Baseline subtraction was accomplished by subtracting the pre-dose concentration of either PL or P5P from subsequent values ​​over time.

[0112] Based on the results obtained (see Figures 9-10), when administered IV, P5P analog 16v was converted to P5P very efficiently, even more so than P5P analog 16i. When administered orally, P5P analog 16v was able to cross the gastrointestinal wall (orally bioavailable) and was detectable in the circulatory system. After oral administration of P5P analog 16v, elevated plasma levels of P5P were detected, showing slightly higher amounts compared to P5P analog 16i. This difference was attributed to a single rat. P5P analog 16v showed no clear advantage over P5P analog 16i when administered orally.

[0113] Pharmacokinetic Study 3 Pharmacokinetic study 2 was conducted to evaluate the effects of P5P analogs not encompassed by the compounds of formula I (compound II.I.), amino acid modifications (P5P analog 16vi) and compounds of formulas 16iii, 16i, and the racemic mixture of 16i (Example 100: P5P analog 16vi and compound II.I.: Pharmacokinetic study 3).

[0114] To determine the effects of administered Compound II.I. and P5P analog 16vi on pyridoxine (PL) and P5P levels, the basal levels of both PL and P5P were subtracted from the measured concentrations. Baseline subtraction was accomplished by subtracting the pre-dose concentration of either PL or P5P from subsequent values ​​over time.

[0115] Based on the results obtained (see Figures 11-13), when administered orally, compound II.I. was able to cross the gastrointestinal wall (orally bioavailable) and was detectable in the circulatory system. Elevated plasma levels of P5P were detected after oral administration of compound II.I., showing similar amounts compared to P5P analog 16i. P5P analog 16vi did not demonstrate significant oral bioavailability.

[0116] Pharmacokinetic Study 4 The objective of this study was to compare the pharmacokinetic (PK) profiles of the S-isomer (16i) and the R-isomer (16iii) at the phosphorus center, and to compare the PK profiles of the D-amino acids (S P and R P The objective of this study was to evaluate the effect of the use of isomeric 16i) on the PK profile.

[0117] To determine the effect of administered drugs on PL and PLP levels, basal levels of both PL and PLP were subtracted from the measured concentrations. Baseline subtraction was accomplished by subtracting the pre-dose concentration of either PL or PLP from subsequent values ​​over time.

[0118] Based on Figures 14 to 17, the 16i(S PThe IV and PO data for 16i (racemic isomer) suggest that this isomer is readily converted to PLP in plasma, which is consistent with the data for 16i (racemic isomer). Both the IV and PO data indicate that R P and S. P Comparing a racemic mixture containing the D-amino acid 16i' with a racemic mixture containing the L-amino acid 16i, PLP exposure was reduced with the D-amino acid, and use of the D-amino acid appears to increase PLP half-life by causing a second increase in plasma PLP (presumably delayed release from the liver). EXAMPLES

[0119] The following examples are illustrative and non-limiting and represent specific embodiments of the present invention.

[0120] General method 1 H NMR spectra were recorded on a Bruker Avance 300 NMR spectrometer operating at 299.992 MHz using the solvent resonance as the secondary standard. Phenyl dichlorophosphate, H-Ala-OiPr hydrochloride, 4-nitrophenol and other reagents used herein were purchased from Sigma Aldrich or Combi Blocks and used as received. N,N-Diisopropylethylamine, trimethylamine, tetrahydrofuran, acetonitrile, dichloromethane, trifluoroacetic acid, diethyl ether, diisopropyl ether, acetone, hexane, ethyl acetate, and methanol were purchased from Sigma Aldrich and used without further drying. All reactions were carried out under a nitrogen or argon atmosphere. Compounds were visualized / located by spraying TLC plates with Ninyhydrin solution, KMnO4 solution, or 2% ceric ammonium sulfate solution in 0.5 M H2SO4 followed by heating on a hotplate until color developed.

[0121] Example 1: Intermediate 5: R1 = phenyl, R2 = methyl with S stereochemistry, R3 = isopropyl. X = H. (2S)-Isopropyl 2-((4-nitrophenoxy)(phenoxy)phosphorylamino)propanoate. [ka] Phenyl phosphorodichloridate (1 eq.) and (S)-isopropyl 2-aminopropanoate hydrochloride (1 eq.) were suspended in dry dichloromethane and the mixture was cooled to −78° C. Triethylamine (2.1 eq.) was added slowly under argon. After addition, the dry ice / acetone bath was removed. 31 Once P NMR confirmed complete consumption of the dichloridate and formation of a new species (1-2 h), the reaction mixture was cooled to 0 °C and 4-nitrophenol (0.9-0.95 equiv.) was added in one portion, followed by trimethylamine (2.1 equiv.). Once TLC confirmed formation of a new product, the mixture was warmed to RT (2-3 h). Diethyl ether was added and most of the triethylammonium salt was filtered off. The filtrate was concentrated and purified using a biotage (hexanes / EtOAc) to give the pure product as a syrup (80-90% yield).

[0122] Example 2: Elucidation of 5 (R1=phenyl, R2=methyl with S stereochemistry, R3=isopropyl) [ka] A typical mixture of 5(P-rac,S) consisting of approximately equimolar amounts of the two diastereomers was dissolved in a minimum amount of diisopropyl ether to give a clear solution. Hexane was slowly added until a slight cloudiness persisted. After the solution was slowly stirred overnight, the colorless precipitate (11% of the original mixture) was filtered off and dried. This is the PR,S diastereomer. The filtrate was concentrated and the process was repeated to give more of the solid PR,S diastereomer.

[0123] Synthesis of pyridoxamine prodrugs Example 3: (2S)-Isopropyl 2-(((4-(aminomethyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (14) [ka] Compound 14 was prepared using the procedure in the general scheme above. Specifically, tert-butyl (3-(tert-butoxycarbonyloxy)-5-(hydroxymethyl)-2-methylpyridin-4-yl)methylcarbamate 11 (1 eq.), intermediate 5 (P-rac,S) (1.2 eq.) and MgCl2 (1 eq.) were suspended in dry acetonitrile and heated to 50° C. under argon for 10 min. DIPEA (2.5 eq.) was then added in one portion, heated and continued stirring at 50° C. until the reaction was complete by TLC (20 min-1 h). Purification using Biotage (hexanes / EtOAc) afforded intermediate 12. Treatment of 12 with TFA / DCM afforded 14 as the TFA salt (typically >80% over two steps). 1 H NMR (299.992 MHz, methanol-d4) δ 1.17-1.28 (m, 6H, 2CH3), 1.31-1.41 (m, 3H, CH3), 2.58-2.65 (br, 3H, ArCH3), 3.85-4.02 (m, 1H, CH), 4.17-4.35 (m, 2H, CH2), 4.94-5.08 (m, 1H, CH), 5.25-5.42 (m, 2H, CH2), 7.12-7.44 (m, 5H, ArH), 8.07-8.18 (m, 1H, ArH). All pyridoxamine prodrugs in Figure 1 were synthesized according to this procedure.

[0124] Characterization data for selected pyridoxamine prodrugs Example 4: (2S)-2-Ethylbutyl 2-(((4-(aminomethyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (14i) 1H NMR(299.992MHz,methanol-d4)δ 0.83-0.99(m,6H,2CH3),1.29-1.69(m,8H,2CH2,CH3,CH),2.66-2.82(br,3H,ArCH3),3.94-4.18(m,3H, CH2,CH),4.29-4.44(m,2H,CH2),5.34-5.53(m,2H,CH2),7.17-7.45(m,5H,ArH),8.23-8.36(m,1H,ArH).

[0125] Example 5: Isopropyl 2-(((4-(aminomethyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)acetate (14ii) 1 H NMR(299.992MHz,methanol-d4)δ 1.08-1.16(m,6H,2CH3),2.58(s,3H,CH3),3.52-3.71(m,3H,CH2,CH),4.24(s,2H,CH2), 4.88-5.00(m,1H,CH),5.26-5.37(m,2H,CH2),7.03-7.32(m,5H,ArH),8.17(s,1H,ArH).

[0126] Example 6: (2S)-Benzyl 2-(((4-(aminomethyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (14iii) 1 H NMR(299.992MHz,methanol-d4)δ 0.041-0.085(m,3H,CH3),1.25-1.40(m,3H,ArCH3),2.59-2.78(m,1H,CH),2.85-3.03(m,2H,CH2) ,3.69-3.83(m,2H,CH2),3.91-4.01(m,2H,CH2),5.69-6.05(m,10H,ArH),6.79-6.95(m,1H,ArH).

[0127] Example 7: (2S)-Isopropyl 2-(((4-(aminomethyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy) (5,6,7,8-Tetrahydronaphthalene-1-yloxy)phosphorylamino)propanoate (14iv) 1 H NMR (299.992MHz, methanol-d4) δ1.21-1.29(m,6H,2CH3),1.37-1.43(m,3H,CH3), 1.72-1.87(m,4H,2CH2),2.61-2.68(m,3H,CH3),2.68-2.84(m,4H,2CH2),3.87- 4.03(m,1H,CH),4.20-4.33(m,2H,CH2),4.96-5.07(m,1H,NH),5.25-5.46(m,2 H,CH2),6.88-6.98(m,1H,ArH),6.99-7.09(m,2H,ArH),8.09-8.22(m,1H,ArH).

[0128] Example 8: (2S)-Isopropyl 2-(((4-(aminomethyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy)(4-chlorophenoxy)phosphorylamino)propanoate (14v) 1 H NMR (299.992MHz, methanol-d4) δ1.07-1.16(m,6H,2CH3),1.20-1.30(m,3H,CH3),2.53-2.60(m,3H,CH3),3.75-3.88(m,1H,CH),4.17-4. 28(m,2H,CH2),4.82-4.94(m,1H,CH),5.18-5.34(m,2H,CH2),7.03-7.15(m,2H,ArH),7.21-7.32(m,2H,ArH),8.06-8.21(m,1H,ArH).

[0129] Example 9: (2S)-Isopropyl 2-(((4-(aminomethyl)-5-(dimethylcarbamoyloxy)-6-methylpyridin-3-yl)methoxy)(phenoxy)(phosphorylamino)propanoate (14vi) 1H NMR(299.992MHz,chloroform-d)δ1.20-1.28(m,6H,CH3),1.38-1.43(m,3H,CH3),2.62-2.64(m,3H,ArCH3),3.12-3.14(m,3H,NCH3),3.27-3.31(m,1H ,NH),3.88-4.07(m,1H,CH),4.35-4.49(m,2H,CH),4.94-5.06(m,2H,CH2 ),5.38-5.51(m,2H,CH2),7.16-7.43(m,6H,ArH),8.59-8.61(m,1H,ArH).

[0130] Example 10: (2S)-p-Tolyl 2-(((4-(aminomethyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (14vii) 1 H NMR(299.992MHz,methanol-d4)δ 1.56-1.48(m,3H,CH3),2.33(s,3H,ArCH3),2.65(s,3H,ArCH3),4.38-4.16(m,3H,CH,CH2),5 .50-5.33(m,2H,CH2),6.95-6.81(m,2H,ArH),7.43-7.10(m,7H,ArH),8.29-8.17(m,1H,ArH).

[0131] Example 11: Pyridoxamine prodrug 14 (14viii) with a deuterated methyl group for the isopropyl group 1 H NMR(299.992MHz,methanol-d4)δ 1.26-1.47(m,3H,CH3),2.69(s,3H,ArCH3),3.16-3.29(m,1H,CH),3.86-4.03(m,1H,CH),4.42-4.49(m,2H,CH2),4. 67-4.84(m,1H,NH),5.30-5.51(m,2H,CH2),7.10-7.27(m,3H,ArH),7.29-7.44(m,2H,ArH),8.15-8.37(m,1H,ArH).

[0132] Example 12: (2S)-Isopropyl 2-(((4-(aminomethyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate (14ix) 1 H NMR (299.992MHz, methanol-d4) δ1.18-1.23(m,6H,CH3),1.35-1.41(m,3H,CH3),2.60-2.62(m,3H,ArCH3),3.30-3.32(m,1H,NH),4.00-4.19(m,1H,C H),5.29-5.40(m,2H,CH),7.37-7.42(m,2H,ArH),7.51-7.57(m,2H,ArH),7.68-7.73(m,1H,ArH),7.85-7.89(m,1H,ArH),8.04-8.09(m,2H,ArH).

[0133] Example 13: (2S)-Cyclopentyl 2-(((4-(aminomethyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (14x) 1 H NMR (299.992MHz, methanol-d4) δ1.36-1.26(m,3H,CH3),1.91-1.55(m,8H,4CH2),2.69-2.59(m,3H,ArCH3),3.98-3.84(m,1H,CH),4.35-4 .25(m,2H,CH2),5.20-5.08(m,1H,CH),5.43-5.28(m,2H,CH2),7.26-7.15(m,3H,ArH),7.41-7.31(m,2H,ArH),8.25-8.15(m,1H,ArH).

[0134] Example 14: (2S)-Isopropyl 2-(((4-(aminomethyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy)(4-(trifluoromethoxy)phenoxy)phosphorylamino)propanoate (14xi) 1H NMR(299.992MHz,methanol-d4)δ 0.95-1.04(m,6H,2CH3),1.11-1.19(m,3H,CH3),2.54(s,3H,CH3),3.66-3.82(m,1H,CH),4.11-4.25(m, 2H,CH2),4.66-4.84(m,1H,CH),5.18-5.33(m,2H,CH2),6.96-7.17(m,4H,ArH),8.11-8.22(m,1H,ArH).

[0135] Example 15: (2S)-5,6,7,8-Tetrahydronaphthalen-2-yl 2-(((4-(aminomethyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (14xii) 1 H NMR(299.992MHz,methanol-d4)δ 1.21(s,3H,CH3),1.36-1.46(m,3H,CH3),1.63-1.78(m,4H,2CH2),2.60-2.72(m,4H,2CH2),4.04-4.26(m,2H,CH2),5.22-5.38(m ,2H,CH2),6.56-6.69(m,2H,ArH),6.90-6.99(m,1H,ArH),7.09-7.21(m,2H,ArH),7.24-7.34(m,2H,ArH),8.13-8.21(m,1H,ArH).

[0136] Example 16: Pyridoxamine prodrug 14 (14xiii) with deuterated methylene and methyl groups of the isopropyl group 1 H NMR(299.992MHz,methanol-d4)δ 2.57(s,3H,ArCH3),4.14-4.38(m,2H,CH2),4.67-4.84(m,1H,NH),5.28-5.39(m, 2H,CH2),7.13-7.27(m,3H,ArH),7.29-7.42(m,2H,ArH),7.95-8.14(m,1H,ArH).

[0137] Example 17: (2S)-Isopropyl 2-(((4-(aminomethyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)-3-(4-(benzyloxy)phenyl)propanoate (14xiv) 1 H NMR (299.992MHz, methanol-d4) δ1.04-1.24(m,6H,2CH3),2.55-2.72(m,3H,ArCH3),2.74-2.88(m,1H,CH),2.90-3.12(m,1H,CH),3.93-4.11(m,1H,NH),4 .14-4.31(m,2H,CH2),4.77-5.38(m,9H,CH,NH2,CH2),6.79-6.94(m,2H,Ar H),6.95-7.20(m,5H,ArH),7.20-7.46(m,7H,ArH),7.98-8.23(m,1H,ArH).

[0138] Example 18: (2S)-1-Methylpiperidin-4-yl 2-(((4-(aminomethyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (14xv) 1 H NMR (299.992MHz, methanol-d4) δ1.51-1.36(m,3H,CH3),2.30-1.80(m,4H,2CH2),2.75-2.69(m,3H,ArCH3),2.93-2.84(m,3H,ArCH3),3.66-3.10(m,4H ,2CH2),4.17-3.97(m,1H,CH),4.41-4.27(m,2H,CH2),5.19-4.91(m,1H,C H),5.51-5.33(m,2H,CH2),7.45-7.17(m,5H,ArH),8.36-8.24(m,1H,ArH).

[0139] Example 19: (2S)-Isopropyl 2-(((4-(aminomethyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy)(p-tolyloxy)phosphorylamino)propanoate (14xvi) 1H NMR (299.992MHz, methanol-d4) δ1.25-1.17(m,6H,2CH3),1.36-1.30(m,3H,CH3),2.32(s,3H,ArCH3),2.60(s,3H,ArCH3),3.96-3.83 (m,1H,CH),4.32-4.23(m,2H,CH2),5.03-4.80(m,1H,CH),5.38-5.24(m,2H,CH2),7.18-7.03(m,5H,ArH),8.16-8.07(m,1H,ArH).

[0140] Example 20: (2S)-4-Chlorophenyl 2-(((4-(aminomethyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (14xvii) 1 H NMR(299.992MHz,methanol-d4)δ1.35-1.46(m,3H,CH3),2.44(br,3H,ArCH3),4.02 -4.17(m,3H,CH,CH2),5.14-5.26(m,2H,CH2),6.83-6.98(m,2H,ArH),7.05-7.18(m,3H,ArH),7.19-7.33(m,4H,ArH),7.88-7.95(m,1H,ArH).

[0141] Example 21: (2S)-Isopropyl 2-(((4-(aminomethyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy)(4-bromo-2-fluorophenoxy)phosphorylamino)propanoate (14xviii) 1 H NMR(299.992MHz,CDCl3)δ1.06-1.17(s,6H,2CH3),1.22-1.33(m,3H,CH3),2.49-2.65(m,3H,CH3),3.69-3.95(m,1H,CH),4.09-4.3 6(m,2H,CH2),4.53-4.77(m,1H,CH),5.14-5.55(m,2H,CH2),7.16-7.30(m,2H,ArH),7.33-7.44(m,1H,ArH),8.08-8.19(m,1H,ArH).

[0142] Synthesis of pyridoxine prodrugs Example 22: (2S)-Isopropyl 2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (15) [ka] Compound 5 (P-rac,S) (1.15 eq.), MgCl2 (1 eq.), and compound 6 (1 eq.) were suspended in dry acetonitrile and under argon, and the mixture was stirred and heated to 50° C. for 10 min. DIPEA (2.5 eq.) was then added and stirring was continued for another 30 min. The solvent was removed under vacuum and purified using Biotage (hexanes / EtOAc) to give the acetonide-protected intermediate 7. After drying, compound 7 was dissolved in dry THF and cooled to 0° C. Concentrated HCl (12 eq.) was added slowly at 0° C. Once the addition was complete, the reaction mixture was allowed to warm to rt with stirring. Mass spectrometry and HPLC showed the reaction had proceeded to 50%, and the reaction was quenched by slowly adding excess TEA at −78° C. The solid salts were filtered off and rinsed using EtOAc. The liquid filtrates were combined, concentrated and purified using a Biotage (EtOAc or DCM / MeOH) to give the pure unreacted acetonide protected product and the desired alcohol product. 1 H NMR (299.992 MHz, chloroform-d) δ 1.08-1.47 (m, 9H, 3CH3), 2.48 (s, 3H, ArCH3), 3.79-4.23 (m, 2H, CH, NH), 4.82-5.17 (m, 5H, 2CH2, CH), 7.07-7.41 (m, 5H, ArH), 7.83-7.97 (m, 1H, ArH). The pyridoxine prodrugs displayed in Figure 2 were all synthesized following the same procedure.

[0143] Characterization data for selected alcohols. Example 23: (S)-Isopropyl 2-((S)-((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (15i) 1 H NMR(299.992MHz,chloroform-d)δ1.14-1.33(m,6H,2CH3),1.34-1.46(m,3H,CH3),2.56(s,3H,ArCH3),3.87-4.09 (m,2H,NH,CH),4.92-5.20(m,5H,2CH2,CH),7.19-7.31(m,3H,ArH),7.33-7.45(m,2H,ArH),7.99(s,1H,ArH).

[0144] Example 24: (S)-Isopropyl 2-((R)-((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (15ii) 1 H NMR(299.992MHz,chloroform-d)δ1.10-1.24(m,6H,2CH3),1.26-1.37(m,3H,CH3),2.45(s,3H,ArCH3),3.76-3.98(m,1H,CH ),4.35-4.56(m,1H,NH),4.82-5.13(m,5H,2CH2,CH),7.08-7.22(m,3H,ArH),7.23-7.36(m,2H,ArH),7.86(s,1H,ArH).

[0145] Example 25: (2S)-Isopropyl 2-((3,4-dichlorophenoxy)((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)phosphorylamino)propanoate (15iii) 1 H NMR(299.992MHz,chloroform-d)δ1.05-1.29(m,9H,3CH3),2.38(s,1H,CH3),3.70-3.88(s,1H,CH),4.06-4.32(m,1H,CH),4.79-5.05(m,5 H,2CH2,NH),6.25-6.86(br,2H,2OH),6.91-6.99(m,1H,ArH),7.15-7.23(m,1H,ArH),7.24-7.30(m,1H,ArH),7.78-7.85(m,1H,ArH).

[0146] Example 26: (2S)-Naphthalen-2-yl 2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (15iv) 1 H NMR (299.992MHz, chloroform-d) δ1.37-1.57(m,3H,CH3),2.41(br,3H,ArCH3),4.06-4.41(m,2H,NH,CH),4.64-5.14(m,4H,2CH2),6.75-7.96(m,13H,ArH).

[0147] Example 27: Isopropyl 2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)acetate (15v) 1 H NMR(299.992MHz,chloroform-d)δ1.18-1.37(m,6H,2CH3),2.56(s,3H,ArCH3),3.57- 3.87(m,2H,CH2),3.94-4.18(m,1H,NH),4.79-5.29(m,5H,ArH),7.99(s,1H,ArH).

[0148] Example 28: (2S)-Methyl 2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (15vi) 1 H NMR(299.992MHz,chloroform-d)δ 1.28-1.42(m,3H,CH3),2.62(s,3H,CH3),3.59-3.81(m,4H,CH2,CH,OH),3.90-4. 13(br,1H,OH),4.87-5.37(m,3H,CH,CH2),7.06-7.41(m,5ArH),8.03(s,1H,ArH).

[0149] Example 29: (2S)-Cyclopentylmethyl 2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (15vii) 1 H NMR(299.992MHz,chloroform-d)δ1.04-1.37(m,7H,CH2),1.43-1.78(m,8H,CH2,CH3),1.96-2.21(m,1H,CH),2.44(s,3H,ArCH3),3. 78-4.04(m,4H,CH,NH,CH2),4.78-5.08(m,4H,CH,CH2),7.04-7.20(m,3H,ArH),7.20-7.35(m,2H,ArH),7.79-7.92(m,1H,ArH).

[0150] Example 30: (2S)-Isopropyl 2-((2,3-dihydro-1H-inden-5-yloxy)((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)phosphorylamino)propanoate (15viii) 1 H NMR(299.992MHz,chloroform-d)δ1.09-1.21(m,6H,2CH3),1.23-1.33(m,3H,CH3),1.94-2.11(m,2H,CH2),2.43(s,3H,CH3),2.76-2.86(m,4H,2CH2),3. 74-4.00(m,2H,CH,NH),4.82-5.01(m,5H,2CH2,CH),6.01-6.88(m,1H,ArH ),6.90-6.98(m,1H,ArH),7.01-7.09(m,1H,ArH),7.82-7.88(m,1H,ArH).

[0151] Example 31: (2S)-Methyl 2-((4-chlorophenoxy)((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)phosphorylamino)propanoate (15ix) 1 H NMR(299.992MHz,chloroform-d)δ1.13-1.42(m,9H,3CH3),2.62(s,3H,ArCH3),3.80-4.12 (br,1H,CH),4.78-5.39(m,5H,CH2,CH),7.09-7.36(m,5H,ArH),7.98-8.16(m,1ArH).

[0152] Example 32: (2S)-Isopropyl 2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate (15x) 1 H NMR(299.992MHz,chloroform-d)δ1.20-1.23(m,6H,CH3),1.37-1.40(m,3H,CH3),2.55(s,3H,ArCH3),3.99-4.09(m,1H,CH),4.89-5.02(m,4H,CH2,NH, CH),5.26-5.34(m,2H,CH2),7.41-7.44(m,2H,ArH),7.51-7.58(m,2H,ArH ),7.69-7.72(m,1H,ArH),7.86-7.96(m,2H,ArH),8.07-8.12(m,1H,ArH).

[0153] Example 33: (2S)-Benzyl 2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (15xi) 1 H NMR(299.992MHz,chloroform-d)δ1.17-1.38(m,3H,3CH3),2.39(br,3H,ArCH3),3.86-4.14(m,1H,OH),4. 54-4.76(m,1H,CH),4.80-5.16(m,6H,3CH2),6.96-7.39(m,9H,ArH),7.52-8.69(m,3H,ArH,NH,ArH).

[0154] Example 34: (2S)-Isopropyl 2-cyclopentyl-2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)acetate (15xii) 1H NMR(299.992MHz,chloroform-d)δ1.17-1.36(m,6H,2CH3),1.33-1.50(m,2H,CH),1.51-1.82(m,6H,CH2),2.09-2.31(m,1H,CH),2.56(s,3H,ArCH3), 3.64-3.86(m,1H,CH),3.98-4.30(m,1H,NH),4.88-5.21(m,5H,CH,CH2),7.17-7.32(m,3H,ArH),7.32-7.46(m,2H,ArH),7.89-8.02(m,1H,ArH).

[0155] Example 35: (2S)-Isopropyl 2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)-4-methylpentanoate (15xiii) 1 H NMR(299.992MHz,chloroform-d)δ0.72-0.90(m,6H,CH3),1.00-1.21(m,6H,CH3),1.29-1.77(m,4H,CH2),2.43(s,3H,ArCH3),3.61-4.0 0(m,2H,NH,CH),4.74-5.10(m,5H,CH,CH2),7.04-7.14(m,3H,ArH),7.20-7.34(m,2H,ArH),7.77-7.93(m,1H,ArH),8.61-9.34(brs s,1H).

[0156] Example 36: Isopropyl 4,4,4-trifluoro-2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)butanoate (15xiv) 1H NMR(299.992MHz,chloroform-d)δ1.25-1.39(m,6H,2CH3),2.57(s,3H,CH3),2.59-2.81(m,2H,CH2),4.21-4.36(m,1H,CH),4 .48-4.72(m,1H,CH),4.96-5.20(m,5H,CH,CH2),7.20-7.33(m,3H,ArH),7.39-7.47(m,2H,ArH),7.95-8.03(m,1H,ArH).

[0157] Example 37: tert-Butyl 3-((2S)-2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)-3-isopropoxy-3-oxopropyl)-1H-indole-1-carboxylate (15xv) 1 H NMR(299.992MHz,chloroform-d)δ0.97-1.28(m,6H,2CH3),1.70(s,9H,3CH3),2.51(s,3H,ArCH3),2.94-3.32(m,2H,CH),3.70 -4.38(m,2H,NH,CH),4.72-5.08(m,5H,CH,CH2),6.93-7.61(m,10H,ArH),7.78-7.98(m,1H,ArH),8.04-8.21(m,1H,ArH).

[0158] Example 38: (2S)-Isopropyl 3-(4-(benzyloxy)phenyl)-2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (15xvi) 1H NMR(299.992MHz,chloroform-d)δ0.96-1.21(m,6H,2CH3),2.44(s,3H,CH3),2.74-2.97(m,2H,CH2),3.63-3.87(m,1H,CH),3.89-4.13(m,1H,NH) ,4.55-4.94(m,5H,CH,CH2),4.99(s,2H,CH2),6.77-6.88(m,2H,ArH),6.93-7.15(m,5H,ArH),7.18-7.43(m,7H,ArH),7.98-7.89(m,1H,ArH).

[0159] Example 39: (2S)-Isopropyl 2-(((5-benzoyloxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (15xvii) 1 H NMR(299.992MHz,chloroform-d)δ1.00-1.07(m,6H,CH3),1.14-1.23(m,3H,CH3),2.39(s,3H,ArCH3),3.51-3.64(m,1H,CH),3.76-3.86(m,1H,NH),4.79-4.85 (m,1H,CH),5.11-5.16(m,2H,CH2),5.26-5.29(m,2H,CH2),6.96-7.17(m,6H, ArH),7.22-7.32(m,3H,ArH),7.39-7.45(m,1H,ArH),7.87-8.00(m,3H,ArH).

[0160] Example 40: (2S)-Isopropyl 2-(((5-(dimethylcarbamoyloxy)-4-((dimethylcarbamoyloxy)methyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (15xviii) 1H NMR (299.992MHz, chloroform-d) δ 1.18-1.23 (m, 6H, CH3), 1.29-1.37 (m, 3H, CH3), 2.45 (s, 3H, ArCH3), 2.81-2.89 (m, 6H, NCH3), 3.01 (s, 3H, NCH3), 3.17 (s, 3H, NCH3), 3.68-3.77 (m ,1H,CH),3.91-3.99(m,1H,NH),4.95-5.01(m,1H,CH),5.11-5.14(m,2H,CH2),5.28-5. 34(m,2H,CH2),7.10-7.20(m,3H,ArH),7.26-7.33(m,3H,ArH),8.37-8.41(m,1H,ArH).

[0161] Example 41: Pyridoxine prodrug 15 (15xix) with a deuterated benzene ring 1 H NMR(299.992MHz,chloroform-d)δ1.08-1.23(m,6H,2CH3),1.22-1.35(m,3H,CH3),2.43(s, 3H,ArCH3),3.76-4.02(m,2H,2CH),4.72-5.12(m,5H,NH,2CH2),7.78-7.91(s,1H,ArH).

[0162] Example 42: Pyridoxine prodrug 15 (15xx) with deuterated isopropyl group 1 H NMR(299.992MHz,chloroform-d)δ 1.31-1.55(m,3H,CH3),2.58(s,3H,ArCH3),3.88-4.11(m,1H,CH),4.18-4.46(m,1H,NH),4.9 4-5.27(m,4H,2CH2),7.11-7.34(m,3H,ArH),7.34-7.47(m,2H,ArH),7.94-8.02(m,1H,ArH).

[0163] Example 43: (2R)-Isopropyl 2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (15xxi) 1H NMR(299.992MHz,chloroform-d)δ1.18-1.51(m,9H,3CH3),2.58(s,3H,ArCH3),3.89-4.24(m ,2H,CH,NH),4.95-5.24(m,5H,2CH2,CH),7.17-7.49(m,5H,ArH),7.96-8.06(m,1H,ArH).

[0164] Example 44: (2S)-Cyclopentyl 2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (15xxii) 1 H NMR(299.992MHz,chloroform-d)δ1.33-1.24(m,3H,CH3),1.90-1.45(m,8H,4CH2),2.49-2.33(m,3H,ArCH3),3.95-3.72(m,2H,NH,CH),4.54(br s,1H,OH),5.21-4.83(m,5H,CH,2CH2),7.34-7.05(m,5H,ArH),7.92(s,1H,ArH).

[0165] Example 45: Pyridoxine prodrug 15 (15xxiii) with a deuterated methyl group at the isopropyl group 1 H NMR(299.992MHz,chloroform-d)δ 1.15-1.37(m,3H,CH3),2.45(s,3H,ArCH3),3.68-3.95(m,2H,2CH),4.77-5.17(m,5 H,2CH2,NH),7.02-7.19(m,3H,ArH),7.22-7.37(m,2H,ArH),7.94-8.02(s,1H,ArH).

[0166] Example 46: (2S)-p-Tolyl 2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (15xxiv): 1H NMR(299.992MHz,chloroform-d)δ1.48-1.39(m,3H,CH3),2.48-2.26(m,6H,2 ArCH3),4.24-4.04(m,2H,NH,CH),4.50(br s,1H,OH),5.07-4.80(m,4H,2CH2),6.86-6.68(m,2H,ArH),7.32-7.05(m,7H,ArH),7.85(s,1H,ArH).

[0167] Example 47: (2S)-Isopropyl 2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(4-(trifluoromethoxy)phenoxy)phosphorylamino)propanoate (15xxv) 1 H NMR(299.992MHz,chloroform-d)δ1.16-1.51(m,9H,3CH3),2.54(s,3H,CH3),3.90-4.07(m,1H,CH),4.45-4.67( m,1H,CH),4.96-5.22(m,4H,2CH2),7.15-7.35(m,4H,ArH),7.43-7.88(br,1H,NH),7.93-8.04(m,1H,ArH).

[0168] Example 48: (2S)-Isopropyl 2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(5,6,7,8-tetrahydronaphthalen-1-yloxy)phosphorylamino)propanoate (15xxvi) 1 H NMR(299.992MHz,chloroform-d)δ1.41-1.49(s,3H,CH3),1.69-1.82(m,4H,2CH2),2.41-2.47(m,3H,CH3),2.62-2.76(m,4H,2CH2),3.95-4.2 3(m,2H,NH,CH),4.80-5.09(m,4H,2CH2),6.50-6.71(m,2H,ArH),6.93-7.03(m,1H,ArH),7.08-7.34(m,5H,ArH),7.85-7.91(m,1H,ArH).

[0169] Example 49: Pyridoxine prodrug 15 (15xxvii) with deuterated methylene groups 1 H NMR(299.992MHz,chloroform-d)δ 1.08-1.20(m,6H,2CH3),1.21-1.33(m,3H,CH3),2.43(s,3H,ArCH3),3.78-4.06(m,2H,2CH),4. 79-5.07(m,3H,CH2,NH),7.04-7.18(m,3H,ArH),7.20-7.31(m,2H,ArH),7.81-7.89(s,1H,ArH).

[0170] Example 50: (2S)-5,6,7,8-tetrahydronaphthalen-2-yl 2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (15xxviii) 1 H NMR(299.992MHz,CDCl3)δ1.41-1.49(s,3H,CH3),1.69-1.82(m,4H,2CH2),2.41-2.47(m,3H,CH3),2.62-2.76(m,4H,2CH2),3.95-4.23 (m,2H,NH,CH),4.80-5.09(m,4H,2CH2),6.50-6.71(m,2H,ArH),6.93-7.03(m,1H,ArH),7.08-7.34(m,5H,ArH),7.85-7.91(m,1H,ArH).

[0171] Example 51: (2S)-1-Methylpiperidin-4-yl 2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (15xxix) 1 H NMR(299.992MHz,methanol-d4)δ1.41-1.25(m,3H,CH3),2.05-1.62(m,4H,2CH2),2.57-3.32(m,8H,CH2,NCH 3,ArCH3),2.84-2.66(m,2H,CH2),3.99-3.85(m,1H,CH),4.96-4.71(m,3H,CH, CH2),5.23-5.10(m,2H,CH2),7.41-7.12(m,5H,ArH),7.93-7.84(m,1H,ArH).

[0172] Example 52: (2S)-Methyl 1-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphoryl)pyrrolidine-2-carboxylate (15xxx) 1 H NMR(299.992MHz,CDCl3)δ1.71-2.24(m,4H,proline),2.46(s,3H,ArCH3),3.12-3.45(m,3H.proline),3.50-3.74(m,3H,COOCH3) ,4.02-4.32(m,1H,CH),4.69-5.21(m,5H,2CH2,NH),7.01-7.20(m,3H,ArH),7.22-7.36(m,2H,ArH),7.89-8.01(m,1H,ArH)

[0173] Example 53: Pyridoxine prodrugs 15 (15xxvi) with deuterated methylene and methyl groups 1 H NMR(299.992MHz,chloroform-d)δ 1.23-1.37(m,6H,2CH3)1.38-1.52(m,3H,CH3),3.92-4.11(m,1H,CH),4.183-4.29(m,1H,CH),4. 97-5.21(m,3H,CH2,NH),7.19-7.34(m,3H,ArH),7.36-7.47(m,2H,ArH),7.94-8.06(m,1H,ArH).

[0174] Example 54: (2S)-Isopropyl 2-(((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)(p-trioxy)phosphorylamino)propanoate (15xxxii) 1H NMR(299.992MHz,chloroform-d)δ1.21-1.12(m,6H,2CH3),1.31-1.26(m,3H,CH3),2.30-2.26(m,3H,ArCH3),2.45(s, 3H,ArCH3),3.94-3.72(m,2H,NH,CH),5.04-4.83(m,5H,CH,2CH2),7.10-7.93(m,4H,ArH),7.91-7.84(m,1H,ArH).

[0175] Example 55: (2S)-Isopropyl 2-((4-bromo-2-fluorophenoxy)((5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl)methoxy)phosphorylamino)propanoate (15xxxiii) 1 H NMR(299.992MHz,chloroform-d)δ1.35-1.09(m,9H,3CH3),2.45(s,3H,ArCH3),4.08-3.79(m ,2H,NH,CH),5.14-4.84(m,5H,CH,2CH2),7.32-7.15(m,3H,ArH),7.93-7.86(m,1H,ArH)

[0176] Example 56: (2S)-Isopropyl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (16) [ka] MnO2 (12 equiv.) was suspended in dry DCM and the mixture was cooled to 0°C. After flushing the system with argon, the alcohol (1 equiv.) dissolved in DCM was then injected into the flask under argon. The ice bath was removed and stirring was continued for an additional 1-2 h when TLC confirmed the disappearance of the starting material. The mixture was filtered through a short silica gel column (EtOAc) to remove excess MnO2 and give the product as a pale yellow thick oil. 1H NMR (299.992 MHz, chloroform-d) δ 1.15-1.53 ​​(m, 9H, 3CH3), 2.59 (br, 3H, ArCH3), 3.67-4.13 (m, 2H, CH, NH), 4.94-5.13 (m, 1H, CH), 5.32-5.54 (m, 2H, CH2), 7.10-7.43 (m, 5H, ArH), 8.09-8.22 (m, 1H, ArH), 10.29-10.46 (m, 1H, CH), 11.31-11.73 (br, 1H, ArOH). The pyridoxal prodrugs displayed in Figures 2 and 3 were all synthesized following the same procedure.

[0177] Characterization data for selected aldehydes Example 57: (S)-Isopropyl 2-((S)-((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (16i) 1 H NMR(299.992MHz,chloroform-d)δ1.16-1.36(m,6H,2CH3),1.38-1.54(m,3H,CH3),2.63(s,3H,ArCH3),3.88-4.13(m,2H,CH,NH),5 .01-5.15(m,1H,CH),5.36-5.55(m,2H,CH2),7.16-7.46(m,5H,ArH),8.18(s,1H,ArH),10.41(s,1H,CH),11.59(br,1H,ArOH).

[0178] Example 58: (S)-Isopropyl 2-((R)-((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (16ii) 1H NMR (299.992MHz, chloroform-d) δ1.19-1.29(m,6H,2CH3),1.36-1.44(m,3H,CH3),2.59(s,3H,ArCH3),3.80-4.04(m,2H,CH,NH),4.94-5.11(m ,1H,CH),5.31-5.49(m,2H,CH2),7.13-7.26(m,3H,ArH),7.27-7.41(m,2H,ArH),8.14(s,1H,ArH),10.36(s,1H,CHO),11.55(br,1H,ArOH).

[0179] Example 59: (2R)-Isopropyl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (16iii) 1 H NMR(299.992MHz,chloroform-d)δ1.17-1.51(m,9H,3CH3),2.56-2.64(br,3H,ArCH3),3.69-4.11(m,2H,CH,NH),4.95-5.14(m,1 H,CH),5.29-5.53(m,2H,CH2),7.12-7.42(m,5H,ArH),8.08-8.21(m,1H,ArH),10.31-10.45(m,1H,CH),11.55(br,1H,ArOH).

[0180] Example 60: (2S)-Isopropyl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate (16iv) 1 H NMR(299.992MHz,chloroform-d)δ1.21-1.26(m,6H,CH3),1.44-1.46(m,3H,CH3),2.73-2.74(m,3H,ArCH3),4.20-4.31(m,1H,CH),4.84-5 .08(m,2H,NH,CH),5.28-5.52(m,2H,CH2),7.28-7.51(m,4H,ArH),7.60-7.78(m,2H,ArH),7.89-8.10(m,2H,ArH),10.18(s,1H,CHO).

[0181] Example 61: (2S)-2-Ethylbutyl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (16v) 1 H NMR(299.992MHz,chloroform-d)δ0.76-0.98(m,6H,2CH3),1.21-1.66(m,9H,CH,CH2),2.82(s,3H,ArCH3),3.88-4.21(m,3H,NH,C H2),4.27-4.53(m,1H,CH),5.34-5.75(m,2H,CH2),7.07-7.41(m,5H,ArH),8.21-8.46(m,1H,ArH),10.36-10.57(m,1H,CHO);

[0182] Example 62: (2S)-Isopropyl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)-3-phenylpropanoate (16vi) 1 H NMR(299.992MHz,chloroform-d)δ1.08-1.21(m,6H,2CH3),2.52(s,3H,ArCH3),2.86-3.05(m,2H,CH2),3.44-3.59(m,1H,CH),4.02-4.27(m,1H,NH), 4.78-5.13(m,2H,CH2),5.14-5.25(m,1H,CH),7.00-7.17(m,4H,ArH),7.18-7.31(m,5H,ArH),7.92-8.03(m,1H,ArH),10.13-10.23(m,1H,CHO).

[0183] Example 63: (2S)-Isopropyl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)-4-methylpentanoate (16vii) 1H NMR(299.992MHz,chloroform-d)δ0.87-1.05(m,6H,2CH3),1.19-1.36(m,6H,2CH3),1.42-1.90(m,3H,CH,CH2),2.63(s,3H,ArCH3),3.58-4.05(m,2H,NH ,CH),4.95-5.13(m,1H,CH),5.32-5.54(m,2H,CH2),7.14-7.29(m,3H,ArH ),7.30-7.42(m,2H,ArH),8.11-8.24(m,1H,ArH,10.31-10.42(m,1H,CHO).

[0184] Example 64: (2S)-Isopropyl 2-((4-chlorophenoxy)((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)phosphorylamino)propanoate (16viii) 1 H NMR(299.992MHz,chloroform-d)δ1.20-1.29(m,6H,2CH3),1.34-1.42(m,3H,CH3),2.59(s,3H,CH3),3.64-3.83(m,1H,CH),3.86(m,1H,CH ),4.96(m,1H,NH),7.07-7.16(m,2H,ArH),7.23-7.32(m,2H,ArH),8.01-8.17(m,1H,ArH),10.33-10.41(m,1H,CHO)11.52(s,1H,OH).

[0185] Example 65: (2S)-Benzyl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (16ix) 1 H NMR(299.992MHz,chloroform-d)δ1.23-1.40(m,3H,CH3),2.40-2.57(m,3H,ArCH3),3.75-4.12(m,2H,CH,NH),4.93-5 .36(m,4H,2CH2),6.95-7.38(m,10H,ArH),7.95-8.07(m,1H,ArH),10.15-10.31(m,1H,CH),11.42(br,1H,ArOH).

[0186] Example 66: (2S)-Cyclopentylmethyl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (16x) 1 H NMR(299.992MHz,chloroform-d)δ1.05-1.43(m,7H,CH,CH2,CH3),1.44-1.81(m,9H,CH ,CH2),2.04-2.26(m,1H,CH),2.54(s,3H,ArCH3),3.47-3.70(m,1H,CH),3.85-4.09 (m,3H,NH,CH2),5.23-5.42(m,2H,CH2),7.06-7.20(m,3H,ArH),7.20-7.35(m,3H, ArH), 8.02-8.14(m,1H,ArH),10.26-10.36(m,1H,CHO),11.44-11.53(m,1H,ArOH).

[0187] Example 67: Isopropyl 4,4,4-trifluoro-2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)butanoate (16xi) 1 H NMR(299.992MHz,chloroform-d)δ1.09-1.33(m,6H,2CH3),2.41-2.73(m,5H,CH2,ArCH3),3.68-3.95(m,1H,CH),4.08-4.32(m,1H,NH),4.91-5.12(m,1H ,CH),5.23-5.47(m,2H,CH2),7.05-7.21(m,3H,ArH),7.22-7.33(m,2H,ArH),8.01-8.13(m,1H,ArH),10.20-10.34(m,1H,CHO),11.48(s,1H,ArOH).

[0188] Example 68: (2S)-Isopropyl 2-((3,4-dichlorophenoxy)((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)phosphorylamino)propanoate (16xii) 1H NMR(299.992MHz,chloroform-d)δ 1.15-1.30(m,9H,3CH3),2.56(s,1H,CH3),3.54-3.71(m,1H,CH),3.80-4.00(m,1H,CH),4.95-5.07(m,1H,NH),5.31-5.43(m, 2H,CH2),6.98-7.08(m,1H,ArH),7.31-7.39(m,1H,ArH),8.07-8.13(m,1H,ArH),10.32-10.38(m,1H,CHO),11.49(s,1H,OH).

[0189] Example 69: tert-Butyl 3-((2S)-2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)-3-isopropoxy-3-oxopropyl)-1H-indole-1-carboxylate (16xiii) 1 H NMR (299.992MHz, chloroform-d) δ 1.09-1.26 (m, 6H, CH3), 1.61-1.75 (m, 9H, 3CH3), 2.48-2.66 (m, 3H, ArCH3), 3.03-3.26 (m, 2H, CH2), 3.72-4.01 (m, 1H, NH), 4.15-4.41 (m, 1H, CH) ,4.89-5.11(m,1H,CH),5.12-5.40(m,2H,CH2),6.99-7.39(m,7H,ArH),7.39-7.56(m, 2H,ArH), 7.94-8.19(m,2H,ArH), 10.14-10.31(m,1H,CHO), 11.42-11.58(m,1H,ArOH).

[0190] Example 70: (2S)-Naphthalen-2-yl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (16xiv) 1H NMR (299.992 MHz, dimethylsulfoxide-d6 / methanol-d4) δ 1.46-1.64 (m, 3H, CH3), 2.55 (s, 3H, ArCH3), 4.30-4.48 (m, 2H, CH, NH), 4.91-5.23 (m, 2H, 2CH), 6.53-6.59 (m, 1H, CH), 6.96-7.71 (m, 12H, ArH), 8.17 (s, 1H, ArH).

[0191] Example 71: Isopropyl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)acetate (16xv) 1 H NMR (299.992 MHz, dimethylsulfoxide-d6 / methanol-d4) δ 1.17-1.28 (m, 6H, 2CH3), 2.59 (s, 3H, ArCH3), 3.70 (s, 2H, CH2), ,NH), 4.93-5.22 (m, 3H, CH2, CH), 6.58-6.63 (m, 1H, CH), 7.03-7.38 (m, 5H, ArH), 8.27 (s, 1H, ArOH).

[0192] Example 72: (2S)-Isopropyl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(5,6,7,8-tetrahydronaphthalen-1-yloxy)phosphorylamino)propanoate (16xvi) 1 H NMR(299.992MHz,chloroform-d)δ1.44-1.50(m,6H,2CH3),1.57-1.66(m,3H,CH3),1.88-2.01(m,4 H,CH2),2.78(s,3H,CH3),2.80-3.01(m,4H,2CH2),3.83-4.02(m,1H,CH),4.10-4.28(m,1H,CH ),5.17-5.32(m,1H,NH),5.44-5.66(m,2H,CH2),7.05-7.13(m,1H,ArH),7.14-7.23(m,1H,ArH ),7.24-7.32(m,1H,ArH),8.26-8.34(m,1H,ArH),10.43-10.52(m,1H,CHO),11.71(s,1H,OH).

[0193] Example 73: (2S,2'S)-isopropyl 2,2'-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate (16xvii) 1 H NMR(299.992MHz,chloroform-d)δ0.98 1.41(m,18H,6CH3),2.57(s,3H,ArCH3),3.39-3.96(m,4H,2CH,2NH),4.76-5.32( m,4H,CH2,2CH),8.05(s,1H,ArH),10.39(s,1H,CH),11.25-11.65(br,1H,ArOH).

[0194] Example 74: (2S)-Isopropyl 2-(((5-(dimethylcarbamoyloxy)-4-formyl-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (16xviii) 1 H NMR(299.992MHz,chloroform-d)δ1.20-1.27(m,6H,CH3),1.36-1.41(m,3H,CH3),2.52(s,3H,ArCH3),3.05(s,3H,NCH3),3.20(s,3H,NCH3),3.61-3.70(m, 1H,CH),3.93-4.08(m,1H,CH),4.97-5.04(m,1H,CH),5.44-5.50(m,2H,CH2 ),7.14-7.35(m,6H,ArH),8.59-8.61(m,1H,ArH),10.26-10.28(m,1H,CHO).

[0195] Example 75: (2R)-Isopropyl 2-(((4-((E)-(4-bromo-3-fluorophenylimino)methyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoic acid (16xix) 1H NMR(299.992MHz,chloroform-d)δ1.10-1.47(m,9H,3CH3),2.49-2.74(m,3H,ArCH3),3.60-4.12(m,2H,CH,NH),4.93-5.51(m,3H, CH2,CH),6.99-7.44(m,7H,ArH),7.57-7.71(m,1H,ArH),8.01-8.20(m,1H,ArH),9.10-9.28(m,1H,CH),13.72(br,1H,ArOH).

[0196] Example 76: Pyridoxal prodrug 16 (16xx) with a deuterated benzene ring 1 H NMR(299.992MHz,chloroform-d)δ1.15-1.29(m,6H,2CH3),1.29-1.39(m,3H,CH3),2.54(s,3H,ArCH3),3.50-3.72(m,1H,NH),3.83- 4.04(m,1H,CH),4.91-5.04(m,1H,CH),5.25-5.43(m,2H,CH2),8.10(s,1H,ArH),10.27-10.36(m,1H,CHO),11.49(br,1H,ArOH).

[0197] Example 77: Pyridoxal prodrug 16 (16xxi) with deuterated isopropyl group 1 H NMR(299.992MHz,chloroform-d)δ1.39-1.52(m,3H,CH3),2.65(s,3H,ArCH3),3.74-3.96(m,1H,NH),3.96-4.15(m,1H,CH),5.41-5. 43(m,2H,CH2),7.18-7.31(m,3H,ArH),7.33-7.44(m,2H,ArH),8.20(s,1H,ArH),10.37-10.47(m,1H,CHO),11.60(br,1H,ArOH).

[0198] Example 78: Pyridoxal prodrug 16 (16xxii) with a deuterated methyl group at the isopropyl group 1H NMR(299.992MHz,chloroform-d)δ1.42-1.52(m,3H,CH3),2.54(s,3H,ArCH3),3.49-3.70(m,1H,CH),3.82-4.02(m,1H,NH),4.04-4.16(m,1H,C H),5.25-5.46(m,2H,CH2),7.08-7.22(m,3H,ArH),7.27-7.42(m,2H,ArH),8.10(s,1H,ArH),10.28-10.37(m,1H,CH),11.49(br,1H,ArOH).

[0199] Example 79: (2S)-p-Tolyl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (16xxiii): 1 H NMR(299.992MHz,chloroform-d)δ1.68-1.57(m,3H,CH3),2.67-2.38(m,6H,2 ArCH3),4.44-3.63(m,2H,NH,CH),5.54-5.39(m,2H,CH2),7.02-7.88(m,2H,ArH), 7.45-7.19(m,7H,ArH),8.20-8.17(m,1H,ArH),10.46-10.37(m,1H,CHO),11.61(br s,1H,ArOH).

[0200] Example 80: (2S)-Cyclopentyl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (16xxiv): 1 H NMR(299.992MHz,chloroform-d)δ1.37-1.28(m,3H,CH3),1.92-1.47(m,8H,4CH2),2.54(s,3H,ArCH3),4.15-3.53(m,2H,N H,CH),5.43-5.09(m,3H,CH,CH2),7.34-7.09(m,5H,ArH),8.13-7.96(m,1H,ArH),10.34-10.30(m,1H,CHO),11.49(br s,1H,ArOH).

[0201] Example 81: (2S)-Isopropyl 2-((2,3-dihydro-1H-inden-5-yloxy)((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)phosphorylamino)propanoate (16xxv) 1 H NMR(299.992MHz,chloroform-d)δ1.18-1.26(m,6H,2CH3),1.32-1.39(m,3H,CH3),2.01-2.13(m,2 H,CH2),2.54(s,3H,CH3),2.79-2.88(m,4H,2CH2),3.52-3.71(m,1H,CH),3.84-4.03(m,1H,NH ),4.93-5.07(m,1H,CH),5.22-5.42(m,2H,CH2),6.80-6.89(m,1H,ArH),6.94-7.00(m,1H,ArH ),7.03-7.10(m,1H,ArH),8.05-8.12(m,1H,ArH),10.23-10.32(m,1H,CHO),11.49(s,1H,OH).

[0202] Example 82: (2S)-Isopropyl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(4-(trifluoromethoxy)phenoxy)phosphorylamino)propanoate (16xxvi) 1 H NMR(299.992MHz,chloroform-d)δ1.26-1.35(m,6H,2CH3),1.41-1.49(m,3H,CH3),2.65(s,3H,CH3),3.68-3.85(m,1H,CH),3.92-4.11(m,1H,CH),4. 97-5.16(m,1H,NH),5.42-5.51(m,2H,CH2),7.18-7.33(m,4H,ArH),8.16-8.25(m,1H,ArH),10.39-10.49(m,1H,CHO),11.04-11.99(br,1H,OH).

[0203] Example 83: Pyridoxal prodrug 16 (16xxvii) with deuterated methylene groups 1H NMR(299.992MHz,chloroform-d)δ1.13-1.28(m,6H,2CH3),1.29-1.40(m,3H,CH3),2.54(s,3H,ArCH3),3.51-3.75(m,1H,CH),3.82-4.02(m,1H,NH ),3.77-4.16(m,1H,CH),7.09-7.19(m,3H,ArH),7.22-7.34(m,2H,ArH),8.03-8.12(m,1H,ArH),10.24-10.36(m,1H,CH),11.50(br,1H,ArOH).

[0204] Example 84: (2S)-Isopropyl 2-cyclopentyl-2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)acetate (16xxviii) 1 H NMR(299.992MHz,chloroform-d)δ1.18-1.31(m,6H,2CH3),1.32-1.83(m,9H,CH,CH 2),2.14-2.32(m,1H,CH),2.63(s,3H,CH3),3.75-4.05(m,2H,NH,CH),4.95-5. 13(m,1H,CH),5.33-5.52(m,5H,CH2),7.15-7.29(m,3H,ArH),7.30-7.43(m,2H ,ArH),8.12-8.22(m,1H,ArH),10.33-10.42(m,1H,CHO),10.59(brs,1H,ArOH).

[0205] Example 85: (2S)-Isopropyl 3-(4-(benzyloxy)phenyl)-2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (16xxix) 1H NMR (299.992MHz, chloroform-d) δ1.07-1.22(m,6H,2CH3),2.53(s,3H,CH3),2.85-2. 98(m,2H,CH2),3.29-3.60(m,3H,CH,CH2),4.02-4.23(m,2H,CH,NH),4.85-5.33(m ,6H,CH,CH2),6.75-6.92(m,2H,ArH),6.94-7.19(m,5H,ArH),7.19-7.46(m,7H,A rH),7.96-8.08(m,1H,ArH),10.16-10.26(m,1H,CHO),11.40-11.57(m,1H,ArOH).

[0206] Example 86: (2S)-Isopropyl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)-3-(4-hydroxyphenyl)propanoate (16xxx) 1 H NMR (299.992MHz, chloroform-d) δ 1.05-1.24 (m, 6H, 2CH3), 2.50 (s, 3H, ArCH3), 2.74-3.04 (m, 2H, CH2), 3.56-3.78 (m, 1H, CH), 3.91-4.26 (m, 1H, NH), 4.72-5.28 (m, 3H, CH, CH 2),6.57-6.76(m,2H,ArH),6.87-7.02(m,2H,ArH),7.02-7.18(m,3H,ArH),7.19-7. 32(m,2H,ArH),7.88-8.00(m,1H,ArH),10.07-10.20(m,1H,CHO),11.44(br,1H,OH).

[0207] Example 87: (2S)-1-Methylpiperidin-4-yl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (16xxxi) 1H NMR (299.992MHz, methanol-d4) δ1.41-1.25(m,3H,CH3),2.01-1.69(m,4H,2CH2),2.53-3.39(m,6H,2CH2),2.9-2.57(m,4H,2CH2),4.03-3.88(m,1H,C H),4.98-4.75(m,1H,CH),5.28-5.18(m,1H,CH2),5.51-5.41(m,1H,CH2), 7.40-7.14(m,5H,ArH),7.96-7.87(m,1H,ArH),10.45-10.40(m,1H,CHO).

[0208] Example 88: (2S)-2-Methoxyethyl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (16xxxii) 1 H NMR(299.992MHz,chloroform-d)1.38(m,3H,CH3),2.54(s,3H,ArCH3),3.33(s,3H,OCH3),3.59-3.50(m,2H,CH2),3.95-4.11(m,1 H,CH),4.17-4.22(m,2H,CH2),5.37-5.28(m,2H,CH2),7.11-7.28(m,5H,ArH),8.20(s,1H,ArH),10.32(s,1H),11.49(s,1H).

[0209] Example 89: (2S)-Methyl 1-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphoryl)pyrrolidine-2-carboxylate (16xxxiii) 1H NMR (299.992 MHz, chloroform-d) δ 1.75-2.21 (m, 4H, proline), 2.54 (s, 3H, ArCH3), 3.18-3.52 (m, 3H, proline), 3.58-3.76 (m, 3H, COOCH3), 4.18-4.42 (m, 1H, CH), 5.24-5.59 (m, 3H, CH2, NH), 7.04-7.21 (m, 3H, ArH), 7.22-7.34 (m, 2H, ArH), 8.05-8.19 (m, 1H, ArH), 10.24-10.42 (m, 1H, CHO), 11.46-11.56 (m, 1H, ArOH).

[0210] Example 90: (2S)-5,6,7,8-tetrahydronaphthalen-2-yl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (16xxxiv) 1 H NMR (299.992MHz, chloroform-d) δ1.49-1.56(s,3H,CH3),1.74-1.81(m,4H,2CH2),2.52-2. 55(m,3H,CH3),2.69-2.77(m,4H,2CH2),4.07-4.15(m,2H,NH,CH),5.34-5.43(m,2H,CH 2),6.65-6.71(m,2H,ArH),6.77-6.85(m,1H,ArH),6.98-7.04(m,1H,ArH),7.08-7.22( m,4H,ArH),7.99-8.19(m,1H,ArH),10.24-10.38(m,1H,ArH),11.40-11.54(m,1H,CHO).

[0211] Example 91: Pyridoxal prodrugs 16 (16xxxv) with deuterated methylene and methyl groups 1H NMR(299.992MHz,chloroform-d)δ1.05-1.28(m,6H,2CH3),1.27-1.41(m,3H,CH3),3.55-3.77(m,1H,CH),3.82-4.02(m,1H,NH),4.04-4 .16(m,1H,CH),4.88-5.05(m,2H,CH),7.08-7.22(m,3H,ArH),7.27-7.42(m,2H,ArH),8.05-8.13(s,1H,ArH),11.49(br,1H,ArOH).

[0212] Example 92: (S)-Isopropyl 2-((S)-((4-((E)-(cyclopentylimino)methyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (16xxxvi) 1 H NMR(299.992MHz,chloroform-d)δ1.19-1.49(m,9H,3CH3),1.67-2.16(M,8H,4CH2),2.63(s,3H,ArCH3),3.69-4.13(m,3 H,2CH,NH),5.00-5.15(m,1H,CH),5.23-5.39(m,2H,CH2),7.18-7.43(m,5H,ArH),8.04(S,1H,ArH),8.83(S,1H,CH).

[0213] Example 93: (2S)-Isopropyl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(p-tolyloxy)phosphorylamino)propanoate (16xxxvii) 1 H NMR(299.992MHz,chloroform-d)δ1.25-1.17(m,6H,2CH3),1.38-1.30(m,3H,CH3),2.30(m,3H,ArCH3),2.54(s,3H,ArCH3),4.03-3.53(m,2H,NH,CH ),5.05-4.93(m,1H,CH),5.41-5.26(m,2H,CH2),7.09-6.96(m,4H,ArH),8.11-8.06(m,1H,ArH),10.33-10.27(m,1H,CHO),11.49(s,1H,ArOH).

[0214] Example 94: (2S)-Benzyl 2-(((4-((E)-(4-cyanophenethylimino)methyl)-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (16xxxviii) 1 H NMR(299.992MHz,chloroform-d)δ1.37-1.50(m,3H,CH3),2.57-2.67(m,3H,ArCH3),3.07-3.19(m,2H,CH2),3.61-4.23(m,4H,CH,NH,CH2),5.0 9-5.34(m,4H,2CH2),7.09-7.54(m,12H,ArH),7.58-7.75(m,2H,ArH),7.94-8.10(m,1H,ArH),8.68-8.89(m,1H,ArH),13.91(br,1H,ArOH).

[0215] Example 95: (2S)-Isopropyl 2-((4-bromo-2-fluorophenoxy)((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)phosphorylamino)propanoate (16xxxix) 1 H NMR(299.992MHz,chloroform-d)δ1.40-1.17(m,9H,3CH3),2.57-2.53(m,3H,ArCH3),4.03-3.67(m,2H,NH,CH),5.06-4.92(m,1H ,CH),5.44-5.34(m,2H,CH2),7.30-7.15(m,3H,ArH),8.13-8.06(m,1H,ArH),10.40-10.33(m,1H,CHO),11.51(s,1H,ArOH).

[0216] Example 96: (2S)-4-Chlorophenyl 2-(((4-formyl-5-hydroxy-6-methylpyridin-3-yl)methoxy)(phenoxy)phosphorylamino)propanoate (16xl) 1H NMR (299.992 MHz, dimethylsulfoxide-d6 / methanol-d4) δ 1.33-1.46 (m, 3H, CH3), 2.58-2.66 (br, 3H, ArCH3), 3.87-3.99 (m, 1H, CH), 5.14-5.34 (m, 2H, CH2), 6.09&8.27 (s&s, 1H, CHO), 6.71-6.80 (m, 2H, ArH), 7.08-7.23 (m, 6H, ArH), 7.29-7.39 (m, 2H, ArH), 8.12-8.18 (m, 1H, ArH).

[0217] Example 97: P5P Analog 16: Single Ascending Dose Study (Figures 3-5) method Formulations were prepared in 1% methylcellulose in water on the day of administration of P5P analog 16.

[0218] Animals and Groups-Seventeen CD male rats with an approximate body weight of about 250 g were used. The animals were divided into four groups plus one other (n=4 for each group). The animals were acclimated for a period of five days in the animal facility. The environment of the animal room was controlled (temperature 22±0.2°C; relative humidity 55±25%; 12-h light / dark cycle, and 12 air changes per hour). The animals were provided with standard certified commercial rodent chow ad libitum. The procedures for the care and use of animals in this study were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) prior to conduction. One day prior to administration of D-1, the rats were divided into four groups (Table 6). The animals were identified and pre-administration blood was collected. The rats in all groups were fasted overnight (12-14 h) with only water available.

[0219] On day 0, animals in groups 1-2-3 were weighed and dosed by oral gavage as described in Table 6. Each remaining dosing solution was stirred (or vortexed slightly), a 50ul sample was taken and placed in a separate tube, and both vials were immediately frozen on dry ice. Two hours after dosing, food trays were returned to the animals.

[0220] Observations were made at the time of dosing, at the end of the day, and 24 hours after dosing (adverse reactions were recorded if observed). Animals were weighed again 24 hours after dosing.

[0221] [Table 15]

[0222] For all groups, blood was collected at the indicated time points: pre-dose, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, and 24 hr.

[0223] Approximately 150 μL of blood was collected using K2EDTA tubes at the indicated time points below. Blood was kept on ice and then centrifuged at 6000 RCF for 10 minutes at 4° C. Plasma was collected, kept on ice and then transferred to −80° C.

[0224] result 1. Oral Administration - C5P plasma profile when administered by oral gavage at 10mg / kg, 30mg / kg, 100mg / kg and 300mg / kg max Both the C and exposure (AUC) increased with increasing dose. max The values ​​were 290, 454, 2105, and 6621 ng / ml, respectively. The corresponding exposure values ​​for these same doses were 3673, 6853, 38288, and 86198 ng / ml*hr. When plotted against dose, these C max and exposure values ​​were linearly associated with R2 values ​​greater than 0.99. 2. There were no adverse reactions in any of the animals at any dose tested.

[0225] Example 98: P5P Analog 16: Pharmacokinetic Study 1 (Figures 6-8) method Formulation - Both P5P (pyridoxal-5-phosphate) and P5P analog 16 were formulated as homogenous solutions in phosphate buffered saline (PBS) on the day of administration.

[0226] Animals and Groups - 13 CD male rats with an approximate body weight of about 250 g were used. The animals were divided into 4 groups + 1 other rat (n=3 for each group). The animals were acclimated for a period of 5 days in the animal facility. The environment of the animal room was controlled (temperature 22±0.2°C; relative humidity 55±25%; 12-h light / dark cycle, and 12 air changes per hour). The animals were provided with standard certified commercial rodent chow ad libitum. The procedures for the care and use of animals in this study were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) prior to conduction. One day before administration of D-1, the rats were divided into 4 groups (Table 7). The rats in groups 3 and 4 were fasted overnight (12-14 h) with only water available.

[0227] On Day 0, animals were identified, weighed, and dosed by intravenous (IV) injection or oral gavage (PO) as described in Table 7. Food trays were returned to Groups 3 and 4 2 hours after dosing.

[0228] [Table 16]

[0229] For all groups, blood was collected at the indicated time points: pre-dose, 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, and 24 hr.

[0230] Approximately 150 uL of blood was collected using K2EDTA tubes at the indicated time points below. Blood was kept on ice and then centrifuged at 6000 RCF for 10 minutes at 4° C. Plasma was collected, kept on ice and then transferred to -80° C.

[0231] result 1. Intravenous (IV) Administration - When administered IV at 1 mg / kg, the plasma concentration-time curve shows that P5P has a C of 3373 ng / ml, which occurs 0.1 hours after administration. maxIt was demonstrated that the P5P assay has value. Plasma P5P was cleared relatively quickly with essentially no compound remaining after 4 hours. The total exposure of P5P was approximately 2200 ng / ml*h. Small amounts of pyridoxal (above baseline) were detected in plasma at a total exposure of 770 ng / ml*h.

[0232] Upon IV administration, P5P analog 16 had a smaller C of 1019 ng / ml. max Both P5P and pyridoxal were detected in plasma, and both compounds had similar C values ​​of approximately 200 ng / ml. max Furthermore, P5P levels were somewhat sustained.

[0233] 2. Oral Administration - When administered by oral gavage at 10 mg / kg, P5P was not detectable in plasma over a 24 hour evaluation period. max A large increase in pyridoxal values ​​was seen in plasma.

[0234] Upon oral administration of P5P analog 16, it was detectable in plasma with a C of 1345 ng / ml with a peak occurring 0.5 hours after administration. max In addition, significant P5P concentrations were detected in plasma. The P5P plasma profile after oral administration of P5P analog 16 showed a C value of 445 ng / ml at 1 hour post-administration. max The P5P plasma profile showed a half-life of approximately 7 hours. Pyridoxal showed a similar plasma profile.

[0235] Example 99: P5P analogs 16 and 16v.: Pharmacokinetic study 2 (Figure 9- method Formulation - Both P5P analog 16 and P5P analog 16v were formulated as homogenous solutions in 40% hydroxypropyl-β-cyclodextrin in water on the day of administration.

[0236] Animals and Groups - 13 CD male rats with an approximate body weight of about 250 g were used. The animals were divided into 4 groups + 1 other rat (n=3 for each group). The animals were acclimated for a period of 5 days in the animal care facility. The environment of the animal care room was controlled (temperature 22±0.2°C; relative humidity 55±25%; 12-h light / dark cycle, and 12 air changes per hour). The animals were provided with standard certified commercial rodent chow ad libitum. The procedures for the care and use of animals in this study were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) prior to conduction. One day before administration of D-1, the rats were divided into 4 groups (Table 8). The rats in groups 3 and 4 were fasted overnight (12-14 h) with only water available.

[0237] On Day 0, animals were identified, weighed, and dosed by intravenous (IV) injection or oral gavage (PO) as described in Table 8. Food trays were returned to Groups 3 and 4 2 hours after dosing.

[0238] [Table 17]

[0239] For all groups, blood was collected at the indicated time points: pre-dose, 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, and 24 hr.

[0240] Approximately 150 uL of blood was collected using K2EDTA tubes at the indicated time points below. Blood was kept on ice and then centrifuged at 6000 RCF for 10 minutes at 4° C. Plasma was collected, kept on ice and then transferred to -80° C.

[0241] result Intravenous (IV) Administration - When administered IV at 1 mg / kg, the plasma concentration-time curve for P5P analog 16v showed a small C of only 285 ng / ml, occurring 0.1 hours after administration. maxConversely, the plasma P5P profile demonstrated that large amounts of P5P were released into the plasma after administration of the P5P analog. The PLP profile showed a C max , T of 0.3 hours max and a half-life of 8.5 hours. Smaller amounts of pyridoxal were also formed and detected in plasma.

[0242] Upon IV administration, P5P analog 16 demonstrated a profile similar to previous studies with similar doses of P5P, demonstrating the presence of pyridoxal in plasma.

[0243] Oral Dosing - When administered by oral gavage at 10 mg / kg, P5P analog 16v showed large differences in the amount of P5P analog and P5P between individual rats. On average, very little P5P analog was found in plasma after oral dosing (C max =198ng / ml). On the other hand, P5P is max P5P analog 16v showed a similar mean plasma profile to P5P analog 16, with a somewhat higher mean plasma concentration (329 ng / ml vs. 238 ng / ml). P5P exposure when given as P5P analog 16v was 3892 ng / ml*hr compared to 3042 ng / ml*hr when given as P5P analog 16. Looking at the individual rat data, this higher value can be attributed to a single rat.

[0244] Concentration-time curves for oral administration of P5P analog 16 showed that the amount of P5P analog was reduced, but the amount of P5P was similar to the previous study.

[0245] Example 100: P5P analog 16vi and compound II.I.: Pharmacokinetic study 3 (Figures 11-13) Compound II.I. is a P5P analog not encompassed by the compounds of formula I.

[0246] method Formulation - On the day of administration, compound II.I. was formulated in 0.9% saline, while P5P analog 16vi was formulated as a homogenous solution in 40% hydroxypropyl-β-cyclodextrin in water.

[0247] Animals and Groups - 13 CD male rats with approximate body weight of about 250 g were used. The animals were divided into 4 groups + 1 other rat (n=3 for each group). The animals were acclimated for a period of 5 days in the animal facility. The environment of the animal room was controlled (temperature 22±0.2°C; relative humidity 55±25%; 12-h light / dark cycle, and 12 air changes per hour). The animals were provided with standard certified commercial rodent chow ad libitum. The procedures for the care and use of animals in this study were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) prior to conduction. One day before administration of D-1, the rats were divided into 4 groups (Table 9). The rats in groups 3 and 4 were fasted overnight (12-14 h) with only water available.

[0248] On Day 0, animals were identified, weighed, and dosed by intravenous (IV) injection or oral gavage (PO) as described in Table 9. Food trays were returned to Groups 3 and 4 2 hours after dosing.

[0249] [Table 18]

[0250] For all groups, blood was collected at the indicated time points: pre-dose, 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, and 24 hr.

[0251] Approximately 150 uL of blood was collected using K2EDTA tubes at the indicated time points below. Blood was kept on ice and then centrifuged at 6000 RCF for 10 minutes at 4° C. Plasma was collected, kept on ice and then transferred to -80° C.

[0252] result Intravenous (IV) Administration - When Compound II.I. was administered IV at 1 mg / kg, very little Compound II.I. or P5P was detected in plasma. Compound II.I. had a C of 777 ng / ml. max and an overall exposure of 346 ng / ml*hr. P5P resulting from administration of this prodrug had an exposure of 1534 ng / ml*hr.

[0253] IV dosing with P5P analog 16vi showed similar rapid clearance of P5P analog 16vi, but somewhat better P5P levels with a half-life of 3666 ng / ml*hr and 10 hours.

[0254] Oral Administration - When administered by oral gavage at 10 mg / kg, compound II.I. exhibited a similar compound II.I. and P5P profile to P5P analog 16i. When P5P analog 16vi was administered orally at 10 mg / kg, P5P analog 16vi had a C of 1652 ng / ml. max The results showed a plasma P5P profile with a Cmax of 190 ng / ml, a half-life of 6.5 hours, and an overall exposure of 1549 ng / ml.

[0255] When administered orally, neither the P5P analog 16vi nor P5P was detected in plasma at any significant levels.

[0256] Example 101: P5P analog 16vi and compound II.I.: Pharmacokinetic study 4 (Figures 14-17) method Formulation - Prodrug 16i(S P isomer), 16i(R P isomer) and 16i' (16i with D-amino acid racemate) were formulated as homogenous solutions in phosphate buffered saline (PBS) on the day of administration.

[0257] Animals and groups - 13 CD male rats with an approximate body weight of about 250 g were used. The animals were divided into 6 groups + 1 other rat (n=3 for each group). The animals were acclimated for a period of 5 days in the animal facility. The environment of the animal room was controlled (temperature 22±0.2°C; relative humidity 55±25%; 12-h light / dark cycle, and 12 air changes per hour). The animals were provided with standard certified commercial rodent chow ad libitum. The procedures for the care and use of animals in this study were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) prior to conduction. One day before administration of D-1, the rats were divided into 6 groups (Table 1). The rats in groups 4, 5, and 6 were fasted overnight (12-14 h) with only water available.

[0258] On Day 0, animals were identified, weighed, and dosed by intravenous (IV) injection or oral gavage (PO) as described in Table 10. Food trays were returned to Groups 4, 5, and 6 2 hours after dosing.

[0259] [Table 19]

[0260] For all groups, blood was collected at the indicated time points: pre-dose, 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, and 24 hr.

[0261] Approximately 150 uL of blood was collected using K2EDTA tubes at the indicated time points below. Blood was kept on ice and then centrifuged at 6000 RCF for 10 minutes at 4° C. Plasma was collected, kept on ice and then transferred to -80° C.

[0262] result Intravenous (IV) administration - two diastereomers of prodrug 16 (S P and R P isomer) is administered IV, P Similar conversion to PLP was achieved with a slight advantage for the isomeric prodrug. PWhen the isomer was given IV, the Cmax and exposure of PLP were 200 ng / ml and 2962 ng / ml* h, respectively. P When the isomers were given IV, Cmax and exposure values ​​were 177 ng / ml and 1886 ng / ml*h, respectively.

[0263] The D-amino acid prodrug 16iii did not convert well to PLP when administered IV, exhibiting a Cmax value of less than 100 ng / ml.

[0264] Oral Administration - When administered by oral gavage at 10 mg / kg, both diastereomers produced nearly identical PLP plasma profiles. P Isomers are R P When compared for the isomers, Cmax values ​​were 472 vs. 409 ng / ml, half-life values ​​were 7.6 vs. 7 hours, and exposure values ​​were 5892 vs. 4673 ng / ml*hr.

[0265] When animals were dosed with the prodrug 16iii, only small amounts of PLP were detected in the plasma, with an overall exposure of 645 ng / ml*h.

[0266] Considering the interanimal variability, the two diastereomers of prodrug 16 (i.e., prodrug S P and R P ) were not significantly different. Furthermore, the D-amino acid prodrug 16iii did not show a better PLP plasma profile compared to prodrug 16-the L-amino acid version of this prodrug.

[0267] Plasma conversion assay The ability of plasma enzymes to convert various prodrugs to P5P was tested by incubating the prodrugs in either whole blood or plasma of rats (Sprague Dawley). Rat blood or plasma (Innovative Research Inc) was spiked with 10 mM (DMSO) of the prodrug to a final concentration of 10 uM. Blood or plasma was then sampled at various time points and analyzed for the presence of P5P.

[0268] Blood (4ml) was pipetted into 15ml Falcon tubes and incubated in a 37°C / 5%CO2 incubator for approximately 30 minutes before being spiked with 10mM (4uL) of prodrug. The Falcon tubes were gently vortexed at low speed and blood was pipetted into 5 separate Eppendorf tubes (approximately 250ul). At various time points (up to 6 hours), the Eppendorf tubes were centrifuged at 554RCF and 50uL of supernatant was removed into separate Eppendorf tubes which were flash frozen and stored at -80°C until analysis.

[0269] Plasma samples were treated in a similar manner (1 ml of plasma was spiked with prodrug (1 uL) and vortexed before pipetting 50 ul into Eppendorf tubes, which were flash frozen for various times.) Plasma samples were also stored at -80°C until analysis.

[0270] The peak amounts of P5P produced from the various prodrugs were normalized to the amount of P5P converted from 16 included in each experiment.

[0271] Analysis (LC / MS) - LC-MS / MS conditions for P5P analysis device MS conditions ESI positive mode in MRM Source temperature 120℃ Desolvation temperature: 400℃ Capillary voltage 3500V

[0272] [Table 20]

[0273] LC conditions Mobile phase-A: 0.3% formic acid in water, Mobile phase-B: 0.1% formic acid in acetonitrile HPLC column: ACQUITY UPLC HSS T3 1.8 μm, 2.1 x 100 mm column gradient

[0274] [Table 21]

[0275] Sample preparation A 50 μL aliquot of the rat plasma sample is added to 950 μL of 50 g / L trichloroacetic acid.

[0276] Vortex for 1 minute.

[0277] Centrifuge at 19,000 RCF for 45 minutes.

[0278] The supernatant (20 μL) was injected into the LC-MS / MS for analysis.

[0279] The results of the ability of plasma enzymes to convert various prodrugs to P5P compared to 16, performed in separate studies, are provided in Table 11 below.

[0280] [Table 22]

[0281] [Table 23]

[0282] [Table 24]

[0283] [Table 25]

[0284] Certain adaptations and modifications of the described embodiments can be made, and therefore the above-described embodiments are to be considered as illustrative and not restrictive.

Claims

1. A compound represented by formula I, its stereoisomers, salts, hydrates, solvates, isomers or crystalline forms thereof, 【Chemistry 1】 wherein X is NH or N; R １ is H or C having one or more heteroatoms １～１５ is a substituent, R ２ is H or C having one or more heteroatoms １～１５ is a substituent, or when X is N, R ２ and C in which N has one or more heteroatoms ３～１５ forming a ring structure with the atoms, R ３ is H or C having one or more heteroatoms １～１５ is a substituent, R ４ but 【Chemistry 2】 where: 【Transformation 3】 is a single bond or a double bond, where: 【Chemistry 4】 is a single bond, A is NH ２ 、NH-PG Ｎ 、 【Transformation 5】 , OH, O-PG ０１ where PG Ｎ is a protecting group attached to the nitrogen, and PG ０１ is a first protecting group attached to the oxygen; 【Transformation 6】 is a double bond, A is O, R ５ is H or PG ０２ where PG ０２ is a second protecting group attached to the oxygen, or PG ０１ and P.G. ０２ A compound represented by Formula I, a stereoisomer thereof, a salt, hydrate, solvate, isomer or crystalline form thereof, wherein:

2. R １ But, -C ６ H ５ , -C ６ H ４ Cl, -C ６ H ３ BrF, -C ６ H ３ Cl ２ , -C ６ D ５ , -C ７ H ７ , -C ７ H ４ OF ３ , -C ７ H ７ O, -C ９ H ９ , -C １０ H １１ or -C １０ H ７ 2. A compound represented by formula I according to claim 1, wherein:

3. R ２ -H, -D, -CH ３ , -C ２ H ２ F ３ , -CH ２ CH ２ CH ２ -, -C ４ H ９ , -C ５ H ９ , -C ６ H ５ , -C ７ H ７ , -C ７ H ７ O, -C １４ H １２ O or -C １４ H １６ NO ２ 2. A compound represented by formula I according to claim 1, wherein:

4. R ３ But -CH ３ , -C ３ H ７ , -C ３ HD ６ , -C ３ D ７ , -C ５ H ９ , -C ６ H ４ Cl, -C ６ H ７ , -C ６ H １１ , -C ６ H １２ N, -C ６ H １３ , -C ７ H ７ , -C １０ H ７ or -C １０ H １１ 2. A compound represented by formula I according to claim 1, wherein:

5. PG Ｎ is a fluorenylmethoxycarbonyl protecting group (Fmoc), tert-butoxycarbonyl (BOC), carbobenzyloxy (Cbz), trifluoroacetamide, phthalimide, trityl (Tr), monomethoxytrityl (MMT), dimethoxytrityl (DMT), or benzylideneamine, a stereoisomer thereof, a salt, a hydrate, a solvate, an isomer, or a crystalline form thereof.

6. Each PG Ｏ１ and P.G. Ｏ２ are independently benzyl (Bn), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl (Piv), or benzyl (Bz), trityl (Tr), monomethoxytrityl (MMT), dimethoxytrityl (DMT), or PG Ｏ１ and P.G. Ｏ２ Together, 【Transformation 7】 5. A compound represented by formula I according to any one of claims 1 to 4, its stereoisomers, its salts, hydrates, solvates, isomers or crystalline forms thereof, which forms:

7. 5. A compound of formula I according to any one of claims 1 to 4, a stereoisomer thereof, a salt thereof, a hydrate, a solvate thereof, an isomer or a crystalline form thereof, wherein one or more of said H is replaced with D.

8. compound 【Transformation 8】 its stereoisomers, salts, hydrates, solvates, isotopes or crystalline forms thereof.

9. compound 【Chemistry 9】 its stereoisomers, salts, hydrates, solvates, isotopes or crystalline forms thereof.

10. compound 【Chemistry 10】 its stereoisomers, salts, hydrates, solvates, isotopes or crystalline forms thereof.

11. Compounds of Formula Ia 【Chemistry 11】 its stereoisomers, salts, hydrates, solvates, isotopes or crystalline forms thereof.

12. 1. A process for preparing a compound of formula I, its stereoisomeric forms, its salts, hydrates, solvates, isotopes or crystalline forms, comprising: 【Chemistry 12】 the process comprises reacting a compound of formula II with a compound of formula III in the presence of a base to form the compound of formula I; 【Chemistry 13】 wherein X is NH or N; R １ is H or C having one or more heteroatoms １～１５ is a substituent, R ２ is H or C having one or more heteroatoms １～１５ is a substituent, or when X is N, R ２ and C in which N has one or more heteroatoms ２～１５ forming a ring structure with the atoms, R ３ is H or C having one or more heteroatoms １～１５ is a substituent, LG is a leaving group; R ４ but 【Chemistry 14】 where: 【Chemistry 15】 is a single bond or a double bond, where: 【Chemistry 16】 is a single bond, A is NH ２ 、NH-PG Ｎ 、 【Chemistry 17】 , OH, O-PG ０１ where PG Ｎ is a protecting group attached to the nitrogen, and PG ０１ is a first protecting group attached to the oxygen; [Chemistry 18] is a double bond, A is O, R ５ is H or PG ０２ where PG ０２ is a second protecting group attached to the oxygen, or PG ０１ and P.G. ０２ together to form a diol protecting group, a process

13. 13. The process of claim 12, further comprising a deprotection step to remove any protecting groups in the compound of formula I. 【Request Item 14】 【Chemistry 19】 is a single bond and A is OH, 【Chemistry 20】 14. The process of claim 12 or 13, further comprising the step of oxidation of said compound to form a compound wherein is a double bond and A is O. 【Request Item 15】 【Chemistry 21】 reacting said compound of formula VII with a compound of formula VI in the presence of a base to form a compound of formula V; In the ceremony, LG １ is a leaving group that is the same as or different from the leaving group LG.

16. LG １ If is different from LG, 【Chemistry 22】 16. The process of claim 15, further comprising reacting the compound of formula V with the compound of formula IV in the presence of a base to form the compound of formula III.

17. 1. A composition comprising: a carrier, diluent or excipient; a compound represented by formula I, its stereoisomers, its salts, hydrates, solvates, isotopes or crystalline forms thereof, 【Chemistry 23】 wherein X is NH or N; R １ is H or C having one or more heteroatoms １～１５ is a substituent, R ２ is H or C having one or more heteroatoms １～１５ is a substituent, or when X is N, R ２ and C in which N has one or more heteroatoms ２～１５ forming a ring structure with the atoms, R ３ is H or C having one or more heteroatoms １～１５ is a substituent, R ４ but 【Chemistry 24】 where: 【Chemistry 25】 is a single bond or a double bond, where: 【Chemistry 26】 is a single bond, A is NH ２ 、NH-PG Ｎ 、 【Chemistry 27】 , OH, O-PG ０１ where PG Ｎ is a protecting group attached to the nitrogen, and PG ０１ is a first protecting group attached to the oxygen; 【Chemistry 28】 is a double bond, A is O, R ５ is H or PG ０２ where PG ０２ is a second protecting group attached to the oxygen, or PG ０１ and P.G. ０２ together form a diol protecting group.

18. In the compounds represented by formula I, their stereoisomers, salts, hydrates, solvates, isotopes or crystalline forms thereof, R １ But, -C ６ H ５ , -C ６ H ４ Cl, -C ６ H ３ BrF, -C ６ H ３ Cl ２ , -C ６ D ５ , -C ７ H ７ , -C ７ H ４ OF ３ , -C ７ H ７ O, -C ９ H ９ , -C １０ H １１ or -C １０ H ７ 18. The composition of claim 17, wherein

19. In the compounds represented by formula I, their stereoisomers, salts, hydrates, solvates, isotopes or crystalline forms thereof, R ２ -H, -D, -CH ３ , -C ２ H ２ F ３ , -CH ２ CH ２ CH ２ -, -C ４ H ９ , -C ５ H ９ , -C ６ H ５ , -C ７ H ７ , -C ７ H ７ O, -C １４ H １２ O or -C １４ H １６ NO ２ 18. The composition of claim 17, wherein

20. In the compounds represented by formula I, their stereoisomers, salts, hydrates, solvates, isotopes or crystalline forms thereof, R ３ But -CH ３ , -C ３ H ７ , -C ３ HD ６ , -C ３ D ７ , -C ５ H ９ , -C ６ H ４ Cl, -C ６ H ７ , -C ６ H １１ , -C ６ H １２ N, -C ６ H １３ , -C ７ H ７ , -C １０ H ７ or -C １０ H １１ 18. The composition of claim 17, wherein

21. In the compounds represented by formula I, their stereoisomers, salts, hydrates, solvates, isotopes or crystalline forms thereof, PG Ｎ is a fluorenylmethoxycarbonyl protecting group (Fmoc), tert-butoxycarbonyl (BOC), carbobenzyloxy (Cbz), trifluoroacetamide, phthalimide, trityl (Tr), monomethoxytrityl (MMT), dimethoxytrityl (DMT), or benzylideneamine.

22. In the compound represented by formula I, its stereoisomers, its salts, hydrates, solvates, isotopes or crystalline forms, each PG Ｏ１ and P.G. Ｏ２ are independently benzyl (Bn), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl (Piv), or benzyl (Bz), trityl (Tr), monomethoxytrityl (MMT), dimethoxytrityl (DMT), or PG Ｏ１ and P.G. Ｏ２ Together, 【Chemistry 29】 The composition according to any one of claims 17 to 20, which forms

23. 21. The composition of any one of claims 17 to 20, wherein one or more of the H's are replaced with D in the compound represented by Formula I, its stereoisomer, its salt, hydrate, solvate, isotope, or crystalline form.

24. The compound is 【Transformation 30】 The composition of any one of claims 17 to 20, in the form of a stereoisomer, a salt, a hydrate, a solvate, an isotope or a crystalline form thereof.

25. The compound is 【Chemistry 31】 The composition of any one of claims 17 to 20, in the form of a stereoisomer, a salt, a hydrate, a solvate, an isotope or a crystalline form thereof.

26. The compound is 【Chemistry 32】 The composition of any one of claims 17 to 20, in the form of a stereoisomer, a salt, a hydrate, a solvate, an isotope or a crystalline form thereof.

27. The compound is a compound of formula Ia 【Transformation 33】 The composition of any one of claims 17 to 20, in the form of a stereoisomer, a salt, a hydrate, a solvate, an isotope or a crystalline form thereof.

28. 1. Use of a compound represented by formula I, its stereoisomers, its salts, hydrates, solvates, isotopes or crystalline forms for the treatment or prevention of a disease, comprising: 【Transformation 34】 wherein X is NH or N; R １ is H or C having one or more heteroatoms １～１５ is a substituent, R ２ is H or C having one or more heteroatoms １～１５ is a substituent, or when X is N, R ２ and C in which N has one or more heteroatoms ２～１５ forming a ring structure with the atoms, R ３ is H or C having one or more heteroatoms １～１５ is a substituent, R ４ but 【Chemistry 35】 where: 【Transformation 36】 is a single bond or a double bond, where: 【Chemistry 37】 is a single bond, A is NH ２ 、NH-PG Ｎ 、 【Transformation 38】 , OH, O-PG ０１ where PG Ｎ is a protecting group attached to the nitrogen, and PG ０１ is a first protecting group attached to the oxygen; 【Chemistry 39】 is a double bond, A is O, R ５ is H or PG ０２ where PG ０２ is a second protecting group attached to the oxygen, or PG ０１ and P.G. ０２ together form a diol protecting group, use

29. In the compounds represented by formula I, their stereoisomers, salts, hydrates, solvates, isotopes or crystalline forms thereof, R １ But, -C ６ H ５ , -C ６ H ４ Cl, -C ６ H ３ BrF, -C ６ H ３ Cl ２ , -C ６ D ５ , -C ７ H ７ , -C ７ H ４ OF ３ , -C ７ H ７ O, -C ９ H ９ , -C １０ H １１ or -C １０ H ７ 29. The use according to claim 28, wherein

30. In the compounds represented by formula I, their stereoisomers, salts, hydrates, solvates, isotopes or crystalline forms thereof, R ２ -H, -D, -CH ３ , -C ２ H ２ F ３ , -CH ２ CH ２ CH ２ -, -C ４ H ９ , -C ５ H ９ , -C ６ H ５ , -C ７ H ７ , -C ７ H ７ O, -C １４ H １２ O or -C １４ H １６ NO ２ 29. The use according to claim 28, wherein

31. In the compounds represented by formula I, their stereoisomers, salts, hydrates, solvates, isotopes or crystalline forms thereof, R ３ But -CH ３ , -C ３ H ７ , -C ３ HD ６ , -C ３ D ７ , -C ５ H ９ , -C ６ H ４ Cl, -C ６ H ７ , -C ６ H １１ , -C ６ H １２ N, -C ６ H １３ , -C ７ H ７ , -C １０ H ７ or -C １０ H １１ 29. The use according to claim 28, wherein

32. In the compounds represented by formula I, their stereoisomers, salts, hydrates, solvates, isotopes or crystalline forms thereof, PG Ｎ is a fluorenylmethoxycarbonyl protecting group (Fmoc), tert-butoxycarbonyl (BOC), carbobenzyloxy (Cbz), trifluoroacetamide, phthalimide, trityl (Tr), monomethoxytrityl (MMT), dimethoxytrityl (DMT), or benzylideneamine.

33. In the compound represented by formula I, its stereoisomers, its salts, hydrates, solvates, isotopes or crystalline forms, each PG Ｏ１ and P.G. Ｏ２ are independently benzyl (Bn), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl (Piv), or benzyl (Bz), trityl (Tr), monomethoxytrityl (MMT), dimethoxytrityl (DMT), or PG Ｏ１ and P.G. Ｏ２ Together, 【Chemistry 40】 Use according to any one of claims 28 to 31, wherein

34. 32. The use according to any one of claims 28 to 31, wherein in the compound represented by formula I, its stereoisomer, its salt, hydrate, solvate, isotope or crystalline form, one or more of the H's are replaced with D.

35. The compound is 【Chemistry 41】 The use according to any one of claims 28 to 31, in the form of a stereoisomer, a salt, a hydrate, a solvate, an isotope or a crystalline form thereof.

36. The compound is 【Chemistry 42】 The use according to any one of claims 28 to 31, in the form of a stereoisomer, a salt, a hydrate, a solvate, an isotope or a crystalline form thereof.

37. The compound is 【Chemistry 43】 The use according to any one of claims 28 to 31, in the form of a stereoisomer, a salt, a hydrate, a solvate, an isotope or a crystalline form thereof.

38. The compound is represented by formula Ia: 【Chemistry 44】 The use according to any one of claims 28 to 31, in the form of a stereoisomer, a salt, a hydrate, a solvate, an isotope or a crystalline form thereof.

39. A method for the medical treatment or prevention of disease, comprising administering to a subject in need thereof a compound represented by formula I, its stereoisomer, its salt, hydrate, solvate, isotope, or crystalline form; 【Chemistry 45】 wherein X is NH or N; R １ is H or C having one or more heteroatoms １～１５ is a substituent, R ２ is H or C having one or more heteroatoms １～１５ is a substituent, or when X is N, R ２ and C in which N has one or more heteroatoms ２～１５ forming a ring structure with the atoms, R ３ is H or C having one or more heteroatoms １～１５ is a substituent, R ４ but 【Chemistry 46】 where: 【Chemistry 47】 is a single bond or a double bond, where: 【Chemistry 48】 is a single bond, A is NH ２ 、NH-PG Ｎ 、 【Chemistry 49】 , OH, O-PG ０１ where PG Ｎ is a protecting group attached to the nitrogen, and PG ０１ is a first protecting group attached to the oxygen; [Transformation 50] is a double bond, A is O, R ５ is H or PG ０２ where PG ０２ is a second protecting group attached to the oxygen, or PG ０１ and P.G. ０２ together form a diol protecting group.

40. In the compounds represented by formula I, their stereoisomers, salts, hydrates, solvates, isotopes or crystalline forms thereof, R １ But, -C ６ H ５ , -C ６ H ４ Cl, -C ６ H ３ BrF, -C ６ H ３ Cl ２ , -C ６ D ５ , -C ７ H ７ , -C ７ H ４ OF ３ , -C ７ H ７ O, -C ９ H ９ , -C １０ H １１ or -C １０ H ７ 40. The method of claim 39, wherein:

41. In the compounds represented by formula I, their stereoisomers, salts, hydrates, solvates, isotopes or crystalline forms thereof, R ２ -H, -D, -CH ３ , -C ２ H ２ F ３ , -CH ２ CH ２ CH ２ -, -C ４ H ９ , -C ５ H ９ , -C ６ H ５ , -C ７ H ７ , -C ７ H ７ O, -C １４ H １２ O or -C １４ H １６ NO ２ 40. The method of claim 39, wherein:

42. In the compounds represented by formula I, their stereoisomers, salts, hydrates, solvates, isotopes or crystalline forms thereof, R ３ But -CH ３ , -C ３ H ７ , -C ３ HD ６ , -C ３ D ７ , -C ５ H ９ , -C ６ H ４ Cl, -C ６ H ７ , -C ６ H １１ , -C ６ H １２ N, -C ６ H １３ , -C ７ H ７ , -C １０ H ７ or -C １０ H １１ 40. The method of claim 39, wherein:

43. In the compounds represented by formula I, their stereoisomers, salts, hydrates, solvates, isotopes or crystalline forms thereof, PG Ｎ is a fluorenylmethoxycarbonyl protecting group (Fmoc), tert-butoxycarbonyl (BOC), carbobenzyloxy (Cbz), trifluoroacetamide, phthalimide, trityl (Tr), monomethoxytrityl (MMT), dimethoxytrityl (DMT), or benzylideneamine.

44. In the compound represented by formula I, its stereoisomers, its salts, hydrates, solvates, isotopes or crystalline forms, each PG Ｏ１ and P.G. Ｏ２ are independently benzyl (Bn), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl (Piv), or benzyl (Bz), trityl (Tr), monomethoxytrityl (MMT), dimethoxytrityl (DMT), or PG Ｏ１ and P.G. Ｏ２ Together, 【Chemistry 51】 The method of any one of claims 39 to 42, wherein

45. 43. The method of any one of claims 39 to 42, wherein one or more of the H's are replaced with D in the compound represented by Formula I, its stereoisomer, its salt, hydrate, solvate, isotope, or crystalline form.

46. The compound is 【Chemistry 52】 43. The method of any one of claims 39 to 42, in the form of a stereoisomer, a salt, a hydrate, a solvate, an isotope or a crystalline form thereof.

47. The compound is 【Chemistry 53】 43. The method of any one of claims 39 to 42, in the form of a stereoisomer, a salt, a hydrate, a solvate, an isotope or a crystalline form thereof.

48. The compound is 【Chemistry 54】 43. The method of any one of claims 39 to 42, in the form of a stereoisomer, a salt, a hydrate, a solvate, an isotope or a crystalline form thereof.

49. The compound is represented by formula Ia: 【Transformation 55】 The use according to any one of claims 39 to 42, in the form of a stereoisomer, a salt, a hydrate, a solvate, an isotope or a crystalline form thereof.

Images