Sulfonyl-containing compounds, their preparation and use

Abstract

The present application provides compounds containing sulfonyl groups and their preparation and use. The compounds are of the formula (I). The compounds of the present application exhibit superior anti-MTB activity over S31-201. At the same time, the compounds of the present application exhibit higher in vitro safety relative to S31-201. (I).

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and more specifically, to a compound containing a sulfonyl group, its preparation, and its application. Background Technology

[0002] Para-aminosalicylic acid is a small molecule compound with various biological activities, including antitumor and antibacterial effects. It was once a first-line drug for treating drug-resistant Mycobacterium tuberculosis (MTB) infection and remains a key focus in anti-tuberculosis drug development. Sulfonic acid compounds (including p-toluenesulfonic acid) possess potent and broad-spectrum pharmacological activities and are currently key structural units in drug design. This invention, through screening a compound library for anti-MTB activity, has for the first time discovered a compound containing both para-aminosalicylic acid and p-toluenesulfonic acid structural units. S31-201 (structure shown below) exhibits certain in vitro anti-MTB activity.

[0003]

[0004] S31-201

[0005] Based on this, a series of N-alkyl-substituted p-aminosalicylic acid compounds or O-alkyl-substituted toluenesulfonic acid compounds were designed and synthesized through structural modification, exhibiting anti-MTB activity comparable to S31-201. More importantly, all compounds showed good in vitro safety. Summary of the Invention

[0006] One object of the present invention is to provide a compound containing a sulfonyl group;

[0007] Another object of the present invention is to provide a method for preparing the compound containing a sulfonyl group;

[0008] Another object of the present invention is to provide the application of the sulfonyl group-containing compound.

[0009] To achieve the above objectives, in one respect, the present invention provides a compound containing a sulfonyl group as shown in formula (I), its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof:

[0010] (I)

[0011] Wherein, R1 is selected from C1-10 straight-chain or branched alkyl, 4- to 14-membered aryl, or 3- to 10-membered cycloalkyl; optionally, the alkyl, aryl, or cycloalkyl is replaced by 1, 2, or 3 substituents selected from F, Cl, Br, I, halogen, nitro, hydroxyl, carboxyl, cyano, C1-6 straight-chain or branched alkyl, or halo-C1-6 straight-chain or branched alkyl; optionally, one or two CH2 groups on the carbon chain of the alkyl are replaced by O or S;

[0012] R2 and R3 may be the same or different, and are each independently selected from OH, NH2, nitro, carboxyl, C1-10 alkoxy, 4- to 10-membered cycloalkyl, 4- to 14-membered aryl, -C(O)O-C1-10 alkyl, -OC(O)-C1-10 alkyl or -C(O)NH2; optionally, the alkyl, cycloalkyl, alkoxy or aryl group is substituted by a substituent selected from F, Cl, Br, I, OH, C1-6 straight-chain or branched alkyl.

[0013] Optionally, R2 and R3 together with the C atoms attached to them form a 3- to 10-membered unsaturated heterocycle; optionally, the heterocycle is substituted by 1, 2 or 3 substituents selected from F, Cl, Br, I, OH, oxy, nitro, carboxyl, cyano, C1-6 straight-chain or branched alkyl; the heterocycle contains 1 or 2 heteroatoms selected from N, O or S;

[0014] R4, R5, and R6 may be the same or different, each independently selected from H, halogens, or C1-6 alkyl groups; optionally, the alkyl group is substituted with at least one F, Cl, Br, or I.

[0015] L1 and L2 may be the same or different, and each is independently selected from O, S, CH2 or NH;

[0016] n1 is a positive integer from 1 to 4;

[0017] The condition is that the compound shown in formula (I) is not:

[0018] .

[0019] According to some specific embodiments of the present invention, wherein,

[0020] R2 is selected from carboxyl, -C(O)O-C1-10 alkyl, -OC(O)-C1-10 alkyl or -C(O)NH2; optionally, the alkyl group is substituted with a substituent selected from F, Cl, Br, I, OH, C1-6 straight-chain or branched alkyl group;

[0021] R3 is selected from OH, NH2, nitro, carboxyl, C1-10 alkoxy, 4- to 10-membered cycloalkyl, 4- to 14-membered aryl, -C(O)O-C1-10 alkyl, -OC(O)-C1-10 alkyl or -C(O)NH2; optionally, the alkyl, cycloalkyl, alkoxy or aryl group is substituted with a substituent selected from F, Cl, Br, I, OH, C1-6 straight-chain or branched alkyl.

[0022] Optionally, R2 and R3 together with the C atoms attached to them form a 3- to 10-membered unsaturated heterocycle; optionally, the heterocycle is substituted by 1, 2 or 3 substituents selected from F, Cl, Br, I, OH, oxy, nitro, carboxyl, cyano, C1-6 straight-chain or branched alkyl; the heterocycle contains 1 or 2 heteroatoms selected from N, O or S.

[0023] According to some specific embodiments of the present invention, R2 and R3 together with the C atoms connected to them form an unsaturated heterocyclic group selected from one of the following structures:

[0024] .

[0025] According to some specific embodiments of the present invention, the aryl group is selected from one of the following structures:

[0026] .

[0027] According to some specific embodiments of the present invention, wherein,

[0028] R1 is selected from C1-6 straight-chain or branched alkyl groups, 4- to 10-membered aryl groups, 3- to 8-membered cycloalkyl groups, or -(CH2). n R 11 Optionally, the alkyl, aryl, cycloalkyl, or alkylene group is substituted with one, two, or three substituents selected from F, Cl, Br, I, nitro, hydroxyl, carboxyl, cyano, or C1-6 straight-chain or branched alkyl, or halogenated C1-3 straight-chain or branched alkyl; optionally, the alkyl group or -(CH2) is substituted. n R 11 One or two CH2 atoms in the carbon chain are replaced by O or S;

[0029] R2 and R3 may be the same or different, and are each independently selected from OH, NH2, nitro, carboxyl, C1-6 alkoxy, 4- to 8-membered cycloalkyl, 4- to 10-membered aryl, -C(O)O-C1-6 alkyl, -OC(O)-C1-6 alkyl, or -C(O)NH2; optionally, the alkyl, cycloalkyl, alkoxy, or aryl group is selected from F, Cl, Br, I, OH, C 1-6 Substituted by substituents of straight-chain or branched alkyl groups;

[0030] Optionally, R2 and R3, together with the C atoms attached to them, form 3- to 8-membered unsaturated heterocycles; optionally, the heterocycle is surrounded by 1, 2, or 3 atoms selected from F, Cl, Br, I, OH, oxy, nitro, carboxyl, cyano, C 1-6 The heterocycle is substituted by a straight-chain or branched alkyl group; the heterocycle contains one or two heteroatoms selected from N, O or S;

[0031] R4, R5, and R6 may be the same or different, each independently selected from H, F, Cl, Br, I, or C1-3 alkyl groups; optionally, the alkyl group is substituted by at least one F, Cl, Br, or I group.

[0032] L1 and L2 may be the same or different, and each is independently selected from O, S, CH2 or NH;

[0033] n1 is 1, 2, 3 or 4;

[0034] n2 can be 1, 2, 3, 4 or 5.

[0035] According to some specific embodiments of the present invention, wherein,

[0036] R2 is selected from carboxyl, -C(O)O-C1-6 alkyl, or -C(O)NH2; optionally, the alkyl group is selected from F, Cl, Br, I, OH, C 1-6 Substituted by substituents of straight-chain or branched alkyl groups;

[0037] R3 is selected from OH, NH2, nitro, carboxyl, C1-6 alkoxy, 4- to 8-membered cycloalkyl, 4- to 10-membered aryl, -C(O)O-C1-6 alkyl, -OC(O)-C1-6 alkyl, or -C(O)NH2; optionally, the alkyl, cycloalkyl, alkoxy, or aryl group is selected from F, Cl, Br, I, OH, C 1-6 Substituted by substituents of straight-chain or branched alkyl groups;

[0038] Optionally, R2 and R3, together with the C atoms attached to them, form 3- to 8-membered unsaturated heterocycles; optionally, the heterocycle is surrounded by 1, 2, or 3 atoms selected from F, Cl, Br, I, OH, oxy, nitro, carboxyl, cyano, C 1-6 The heterocycle is substituted by a straight-chain or branched alkyl group; the heterocycle contains one or two heteroatoms selected from N, O or S.

[0039] According to some specific embodiments of the present invention, wherein,

[0040] R1 is selected from 6- to 10-membered aryl or 6- to 8-membered cycloalkyl; optionally, the aryl and cycloalkyl are substituted by 1, 2 or 3 substituents selected from F, Cl, Br, I, nitro, hydroxyl, carboxyl, cyano, C1-3 straight-chain or branched alkyl, or C1-3 straight-chain or branched alkyl substituted by 1, 2 or 3 F.

[0041] R2 and R3 may be the same or different, and are each independently selected from OH, NH2, nitro, carboxyl, C1-6 alkoxy, -C(O)O-C1-3 alkyl, -OC(O)-C1-3 alkyl, or -C(O)NH2; optionally, the alkyl or alkoxy group is selected from F, Cl, Br, I, OH, C 1-3 Substituted by substituents of straight-chain or branched alkyl groups;

[0042] Optionally, R2 and R3, together with the C atoms attached to them, form a 5- or 6-membered unsaturated heterocycle; optionally, the heterocycle is surrounded by 1, 2, or 3 atoms selected from F, Cl, Br, I, OH, oxy, nitro, carboxyl, cyano, C 1-3 The heterocycle is substituted by a straight-chain or branched alkyl group; the heterocycle contains one heteroatom selected from N, O or S;

[0043] R4 is selected from H, F, Cl, Br, or I;

[0044] R5 and R6 are selected from H;

[0045] L1 is selected from O, S, CH2, or NH; L2 is selected from O, S, or NH;

[0046] n1 is selected from 1 or 2.

[0047] According to some specific embodiments of the present invention, wherein,

[0048] R2 is selected from carboxyl, -C(O)O-C1-3 alkyl, or -C(O)NH2; optionally, the alkyl group is selected from F, Cl, Br, I, OH, C 1-3 Substituted by substituents of straight-chain or branched alkyl groups;

[0049] R3 is selected from OH, NH2, nitro, carboxyl, C1-6 alkoxy, -C(O)O-C1-3 alkyl, or -OC(O)-C1-3 alkyl; optionally, the alkyl or alkoxy group is selected from F, Cl, Br, I, OH, C 1-3 Substituted by substituents of straight-chain or branched alkyl groups;

[0050] Optionally, R2 and R3, together with the C atoms attached to them, form a 5- or 6-membered unsaturated heterocycle; optionally, the heterocycle is surrounded by 1, 2, or 3 atoms selected from F, Cl, Br, I, OH, oxy, nitro, carboxyl, cyano, C 1-3 The heterocycle is substituted by a straight-chain or branched alkyl group; the heterocycle contains one heteroatom selected from N, O or S.

[0051] According to some specific embodiments of the present invention, wherein,

[0052] R1 is selected from 6- to 8-membered aryl groups; the aryl group is substituted by a substituent of a C1-3 straight-chain or branched alkyl group, or a C1-3 straight-chain or branched alkyl group substituted by 1, 2 or 3 F groups;

[0053] R2 and R3 may be the same or different, each independently selected from OH, carboxyl or -OC(O)-C1-3 alkyl; optionally, the alkyl group is substituted with a substituent selected from F, Cl, Br or I;

[0054] R4 is selected from H, F, Cl, Br, or I;

[0055] R5 and R6 are selected from H;

[0056] L1 is selected from O, S, CH2, or NH; L2 is selected from NH;

[0057] n1 is selected from 1 or 2.

[0058] According to some specific embodiments of the present invention, wherein,

[0059] R2 is selected from carboxyl or -OC(O)-C1-3 alkyl; optionally, the alkyl group is substituted with a substituent selected from F, Cl, Br, I;

[0060] R3 is selected from OH or -OC(O)-C1-3 alkyl; optionally, the alkyl group is substituted with a substituent selected from F, Cl, Br, I.

[0061] According to some specific embodiments of the present invention, the compound is as shown in formula (I-1) or formula (I-2):

[0062] .

[0063] According to some specific embodiments of the present invention, the compound is selected from one of the following structures:

[0064] .

[0065] On the other hand, the present invention also provides a method for preparing the compound, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, wherein the method comprises:

[0066] Compound (I-1) was prepared using compounds of formula (I-1-1) and (I-1-2) as raw materials:

[0067]

[0068] Alternatively, compound (I-2) can be prepared using compounds of formula (I-2-1) and (I-2-2) as raw materials:

[0069] .

[0070] According to some specific embodiments of the present invention, the compound of formula (I-1-1) and the compound of formula (I-1-2) are prepared by reacting at 20-30°C; preferably at 25-30°C.

[0071] According to some specific embodiments of the present invention, the reaction time of the compound of formula (I-1-1) and the compound of formula (I-1-2) is 10-16 h; preferably 12-15 h.

[0072] According to some specific embodiments of the present invention, the molar ratio of compound (I-1-1) and compound (I-1-2) is 1:(1.2-1.8); preferably 1:(1.3-1.6); more preferably 1:(1.5-1.6).

[0073] According to some specific embodiments of the present invention, the compound of formula (I-2-1) and the compound of formula (I-2-2) are prepared by reacting at 20-30°C; preferably at 25-30°C.

[0074] According to some specific embodiments of the present invention, the reaction time of the compound of formula (I-2-1) and the compound of formula (I-2-2) is 2-5 h; preferably 2-3 h.

[0075] According to some specific embodiments of the present invention, the molar ratio of compound (I-2-1) and compound (I-2-2) is 1:(1-1.5)h; preferably 1:(1-1.2).

[0076] According to some specific embodiments of the present invention, the compounds of formula (I-2-1) and (I-2-2) are reacted in the presence of TEA.

[0077] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (I-2-1) to TEA is 1:(1.8-2.2); preferably 1:2.

[0078] According to some specific embodiments of the present invention, the method further includes preparing a compound of formula (I-1-1) using a compound of formula (I-1-3) as a raw material:

[0079] .

[0080] According to some specific embodiments of the present invention, the compound of formula (I-1-3) is prepared by reacting it with thionyl chloride to prepare the compound of formula (I-1-1).

[0081] According to some specific embodiments of the present invention, the mass-to-volume ratio (g / ml) of the compound of formula (I-1-3) to thionyl chloride is 1:(10-30); preferably 1:(15-25); more preferably 1:20.

[0082] According to some specific embodiments of the present invention, the compound of formula (I-1-3) is prepared by reacting at 70-80°C to obtain the compound of formula (I-1-1).

[0083] According to some specific embodiments of the present invention, the compound of formula (I-1-3) is reacted for 2-5 hours to obtain the compound of formula (I-1-1); preferably, the reaction is carried out for 2-3 hours.

[0084] According to some specific embodiments of the present invention, the compound of formula (I-1-3) is prepared by reaction in an organic solvent to obtain the compound of formula (I-1-1); the organic solvent is selected from tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, acetone, dimethyl sulfoxide, etc.

[0085] According to some specific embodiments of the present invention, the method further includes preparing a compound of formula (I-2-1) using a compound of formula (I-2-3) and thionyl chloride as raw materials:

[0086] .

[0087] According to some specific embodiments of the present invention, the reaction of the compound of formula (I-2-3) and thionyl chloride is carried out at 70-90°C; preferably at 80-90°C.

[0088] According to some specific embodiments of the present invention, the reaction time of the compound of formula (I-2-3) and thionyl chloride is 5-10 h; preferably 6-8 h.

[0089] According to some specific embodiments of the present invention, the weight-volume ratio (g / ml) of the compound of formula (I-2-3) and thionyl chloride is 1:(20-30); preferably 1:(25-30).

[0090] According to some specific embodiments of the present invention, the method further includes preparing a compound of formula (I-1-3) using a compound of formula (I-1-4) as a raw material:

[0091] .

[0092] According to some specific embodiments of the present invention, the compound of formula (I-1-4) is prepared by reacting at 0°C to 25°C to obtain the compound of formula (I-1-3).

[0093] According to some specific embodiments of the present invention, the compound of formula (I-1-4) is reacted for 2-5 hours to obtain the compound of formula (I-1-3); preferably, the reaction is carried out for 2-3 hours.

[0094] According to some specific embodiments of the present invention, the compound of formula (I-1-4) is reacted under alkaline conditions to obtain the compound of formula (I-1-3).

[0095] According to some specific embodiments of the present invention, the alkaline conditions are achieved by adding an inorganic base to the reaction system; the molar ratio of the compound of formula (I-1-4) to the inorganic base is 1:(1.5-2.0).

[0096] According to some specific embodiments of the present invention, the inorganic base is selected from sodium hydroxide and / or potassium hydroxide.

[0097] According to some specific embodiments of the present invention, the compound of formula (I-1-4) is prepared by reaction in a reaction solvent to obtain the compound of formula (I-1-3); the reaction solvent is selected from an aqueous solution of an alcohol; preferably an aqueous solution of methanol or an aqueous solution of ethanol.

[0098] According to some specific embodiments of the present invention, the volume concentration of the aqueous solution of alcohol is 50-80%; preferably 60-80%.

[0099] According to some specific embodiments of the present invention, the method further includes preparing a compound of formula (I-1-4) using compounds of formula (I-1-5) and formula (I-1-6) as raw materials:

[0100] .

[0101] According to some specific embodiments of the present invention, the compounds of formula (I-1-5) and formula (I-1-6) are prepared by reacting at -5 to 5°C to prepare the compound of formula (I-1-4); preferably, the compound of formula (I-1-4) is prepared by reacting at 0 to 5°C.

[0102] According to some specific embodiments of the present invention, the compound of formula (I-1-5) and the compound of formula (I-1-6) react for 2-5 hours to obtain the compound of formula (I-1-4); preferably, the reaction takes 2-3 hours.

[0103] According to some specific embodiments of the present invention, the molar ratio of compound (I-1-5) to compound (I-1-6) is 1:(2-4); preferably 1:(3-4).

[0104] According to some specific embodiments of the present invention, the compounds of formula (I-1-5) and formula (I-1-6) are reacted under the activation of an organic base.

[0105] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (I-1-5) to the organic base is 1:(2-4); preferably 1:(3-4).

[0106] According to some specific embodiments of the present invention, the organic base is selected from one or more of N,N-diisopropylethylamine (DIEA), lithium diisopropylamino (LDA), lithium hexamethyldisilamide (LiHMDS), potassium tert-butoxide (t-BuOK), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), and triethylamine (Et3N).

[0107] According to some specific embodiments of the present invention, the compounds of formula (I-1-5) and (I-1-6) are prepared by reacting in an organic solvent to prepare the compound of formula (I-1-4); the organic solvent is selected from dichloromethane or chloroform.

[0108] In another aspect, the present invention also provides a pharmaceutical composition comprising the compound described herein, its stereoisomer, deuterated form or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0109] According to some specific embodiments of the present invention, the compound, its stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof constitute 0.1%-99.9% by weight in the composition.

[0110] The pharmaceutical compositions of the present invention can be prepared into any pharmaceutically acceptable dosage form. Preferably, pharmaceutically acceptable dosage forms are tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, capsules, hard capsules, soft capsules, sustained-release capsules, and powders.

[0111] According to some specific embodiments of the present invention, the pharmaceutical composition is a tablet, powder, capsule, or tablet.

[0112] When the pharmaceutical composition of the present invention is in solid form, the pharmaceutically acceptable carrier is selected from one or more of diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, swelling agents, etc.

[0113] When the pharmaceutical composition of the present invention is in an encapsulated form, the pharmaceutically acceptable carrier is selected from one or more of magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, and cocoa butter.

[0114] For ease of administration and uniform dosage, it is particularly advantageous to formulate the above-mentioned pharmaceutical preparations in unit dosage form. Unit dosage form refers to a physically separated unit suitable for single-dose administration, each unit containing a calculated, predetermined amount of active ingredient to produce the desired therapeutic effect. This unit dosage form can be in package form, such as tablets, capsules, or powder packaged in tubes or vials.

[0115] The pharmaceutical composition of the present invention, as a formulation, contains an effective amount of the compound of the present invention in each dose of 0.1 to 1000 mg.

[0116] Although the amount of active ingredient contained in the dosage unit can vary, it is generally adjusted within the range of 1 to 800 mg, depending on the potency of the selected active ingredient.

[0117] Each dose refers to each unit of preparation, such as each tablet or each capsule, or it can refer to the dosage taken each time, such as 100mg per dose.

[0118] In another aspect, the present invention also provides the use of the said compound, its stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or the said pharmaceutical composition in the preparation of a medicament for treating mycobacterial infections.

[0119] According to some specific embodiments of the present invention, the mycobacterium is selected from Mycobacterium tuberculosis.

[0120] According to some specific embodiments of the present invention, when the active compound of formula (I) of the present invention is used as a drug for treating Mycobacterium tuberculosis infection, it is preferred to administer an amount of 6 to 14 mg / kg body weight in the first stage.

[0121] In some cases, those skilled in the art can determine the preferred dosage suitable for a particular situation using conventional methods. Generally, the initial treatment dose is lower than the optimal dose of the active ingredient, and then the dosage is gradually increased until the optimal therapeutic effect is achieved. For convenience, the total daily dose may be divided into several portions and administered in multiple doses.

[0122] It is understood that, without contradiction, the various specific embodiments of the present invention can be combined with each other.

[0123] Unless otherwise specified in this invention, the following terms are explained as follows (the explanations are merely general examples and not limitations on the invention):

[0124] "Substitution" refers to the replacement of a hydrogen atom on a carbon atom or heteroatom by one or more defined substituents. The upper limit of the number of substituents is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted group. Generally, the number of substituents is any integer between 1 and this upper limit. When the number of halogen substituents is greater than 1, the same or different substituents can be used for substitution.

[0125] "Optional" is a selective expression, meaning that the subsequent event may or may not occur. For example, "optionally, the aryl and alkyl groups are separated by 1, 2, or 3 elements selected from F, Cl, Br, I, or C." 1-6 "Substituted by straight-chain or branched alkyl groups" means that substitution may or may not occur. Specifically, it means that the aryl and alkyl groups mentioned above may or may not be substituted by the substituents mentioned above.

[0126] "Deuterated product" refers to a group containing hydrogen atoms in which at least one deuterium atom is replaced. The upper limit of the number of deuterated atoms is equal to the sum of the number of hydrogen atoms that can be replaced in the substituted group. Generally, the number of deuterated atoms is any integer between 1 and the upper limit. Preferably, 1-20 deuterium atoms are substituted, more preferably 1-10 deuterium atoms are substituted, even more preferably 1-5 deuterium atoms are substituted, and even more preferably 1-3 deuterium atoms are substituted.

[0127] "Alkyl" refers to a monovalent straight-chain or branched saturated aliphatic hydrocarbon group, generally an alkyl group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 10 carbon atoms, more preferably an alkyl group with 1 to 5 carbon atoms, further preferably an alkyl group with 1 to 3 carbon atoms, and even more preferably an alkyl group with 1 to 2 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their various branched isomers.

[0128] "Alkoxy" refers to -O-alkyl, and unless otherwise specified, it is -OC. 1-8 Alkyl group, preferably -OC 1-6 Alkyl, more preferably -OC 1-4 Alkyl groups, more preferably -OC 1-2 Alkyl groups. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

[0129] "Aryl" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 4 to 10, 4 to 8, or 6 to 8 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring. Non-limiting embodiments include benzene rings, naphthalene rings, etc. .

[0130] In summary, this invention provides a compound containing a sulfonyl group, its preparation, and its application. The technical solution of this invention has the following advantages:

[0131] The compounds of this invention exhibit superior anti-MTB activity compared to S31-201. Furthermore, compared to S31-201, the compounds of this invention demonstrate higher in vitro safety. Detailed Implementation

[0132] The following detailed embodiments illustrate the implementation process and beneficial effects of the present invention, aiming to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of this case.

[0133] Example 1: 2-Hydroxy-4-(2-((4-trifluoromethylphenyl)sulfonyl)oxy)acetamido)benzoic acid

[0134]

[0135] At 0 °C, DIEA (7.93 g, 61.3 mmol, 3.00 eq) was added to a DCM (50.0 mL) solution of 4-trifluoromethylbenzenesulfonyl chloride (5.00 g, 20.4 mmol, 1.00 eq), followed by the addition of methyl 2-hydroxyacetate (5.52 g, 61.3 mmol, 3.00 eq). The mixture was stirred at 0 °C for 2 hours. Post-treatment: The reaction mixture was diluted with H2O, extracted with DCM, and the combined organic layers were washed with H2O (100 mL), dried over Na2SO4, filtered, and concentrated to obtain a yellow oil, which was used to prepare methyl 2-(((4-trifluoromethylphenyl)sulfonyl)oxy)acetate (3.00 g).

[0136] Sodium hydroxide (603 mg, 15.0 mmol, 1.50 eq) was added to a methanol (20.0 mL) and water (10.0 mL) solution of the above compound (3.00 g, 10.0 mmol, 1.00 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hours. Post-treatment: concentration was performed, the pH was adjusted to 4 with 1N HCl, the mixture was stirred at 25 °C for 0.5 hours, filtered, and the filter cake was concentrated to give a white solid 2-(((4-trifluoromethylphenyl)sulfonyl)oxy)acetic acid (2.80 g).

[0137] The above compound (1.00 g, 3.52 mmol, 1.00 eq) was stirred in SOCl2 (20.0 mL) at 80 °C for 2 hours. Post-treatment: concentration under reduced pressure to give 2-chloro-2-oxoethyl-4-trifluoromethylbenzenesulfonate (1.20 g).

[0138] Add p-aminosalicylic acid (379 mg, 2.48 mmol, 1.50 eq) to a THF (10.0 mL) solution of the above intermediate (0.50 g, 1.65 mmol, 1.00 eq). Stir the mixture at 25 °C for 12 hours. Post-treatment: Filter the resulting mixture, concentrate the filter cake, and obtain the residue. Purify the residue by preparative HPLC (0.06% FA conditions: ACN / H2O = 0-40%) to give a white solid final product (yield: 20.47%).

[0139] 1H NMR(400 MHz, DMSO-d6) δ 13.77 (s, 1H), 11.50 (s, 1H), 10.37 (s,1H), 8.19 (d, 2H), 8.07 (d, 2H), 7.71 (d, 1H), 7.20 (d, 1H), 6.95 (dd, 1H), 4.84 (s, 2H).

[0140] ESI (m / z): 418.0 (M - H) - .

[0141] Example 2, 2-hydroxy-4-(2-((4-nitrophenyl)sulfonyl)oxy)acetamido)benzoic acid

[0142]

[0143] The preparation method was the same as in Example 1, using compound 4-trifluoromethylbenzenesulfonyl chloride as the starting material to obtain a white final product (yield: 15.55%).

[0144] 1 H NMR: 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.49 (d, 2H), 8.26(d, 2H), 7.74 (d, 1H), 7.24 (d, 1H), 6.99 (dd, 1H), 4.90 (s, 2H).

[0145] MS-ESI (m / z): 395.0 (M + H) + .

[0146] Example 3: 2-Hydroxy-4-(3-p-Tolylpropionamido)benzoic acid

[0147]

[0148] The preparation method was the same as in Example 1, using compound 4-methylbenzenesulfonyl chloride and methyl propionate as starting materials to obtain a white final product (yield: 18.55%).

[0149] 1 H NMR(400 MHz, DMSO-d6) δ 11.36 (s, 1H), 10.29 (s, 1H), 7.81 (d, 2H), 7.72 (d, 1H), 7.47 (d, 2H), 7.25 (d, 1H), 6.97 (dd, 1H), 3.60 (t, 2H), 2.71(t, 2H), 2.40 (s, 3H).

[0150] MS-ESI (m / z): 364.0 (M + H) + .

[0151] Example 4: 2-hydroxy-4-(2-((4-methylphenyl)sulfonamido)acetamido)benzoic acid

[0152]

[0153] The preparation method was the same as in Example 1, using compound 4-methylbenzenesulfonyl chloride and methyl methylcarbamate as starting materials to obtain a white final product (yield: 16.35%).

[0154] 1 H NMR (400 MHz, DMSO-) d 6) δ 11.44 (s, -2H), 10.16 (s, 1H), 8.02 (t,1H), 7.72 (d, 3H), 7.39 (d, 2H), 7.24 (d,1H), 6.97 (dd, 1H), 3.69 (d, 2H), 2.37 (s, 3H).

[0155] MS-ESI (m / z): 365.1 (M + H) + .

[0156] Example 5: 4-(2-(((4-fluorophenyl)sulfonyl)oxy)acetamido)-2-hydroxybenzoic acid

[0157]

[0158] The preparation method was the same as in Example 1, using compound 4-fluorobenzenesulfonyl chloride as the starting material to obtain a white final product (yield: 16.34%).

[0159] 1 H NMR (400 MHz, DMSO- d 6) δ 11.36 (s, 1H), 10.38 (s, 1H), 8.11 – 8.01(m, 2H), 7.72 (d, 1H), 7.54 (t, 2H), 7.24 (d, 1H), 6.98 (dd, 1H), 4.77 (s,2H).

[0160] MS-ESI (m / z): 370.0 (M + H) + .

[0161] Example 6: 4-(2-((cyclohexylsulfonyl)oxy)acetamido)-2-hydroxybenzoic acid

[0162]

[0163] The preparation method was the same as in Example 1, using cyclohexanesulfonyl chloride as the starting material to obtain a white final product (yield: 12.85%).

[0164] 1 H NMR: (400 MHz, DMSO- d6 ) δ 11.41 (s, 1H), 10.43 (s, 1H), 7.75 (d,1H), 7.32 (d, 1H), 7.06 (dd, 1H), 4.84 (s, 2H), 3.47 (t, 1H), 2.13 (dd, 2H),1.81 (dt, 2H), 1.63 (dd, 1H), 1.52 - 1.42 (m, 2H), 1.30 (m, 2H), 1.18 (m,1H).

[0165] MS-ESI (m / z): 358.2 (M + H) + .

[0166] Example 7: 2-Hydroxy-4-(2-(Toluenesulfonyloxy)acetoxy)benzoic acid

[0167]

[0168] A solution of 2-(toluenesulfonyloxy)acetic acid (200 mg, 0.87 mmol, 1.00 eq) in SOCl2 (5.0 mL) was stirred at 80 °C for 6 hours. Post-treatment: The resulting mixture was concentrated under reduced pressure to give 2-chloro-2-oxoethyl 4-methylbenzenesulfonate (200 mg).

[0169] The above compounds were added to a stirred solution of 2,4-dihydroxybenzoic acid (130 mg, 0.87 mmol, 1.00 eq) and TEA (176 mg, 1.74 mmol, 2.00 eq) in DCM (10.0 mL) at 0 °C. The mixture was stirred at room temperature for 2.0 h. Post-treatment: The reaction mixture was diluted with H2O, extracted with DCM, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by pre-HPLC to give a white solid final product (yield: 44.52%).

[0170] 1 H NMR: (400 MHz, DMSO- d6 ) δ 7.94 - 7.84 (m, 3H), 7.54 (d, 2H), 6.75- 6.66 (m, 2H), 5.09 (s, 2H), 2.46 (s, 3H).

[0171] MS-ESI (m / z): 367.0 (M + H) + .

[0172] Example 8: Methyl 2-(propionyloxy)-4-(2-(toluenesulfonyloxy)acetamido)benzoate

[0173]

[0174] Referring to Example 7, 2-chloro-2-oxoethyl 4-methylbenzenesulfonate and methyl 4-amino-2-(propionyloxy)benzoate were reacted to produce a white solid (yield: 62.35%).

[0175] 1 H NMR: (400 MHz, DMSO- d6 ) δ 10.57 (s, 1H), 7.94 (d, 1H), 7.88 - 7.83 (m, 2H), 7.53 - 7.48 (m, 3H), 7.42 (dd, 1H), 4.75 (s, 2H), 3.79 (s, 3H), 2.65(q, 2H), 2.42 (s, 3H), 1.17 (t, 3H).

[0176] MS-ESI (m / z): 436.1 (M + H) + .

[0177] Example 9: Methyl 2-(pentoxy)-4-(2-(toluenesulfonyloxy)acetamido)benzoate

[0178]

[0179] Referring to Example 7, methyl 4-chloro-2-oxoethyl 4-methylbenzenesulfonate and methyl 4-amino-2-(pentoxy)benzoate were reacted to produce a white solid (yield: 62.04%).

[0180] 1 H NMR: (400 MHz, DMSO- d6 ) δ 10.36 (s, 1H), 7.91 - 7.83 (m, 2H), 7.68(d, 1H), 7.51 (d, 2H), 7.39 (d, 1H), 7.13 (dd, 1H), 4.71 (s, 2H), 3.97 (t,2H), 3.77 (s, 3H), 2.42 (s, 3H), 1.75 (m, 2H), 1.49 - 1.34 (m, 4H), 0.92 (t,3H).

[0181] MS-ESI (m / z): 450.2 (M + H) + .

[0182] Example 10: Ethyl 2-oxo-2-((1-oxo-1,3-dihydroisobenzofuran-5-yl)amino)4-methylbenzenesulfonate

[0183]

[0184] Referring to Example 7, 2-chloro-2-oxoethyl 4-methylbenzenesulfonate was reacted with 5-aminoisobenzofuran-1(3H)-one to prepare a white solid (yield: 68.35%).

[0185] 1 H NMR: δ 10.57 (s, 1H), 8.21 (d, 1H), 7.93 - 7.85 (m, 2H), 7.78 (dd,1H), 7.63 - 7.58 (m, 1H), 7.18 (t, 1H), 3.84 (s, 3H), 3.80 (s, 4H).

[0186] MS-ESI (m / z): 362.0 (M + H) + .

[0187] Example 11, 2-((4-carbamoyl-3-methoxyphenyl)amino)-2-oxoethyl-4-methylbenzenesulfonate

[0188]

[0189] Referring to Example 7, 2-chloro-2-oxoethyl 4-methylbenzenesulfonate and 2-methoxy-4-(methylamino)benzamide were reacted to produce a white solid (yield: 22.25%).

[0190] 1 H NMR(400 MHz, Methanol-d4) δ 8.11 (s, 1H), 7.96 (d, 1H), 7.90 (d,2H), 7.60 (d, 1H), 7.47 (d, 2H), 7.10 (dd,1H), 4.70 (s, 2H), 3.99 (s, 3H),2.45 (s, 3H).

[0191] MS-ESI (m / z): 379.1 (M + H) + .

[0192] Biological Example 1

[0193] In vitro anti-mycobacterial activity assay

[0194] The anti-tuberculosis activity of the compounds of this invention was determined by measuring their activity against the standard strain MTBH of Mycobacterium tuberculosis. 37 The minimum inhibitory concentration (MIC, μg / mL) of RvATCC 27294 is used as the control drug. In this experiment, S31-201 was used as the control. The MIC was determined as follows: In a sterile 48-well plate (a micro-culture plate specifically for rapid drug susceptibility testing of Mycobacterium tuberculosis), the drug diluted with twice the concentration of culture medium (modified Michaelis 7H9 liquid medium) was added to each well according to the drug susceptibility test design. Initial solutions of each compound were prepared at appropriate concentrations, and then diluted with 2× medium to twice the concentration of each compound. Ten gradients were prepared for each compound, and 100 μL was added to each well of the 48-well plate. The final concentrations of the test drug were 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625, 0.03125, and 0.015 μg / mL. Standard strain H... 37 Rv ATCC 27294, inoculate 100 μL per well, with a bacterial count of 4 × 10⁻⁶ per well. -3mg. Each plate contained two positive control wells without antibiotics and two negative control wells with distilled water instead of culture medium. The 48-well plates were capped and sealed with transparent tape, then incubated in a humidified chamber at 37°C. On day 3, the positive and negative control wells were observed. When a clear difference was observed, the number and morphology of bacteria in each well were observed to determine inhibition or resistance, and the results were recorded. A second observation and recording were performed on day 7 for confirmation. The lowest concentration of drug in the control wells without sterile growth is the minimum inhibitory concentration (MIC). The results are listed in Table 1.

[0195] Table 1. In vitro activity of the compounds in the examples against Mycobacterium tuberculosis.

[0196]

[0197] Example: Compounds against Mycobacterium tuberculosis standard strain H 37 The in vitro activity of Rv ATCC 27294 is comparable to or better than that of S31-201. Among them, the activities of Examples 3, 4 and 8 are superior to those of S31-201.

Claims

1. Use of the compound containing a sulfonyl group as shown in formula (I) or a pharmaceutically acceptable salt thereof in the preparation of medicaments for treating mycobacterial infections: (I) in, R1 is selected from a 6-membered aryl group; the aryl group is substituted by a substituent of a C1-3 straight-chain or branched alkyl group, or a C1-3 straight-chain or branched alkyl group substituted by 1, 2 or 3 F groups; R2 is selected from carboxyl or -C(O)O-C1-3 alkyl; optionally, the alkyl group is substituted with a substituent selected from F, Cl, Br or I; R3 is selected from OH or -OC(O)-C1-3 alkyl; optionally, the alkyl group is substituted with a substituent selected from F, Cl, Br or I; R5 and R6 are selected from H; L1 is selected from O, CH2, or NH; L2 is selected from NH; The condition is that the compound shown in formula (I) is not: 。 2. The application according to claim 1, wherein, The compounds are shown as those of formula (I-1) or formula (I-2): 。 3. The application according to claim 1, wherein, The compound is selected from one of the following structures: 。 4. The application according to claim 1, wherein, The mycobacteria were selected from Mycobacterium tuberculosis.

5. A compound containing a sulfonyl group, as shown in formula (I-2), or a pharmaceutically acceptable salt thereof: R2 is selected from -C(O)O-C1-3 alkyl; optionally, the alkyl group is substituted with a substituent selected from F, Cl, Br or I; R3 is selected from -OC(O)-C1-3 alkyl; optionally, the alkyl group is substituted with a substituent selected from F, Cl, Br or I; L2 is selected from NH.

6. The sulfonyl compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein, The compound is: 。

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