Pharmaceutical composition and application

Abstract

The invention discloses a pharmaceutical composition containing a substance X, a substance Y and an optional substance z and application of the pharmaceutical composition in preparation of drugs for treating diseases caused by mycobacterium tuberculosis. The substance X is a compound I or a pharmaceutically acceptable salt thereof, and the substance Y and the substance Z are selected from pyrazinamide, linezolid, moxifloxacin, preremanib or deramanib. # imgabs0 #

Description

A drug combination and application

[0001] This application claims priority to Chinese patent application No. 2023112288517, filed on September 21, 2023. This application cites the full text of the aforementioned Chinese patent application Technical Field

[0002] The present invention relates to a drug combination and application, in particular to a drug combination for treating diseases caused by Mycobacterium tuberculosis. Background Art

[0003] Tuberculosis (TB), a chronic infectious disease caused by Mycobacterium tuberculosis (MTB), remains the single leading cause of death by infectious disease. A major challenge in achieving the global goal of ending the TB epidemic by 2035 is the increasing incidence of drug-resistant and multidrug-resistant TB. Currently, TB treatment cycles are long, and cure rates for multidrug-resistant TB are low. The treatment of TB, especially drug-resistant TB, urgently requires new drugs with novel mechanisms of action. There is also an urgent need to develop new chemotherapy regimens that shorten treatment courses, simplify treatment, and improve efficacy.

[0004] Due to the presence of different bacterial communities in tuberculosis lesions and the fact that MTB quickly develops resistance to a single drug, drug combination is a key weapon in the treatment of tuberculosis, that is, tuberculosis treatment must be carried out in the form of a combination of drugs. In addition, the elimination of dormant MTB retained in the host body is a key factor in determining the length of tuberculosis chemotherapy. Therefore, the development of new and effective combination treatment regimens is crucial to shortening the course of tuberculosis treatment. The development of new anti-tuberculosis combination regimens can improve efficacy and shorten treatment time, which will improve patient compliance, reduce side effects, reduce costs, and increase cure rates. Therefore, there is a need in this field for new regimens that are more effective than the current first-line regimens and are not affected by resistance to existing drugs.

[0005] Compound I (WX-081) has demonstrated excellent anti-TB activity both in vitro and in vivo. Currently, Compound I has entered a Phase III pivotal clinical study (CTR20221162). To date, there have been no reports of Compound I being used in combination with other anti-TB drugs, either domestically or internationally.

[0006] Summary of the Invention

[0007] The present invention provides a drug combination and application thereof. The drug combination can prevent and / or treat diseases caused by Mycobacterium tuberculosis.

[0008] In a first aspect, the present invention provides a pharmaceutical combination comprising

[0009] i) substance X, wherein the substance X is compound 1 or a pharmaceutically acceptable salt thereof;

[0010] ii) substance Y, wherein substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the second therapeutic agent is pyrazinamide, linezolid, moxifloxacin, premanid or delamanid;

[0011] The structure of the compound I is shown below:

[0012] In some embodiments, the substance X is a pharmaceutically acceptable salt of Compound 1; preferably, the substance X is the hydrochloride, sulfate, citrate, maleate or fumarate of Compound 1; more preferably, the substance X is the fumarate of Compound 1.

[0013] In some embodiments, the substance X is compound I.

[0014] In some embodiments, the second therapeutic agent is selected from pyrazinamide, moxifloxacin, delamanid, or premanid.

[0015] In some embodiments, the second therapeutic agent is delamanid or pyrazinamide.

[0016] In some embodiments, the pharmaceutical combination consists of the substance X and the substance Y.

[0017] In some embodiments, the substance X and substance Y are administered simultaneously or separately.

[0018] In some embodiments, the substance X is administered orally.

[0019] In some embodiments, the substance Y is administered orally or by injection; preferably, the substance Y is administered orally.

[0020] In a second aspect, the present invention provides a pharmaceutical composition A comprising a substance X, a substance Y, and a pharmaceutically acceptable carrier or medium, wherein the substance X is compound I or a pharmaceutically acceptable salt thereof; the substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the second therapeutic agent is pyrazinamide, linezolid, moxifloxacin, premanid, or delamanid;

[0021] The structure of the compound I is shown below:

[0022] In some embodiments, the substance X is compound I.

[0023] In some embodiments, the substance X is a pharmaceutically acceptable salt of Compound 1; preferably, the substance X is the hydrochloride, sulfate, citrate, maleate or fumarate of Compound 1; more preferably, the substance X is the fumarate of Compound 1.

[0024] In some embodiments, the substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, and the second therapeutic agent is pyrazinamide, linezolid, moxifloxacin, premanid, or delamanid.

[0025] In some embodiments, the second therapeutic agent is pyrazinamide or delamanid.

[0026] In some embodiments, the pharmaceutical composition A is in the form of an oral dosage form.

[0027] In some embodiments, the pharmaceutical composition A consists of the substance X, the substance Y and a pharmaceutically acceptable carrier or medium.

[0028] In a third aspect, the present invention provides a pharmaceutical composition B comprising a first pharmaceutical composition and a second pharmaceutical composition;

[0029] The first pharmaceutical composition comprises a substance X and a pharmaceutically acceptable carrier or medium, wherein the substance X is Compound 1 or a pharmaceutically acceptable salt thereof;

[0030] The second pharmaceutical composition comprises substance Y and a pharmaceutically acceptable carrier or medium, wherein substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, and the second therapeutic agent is pyrazinamide, linezolid, moxifloxacin, premanid or delamanid;

[0031] The structure of the compound I is shown below:

[0032] In some embodiments, the substance X is compound I.

[0033] In some embodiments, the substance X is a pharmaceutically acceptable salt of Compound 1; preferably, the substance X is the hydrochloride, sulfate, citrate, maleate or fumarate of Compound 1; more preferably, the substance X is the fumarate of Compound 1.

[0034] In some embodiments, the substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, and the second therapeutic agent is pyrazinamide, linezolid, moxifloxacin, premanid, or delamanid.

[0035] In some embodiments, the second therapeutic agent is pyrazinamide or delamanid.

[0036] In some embodiments, the first pharmaceutical composition is in the form of an oral dosage form.

[0037] In some embodiments, the second pharmaceutical composition is in the form of an oral dosage form.

[0038] In some embodiments, the pharmaceutical composition B consists of the first pharmaceutical composition and the second pharmaceutical composition.

[0039] In a fourth aspect, the present invention provides a pharmaceutical combination comprising

[0040] i) substance X, wherein the substance X is compound 1 or a pharmaceutically acceptable salt thereof;

[0041] ii) substance Y, wherein the substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, and the second therapeutic agent is premanid or delamanid;

[0042] iii) substance Z, wherein the substance Z is linezolid or a pharmaceutically acceptable salt thereof;

[0043] The structure of the compound I is shown below:

[0044] In some embodiments, the substance X is compound I.

[0045] In some embodiments, the substance X is a pharmaceutically acceptable salt of Compound 1; preferably, the substance X is the hydrochloride, sulfate, citrate, maleate or fumarate of Compound 1; more preferably, the substance X is the fumarate of Compound 1.

[0046] In some embodiments, the second therapeutic agent is purimanid.

[0047] In some embodiments, the pharmaceutical combination consists of substance X, substance Y, and substance Z.

[0048] In some embodiments, the substance X, substance Y, and substance Z are administered simultaneously or separately.

[0049] In some embodiments, the substance X is administered orally.

[0050] In some embodiments, the substance Y is administered orally.

[0051] In some embodiments, the substance Z is administered orally or by injection; preferably, the substance Z is administered orally.

[0052] In some embodiments, the pharmaceutical combination comprises 100 mg to 1000 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the pharmaceutical combination comprises 100 mg to 800 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the pharmaceutical combination comprises 150 mg to 800 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, the pharmaceutical combination comprises 150 mg to 500 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the pharmaceutical combination comprises 150 mg to 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the pharmaceutical combination comprises 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg or 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the pharmaceutical combination comprises 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the pharmaceutical combination comprises 300 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the pharmaceutical combination comprises 150 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the second therapeutic agent is pramanid, and the pharmaceutical combination comprises 25 mg to 1000 mg of pramanid or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the second therapeutic agent is pramanid, and the pharmaceutical combination comprises 50 mg to 1000 mg of pramanid or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the second therapeutic agent is pramanid, and the pharmaceutical combination comprises 50 mg to 800 mg of pramanid or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the second therapeutic agent is pramanid, and the pharmaceutical combination comprises 50 mg to 600 mg of pramanid or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the second therapeutic agent is premanid, and the pharmaceutical combination comprises 100 mg to 800 mg of premanid or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, the second therapeutic agent is premanid, and the pharmaceutical combination comprises 100 mg to 600 mg of premanid or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the second therapeutic agent is pramanid, and the pharmaceutical combination comprises 150 mg to 600 mg of pramanid or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the second therapeutic agent is premanid, and the pharmaceutical combination comprises 200 mg to 600 mg of premanid or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the second therapeutic agent is premanid, and the pharmaceutical combination comprises 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of premanid or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the pharmaceutical combination comprises 50 mg to 2000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, the pharmaceutical combination comprises 10 mg to 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, the pharmaceutical combination comprises 50 mg to 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, the pharmaceutical combination comprises 100 mg to 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, the pharmaceutical combination comprises 200 mg to 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, the pharmaceutical combination comprises 50 mg to 1000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, the pharmaceutical combination comprises 100 mg to 1000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the pharmaceutical combination comprises 150 mg to 1000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the pharmaceutical combination comprises 150 mg to 800 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, the pharmaceutical combination comprises 150 mg to 600 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, the pharmaceutical combination comprises 200 mg to 600 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, the pharmaceutical combination comprises 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg or 1600 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the pharmaceutical combination comprises 150 mg to 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, 200 mg to 600 mg of premanid or a pharmaceutically acceptable salt thereof, and 200 mg to 1200 mg (preferably 200 mg to 600 mg) of linezolid or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the pharmaceutical combination comprises: (1) 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg or 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof; (2) 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of premanid or a pharmaceutically acceptable salt thereof; and (3) 200 mg, 300 mg, 400 mg, 500 mg, 600 mg or 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0084] In a fifth aspect, the present invention provides a pharmaceutical composition C comprising a substance X, a substance Y, a substance Z, and a pharmaceutically acceptable carrier or medium, wherein the substance X is compound I or a pharmaceutically acceptable salt thereof;

[0085] The substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, and the second therapeutic agent is premanid or delamanid;

[0086] The substance Z is linezolid or a pharmaceutically acceptable salt thereof;

[0087] The structure of the compound I is shown below:

[0088] In some embodiments, the substance X is compound I.

[0089] In some embodiments, the substance X is a pharmaceutically acceptable salt of Compound 1; preferably, the substance X is the hydrochloride, sulfate, citrate, maleate or fumarate of Compound 1; more preferably, the substance X is the fumarate of Compound 1.

[0090] In some embodiments, the second therapeutic agent is purimanid.

[0091] In some embodiments, the pharmaceutical composition C is in the form of an oral dosage form.

[0092] In some embodiments, the pharmaceutical composition C consists of the substance X, substance Y, substance Z and a pharmaceutically acceptable carrier or medium.

[0093] In some embodiments, the pharmaceutical composition C comprises 100 mg to 1000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the pharmaceutical combination composition C comprises 100 mg to 800 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, the pharmaceutical composition C comprises 150 mg to 800 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the pharmaceutical composition C comprises 150 mg to 500 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, the pharmaceutical composition C comprises 150 mg to 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the pharmaceutical composition C comprises 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg or 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the pharmaceutical composition C comprises 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, the pharmaceutical composition C comprises 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, the pharmaceutical composition C comprises 150 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, the second therapeutic agent is primanib, and the pharmaceutical composition C contains 25 mg to 1000 mg of primanib or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments, the second therapeutic agent is primanib, and the pharmaceutical composition C contains 50 mg to 1000 mg of primanib or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the second therapeutic agent is primanib, and the pharmaceutical composition C contains 50 mg to 800 mg of primanib or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, the second therapeutic agent is primanib, and the pharmaceutical composition C contains 50 mg to 600 mg of primanib or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the second therapeutic agent is primanib, and the pharmaceutical composition C contains 100 mg to 800 mg of primanib or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the second therapeutic agent is primanib, and the pharmaceutical composition C contains 100 mg to 600 mg of primanib or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the second therapeutic agent is primanib, and the pharmaceutical composition C contains 150 mg to 600 mg of primanib or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the second therapeutic agent is primanib, and the pharmaceutical composition C contains 200 mg to 600 mg of primanib or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, the second therapeutic agent is primanib, and the pharmaceutical composition C comprises 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of primanib or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the pharmaceutical composition C comprises 50 mg to 2000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the pharmaceutical composition C comprises 10 mg to 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the pharmaceutical composition C comprises 50 mg to 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments, the pharmaceutical composition C comprises 100 mg to 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the pharmaceutical composition C comprises 200 mg to 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments, the pharmaceutical composition C comprises 10 mg to 1000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, the pharmaceutical composition C comprises 50 mg to 1000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, the pharmaceutical composition C comprises 100 mg to 1000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, the pharmaceutical composition C comprises 150 mg to 1000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, the pharmaceutical composition C comprises 150 mg to 800 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the pharmaceutical composition C comprises 150 mg to 600 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, the pharmaceutical composition C comprises 200 mg to 600 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, the pharmaceutical composition C comprises 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg or 1600 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, the pharmaceutical composition C comprises 150 mg to 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, 200 mg to 600 mg of premanid or a pharmaceutically acceptable salt thereof, and 200 mg to 1200 mg (preferably 200 mg to 600 mg) of linezolid or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the pharmaceutical composition C comprises: (1) 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg or 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof; (2) 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of premanid or a pharmaceutically acceptable salt thereof; and (3) 200 mg, 300 mg, 400 mg, 500 mg, 600 mg or 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0126] In a sixth aspect, the present invention provides a pharmaceutical composition D comprising a first pharmaceutical composition, a second pharmaceutical composition, and a third pharmaceutical composition;

[0127] The first pharmaceutical composition comprises a substance X and a pharmaceutically acceptable carrier or medium, wherein the substance X is Compound 1 or a pharmaceutically acceptable salt thereof;

[0128] The second pharmaceutical composition comprises substance Y and a pharmaceutically acceptable carrier or medium, wherein substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, and the second therapeutic agent is premanid or delamanid;

[0129] The third pharmaceutical composition comprises a substance Z and a pharmaceutically acceptable carrier or medium, wherein the substance Z is a third therapeutic agent or a pharmaceutically acceptable salt thereof, and the third therapeutic agent is linezolid;

[0130] The structure of the compound I is shown below:

[0131] In some embodiments, the substance X is compound I.

[0132] In some embodiments, the substance X is a pharmaceutically acceptable salt of Compound 1; preferably, the substance X is the hydrochloride, sulfate, citrate, maleate or fumarate of Compound 1; more preferably, the substance X is the fumarate of Compound 1.

[0133] In some embodiments, the second therapeutic agent is purimanid.

[0134] In some embodiments, the first pharmaceutical composition is in the form of an oral dosage form.

[0135] In some embodiments, the second pharmaceutical composition is in the form of an oral dosage form.

[0136] In some embodiments, the third pharmaceutical composition is in the form of an oral dosage form.

[0137] In some embodiments, the pharmaceutical composition D consists of the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition.

[0138] In some embodiments, the first pharmaceutical composition comprises 100 mg to 1000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, the first pharmaceutical composition comprises 100 mg to 800 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments, the first pharmaceutical composition comprises 150 mg to 800 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments, the first pharmaceutical composition comprises 150 mg to 500 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments, the first pharmaceutical composition comprises 150 mg to 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments, the first pharmaceutical composition comprises 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0144] In some embodiments, the first pharmaceutical composition comprises 450 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments, the first pharmaceutical composition comprises 300 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the first pharmaceutical composition comprises 150 mg of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, the second therapeutic agent is primanib, and the second pharmaceutical composition comprises 25 mg to 1000 mg of primanib or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the second therapeutic agent is primanib, and the second pharmaceutical composition comprises 50 mg to 1000 mg of primanib or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments, the second therapeutic agent is primanib, and the second pharmaceutical composition comprises 50 mg to 800 mg of primanib or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the second therapeutic agent is primanib, and the second pharmaceutical composition comprises 50 mg to 600 mg of primanib or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, the second therapeutic agent is primanib, and the second pharmaceutical composition comprises 100 mg to 800 mg of primanib or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, the second therapeutic agent is primanib, and the second pharmaceutical composition comprises 100 mg to 600 mg of primanib or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, the second therapeutic agent is primanib, and the second pharmaceutical composition comprises 150 mg to 600 mg of primanib or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, the second therapeutic agent is primanib, and the second pharmaceutical composition comprises 200 mg to 600 mg of primanib or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, the second therapeutic agent is primanib, and the second pharmaceutical composition comprises 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of primanib or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the third pharmaceutical composition comprises 50 mg to 2000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, the third pharmaceutical composition comprises 10 mg to 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, the third pharmaceutical composition comprises 50 mg to 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the third pharmaceutical composition comprises 100 mg to 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the third pharmaceutical composition comprises 200 mg to 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the third pharmaceutical composition comprises 10 mg to 1000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments, the third pharmaceutical composition comprises 50 mg to 1000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0163] In some embodiments, the third pharmaceutical composition comprises 100 mg to 1000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the third pharmaceutical composition comprises 150 mg to 1000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, the third pharmaceutical composition comprises 150 mg to 800 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, the third pharmaceutical composition comprises 150 mg to 600 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0167] In some embodiments, the third pharmaceutical composition comprises 200 mg to 600 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the third pharmaceutical composition comprises 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg or 1600 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the pharmaceutical combination comprises 150 mg to 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, 200 mg to 600 mg of premanid or a pharmaceutically acceptable salt thereof, and 200 mg to 1200 mg (preferably 200 mg to 600 mg) of linezolid or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the pharmaceutical combination comprises: (1) 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg or 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof; (2) 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of premanid or a pharmaceutically acceptable salt thereof; and (3) 200 mg, 300 mg, 400 mg, 500 mg, 600 mg or 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0171] In a seventh aspect, the present invention provides a use of the drug combination as described in the first aspect or the fourth aspect, the pharmaceutical composition A as described in the second aspect, the pharmaceutical composition B as described in the third aspect, the pharmaceutical composition C as described in the fifth aspect, or the pharmaceutical composition D as described in the sixth aspect in the preparation of a medicament for preventing or treating diseases caused by Mycobacterium tuberculosis.

[0172] In some embodiments, the disease caused by Mycobacterium tuberculosis is pulmonary tuberculosis, tuberculous peritonitis, tuberculous pleurisy or bone tuberculosis; preferably, the disease caused by Mycobacterium tuberculosis is pulmonary tuberculosis.

[0173] In an eighth aspect, the present invention provides a use of a substance X in the preparation of a medicament for preventing or treating a disease caused by Mycobacterium tuberculosis, wherein the substance X is Compound I or a pharmaceutically acceptable salt thereof, characterized in that the substance X is used in combination with a substance Y, wherein the substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, and the second therapeutic agent is pyrazinamide, linezolid, moxifloxacin, premanid, or delamanid;

[0174] The structure of the compound I is shown below:

[0175] In some embodiments, the second therapeutic agent is pyrazinamide or delamanid.

[0176] In some embodiments, the disease caused by Mycobacterium tuberculosis is pulmonary tuberculosis, tuberculous peritonitis, tuberculous pleurisy or bone tuberculosis; preferably, the disease caused by Mycobacterium tuberculosis is pulmonary tuberculosis.

[0177] In a ninth aspect, the present invention provides a use of a substance X in the preparation of a medicament for preventing or treating a disease caused by Mycobacterium tuberculosis, wherein the substance X is Compound I or a pharmaceutically acceptable salt thereof, characterized in that the substance X is used in combination with a substance Y and a substance Z, wherein the substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, the second therapeutic agent is premanid or delamanid, and the substance Z is linezolid or a pharmaceutically acceptable salt thereof;

[0178] The structure of the compound I is shown below:

[0179] In some embodiments, the second therapeutic agent is purimanid.

[0180] In some embodiments, the disease caused by Mycobacterium tuberculosis is pulmonary tuberculosis, tuberculous peritonitis, tuberculous pleurisy or bone tuberculosis; preferably, the disease caused by Mycobacterium tuberculosis is pulmonary tuberculosis.

[0181] In a tenth aspect, the present invention provides a pharmaceutical combination for preventing and / or treating diseases caused by Mycobacterium tuberculosis, wherein the pharmaceutical combination is as described in the first aspect or the fourth aspect above.

[0182] In some embodiments, the disease caused by Mycobacterium tuberculosis is pulmonary tuberculosis, tuberculous peritonitis, tuberculous pleurisy or bone tuberculosis; preferably, the disease caused by Mycobacterium tuberculosis is pulmonary tuberculosis.

[0183] In the eleventh aspect, the present invention provides a pharmaceutical composition for preventing and / or treating diseases caused by Mycobacterium tuberculosis, wherein the pharmaceutical composition is as described in the second aspect pharmaceutical composition A, the third aspect pharmaceutical composition B, the fifth aspect pharmaceutical composition C or the sixth aspect pharmaceutical composition D.

[0184] In some embodiments, the disease caused by Mycobacterium tuberculosis is pulmonary tuberculosis, tuberculous peritonitis, tuberculous pleurisy or bone tuberculosis; preferably, the disease caused by Mycobacterium tuberculosis is pulmonary tuberculosis.

[0185] In a twelfth aspect, the present invention provides a method for preventing and / or treating diseases caused by Mycobacterium tuberculosis, comprising administering to a subject in need thereof an effective amount of the drug combination described in the first aspect or the fourth aspect, or administering to a subject in need thereof an effective amount of the pharmaceutical composition A described in the second aspect, the pharmaceutical composition B described in the third aspect, the pharmaceutical composition C described in the fifth aspect, or the pharmaceutical composition D described in the sixth aspect.

[0186] In some embodiments, an effective amount of the pharmaceutical combination of the fourth aspect, the pharmaceutical composition C of the fifth aspect, or the pharmaceutical composition D of the sixth aspect is administered to a subject in need thereof.

[0187] In some embodiments, the administration regimens (including administration routes, administration doses, administration intervals, etc.) of substance X, substance Y, and substance Z may be the same or different, and may be adjusted as needed by those skilled in the art to provide the optimal therapeutic effect.

[0188] In some embodiments, the substance X, substance Y, and substance Z may be administered simultaneously or separately.

[0189] In some embodiments, the substance X can be administered by any suitable route known in the art, including oral administration, injection (eg, intravenous, intramuscular, subcutaneous), and the like.

[0190] In some embodiments, the substance X is administered orally.

[0191] In some embodiments, the substance X is administered to the subject as a fixed dose, i.e., a fixed or predetermined dose is given to the subject. Non-limiting examples of fixed doses (referring to single doses) can range from 10 mg to 2000 mg, preferably from 50 mg to 1000 mg, more preferably from 100 mg to 1000 mg, further preferably from 100 mg to 800 mg, even more preferably from 150 mg to 800 mg, even more preferably from 150 mg to 500 mg, and even more preferably from 150 mg to 450 mg.

[0192] In some embodiments, the substance X is administered to the subject as a fixed dose, ie, the subject is given a dose of a fixed or predetermined amount. Non-limiting examples of fixed doses (referring to single doses) can be, for example, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg.

[0193] In some embodiments, the substance Y can be administered by any suitable route known in the art, including oral administration, injection (eg, intravenous, intramuscular, subcutaneous), and the like.

[0194] In some embodiments, the substance Y is administered orally.

[0195] In some embodiments, the substance Y is administered to the subject as a fixed dose, i.e., a fixed or predetermined dose is given to the subject. Non-limiting examples of fixed doses (referring to single doses) can range from 10 mg to 2000 mg, preferably from 50 mg to 1000 mg, more preferably from 100 mg to 1000 mg, further preferably from 100 mg to 800 mg, even more preferably from 150 mg to 800 mg, even more preferably from 150 mg to 500 mg, and even more preferably from 150 mg to 450 mg.

[0196] In some embodiments, the substance Y is administered to the subject as a fixed dose, ie, the subject is given a dose of a fixed or predetermined amount. Non-limiting examples of fixed doses (referring to single doses) can be, for example, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg.

[0197] In some embodiments, the substance Z can be administered by any suitable route known in the art, including oral administration, injection (eg, intravenous, intramuscular, subcutaneous), and the like.

[0198] In some embodiments, the substance Z is administered orally.

[0199] In some embodiments, the substance Z is administered to the subject as a fixed dose, i.e., a fixed or predetermined dose is given to the subject. Non-limiting examples of fixed doses (referring to single doses) can range from 10 mg to 2000 mg, preferably from 50 mg to 1000 mg, more preferably from 100 mg to 1000 mg, further preferably from 100 mg to 800 mg, even more preferably from 150 mg to 800 mg, even more preferably from 150 mg to 500 mg, even more preferably from 150 mg to 450 mg.

[0200] In some embodiments, the substance Z is administered to the subject as a fixed dose, ie, the subject is given a dose of a fixed or predetermined amount. Non-limiting examples of fixed doses (referring to single doses) can be, for example, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg.

[0201] In some embodiments, the substance Y is purimanid or a pharmaceutically acceptable salt thereof, the substance Z is linezolid or a pharmaceutically acceptable salt thereof, and the substance X is administered to the subject at a fixed dose (referring to a single dose) of 150 mg, the substance Y is administered to the subject at a fixed dose (referring to a single dose) of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg or 800 mg, and the substance Z is administered to the subject at a fixed dose (referring to a single dose) of 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 900 mg, 1000 mg, 1100 mg or 1200 mg.

[0202] In some embodiments, the substance Y is purimanid or a pharmaceutically acceptable salt thereof, the substance Z is linezolid or a pharmaceutically acceptable salt thereof, and the substance X is administered to the subject at a fixed dose (referring to a single dose) of 300 mg, the substance Y is administered to the subject at a fixed dose (referring to a single dose) of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg or 800 mg, and the substance Z is administered to the subject at a fixed dose (referring to a single dose) of 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 900 mg, 1000 mg, 1100 mg or 1200 mg.

[0203] In some embodiments, the substance Y is purimanid or a pharmaceutically acceptable salt thereof, the substance Z is linezolid or a pharmaceutically acceptable salt thereof, and the substance X is administered to the subject at a fixed dose (referring to a single dose) of 450 mg, the substance Y is administered to the subject at a fixed dose (referring to a single dose) of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg or 800 mg, and the substance Z is administered to the subject at a fixed dose (referring to a single dose) of 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 900 mg, 1000 mg, 1100 mg or 1200 mg.

[0204] In some embodiments, the fixed dose of substance X can be administered once a day, every other day, three times a week, twice a week, or once a week.

[0205] In some embodiments, the substance X is administered once a day.

[0206] In some embodiments, the substance X is orally administered at a fixed dose and frequency as described above.

[0207] In some embodiments, the fixed dose of substance Y can be administered once a day, every other day, three times a week, twice a week, or once a week.

[0208] In some embodiments, the substance Y is administered once a day.

[0209] In some embodiments, the substance Y is orally administered at the fixed dose and frequency described above.

[0210] In some embodiments, the fixed dose of substance Z can be administered once a day, every other day, three times a week, twice a week, or once a week.

[0211] In some embodiments, the substance Z is administered once a day.

[0212] In some embodiments, the substance Z is orally administered at the fixed dose and frequency described above.

[0213] In a thirteenth aspect, the present invention provides a pharmaceutical combination comprising

[0214] i) substance X, wherein the substance X is compound 1 or a pharmaceutically acceptable salt thereof;

[0215] ii) substance Y, wherein substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the second therapeutic agent is pyrazinamide, linezolid, moxifloxacin, premanid or delamanid;

[0216] iii) one or more pharmaceutically acceptable carriers or vehicles;

[0217] Optionally, it further comprises iv) a substance Z, wherein the substance Z is a third therapeutic agent or a pharmaceutically acceptable salt thereof, and the third therapeutic agent is pyrazinamide, linezolid, moxifloxacin, premanid or delamanid;

[0218] The structure of the compound I is shown below:

[0219] Provided that, when substance Z is included, the second therapeutic agent and the third therapeutic agent are different.

[0220] In some embodiments, the substance X is compound I.

[0221] In some embodiments, the substance X is a pharmaceutically acceptable salt of Compound 1.

[0222] In some embodiments, the pharmaceutical combination comprises substance X, substance Y, and one or more pharmaceutically acceptable carriers or vehicles; preferably, the pharmaceutical combination consists of substance X, substance Y, and one or more pharmaceutically acceptable carriers or vehicles.

[0223] In some embodiments, the pharmaceutical combination is a single pharmaceutical composition A1.

[0224] In some embodiments, the pharmaceutical composition A1 can be prepared into various suitable dosage forms according to different administration methods, including enteral dosage forms (eg, oral dosage forms) and parenteral dosage forms (eg, injection dosage forms).

[0225] In some embodiments, the pharmaceutical composition A1 is in the form of an oral dosage form.

[0226] In some embodiments, the pharmaceutical composition A1 is in the form of an injection.

[0227] In some embodiments, the pharmaceutical combination is pharmaceutical composition B1, which comprises a first pharmaceutical composition and a second pharmaceutical composition; the first pharmaceutical composition comprises substance X and a pharmaceutically acceptable carrier or vehicle; and the second pharmaceutical composition comprises substance Y and a pharmaceutically acceptable carrier or vehicle.

[0228] In some embodiments, the first pharmaceutical composition is a separate pharmaceutical composition; and / or the second pharmaceutical composition is a separate pharmaceutical composition.

[0229] In some embodiments, the pharmaceutical composition B1 consists of the first pharmaceutical composition and the second pharmaceutical composition.

[0230] In some embodiments, the first pharmaceutical composition is in the form of an oral dosage form or an injection (eg, intravenous, subcutaneous, or intramuscular) dosage form.

[0231] In some embodiments, the second pharmaceutical composition is in the form of an oral dosage form or an injection (eg, intravenous, subcutaneous, or intramuscular) dosage form.

[0232] In some embodiments, the first pharmaceutical composition is in an oral dosage form, and the second pharmaceutical composition is in an oral dosage form.

[0233] In some embodiments, the second therapeutic agent is selected from pyrazinamide, moxifloxacin, or premanid; preferably, the second therapeutic agent is pyrazinamide.

[0234] In some embodiments, the pharmaceutical combination comprises substance X, substance Y, substance Z and one or more pharmaceutically acceptable carriers or media; preferably, the pharmaceutical composition consists of substance X, substance Y, substance Z and one or more pharmaceutically acceptable carriers or media.

[0235] In some embodiments, the substance X is compound I.

[0236] In some embodiments, the substance X is a pharmaceutically acceptable salt of Compound I

[0237] In some embodiments, the pharmaceutical combination is a single pharmaceutical composition A2.

[0238] In some embodiments, the pharmaceutical composition A2 can be prepared into various suitable dosage forms according to different administration methods, including enteral dosage forms (eg, oral dosage forms) and parenteral dosage forms (eg, injection dosage forms).

[0239] In some embodiments, the pharmaceutical composition A2 is in the form of an oral dosage form.

[0240] In some embodiments, the pharmaceutical composition A2 is in the form of an injection.

[0241] In some embodiments, the pharmaceutical combination is pharmaceutical composition C1, which comprises a third pharmaceutical composition, a fourth pharmaceutical composition, and a fifth pharmaceutical composition; the third pharmaceutical composition comprises substance X and a pharmaceutically acceptable carrier or medium; the fourth pharmaceutical composition comprises substance Y and a pharmaceutically acceptable carrier or medium; and / or the fifth pharmaceutical composition comprises substance Z and a pharmaceutically acceptable carrier or medium.

[0242] In some embodiments, the third pharmaceutical composition is a separate pharmaceutical composition; the fourth pharmaceutical composition is a separate pharmaceutical composition; and / or the fifth pharmaceutical composition is a separate pharmaceutical composition.

[0243] In some embodiments, the pharmaceutical composition C1 consists of the third pharmaceutical composition, the fourth pharmaceutical composition, and the fifth pharmaceutical composition.

[0244] In some embodiments, the third pharmaceutical composition is in the form of an oral dosage form or an injection (eg, intravenous, subcutaneous, or intramuscular) dosage form.

[0245] In some embodiments, the fourth pharmaceutical composition is in the form of an oral dosage form or an injection (eg, intravenous, subcutaneous, or intramuscular) dosage form.

[0246] In some embodiments, the fifth pharmaceutical composition is in the form of an oral dosage form or an injection (eg, intravenous, subcutaneous, or intramuscular) dosage form.

[0247] In some embodiments, the third pharmaceutical composition is in an oral dosage form, the fourth pharmaceutical composition is in an oral dosage form, and the fifth pharmaceutical composition is in an oral dosage form.

[0248] In some embodiments, the second therapeutic agent is premanid or delamanid; and / or, the third therapeutic agent is linezolid.

[0249] In some embodiments, the pharmaceutical combination is presented in an oral dosage form.

[0250] In a fourteenth aspect, the present invention provides a pharmaceutical combination comprising

[0251] i) substance X, wherein the substance X is compound 1 or a pharmaceutically acceptable salt thereof;

[0252] ii) substance Y, wherein substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the second therapeutic agent is pyrazinamide, linezolid, moxifloxacin, premanid or delamanid;

[0253] iii) one or more pharmaceutically acceptable carriers or vehicles;

[0254] The structure of the compound I is shown below:

[0255] In some embodiments, the pharmaceutical combination consists of substance X, substance Y, and one or more pharmaceutically acceptable carriers or vehicles.

[0256] In some embodiments, the pharmaceutical combination is a single pharmaceutical composition A1.

[0257] In some embodiments, the pharmaceutical composition A1 can be prepared into various suitable dosage forms according to different administration methods, including enteral dosage forms (eg, oral dosage forms) and parenteral dosage forms (eg, injection dosage forms).

[0258] In some embodiments, the pharmaceutical composition A1 is in the form of an oral dosage form.

[0259] In some embodiments, the pharmaceutical composition A1 is in the form of an injection.

[0260] In some embodiments, the pharmaceutical combination is pharmaceutical composition B1, which comprises a first pharmaceutical composition and a second pharmaceutical composition; the first pharmaceutical composition comprises substance X and a pharmaceutically acceptable carrier or vehicle; and the second pharmaceutical composition comprises substance Y and a pharmaceutically acceptable carrier or vehicle.

[0261] In some embodiments, the first pharmaceutical composition is a separate pharmaceutical composition; and / or the second pharmaceutical composition is a separate pharmaceutical composition.

[0262] In some embodiments, the pharmaceutical composition B1 consists of the first pharmaceutical composition and the second pharmaceutical composition.

[0263] In some embodiments, the first pharmaceutical composition is in the form of an oral dosage form or an injection (eg, intravenous, subcutaneous, or intramuscular) dosage form.

[0264] In some embodiments, the second pharmaceutical composition is in the form of an oral dosage form or an injection (eg, intravenous, subcutaneous, or intramuscular) dosage form.

[0265] In some embodiments, the first pharmaceutical composition is in an oral dosage form, and the second pharmaceutical composition is in an oral dosage form.

[0266] In some embodiments, the substance X is compound I.

[0267] In some embodiments, the substance X is a pharmaceutically acceptable salt of Compound 1; preferably, the substance X is the hydrochloride, sulfate, citrate, maleate or fumarate of Compound 1; more preferably, the substance X is the fumarate of Compound 1.

[0268] In some embodiments, the second therapeutic agent is selected from pyrazinamide, moxifloxacin, or premanid; preferably, the second therapeutic agent is pyrazinamide.

[0269] In some embodiments, the pharmaceutical combination is presented in an oral dosage form.

[0270] In some embodiments, the substance X and substance Y are administered simultaneously or separately;

[0271] In some embodiments, the substance X and substance Y are administered orally.

[0272] In some embodiments, substance X is administered once daily (QD) or twice daily (BID), and / or substance Y is administered once daily (QD) or twice daily (BID).

[0273] In some embodiments, substance X is administered once a week, twice a week, three times a week, or every other day, and / or substance Y is administered once a week, twice a week, three times a week, or every other day.

[0274] In some embodiments, the pharmaceutical combination comprises 10 mg to 2000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, the pharmaceutical combination comprises 50 mg to 1000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0276] In some embodiments, the pharmaceutical combination comprises 100 mg to 1000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0277] In some embodiments, the pharmaceutical combination comprises 100 mg to 800 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments, the pharmaceutical combination comprises 150 mg to 800 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0279] In some embodiments, the pharmaceutical combination comprises 150 mg to 500 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0280] In some embodiments, the pharmaceutical combination comprises 150 mg to 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0281] In some embodiments, the pharmaceutical combination comprises 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg or 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0282] In some embodiments, the pharmaceutical combination comprises 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, the pharmaceutical combination comprises 300 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0284] In some embodiments, the pharmaceutical combination comprises 150 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0285] In some embodiments, the second therapeutic agent is pyrazinamide, and the pharmaceutical combination comprises 10 mg to 4000 mg of pyrazinamide or a pharmaceutically acceptable salt thereof.

[0286] In some embodiments, the second therapeutic agent is pyrazinamide, and the pharmaceutical combination comprises 50 mg to 4000 mg of pyrazinamide or a pharmaceutically acceptable salt thereof.

[0287] In some embodiments, the second therapeutic agent is pyrazinamide, and the pharmaceutical combination comprises 100 mg to 4000 mg of pyrazinamide or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments, the second therapeutic agent is pyrazinamide, and the pharmaceutical combination comprises 150 mg to 3000 mg of pyrazinamide or a pharmaceutically acceptable salt thereof.

[0289] In some embodiments, the second therapeutic agent is pyrazinamide, and the pharmaceutical combination comprises 200 mg to 3000 mg of pyrazinamide or a pharmaceutically acceptable salt thereof.

[0290] In some embodiments, the second therapeutic agent is pyrazinamide, and the pharmaceutical combination comprises 250 mg to 3000 mg of pyrazinamide or a pharmaceutically acceptable salt thereof.

[0291] In some embodiments, the second therapeutic agent is pyrazinamide, and the pharmaceutical combination comprises 300 mg to 2000 mg of pyrazinamide or a pharmaceutically acceptable salt thereof.

[0292] In some embodiments, the second therapeutic agent is pyrazinamide, and the pharmaceutical combination comprises 400 mg to 1500 mg of pyrazinamide or a pharmaceutically acceptable salt thereof.

[0293] In some embodiments, the second therapeutic agent is pyrazinamide, and the pharmaceutical combination comprises 400 mg to 1000 mg of pyrazinamide or a pharmaceutically acceptable salt thereof.

[0294] In some embodiments, the second therapeutic agent is pyrazinamide, and the pharmaceutical combination comprises 400 mg to 800 mg of pyrazinamide or a pharmaceutically acceptable salt thereof.

[0295] In some embodiments, the second therapeutic agent is pyrazinamide, and the pharmaceutical combination comprises 400 mg to 500 mg of pyrazinamide or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, the second therapeutic agent is pyrazinamide, and the pharmaceutical combination comprises 300 mg, 400 mg, 500 mg, 600 mg, or 800 mg of pyrazinamide or a pharmaceutically acceptable salt thereof.

[0297] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 10 mg to 1000 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0298] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 25 mg to 1000 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0299] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 50 mg to 1000 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0300] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 50 mg to 800 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0301] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 50 mg to 600 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0302] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 100 mg to 800 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0303] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 100 mg to 600 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0304] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 150 mg to 600 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 200 mg to 600 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0306] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0307] In some embodiments, the second therapeutic agent is pramanid, and the pharmaceutical combination comprises 10 mg to 1000 mg of pramanid or a pharmaceutically acceptable salt thereof.

[0308] In some embodiments, the second therapeutic agent is pramanid, and the pharmaceutical combination comprises 25 mg to 1000 mg of pramanid or a pharmaceutically acceptable salt thereof.

[0309] In some embodiments, the second therapeutic agent is pramanid, and the pharmaceutical combination comprises 50 mg to 1000 mg of pramanid or a pharmaceutically acceptable salt thereof.

[0310] In some embodiments, the second therapeutic agent is pramanid, and the pharmaceutical combination comprises 50 mg to 800 mg of pramanid or a pharmaceutically acceptable salt thereof.

[0311] In some embodiments, the second therapeutic agent is pramanid, and the pharmaceutical combination comprises 50 mg to 600 mg of pramanid or a pharmaceutically acceptable salt thereof.

[0312] In some embodiments, the second therapeutic agent is premanid, and the pharmaceutical combination comprises 100 mg to 800 mg of premanid or a pharmaceutically acceptable salt thereof.

[0313] In some embodiments, the second therapeutic agent is premanid, and the pharmaceutical combination comprises 100 mg to 600 mg of premanid or a pharmaceutically acceptable salt thereof.

[0314] In some embodiments, the second therapeutic agent is pramanid, and the pharmaceutical combination comprises 150 mg to 600 mg of pramanid or a pharmaceutically acceptable salt thereof.

[0315] In some embodiments, the second therapeutic agent is premanid, and the pharmaceutical combination comprises 200 mg to 600 mg of premanid or a pharmaceutically acceptable salt thereof.

[0316] In some embodiments, the second therapeutic agent is premanid, and the pharmaceutical combination comprises 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of premanid or a pharmaceutically acceptable salt thereof.

[0317] In some embodiments, the pharmaceutical combination comprises 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg or 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the pharmaceutical combination comprises 300 mg, 400 mg, 500 mg, 600 mg or 800 mg of pyrazinamide or a pharmaceutically acceptable salt thereof.

[0318] In some embodiments, the pharmaceutical combination comprises 150 mg, 300 mg or 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the pharmaceutical combination comprises 300 mg, 400 mg, 500 mg, 600 mg or 800 mg of pyrazinamide or a pharmaceutically acceptable salt thereof.

[0319] In a fifteenth aspect, the present invention provides a pharmaceutical combination comprising

[0320] i) substance X, wherein the substance X is compound 1 or a pharmaceutically acceptable salt thereof;

[0321] ii) substance Y, wherein substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the second therapeutic agent is pyrazinamide, linezolid, moxifloxacin, premanid or delamanid;

[0322] iii) one or more pharmaceutically acceptable carriers or vehicles;

[0323] iv) substance Z, wherein the substance Z is a third therapeutic agent or a pharmaceutically acceptable salt thereof, and the third therapeutic agent is pyrazinamide, linezolid, moxifloxacin, premanid, or delamanid;

[0324] The structure of the compound I is shown below:

[0325] Provided that the second therapeutic agent and the third therapeutic agent are different.

[0326] In some embodiments, the pharmaceutical combination consists of substance X, substance Y, substance Z, and one or more pharmaceutically acceptable carriers or vehicles.

[0327] In some embodiments, the pharmaceutical combination is a single pharmaceutical composition A2.

[0328] In some embodiments, the pharmaceutical composition A2 can be prepared into various suitable dosage forms according to different administration methods, including enteral dosage forms (eg, oral dosage forms) and parenteral dosage forms (eg, injection dosage forms).

[0329] In some embodiments, the pharmaceutical composition A2 is in the form of an oral dosage form.

[0330] In some embodiments, the pharmaceutical composition A2 is in the form of an injection.

[0331] In some embodiments, the pharmaceutical combination is pharmaceutical composition C1, which comprises a third pharmaceutical composition, a fourth pharmaceutical composition, and a fifth pharmaceutical composition; the third pharmaceutical composition comprises substance X and a pharmaceutically acceptable carrier or medium; the fourth pharmaceutical composition comprises substance Y and a pharmaceutically acceptable carrier or medium; and / or the fifth pharmaceutical composition comprises substance Z and a pharmaceutically acceptable carrier or medium.

[0332] In some embodiments, the third pharmaceutical composition is a separate pharmaceutical composition; the fourth pharmaceutical composition is a separate pharmaceutical composition; and / or the fifth pharmaceutical composition is a separate pharmaceutical composition.

[0333] In some embodiments, the pharmaceutical composition C1 consists of the third pharmaceutical composition, the fourth pharmaceutical composition, and the fifth pharmaceutical composition.

[0334] In some embodiments, the third pharmaceutical composition is in the form of an oral dosage form or an injection (eg, intravenous, subcutaneous, or intramuscular) dosage form.

[0335] In some embodiments, the fourth pharmaceutical composition is in the form of an oral dosage form or an injection (eg, intravenous, subcutaneous, or intramuscular) dosage form.

[0336] In some embodiments, the fifth pharmaceutical composition is in the form of an oral dosage form or an injection (eg, intravenous, subcutaneous, or intramuscular) dosage form.

[0337] In some embodiments, the third pharmaceutical composition is in an oral dosage form, the fourth pharmaceutical composition is in an oral dosage form, and the fifth pharmaceutical composition is in an oral dosage form.

[0338] In some embodiments, the substance X is compound I.

[0339] In some embodiments, the substance X is a pharmaceutically acceptable salt of Compound 1.

[0340] In some embodiments, the second therapeutic agent is premanid or delamanid; and / or, the third therapeutic agent is linezolid.

[0341] In some embodiments, the second therapeutic agent is premanid and the third therapeutic agent is linezolid, or the second therapeutic agent is delamanid and the third therapeutic agent is linezolid.

[0342] In some embodiments, the pharmaceutical combination is presented in an oral dosage form.

[0343] In some embodiments, the substance X, substance Y, and substance Z are administered simultaneously or separately;

[0344] In some embodiments, the substance X, substance Y, and substance Z are administered orally.

[0345] In some embodiments, the pharmaceutical combination comprises 10 mg to 2000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0346] In some embodiments, the pharmaceutical combination comprises 50 mg to 1000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0347] In some embodiments, the pharmaceutical combination comprises 100 mg to 1000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0348] In some embodiments, the pharmaceutical combination comprises 100 mg to 800 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0349] In some embodiments, the pharmaceutical combination comprises 150 mg to 800 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0350] In some embodiments, the pharmaceutical combination comprises 150 mg to 500 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0351] In some embodiments, the pharmaceutical combination comprises 150 mg to 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0352] In some embodiments, the pharmaceutical combination comprises 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg or 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0353] In some embodiments, the pharmaceutical combination comprises 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0354] In some embodiments, the pharmaceutical combination comprises 300 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0355] In some embodiments, the pharmaceutical combination comprises 150 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0356] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 10 mg to 1000 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0357] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 25 mg to 1000 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0358] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 50 mg to 1000 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0359] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 50 mg to 800 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0360] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 50 mg to 600 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0361] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 100 mg to 800 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0362] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 100 mg to 600 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0363] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 150 mg to 600 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0364] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 200 mg to 600 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0365] In some embodiments, the second therapeutic agent is delamanid, and the pharmaceutical combination comprises 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg of delamanid or a pharmaceutically acceptable salt thereof.

[0366] In some embodiments, the second therapeutic agent is pramanid, and the pharmaceutical combination comprises 10 mg to 1000 mg of pramanid or a pharmaceutically acceptable salt thereof.

[0367] In some embodiments, the second therapeutic agent is pramanid, and the pharmaceutical combination comprises 25 mg to 1000 mg of pramanid or a pharmaceutically acceptable salt thereof.

[0368] In some embodiments, the second therapeutic agent is pramanid, and the pharmaceutical combination comprises 50 mg to 1000 mg of pramanid or a pharmaceutically acceptable salt thereof.

[0369] In some embodiments, the second therapeutic agent is pramanid, and the pharmaceutical combination comprises 50 mg to 800 mg of pramanid or a pharmaceutically acceptable salt thereof.

[0370] In some embodiments, the second therapeutic agent is pramanid, and the pharmaceutical combination comprises 50 mg to 600 mg of pramanid or a pharmaceutically acceptable salt thereof.

[0371] In some embodiments, the second therapeutic agent is premanid, and the pharmaceutical combination comprises 100 mg to 800 mg of premanid or a pharmaceutically acceptable salt thereof.

[0372] In some embodiments, the second therapeutic agent is premanid, and the pharmaceutical combination comprises 100 mg to 600 mg of premanid or a pharmaceutically acceptable salt thereof.

[0373] In some embodiments, the second therapeutic agent is pramanid, and the pharmaceutical combination comprises 150 mg to 600 mg of pramanid or a pharmaceutically acceptable salt thereof.

[0374] In some embodiments, the second therapeutic agent is premanid, and the pharmaceutical combination comprises 200 mg to 600 mg of premanid or a pharmaceutically acceptable salt thereof.

[0375] In some embodiments, the second therapeutic agent is premanid, and the pharmaceutical combination comprises 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of premanid or a pharmaceutically acceptable salt thereof.

[0376] In some embodiments, the third therapeutic agent is linezolid, and the drug combination comprises 10 mg to 2000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0377] In some embodiments, the third therapeutic agent is linezolid, and the drug combination comprises 50 mg to 2000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0378] In some embodiments, the third therapeutic agent is linezolid, and the drug combination comprises 10 mg to 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0379] In some embodiments, the third therapeutic agent is linezolid, and the drug combination comprises 50 mg to 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0380] In some embodiments, the third therapeutic agent is linezolid, and the drug combination comprises 100 mg to 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0381] In some embodiments, the third therapeutic agent is linezolid, and the drug combination comprises 200 mg to 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0382] In some embodiments, the third therapeutic agent is linezolid, and the drug combination comprises 10 mg to 1000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0383] In some embodiments, the third therapeutic agent is linezolid, and the drug combination comprises 50 mg to 1000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0384] In some embodiments, the third therapeutic agent is linezolid, and the pharmaceutical combination comprises 100 mg to 1000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0385] In some embodiments, the third therapeutic agent is linezolid, and the drug combination comprises 150 mg to 1000 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0386] In some embodiments, the third therapeutic agent is linezolid, and the drug combination comprises 150 mg to 800 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0387] In some embodiments, the third therapeutic agent is linezolid, and the drug combination comprises 150 mg to 600 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0388] In some embodiments, the third therapeutic agent is linezolid, and the drug combination comprises 200 mg to 600 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0389] In some embodiments, the third therapeutic agent is linezolid, and the drug combination comprises 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg or 1600 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0390] In some embodiments, the pharmaceutical combination comprises 150 mg to 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, 200 mg to 600 mg of premanid or a pharmaceutically acceptable salt thereof, and 200 mg to 1200 mg (preferably 200 mg to 600 mg) of linezolid or a pharmaceutically acceptable salt thereof.

[0391] In some embodiments, the pharmaceutical combination comprises 150 mg to 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, 200 mg to 600 mg of delamanid or a pharmaceutically acceptable salt thereof, and 200 mg to 1200 mg (preferably 200 mg to 600 mg) of linezolid or a pharmaceutically acceptable salt thereof.

[0392] In some embodiments, the pharmaceutical combination comprises: (1) 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg or 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof; (2) 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of premanid or a pharmaceutically acceptable salt thereof; and (3) 200 mg, 300 mg, 400 mg, 500 mg, 600 mg or 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0393] In some embodiments, the pharmaceutical combination comprises: (1) 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof; (2) 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg of delamanid or a pharmaceutically acceptable salt thereof; and (3) 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 1200 mg of linezolid or a pharmaceutically acceptable salt thereof.

[0394] In a sixteenth aspect, the present invention provides use of the drug combination according to any one of aspects 13 to 15 in the preparation of a drug for preventing and / or treating diseases caused by Mycobacterium tuberculosis.

[0395] In some embodiments, the disease caused by Mycobacterium tuberculosis is pulmonary tuberculosis, tuberculous peritonitis, tuberculous pleurisy or bone tuberculosis; preferably, the disease caused by Mycobacterium tuberculosis is pulmonary tuberculosis.

[0396] In a seventeenth aspect, the present invention provides a drug combination for preventing and / or treating diseases caused by Mycobacterium tuberculosis, wherein the drug combination is as described in the thirteenth aspect, fourteenth aspect or fifteenth aspect above.

[0397] In some embodiments, the disease caused by Mycobacterium tuberculosis is pulmonary tuberculosis, tuberculous peritonitis, tuberculous pleurisy or bone tuberculosis; preferably, the disease caused by Mycobacterium tuberculosis is pulmonary tuberculosis.

[0398] In an eighteenth aspect, the present invention provides a method for preventing and / or treating diseases caused by Mycobacterium tuberculosis, comprising administering an effective amount of the drug combination according to any one of aspects 13 to 15 to a subject in need thereof.

[0399] In some embodiments, an effective amount of the pharmaceutical combination of the thirteenth aspect is administered to a subject in need thereof.

[0400] In some embodiments, an effective amount of the pharmaceutical combination of aspect 14 is administered to a subject in need thereof.

[0401] In some embodiments, the substance Y is pyrazinamide or a pharmaceutically acceptable salt thereof.

[0402] In some embodiments, the substance Y is moxifloxacin or a pharmaceutically acceptable salt thereof.

[0403] In some embodiments, the substance Y is delamanid or a pharmaceutically acceptable salt thereof.

[0404] In some embodiments, the substance Y is linezolid or a pharmaceutically acceptable salt thereof.

[0405] In some embodiments, the substance Y is primanib or a pharmaceutically acceptable salt thereof.

[0406] In some embodiments, the administration regimens (including administration routes, administration dosages, administration intervals, etc.) of substance X and substance Y may be the same or different, and may be adjusted as needed by those skilled in the art to provide the optimal therapeutic effect.

[0407] In some embodiments, the substance X and substance Y can be administered simultaneously or separately.

[0408] In some embodiments, the substance X can be administered by any suitable route known in the art, including oral administration, injection (eg, intravenous, intramuscular, subcutaneous), and the like.

[0409] In some embodiments, the substance X is administered orally.

[0410] In some embodiments, the substance X is administered to the subject as a fixed dose, i.e., a fixed or predetermined dose is given to the subject. Non-limiting examples of fixed doses (referring to single doses) can range from 10 mg to 2000 mg, preferably from 50 mg to 1000 mg, more preferably from 100 mg to 1000 mg, further preferably from 100 mg to 800 mg, even more preferably from 150 mg to 800 mg, even more preferably from 150 mg to 500 mg, and even more preferably from 150 mg to 450 mg.

[0411] In some embodiments, the substance X is administered to the subject as a fixed dose, ie, the subject is given a dose of a fixed or predetermined amount. Non-limiting examples of fixed doses (referring to single doses) can be, for example, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg.

[0412] In some embodiments, the substance Y can be administered by any suitable route known in the art, including oral administration, injection (eg, intravenous, intramuscular, subcutaneous), and the like.

[0413] In some embodiments, the substance Y is administered orally.

[0414] In some embodiments, the substance Y is administered to the subject as a fixed dose, i.e., a fixed or predetermined dose is given to the subject. Non-limiting examples of fixed doses (referring to single doses) can range from 10 mg to 2000 mg, preferably from 50 mg to 1000 mg, more preferably from 100 mg to 1000 mg, further preferably from 100 mg to 800 mg, even more preferably from 150 mg to 800 mg, even more preferably from 150 mg to 500 mg, and even more preferably from 150 mg to 450 mg.

[0415] In some embodiments, the substance Y is administered to the subject as a fixed dose, ie, the subject is given a dose of a fixed or predetermined amount. Non-limiting examples of fixed doses (referring to single doses) can be, for example, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg.

[0416] In some embodiments, the substance X is administered to the subject at a fixed dose (referring to a single dose) of 150 mg, and the substance Y is pyrazinamide or a pharmaceutically acceptable salt thereof, and the substance Y is administered to the subject at a fixed dose (referring to a single dose) of 300 mg, 400 mg, 500 mg, 600 mg, or 800 mg.

[0417] In some embodiments, the substance X is administered to the subject at a fixed dose (referring to a single dose) of 300 mg, and the substance Y is pyrazinamide or a pharmaceutically acceptable salt thereof, and the substance Y is administered to the subject at a fixed dose (referring to a single dose) of 300 mg, 400 mg, 500 mg, 600 mg or 800 mg.

[0418] In some embodiments, the substance X is administered to the subject at a fixed dose (referring to a single dose) of 450 mg, and the substance Y is pyrazinamide or a pharmaceutically acceptable salt thereof, and the substance Y is administered to the subject at a fixed dose (referring to a single dose) of 300 mg, 400 mg, 500 mg, 600 mg, or 800 mg.

[0419] In some embodiments, the fixed dose of substance X can be administered once a day, every other day, three times a week, twice a week, or once a week.

[0420] In some embodiments, the substance X is administered once a day.

[0421] In some embodiments, the substance X is orally administered at a fixed dose and frequency as described above.

[0422] In some embodiments, the fixed dose of substance Y can be administered once a day, every other day, three times a week, twice a week, or once a week.

[0423] In some embodiments, the substance Y is administered once a day.

[0424] In some embodiments, the substance Y is orally administered at the fixed dose and frequency described above.

[0425] In some embodiments, an effective amount of the pharmaceutical combination of aspect 15 is administered to a subject in need thereof.

[0426] In some embodiments, the administration regimens (including administration routes, administration doses, administration intervals, etc.) of substance X, substance Y, and substance Z may be the same or different, and may be adjusted as needed by those skilled in the art to provide the optimal therapeutic effect.

[0427] In some embodiments, the substance X, substance Y, and substance Z may be administered simultaneously or separately.

[0428] In some embodiments, the substance X can be administered by any suitable route known in the art, including oral administration, injection (eg, intravenous, intramuscular, subcutaneous), and the like.

[0429] In some embodiments, the substance X is administered orally.

[0430] In some embodiments, the substance X is administered to the subject as a fixed dose, i.e., a fixed or predetermined dose is given to the subject. Non-limiting examples of fixed doses (referring to single doses) can range from 10 mg to 2000 mg, preferably from 50 mg to 1000 mg, more preferably from 100 mg to 1000 mg, further preferably from 100 mg to 800 mg, even more preferably from 150 mg to 800 mg, even more preferably from 150 mg to 500 mg, and even more preferably from 150 mg to 450 mg.

[0431] In some embodiments, the substance X is administered to the subject as a fixed dose, ie, the subject is given a dose of a fixed or predetermined amount. Non-limiting examples of fixed doses (referring to single doses) can be, for example, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg.

[0432] In some embodiments, the substance Y can be administered by any suitable route known in the art, including oral administration, injection (eg, intravenous, intramuscular, subcutaneous), and the like.

[0433] In some embodiments, the substance Y is administered orally.

[0434] In some embodiments, the substance Y is administered to the subject as a fixed dose, i.e., a fixed or predetermined dose is given to the subject. Non-limiting examples of fixed doses (referring to single doses) can range from 10 mg to 2000 mg, preferably from 50 mg to 1000 mg, more preferably from 100 mg to 1000 mg, further preferably from 100 mg to 800 mg, even more preferably from 150 mg to 800 mg, even more preferably from 150 mg to 500 mg, and even more preferably from 150 mg to 450 mg.

[0435] In some embodiments, the substance Y is administered to the subject as a fixed dose, ie, the subject is given a dose of a fixed or predetermined amount. Non-limiting examples of fixed doses (referring to single doses) can be, for example, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg.

[0436] In some embodiments, the substance Z can be administered by any suitable route known in the art, including oral administration, injection (eg, intravenous, intramuscular, subcutaneous), and the like.

[0437] In some embodiments, the substance Z is administered orally.

[0438] In some embodiments, the substance Z is administered to the subject as a fixed dose, i.e., a fixed or predetermined dose is given to the subject. Non-limiting examples of fixed doses (referring to single doses) can range from 10 mg to 2000 mg, preferably from 50 mg to 1000 mg, more preferably from 100 mg to 1000 mg, further preferably from 100 mg to 800 mg, even more preferably from 150 mg to 800 mg, even more preferably from 150 mg to 500 mg, even more preferably from 150 mg to 450 mg.

[0439] In some embodiments, the substance Z is administered to the subject as a fixed dose, ie, the subject is given a dose of a fixed or predetermined amount. Non-limiting examples of fixed doses (referring to single doses) can be, for example, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg.

[0440] In some embodiments, the substance Y is purimanid or a pharmaceutically acceptable salt thereof, the substance Z is linezolid or a pharmaceutically acceptable salt thereof, and the substance X is administered to the subject at a fixed dose (referring to a single dose) of 150 mg, the substance Y is administered to the subject at a fixed dose (referring to a single dose) of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg or 800 mg, and the substance Z is administered to the subject at a fixed dose (referring to a single dose) of 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 900 mg, 1000 mg, 1100 mg or 1200 mg.

[0441] In some embodiments, the substance Y is purimanid or a pharmaceutically acceptable salt thereof, the substance Z is linezolid or a pharmaceutically acceptable salt thereof, and the substance X is administered to the subject at a fixed dose (referring to a single dose) of 300 mg, the substance Y is administered to the subject at a fixed dose (referring to a single dose) of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg or 800 mg, and the substance Z is administered to the subject at a fixed dose (referring to a single dose) of 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 900 mg, 1000 mg, 1100 mg or 1200 mg.

[0442] In some embodiments, the substance Y is purimanid or a pharmaceutically acceptable salt thereof, the substance Z is linezolid or a pharmaceutically acceptable salt thereof, and the substance X is administered to the subject at a fixed dose (referring to a single dose) of 450 mg, the substance Y is administered to the subject at a fixed dose (referring to a single dose) of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg or 800 mg, and the substance Z is administered to the subject at a fixed dose (referring to a single dose) of 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 900 mg, 1000 mg, 1100 mg or 1200 mg.

[0443] In some embodiments, the substance Y is delamanid or a pharmaceutically acceptable salt thereof, the substance Z is linezolid or a pharmaceutically acceptable salt thereof, and the substance X is administered to the subject at a fixed dose (referring to a single dose) of 150 mg, the substance Y is administered to the subject at a fixed dose (referring to a single dose) of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 800 mg, and the substance Z is administered to the subject at a fixed dose (referring to a single dose) of 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mg.

[0444] In some embodiments, the substance Y is delamanid or a pharmaceutically acceptable salt thereof, the substance Z is linezolid or a pharmaceutically acceptable salt thereof, and the substance X is administered to the subject at a fixed dose (referring to a single dose) of 300 mg, the substance Y is administered to the subject at a fixed dose (referring to a single dose) of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 800 mg, and the substance Z is administered to the subject at a fixed dose (referring to a single dose) of 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mg.

[0445] In some embodiments, the substance Y is delamanid or a pharmaceutically acceptable salt thereof, the substance Z is linezolid or a pharmaceutically acceptable salt thereof, and the substance X is administered to the subject at a fixed dose (referring to a single dose) of 450 mg, the substance Y is administered to the subject at a fixed dose (referring to a single dose) of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 800 mg, and the substance Z is administered to the subject at a fixed dose (referring to a single dose) of 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mg.

[0446] In some embodiments, the fixed dose of substance X can be administered once a day, every other day, three times a week, twice a week, or once a week.

[0447] In some embodiments, the substance X is administered once a day.

[0448] In some embodiments, the substance X is orally administered at a fixed dose and frequency as described above.

[0449] In some embodiments, the fixed dose of substance Y can be administered once a day, every other day, three times a week, twice a week, or once a week.

[0450] In some embodiments, the substance Y is administered once a day.

[0451] In some embodiments, the substance Y is orally administered at the fixed dose and frequency described above.

[0452] In some embodiments, the fixed dose of substance Z can be administered once a day, every other day, three times a week, twice a week, or once a week.

[0453] In some embodiments, the substance Z is administered once a day.

[0454] In some embodiments, the substance Z is orally administered at the fixed dose and frequency described above.

[0455] Definition and Description

[0456] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0457] As used herein, the terms "optional," "optionally," or "optionally" mean that the subsequently described event or circumstance may or may not occur.

[0458] As used herein, the term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively prevent or treat a disease or condition described herein. The amount of compound that constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

[0459] The term "pharmaceutical composition" as used herein refers to a composition containing specified active ingredients that can be prepared into a single dosage form.

[0460] As used herein, the term "subject in need thereof" refers to any animal, preferably a mammal, and most preferably a human, that is about to receive or has received a compound or composition according to an embodiment of the present invention. As used herein, the term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.

[0461] As used herein, the term "pharmaceutically acceptable carrier or medium" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. These are all substances contained in pharmaceutical preparations, in addition to the active ingredient. For more information, see the Pharmacopoeia of the People's Republic of China (2020 Edition), Part IV, or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0462] The term "pharmaceutically acceptable" as used herein means that the acid or base, solvent, excipient, etc. (used in preparing salts) are generally non-toxic, safe, and suitable for use by patients. The "patient" is preferably a mammal, more preferably a human.

[0463] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a compound with a relatively nontoxic, pharmaceutically acceptable acid or base. When a compound contains relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, and diethanolamine salts. When a compound contains relatively basic functional groups, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a neat solution or a suitable inert solvent. Pharmaceutically acceptable acids include, but are not limited to, inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, phosphorous acid, sulfuric acid, and bisulfate. The pharmaceutically acceptable acid includes organic acids, including but not limited to acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compound contains relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0464] The terms "Compound I" and "pharmaceutically acceptable salt of Compound I" as used herein are defined to include all forms of the compound of Formula (I) or its salts, including crystals and amorphous solids, isomorphs, polymorphs, solvates and hydrates of the compound of Formula (I), and crystals and amorphous solids, isomorphs, polymorphs, solvates and hydrates of pharmaceutically acceptable salts of Compound I.

[0465] As used herein, the term "solvate" describes a non-covalent or readily reversible combination or dispersion or dispersed phase between a solvent and a solute. It will be understood that a solvate can be in the form of a solid, a slurry (e.g., a suspension or dispersion), or a solution. Non-limiting examples of solvents include ethanol, methanol, propanol, acetonitrile, dimethyl ether, diethyl ether, tetrahydrofuran, dichloromethane, and water. When the solvent is water, the term "hydrate" is used.

[0466] As used herein, the term "simultaneous administration" refers to the simultaneous administration of each substance in a pharmaceutical combination contained in a separate pharmaceutical composition, or the simultaneous administration of separate pharmaceutical compositions containing a substance in the pharmaceutical combination. For example, simultaneous administration of a pharmaceutical combination containing substance X and substance Y means that substances X and Y are contained in a separate pharmaceutical composition and administered simultaneously; or, alternatively, "a separate pharmaceutical composition containing substance X" and "a separate pharmaceutical composition containing substance Y" are administered simultaneously. For another example, simultaneous administration of a pharmaceutical composition containing substance X, substance Y, and substance Z means that substances X, substance Y, and substance Z are contained in a separate pharmaceutical composition and administered simultaneously; or, "a separate pharmaceutical composition containing substance X," "a separate pharmaceutical composition containing substance Y," and "a separate pharmaceutical composition containing substance Z" are administered simultaneously.

[0467] As used herein, the term "separate administration" means that each separate pharmaceutical composition comprising a substance in a pharmaceutical combination is administered separately at different times, and the separate administration may be close in time or distant in time. For example, separate administration of a pharmaceutical combination comprising substance X and substance Y means that "a separate pharmaceutical composition comprising substance X" and "a separate pharmaceutical composition comprising substance Y" are administered separately at different times. For another example, separate administration of a pharmaceutical composition comprising substance X, substance Y, and substance Z means that "a separate pharmaceutical composition comprising substance X," "a separate pharmaceutical composition comprising substance Y," and "a separate pharmaceutical composition comprising substance Z" are administered separately at different times.

[0468] Whether administered simultaneously or separately, the administration regimen of each substance in the drug combination (including administration route, administration dosage, administration interval, etc.) can be the same or different, which can be adjusted by those skilled in the art as needed to provide the optimal therapeutic effect.

[0469] As used herein, the term "a certain mass (e.g., 150 mg) of a compound or a pharmaceutically acceptable salt thereof" refers to the free base of the active ingredient in the compound or its pharmaceutically acceptable salt. For example, if the pharmaceutical combination contains 150 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, it means that the mass of the free base of the active ingredient in the compound of formula (I) or its pharmaceutically acceptable salt contained in the pharmaceutical combination (i.e., the compound of formula (I)) is 150 mg.

[0470] The term "fixed dose" as used herein is calculated as the free base of the active ingredient in the administered substance. For example, if a substance Y is administered to the subject at a fixed dose (referring to a single dose) of 100 mg, the free base mass of the active ingredient in the substance Y administered to the subject is 100 mg.

[0471] The term "pyrazinamide" used herein has an English name of Pyrazinamide, a chemical formula of C5H5N3O, and a CAS registration number of 98-96-4.

[0472] The term "moxifloxacin" used herein has an English name of Moxifloxacin, a chemical formula of C21H24FN3O4, and a CAS registration number of 151096-09-2.

[0473] The term "linezolid" used herein has an English name of Linezolid, a chemical formula of C16H20FN3O4, and a CAS registration number of 165800-03-3.

[0474] The term "Pretomanid" used herein has an English name of Pretomanid, a chemical formula of C14H12F3N3O5, and a CAS registration number of 187235-37-6.

[0475] The term "Delamanid" used herein has an English name of Delamanid, a chemical formula of C25H25F3N4O6, and a CAS registration number of 681492-22-8.

[0476] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0477] The positive advances of the present invention include providing a novel drug combination comprising Compound I and other anti-TB drugs, which helps overcome drug resistance, improve efficacy, shorten treatment time, improve patient compliance, reduce side effects, lower costs, and increase cure rates. Compared to most single drugs, the drug combination of the present invention significantly improves in vivo efficacy, with some drug combinations showing particularly significant in vivo efficacy. DETAILED DESCRIPTION

[0478] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0479] The following abbreviations are used in the following examples and have the definitions shown unless otherwise specified: CFU is colony forming unit; INH is isoniazid; RFP is rifampicin; PZA is pyrazinamide; MFX is moxifloxacin; LZD is linezolid; BDQ is bedaquiline; PMD is premanid; DLM is delamanid.

[0480] Materials and methods

[0481] 1) Strain: Mycobacterium tuberculosis standard strain H 37 Rv (ATCC 27294) was purchased and stored in the Pharmacology Laboratory of the Beijing Institute of Pulmonary Tuberculosis and Thoracic Oncology. Clinical isolates of Mycobacterium tuberculosis were provided by the National Tuberculosis Clinical Laboratory of the Beijing Institute of Tuberculosis and Thoracic Oncology. Basic information on each clinical isolate is shown in Table 1.

[0482] Table 1 Basic information of clinically isolated Mycobacterium tuberculosis strains

[0483] 2) Reagents

[0484] Alamar Blue (AbD Serotec, UK);

[0485] Middlebrook OADC broth, 7H9 liquid culture medium (Becton Dickinson Company, USA)

[0486] Middlebrook OADC broth, 7H10 solid culture medium (Middlebrook OADC broth, 7H9 solid culture medium, Becton Dickinson Company, USA)

[0487] DMSO (Beijing Solebo Technology Co., Ltd.);

[0488] Glycerol (Beijing Chemical Factory);

[0489] Tween-80 (Tween-80, Beijing solarbio science & technology co., ltd.).

[0490] 3) Compounds

[0491] INH, RFP (Sigma, USA); Compound I (Shanghai Jiatan Pharmaceutical, or can be prepared by the method disclosed in WO2017121323A1); BDQ, MFX, PMD (Shanghai Hanxiang Biotechnology Co., Ltd.); DLM (TargetMol, USA); LZD (ArRPharm).

[0492] 4) Preparation of drug stock solution

[0493] Weigh an appropriate amount of the anti-TB drug powder listed in the table below into a 15 mL sterile centrifuge tube. Dissolve water-soluble drugs in ultrapure water and fat-soluble drugs in DMSO. After sonication and membrane filtration, aliquot the stock solutions of each anti-TB drug into sterile EP tubes and store in a -80°C freezer until needed. The specific preparation methods for each drug stock solution are shown in Table 2.

[0494] Table 2 Preparation methods of each drug stock solution

[0495] Example 1 MIC determination of anti-tuberculosis drugs

[0496] 1) Culture and subculture of Mycobacterium tuberculosis

[0497] Take out the standard strain H from the -80℃ freezer 37 The frozen liquid of Rv and four clinical strains (strain numbers: 30031, 30091, 29925, 30611) was placed at room temperature for dissolution. After complete thawing, 200 μL of bacterial liquid was respectively aspirated and added to 7H9 liquid culture medium containing 0.05% Tween-80. The culture was carried out in a constant temperature incubator at 37°C and 5% CO2 for about 2 weeks until the logarithmic growth phase.

[0498] 2) Serial dilution of drug stock solution

[0499] Because the MIC value of DLM is too low, DLM was diluted 256 times in advance. First, 100 μL of 7H9 liquid culture medium was added to the first 6 wells of row A of a 96-well plate, and then 200 μL of 7H9 liquid culture medium was added to the last 6 wells (100 μL of diluted bacterial solution was added to the first 6 wells as positive control wells, and the last 6 wells as negative control wells). Then, 198 μL of 7H9 liquid culture medium was added to the first column of microwells in rows BH of the 96-well plate, and 100 μL of 7H9 liquid culture medium was added to the remaining microwells. 2 μL of each drug stock solution was added to the first column of microwells in rows BH. After the drug solution and 7H9 liquid culture medium were thoroughly mixed, 100 μL of the mixed solution was pipetted to the next column using the two-fold dilution method. This operation was repeated until the last column of microwells, and the last 100 μL of liquid was discarded.

[0500] 3) Determination and dilution of bacterial solution concentration

[0501] One standard strain and four clinical strains cultured to the logarithmic growth phase were taken out of a constant temperature incubator at 37°C and 5% CO2. 200 μL of bacterial solution and 7H9 liquid culture medium were respectively aspirated into a 96-well plate in a biosafety cabinet, with two replicate wells set for each sample. The 96-well plate was placed in a multifunctional microplate reader, and the OD value of each well was measured at a wavelength of 570 nm, where OD (strain) = OD (bacterial solution) - OD (7H9 culture medium). The final concentration of each strain was set to 1 × 10 5 CFU / mL, add the corresponding volume of 7H9 liquid culture medium to dilute each bacterial solution, where OD = 0.1 is equivalent to 1×10 7 CFU / mL.

[0502] Except for the negative control well, 100 μL / well of diluted bacterial solution was added to the remaining wells. At this time, the total volume of all wells was 200 μL. After sealing with sealing film, the wells were placed in a constant temperature incubator at 37°C and 5% CO2 for 7 days.

[0503] 4) Addition of Alamar Blue indicator

[0504] Remove the 96-well plate from the incubator and protect from light throughout the process. Add Alamar Blue indicator at a volume of 20 μL / well and 20% Tween-80 at a volume of 12.5 μL / well. After sealing, place the 96-well plate in a constant temperature incubator at 37°C containing 5% CO2 and observe the color change the next day.

[0505] 5) Determination of fluorescence value

[0506] Place the 96-well plate in a multi-function microplate reader and measure the fluorescence value of each microwell at an excitation wavelength of 530nm and an emission wavelength of 590nm. Record the color of each well. Blue wells represent no growth, pink wells represent growth. Continue incubating purple-red wells at 37°C for 24 hours. If the purple-red wells do not turn pink and the adjacent blue wells remain blue, then growth is recorded.

[0507] The MIC results of anti-tuberculosis drugs (Compound I, BDQ, INH, RFP, LZD, DLM, MFX and PMD) against tuberculosis strains determined by MABA method are shown in Table 3.

[0508] Table 3 Minimum inhibitory concentrations (μg / mL) of anti-tuberculosis drugs against H37Rv and four clinical strains

[0509] Example 2 Two-dimensional chessboard method for determining the FICI of a two-drug combination containing Compound I

[0510] 1) Chessboard design

[0511] Based on the MIC value of each drug when applied alone, a total of 7 concentration gradients were set up, with a concentration range of 2×MIC to 1 / 32×MIC. The drugs were distributed in a checkerboard manner, as shown in Table 4. In a 96-well plate, A3-H9 were drug A (LZD, DLM, MFX, PMD) at 2×MIC-1 / 32×MIC, and B2-H9 were drug B (compound I) at 2×MIC to 1 / 32×MIC. Drug A was diluted twofold horizontally, and drug B was diluted twofold vertically. Columns B10-H10 and B11-H11 were negative control wells and positive control wells, respectively.

[0512] Table 4 Two-dimensional chessboard design

[0513] 2) Plating of the drug to be tested

[0514] Plating Drug A: Dilute all drug stock solutions to 10× MIC in advance. Add 95 μL of 7H9 liquid medium to wells B2-B9 of a 96-well plate, and 50 μL of 7H9 liquid medium to wells C2-H9. Add 5 μL of diluted Drug A to wells B2-B9. Mix the drug and 7H9 liquid medium thoroughly. Pipette 50 μL of the mixed solution into the next column using a two-fold dilution method. Repeat this process until the wells in row H are reached. Discard the final 50 μL of liquid.

[0515] Plating Drug B: Dilute all drug stock solutions to 10× MIC in advance. Add 125 μL of 7H9 liquid medium to wells A3-H3 of a 96-well plate, and 65 μL of 7H9 liquid medium to wells A4-H9. Add 5 μL of diluted Drug A to wells A3-H3. Mix the drug and 7H9 liquid medium thoroughly. Pipette 65 μL of the mixed solution into the next column using a two-fold dilution method. Repeat this process until the 9th column of microwells. Discard the final 65 μL of liquid.

[0516] 3) Crosstalk between drug A and drug B

[0517] After drug A and drug B are plated as described above, pipette 50 μL of diluted drug B into the corresponding wells of the 96-well plate containing drug A. Add 50 μL of 7H9 liquid culture medium to the single-drug wells B2-H2 and A3-A9, bringing the liquid volume in each 96-well plate to 100 μL. Add 200 μL of 7H9 liquid culture medium to the wells in column 10 as negative controls, and add 100 μL of 7H9 liquid culture medium (100 μL of diluted bacterial solution will need to be added later) to the wells in column 11 as positive controls.

[0518] 4) Determination of bacterial concentration and addition

[0519] Please refer to Example 1 for the specific operation steps.

[0520] 5) Addition of fluorescent indicator

[0521] Refer to Example 1 for the specific operation steps.

[0522] 6) Judgment of drug interaction

[0523] After 24 h of adding Alamar Blue indicator, take out the 96-well plate from the incubator. First, observe the color changes of drug A alone and drug B alone to determine their respective MIC wells. The combination effect of the two drugs is determined by calculating the FICI value. According to the calculation formula:

[0524] Among them, MIC A alone and MIC B alone respectively represent the MIC of drug A and drug B against Mycobacterium tuberculosis when used alone, and MIC A combined and MIC B combined respectively represent the lowest concentrations of drug A and drug B that prevent the color from changing from blue to pink after the combined use of drug A and drug B. The in vitro activity judgment criteria for the combination of the two drugs are as follows: FICI ≤ 0.5, synergistic effect; 0.5 < FICI < 1, partial synergistic effect; FICI = 1, additive effect; 1 < FICI < 4, irrelevant effect; FICI ≥ 4, antagonistic effect. Partial results of the FICI of the combination of two drugs containing compound I determined by the checkerboard method are shown in Table 5 below.

[0525] Table 5 Results of FICI of the combination of two drugs containing compound I determined by the checkerboard method

[0526] The test results show that the combination of compound I with other anti-tuberculosis drugs can synergistically inhibit the growth of Mycobacterium tuberculosis, especially the combination of compound I with DLM and PMD has a more significant synergistic effect on inhibiting the growth of Mycobacterium tuberculosis.

[0527] Example 3 Determination of FICI of the combination of three drugs containing compound I by three-dimensional checkerboard method

[0528] 1) Checkerboard design

[0529] Based on the MIC values of each drug when used alone, a total of 6 concentration gradients are set, and the concentration range is 2×MIC~1 / 16×MIC. The drugs are distributed in a checkerboard manner. As shown in Table 6, in the 96-well plate, A3 - G8 are drugs A (DLM, PMD) with concentrations of 2×MIC~1 / 16×MIC, B2 - G8 are drug B (compound I) with concentrations of 2×MIC~1 / 16×MIC, and H3 - H8 are drug C (LZD) with concentrations of 2×MIC~1 / 16×MIC. Dilute drug A in a two-fold dilution horizontally and drug B in a two-fold dilution vertically. The concentration of drug C remains unchanged in the composite wells. Columns B9 - G9 and B10 - G10 are negative control wells and positive control wells respectively.

[0530] Table 6 Three-dimensional chessboard design

[0531] 2) Plating of the drug to be tested

[0532] Plating Drug A: Dilute all drug stock solutions to 10× MIC in advance. Add 78 μL of 7H9 liquid medium to wells B2-B8 of a 96-well plate, and 40 μL of 7H9 liquid medium to wells C2-G8. Add 2 μL of diluted Drug A to wells B2-B8. Mix the drug and 7H9 liquid medium thoroughly. Pipette 40 μL of the mixed solution into the next column using a two-fold dilution method. Repeat this process until the wells in row G. Discard the final 40 μL.

[0533] Plating Drug B: Dilute all drug stock solutions to 10× MIC in advance. Add 118 μL of 7H9 liquid medium to wells A3-G3 of a 96-well plate, and 60 μL of 7H9 liquid medium to wells A4-G8. Add 2 μL of diluted Drug A to wells A3-G3. Mix the drug and 7H9 liquid medium thoroughly. Pipette 60 μL of the mixed solution into the next column using a two-fold dilution method. Repeat this process until the 8th column of microwells. Discard the final 60 μL of liquid.

[0534] 3) Crosstalk between drug A and drug B

[0535] After drug A and drug B are plated as described above, pipette 40 μL of diluted drug B into the corresponding wells of the 96-well plate containing drug A. Add 60 μL of 7H9 liquid culture medium to the single-drug wells B2-G2 and A3-A8, bringing the liquid volume in each 96-well plate to 100 μL. Add 200 μL of 7H9 liquid culture medium to the wells in column 9 as negative controls, and add 100 μL of 7H9 liquid culture medium (100 μL of diluted bacterial solution will need to be added later) to the wells in column 10 as positive controls.

[0536] 4) Addition and dilution of drug C

[0537] Drug C single-drug wells: Dilute the drug C stock solution to 4×MIC in advance, aspirate 200 μL and place it in well H3. Add 100 μL of 7H9 liquid culture medium to wells H4 to H8, dilute drug C by two times, aspirate 100 μL of the mixed solution into well H8 and discard it.

[0538] Drug C composite wells: First, dilute the initial concentration of Drug C single-drug wells 16-fold, and then add the diluted Drug C to wells B3 to G8 at a volume of 20 μL / well. At this time, the concentration of Drug C in the composite wells is 1 / 4×MIC.

[0539] 5) Determination of bacterial concentration and addition

[0540] For the specific operation steps, refer to Example 1.

[0541] 6) Addition of Alamar Blue indicator

[0542] For the addition of the chromogenic agent, refer to Example 1.

[0543] 7) Judgment criteria for drug interaction

[0544] After 24 h of adding the Alamar Blue indicator, take out the 96-well plate from the incubator. First, observe the color changes of the wells with drug A alone, drug B alone, and drug C alone, and determine their respective MIC wells. The triple-drug combination effect is determined by calculating the FICI value according to the following calculation formula:

[0545] Among them, MIC A alone, MIC B alone, and MIC C alone respectively represent the MIC of drug A, drug B, and drug C against each strain when used alone. MIC A combination and MIC B combination respectively represent the lowest concentrations of drug A and drug B that prevent the color change from blue to pink after the combined use of drug A and drug B. When the MIC value of drug C appears in well H4, the drug concentration of MIC C combination is 1 / 4 × MIC of drug C; if it appears in well H5, the drug concentration of MIC C combination is 1 / 8 MIC of drug C. The in vitro activity judgment criteria for the triple-drug combination are as follows: FICI ≤ 0.75, synergistic effect; 0.75 < FICI < 4, additive / irrelevant effect; FICI ≥ 4, antagonistic effect. Some of the results of the FICI of the triple-drug combination containing compound I determined by the checkerboard method are shown in Table 7 below.

[0546] Table 7 Results of FICI of the triple-drug combination containing compound I determined by the checkerboard method

[0547] The test results show that the combined use of compound I, PMD, and LZD or the combined use of compound I, DLM, and LZD can synergistically inhibit the growth of Mycobacterium tuberculosis.

[0548] Example 4 In vivo activity of the combination of two drugs

[0549] Use an aerosol infection device (model: Glas-Collin halation Exposure System 099C A4224) to infect SPF-grade female BALB / c mice (6–8 weeks old, body weight 19.52 ± 0.52 g) by aerosol inhalation with the standard strain H 37 R V (ATCC 27294) at an infection dose of 2 × 10 7 CFU / mL. Sacrifice 6 mice on the 15th day after infection and 4 weeks after infection respectively to determine the bacterial counts at the corresponding time points.

[0550] Treatment began 4 weeks after aerosol infection, and the mice were divided into groups according to different treatment regimens, including untreated group (0.5% sodium carboxymethylcellulose solution), compound I group (20 mg / kg), LZD group (100 mg / kg), MFX group (50 mg / kg), PMD group (100 mg / kg), DLM group (5 mg / kg), PZA group (150 mg / kg), compound I (20 mg / kg) combined with LZD (100 mg / kg) group, compound I (20 mg / kg) combined with MFX (50 mg / kg) group, compound I (20 mg / kg) combined with PMD (100 mg / kg) group, compound I (20 mg / kg) combined with DLM (5 mg / kg), and compound I (20 mg / kg) combined with PZA (150 mg / kg) group, with 12 mice in each group. All drugs were dissolved or suspended in 0.5% sodium carboxymethylcellulose solution. A single dose for five weekly doses was prepared and stored at 4°C. Administration was made via gavage daily from Monday to Friday in a 0.2 mL volume. Six mice in each group were sacrificed after four and eight weeks of treatment. CFU counts of Mycobacterium tuberculosis were performed in the lungs and spleens to assess the bactericidal activity of each regimen. Specific lung results are shown in Table 8.

[0551] Table 8: CFU counts in the lungs of BALB / c mice at each time point (x±s) (values ​​are mean±SD, standard deviation)

[0552] D-15: 15th day after infection; D0: date of administration and treatment; 4 weeks / 8 weeks: 4 weeks / 8 weeks after administration.

[0553] Based on the above test results, all five combination regimens containing Compound I demonstrated excellent anti-TB activity in mice. Combination therapy with Compound I significantly enhanced the antibacterial activity of LZD, DLM, PZA, and PMD. After eight weeks of treatment, the combination regimens were more effective than the corresponding single-agent regimens of LZD, DLM, PZA, and PMD. In particular, the Compound I combined with PZA treatment group achieved lung sterility after eight weeks of oral administration, and lung cultures in all mice were negative.

[0554] Example 5 In vivo activity of the three-drug combination

[0555] SPF female BALB / c mice (6–8 weeks old, weighing 20.73 ± 0.47 g) were infected with Mycobacterium tuberculosis standard strain H by aerosol inhalation using an aerosol infection device (model: Glas-Collin aeration exposure system 099C A4224). 37 RV (ATCC 27294), infectious dose 5.15×10 7 CFU / mL. Three mice and five mice were sacrificed on day 14 and week 4 post-infection, respectively, to determine bacterial counts at the corresponding time points.

[0556] Treatment began 4 weeks after aerosol infection, and the mice were divided into groups according to different treatment regimens, with 15 mice in each group, divided into untreated group (0.5% sodium carboxymethylcellulose solution), HRZ group (25 mg / kg INH + 50 mg / kg RFP + 150 mg / kg PZA), DLM group (5 mg / kg), compound I group (25 mg / kg), compound I (25 mg / kg) combined with DLM (5 mg / kg) group, compound I (25 mg / kg) combined with DLM (5 mg / kg) and LZD (100 mg / kg) group, BDQ (25 mg / kg) combined with DLM (5 mg / kg) and LZD (100 mg / kg) group, BDQ (25 mg / kg) combined with PMD (100 mg / kg) and LZD (100 mg / kg) group, and compound I (25 mg / kg) combined with PMD (100 mg / kg) and LZD (100 mg / kg) group. All drugs were dissolved or suspended in 0.5% sodium carboxymethylcellulose solution. The dose for administration five times a week was prepared once and stored at 4°C. The drugs were administered by gavage every day from Monday to Friday in a volume of 0.2 mL.

[0557] After 4, 8, and 12 weeks of treatment, 5 mice in each group were sacrificed and the CFU in their lungs and spleens were counted to evaluate the bactericidal activity of each regimen. The specific results are shown in Tables 9 and 10:

[0558] Table 9: CFU counts in the lungs of BALB / c mice at various time points (values ​​are mean ± SD, standard deviation)

[0559] D-16: 14 days after infection; D0: date of administration and treatment; 4 weeks / 8 weeks / 12 weeks: 4 weeks / 8 weeks / 12 weeks after administration.

[0560] Table 10: CFU counts in spleen of BALB / c mice at different time points

[0561] D-16: 14 days after infection; D0: date of administration and treatment; 4 weeks / 8 weeks / 12 weeks: 4 weeks / 8 weeks / 12 weeks after administration.

[0562] According to the above test results, the positive control group (HRZ group) achieved sterility in the mouse lungs after 8 weeks of treatment, but the lung colony count increased to 1.51 (log10 CFU) after 12 weeks of treatment. The lung culture of the Compound I + PMD + LZD group showed negative results after 12 weeks of treatment, and the Compound I + PMD + LZD group had better activity than the BDQ + PMD + LZD group after 12 weeks of treatment.

[0563] In summary, various drug combinations containing compound I showed good antibacterial activity in animal experiments, especially when compound I and PMD were present at the same time, compound I combined with PMD and compound I combined with PMD and LZD showed stronger efficacy than the single drug group.

[0564] Although specific embodiments of the present invention have been described above, those skilled in the art will appreciate that these are merely examples and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention.

Claims

1. A drug combination comprising: i) substance X, wherein substance X is compound I or a pharmaceutically acceptable salt thereof; ii) substance Y, wherein substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the second therapeutic agent is pyrazinamide, linezolid, moxifloxacin, premanid or delamanid; the structure of compound I is as follows:

2. The pharmaceutical combination according to claim 1, characterized in that The substance X is a pharmaceutically acceptable salt of Compound I; preferably, the substance X is a hydrochloride, sulfate, citrate, maleate or fumarate of Compound I; more preferably, the substance X is a fumarate of Compound I; and / or, the second therapeutic agent is selected from pyrazinamide, moxifloxacin, delamanid or premanid; preferably, the second therapeutic agent is delamanid or pyrazinamide; and / or, the drug combination consists of the substance X and the substance Y; And / or, the substance X and substance Y are administered simultaneously or separately.

3. The pharmaceutical combination according to claim 1 or 2, characterized in that The substance X is administered orally; and / or, the substance Y is administered orally.

4. A pharmaceutical composition A, comprising a substance X, a substance Y and a pharmaceutically acceptable carrier or medium, wherein the substance X is compound I or a pharmaceutically acceptable salt thereof; the substance X is preferably a pharmaceutically acceptable salt of compound I; the substance X is more preferably a hydrochloride, sulfate, citrate, maleate or fumarate of compound I; the substance X is further preferably a fumarate of compound I; The substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, and the second therapeutic agent is pyrazinamide, linezolid, moxifloxacin, premanid or delamanid; the second therapeutic agent is preferably pyrazinamide or delamanid; The structure of the compound I is shown below:

5. The pharmaceutical composition A according to claim 4, characterized in that The pharmaceutical composition A is presented in the form of an oral dosage form; And / or, the pharmaceutical composition A consists of the substance X, the substance Y and a pharmaceutically acceptable carrier or medium.

6. A pharmaceutical composition B comprising a first pharmaceutical composition and a second pharmaceutical composition; The first pharmaceutical composition comprises a substance X and a pharmaceutically acceptable carrier or medium, wherein the substance X is compound I or a pharmaceutically acceptable salt thereof; the substance X is preferably a pharmaceutically acceptable salt of compound I; and the substance X is more preferably a salt of compound I. acid salt, sulfate, citrate, maleate or fumarate; the substance X is further preferably a fumarate of compound I; The second pharmaceutical composition comprises a substance Y and a pharmaceutically acceptable carrier or medium, wherein the substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, and the second therapeutic agent is pyrazinamide, linezolid, moxifloxacin, premanid or delamanid; the second therapeutic agent is preferably pyrazinamide or delamanid; The structure of the compound I is shown below:

7. The pharmaceutical composition B according to claim 6, characterized in that The first pharmaceutical composition is presented in an oral dosage form; and / or, the second pharmaceutical composition is presented in an oral form.

8. The pharmaceutical composition B according to claim 7, characterized in that The pharmaceutical composition B consists of the first pharmaceutical composition and the second pharmaceutical composition.

9. A pharmaceutical combination comprising i) substance X, wherein substance X is compound I or a pharmaceutically acceptable salt thereof; ii) substance Y, wherein substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the second therapeutic agent is premanid or delamanid; iii) substance Z, wherein the substance Z is linezolid or a pharmaceutically acceptable salt thereof; The structure of the compound I is shown below:

10. The pharmaceutical combination according to claim 9, characterized in that The substance X is a pharmaceutically acceptable salt of Compound I; preferably, the substance X is a hydrochloride, sulfate, citrate, maleate or fumarate of Compound I; more preferably, the substance X is a fumarate of Compound I; and / or, the second therapeutic agent is selected from Primanid; And / or, the drug combination consists of the substance X, the substance Y and the substance Z; And / or, the substance X, substance Y and substance Z are administered simultaneously or separately.

11. The pharmaceutical combination according to claim 9 or 10, characterized in that: The substance X is administered orally; and / or, the substance Y is administered orally; and / or, the substance Z is administered orally.

12. A pharmaceutical composition C, comprising substance X, substance Y, substance Z and a pharmaceutically acceptable carrier or medium, wherein the substance X is compound I or a pharmaceutically acceptable salt thereof; the substance X is preferably a pharmaceutically acceptable salt of compound I; the substance X is more preferably a hydrochloride, sulfate, citrate, maleate or fumarate of compound I; the substance X is further preferably a fumarate of compound I; The substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, and the second therapeutic agent is purmanid or delamanid; the second therapeutic agent is preferably purmanid; The substance Z is linezolid or a pharmaceutically acceptable salt thereof; The structure of the compound I is shown below:

13. The pharmaceutical composition C according to claim 12, characterized in that: The pharmaceutical composition C is presented in the form of an oral dosage form; and / or, the pharmaceutical composition C consists of the substance X, substance Y, substance Z and a pharmaceutically acceptable carrier or medium.

14. A pharmaceutical composition D comprising a first pharmaceutical composition, a second pharmaceutical composition and a third pharmaceutical composition; The first pharmaceutical composition comprises a substance X and a pharmaceutically acceptable carrier or medium, wherein the substance X is compound I or a pharmaceutically acceptable salt thereof; the substance X is preferably a pharmaceutically acceptable salt of compound I; the substance X is more preferably a hydrochloride, sulfate, citrate, maleate or fumarate of compound I; the substance X is further preferably a fumarate of compound I; The second pharmaceutical composition comprises substance Y and a pharmaceutically acceptable carrier or medium, wherein substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, and the second therapeutic agent is primanid or delamanid; the second therapeutic agent is preferably primanid; The third pharmaceutical composition comprises a substance Z and a pharmaceutically acceptable carrier or medium, wherein the substance Z is linezolid or a pharmaceutically acceptable salt thereof; The structure of the compound I is shown below:

15. The pharmaceutical composition D according to claim 14, characterized in that: The first pharmaceutical composition is presented in an oral dosage form; And / or, the second pharmaceutical composition is presented in an oral form; And / or, the third pharmaceutical composition is presented in oral form.

16. The pharmaceutical composition D according to claim 15, characterized in that: The pharmaceutical composition D consists of the first pharmaceutical composition, the second pharmaceutical composition and the third pharmaceutical composition.

17. Use of the pharmaceutical combination according to any one of claims 1 to 3, 9 to 11, the pharmaceutical composition A according to claim 4 or 5, the pharmaceutical composition B according to any one of claims 6 to 8, the pharmaceutical composition C according to claim 12 or 13, or the pharmaceutical composition D according to any one of claims 14 to 16 in the preparation of a medicament for preventing or treating a disease caused by Mycobacterium tuberculosis.

18. Use of a substance X in the preparation of a drug for preventing or treating a disease caused by Mycobacterium tuberculosis, wherein the substance X is compound I or a pharmaceutically acceptable salt thereof, characterized in that: The substance X is used in combination with a substance Y, wherein the substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, and the second therapeutic agent is pyrazinamide, linezolid, moxifloxacin, premanid or delamanid; the second therapeutic agent is preferably pyrazinamide or delamanid; the structure of the compound I is shown below:

19. Use of a substance X in the preparation of a drug for preventing or treating a disease caused by Mycobacterium tuberculosis, wherein the substance X is compound I or a pharmaceutically acceptable salt thereof, characterized in that: The substance X is used in combination with substance Y and substance Z, wherein the substance Y is a second therapeutic agent or a pharmaceutically acceptable salt thereof, the second therapeutic agent is primanid or delamanid, and the substance Z is linezolid or a pharmaceutically acceptable salt thereof; the structure of the compound I is shown below:

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