An antifungal prodrug, pharmaceutical compositions thereof, intermediates thereof, and methods of making and using the same

Abstract

The application discloses an antifungal drug prodrug, a pharmaceutical composition thereof, an intermediate thereof, and a preparation method and application thereof. Specifically provided is a compound shown in formula (I) or a pharmaceutically acceptable salt thereof. The compound of the application has one or more of the following effects: (1) good solubility; meeting the injection administration requirement; (2) rapid metabolism into an active metabolite; (3) rapid oral absorption; (4) fast in vivo conversion and distribution; (5) high bioavailability; (6) fast onset speed; (7) balanced pharmacokinetic characteristics; (8) no formaldehyde in the metabolite, low potential side effect; (9) good medicine property, and the like.

Description

[0001] This application claims priority to Chinese Patent Application No. 2024117632638, filed on December 2, 2024, and Chinese Patent Application No. 2025115660869, filed on October 29, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of biopharmaceuticals, specifically relating to an antifungal drug prodrug, its pharmaceutical composition, its intermediate, its preparation method, and its application. Background Technology

[0003] Invasive fungal infections refer to the pathological changes and pathophysiological processes in which fungi invade human tissues and bloodstreams, grow and multiply within them, leading to tissue damage, organ dysfunction, and inflammatory responses. They can affect multiple systems, such as the respiratory, digestive, and urinary systems, as well as the skin and mucous membranes. Patients may experience symptoms of skin damage, such as local rashes, itching, and ulceration, or cough, chest pain, abdominal pain, headache, fever, and fatigue. In recent years, with the increasing number of patients whose immune systems are compromised due to chemotherapy for cancer, organ transplantation, viral infections, or other diseases, the incidence of infections caused by deep fungal invasion has been rising steadily, posing a significant threat to human health. Therefore, the research and application of antifungal drugs have received increasingly widespread attention.

[0004] Fungal acyltransferase (Gwt1) is a conserved enzyme that catalyzes the acylation of inositol, acylating glycosylphosphatidylinositol (GPI) on the endoplasmic reticulum membrane and participating in the biosynthesis of the GPI-anchor. Inhibition of Gwt1 activity interferes with the maturation and localization of GPI-anchored mannose proteins in the fungal cell wall, significantly impacting their transfer and anchoring to the cell membrane and outer cell wall. These mannose proteins are essential for cell wall integrity, adhesion, pathogenicity, and evasion of the host immune system. Therefore, Gwt1 inhibitors can induce biological effects such as reduced mannose proteins connecting the fungal cell wall, decreased hyphal formation, reduced biofilm formation, abnormal cell size and shape, exposure of the dextran layer, and endoplasmic reticulum stress, thereby inhibiting fungal pathogen growth.

[0005] Fosmanogepix (APX001) is the first antifungal drug to inhibit the fungal Gwt1 gene and is a prodrug. After entering the body, it is metabolized into its active form, Manogepix (E1210 or APX001A), which effectively inhibits the proliferation of important fungal pathogens, including Candida and Aspergillus niger, without inhibiting the human homolog PIGW, which is closest to Gwt1, exhibiting good selectivity. However, E1210 has poor solubility, low oral bioavailability, and is difficult to formulate into a common intravenous preparation, resulting in poor drug-likeness. In clinical practice, E1210 is formulated as the prodrug Fosmanogepix (APX001). When administered orally or intravenously, it generates one molecule of formaldehyde in addition to E1210. Based on the clinical dosage of APX001, a dose of 1000 mg produces more than 50 mg of formaldehyde. Formaldehyde is classified as a Group 1 carcinogen by the World Health Organization, possessing carcinogenic, teratogenic, and strong irritant properties, which may limit its clinical use. Developing Gwt1 antifungal drugs with balanced pharmacokinetic characteristics, good drug-like properties, and low potential side effects is of great significance.

[0006] Summary of the Invention

[0007] This invention provides an antifungal drug prodrug, a pharmaceutical composition thereof, an intermediate thereof, a method for its preparation, and its application. The compounds of this invention have one or more of the following effects: (1) good solubility; meeting the requirements for injection administration; (2) rapid metabolism into active metabolites; (3) rapid oral absorption; (4) rapid in vivo conversion and distribution; (5) high bioavailability; (6) rapid onset of action; (7) balanced pharmacokinetic characteristics; (8) formaldehyde-free metabolites with low potential side effects; (9) good drug-like properties, etc.

[0008] This invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0009] ,

[0010] Where L is a single bond, -OC(O)-NL 1 -、-OC(O)-NL 2 -(CL 3 L 4 ) m -or-OC(O)-(CL) 5 L 6 ) n -;

[0011] L 1 L 2 L 3 L 4 L 5and L 6 Each independently is H or C 1-3 alkyl;

[0012] m and n are each independently 1 or 2;

[0013] X is a phenyl, pyridyl, or pyrrolidinyl group optionally substituted with one or more R groups;

[0014] R is independently C 1-3 Alkyl group, -(CH2) o -OP(=O)(OH)O - -(CH2) o -OP(=O)(O - )2·M + -(CH2) o -OP(=O)(O - )2·1 / 2D 2+ -(CH2) o -OP(=O)(O - )2·2M + -(CH2) o -OP(=O)(O - )2·D 2+ or ;

[0015] o can be 0, 1, 2, or 3;

[0016] M + It is a Group I main metal cation;

[0017] D 2+ It is a Group II main metal cation;

[0018] Y - It is a monovalent anion;

[0019] q is 0 or 1;

[0020] The compound represented by formula (I) contains at most one molecule selected from -(CH2). o -OP(=O)(OH)O - -(CH2) o -OP(=O)(O - )2·M + and -(CH2) o -OP(=O)(O - )2·1 / 2D 2+ A fragment;

[0021] When the compound shown in formula (I) contains one molecule selected from -(CH2) o -OP(=O)(OH)O- -(CH2) o -OP(=O)(O - )2·M + and -(CH2) o -OP(=O)(O - )2·1 / 2D 2+ When the fragment is q, it is 0; when the compound shown in formula (I) does not contain any compound selected from -(CH2) o -OP(=O)(OH)O - -(CH2) o -OP(=O)(O - )2·M + and -(CH2) o -OP(=O)(O - )2·1 / 2D 2+ When q is 1, Y - It is a monovalent anion.

[0022] In some implementations, in R, o is 0, 1, or 2 (preferably 0 or 1).

[0023] In some implementations, in R, M + for Na + or K + (Preferred to be Na) + ).

[0024] In some implementations, in R, D 2+ For Ca 2+ or Mg 2+ (Preferred to be Ca) 2+ ).

[0025] In some implementations, R contains -(CH2). o -OP(=O)(O - )2·M + for , , or .

[0026] In some implementations, R contains -(CH2). o -OP(=O)(O - )2·M + for or .

[0027] In some implementations, R contains -(CH2). o -OP(=O)(O - )2·M + for .

[0028] In some implementations, R contains -(CH2). o -OP(=O)(O - )2·1 / 2D 2+ for , , or .

[0029] In some implementations, R contains -(CH2). o -OP(=O)(O - )2·1 / 2D 2+ for or .

[0030] In some implementations, R contains -(CH2). o -OP(=O)(O - )2·1 / 2D 2+ for .

[0031] In some implementations, R contains -(CH2). o -OP(=O)(O - )2·2M + for , , or .

[0032] In some implementations, R contains -(CH2). o -OP(=O)(O - )2·2M + for .

[0033] In some implementations, R contains -(CH2). o -OP(=O)(O - )2·D 2+ -CH2-OP(=O)(O - )2·Ca 2+ -OP(=O)(O) - )2·Ca 2+ -CH2-OP(=O)(O - )2·Mg 2+ or -OP(=O)(O) - )2·Mg 2+ .

[0034] In some implementation schemes, Y- HCO3 - HCOO - or Cl - .

[0035] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0036] ,

[0037] Where L is a single bond, -OC(O)-NL 1 -、-OC(O)-NL 2 -(CL 3 L 4 ) m -or-OC(O)-(CL) 5 L 6 ) n -;

[0038] L 1 L 2 L 3 L 4 L 5 and L 6 Each independently is H or C 1-3 alkyl;

[0039] m and n are each independently 1 or 2;

[0040] X is a phenyl, pyridyl, or pyrrolidinyl group optionally substituted with one or more R groups;

[0041] R is independently C 1-3 alkyl, , , , or ;

[0042] Y - HCO3 - HCOO - or Cl - ;

[0043] q is 0 or 1;

[0044] The compound represented by formula (I) contains at most one ingredient selected from... , and A fragment;

[0045] When the compound shown in formula (I) contains one selected from , and When the fragment is q, it is 0; when the compound shown in formula (I) does not contain any of the following: , and When q is 1, Y - HCO3 - HCOO - or Cl - .

[0046] In some implementation schemes, R, L 1 L 2 L 3 L 4 L 5 and L 6 In, the C 1-3 The alkyl group is methyl, ethyl, n-propyl or isopropyl, preferably methyl.

[0047] In some embodiments, in X, the pyridyl group is , or Preferred .

[0048] In some embodiments, in X, the pyrroleyl group is... or Preferred .

[0049] In some implementations, X is described as "optionally replaced by one or more Rs" as "optionally replaced by 1, 2, 3, 4 or 5 Rs".

[0050] In some implementations, L is a single bond, -OC(O)-NL 1 -or-OC(O)-(CL) 5 L 6 ) n -; preferably a single bond or -OC(O)-(CL 5 L 6 ) n -

[0051] In some implementations, L 1 L 2 L 3 L 4 L 5 and L 6 Each can be either H or methyl.

[0052] In some implementations, L 1 and L 2 Each is independently a methyl group.

[0053] In some implementations, L3 and L 4 Each is independently represented by H.

[0054] In some implementations, L 5 and L 6 Each can be either H or methyl.

[0055] In some implementations, m is 1.

[0056] In some implementations, n is 2.

[0057] In some embodiments, X is a phenyl or pyridyl group substituted with one or more R groups; preferably, it is a phenyl group substituted with one or more R groups.

[0058] In some implementations, R is independently C. 1-3 alkyl, , , or .

[0059] In some implementations, R is preferably C independently. 1-3 alkyl, , or More preferably, C 1-3 alkyl or .

[0060] In some implementations, X is described as "optionally replaced by one or more Rs" as "optionally replaced by 1, 2 or 3 Rs".

[0061] In some implementations, when X is "optionally replaced by one or more R" instead of "replaced by 1 R", R is... , or Preferred or More preferably .

[0062] In some implementations, when X is "optionally replaced by one or more Rs" instead of "replaced by two Rs", one of the Rs is... , or Preferred or More preferably The other R is C. 1-3 alkyl or Preferred .

[0063] In some implementations, when X is "optionally replaced by one or more Rs" instead of "replaced by three Rs", one of the Rs is... , or Preferred or More preferably The other R is C. 1-3 alkyl or C is preferred. 1-3 alkyl.

[0064] In some embodiments, the compound represented by formula (I) contains one selected from , and The fragment has q = 0.

[0065] In some embodiments, the compound represented by formula (I) preferably contains one The fragment has q = 0.

[0066] In some embodiments, the compound represented by formula (I) does not contain any compound selected from... , and The fragment, q is 1, Y - HCO3 - or HCOO - .

[0067] In some embodiments, L is a single bond; X is a phenyl or pyridyl group substituted with one or more R groups, preferably a phenyl group substituted with one or more R groups.

[0068] In some embodiments, L is a single bond; X is a phenyl group substituted with one or two R atoms, each R being independently... , , or Furthermore, the compound represented by formula (I) contains one ingredient selected from... , and The fragment; q is 0.

[0069] In some embodiments, L is a single bond; X is a phenyl group substituted with one R, where R is... , or Preferred or More preferably q is 0.

[0070] In some embodiments, L is a single bond; X is a phenyl group substituted with two Rs, one of which is a phenyl group. , or Preferred or More preferably The other R is q is 0.

[0071] In some implementations, X is , , , , , , , , (For example )or .

[0072] In some implementations, X is , (For example ), , , or .

[0073] In some implementations, L is a single bond, -OC(O)-N(CH3)-CH2-, -OC(O)-N(CH3)-, or -OC(O)-CH2-C(CH3)2-.

[0074] In some embodiments, L is preferably a single bond, -OC(O)-N(CH3)- or -OC(O)-CH2-C(CH3)2-; more preferably a single bond or -OC(O)-CH2-C(CH3)2-.

[0075] In some implementations, R is independently methyl, , , , or .

[0076] In some implementations, R is preferably methyl, , , or More preferably, methyl or .

[0077] In some implementation schemes, X is , , (For example ), , , , , or .

[0078] In some implementation schemes, X is preferably... , , , , or More preferably or .

[0079] In some embodiments, the compound represented by formula (I) is the compound represented by formula (II).

[0080] ,

[0081] Wherein, L and X are defined as described above; and the compound shown in formula (II) contains one molecule selected from -(CH2). o -OP(=O)(OH)O - -(CH2) o -OP(=O)(O - )2·M + and -(CH2) o -OP(=O)(O - )2·1 / 2D 2+ fragments; o, D 2+ and M + The definition is as described above.

[0082] In some embodiments, in the compound represented by formula (II), L and X are defined as described above; and the compound represented by formula (II) contains one ingredient selected from... , and A fragment.

[0083] In some embodiments, in the compound represented by formula (II), L is a single bond, -OC(O)-NL 1 -or-OC(O)-(CL) 5 L 6 ) n -, preferably a single bond or -OC(O)-(CL) 5 L 6 ) n -

[0084] In some embodiments, in the compound represented by formula (II), L 1 It is a methyl group.

[0085] In some embodiments, in the compound represented by formula (II), L 5 and L 6 Each can be either H or methyl.

[0086] In some embodiments, n is 2 in the compound represented by formula (II).

[0087] In some embodiments, in the compound represented by formula (II), X is a phenyl or pyridyl group substituted with one or more R groups, preferably a phenyl group substituted with one or more R groups.

[0088] In some embodiments, in the compound represented by formula (II), the phrase “optionally substituted with one or more R” in X means “optionally substituted with 1, 2 or 3 R”.

[0089] In some embodiments, in the compound represented by formula (II), R is each independently C. 1-3 alkyl, , , or C is preferred. 1-3 alkyl, , or More preferably, C 1-3 alkyl or .

[0090] In some embodiments, when "optionally substituted by one or more Rs" in X of the compound represented by formula (II) is "substituted by one R", R is , or Preferred or More preferably .

[0091] In some embodiments, when "optionally substituted by one or more Rs" in X of the compound represented by formula (II) is "substituted by two Rs", one of the Rs is , or Preferred or More preferably The other R is C. 1-3 alkyl or Preferred .

[0092] In some embodiments, when "optionally substituted by one or more Rs" in X of the compound represented by formula (II) is "substituted by three Rs", one of the Rs is , or Preferred or More preferably The other R values ​​are each independently C. 1-3 alkyl or C is preferred. 1-3 alkyl.

[0093] In some embodiments, the compound represented by formula (II) contains one A fragment.

[0094] In some embodiments, in the compound represented by formula (II), L is a single bond, -OC(O)-NL 1 -or-OC(O)-(CL) 5 L 6 ) n -;L 1 L 5 and L 6 Each independently is H or C 1-3 Alkyl; n is 1 or 2; X is a phenyl or pyridyl group substituted with 1, 2 or 3 Rs; each R is independently C 1-3 alkyl, , , or Furthermore, the compound represented by formula (II) contains one ingredient selected from... , and A fragment.

[0095] In some embodiments, in the compound represented by formula (II), L is a single bond or -OC(O)-(CL) 5 L 6 ) n -;L 5 and L 6 Each is independently H or methyl; n is 2; X is a phenyl group substituted with 1, 2, or 3 Rs; each R is independently methyl, , or Furthermore, the compound represented by formula (II) contains one ingredient selected from... and A fragment.

[0096] In some embodiments, the compound represented by formula (I) is the compound represented by formula (III).

[0097] ,

[0098] Where p is 1, 2, 3, 4, or 5; L and R are defined as described above; and the compound represented by formula (III) contains one molecule selected from -(CH2). o -OP(=O)(OH)O - -(CH2) o -OP(=O)(O - )2·M + and -(CH2) o -OP(=O)(O - )2·1 / 2D 2+ fragments; o, D 2+ and M + The definition is as described above.

[0099] In some embodiments, in the compound represented by formula (III), p is 1, 2, 3, 4, or 5; L and R are defined as described above; and the compound represented by formula (III) contains one selected from... , and A fragment.

[0100] In some embodiments, in the compound represented by formula (III), L is a single bond, -OC(O)-NL 1 -or-OC(O)-(CL) 5 L 6 ) n -, preferably a single bond or -OC(O)-(CL) 5 L 6 ) n -

[0101] In some embodiments, in the compound represented by formula (III), L 1 It is a methyl group.

[0102] In some embodiments, in the compound represented by formula (III), L 5 and L 6 Each can be either H or methyl.

[0103] In some embodiments, n is 2 in the compound represented by formula (III).

[0104] In some embodiments, p is 1, 2 or 3 in the compound represented by formula (III), preferably 1 or 3.

[0105] In some embodiments, in the compound represented by formula (III), R is each independently C. 1-3 alkyl, , or C is preferred. 1-3alkyl or .

[0106] In some embodiments, in the compound represented by formula (III), when p is 1, R is... or Preferred .

[0107] In some embodiments, in the compound represented by formula (III), when p is 2, one of R is or Preferred The other R is C. 1-3 alkyl or Preferred .

[0108] In some embodiments, in the compound represented by formula (III), when p is 3, one of R is or Preferred The other Rs are each independently C. 1-3 alkyl or C is preferred. 1-3 alkyl.

[0109] In some embodiments, the compound represented by formula (III) contains one Excerpt.

[0110] In some embodiments, in the compound represented by formula (III), L is a single bond, -OC(O)-NL 1 -or-OC(O)-(CL) 5 L 6 ) n -;L 1 L 5 and L 6 Each independently is H or C 1-3 Alkyl; n is 1 or 2; p is 1, 2 or 3; R is C1 each. 1-3 alkyl, , or Furthermore, the compound represented by formula (III) contains one ingredient selected from... and A fragment.

[0111] In some embodiments, in the compound represented by formula (III), L is a single bond or -OC(O)-(CL) 5 L 6 ) n -;L 5 and L 6Each is independently H or methyl; n is 2; p is 1, 2 or 3; R is independently methyl, , or Furthermore, the compound represented by formula (III) contains one ingredient selected from... and A fragment.

[0112] In some embodiments, the compound represented by formula (I) is the compound represented by formula (IV).

[0113] ,

[0114] Where p is 1, 2, 3, 4, or 5; R is defined as described above; and the compound represented by formula (IV) contains one molecule selected from -(CH2). o -OP(=O)(OH)O - -(CH2) o -OP(=O)(O - )2·M + and -(CH2) o -OP(=O)(O - )2·1 / 2D 2+ fragments; o, D 2+ and M + The definition is as described above.

[0115] In some embodiments, in the compound represented by formula (IV), p is 1, 2, 3, 4, or 5; R is defined as described above; and the compound represented by formula (IV) contains one selected from... , and A fragment.

[0116] In some embodiments, in the compound represented by formula (IV), p is 1, 2 or 3, preferably 1 or 2, more preferably 1.

[0117] In some embodiments, in the compound represented by formula (IV), R is each independently C. 1-3 alkyl, , or Preferred .

[0118] In some embodiments, in the compound represented by formula (IV), when p is 1, R is... or Preferred .

[0119] In some embodiments, in the compound represented by formula (IV), when p is 2, one of R is or Preferred The other R is C. 1-3 alkyl or Preferred .

[0120] In some embodiments, in the compound represented by formula (IV), R is... .

[0121] In some embodiments, the compound represented by formula (IV) contains one Excerpt.

[0122] In some embodiments, in the compound represented by formula (IV), p is 1, 2, or 3; R is each independently C 1-3 alkyl, , or Furthermore, the compound represented by formula (IV) contains one ingredient selected from... and A fragment.

[0123] In some embodiments, in the compound represented by formula (IV), p is 1; R is... , or Preferred .

[0124] In some embodiments, the compound represented by formula (IV) is the compound represented by formula (IV-1).

[0125] ,

[0126] Wherein, R is selected from -(CH2). o -OP(=O)(OH)O - -(CH2) o -OP(=O)(O - )2·M + and -(CH2) o -OP(=O)(O - )2·1 / 2D 2+ fragments; o, D 2+ and M + The definition is as described above.

[0127] In some embodiments, in the compound represented by formula (IV-1), R is... , or .

[0128] In some embodiments, in the compound represented by formula (IV-1), R is... or .

[0129] In some embodiments, in the compound represented by formula (IV-1), R is... .

[0130] In some embodiments, the compound represented by formula (I) is the compound represented by formula (V).

[0131] ,

[0132] Where p is 1, 2, 3, 4 or 5; R, n, L 5 and L 6 The definition is as described above; and the compound represented by formula (V) contains one molecule selected from -(CH2). o -OP(=O)(OH)O - -(CH2) o -OP(=O)(O - )2·M + and -(CH2) o -OP(=O)(O - )2·1 / 2D 2+ fragments; o, D 2+ and M + The definition is as described above.

[0133] In some embodiments, in the compound represented by formula (V), p is 1, 2, 3, 4, or 5; R, n, L 5 and L 6 The definition is as stated above; and the compound represented by formula (V) contains one ingredient selected from... , and A fragment.

[0134] In some embodiments, p is 1, 2 or 3 in the compound represented by formula (V), preferably 3.

[0135] In some embodiments, in the compound represented by formula (V), R is each independently C. 1-3 alkyl, , or .

[0136] In some embodiments, in the compound represented by formula (V), R is each independently preferred to be C. 1-3 alkyl or .

[0137] In some embodiments, in the compound represented by formula (V), when p is 3, one of R is or Preferred The other R values ​​are each independently C. 1-3 alkyl or C is preferred. 1-3 alkyl.

[0138] In some embodiments, the compound represented by formula (V) contains one Excerpt.

[0139] In some embodiments, n is 2 in the compound represented by formula (V).

[0140] In some embodiments, L in the compound represented by formula (V) 5 and L 6 Each can be either H or methyl.

[0141] In some embodiments, in the compound represented by formula (V), n is 1 or 2; L 5 and L 6 Each independently is H or C 1-3 Alkyl group; p is 1, 2 or 3; R is preferably C1 each independently. 1-3 alkyl, , or Furthermore, the compound represented by formula (V) contains one ingredient selected from... and A fragment.

[0142] In some embodiments, in the compound represented by formula (V), n is 2; L 5 and L 6 Each is independently H or methyl; p is 3; R is independently methyl, , or Furthermore, the compound represented by formula (V) contains one ingredient selected from... and A fragment.

[0143] In some embodiments, the compound represented by formula (I) is the compound represented by formula (VII).

[0144] ,

[0145] Where p is 1, 2, 3, 4 or 5, and R and L 1 The definition is as described above; and the compound shown in formula (VII) contains one molecule selected from -(CH2). o -OP(=O)(OH)O- -(CH2) o -OP(=O)(O - )2·M + and -(CH2) o -OP(=O)(O - )2·1 / 2D 2+ fragments; o, D 2+ and M + The definition is as described above.

[0146] In some embodiments, in the compound represented by formula (VII), p is 1, 2, 3, 4, or 5, and R and L 1 The definition is as described above; and the compound represented by formula (VII) contains one ingredient selected from... , and A fragment.

[0147] In some embodiments, p is 1 in the compound represented by formula (VII).

[0148] In some embodiments, in the compound represented by formula (VII), when p is 1, R is... , or Preferred or More preferably .

[0149] In some embodiments, in the compound represented by formula (VII), L 1 C 1-3 Alkyl group, preferably methyl group.

[0150] In some embodiments, in the compound represented by formula (VII), R is .

[0151] In some embodiments, the compound represented by formula (VII) preferably contains one Excerpt.

[0152] In some embodiments, in the compound represented by formula (VII), p is 1; R is , or Preferred L 1 C 1-3 Alkyl group, preferably methyl group.

[0153] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is any of the following compounds:

[0154] , , , , , , , , , , , or .

[0155] The present invention also provides a pharmaceutical composition comprising:

[0156] (1) The compound shown in formula (I) above, or a pharmaceutically acceptable salt thereof, and

[0157] (2) Pharmaceutically acceptable excipients.

[0158] The present invention also provides the use of the compound of formula (I) above, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, as a medicine.

[0159] The present invention also provides a compound of formula (I) above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament.

[0160] The present invention also provides the use of the compound of formula (I) above or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition in the preparation of a fungal acyltransferase (Gwt1) inhibitor.

[0161] The present invention also provides the use of the compound of formula (I) above or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition in the preparation of a medicament for the prevention or treatment of a disease.

[0162] In some embodiments, the disease is a fungal infection, such as a fungal infection associated with fungal acyltransferase (Gwt1).

[0163] The present invention also provides the use of the compound of formula (I) above or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition in the preparation of an antifungal agent.

[0164] In some embodiments, the antifungal agent is an antifungal agent that inhibits fungal acyltransferase (Gwt1).

[0165] The present invention also provides the use of the compound of formula (I) above or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition in the preparation of a medicament for the prevention or treatment of fungal infections.

[0166] In some embodiments, the fungal infection is a fungal infection associated with fungal acyltransferase (Gwt1).

[0167] The present invention also provides a therapeutic composition / pharmaceutical composition for the prevention or treatment of fungal infections comprising the compound shown in formula (I) above or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the fungal infection is a fungal infection associated with fungal acyltransferase (Gwt1).

[0169] The present invention also provides the use of the compound of formula (I) above or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition in the treatment of a patient with a fungal infection.

[0170] In some embodiments, the fungal infection is a fungal infection associated with fungal acyltransferase (Gwt1).

[0171] The present invention also provides a method for preventing or treating fungal infections, comprising administering to a patient an effective amount of the compound represented by formula (I) above or a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, the fungal infection is a fungal infection associated with fungal acyltransferase (Gwt1).

[0173] The present invention also provides any of the following compounds or pharmaceutically acceptable salts thereof:

[0174] , , , , , , , , , , , , , , or .

[0175] The present invention also provides a method for preparing the compound of formula (VI) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0176] In a solvent, the compound of formula (VI-1) reacts to form the compound of formula (VI); preferably, in a solvent, in the presence of a metal-type ion exchange resin, the compound of formula (VI-1) undergoes an ion exchange reaction to obtain the compound of formula (VI).

[0177] ;

[0178] Wherein, L is defined as described above; R 1 C1-3 Alkyl; M + It is a group I metal cation; s and t are each independent integers from 0 to 4, and 0≤(s+t)≤4.

[0179] In the method for preparing the compound of formula (VI) or a pharmaceutically acceptable salt thereof, C 1-3 The alkyl group can be methyl, ethyl, n-propyl, or isopropyl, for example, methyl. The Group I metal cation can be Li, Na, K, Rb, or Cs ions, for example, Na ions. The reaction conditions for the ion exchange reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The metal-type ion exchange resin can be a conventional metal-type ion exchange resin for such reactions in the art, for example, when M... + When the ion is Na, the metal-type ion exchange resin is a sodium-type ion exchange resin.

[0180] The present invention also provides a method for preparing the compound of formula (VI-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0181] In a solvent, in the presence of a deprotecting agent, the compound shown in formula (VI-2) and / or the compound shown in formula (VI-3) undergo a deprotection reaction to give the compound shown in formula (VI-1);

[0182] ;

[0183] Wherein, L is defined as described above; R 1 C 1-3 Alkyl; R 2 It is a hydroxyl protecting group; Z - It is a monovalent anion (preferably HCO3-). - HCOO - or Cl - ); s and t are each independent integers from 0 to 4, and 0≤(s+t)≤4.

[0184] In the preparation method of the compound shown in formula (VI-1), the hydroxyl protecting group can be a hydroxyl protecting group conventional for such reactions in the art, such as tert-butyl or allyl. The deprotecting agent can be a deprotecting agent conventional for such reactions in the art; for example, when the hydroxyl protecting group is tert-butyl, the deprotecting agent can be trifluoroacetic acid; when the hydroxyl protecting group is allyl, the deprotecting agent can be morpholine and tetrakis(triphenylphosphine)palladium. The C 1-3The alkyl group can be methyl, ethyl, n-propyl, or isopropyl, for example, methyl. The deprotection reaction conditions can be those conventional for such reactions in the art, and different reaction conditions are suitable for different hydroxyl protecting groups. The solvent can be a conventional solvent for such reactions in the art, for example, dichloromethane.

[0185] The present invention also provides a method for preparing a compound of formula (VI-2) or a pharmaceutically acceptable salt thereof and / or a compound of formula (VI-3) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0186] In a solvent, in the presence of an optional catalyst, the compounds shown in formulas (1-4) and (VI-5) react to give the compounds shown in formula (VI-2) and / or (VI-3).

[0187] ;

[0188] Wherein, L is defined as described above; W is a halogenated or substituted sulfonate group; R 1 C 1-3 Alkyl; R 2 It is a hydroxyl protecting group; Z - It is a monovalent anion (preferably HCO3-). - HCOO - or Cl - ); s and t are each independent integers from 0 to 4, and 0≤(s+t)≤4.

[0189] In the preparation methods of the compounds shown in formula (VI-2) and / or formula (VI-3), the halogen can be a halogen conventional for such reactions in the art, such as I, Br, or Cl. The substituted sulfonate group can be a substituted sulfonate group conventional for such reactions in the art, such as p-toluenesulfonate or methanesulfonate. The catalyst can be a catalyst conventional for such reactions in the art, such as potassium iodide or sodium iodide. The C 1-3 The alkyl group may be methyl, ethyl, n-propyl, or isopropyl, for example, methyl. The hydroxyl protecting group may be a hydroxyl protecting group conventional for this type of reaction in the art, such as tert-butyl or allyl. The reaction conditions for the substitution reaction may be conventional reaction conditions for this type of reaction in the art. The solvent may be a conventional solvent for this type of reaction in the art, such as N,N-dimethylformamide or tetrahydrofuran.

[0190] In some embodiments, the method for preparing the compound represented by formula (VI) further includes the method for preparing the compound represented by formula (VI-1).

[0191] In some embodiments, the method for preparing the compound shown in formula (VI-1) further includes the method for preparing the compound shown in formula (VI-2) and / or the compound shown in formula (VI-3).

[0192] The present invention also provides a method for preparing the compound shown in formula (I), which is prepared by one or more of the compounds shown in formula (VI), formula (VI-1), formula (VI-2), and formula (VI-3). Preferably, the compounds shown in formula (VI), formula (VI-1), formula (VI-2), and formula (VI-3) are prepared by the aforementioned method.

[0193] The present invention also provides a method for preparing the compound of formula (IV-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0194] In a solvent, the compound of formula (IV-2) reacts to form the compound of formula (IV-1) (preferably, in the presence of a metal-type ion exchange resin, the compound of formula (IV-2) undergoes an ion exchange reaction to obtain the compound of formula (IV-1).

[0195] ;

[0196] Where R is -O-PO(O) - )2·M + M + It is a group I main metal cation.

[0197] In the preparation method of the compound shown in formula (IV-1), the Group I metal cation can be Li, Na, K, Rb, or Cs ions, for example, Na ions. The reaction conditions for the ion exchange reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a conventional solvent for such reactions in the art. The metal-type ion exchange resin can be a conventional metal-type ion exchange resin for such reactions in the art, for example, when M... + When the ion is Na, the metal-type ion exchange resin is a sodium-type ion exchange resin.

[0198] The present invention also provides a method for preparing the compound of formula (IV-2) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0199] In a solvent, in the presence of a deprotecting agent, the compound shown in formula (IV-3) and / or the compound shown in formula (IV-4) undergo a deprotection reaction to give the compound shown in formula (IV-2);

[0200] ;

[0201] Among them, R 2 It is a hydroxyl protecting group; Z - It is a monovalent anion (preferably HCO3-). - HCOO - or Cl - ).

[0202] In the preparation method of the compound shown in formula (IV-2), the hydroxyl protecting group can be a conventional hydroxyl protecting group for this type of reaction in the art, such as tert-butyl or allyl. The deprotecting agent can be a conventional deprotecting agent for this type of reaction in the art; for example, when the hydroxyl protecting group is tert-butyl, the deprotecting agent can be trifluoroacetic acid; when the hydroxyl protecting group is allyl, the deprotecting agent can be morpholine and tetrakis(triphenylphosphine)palladium. The reaction conditions for the deprotection reaction can be conventional reaction conditions for this type of reaction in the art, and different reaction conditions are suitable for different hydroxyl protecting groups. The solvent can be a conventional solvent for this type of reaction in the art, such as dichloromethane.

[0203] The present invention also provides a method for preparing the compound of formula (IV-3) or a pharmaceutically acceptable salt thereof and / or the compound of formula (IV-4) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0204] In a solvent, in the presence of an optional catalyst, the compounds shown in formulas (1-4) and (IV-5) react to give the compounds shown in formula (IV-3) and / or (IV-4).

[0205] ;

[0206] Where W is a halogen; R 2 It is a hydroxyl protecting group; Z - It is a monovalent anion (preferably HCO3-). - HCOO - or Cl - ).

[0207] In the preparation methods of the compounds shown in formula (IV-3) and / or formula (IV-4), the halogen can be a halogen conventional for such reactions in the art, such as I, Br, or Cl. The catalyst can be a catalyst conventional for such reactions in the art, such as potassium iodide or sodium iodide. The hydroxyl protecting group can be a hydroxyl protecting group conventional for such reactions in the art, such as tert-butyl or allyl. The reaction conditions for the substitution reaction can be conventional reaction conditions for such reactions in the art. The solvent can be a solvent conventional for such reactions in the art, such as N,N-dimethylformamide or tetrahydrofuran.

[0208] In some embodiments, the method for preparing the compound represented by formula (IV-1) further includes the method for preparing the compound represented by formula (IV-2).

[0209] In some embodiments, the method for preparing the compound shown in formula (IV-2) further includes the method for preparing the compound shown in formula (IV-3) and / or the compound shown in formula (IV-4).

[0210] The present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising any or more of the steps described above for preparing (VI), (VI-1), (VI-2), (VI-3), (IV-1), (IV-2), (IV-3), and (IV-4).

[0211] Terminology Explanation

[0212] In addition to the foregoing, when used in the specification and claims of this invention, the following terms shall have the following meanings unless otherwise specifically indicated.

[0213] In this invention, the term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition) for details.

[0214] The term "pharmaceuticalally acceptable excipients" refers to excipients and additives used in the manufacture and dispensing of pharmaceutical products. These are all substances included in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2015 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0215] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure.

[0216] The term “treatment” refers to a therapeutic approach or a remission measure. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment; or (4) slowing the progression of the condition or one or more biological manifestations of the condition. “Treatment” can also mean prolonging survival compared to expected survival without treatment.

[0217] Unless otherwise stated, this invention employs traditional methods of mass spectrometry and elemental analysis, and the steps and conditions can be referred to conventional operating procedures and conditions in the field.

[0218] Unless otherwise specified, this invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, organic synthetic chemistry, and optics. In some cases, standard techniques are used in chemical synthesis and chemical analysis.

[0219] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently (as / selected from)" used in this invention should be interpreted broadly, meaning that the described entities are independent of each other and can independently be the same or different specific functional groups. More specifically, the descriptive phrase "...independently (as / selected from)" can mean either that the specific options expressed by the same symbol in different functional groups do not affect each other, or that the specific options expressed by the same symbol in the same functional group do not affect each other.

[0220] The term "optionally replaced by one or more Rs" refers to both cases of not being replaced by R and being replaced by one or more Rs.

[0221] The term "replaced by" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the substituted compound is stable.

[0222] Based on common knowledge in the field, the above-mentioned preferred conditions / implementations can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0223] The reagents and raw materials used in this invention are all commercially available.

[0224] The positive and progressive effects of the present invention are as follows: the compounds of the present invention have one or more of the following effects: (1) good solubility; meeting the requirements for injection administration; (2) rapid metabolism into active metabolites; (3) rapid oral absorption; (4) rapid in vivo conversion and distribution; (5) high bioavailability; (6) rapid onset of action; (7) balanced pharmacokinetic characteristics; (8) formaldehyde-free metabolites and low potential side effects; (9) good drug-like properties, etc. Attached Figure Description

[0225] Figure 1 The two-dimensional NMR NOESY spectrum of compound I-002 is shown. Detailed Implementation

[0226] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0227] Example 1

[0228] Synthesis method 1 for compound I-001:

[0229]

[0230] Step 1: Synthesis of Intermediate 1-1

[0231] The synthesis method of intermediate 1-1 is based on the literature (European Journal of Medicinal Chemistry, 2022, vol. 238, art. no. 114515), and it is a colorless oil. LCMS (ESI): m / z calculated value C 13 H 18 O5P + [M+H] + = 285.09, measured value [M+H] + = 285.1. 1 H NMR (400 MHz, CD3Cl) δ ppm 7.36 (dd,J=8.7, 2.0 Hz, 2H), 7.23 (dd, J=8.5, 2.9 Hz, 2H), 6.03-5.89 (m, 2H), 5.40(dt, J=17.1, 1.3 Hz, 2H), 5.29 (dd, J=10.4, 1.0 Hz, 2H), 4.72-4.62 (m, 6H), 1.81 (s, 1H).

[0232] Step 2: Synthesis of intermediates 1-2

[0233] Intermediate 1-1 (1 g, 3.52 mmol, 1 eq) was dissolved in 10 mL of dichloromethane, and triphenylphosphine (1.38 g, 5.28 mmol, 1.5 eq) and carbon tetrabromide (1.75 g, 5.28 mmol, 1.5 eq) were added. The reaction system was heated to 20 °C. o Stirred at C for 12 hours. TLC (petroleum ether:ethyl acetate = 5:1) monitored complete consumption of the starting material and the formation of product spots. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to the residue, which was then subjected to silica gel column chromatography (ISCO Preparative Liquid Chromatography; column type: 40 g SepaFlash® Silica Flash Column; mobile phase gradient: 0–50% ethyl acetate / petroleum ether; flow rate: 40 mL / min) to prepare intermediates 1–2 as a colorless oil (785 mg, yield: 64.28%). LCMS (ESI): m / z calculated value C 13 H 17 BrO4P + [M+H] + = 347.0, 349.0, Measured values ​​[M+H] + = 347.0, 349.0. 1 H NMR (400MHz, DMSO-d6) δ ppm 7.50 (d, J = 8.5 Hz, 2H), 7.24 - 7.17 (m, 2H), 5.95 (tt,J = 5.3, 11.1 Hz, 2H), 5.39 (q, J = 1.5 Hz, 1H), 5.35 (d, J = 1.5 Hz, 1H), 5.28 (d, J = 1.3 Hz, 1H), 5.25 (d, J = 1.3 Hz, 1H), 4.72 (s, 2H), 4.65 (tdd,J = 1.3, 5.5, 8.5 Hz, 4H).

[0234] Step 3: Synthesis of intermediates 1-3

[0235] Intermediate 1-2 (330 mg, 950.62 μmol, 1 eq) was dissolved in 10 mL of acetone, and sodium iodide (284.98 mg, 1.90 mmol, 2 eq) was added. The reaction system was heated at 60 °C. oThe mixture was stirred at C for 5 hours. LCMS monitoring showed some remaining raw material and the formation of the main product. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to the residue. Intermediates 1-3 were then prepared by silica gel column chromatography (ISCO Preparative Liquid Chromatography; Column type: 12 g SepaFlash® Silica Flash Column; Mobile phase gradient: 0-30% ethyl acetate / petroleum ether; Flow rate: 40 mL / min), which was a colorless oil (250 mg, yield: 66.7%). LCMS (ESI): m / z calculated value C 13 H 17 IO4P + [M+H] + = 394.99, measured value [M+H] + = 394.9. 1 H NMR (400 MHz, CD3Cl) δ ppm 7.36 (d, J = 8.5 Hz, 2H), 7.15 (dd, J = 1.0, 8.6Hz, 2H), 5.95 - 5.91 (m, 2H), 5.40 - 5.36 (m, 2H), 5.30 - 5.26 (m, 2H), 4.66- 4.63 (m, 4H), 4.44 (s, 2H).

[0236] Step 4: Synthesis of intermediates 1-4

[0237] The synthesis method of intermediates 1-4 is based on patent document (US2009 / 233883A1), and they are light yellow solids. LCMS(ESI): m / z calculated value C 21 H 19 N4O2 + [M+H] + = 359.15, measured value [M+H] + = 359.1. 1H NMR (400MHz, DMSO-d6) δ ppm 8.17 (dd, J = 1.4, 5.0 Hz, 1H), 8.09 (dd, J = 1.8, 4.8Hz, 1H), 7.87 (dd, J = 1.8, 7.6 Hz, 1H), 7.72 (ddd, J = 2.0, 6.9, 8.5 Hz,1H), 7.46 - 7.39 (m, 2H), 7.37 - 7.32 (m, 2H), 6.99 (dd, J = 5.5, 6.7 Hz,1H), 6.86 (d, J = 8.3 Hz, 1H), 6.82 (s, 1H), 6.70 (dd, J = 4.8, 7.6 Hz, 1H), 6.27 (s, 2H), 5.32 (s, 2H), 4.04 (s, 2H).

[0238] Step 5: Synthesis of intermediates 1-5 and 1-6

[0239] Compound I-4 (200 mg, 558.05 μmol, 1 eq) was dissolved in 5 mL of DMF, and intermediate 1-3 (329.92 mg, 837.07 μmol, 1.5 eq) was added. The reaction system was heated at 60 °C. o The mixture was stirred at C for 12 hours. LCMS monitoring showed some remaining reactants and product formation. The reaction solution was concentrated under reduced pressure to the residue and then subjected to reversed-phase column chromatography (column type: Welch Ultimate C18; size: 150×30mm; particle size: 5μm; mobile phase: [phase A: water (0.08% ammonium bicarbonate) - phase B: acetonitrile]; gradient: 70%-100% B, 7 min) to prepare intermediates 1-5, which were pale yellow solids (12 mg, yield: 3.13%). LCMS (ESI): m / z calculated value C 34 H 34 N4O6P + [M+H] + = 625.22, measured value [M+H] + =625.2. 1H NMR (400 MHz, CD3OD) δ ppm 8.16 - 8.08 (m, 2H), 7.84 (dd, J = 1.8,7.6 Hz, 1H), 7.65-7.75 (m, 1H), 7.48 - 7.28 (m, 6H), 7.23 - 7.12 (m, 2H),6.96 (dd, J = 5.5, 6.6 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.71 (dd, J = 4.9,7.6 Hz, 1H), 6.61 (s, 1H), 6.07-5.90 (m, 2H), 5.44 - 5.35 (m, 2H), 5.34 (s, 2H), 5.27 (dd, J = 1.2, 10.5 Hz, 2H), 4.72 (s, 2H), 4.69 - 4.64 (m, 4H), 4.08 (s, 2H). Simultaneously, crude intermediates 1-6 (approximately 190 mg) were prepared and further purified by reversed-phase column chromatography (column type: Welch Ultimate C18; size: 150*30mm; particle size: 5μm; mobile phase: [phase A: water (0.08% ammonium bicarbonate) - phase B: acetonitrile]; gradient: 33%-63% B, 7 min) to obtain intermediates 1-6 as a light yellow oily substance (132 mg, yield: 40.39%). LCMS (ESI): m / z calculated value C 31 H 30 N4O6P + [M+H] + = 585.19, measured value [M+H] + =585.2. 1H NMR (400 MHz, CD3Cl) δ ppm 8.09 (dd, J = 1.5, 4.9 Hz, 1H), 7.83 (d, J= 7.4 Hz, 1H), 7.72 (br d, J = 6.0 Hz, 1H), 7.52 - 7.50 (m, 1H), 7.37(d, J =8.0 Hz, 2H), 7.22 (s, 1H), 7.20 (br s, 1H), 7.05 (d, J = 8.5 Hz, 2H), 6.88(br d, J = 8.6 Hz, 2H), 6.81 (dd, J = 5.5, 6.7 Hz, 1H), 6.75 - 6.64 (m, 2H),6.42 (s, 1H), 6.03 - 5.84 (m, 1H), 5.39 (s, 2H), 5.28 (s, 2H), 5.28 - 5.21(m, 1H), 5.05 (dd, J = 1.3, 10.3 Hz, 1H), 4.51-4.47 (m, 2H), 4.01 (s, 2H).

[0240] Step 6: Synthesis of Compound I-001

[0241] Intermediate 1-6 (132 mg, 225.42 μmol, 1 eq) was dissolved in 10 mL of dichloromethane, and morpholine (196.39 mg, 2.25 mmol, 10 eq) and Pd(PPh3)4 (52.09 mg, 45.08 μmol, 0.2 eq) were added. The reaction system was protected under nitrogen and stirred at 25 °C for 2 hours. LC-MS monitoring showed the disappearance of the starting material and the formation of the main product. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to the residue, which was then separated by reversed-phase column chromatography (column type: Boston Green ODS; size: 150*30 mm; particle size: 5 μm; mobile phase [A: water (0.1% formic acid)-B: acetonitrile]; gradient: 28%-58%B) to prepare compound I-001 as a pale yellow solid powder (65 mg, yield: 52.96%). LCMS (ESI): m / z calculated value C 28 H 26 N4O6P + [M+H] + = 545.16, Measured value [M+H] + = 545.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22(s, 1H), 8.19 - 8.14 (m, 1H), 8.00 - 7.93 (m, 1H), 7.79 - 7.67 (m, 1H), 7.43- 7.38 (m, 2H), 7.32 (br d, J = 8.2 Hz, 2H), 7.20 - 7.09 (m, 4H), 7.02 - 6.95(m, 2H), 6.86 (d, J = 8.3 Hz, 1H), 6.72 - 6.47 (m, 1H), 5.33 - 5.30 (m, 2H),5.28 (br s, 2H), 4.07 - 4.02 (m, 2H).

[0242] Using the same deprotection method as intermediates 1-6, and with intermediates 1-5 as raw materials, the deprotected product was prepared and confirmed by LCMS and NMR to be compound I-001.

[0243] Method 2 for synthesizing compound I-001:

[0244] Step 1: Synthesis of intermediates 1-8

[0245] Carbon tetrabromide (17.09 g, 51.4 mmol, 0.5 eq) and triethylbenzylammonium chloride (1.17 g, 5.14 mmol, 0.05 eq) were dissolved in 50 mL of dichloromethane. While stirring at 20°C, 50 mL of NaOH aqueous solution (20% w / w) was added. The reaction mixture was cooled to 0°C. A 20 mL solution of dichloromethane containing compounds 1-7 (20 g, 102.9 mmol, 1 eq) was added dropwise to the above reaction mixture. After the addition was complete, the reaction system was heated from 0°C to room temperature (<25°C) and stirred continuously for 1 hour. The reaction system was diluted with 50 mL of dichloromethane and separated. The combined organic layers were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate, a pale yellow solution (approximately 120 mL) containing intermediates 1-8, was used directly for the next reaction.

[0246] Step 2: Synthesis of intermediates 1-9

[0247] Compounds 1-8a (5.4 g, 44.3 mmol, 1 eq) and DMAP (10.8 g, 88.6 mmol, 2 eq) were dissolved in 100 mL of dichloromethane, and the system was cooled to 0°C. Approximately 120 mL of the dichloromethane solution containing intermediates 1-8, prepared in step 1, was added dropwise to the above reaction solution. After the addition was complete, the reaction system was stirred at 0°C for 1 hour and then slowly raised to 25°C. 100 mL of saturated sodium bicarbonate solution was added to the reaction system. The organic phase was separated and washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the residue. The residue was then subjected to silica gel column chromatography (ethyl acetate (1% triethylamine) / petroleum ether, mobile phase gradient: 50%-100%) to prepare intermediates 1-9 (7.1 g, yield: 51.0%), a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 9.89 (s, 1H), 7.80 (d,J = 8.5 Hz, 2H), 7.30 (d,J = 8.5 Hz, 2H), 1.45 (s, 18H).

[0248] Step 3: Synthesis of intermediates 1-10

[0249] Intermediate 1-9 (7.1 g, 22.6 mmol, 1 eq) was dissolved in 50 mL of methanol and 50 mL of dichloromethane. The reaction solution was cooled to -30°C. Sodium borohydride (1.72 g, 45.2 mmol, 2 eq) was added slowly in batches. The reaction system was stirred at -30°C for 1 hour. The reaction solution was diluted with 100 mL of dichloromethane and slowly quenched with 60 mL of water. The organic phase was separated and washed successively with saturated sodium bicarbonate solution (60 mL × 2), saturated brine (60 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the residue. The residue was then subjected to silica gel column chromatography (ethyl acetate (1% triethylamine) / petroleum ether, mobile phase gradient: 50%-100%) to prepare intermediate 1-10 (4.0 g, yield: 56%), which was a colorless oil. 1 HNMR (400 MHz, CDCl3) δ ppm 7.32 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 4.66 (s, 2H), 2.06 (s, 1H), 1.52 (s, 18H).

[0250] Step 4: Synthesis of intermediates 1-11

[0251] Intermediate 1-10 (4.0 g, 12.6 mmol, 1 eq) and triphenylphosphine (3.65 g, 13.9 mmol, 1.1 eq) were dissolved in 40 mL of dichloromethane. The reaction mixture was cooled to 0°C, and N-bromosuccinimide (2.47 g, 13.9 mmol, 1.1 eq) was slowly added. The reaction mixture was stirred at 0°C for 0.5 h. LCMS monitoring showed complete consumption of the starting material and product formation. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate (1% triethylamine) / petroleum ether, mobile phase gradient: 25%) to prepare intermediate 1-11 (2.8 g, yield: 58.6%), a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 7.27 (d, J = 8.6 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 4.41 (s, 2H), 1.44 (s, 18H).

[0252] Step 5: Synthesis of intermediates 1-12

[0253] Compound 1-4 (50 mg, 139.51 μmol, 1 eq) was dissolved in 3 mL of DMF, and intermediate 1-11 (105.81 mg, 279.02 μmol, 2 eq) was added. The reaction system was protected with nitrogen and heated at 50 °C. o The mixture was stirred at C for 12 hours. LCMS monitoring showed that the reactants were almost completely consumed and the main product was formed. The reaction solution was evaporated to dryness under reduced pressure to obtain the residue, which was then separated by reversed-phase column chromatography (column type: Welch Xtimate C18; size: 150*30 mm; particle size: 5 μm; mobile phase [A: water (0.08% ammonium bicarbonate)-B: acetonitrile]; gradient: 78%-100%B) to prepare intermediates 1-12, which were pale yellow solid powders (25 mg, yield: 24.93%). LCMS (ESI): m / z calculated value C 36 H 42 N4O6P + [M+H] + = 657.28, Measured value [M+H] + =657.3. 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (dd, J = 1.6, 4.9 Hz, 1H), 7.83 (d, J= 6.8 Hz, 1H), 7.74 - 7.65 (m, 1H), 7.45 - 7.40 (m, 2H), 7.35 (dd, J = 8.2,12.9 Hz, 5H), 7.14 (d, J = 8.2 Hz, 2H), 6.99 - 6.92 (m, 1H), 6.88 - 6.79 (m,1H), 6.70 (dd, J = 4.9, 7.5 Hz, 1H), 6.60 (s, 1H), 5.33 (s, 2H), 4.69 (s, 2H), 4.07 (s, 2H), 1.53 - 1.50 (m, 18H).

[0254] Step 6: Synthesis of Compound I-001

[0255] Intermediate 1-12 (21.56 mg, 30.0 μmol, 1 eq) was dissolved in 4 mL of dichloromethane and then... o 1 mL of trifluoroacetic acid was slowly added dropwise at C. After the addition was complete, the reaction system was kept at 0 °C. o The mixture was stirred at C for 12 hours. LCMS monitoring showed the formation of the main product. After the solvent was evaporated under reduced pressure, the residue was slurried with a small amount of ethanol, filtered, and the filter cake was washed with ethanol and dried to obtain compound I-001, a pale yellow powder (13 mg, yield: 79.58%). LCMS and NMR confirmed that the structure was consistent with that of compound I-001 prepared by synthesis method 1 in Example 1.

[0256] Example 2 Synthesis of Compound I-002

[0257]

[0258] Take 20 g of ion exchange resin (Dowex 50W × 8, 100-200 mesh), add it to a beaker, and add 50 mL of deionized water and 50 mL of 15% dilute deionized sulfuric acid solution. Stir the mixture slowly for 15 minutes. Transfer the mixture to a glass chromatography column containing sintered glass. Elute with 15% deionized sulfuric acid solution (50 mL × 4), and wash with deionized water until neutral. Then transfer the resin to a beaker, add 15% deionized NaOH solution (50 mL), stir the mixture slowly for 15 minutes, and pour it into the glass column. Wash with 15% deionized NaOH solution (50 mL × 4), then rinse with deionized water until the wash water is neutral. Vacuum dry the resulting resin for later use.

[0259] Compound I-001 (14 mg, 25.17 μmol, 1 eq) was suspended in 15 mL of deionized water. 5 g of the prepared sodium-type ion exchange resin was added to the system. The system was slowly shaken and stirred at 25 °C for 6 hours, filtered, and the filtrate was freeze-dried to obtain compound I-002 as a yellow solid (11.5 mg, yield: 80.65%). LCMS (ESI): m / z calculated value C 28 H 26 N4O6P + [M+H] + = 545.16, Measured value [M+H] + = 545.1. 1 H NMR (400 MHz, D2O) δ ppm7.94-7.84 (m, 2H, H6 and H 19 ), 7.76 (br d, J = 7.9 Hz, 1H, H8), 7.51 (br t, J= 7.7 Hz, 1H, H 17 ), 7.25 - 7.20 (m, 2H, H 13 and H 14 ), 7.19 - 7.10 (m, 6H, H 11,12 and H 1,2 and H 3,4 ), 6.83 (br d, J = 4.5 Hz, 2H, H7 and H 18 ), 6.60 (br d, J = 8.3Hz, 1H, H 16 ), 6.50 (s, 1H, H9), 5.28 (br s, 2H, H5), 5.05 (s, 2H, H 15), 3.91(br s, 2H, H 10 ). 31 P NMR (162 MHz, D2O) δ ppm 0.009 (s). Two-dimensional NMR NOESY spectra show correlated signals in H5 and H6, see details... Figure 1 .

[0260]

[0261] Example 3 Synthesis of Compound I-003

[0262]

[0263] Step 1: Synthesis of intermediate 3-2

[0264] Compound 3-1 (5.00 g, 25.1 mmol, 1 eq) was dissolved in 150 mL of methanol, and 5.00 g of molecular sieve was added. The system was cooled to 0 °C, and methylamine hydrochloride (1.69 g, 25.1 mmol, 1 eq) was added. The reaction was stirred at 0 °C for 3 hours. Sodium borohydride acetate (21.27 g, 100.4 mmol, 4 eq) was added in portions, and the system was slowly heated to 25 °C and stirred for another 6 hours. LCMS monitoring showed complete consumption of the starting material and product formation. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to the residue. Intermediate 3-2 was prepared by silica gel column chromatography (methanol / ethyl acetate, mobile phase gradient: 0%-100%) as a light yellow oil (3.7 g, yield: 68.78%). LCMS (ESI): m / z calculated value C 11 H 23 N2O2 + [M+H] + = 215.18, Measured value = 215.19. 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.77 (s, 1H), 3.20 (s, 2H), 2.69-2.49 (m, 2H), 2.33 (s, 3H), 1.85 (s, 1H), 1.83 – 1.63 (m, 4H), 1.39 (s, 9H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 154.48, 78.96, 60.13, 53.33, 46.25, 35.72,29.26, 28.65, 23.67.

[0265] Step 2: Synthesis of intermediate 3-3

[0266] Compound 3-2 (3.70 g, 17.3 mmol, 1 eq) was dissolved in 100 mL of dichloromethane, and diisopropylethylamine (17.85 g, 138.1 mmol, 7.98 eq) was added. The system was cooled to -20 °C. Chloromethyl chloroformate 3-2a (7.79 g, 60.4 mmol, 3.5 eq) was slowly added dropwise to the above system. After the addition was complete, the system was heated to -10 °C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure to the residue, and purified by silica gel column chromatography (n-heptane / ethyl acetate = 20:1) to give intermediate 3-3 as 1.46 g of colorless oil (1.46 g, yield: 27.5%). LCMS (ESI): m / z Calculated value C 13 H 23 ClN2NaO4 + , [M+Na] + = 329.12, Measured value = 329.14.

[0267] Step 3: Synthesis of intermediates 3-4

[0268] Compound 1-4 (100 mg, 279.02 μmol, 1 eq) was dissolved in 5 mL of tetrahydrofuran, and sodium iodide (41.82 mg, 279.02 μmol, 1 eq) and intermediate 3-3 (428.00 mg, 1.40 mmol, 5 eq) were added. The reaction system was heated at 40 °C. o Stirred at C for 72 hours. LCMS monitoring showed complete consumption of the starting material and product formation. The reaction solution was concentrated under reduced pressure to the residue and then separated by reversed-phase column chromatography (column type: Welch Xtimate C18; size: 150×30 mm; particle size: 5 μm; mobile phase [A: water (0.25% formic acid)-B: acetonitrile]; gradient: 25%-55%B) to prepare intermediate 3-4, a pale yellow solid powder (55 mg, yield: 29.21%). LCMS (ESI): m / z calculated value C 34 H 41 N6O6 + [M+H] + = 629.31, Measured value [M+H] + = 629.3. 1H NMR (400 MHz, CD3OD) δ ppm 8.56 (s, 1H), 8.32 - 8.08 (m, 3H), 7.71 - 7.69 (m, 1H), 7.47 - 7.42 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H), 6.97 (dd, J = 5.4, 6.6 Hz, 2H), 6.87 - 6.70 (m, 2H), 6.35 - 6.03 (m, 2H), 5.34 (s, 2H), 4.13 (s, 3H), 3.54 - 3.41 (m, 1H), 3.20 - 3.09 (m, 1H), 3.08 -2.88 (m, 3H), 2.00 - 1.80 (m, 3H), 1.73 - 1.54 (m, 1H), 1.48 - 1.20 (m, 10H).

[0269] Step 4: Synthesis of Compound I-003

[0270] Intermediate 3-4 (20 mg, 29.64 μmol, 1 eq) was dissolved in 1 mL of dichloromethane. The system was kept at 0 °C, and 1 mL of trifluoroacetic acid was added dropwise. After the addition was complete, the reaction system was stirred at 0 °C for 2 hours. LCMS monitoring showed product formation. The reaction solution was evaporated to dryness under reduced pressure to obtain the residue, which was then separated and collected by reversed-phase column chromatography (column type: Welch Xtimate C18; size: 150 × 40 mm; particle size: 10 μm; mobile phase [A: water (0.25% formic acid) - B: acetonitrile]; gradient: 0%-30%B). The fraction containing compound I-003 was collected and monitored by LCMS. LCMS (ESI): m / z calculated value C 29 H 33 N6O4 + [M+H] + =529.26, Measured value [M+H] + =529.2.

[0271] Example 4 Synthesis of Compound I-004

[0272]

[0273] Step 1: Synthesis of intermediate 4-2

[0274] Compound 4-1 (15.00 g, 48.5 mmol, 1 eq) was dissolved in 150 mL of dichloromethane. Under nitrogen protection, diisopropylethylamine (31.33 g, 243 mmol, 5 eq) was added, and the mixture was cooled to 0 °C. Chloromethyl chloroformate 3-2a (25.00 g, 194 mmol, 4 eq) was added dropwise to the above system. After the addition was complete, the reaction was stirred at 0 °C for 2 hours and then slowly raised to room temperature. LCMS monitoring showed product formation. The reaction mixture was concentrated under reduced pressure to the residue and purified by silica gel column chromatography (mobile phase gradient: ethyl acetate / n-heptane = 0.5:1 to 1:1) to give intermediate 4-2 as a pale yellow oil (13.9 g, yield: 71.32%). LCMS (ESI): m / z Calculated value C 17 H 24 ClN3NaO6 + , [M+Na] + = 424.12, measured value = 424.1. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (m, 1H), 7.94 (m, 1H), 7.46 (m,1H), 5.96 – 5.76 (m, 2H), 5.12 (s, 2H), 4.04-4.02 (m, 2H), 3.23 (s, 3H), 2.49(s, 3H),1.27 (s, 9H); 13 C NMR (101 MHz, DMSO-d6) δ ppm 169.97, 155.80, 155.21,152.43, 149.21, 139.22, 129.00, 79.57, 71.97, 62.02, 50.85, 50.31, 36.46, 35.78, 28.22.

[0275] Step 2: Synthesis of intermediate 4-3

[0276] Compound 1-4 (100 mg, 279.02 μmol, 1 eq) was dissolved in 5 mL of tetrahydrofuran, and sodium iodide (41.82 mg, 279.02 μmol, 1 eq) and intermediate 4-2 (560.62 mg, 1.40 mmol, 5 eq) were added. The reaction system was heated at 40 °C. oThe mixture was stirred at C for 72 hours. LCMS monitoring showed product formation and some raw material remaining. The reaction solution was concentrated under reduced pressure to the residue and then separated by reversed-phase column chromatography (column type: Welch Xtimate C18; size: 150×30 mm; particle size: 5μm; mobile phase [A: water (0.25% formic acid)-B: acetonitrile]; gradient: 23%-53%B) to prepare intermediate 4-3 as a yellow solid powder (38 mg, yield: 17.69%). LCMS (ESI): m / z calculated value C 38 H 42 N7O8 + , [M+H]+ =724.31, Measured value [M+H]+ = 724.3. 1 H NMR (400 MHz, CD3OD) δ ppm 8.57 - 8.42 (m,2H), 8.32 - 8.21 (m, 2H), 8.14 (dd, J = 1.3, 5.1 Hz, 1H), 8.00 (d, J = 7.4Hz, 1H), 7.70 (ddd, J = 2.0, 7.0, 8.5 Hz, 1H), 7.46 (d, J = 8.1 Hz, 3H), 7.42- 7.31 (m, 2H), 7.05 - 6.93 (m, 2H), 6.91 - 6.75 (m, 2H), 6.31 (s, 1H), 6.14(s, 1H), 5.35(s, 2H), 5.27 - 5.04 (m, 2H), 4.14 (s, 2H), 4.04 - 3.93 (m,2H), 3.38 - 3.33 (m, 1H), 3.29 - 3.23 (m, 2H), 2.97 - 2.82 (m, 3H), 1.46 -1.40 (m, 5H), 1.37 – 1.28 (m, 4H).

[0277] Step 3: Synthesis of Compound I-004

[0278] Intermediate 4-3 (30 mg, 38.974 μmol, 1 eq) was dissolved in 2 mL of dichloromethane. The system was kept at 0 °C, and 1 mL of trifluoroacetic acid was added dropwise. After the addition was complete, the reaction system was stirred at 0 °C for 3 hours. LCMS monitoring showed product formation. The reaction solution was evaporated to dryness under reduced pressure to obtain the residue, which was then separated by reversed-phase column chromatography (column type: Welch Xtimate C18; size: 150 × 30 mm; particle size: 5 μm; mobile phase [A: water (0.08% NH4HCO3)-B: acetonitrile]; gradient: 50%-80%B). The fraction containing compound I-004 was collected and monitored by LCMS. LCMS (ESI): m / z calculated value C 33 H 34 N7O6 + [M+H] + =624.26, Measured value [M+H] + = 624.3.

[0279] Example 5 Synthesis of Compound I-005

[0280]

[0281] Step 1: Synthesis of intermediate 5-3

[0282] Intermediate 5-3 was prepared according to the method described in the literature (J. Med. Chem. 2020, 63, 19, 11034–11044), using compound 5-1 as the starting material. Intermediate 5-3 was a light yellow oily substance. LCMS (ESI): m / z calculated value C9H 13 ClN2O6P + [M+H] + = 311.02, measured value = 310.9. 1 H NMR (400 MHz, DMSO-d6) δ ppm8.56 – 8.40 (m,1H), 7.99 (dd, J = 7.7, 1.8 Hz, 1H), 7.32 (d, J = 6.9 Hz, 1H),5.89-5.35 (s, 2H), 4.96 (d, J = 7.5 Hz, 2H), 3.36 (s, 3H), 1.47 (s, 18H).

[0283] Step 2: Synthesis of intermediate 5-4

[0284] Compounds 1-4 (30 mg, 83.71 μmol, 1 eq) were dissolved in 4 mL of tetrahydrofuran, and intermediates 5-3 (35.39 mg, 83.71 μmol, 1 eq) and potassium iodide (27.79 mg, 167.41 μmol, 2 eq) were added. The reaction system was heated at 50 °C. o The mixture was stirred at C for 36 hours. LCMS monitoring showed product formation. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to the residue. Reversed-phase column chromatography (column type: Welch Xtimate C18; size: 150×30 mm; particle size: 5 μm; mobile phase [A: water (0.25% formic acid)-B: acetonitrile]; gradient: 25%-55%B) was used to prepare intermediate 5-4, a pale yellow oil (12 mg, yield: 18.13%). LCMS (ESI): m / z calculated value C 38 H 46 N6O8P + [M+H] + = 745.31, Measured value [M+H] + =745.3.

[0285] Step 3: Synthesis of Compound I-005

[0286] Intermediate 5-4 (5 mg, 6.70 μmol, 1 eq) was dissolved in 3 mL of dichloromethane, and trifluoroacetic acid (687.99 mg, 6.03 mmol) was added dropwise. The reaction mixture was stirred at 25 °C for 10 min. LCMS monitoring showed complete consumption of the starting material and product formation. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was subjected to reversed-phase column chromatography (Welch Xtimate C18 column; size: 150 × 30 mm; particle size: 5 μm; mobile phase [A: water (0.25% formic acid) - B: acetonitrile]; gradient: 25%-55%B) to prepare intermediate 5-5, a pale yellow solid (2.0 mg, yield: 47.08%). LCMS (ESI): m / z calculated value C 30 H 30 N6O8P + [M+H] + = 633.19, Measured value [M+H] + = 633.2. 1H NMR (400 MHz, CD3OD) δ ppm8.45 - 8.31 (m, 1H), 8.30 - 8.04 (m, 4H), 7.78 - 7.66 (m, 1H), 7.50 - 7.42(m, 3H), 7.40 - 7.33 (m, 2H), 7.07 - 6.95 (m, 2H), 6.91 - 6.77 (m, 2H), 6.34- 5.96 (m, 2H), 5.33 (s, 2H), 5.16 (s, 2H), 4.14 (s, 2H), 3.38 - 3.26 (m,3H). Referring to the sodium salt preparation method in Example 2, intermediate 5-5 was prepared into sodium salt form, namely compound I-005 (1.9 mg, purity: 98%).

[0287] Example 6 Synthesis of Compound I-006

[0288]

[0289] Step 1: Synthesis of intermediate 6-2

[0290] Triethylbenzylammonium chloride (1.17 g, 5.14 mmol, 0.08 eq) was dissolved in 30 mL of DCM, and carbon tetrabromide (10.245 g, 30.9 mol, 0.5 eq) was added. The reaction system was cooled to 0°C, and NaOH aqueous solution (30 mL, 20% w / w) was added dropwise to the above solution with stirring. After the addition was complete, a dichloromethane solution (20 mL) of compound 1-7 (12 g, 61.8 mmol, 1 eq) was added dropwise to the above solution. The reaction system was heated from 0°C to room temperature (<25°C) and stirred for 1 hour. The reaction system was diluted with 50 mL of dichloromethane, and after separation of the organic phase, it was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain a colorless oil (16.9 g, crude product), which was directly used in the next reaction.

[0291] Intermediate 6-1 (16.06 g, 49.87 mmol, 1 eq) was dissolved in 200 mL of tetrahydrofuran, and potassium tert-butoxide (6.15 g, 54.86 mmol, 1.1 eq) was added. The reaction mixture was stirred at 60°C for 10 minutes. The above oily substance (16.9 g, crude product) was slowly added to the reaction mixture, and a white precipitate formed. After the addition was complete, the reaction mixture was stirred at 60°C for 50 minutes. The reaction mixture was cooled to room temperature and diluted with petroleum ether (200 mL). After filtration through diatomaceous earth, the filtrate was evaporated to dryness under reduced pressure to obtain the residue, which was then subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 1:10) to prepare intermediate 6-2, a colorless oily substance (22.1 g, yield: 86.2%). 1 H NMR (400 MHz, CDCl3) δ ppm 7.30 (s, 1H), 6.73 - 6.69 (m, 1H), 3.58 -3.47 (m, 2H), 2.54 (s, 3H), 2.25 (s, 3H), 2.14 (t, J = 7.4 Hz, 2H), 1.57 (s, 6H), 1.53 (s, 18H), 0.88 (s, 9H), -0.00 (s, 6H).

[0292] Step 2: Synthesis of intermediate 6-3

[0293] Intermediate 6-2 (14.34 g, 27.86 mmol, 1 eq) was dissolved in 100 mL of tetrahydrofuran and cooled to 0°C. A 1N tetrabutylammonium fluoride (42 mL, 42 mmol) tetrahydrofuran solution was slowly added dropwise to the above solution. After the addition was complete, the reaction system was slowly heated to 25°C and stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 100 mL of ethyl acetate, washed successively with saturated ammonium chloride solution, water, and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. Intermediate 6-3 (9.56 g, yield: 85%) was prepared by silica gel column chromatography (ethyl acetate / petroleum ether = 1:3) as a colorless oil. LCMS (ESI): m / z Calculated value C 21 H 38 O5P + [M+H] + = 401.25, measured value = 401.2.

[0294] Step 3: Synthesis of intermediate 6-4

[0295] Intermediate 6-3 (1.2 g, 3 mmol, 1 eq) was dissolved in 15 mL of acetonitrile and 15 mL of water, and then TEMPO (24.5 mg, 0.15 mmol, 0.05 eq), KH₂PO₄ (204 mg, 1.5 mmol, 0.5 eq), and Na₂HPO₄ (213 mg, 1.5 mmol, 0.5 eq) were added sequentially. The reaction mixture was cooled to 0°C, and NaClO (3.57 g, 3.6 mmol, 7.5% wt) and NaClO₂ (407 mg, 4.5 mmol) were slowly added dropwise to the above system. The reaction mixture was stirred at 0°C for 1 hour, and then slowly raised to 25°C and stirred for another 4 hours. The system was diluted with 30 mL of ethyl acetate. After separation of the organic phase, the mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the residue. The residue was then prepared by reverse column chromatography to obtain intermediate 6-4, which was a white solid (610 mg, yield: 49.1%). 1 H NMR (400 MHz, CDCl3) δ ppm 7.07 (s, 1H), 6.64 (s,1H), 2.88 (s, 2H), 2.45 (s, 3H), 2.15 (s, 3H), 1.57 (s, 6H), 1.44 (s, 18H).

[0296] Step 4: Synthesis of intermediate 6-5

[0297] Intermediate 6-4 (740 mg, 1.78 mmol, 1 eq) was dissolved in 15 mL of dichloromethane and 15 mL of water, and sodium bicarbonate (600 mg, 7.15 mmol, 4 eq) and tetrabutylammonium bisulfate (60.43 mg, 0.178 mmol, 0.1 eq) were added. The reaction mixture was cooled to 0°C, and then compound 6-4a (354 mg, 2.15 mmol, 1.2 eq) was slowly added. The reaction mixture was stirred at 0°C for 2 hours, and then slowly raised to 25°C, and stirred for another 10 hours. The system was diluted with 10 mL of dichloromethane. After separation of the organic phase, it was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to the residue. Intermediate 6-5 was prepared by C18 column chromatography (acetonitrile / water = 80:20), which was a colorless oil (620 mg, yield: 75.2%). 1H NMR(400 MHz, CDCl3) δ ppm 7.18 (s, 1H), 6.62 (s, 1H), 5.50 (s, 2H), 2.98 (s,2H), 2.46 (s, 3H), 2.14 (s, 3H), 1.55 (s, 6H), 1.42 (s, 18H).

[0298] Step 5: Synthesis of intermediate 6-6

[0299] Intermediate 1-4 (200 mg, 558.05 μmol, 1 eq) was dissolved in 20 mL of tetrahydrofuran, and intermediate 6-5 (1.29 g, 2.79 mmol, 5 eq) and potassium iodide (185.27 mg, 1.12 mmol, 2 eq) were added. The reaction system was heated at 40 °C. o The mixture was stirred at C for 72 hours. LCMS monitoring showed product formation. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to the residue. Reversed-phase column chromatography (column type: Welch Xtimate C18; size: 150 × 40 mm; particle size: 10 μm; mobile phase [A: water (0.25% formic acid) - B: acetonitrile]; gradient: 38%-68% B) yielded intermediate 6-6, a pale yellow oil (35 mg, yield: 7.54%). LCMS (ESI): m / z calculated value C 43 H 54 N4O8P + [M+H] + = 785.37, Measured value [M+H] + =785.3.

[0300] Step 6: Synthesis of Compound I-006

[0301] Intermediate 6-6 (35 mg, 42.12 μmol, 1 eq) was dissolved in 3 mL of dichloromethane, and 2.85 mL of trifluoroacetic acid was added dropwise. The reaction system was stirred at 25 °C for 10 min. LCMS monitoring showed complete consumption of the starting material and product formation. The reaction solution was evaporated to dryness under reduced pressure to obtain the residue, which was then subjected to reversed-phase column chromatography (Welch Xtimate C18 column; size: 150 × 30 mm; particle size: 5 μm; mobile phase [A: water (0.25% formic acid) - B: acetonitrile]; gradient: 25%-55% B) to prepare intermediate 6-7 as a light yellow solid (13.5 mg, yield: 47.64%). LCMS (ESI): m / z calculated value C 35 H 38 N4O8P +[M+H] + =673.24, Measured value [M+H] + = 673.2. 1 H NMR (400 MHz, CD3OD) δ ppm 8.29 (d, J = 7.4Hz, 1H), 8.20 - 8.08 (m, 2H), 8.04 - 7.83 (m, 1H), 7.51 - 7.45 (m, 2H), 7.45- 7.39 (m, 2H), 7.16 - 7.08 (m, 2H), 7.00 (t, J = 7.2 Hz, 1H), 6.96 (s, 1H), 6.91 (s, 1H), 6.14 (s, 1H), 5.96 (s, 2H), 5.39 (s, 2H), 4.16 (s, 2H), 3.13(s, 2H), 2.13 (s, 3H), 1.72 (s, 3H), 1.57 (s, 6H). Following the sodium salt preparation method of Example 2, intermediates 6-7 were prepared into sodium salt form, namely compound I-006 (10.8 mg, purity: 92%).

[0302] Example 7 Synthesis of Compound I-007

[0303]

[0304] Following the synthesis methods of Method 2 in Example 1 and Example 2, and replacing the corresponding starting materials, compound I-007 was prepared using compound 7-1a as the starting material. It is a light yellow solid. LCMS (ESI): m / z calculated value C 28 H 27 N4O 10 P2 + [M+H] + = 641.12, Measured value [M+H] + = 641.2. 1H NMR (400 MHz, D2O) δ ppm 7.85 (s, 1H), 7.74(d, J = 6.1 Hz, 1H), 7.58 - 7.44 (m, 2H), 7.41 - 7.31 (m, 2H), 7.23 - 7.18(m, 2H), 7.17 - 7.11 (m, 2H), 6.80 (t, J = 5.7 Hz, 1H), 6.62 (d, J = 8.0 Hz,1H), 6.59 - 6.50 (m, 2H), 6.41 (s, 1H), 5.15 (s, 2H), 5.02 (s, 2H), 3.88(s,2H).

[0305] Example 8 Synthesis of Compound I-008

[0306]

[0307] Following the synthesis methods of Method 2 in Example 1 and Example 2, and replacing the corresponding starting materials, compound I-008 was prepared using compound 8-1a as the starting material. It is a light yellow solid. LCMS (ESI): m / z calculated value C 28 H 27 N4O 10 P2 + [M+H] + = 641.12, Measured value [M+H] + = 641.1. 1 H NMR (400 MHz, D2O) δ ppm 7.99 (d, J = 6.6Hz, 1H), 7.90 - 7.82 (m, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.51 (t, J = 7.8 Hz,1H), 7.27 - 7.20(m, J = 8.0 Hz, 2H), 7.20 - 7.14 (m, J = 8.1Hz, 2H), 7.03 (s,1H), 6.92 - 6.84 (m, 2H), 6.83 - 6.74(m, 2H), 6.62(d, J = 8.3 Hz, 1H), 6.52(s, 1H), 5.32(s, 2H), 5.07 (s, 2H), 3.92 (s, 2H).

[0308] Biological Test Example 1: Pharmacokinetic Study of Compounds in Rats

[0309] 1. Experimental objective:

[0310] The pharmacokinetic characteristics of the compounds of this invention in rats were evaluated.

[0311] 2. Test methods:

[0312] Three male SD rats were divided into groups for intravenous administration. The test compound was prepared using 10% (v / v) DMSO + 10% (v / v) Kolliphor® Solutol HS15 + 80% 0.9% sodium chloride solution. The compound was administered intravenously once at a dose of 1 mg / kg (0.2 mg / mL, 5 mL / kg). Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration.

[0313] Three male SD rats were divided into groups for oral administration. The test compound was prepared by Solutol Hs15: 20% Hp-β-CD=6:94 (v:v) and administered by gavage at a dose of 5 mg / kg (1 mg / mL, 5 mL / kg). Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration.

[0314] The collected samples were placed in EDTA-K2 tubes, centrifuged at 3500 rpm for 10 min, the plasma was separated, and stored frozen at -20°C. The blood concentration of E1210 was detected by LC-MS-MS, and the pharmacokinetic parameters were calculated.

[0315] 3. Experimental Results:

[0316] After administration, the compound of this invention is rapidly metabolized into the active metabolite E1210, and the original drug is almost undetectable. The pharmacokinetic parameters of the active metabolite after administration are shown in Tables 1-1 and 1-2.

[0317] Table 1-1. Pharmacokinetic parameters of the test compounds in rats after a single intravenous administration

[0318]

[0319] Table 1-2. Pharmacokinetic parameters of the test compounds after a single oral administration in rats.

[0320]

[0321] The compound of this invention is rapidly absorbed orally and quickly metabolized in vivo into the active metabolite E1210. The active metabolite has relatively lower blood exposure and relatively higher Vz_obs, suggesting faster in vivo conversion and distribution, and potentially a faster onset of action, resulting in good clinical therapeutic effects.

[0322] Biological Test Example 2: Compound Solubility Study

[0323] 1. Experimental objective:

[0324] Evaluate the solubility of the compound to be tested.

[0325] 2. Test methods:

[0326] Reference solution: Take an appropriate amount of each compound to be tested, accurately weigh it, add diluent (diluent: TFA-acetonitrile-water (1:500:500)) to dissolve and quantitatively dilute to prepare a solution containing about 100 μg per 1 mL, which is used as the reference solution.

[0327] Accurately weigh 10 mg of the test compound using a balance, add 1 mL of solvent, shake thoroughly and observe whether it dissolves. If it does not dissolve, continue adding solvent, up to a maximum of 100 mL. After dissolution, centrifuge the test solution (3000 rpm) for 5 minutes, and transfer the supernatant to a liquid chromatogram for analysis.

[0328]

[0329] In the formula: The concentration of each main component in the reference solution, in mg / mL; Peak areas of each main component in the test solution; : Peak area of ​​each main component in the reference solution; V: Dilution factor.

[0330] 3. Experimental Results:

[0331] The experimental results are shown in Table 2.

[0332] Table 2: Solubility of the test compounds in the solvent

[0333]

[0334] The solubility of the compound of this invention in pure water is significantly improved, meeting the requirements for injection administration.

[0335] Biological Test Example 3: Study on Formaldehyde Formation After Incubation with Rats' Serum Using Compound

[0336] 1. Experimental objective:

[0337] The formaldehyde formation effect of the compound of the present invention when incubated in rat serum was evaluated.

[0338] 2. Experimental materials:

[0339] Formaldehyde (37%) (Sigma-Aldrich, 252549), 0.1% perchloric acid standard titration solution (0.1%) (Krypton, batch number: 20341594), dinitrophenylhydrazine (Annegi, batch number: 8XEUARAR).

[0340] 3. Test methods:

[0341] 3.1 Preparation of derivatization reagents

[0342] 3.1.1 Prepare 1.5 mg / mL dinitrophenylhydrazine

[0343] Weigh 60 mg of dinitrophenylhydrazine and dissolve it in 40 mL of acetonitrile to obtain a 1.5 mg / mL dinitrophenylhydrazine solution.

[0344] 3.1.2 Preparation of Derivatization Reagents

[0345] The derivatization reagent was prepared by adding 203 μL of perchloric acid (0.1%) to the above-mentioned dinitrophenylhydrazine solution (1.5 mg / mL) at a ratio of 197:1.

[0346] 3.2 Prepare formaldehyde standard samples

[0347] 3.2.1 Serum treatment

[0348] After collecting whole blood from rats and allowing it to stand at room temperature for 2 hours, centrifuge at 3000g for 5 minutes. Take the supernatant and adjust the pH to 9.3 with 1M NaOH for later use.

[0349] 3.2.2 Prepare the first working standard solution

[0350] Add 2 μL of formaldehyde stock solution (37%) to 1998 μL of serum to obtain a first working standard solution of formaldehyde with a concentration of 403 ng / μL.

[0351] 3.2.3 Prepare the final working standard solution:

[0352] The first working standard solution (403 ng / μL) was further diluted with serum to obtain the following concentrations:

[0353] • 0.403 ng / μL

[0354] • 2.02 ng / μL

[0355] • 4.03 ng / μL

[0356] • 10.1 ng / μL

[0357] • 20.2 ng / μL

[0358] • 40.3 ng / μL.

[0359] 3.3 Incubation and Derivatization of Samples to be Tested

[0360] The experimental groups are shown in Table 3-1:

[0361] Table 3-1 Grouping of Rat Serum Incubation Test for Test Compounds

[0362]

[0363] 3.3.1 Preparation and derivatization of plasma incubation samples from groups G1-G3

[0364] Aliquot the derivatization reagent into 1.5mL EP tubes, 900μL per tube, for later use.

[0365] Accurately weigh 1 mg of each of the test compounds and dissolve them in 1 mL of DMSO to prepare 1 mg / mL stock solutions. Add 80 μL of each stock solution to 3920 μL of serum and mix well to prepare a 20 μg / mL solution. Incubate at 37°C. At time points 0 h, 1 h, and 2 h, take 100 μL of each solution and add it to 900 μL of the test sample derivatization reagent. After shaking well, centrifuge at 3000 rpm for 3 minutes. Transfer 200 μL of the supernatant to a 2 mL vial for instrumentation.

[0366] 3.3.2 Derivatization treatment of formaldehyde standard in group G4

[0367] Aliquot the derivatization reagent into 1.5 mL EP tubes, 990 μL each.

[0368] Add 10 μL of formaldehyde standard to 990 μL of derivatization reagent, vortex until homogeneous, and centrifuge at 3000 rpm for 3 minutes. Transfer 200 μL of the supernatant to a 2 mL vial for instrumentation.

[0369] 4. HPLC detection:

[0370] 4.1 Test Parameters

[0371] Instrument model: Waters e2695 & 2489 UV / Vis Detector;

[0372] Column: Welch Xtimeta C18 4.6*250mm, 5µm;

[0373] Mobile phase: 50% acetonitrile; injection volume: 20 µL; detection wavelength: 360 nm; isocratic elution time: 30 min.

[0374] 4.2 Formaldehyde content generated by the compound

[0375] The experimental results are shown in Table 3-2.

[0376] Table 3-2 Formaldehyde generation after incubation with rat serum of the test compounds

[0377]

[0378] NA: Below the limit of quantitative detection

[0379] No formaldehyde was generated in rat serum after incubation at 37°C for 1 h and 2 h, indicating low potential carcinogenicity and other side effects, and good long-term safety. Formaldehyde generation in APX001 serum after incubation at 37°C for 1 h and 2 h was 0.29 ng / μL and 0.76 ng / μL, respectively, representing a 35-fold and 92-fold increase in formaldehyde compared to serum at 0 h.

[0380] Biological Test Example 4: Study on the metabolic stability of compounds in human whole blood

[0381] 1. Experimental objective:

[0382] Human whole blood was used as an in vitro model to evaluate the metabolic stability of the test compounds.

[0383] 2. Test methods:

[0384] 1) Prepare a stock solution of the test compound at 1 mg / mL using PBS and incubate it at 35℃±1℃ to obtain the pre-incubation working solution.

[0385] 2) Human whole blood (heparin sodium anticoagulation) matrix to be incubated.

[0386] 3) First, add 996 μL of human whole blood matrix to the centrifuge tube and preheat at 35℃±1℃ for 5 min. Then, add 4 μL of the pre-incubation working solution of the test compound from step 1) to the incubation tube, gently invert to mix, and place in a water bath for incubation at a shaking speed of less than 450 rpm.

[0387] 4) Take 100 μL of the incubated whole blood sample at 0, 15, 30, 60, 120 and 180 min and add it to the corresponding EP tube (containing 300 μL of ice acetonitrile (1% FA)) to terminate the reaction. Then vortex for 5 min to ensure that the sample is fully precipitated and then place it on wet ice for temporary storage (< 30 min).

[0388] 5) Centrifuge the sample placed on wet ice (4℃, 14000 rpm, 5 min, vortex for 1 min before centrifugation) to separate the supernatant. Take 100 μL of the supernatant and use LC-MS / MS to detect the amount of active metabolite (E1210) generated in the incubation system and calculate the generation rate of metabolite (E1210).

[0389] Metabolite (E1210) generation rate % = LC-MS / MS actual metabolite generation (nM) / Theoretical generation of all metabolites from the original form (nM) * 100%.

[0390] 3. Experimental Results:

[0391] The experimental results are shown in Table 4.

[0392] Table 4. Formation rate of metabolites of the test compounds after whole blood incubation.

[0393]

[0394] The compound of this invention can be rapidly activated into an active metabolite in a human whole blood incubation system; the metabolite generation rate is higher than that of APX001.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, ， in, L represents a single bond, -OC(O)-NL 1 -、-OC(O)-NL 2 -(CL 3 L 4 ) m -or-OC(O)-(CL) 5 L 6 ) n -; L 1 L 2 L 3 L 4 L 5 and L 6 Each independently is H or C 1-3 alkyl; m and n are each independently 1 or 2; X is a phenyl, pyridyl, or pyrrolidinyl group optionally substituted with one or more Rs; R is independently C 1-3 Alkyl group, -(CH2) o -OP(=O)(OH)O - -(CH2) o -OP(=O)(O - )2·M + -(CH2) o -OP(=O)(O - )2·1 / 2D 2+ -(CH2) o -OP(=O)(O - )2·2M + -(CH2) o -OP(=O)(O - )2·D 2+ or ; o can be 0, 1, 2, or 3; M + It is a Group I main metal cation; D 2+ It is a Group II main metal cation; Y - It is a monovalent anion; q is 0 or 1; The compound represented by formula (I) contains at most one molecule selected from -(CH2). o -OP(=O)(OH)O - -(CH2) o -OP(=O)(O - )2·M + and -(CH2) o -OP(=O)(O - )2·1 / 2D 2+ A fragment; When the compound shown in formula (I) contains one molecule selected from -(CH2) o -OP(=O)(OH)O - -(CH2) o -OP(=O)(O - )2·M + and -(CH2) o -OP(=O)(O - )2·1 / 2D 2+ When the fragment is q, it is 0; when the compound shown in formula (I) does not contain any compound selected from -(CH2) o -OP(=O)(OH)O - -(CH2) o -OP(=O)(O - )2·M + and -(CH2) o -OP(=O)(O - )2·1 / 2D 2+ When q is 1, Y - It is a monovalent anion.

2. The compound of formula (I) as claimed in claim 1, characterized in that, It meets one or more of the following conditions: (1) In R, o is 0, 1 or 2 (preferably 0 or 1); (2) In R, M + for Na + or K + (Preferred to be Na) + ); (3) In R, D 2+ For Ca 2+ or Mg 2+ (Preferred to be Ca) 2+ ); (4) In R, -(CH2) o -OP(=O)(O - )2·M + for , , or Preferred or More preferably ; (5) In R, -(CH2) o -OP(=O)(O - )2·1 / 2D 2+ for , , or Preferred or More preferably ; (6) In R, -(CH2) o -OP(=O)(O - )2·2M + for , , or Preferred ; (7) In R, -(CH2) o -OP(=O)(O - )2·D 2+ -CH2-OP(=O)(O - )2·Ca 2+ -OP(=O)(O) - )2·Ca 2 + -CH2-OP(=O)(O - )2·Mg 2+ or -OP(=O)(O) - )2·Mg 2+ ; (8) Y - HCO3 - HCOO - or Cl - .

3. The compound of formula (I) as claimed in claim 1, characterized in that, L represents a single bond, -OC(O)-NL 1 -、-OC(O)-NL 2 -(CL 3 L 4 ) m -or-OC(O)-(CL) 5 L 6 ) n -; L 1 L 2 L 3 L 4 L 5 and L 6 Each independently is H or C 1-3 alkyl; m and n are each independently 1 or 2; X is a phenyl, pyridyl, or pyrrolidinyl group optionally substituted with one or more R groups; R is independently C 1-3 alkyl, , , , or ; Y - HCO3 - HCOO - or Cl - ; q is 0 or 1; The compound represented by formula (I) contains at most one ingredient selected from... , and A fragment; When the compound shown in formula (I) contains one selected from , and When the fragment is q, it is 0; when the compound shown in formula (I) does not contain any of the following: , and When q is 1, Y - HCO3 - HCOO - or Cl - .

4. The compound of formula (I) as described in any one of claims 1-3, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) R, L 1 L 2 L 3 L 4 L 5 and L 6 In, the C 1-3 The alkyl group is methyl, ethyl, n-propyl, or isopropyl, preferably methyl; (2) In X, the pyridinyl group is , or Preferred ; (3) In X, the pyrroleyl group is or Preferred ; (4) In X, "optionally replaced by one or more R" means "optionally replaced by 1, 2, 3, 4 or 5 R".

5. The compound of formula (I) as described in any one of claims 1-4, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) L is a single bond, -OC(O)-NL 1 -or-OC(O)-(CL) 5 L 6 ) n -; preferably a single bond or -OC(O)-(CL 5 L 6 ) n -; (2) L 1 L 2 L 3 L 4 L 5 and L 6 Each can be independently H or methyl; (3) m is 1; (4) n is 2; (5) X is a phenyl or pyridyl group substituted with one or more R groups; preferably a phenyl group substituted with one or more R groups; (6) R is independently C 1-3 alkyl, , , or C is preferred. 1-3 alkyl, , or More preferably, C 1-3 alkyl or ; (7) In X, "optionally replaced by one or more R" means "optionally replaced by 1, 2 or 3 R"; (8) In X, when "optionally replaced by one or more R" is "replaced by 1 R", R is , or Preferred or More preferably ; (9) In X, when "optionally replaced by one or more R" is "replaced by 2 R", one of the R is , or Preferred or More preferably The other R is C. 1-3 alkyl or Preferred ; (10) In X, when "optionally replaced by one or more R" is "replaced by 3 R", one of the R is , or Preferred or More preferably The other R is C. 1-3 alkyl or C is preferred. 1-3 alkyl; (11) The compound shown in formula (I) contains one ingredient selected from... , and The fragment has q = 0; preferably containing 1 The fragment, where q is 0; or, the compound shown in formula (I) does not contain any of the following: , and The fragment, q is 1, Y - HCO3 - or HCOO - ; Preferably, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof satisfies any one of the following conditions: (1) L is a single bond; X is a phenyl or pyridyl group substituted with one or more R, preferably a phenyl group substituted with one or more R; (2) L is a single bond; X is a phenyl group substituted with one or two R atoms, each R being an independent single bond. , , or Furthermore, the compound represented by formula (I) contains one ingredient selected from... , and The fragment; q is 0; (3) L is a single bond; X is a phenyl group substituted by one R, where R is... , or Preferred or More preferably ;q is 0; (4) L is a single bond; X is a phenyl group substituted with two Rs, one of which is a single bond. , or Preferred or More preferably The other R is ;q is 0; (5) X is , , , , , , , , (For example )or Preferred , (For example ), , , or .

6. The compound of formula (I) as described in any one of claims 1-5, or a pharmaceutically acceptable salt thereof, characterized in that, It meets one or more of the following conditions: (1) L 1 and L 2 Each is independently a methyl group; (2) L 3 and L 4 Each is independently represented by H; (3) L 5 and L 6 Each can be independently H or methyl; (4) L is a single bond, -OC(O)-N(CH3)-CH2-, -OC(O)-N(CH3)- or -OC(O)-CH2-C(CH3)2-, preferably a single bond, -OC(O)-N(CH3)- or -OC(O)-CH2-C(CH3)2-; more preferably a single bond or -OC(O)-CH2-C(CH3)2-; (5) R is independently methyl, , , , or Preferably methyl, , , or More preferably, methyl or ; (6) X is , , (For example ), , , , , or Preferred , , , , or More preferably or .

7. The compound of formula (I) as described in any one of claims 1-6, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (I) is the compound represented by formula (II), formula (III), formula (IV), formula (V), or formula (VII). , , , or ; Among them, L, X, R, n, L 5 L 6 and L 1 The definition is as described in any one of claims 1-6, where p is 1, 2, 3, 4, or 5, and the compound represented by formula (II), the compound represented by formula (III), the compound represented by formula (IV), the compound represented by formula (V), or the compound represented by formula (VII) contains one atom selected from -(CH2). o -OP(=O)(OH)O - -(CH2) o -OP(=O)(O - )2·M + and -(CH2) o -OP(=O)(O - )2·1 / 2D 2+ fragments; o, D 2+ and M + The definition is as described in any one of claims 1-6 (preferably containing one selected from...). , and (segment) Preferably, the compound represented by formula (IV) is the compound represented by formula (IV-1). ， Wherein, R is selected from -(CH2). o -OP(=O)(OH)O - -(CH2) o -OP(=O)(O - )2·M + and -(CH2) o -OP(=O)(O - )2·1 / 2D 2+ fragments; o, D 2+ and M + The definition is as described in any one of claims 1-6 (R is preferably...) , or ).

8. The compound of formula (I) as described in any one of claims 1-7, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from any of the following compounds: , , , , , , , , , , , and .

9. A pharmaceutical composition comprising: (1) the compound of formula (I) as claimed in any one of claims 1-8 or a pharmaceutically acceptable salt thereof, and (2) a pharmaceutically acceptable excipient.

10. The use of a compound of formula (I) as described in any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 9, characterized in that, The application is selected from one or more of the following: (i) The use of the compound of formula (I) as described in any one of claims 1-8 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as described in claim 9 in the preparation of a fungal acyltransferase (Gwt1) inhibitor; (ii) The use of the compound of formula (I) as described in any one of claims 1-8 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as described in claim 9 in the preparation of a medicament for the prevention or treatment of a disease; preferably, the disease is a fungal infection, such as a fungal infection associated with a fungal acyltransferase (Gwt1); (iii) The use of the compound of formula (I) as described in any one of claims 1-8 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as described in claim 9 in the preparation of an antifungal agent; preferably, the antifungal agent is an antifungal agent that inhibits fungal acyltransferase (Gwt1).

11. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The compound is any one of the following compounds: , , , , , , , , , , , , , , or .

12. A method for preparing a compound of formula (VI) or a pharmaceutically acceptable salt thereof, or a compound of formula (VI-1) or a pharmaceutically acceptable salt thereof, or a compound of formula (VI-2) or a pharmaceutically acceptable salt thereof and / or a compound of formula (VI-3) or a pharmaceutically acceptable salt thereof, characterized in that, The preparation method of the compound of formula (VI) or its pharmaceutically acceptable salt comprises the following steps: in a solvent, the compound of formula (VI-1) reacts to generate the compound of formula (VI) (preferably, in a solvent, in the presence of a metal-type ion exchange resin, the compound of formula (VI-1) undergoes an ion exchange reaction to obtain the compound of formula (VI)). ； Among them, R 1 C 1-3 Alkyl; M + It is a group I metal cation; s and t are each independent integers from 0 to 4, and 0≤(s+t)≤4; The preparation method of the compound shown in formula (VI-1) or its pharmaceutically acceptable salt comprises the following steps: in a solvent, in the presence of a deprotecting agent, the compound shown in formula (VI-2) and / or the compound shown in formula (VI-3) undergoes a deprotection reaction to obtain the compound shown in formula (VI-1); ； Wherein, L is defined as described in any one of claims 1-6; R 1 C 1-3 Alkyl; R 2 It is a hydroxyl protecting group; Z - It is a monovalent anion (preferably HCO3-). - HCOO - or Cl - ); s and t are each independent integers from 0 to 4, and 0≤(s+t)≤4; The preparation method of the compound shown in formula (VI-2) and / or the compound shown in formula (VI-3) includes the following steps: in a solvent, in the presence of an optional catalyst, the compound shown in formula (1-4) and the compound shown in formula (VI-5) react to obtain the compound shown in formula (VI-2) and / or the compound shown in formula (VI-3). ； Wherein, L is defined as described in any one of claims 1-6; W is a halogenated or substituted sulfonate group; R 1 C 1-3 Alkyl; R 2 It is a hydroxyl protecting group; Z - It is a monovalent anion (preferably HCO3-). - HCOO - or Cl - ); s and t are each independent integers from 0 to 4, and 0≤(s+t)≤4.

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