Vancomycin derivatives, intermediates thereof, preparation methods, compositions and uses

Abstract

The present invention discloses a vancomycin derivative, an intermediate, a preparation method, a composition and a use thereof. The present invention discloses a compound as shown in formula I, a pharmaceutically acceptable salt, an enantiomer, a solvate, or a solvate of a pharmaceutically acceptable salt thereof, wherein R is one or more R 1 Substituted C 6‑20 Aryl, C 6‑20 Aryl, one or more R 2 Substituted 3-20 membered heterocycloalkenyl, 5-20 membered heteroaryl, one or more R 3 Substituted C 1‑10 Alkyl, C 1‑10 Alkyl or C 3‑10 Cycloalkyl; the 5-20 membered heteroaryl and the one or more R 2 The heteroatom in the substituted 3-20-membered heterocycloalkenyl is selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4. The vancomycin derivative of the present invention has a good antibacterial effect.

Description

Technical Field

[0001] The present invention relates to a vancomycin derivative, an intermediate thereof, a preparation method, a composition and use thereof. Background Art

[0002] Vancomycin is a glycopeptide antibiotic against Gram-positive bacteria. It was isolated by McCormick from the fermentation broth of Amycolatopsis orientalis in 1956. It is currently the drug of choice for clinical treatment of serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA). It is hailed by international antibiotic experts as "the last line of defense for mankind against stubborn drug-resistant strains" and "the trump card antibiotic."

[0003]

[0004] In 2005, Fu et al. used a biosynthetic method to introduce amino sugars into the vancomycin nucleus without the sugar group to obtain vancomycin derivatives. They then introduced an azide group into the glycoside and used this group to derive a series of compounds. Unfortunately, the alkynyl compounds used in this paper had too little structural diversity, so the antibacterial activity of the triazole compounds obtained was not significantly improved (Org Lett, 2005, 7(8): 1513-1515).

[0005] Summary of the invention

[0006] The technical problem to be solved by the present invention is to overcome the defect of the existing vancomycin derivatives being single in type, and to provide a vancomycin derivative, its intermediate, preparation method, composition and use. The vancomycin derivative of the present invention has a good antibacterial effect.

[0007] The present invention solves the above technical problems through the following technical solutions.

[0008] The present invention provides a compound as shown in Formula I, a pharmaceutically acceptable salt, enantiomer, solvate, or solvate of a pharmaceutically acceptable salt thereof,

[0009]

[0010] Where R is one or more R 1 Substituted C 6-20 Aryl, C 6-20 Aryl, one or more R 2 substituted 3-20 membered heterocycloalkenyl, 5-20 membered heteroaryl, one or more R 3 Substituted C 1-10 Alkyl, C 1-10 Alkyl or C3-10 Cycloalkyl; the heteroatoms in the 5-20 membered heteroaryl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; the one or more R 2 The heteroatom in the 3-20-membered heterocycloalkenyl in the substituted 3-20-membered heterocycloalkenyl is selected from one or more of nitrogen, oxygen and sulfur, and the number of the heteroatom is 1, 2, 3 or 4;

[0011] R 1 Independently for C 1-6 Alkoxy, one or more halogen-substituted C 1-6 Alkyl (when one or more halogen substituted C 1-6 When there are multiple halogens in the alkyl group, the halogens are the same or different), or halogen;

[0012] R 2 Independently one or more R 2-1 substituted 3-10 membered heterocycloalkyl, or oxo, wherein one or more R 2-1 The heteroatoms in the 3-10-membered heterocycloalkyl group of the substituted 3-10-membered heterocycloalkyl group are selected from one or more of nitrogen, oxygen and sulfur, and the number of the heteroatoms is 1, 2, 3 or 4; R 2-1 are independently hydroxyl, or one or more hydroxyl-substituted C 1-6 alkyl;

[0013] R 3 are independently -(C=O)OR 3-1 、-NR 3-2 R 3-3 、-OR 3-4 , or "5-20 membered heteroaryl substituted with one or more amino groups"; R 3-1 is hydrogen or C 1-6 Alkyl; R 3-2 and R 3-3 Independently for C 1-6 Alkyl; R 3-4 -(CH2) m O(CH2) n OH, "one or more halogen-substituted C 6-20 "Aryl" or "one or more R 3-4-1 Substituted C 6-20 Aryl" (the one or more halogen-substituted C 6-20 When there are multiple halogens in the aryl group, the halogens are the same or different), m and n are independently 1, 2, 3 or 4; the heteroatoms in the 5-20-membered heteroaryl group in the one or more amino-substituted 5-20-membered heteroaryl group are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; R 3-4-1 Independently for C1-6 Alkoxy or -(C=O)-C 1-6 alkyl.

[0014] The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof,

[0015]

[0016] Where R is one or more R 1 Substituted C 6-20 Aryl, C 6-20 Aryl, one or more R 2 substituted 3-20 membered heterocycloalkenyl, 5-20 membered heteroaryl, one or more R 3 Substituted C 1-10 Alkyl, C 1-10 Alkyl or C 3-10 Cycloalkyl; the heteroatoms in the 5-20 membered heteroaryl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; the one or more R 2 The heteroatom in the 3-20-membered heterocycloalkenyl in the substituted 3-20-membered heterocycloalkenyl is selected from one or more of nitrogen, oxygen and sulfur, and the number of the heteroatom is 1, 2, 3 or 4;

[0017] R 1 Independently for C 1-6 Alkoxy, one or more halogen-substituted C 1-6 Alkyl (when one or more halogen substituted C 1-6 When there are multiple halogens in the alkyl group, the halogens are the same or different), or halogen;

[0018] R 2 Independently one or more R 2-1 substituted 3-10 membered heterocycloalkyl, or oxo, wherein one or more R 2-1 The heteroatoms in the 3-10-membered heterocycloalkyl group of the substituted 3-10-membered heterocycloalkyl group are selected from one or more of nitrogen, oxygen and sulfur, and the number of the heteroatoms is 1, 2, 3 or 4; R 2-1 are independently hydroxyl, or one or more hydroxyl-substituted C 1-6 alkyl;

[0019] R 3 are independently -(C=O)OR 3-1 、-NR 3-2 R 3-3 、-OR 3-4 , or "5-20 membered heteroaryl substituted with one or more amino groups"; R 3-1 is hydrogen or C 1-6 Alkyl; R 3-2 and R3-3 Independently for C 1-6 Alkyl; R 3-4 -(CH2) m O(CH2) n OH, "one or more halogen-substituted C 6-20 "Aryl" or "one or more R 3-4-1 Substituted C 6-20 Aryl" (the one or more halogen-substituted C 6-20 When there are multiple halogens in the aryl group, the halogens are the same or different), m and n are independently 1, 2, 3 or 4; the heteroatoms in the 5-20-membered heteroaryl group in the one or more amino-substituted 5-20-membered heteroaryl group are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; R 3-4-1 Independently for C 1-6 Alkoxy or -(C=O)-C 1-6 alkyl.

[0020] When the R 1 , R 2 , R 3 , R 2-1 , or R 3-4-1 When there are multiple R 1 , R 2 , R 3 , R 2-1 or R 3-4-1 Same or different.

[0021] In a preferred embodiment of the present invention, when R is one or more R 1 Substituted C 6-20 When the C 6-20 The aryl group is preferably C 6-14 The aryl group is more preferably phenyl, naphthyl or anthracenyl, and most preferably phenyl.

[0022] In a preferred embodiment of the present invention, when R is C 6-20 When the C 6-20 The aryl group is preferably C 6-14 The aryl group is more preferably a phenyl group, a naphthyl group or an anthracenyl group.

[0023] In a preferred embodiment of the present invention, when R is one or more R 2When the 3-20 membered heterocycloalkenyl is substituted, the 3-20 membered heterocycloalkenyl is preferably a 3-10 membered heterocycloalkenyl, and more preferably a 6 membered heterocycloalkenyl; the heteroatom in the 3-20 membered heterocycloalkenyl, 3-10 membered heterocycloalkenyl and 6 membered heterocycloalkenyl is preferably nitrogen, and the number of heteroatoms is preferably 2. The number of carbon-carbon double bonds in the 3-20 membered heterocycloalkenyl, 3-10 membered heterocycloalkenyl and 6 membered heterocycloalkenyl is preferably 1. The 3-20 membered heterocycloalkenyl is preferably

[0024] In a preferred embodiment of the present invention, when R is a 5-20 membered heteroaryl group, the 5-20 membered heteroaryl group is preferably a 5-10 membered heteroaryl group, and more preferably a 5-membered heteroaryl group or a 6-membered heteroaryl group; the heteroatoms in the 5-20 membered heteroaryl group, the 5-10 membered heteroaryl group, the 5-membered heteroaryl group and the 6-membered heteroaryl group are preferably nitrogen or sulfur, and the number of heteroatoms is preferably 1 or 2. When R is a 5-membered heteroaryl group, the heteroatoms in the 5-membered heteroaryl group are preferably sulfur, and the number of heteroatoms is preferably 1. When R is a 6-membered heteroaryl group, the heteroatoms in the 6-membered heteroaryl group are preferably nitrogen, and the number of heteroatoms is preferably 2. The 5-20 membered heteroaryl group is preferably

[0025] In a preferred embodiment of the present invention, when R is one or more R 3 Substituted C 1-10 When the C 1-10 The alkyl group is preferably C 1-4 The alkyl group is more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group, and most preferably a methyl group or an ethyl group.

[0026] In a preferred embodiment of the present invention, when R is C 1-10 When the C 1-10 The alkyl group is preferably C 1-4 The alkyl group is more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group.

[0027] In a preferred embodiment of the present invention, when R is C 3-10 When cycloalkyl, the C 3-10 The cycloalkyl group is preferably C 4-7 The cycloalkyl group is more preferably cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and most preferably cyclopentyl.

[0028] In a preferred embodiment of the present invention, when R 1 Independently for C 1-6 In the case of an alkoxy group, the C 1-6 The alkoxy group is preferably C 1-4The alkoxy group is more preferably a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group or a tert-butoxy group, and most preferably a methoxy group.

[0029] In a preferred embodiment of the present invention, when R 1 are independently one or more halogen-substituted C 1-6 When the halogen is alkyl, the halogen is preferably fluorine, chlorine, bromine or iodine, more preferably fluorine; the C 1-6 The alkyl group is preferably C 1-4 The alkyl group is more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group, and most preferably a methyl group.

[0030] In a preferred embodiment of the present invention, when R 1 When they are independently halogen, the halogen is preferably fluorine, chlorine, bromine or iodine, more preferably chlorine.

[0031] In a preferred embodiment of the present invention, when R 2 Independently one or more R 2-1 When the substituted 3-10 membered heterocycloalkyl is a substituted 3-10 membered heterocycloalkyl, the 3-10 membered heterocycloalkyl is preferably a 3-7 membered heterocycloalkyl, and further preferably a 5 membered heterocycloalkyl; the heteroatom in the 3-10 membered heterocycloalkyl, the 3-7 membered heterocycloalkyl and the 5 membered heterocycloalkyl is preferably oxygen, and the number of the heteroatom is preferably 1.

[0032] In a preferred embodiment of the present invention, when R 2-1 are independently one or more hydroxy-substituted C 1-6 When the C 1-6 The alkyl group is preferably C 1-4 The alkyl group is more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group, and most preferably a methyl group.

[0033] In a preferred embodiment of the present invention, when R 3 When the 5-20 membered heteroaryl is independently substituted by one or more amino groups, the 5-20 membered heteroaryl is preferably a 6-12 membered heteroaryl, and more preferably a 9 membered heteroaryl; the heteroatom in the 5-20 membered heteroaryl, the 6-12 membered heteroaryl and the 9 membered heteroaryl is preferably nitrogen, and the number of heteroatoms is preferably 4. The 5-20 membered heteroaryl is preferably

[0034] In a preferred embodiment of the present invention, when R 3-1 C 1-6 When the C 1-6 The alkyl group is preferably C 1-4The alkyl group is more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group.

[0035] In a preferred embodiment of the present invention, the R 3-2 and R 3-3 Preferably, C 1-4 The alkyl group is more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, and most preferably ethyl.

[0036] In a preferred embodiment of the present invention, when the R 3-4 C is substituted with one or more halogens 6-20 When aryl, the one or more halogen-substituted C 6-20 The halogen in the aryl group is preferably fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or iodine; the one or more halogen-substituted C 6-20 C in aromatic groups 6-20 The aryl group is preferably C 6-14 The aryl group is more preferably phenyl, naphthyl or anthracenyl, and most preferably phenyl.

[0037] In a preferred embodiment of the present invention, when the R 3-4 For one or more R 3-4-1 Substituted C 6-20 Aryl, one or more R 3-4-1 Substituted C 6-20 C in aromatic groups 6-20 The aryl group is preferably C 6-14 The aryl group is more preferably phenyl, naphthyl or anthracenyl, and most preferably phenyl.

[0038] In a preferred embodiment of the present invention, when the R 3-4-1 Independently for C 1-6 In the case of an alkoxy group, the C 1-6 The alkoxy group is preferably C 1-4 The alkoxy group is more preferably a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group or a tert-butoxy group, and most preferably a methoxy group.

[0039] In a preferred embodiment of the present invention, when the R 3-4-1 are independently -(C=O)-C 1-6 When the -(C=O)-C 1-6 C in the alkyl group 1-6 The alkyl group is preferably C 1-4 The alkyl group is more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group, and most preferably a methyl group.

[0040] In a preferred embodiment of the present invention, R is preferably one or more R1 Substituted C 6-20 Aryl, one or more R 2 substituted 3-20 membered heterocycloalkenyl, 5-20 membered heteroaryl, one or more R 3 Substituted C 1-10 Alkyl, or, C 3-10 Cycloalkyl.

[0041] In a preferred embodiment of the present invention, R 3-1 Preferred is hydrogen.

[0042] In a preferred embodiment of the present invention, m is preferably 2.

[0043] In a preferred embodiment of the present invention, n is preferably 2.

[0044] In a preferred embodiment of the present invention, when R 1 are independently one or more halogen-substituted C 1-6 When the R 1 It is trifluoromethyl.

[0045] In a preferred embodiment of the present invention, when R 2-1 are independently one or more hydroxy-substituted C 1-6 When alkyl, the R 2-1 It is -CH2OH.

[0046] In a preferred embodiment of the present invention, when R 2 Independently one or more R 2-1 When the 3-10 membered heterocycloalkyl is substituted, the R 2 for

[0047] In a preferred embodiment of the present invention, when R 3 When R is independently a 5-20 membered heteroaryl group substituted with one or more amino groups, 3 for

[0048] In a preferred embodiment of the present invention, when R 3-4 C is substituted with one or more halogens 6-20 When the group is aryl, the R 3-4 for

[0049] In a preferred embodiment of the present invention, when R 3-4 For one or more R 3-4-1 Substituted C 6-20 When the group is aryl, the R 3-4 for

[0050] In a preferred embodiment of the present invention, R is one or more R 1 Substituted C 6-20 Aryl, one or more R 2 substituted 3-20 membered heterocycloalkenyl, 5-20 membered heteroaryl, one or more R 3 Substituted C 1-10 Alkyl, or, C 3-10 Cycloalkyl; the heteroatoms in the 5-20 membered heteroaryl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; the one or more R 2 The heteroatom in the 3-20-membered heterocycloalkenyl in the substituted 3-20-membered heterocycloalkenyl is selected from one or more of nitrogen, oxygen and sulfur, and the number of the heteroatom is 1, 2, 3 or 4;

[0051] R 1 Independently for C 1-6 Alkoxy, one or more halogen-substituted C 1-6 Alkyl, or halogen;

[0052] R 2 Independently one or more R 2-1 substituted 3-10 membered heterocycloalkyl, or oxo, wherein one or more R 2-1 The heteroatoms in the substituted 3-10 membered heterocycloalkyl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; R 2-1 are independently hydroxy or one or more hydroxy-substituted C 1-6 alkyl;

[0053] R 3 are independently -(C=O)OR 3-1 、-NR 3-2 R 3-3 、-OR 3-4 , or "5-20 membered heteroaryl substituted with one or more amino groups"; R 3-1 is hydrogen; R 3-2 and R 3-3 Independently for C 1-6 Alkyl; R 3-4 -(CH2) m O(CH2) n OH, one or more halogen-substituted C 6-20 Aryl, or one or more R 3-4-1 Substituted C 6-20 Aryl, m and n are independently 1, 2, 3 or 4; the heteroatoms in the 5-20-membered heteroaryl group substituted with one or more amino groups are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; R 3-4-1 Independently for C1-6 Alkoxy or -(C=O)-C 1-6 alkyl.

[0054] In a preferred embodiment of the present invention, R is one or more R 1 Substituted C 6-14 Aryl, C 6-20 Aryl, one or more R 2 substituted 3-10 membered heterocycloalkenyl, 5-10 membered heteroaryl, one or more R 3 Substituted C 1-4 Alkyl, or C 4-7 Cycloalkyl; said one or more R 2 The heteroatoms in the substituted 3-10 membered heterocycloalkenyl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; the heteroatoms in the 5-10 membered heteroaryl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4;

[0055] R 1 Independently for C 1-4 Alkoxy, or "one or more halogen-substituted C 1-4 alkyl";

[0056] R 2 Independently one or more R 2-1 substituted 3-7 membered heterocycloalkyl, or oxo, wherein one or more R 2-1 The heteroatoms in the substituted 3-7 membered heterocycloalkyl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; R 2-1 are independently hydroxy or one or more hydroxy-substituted C 1-4 alkyl;

[0057] R 3 Independently for NR 3-2 R 3-3 、-OR 3-4 , or "a 6-12 membered heteroaryl group substituted with one or more amino groups"; R 3-2 and R 3-3 Independently for C 1-4 Alkyl; R 3-4 -(CH2) m O(CH2) n OH, one or more halogen-substituted C 6-14 Aryl, or one or more R 3-4-1 Substituted C 6-20 Aryl, m and n are independently 1, 2, 3 or 4; the heteroatoms in the one or more amino-substituted 6-12-membered heteroaryl groups are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; R3-4-1 Independently for C 1-4 Alkoxy or -(C=O)-C 1-4 alkyl.

[0058] In a preferred embodiment of the present invention, R is preferably one or more R 3 Substituted C 1-10 Alkyl; R 3 Preferably -OR 3-4 ; R 3-4 Preferably one or more halogen-substituted C 6-20 Aryl.

[0059] In a preferred embodiment of the present invention, the compound as shown in formula I is preferably any of the following compounds:

[0060]

[0061]

[0062] The present invention provides a compound as shown in Formula I, a pharmaceutically acceptable salt, enantiomer, solvate, or solvate of a pharmaceutically acceptable salt thereof,

[0063]

[0064] Where R is one or more R 1 Substituted C 6-20 Aryl, C 6-20 Aryl, one or more R 2 substituted 3-20 membered heterocycloalkenyl, 5-20 membered heteroaryl, one or more R 3 Substituted C 1-10 Alkyl, C 1-10 Alkyl or C 3-10 Cycloalkyl; the heteroatoms in the 5-20 membered heteroaryl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; the one or more R 2 The heteroatoms in the substituted 3-20 membered heterocycloalkenyl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4;

[0065] R 1 Independently for C 1-6 Alkoxy, one or more halogen-substituted C 1-6 Alkyl (when one or more halogen substituted C 1-6 When there are multiple halogens in the alkyl group, the halogens are the same or different), or halogen;

[0066] R 2 Independently one or more R 2-1 substituted 3-10 membered heterocycloalkyl or oxo, wherein one or more R 2-1 The heteroatoms in the substituted 3-10 membered heterocycloalkyl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; R 2-1 are independently hydroxyl, or one or more hydroxyl-substituted C 1-6 alkyl;

[0067] R 3 are independently -(C=O)OR 3-1 、-NR 3-2 R 3-3 、-OR 3-4 , or "5-20 membered heteroaryl substituted with one or more amino groups"; R 3-1 is hydrogen or C 1-6 Alkyl; R 3-2 and R 3-3 Independently for C 1-6 Alkyl; R 3-4 -(CH2) m O(CH2) n OH, or "one or more halogen-substituted C 6-20 Aryl" (the one or more halogen-substituted C 6-20 When there are multiple halogens in the aryl group, the halogens are the same or different), m and n are independently 1, 2, 3 or 4; the heteroatoms in the one or more amino-substituted 5-20 membered heteroaryl groups are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4.

[0068] The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof,

[0069]

[0070] Where R is one or more R 1 Substituted C 6-20 Aryl, C 6-20 Aryl, one or more R 2 substituted 3-20 membered heterocycloalkenyl, 5-20 membered heteroaryl, one or more R 3 Substituted C 1-10 Alkyl, C 1-10 Alkyl or C 3-10 Cycloalkyl; the heteroatoms in the 5-20 membered heteroaryl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; the one or more R 2The heteroatoms in the substituted 3-20 membered heterocycloalkenyl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4;

[0071] R 1 Independently for C 1-6 Alkoxy, one or more halogen-substituted C 1-6 Alkyl (when one or more halogen substituted C 1-6 When there are multiple halogens in the alkyl group, the halogens are the same or different), or halogen;

[0072] R 2 Independently one or more R 2-1 substituted 3-10 membered heterocycloalkyl or oxo, wherein one or more R 2-1 The heteroatoms in the substituted 3-10 membered heterocycloalkyl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; R 2-1 are independently hydroxyl, or one or more hydroxyl-substituted C 1-6 alkyl;

[0073] R 3 are independently -(C=O)OR 3-1 、-NR 3-2 R 3-3 、-OR 3-4 , or "5-20 membered heteroaryl substituted with one or more amino groups"; R 3-1 is hydrogen or C 1-6 Alkyl; R 3-2 and R 3-3 Independently for C 1-6 Alkyl; R 3-4 -(CH2) m O(CH2) n OH, or "one or more halogen-substituted C 6-20 Aryl" (the one or more halogen-substituted C 6-20 When there are multiple halogens in the aryl group, the halogens are the same or different), m and n are independently 1, 2, 3 or 4; the heteroatoms in the one or more amino-substituted 5-20 membered heteroaryl groups are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4.

[0074] When the R 1 , R 2 , R 3 or R 2-1 When there are multiple R 1 , R 2 , R 3 or R 2-1 Same or different.

[0075] In a preferred embodiment of the present invention, when said R is one or more R 1 Substituted C 6-20 When the C 6-20 The aryl group is preferably C 6-14 The aryl group is more preferably phenyl, naphthyl or anthracenyl, and most preferably phenyl.

[0076] In a preferred embodiment of the present invention, when the R 1 Independently for C 1-6 In the case of an alkoxy group, the C 1-6 The alkoxy group is preferably C 1-4 The alkoxy group is more preferably a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group or a tert-butoxy group, and most preferably a methoxy group.

[0077] In a preferred embodiment of the present invention, when the R 1 are independently one or more halogen-substituted C 1-6 When the halogen is alkyl, the halogen is preferably fluorine, chlorine, bromine or iodine, more preferably fluorine; the C 1-6 The alkyl group is preferably C 1-4 Alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, most preferably methyl. 1-6 The alkyl group is preferably trifluoromethyl.

[0078] In a preferred embodiment of the present invention, when the R 1 When they are independently halogen, the halogen is preferably fluorine, chlorine, bromine or iodine, more preferably chlorine.

[0079] In a preferred embodiment of the present invention, when said R is one or more R 1 Substituted C 6-20 When the group is aryl, the R 1 Substituted C 6-20 The aryl group is preferably More preferably

[0080] In a preferred embodiment of the present invention, when said R is C 6-20 When the C 6-20 The aryl group is preferably C 6-14 The aryl group is more preferably a phenyl group, a naphthyl group or an anthracenyl group.

[0081] In a preferred embodiment of the present invention, when said R is one or more R 2When the 3-20 membered heterocycloalkenyl is substituted, the 3-20 membered heterocycloalkenyl is preferably a 3-10 membered heterocycloalkenyl, and more preferably a 6 membered heterocycloalkenyl; the heteroatom in the 3-20 membered heterocycloalkenyl, 3-10 membered heterocycloalkenyl and 6 membered heterocycloalkenyl is preferably nitrogen, and the number of heteroatoms is preferably 2. The number of carbon-carbon double bonds in the 3-20 membered heterocycloalkenyl, 3-10 membered heterocycloalkenyl and 6 membered heterocycloalkenyl is preferably 1. The 3-20 membered heterocycloalkenyl is preferably

[0082] In a preferred embodiment of the present invention, when the R 2 Independently one or more R 2-1 When the substituted 3-10 membered heterocycloalkyl is a substituted 3-10 membered heterocycloalkyl, the 3-10 membered heterocycloalkyl is preferably a 3-7 membered heterocycloalkyl, and further preferably a 5 membered heterocycloalkyl; the heteroatom in the 3-10 membered heterocycloalkyl, the 3-7 membered heterocycloalkyl and the 5 membered heterocycloalkyl is preferably oxygen, and the number of the heteroatom is preferably 1.

[0083] In a preferred embodiment of the present invention, when the R 2-1 are independently one or more hydroxy-substituted C 1-6 When the C 1-6 The alkyl group is preferably C 1-4 Alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, most preferably methyl. 1-6 The alkyl group is preferably -CH2OH.

[0084] In a preferred embodiment of the present invention, the one or more R 2-1 The substituted 3-10 membered heterocycloalkyl group is preferably

[0085] In a preferred embodiment of the present invention, when said R is one or more R 2 When the 3-20 membered heterocycloalkenyl is substituted, one or more of the R 2 The substituted 3-20 membered heterocycloalkenyl group is preferably

[0086] In a preferred embodiment of the present invention, when R is a 5-20 membered heteroaryl group, the 5-20 membered heteroaryl group is preferably a 5-10 membered heteroaryl group, and is further preferably a 5-membered heteroaryl group or a 6-membered heteroaryl group; the heteroatoms in the 5-20 membered heteroaryl group, the 5-10 membered heteroaryl group, the 5-membered heteroaryl group and the 6-membered heteroaryl group are preferably nitrogen or sulfur, and the number of heteroatoms is preferably 1 or 2. When R is a 5-membered heteroaryl group, the heteroatoms in the 5-membered heteroaryl group are preferably sulfur, and the number of heteroatoms is preferably 1. When R is a 6-membered heteroaryl group, the heteroatoms in the 6-membered heteroaryl group are preferably nitrogen, and the number of heteroatoms is preferably 2. The 5-20 membered heteroaryl group is preferably

[0087] In a preferred embodiment of the present invention, when said R is one or more R 3 Substituted C 1-10 When the C 1-10 The alkyl group is preferably C 1-4 The alkyl group is more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group, and most preferably a methyl group or an ethyl group.

[0088] In a preferred embodiment of the present invention, when the R 3 are independently -(C=O)OR 3-1 When the R 3-1 Preferred is hydrogen.

[0089] In a preferred embodiment of the present invention, when R 3-1 C 1-6 When the C 1-6 The alkyl group is preferably C 1-4 The alkyl group is more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group.

[0090] In a preferred embodiment of the present invention, the R 3-2 and R 3-3 Preferably, C 1-4 The alkyl group is more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, and most preferably ethyl.

[0091] In a preferred embodiment of the present invention, when R 3-4 -(CH2) m O(CH2) n When OH, m and n are independently preferably 2.

[0092] In a preferred embodiment of the present invention, when R 3-4 C is substituted with one or more halogens 6-20 When the C 6-20 The aryl group is preferably C6-14 Aryl, more preferably phenyl, naphthyl or anthracenyl, most preferably phenyl; the halogen is preferably fluorine, chlorine, bromine or iodine, more preferably chlorine. The one or more halogen-substituted C 6-20 The aryl group is preferably

[0093] In a preferred embodiment of the present invention, when the R 3 When the 5-20 membered heteroaryl is independently substituted by one or more amino groups, the 5-20 membered heteroaryl is preferably a 6-12 membered heteroaryl, and more preferably a 9 membered heteroaryl; the heteroatom in the 5-20 membered heteroaryl, the 6-12 membered heteroaryl and the 9 membered heteroaryl is preferably nitrogen, and the number of heteroatoms is preferably 4. The 5-20 membered heteroaryl is preferably The one or more amino-substituted 5-20 membered heteroaryl groups are preferably

[0094] In a preferred embodiment of the present invention, the one or more R 3 Substituted C 1-10 The alkyl group is preferably

[0095] In a preferred embodiment of the present invention, when R is C 1-10 When the C 1-10 The alkyl group is preferably C 1-4 The alkyl group is more preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a tert-butyl group.

[0096] In a preferred embodiment of the present invention, when R is C 3-10 When cycloalkyl, the C 3-10 The cycloalkyl group is preferably C 4-7 The cycloalkyl group is more preferably cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and most preferably cyclopentyl.

[0097] In a preferred embodiment of the present invention, R is one or more R 1 Substituted C 6-20 Aryl, C 6-20 Aryl, one or more R 2 substituted 3-20 membered heterocycloalkenyl, 5-20 membered heteroaryl, one or more R 3 Substituted C 1-10 Alkyl, or C 3-10 Cycloalkyl; the heteroatoms in the 5-20 membered heteroaryl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; the one or more R 2The heteroatoms in the substituted 3-20 membered heterocycloalkenyl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4;

[0098] R 1 Independently for C 1-6 Alkoxy, one or more halogen-substituted C 1-6 Alkyl, or halogen;

[0099] R 2 Independently one or more R 2-1 substituted 3-10 membered heterocycloalkyl or oxo, wherein one or more R 2-1 The heteroatoms in the substituted 3-10 membered heterocycloalkyl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; R 2-1 are independently hydroxy or one or more hydroxy-substituted C 1-6 alkyl;

[0100] R 3 are independently -(C=O)OR 3-1 、-NR 3-2 R 3-3 、-OR 3-4 , or "5-20 membered heteroaryl substituted with one or more amino groups"; R 3-1 is hydrogen; R 3-2 and R 3-3 Independently for C 1-6 Alkyl; R 3-4 -(CH2) m O(CH2) n OH, or one or more halogen-substituted C 6-20 Aryl, m and n are independently 1, 2, 3 or 4; the heteroatoms in the one or more amino-substituted 5-20 membered heteroaryl groups are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4.

[0101] In a preferred embodiment of the present invention, R is preferably one or more R 1 Substituted C 6-14 Aryl, C 6-20 Aryl, one or more R 2 substituted 3-10 membered heterocycloalkenyl, 5-10 membered heteroaryl, one or more R 3 Substituted C 1-4 Alkyl, or C 4-7 Cycloalkyl; said one or more R 2The heteroatoms in the substituted 3-10 membered heterocycloalkenyl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; the heteroatoms in the 5-10 membered heteroaryl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4.

[0102] In a preferred embodiment of the present invention, R 1 Preferably, C 1-4 Alkoxy, or "one or more halogen-substituted C 1-4 alkyl".

[0103] In a preferred embodiment of the present invention, R 2 Preferably, one or more R 2-1 substituted 3-7 membered heterocycloalkyl or oxo, wherein one or more R 2-1 The heteroatoms in the substituted 3-7 membered heterocycloalkyl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; R 2-1 are independently hydroxy or one or more hydroxy-substituted C 1-4 alkyl.

[0104] In a preferred embodiment of the present invention, R 3 Preferably, NR 3-2 R 3-3 、-OR 3-4 , or "a 6-12 membered heteroaryl group substituted with one or more amino groups"; R 3-2 and R 3-3 Independently for C 1-4 Alkyl; R 3-4 -(CH2) m O(CH2) n OH, or one or more halogen-substituted C 6-14 Aryl, m and n are independently 1, 2, 3 or 4; the heteroatoms in the one or more amino-substituted 6-12 membered heteroaryl groups are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4.

[0105] In a preferred embodiment of the present invention, R is one or more R 1 Substituted C 6-14 Aryl, C 6-20 Aryl, one or more R 2 substituted 3-10 membered heterocycloalkenyl, 5-10 membered heteroaryl, one or more R 3 Substituted C 1-4 Alkyl, or C 4-7 Cycloalkyl; said one or more R 2The heteroatoms in the substituted 3-10 membered heterocycloalkenyl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; the heteroatoms in the 5-10 membered heteroaryl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4;

[0106] R 1 Independently for C 1-4 Alkoxy, or "one or more halogen-substituted C 1-4 alkyl";

[0107] R 2 Independently one or more R 2-1 substituted 3-7 membered heterocycloalkyl or oxo, wherein one or more R 2 -1 The heteroatoms in the substituted 3-7 membered heterocycloalkyl are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4; R 2-1 are independently hydroxy or one or more hydroxy-substituted C 1-4 alkyl;

[0108] R 3 Independently for NR 3-2 R 3-3 、-OR 3-4 , or "a 6-12 membered heteroaryl group substituted with one or more amino groups"; R 3-2 and R 3-3 Independently for C 1-4 Alkyl; R 3-4 -(CH2) m O(CH2) n OH, or one or more halogen-substituted C 6-14 Aryl, m and n are independently 1, 2, 3 or 4; the heteroatoms in the one or more amino-substituted 6-12 membered heteroaryl groups are selected from one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is 1, 2, 3 or 4.

[0109] In a preferred embodiment of the present invention, the R is preferably one or more R 3 Substituted C 1-10 Alkyl; said R 3 Preferably -OR 3-4 ; The R 3-4 Preferably one or more halogen-substituted C 6-20 Aryl.

[0110] In a preferred embodiment of the present invention, the compound as shown in formula I is preferably any of the following compounds:

[0111]

[0112]

[0113] The present invention also provides a method for preparing a compound as shown in formula I, which comprises the following steps: in a solvent, under the action of a catalyst and a ligand, subjecting a compound as shown in formula III and a compound as shown in formula IV to a cycloaddition reaction as shown below:

[0114]

[0115] Wherein, R is as defined above.

[0116] In the method for preparing the compound as shown in Formula I, the solvent can be a conventional solvent for this type of reaction in the art. The present invention particularly preferably uses a mixed solvent of a sulfoxide solvent and water, further preferably a mixed solvent of dimethyl sulfoxide and water, and most preferably a mixed solvent of dimethyl sulfoxide and water in a volume ratio of 33:17.

[0117] In the preparation method of the compound as shown in Formula I, the catalyst can be a conventional catalyst for such reactions in the art, and the present invention is particularly preferably a Cu(I) compound, and further preferably cuprous sulfate. The Cu(I) compound is preferably obtained by a reduction reaction of a Cu(II) compound and a reducing agent. The reducing agent is preferably sodium ascorbate. The molar ratio of the Cu(II) compound to the reducing agent is preferably 1:25. The reduction reaction is preferably carried out in the same reaction system as the cycloaddition reaction.

[0118] In the method for preparing the compound of formula I, the molar ratio of the catalyst to the compound of formula III can be a conventional molar ratio for this type of reaction in the art, and is particularly preferably 1:1 to 1:30, and further preferably 1:5 to 1:10.

[0119] In the method for preparing the compound as shown in Formula I, the ligand can be a conventional ligand for this type of reaction in the art, and tris[(1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)methyl]amine is particularly preferred in the present invention.

[0120] In the method for preparing the compound of formula I, the molar ratio of the ligand to the compound of formula III can be a conventional molar ratio for this type of reaction in the art, and is particularly preferably 1:1 to 1:30, and further preferably 1:1 to 1:5 (e.g. 2:5).

[0121] In the method for preparing the compound of formula I, the molar concentration of the compound of formula III in the solvent may be the conventional molar concentration for this type of reaction in the art, and is particularly preferably 0.001 to 1 mol / L, and further preferably 0.005 to 0.05 mol / L (e.g. 0.01 mol / L).

[0122] In the method for preparing the compound of formula I, the molar ratio of the compound of formula IV to the compound of formula III can be a conventional molar ratio for this type of reaction in the art, and is particularly preferably 1:1 to 1:10, and further preferably 1:1 to 1:5 (e.g. 1:1).

[0123] In the method for preparing the compound of formula I, the reaction temperature of the reaction can be a conventional reaction temperature for this type of reaction in the art, and is particularly preferably 20 to 25°C in the present invention.

[0124] In the method for preparing the compound of formula I, the progress of the reaction can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the disappearance of the vancomycin hydrochloride is generally used as the reaction endpoint. The reaction time of the reaction is particularly preferably 6 to 24 hours, and more preferably 10 to 15 hours (such as 12 hours).

[0125] In a preferred embodiment of the present invention, the method for preparing the compound as shown in formula I comprises the following steps: mixing the compound as shown in formula III, the compound as shown in formula IV, the ligand, the reducing agent, the Cu(II) compound and the solvent for reaction.

[0126] The present invention provides a compound as shown in formula III, a pharmaceutically acceptable salt, an enantiomer, a solvate, or a solvate of a pharmaceutically acceptable salt thereof,

[0127]

[0128] The present invention also provides a compound as shown in formula III or a pharmaceutically acceptable salt thereof,

[0129]

[0130] The present invention also provides a method for preparing a compound as shown in formula III, which comprises the following steps: in a solvent, vancomycin hydrochloride, a base and fluorosulfonyl azide are reacted as shown below:

[0131]

[0132] In a preferred embodiment of the present invention, in the method for preparing the compound shown in Formula III, the solvent can be a conventional solvent for such reactions in the art, and the present invention particularly preferably comprises a mixed solvent of a sulfoxide solvent, water and an ether solvent. The sulfoxide solvent is preferably dimethyl sulfoxide. The ether solvent is preferably methyl tert-butyl ether. The solvent is preferably a mixed solvent of dimethyl sulfoxide, water and methyl tert-butyl ether.

[0133] In a preferred embodiment of the present invention, in the method for preparing the compound of formula III, the molar concentration of vancomycin hydrochloride in the solvent may be the conventional molar concentration for such reactions in the art, and is particularly preferably 0.01 to 1 mol / L, and further preferably 0.03 to 0.1 mol / L (e.g., 0.056 mol / L).

[0134] In a preferred embodiment of the present invention, in the method for preparing the compound of formula III, the base can be a conventional base for this type of reaction in the art, and bicarbonate is particularly preferred in the present invention, and potassium bicarbonate is further preferred.

[0135] In a preferred embodiment of the present invention, in the method for preparing the compound of formula III, the molar ratio of the base to the vancomycin hydrochloride can be a conventional molar ratio for such reactions in the art, and is particularly preferably 1:1 to 1:10, and further preferably 1:2 to 1:5 (e.g. 1:4).

[0136] In a preferred embodiment of the present invention, in the method for preparing the compound of formula III, the molar ratio of the fluorosulfonyl azide to the vancomycin hydrochloride can be a conventional molar ratio for such reactions in the art, and is particularly preferably 10:1 to 1:1, and further preferably 3:1 to 1:1 (e.g., 1.5:1).

[0137] In a preferred embodiment of the present invention, in the method for preparing the compound of formula III, the reaction temperature of the reaction can be the conventional reaction temperature of this type of reaction in the art, and room temperature is particularly preferred in the present invention.

[0138] In a preferred embodiment of the present invention, in the method for preparing the compound as shown in Formula III, the progress of the reaction can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the disappearance of the vancomycin hydrochloride is generally used as the reaction endpoint. The reaction time of the reaction is particularly preferably 1 to 8 hours, and more preferably 1 to 3 hours (such as 1.5 hours).

[0139] In a preferred embodiment of the present invention, the method for preparing the compound as shown in Formula III comprises the following steps: mixing the vancomycin hydrochloride, the base, the fluorosulfonyl azide and the solvent for reaction.

[0140] In a preferred embodiment of the present invention, the method for preparing the compound as shown in Formula III may further include a post-treatment step. The post-treatment step is preferably washing the reaction solution with n-hexane, slowly adding the washed reaction solution to vigorously stirred acetone at room temperature, separating the precipitated insoluble pink solid, drying it in the air, crushing it into powder, adding distilled water to the powder, stirring, standing, separating, washing, standing to dry, crushing it into powder, adding acetone to stir, separating the solid, washing it with acetone, and draining it.

[0141] The present invention also provides a pharmaceutical composition, which contains a therapeutically effective dose of substance X' or substance Z', and a pharmaceutically acceptable carrier;

[0142] The substance X' is a compound as shown in I, a pharmaceutically acceptable salt, enantiomer, solvate, or a solvate of a pharmaceutically acceptable salt thereof;

[0143] The substance Z' is a compound as shown in III, or a pharmaceutically acceptable salt, enantiomer, solvate, or solvate of a pharmaceutically acceptable salt thereof.

[0144] The present invention also provides a use of the substance X', the substance Z' or the pharmaceutical composition in preparing a drug for treating related diseases caused by MRSA.

[0145] The present invention also provides a pharmaceutical composition, which contains a therapeutically effective dose of substance X or substance Z, and a pharmaceutically acceptable carrier;

[0146] The substance X is a compound as shown in I or a pharmaceutically acceptable salt thereof;

[0147] The substance Z is a compound as shown in III or a pharmaceutically acceptable salt thereof.

[0148] The present invention also provides a use of the substance X, the substance Z or the pharmaceutical composition in preparing a drug for treating related diseases caused by MRSA.

[0149] The related diseases caused by MRSA are preferably pneumonia, endocarditis or sepsis.

[0150] In the present invention, the term "heterocycloalkyl" refers to a non-aromatic, saturated, monovalent cyclic hydrocarbon group in which at least one ring carbon atom in a cycloalkyl group is replaced by a heteroatom selected from N, O and S. The heterocycloalkyl group can be connected to other parts in the molecule through a heteroatom or a carbon atom therein.

[0151] In the present invention, the term "heterocycloalkenyl" refers to a cyclic non-aromatic unsaturated monovalent hydrocarbon group having a specified number of ring atoms and at least one double bond, wherein at least one ring atom is a heteroatom selected from N, O and S. The heterocycloalkenyl group can be connected to other parts in the molecule through a heteroatom or a carbon atom therein.

[0152] In the present invention, the term "alkylene" includes alkylene, alkenylene, alkynylene, arylene, cycloalkylene, cycloalkenylene, cycloalkynylene.

[0153] In the present invention, the term "alkylene" refers to a saturated straight-chain divalent hydrocarbon group having a specified number of carbon atoms.

[0154] In the present invention, the term "cycloalkylene group" refers to a saturated cyclic divalent hydrocarbon group having a specified number of carbon atoms.

[0155] In the present invention, the term "alkenylene" refers to a straight-chain divalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon double bond, wherein the carbon-carbon double bond may be located at any position within the alkenylene group.

[0156] In the present invention, the term "cycloalkenylene" refers to a cyclic divalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon double bond, wherein the carbon-carbon double bond may be located at any position within the cycloalkenylene group.

[0157] In the present invention, the term "alkynylene" refers to a straight-chain divalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon triple bond, wherein the carbon-carbon triple bond may be located at any position within the alkynylene group.

[0158] In the present invention, the term "cycloalkynylene" refers to a cyclic divalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon triple bond, wherein the carbon-carbon triple bond may be located at any position within the cycloalkynylene group.

[0159] In the present invention, the term "arylene group" refers to a divalent aromatic group.

[0160] In the present invention, the term "heteroalkylene" includes an alkylene group having at least one atom which is a heteroatom selected from N, O and S. The heteroalkylene group may be linked to other parts in the molecule through a heteroatom or a carbon atom therein.

[0161] In the present invention, the term "heterocycloalkyl" refers to a non-aromatic saturated monovalent cyclic hydrocarbon group in which at least one ring carbon atom in a cycloalkyl group is replaced by a heteroatom selected from N, O and S. The heterocycloalkyl group can be connected to other parts in the molecule through a heteroatom or a carbon atom therein.

[0162] In the present invention, the term "oxo group" refers to a case where an oxygen atom directly serves as a substituent of a carbon atom or a nitrogen atom, for example, forming a carbonyl group with a carbon atom, forming a nitrogen oxide with a nitrogen atom, and the like.

[0163] In the present invention, the term "therapeutically effective dose" refers to the amount of a compound that is sufficient to effectively treat a disease or condition described herein when administered to a subject. Although the amount of a compound that constitutes a "therapeutically effective dose" will vary depending on the compound, the condition and its severity, and the age of the subject to be treated, it can be determined in a routine manner by those skilled in the art.

[0164] The terms "compound", "pharmaceutically acceptable salt", "enantiomer", "solvate" and "solvate of a pharmaceutically acceptable salt" may exist in crystalline or amorphous form. The term "crystalline form" means that the ions or molecules therein are arranged in a strictly periodic manner in three-dimensional space in a certain manner and have a regularity of periodic repetition at a certain distance; due to the different periodic arrangements mentioned above, there may be multiple crystalline forms, i.e., polymorphism. The term "amorphous form" means that the ions or molecules therein are in a disorderly distribution state, i.e., there is no periodic arrangement between the ions and molecules.

[0165] The term "solvate" refers to a substance formed by the combination of a compound of the present invention and a stoichiometric or non-stoichiometric solvent. The solvent molecules in the solvate may exist in an ordered or non-ordered arrangement. The solvent includes, but is not limited to, water, methanol, ethanol, etc.

[0166] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0167] The reagents and raw materials used in the present invention are commercially available.

[0168] The positive and progressive effect of the present invention is that the compound of the present invention has a good antibacterial effect and can treat related diseases caused by MRSA. DETAILED DESCRIPTION

[0169] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0170] Fluorosulfonyl azide application example 1

[0171]

[0172] Prepare a solution of fluorosulfonyl azide (FSO2N3) in methyl tert-butyl ether (about 20 ml) and dilute it into dimethyl sulfoxide (DMSO, 20 ml). Take a known volume of the resulting solution and add a known number of moles of an internal standard. By 19 The concentration of fluorosulfonyl azide (FSO2N3, δ+62.6ppm) in the diluted solution was calculated to be 97mM based on the integral ratio of the signal of fluorosulfonyl azide (FSO2N3, δ+62.6ppm) and the internal standard (δ+37.8ppm) in F NMR. The diluted fluorosulfonyl azide (FSO2N3) solution can be directly used in the following diazo transfer reaction of primary amine.

[0173] At room temperature (25°C), R'-NH2 (100mM DMSO solution, 100μl, containing 10μmol R'-NH2) (see the table below for details), fluorosulfonyl azide (97mM solution, solvent is DMSO / MTBE 1:1, 103μl, containing 10μmol FSO2N3), potassium bicarbonate aqueous solution (3.0M, 13.3μl, 40μmol) were added to each well of a 96-well plate in sequence. The 96-well plate was sealed with a film and shaken at 600rpm for 1 hour at 25°C to obtain the azide compound R'-N3 corresponding to each primary amine R'-NH2.

[0174] After shaking for one hour, the reaction solution in each well was diluted to 1 ml with acetonitrile / methanol mixed solvent, and the insoluble matter was removed by filter membrane and then detected by LC-MS (Waters ACQUITY UPLC H-Class system and ACQUITY QDa mass spectrometer detector (eluent: 0.1% trifluoroacetic acid aqueous solution and acetonitrile). [Method: 7000 psi, flow rate = 0.6 ml / min. t = 0 min, 95% H2O; t = 0.10 min, 95% H2O; t = 1.20 min, 5% H2O; t = 2.00 min, 5% H2O; t = 2.50 min, 95% H2O. Total aquisition time = 2.50 min.], stationary phase model ACQUITY BEHC18 1.7μm). Some raw material substrates, products and their LC-MS analysis data are as follows:

[0175]

[0176]

[0177] Example 1 Synthesis of Vancomycin Azide

[0178]

[0179] In a 20 ml glass bottle, vancomycin hydrochloride (compound 3, 742 mg, 0.5 mmol; 90% purity) was dissolved in dimethyl sulfoxide (5 ml), followed by addition of potassium bicarbonate aqueous solution (3 M, 0.67 ml) and fluorosulfonyl azide solution (500 mM, 1.5 ml, containing 0.75 mmol fluorosulfonyl azide, solvent: methyl tert-butyl ether). The reaction solution was stirred at room temperature for 90 minutes, during which LC-MS detection was used. After the reaction was completed, the reaction solution was washed with n-hexane (8 ml × 3). The washed reaction solution was slowly added to vigorously stirred acetone (125 ml) at room temperature. The precipitated insoluble pink solid (992 mg) was separated by suction filtration, placed in air at room temperature for 20 minutes to dry, and lightly crushed into powder using a mortar. Distilled water (4 ml) was added to the powder, stirred at room temperature for 20 minutes, and then allowed to stand at 4°C for 2 hours. The solid in the mixture was separated by suction filtration and washed with distilled water (2 ml), left to stand in the air at room temperature for 2 hours to dry, then lightly crushed into powder, added with acetone (15 ml) and stirred at room temperature for 20 minutes. The solid was separated by suction filtration and washed with acetone (10 ml), and the target product 1 (496 mg, 67%) was obtained as a beige solid, which decomposed at 230°C.

[0180] 1H NMR(400MHz,(CD3)2CO)δ9.69-9.36(br,2H),9.16-8.91(br,2H),8.60(br,1H),8.41(br,1H),8.19(br,1H),7.87(s,1H),7.80(br,1H),7.51(d,J=7.9Hz,1H),7.46(d,J=8.0Hz,1H),7.42-7.14(m,5H),6.88(br,1H),6.82-6.54(m,4H),6.36(s,2H),6.07(br,1H),5.83(br,1H),5.73(d,J=7.1Hz,1H),5.54(s,1H),5.43(br,1H),5.37-5.24(m,3H),5.20(s,1H),5.18-5.09(m,2H),5.03(d,J=6.4Hz,1H),4.87(br,1H),4.65(m,1H),4.44(br,1H),4.38(d,J=5.1Hz,2H),4.23-4.05(m,2H),3.72-3.64(m,2H),3.60-3.44(m,6H),3.15(d,J=6.0Hz,1H),3.06(t,J=7.2Hz,1H),2.37(br,1H),2.31(s,3H),2.16(br,1H),1.78-1.63(m,2H),1.53-1.36(m,2H),1.22(s,3H),1.05(d,J=5.6Hz,3H),0.90(d,J=6.4Hz,3H),0.85(d,J=6.4Hz,3H); 13C NMR (101MHz, (CD3)2CO) δ174.5,173.2,171.0,170.9,169.8,169.3,167.5,167.4,157.2,156.3,155.2,152.2,151.4,150. 0,148.3,142.6,139.9,137.5,135.8,134.4,132.0,128.8,127.5,127.4,127.3,127.2,126.3,126.2,125.4,124.4,123.4 ,122.1,118.0,116.2,107.2,106.5,104.7,102.1,101.1,97.4,78.1,77.1,76.8,73.8,71.6,71.1,70.3,64.4,62.4,62.2 ,61.9,61.3,58.3,57.7,55.0,53.8,51.0,41.1,33.8,33.1,33.0,24.3,24.0,23.1,22.5,17.2.HRMS(ESI-TOF,m / z):calcd forC 66 H 74 O 24 N 11 Cl2:1474.4280[M+H] + ,found:1474.4280.

[0181] Example 2

[0182]

[0183] Dimethyl sulfoxide (18 μL), water (7 μL), vancomycin-derived azide (compound 1, 50 mM solution, solvent is dimethyl sulfoxide, 10 μL, containing 0.5 μmol compound 1), corresponding terminal alkyne substrate (compound 4, 100 mM, solvent is dimethyl sulfoxide, 5 μL, containing 0.5 μmol terminal alkyne), copper sulfate and tris[(1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)methyl]amine (TH) were added to a 1.5 ml reaction tube in sequence. A mixed aqueous solution of 500 mM THPTA (5 μL, containing 0.1 μmol copper sulfate and 0.2 μmol THPTA) and an aqueous solution of sodium ascorbate (500 mM, 5 μL, containing 2.5 μmol sodium ascorbate) was shaken on a shaker at room temperature for 12 hours. After the reaction, the reaction solution was directly diluted to obtain a solution containing the corresponding vancomycin-derived 1,2,3-triazole compounds (i.e., compounds 2-1 to 2-4, 2-7 to 2-17) (as shown in Tables 1 and 2) for biological activity testing.

[0184] Table 1

[0185]

[0186]

[0187] Table 2

[0188]

[0189] Example 3 Biological Activity Test

[0190] MRSA USA300 bacteria were diluted with MH medium to a concentration of 1*10 5 CFU / mL, add 120μL of bacterial suspension to each well of a 96-well plate, then add different concentrations of compounds (the compound concentration is diluted from 100μM in a 2-fold gradient), and set up three replicate wells for each compound at different concentrations. After culturing in a 37℃ incubator for 18h, use an ELISA reader to test the absorbance value. The concentration at which bacteria do not significantly proliferate is the minimum inhibitory concentration (MIC).

[0191] The MIC data of compounds 1, 2-1 to 2-4, 2-7 to 2-17 obtained in Examples 1 and 2 are as follows, and the blank control item is the reaction solution prepared according to Example 2 but without compound 1 and terminal alkyne substrate. The test results are shown in Table 3.

[0192] Table 3 Minimum inhibitory concentration of compounds 1, 2-1 to 2-4, 2-7 to 2-17 against MRSA bacteria

[0193] Compound No. MIC(μM) 2-1 3.13 2-2 3.13 2-3 3.13 2-4 3.13 2-7 3.13 2-8 3.13 2-9 0.0977 2-10 3.13 2-11 1.56 2-12 6.25 2-13 3.13 2-14 3.13 1 3.13 Blank control >100 Vancomycin 0.781

[0194] Example 4 Biological Activity Test

[0195] MRSAATCC43300 bacteria (from ATCC) were diluted with MH medium to a concentration of 1*10 5 CFU / mL, add 120μL of bacterial suspension to each well of a 96-well plate, then add different concentrations of compounds (the compound concentration is diluted from 100μM in a 2-fold gradient), and set up three replicate wells for each compound at different concentrations. After culturing in a 37℃ incubator for 18h, use an ELISA reader to test the absorbance value. The concentration at which bacteria do not significantly proliferate is the minimum inhibitory concentration (MIC).

[0196] The MIC data of compounds 2-9, 2-15 to 2-17 obtained in Example 2 are as follows. The test results are shown in Table 4.

[0197] Table 4 Minimum inhibitory concentration of compounds 2-9, 2-15 to 2-17 against MRSA bacteria

[0198]

[0199]

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt thereof, in, R is one or more R 3 Substituted C 1-10 Alkyl; R 3 For-OR 3-4 ; R 3-4 is phenyl substituted with one or more halogens.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The C 1-10 Alkyl is C 1-4 alkyl; Or, the halogen is fluorine, chlorine, bromine or iodine.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: The C 1-10 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; Or, the halogen is fluorine, chlorine or iodine.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound as shown in formula I is any of the following compounds:

5. A method for preparing a compound of formula I according to any one of claims 1 to 4, characterized in that: It includes the following steps: In a solvent, under the action of a catalyst and a ligand, the compound represented by formula III and the compound represented by formula IV are subjected to a cycloaddition reaction as shown below:

6. The method for preparing the compound of formula I as claimed in claim 5, characterized in that: The solvent is a mixed solvent of a sulfoxide solvent and water; Or, the catalyst is a Cu(I) compound; Or, the molar ratio of the catalyst to the compound represented by formula III is 1:1 to 1:30; Or, the ligand is tris[(1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)methyl]amine; Or, the molar ratio of the ligand to the compound of formula III is 1:1 to 1:30; Or, the molar concentration of the compound represented by formula III in the solvent is 0.001 to 1 mol / L; Or, the molar ratio of the compound represented by formula IV to the compound represented by formula III is 1:1 to 1:10; Or, the reaction temperature of the reaction is 20-25°C; Alternatively, the reaction time of the reaction is 6 to 24 hours.

7. The method for preparing the compound of formula I according to claim 6, characterized in that: The solvent is a mixed solvent of dimethyl sulfoxide and water; Or, the Cu(I) compound is cuprous sulfate; Or, the molar ratio of the catalyst to the compound represented by formula III is 1:5 to 1:10; Or, the molar ratio of the ligand to the compound of formula III is 1:1 to 1:5; Or, the molar concentration of the compound represented by formula III in the solvent is 0.005-0.05 mol / L; Or, the molar ratio of the compound represented by formula IV to the compound represented by formula III is 1:1 to 1:5; Alternatively, the reaction time of the reaction is 10 to 15 hours.

8. The method for preparing the compound of formula I according to claim 7, characterized in that: The solvent is dimethyl sulfoxide and water in a volume ratio of 33:17; Alternatively, the Cu(I) compound is obtained by a reduction reaction between a Cu(II) compound and a reducing agent.

9. The method for preparing the compound of formula I as claimed in claim 8, characterized in that: The reducing agent is sodium ascorbate.

10. The method for preparing the compound of formula I according to claim 9, characterized in that: The molar ratio of the Cu(II) compound to the reducing agent is 1:

25.

11. The method for preparing the compound of formula I according to claim 10, characterized in that: The reduction reaction and the cycloaddition reaction are carried out in the same reaction system.

12. A compound of formula III or a pharmaceutically acceptable salt thereof, 13. A method for preparing the compound of formula III as claimed in claim 12, characterized in that: It includes the following steps: In a solvent, vancomycin hydrochloride, a base and fluorosulfonyl azide are reacted as shown below:

14. The method for preparing the compound of formula III as claimed in claim 13, characterized in that: The solvent is a mixed solvent of sulfoxide solvent, water and ether solvent; Or, the molar concentration of the vancomycin hydrochloride in the solvent is 0.01 to 1 mol / L; Or, the base is bicarbonate; Or, the molar ratio of the base to the vancomycin hydrochloride is 1:1 to 1:10; Or, the molar ratio of the fluorosulfonyl azide to the vancomycin hydrochloride is 10:1 to 1:1; Or, the reaction temperature of the reaction is 20-25°C; Alternatively, the reaction time of the reaction is 1 to 8 hours.

15. The method for preparing the compound of formula III as claimed in claim 14, characterized in that: The sulfoxide solvent is dimethyl sulfoxide; Or, the ether solvent is methyl tert-butyl ether; Or, the solvent is a mixed solvent of dimethyl sulfoxide, water and methyl tert-butyl ether; Or, the molar concentration of the vancomycin hydrochloride in the solvent is 0.03-0.1 mol / L; Or, the base is potassium bicarbonate; Or, the molar ratio of the base to the vancomycin hydrochloride is 1:2 to 1:5; Or, the molar ratio of the fluorosulfonyl azide to the vancomycin hydrochloride is 3:1 to 1:1; Alternatively, the reaction time of the reaction is 1 to 3 hours.

16. A pharmaceutical composition comprising a therapeutically effective dose of substance X' or substance Z' and a pharmaceutically acceptable carrier; The substance X' is a compound of formula I as described in any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof; The substance Z' is a compound as shown in formula III as claimed in claim 12 or a pharmaceutically acceptable salt thereof.

17. Use of a substance X', a substance Z' or a pharmaceutical composition as claimed in claim 16 in the preparation of a drug for treating a disease caused by MRSA; The substance X' is a compound of formula I as described in any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof; The substance Z' is a compound as shown in formula III as claimed in claim 12 or a pharmaceutically acceptable salt thereof.

18. The use according to claim 17, wherein the disease caused by MRSA is pneumonia, endocarditis or sepsis.

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