Use of imidazolinone derivatives in combination with doxorubicin in the treatment of tumors - Patent Application 20070122999

Abstract

There is provided the use of a compound represented by general formula (I) in combination with doxorubicin in the preparation of an anti-cancer medicament. [Formula 1] TIFF2025531951000082.tif4476

Description

[Technical Field]

[0001] The present invention relates to the use of imidazolinone derivatives in combination with doxorubicin for the treatment of tumors. [Background technology]

[0002] Doxorubicin is a broad-spectrum antitumor drug, and one of its primary mechanisms for treating cancer is to directly disrupt the DNA of cancer cells, causing extensive DNA damage and ultimately killing the cancer cells. DNA damage response repair (DDR) is a self-defense mechanism initiated when cells experience DNA damage, which leads to cell cycle arrest and repair of damaged DNA, potentially reducing the sensitivity of cancer cells to doxorubicin. In clinical practice, this reduced sensitivity is observed as a reduced therapeutic effect of doxorubicin.

[0003] DNA double-strand breaks (DSBs) are highly harmful forms of DNA damage in cells, and untimely repair of DSBs is closely related to cellular carcinogenesis. Non-homologous end joining (NHEJ) is one of the major pathways for DNA double-strand break repair in cells. In NHEJ, DSB ends are first recognized and bound by Ku70 / 80, which then binds to the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form the DNA-dependent protein kinase (DNAPK), or NHEJ initiation complex (DNAPK). Subsequently, the two DNAPKs bind to the damaged DNA ends and simultaneously recruit subsequent NHEJ repair factors (XRCC4 and XLF) and DNA ligase IV (LigIV) to repair the damaged DNA.

[0004] WO2021209055 discloses the use of imidazolinone derivatives in the preparation of drugs for use in the treatment of cancer, where the compounds described therein have high selectivity and significant inhibitory activity against DNA-PK. Summary of the Invention

[0005] The object of the present invention is to provide the use of imidazolinone derivatives in combination with doxorubicin for the treatment of tumors in order to overcome the deficiencies of the prior art.

[0006] In one or more embodiments of the present application, there is provided the use of a compound of general formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, in combination with doxorubicin as an active ingredient for treating tumors:

[0007] [ka] (In the formula,

[0008] [ka] teeth,

[0009] [ka] and

[0010] [ka] is a single or double bond,

[0011] [ka] wherein A, B, C, and D are each independently C or N, and at least one of A, B, C, and D is N; R0 is H, C 1~6 alkyl or cyclopropyl, C 1~6 the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is

[0012] [ka] or pyridyl, and R1 is D, halogen, cyano, hydroxyl, C 1~6 Alkyl and C 1~6 optionally further substituted with one or two substituents selected from alkoxy; R 1a is H or C 1~6 is alkyl, R 1b is H, OH, cyano or hydroxyl substituted C 1~6 is alkyl, R2 is H, cyano, =O, carboxyl, -C(=O)NR 2a R 2b , C 1~6 Alkoxy, C 1~6 Alkyl, halogen, -S(=O)2R 2a or -C(=O)OC 1~6 alkyl, C 1~6 Alkyl, -C(=O)OC 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium; R 2a and R 2b are independently H, C 1~6 alkyl or 3- to 5-membered cycloalkyl, C 1~6 Alkyl is OH, D, halogen, C 1~6 Alkyl and C 1~6 and optionally further substituted with one or more substituents selected from alkoxy; Alternatively, R 2a and R 2b together with the atoms to which they are attached form a 5-6 membered heterocyclyl, which contains 1, 2 or 3 heteroatoms selected from N, O and S, and C 1~6 optionally further substituted with one or more substituents selected from alkyl, OH and halogen; R3 is halogen or C 1~6 alkyl, C 1~6the alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1, n is 0, 1 or 2; x and y are each independently 1, 2, or 3; however,

[0013] [ka] , R0, R2 and R3 simultaneously satisfy the following conditions:

[0014] [ka] isn't it:

[0015] [ka] but,

[0016] [ka] wherein n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl).

[0017] In one or more embodiments of the present application, R1 is

[0018] [ka] and R 1a is H or C 1~6 is alkyl, R2 is H, cyano, -C(=O)NR 2a R 2b , C 1~6 Alkoxy, halogen, -S(=O)2R 2a or -C(=O)OC 1~6 Alkyl, -C(=O)OC1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium; R 2a and R 2b are independently H, C 1~6 alkyl or 3-5 membered cycloalkyl, C 1~6 the alkyl is optionally further substituted with one or more substituents selected from OH, D or halogen; Alternatively, R 2a and R 2b taken together with the atoms to which they are attached form a 5-6 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, and optionally further substituted with one or more substituents selected from OH and halogen; R3 is halogen or C 1~6 alkyl, C 1~6 the alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1, n is 0, 1 or 2; however,

[0019] [ka] , R0, R2 and R3 simultaneously satisfy the following conditions:

[0020] [ka] isn't it:

[0021] [ka] but,

[0022] [ka] wherein n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

[0023] In one or more embodiments of the present application,

[0024] [ka] teeth,

[0025] [ka] and R0 is H, C 1~4 alkyl or cyclopropyl, C 1~4 The alkyl is optionally further substituted with one or more substituents selected from halogen and D; R1 is

[0026] [ka] and R 1a is H, C 1~6 Alkyl or -C(=O)C 1~6 is alkyl, R2 is H, cyano, -C(=O)NR 2a R 2b , C 1~6 Alkoxy, halogen, -S(=O)2R 2a or -C(=O)OC 1~6 Alkyl, -C(=O)OC 1~6 Alkyl or C 1~6 The alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium; R 2a and R 2b are independently H, C 1~6 alkyl or 3-5 membered cycloalkyl, C 1~6the alkyl is optionally further substituted with one or more substituents selected from OH, D and halogen; Alternatively, R 2a and R 2b taken together with the atoms to which they are attached form a 5-6 membered heterocyclyl, which contains 1-3 heteroatoms selected from N, O and S, and which is also optionally further substituted with one or more substituents selected from OH and halogen; R3 is halogen or C 1~6 alkyl, C 1~6 the alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1, n is 0, 1 or 2; however,

[0027] [ka] , R0, R2 and R3 simultaneously satisfy the following conditions:

[0028] [ka] isn't it:

[0029] [ka] but,

[0030] [ka] When n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

[0031] In one or more embodiments of the present application, there is provided the use of a compound of general formula (II), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, in combination with doxorubicin as an active ingredient for treating tumors:

[0032] [ka] (In the formula, R0 is H, C 1~6 alkyl or cyclopropyl, C 1~6 the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is

[0033] [ka] or pyridyl, and R1 is D, halogen, cyano, hydroxyl, C 1~6 Alkyl and C 1~6 optionally further substituted with 1 to 2 substituents selected from alkoxy; R 1a is H or C 1~6 is alkyl, R 1b is H, OH, cyano or hydroxyl substituted C 1~6 is alkyl, R 2c is H, cyano, halogen or C 1~6 is an alkoxy; R 2d is H, cyano, carboxyl, -C(=O)NR 2a R 2b , C 1~6 Alkyl, halogen, -S(=O)2R 2a or -C(=O)OC 1~6 alkyl, C 1~6 Alkyl and -C(=O)OC 1~6 the alkyl is optionally substituted with one or more substituents selected from halogen and deuterium; R2a and R 2b is H, C 1~6 alkyl or 3-5 membered cycloalkyl, C 1~6 Alkyl is OH, D, halogen, C 1~6 Alkyl and C 1~6 and optionally further substituted with one or more substituents selected from alkoxy; Alternatively, R 2a and R 2b together with the atoms to which they are attached form a 5-6 membered heterocyclyl, which contains 1-3 heteroatoms selected from N, O and S, and C 1~6 optionally further substituted with one or more substituents selected from alkyl, OH and halogen; R3 is halogen or C 1~6 alkyl, C 1~6 the alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1, n is 0, 1 or 2; x and y are each independently 1, 2, or 3; however,

[0034] [ka] , R0, R2 and R3 simultaneously satisfy the following conditions:

[0035] [ka] isn't it:

[0036] [ka] but,

[0037] [ka] wherein n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

[0038] In one or more embodiments of the present application, there is provided the use of a compound of general formula (III), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, in combination with doxorubicin as an active ingredient for treating tumors:

[0039] [ka] (In the formula, R0 is H, C 1~6 alkyl or cyclopropyl, C 1~6 the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is

[0040] [ka] or pyridyl, and R1 is D, halogen, cyano, hydroxyl, C 1~6 Alkyl and C 1~6 optionally further substituted with 1 to 2 substituents selected from alkoxy; R 1b is H, OH, cyano or hydroxyl substituted C 1~6 is alkyl, R 2a and R 2b are independently H, C 1~6 alkyl or 3- to 5-membered cycloalkyl, C 1~6 the alkyl is optionally further substituted with one or more substituents selected from D or halogen; Alternatively, R 2a and R 2b together with the atoms to which they are attached form a 5-6 membered heterocyclyl, which contains 1-3 heteroatoms selected from N, O and S, and C1~6 optionally further substituted with one or more substituents selected from alkyl, OH and halogen; R 2c is H, cyano, halogen or C 1~6 Alkoxy, C 1~6 the alkoxy is optionally substituted with one or more deuterium atoms; R3 is halogen or C 1~6 alkyl, C 1~6 the alkyl is optionally further substituted with 1 to 3 substituents selected from D or halogen; m is 0 or 1, n is 0, 1 or 2; x and y are each independently 1, 2, or 3.

[0041] In one or more embodiments of the present application, there is provided the use of a compound of general formula (IV), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, in combination with doxorubicin as an active ingredient for treating tumors:

[0042] [ka] (In the formula, R0 is H, C 1~6 alkyl or cyclopropyl, C 1~6 the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is -(CH) m -4 to 7-membered carbocyclyl, -(CH) m -4 to 7-membered heterocyclyl, -(CH) m -8 to 12-membered bridged ring, -(CH) m -7 to 12-membered spiro ring, -(CH) m -4 to 7-membered carbocyclyl, -(CH) m -4 to 7-membered heterocyclyl, -(CH) m -8 to 12-membered bridged ring or -(CH) m-7 to 12 membered spiro rings are hydroxy, cyano, halogen, ═O, C 1~6 Alkyl, C 1~6 Alkoxy and Hydroxy Substituted C 1~6 alkyl).

[0043] In one or more embodiments of the present application, R0 is H, C 1~6 alkyl or cyclopropyl, C 1~6 the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is

[0044] [ka] or pyridyl, and R1 is D, halogen, cyano, hydroxyl, C 1~6 Alkyl and C 1~6 optionally further substituted with 1 to 2 substituents selected from alkoxy; R 1a is H or C 1~6 is alkyl, R 1b is H, OH, cyano or hydroxyl substituted C 1~6 is alkyl, m is 0 or 1, x and y are each independently 1, 2, or 3.

[0045] In one or more embodiments of the present application, R0 is C 1~4 alkyl, C 1~4 the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R1 is

[0046] [ka] is.

[0047] In one or more embodiments of the present application, the active ingredient is

[0048] [ka] Selected from TIFF2025531951000036.tif215160TIFF2025531951000037.tif227165TIFF2025531951000038.tif87161.

[0049] In one or more embodiments of the present application, the active ingredients exhibit demonstrable synergistic therapeutic effects when used in combination with doxorubicin.

[0050] In one or more embodiments of the present application, the tumor is selected from a solid tumor.

[0051] In one or more embodiments of the present application, the daily dose of the active ingredient is 25 to 500 mg, preferably 50 to 400 mg, and more preferably 100 to 300 mg, and the administered dose of doxorubicin or a pharmaceutically acceptable salt thereof is 0.02 to 10 mg / kg.

[0052] In one or more embodiments of the present application, the administered dose of doxorubicin or a pharmaceutically acceptable salt thereof is determined based on the body surface area m of the subject. 2 It is less than 50 mg per serving. [Brief explanation of the drawings]

[0053] [Figure 1] FIG. 1 shows Compound A. [Figure 2] FIG. 1 shows a graph of tumor volume trends in the H1299 mouse tumor-bearing model. [Figure 3] FIG. 1 shows a graph of the trend of weight change in tumor-bearing nude mice in the H1299 mouse tumor-bearing model. DETAILED DESCRIPTION OF THE INVENTION

[0054] The implementation process and beneficial effects of the present invention are described in detail below with examples, which are intended to help the reader better understand the essential matters and features of the present invention, but are not intended to limit the implementation scope of the present invention.

[0055] The invention will be described in further detail below with reference to the accompanying drawings.

[0056] Compound A in the examples is Compound 62 of WO 2021209055 and is prepared in accordance with the preparation method thereof.

[0057] Efficacy testing in the H1299 mouse tumor-bearing model 1. Experimental steps: 1.1 Cell culture H1299 human lung cancer cells were purchased from ATCC. H1299 cells were cultured in adherent culture on 15-cm culture dishes in DMEM medium supplemented with 10% fetal bovine serum, penicillin, and streptomycin at 37°C in a 5% CO2 incubator. Cells in the logarithmic growth phase were digested with trypsin, harvested, counted, and then inoculated.

[0058] 1.2. Grouping and administration BALB / c-nude mice were allowed to acclimate to the laboratory environment, and then 7.6 × 10 H1299 cell suspensions were inoculated into the right flank at an inoculum volume of 0.2 mL (with added gel). 6 The tumors were subcutaneously inoculated at an inoculum of 120 mm2. 3 Once the tumors reached 100 mg / kg, 24 animals were screened for group assignment. The animals were divided into three groups, each with 8 mice, using a zigzag pattern based on tumor volume. The day of group assignment was defined as day 1 of the experiment (PG-D1), and treatment began on day 1. The group assignment and treatment regimen are shown in Table 1.

[0059] [Table 1]

[0060] 2. Assay Method 2.1 Tumor volume: During the drug treatment cycle, the major axis (a) and minor axis (b) of the tumor tissue were measured twice a week using an electronic Vernier caliper, and the tumor volume was calculated (tumor volume = 0.5 × a × b 2 ).

[0061] 2.2 Mouse weight: Mice were weighed at least twice a week during the drug treatment cycle.

[0062] 3. Data Analysis All data were entered into SPSS16.0 software, and data were compared using one-way ANOVA, with P<0.05 considered as a statistically significant difference.

[0063] 4. Experimental Results 4.1 Tumor volume results

[0064] [Table 2]

[0065] [Table 3]

[0066] As shown in Table 2-1, Table 2-2 and Figure 2, by the end of administration (PG-D29), the tumor volume in the group administered with compound A in combination with doxorubicin was significantly smaller than that in the blank group and the doxorubicin liposome group (P<0.01), indicating that compound A can significantly improve the antitumor effect of doxorubicin liposome.

[0067] 4.2 Weight results

[0068] [Table 4]

[0069] [Table 5]

[0070] As shown in Table 3-1, Table 3-2 and Figure 3, by the end of administration (PG-D29), animals in the group administered Compound A in combination with doxorubicin liposomes showed a slight decrease in body weight compared to their initial body weight, but were overall well tolerated.

[0071] Specific embodiments are described in detail in the description of the present invention. Those skilled in the art should realize that the above embodiments are illustrative and cannot be construed as limiting the present invention. In addition, those skilled in the art can make some improvements and modifications to the present invention without departing from the principle of the present invention, and the technical solutions obtained based on these improvements and modifications will still fall within the scope of protection of the claims of the present invention.

Claims

1. Use of a compound represented by formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, as an active ingredient for the preparation of an antitumor drug in combination with doxorubicin: 【Chemical 1】 (In the formula, 【Chemistry 2】 teeth, 【Chemistry 3】 and 【Chemistry 4】 is a single or double bond, 【Chemistry 5】 wherein A, B, C, and D are each independently C or N, and at least one of A, B, C, and D is N; R ０ is H, C １～６ alkyl or cyclopropyl, １～６ the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R １ teeth, 【Chemistry 6】 or pyridyl, and R １ is D, halogen, cyano, hydroxyl, C １～６ Alkyl and C １～６ optionally further substituted with one or two substituents selected from alkoxy; R １ａ is H or C １～６ is alkyl, R １ｂ is H, OH, cyano or hydroxyl substituted C １～６ is alkyl, R ２ is H, cyano, ═O, carboxyl, —C(═O)NR ２ａ R ２ｂ , C １～６ Alkoxy, C １～６ Alkyl, halogen, -S(=O) ２ R ２ａ or -C(=O)OC １～６ alkyl, １～６ Alkyl, —C(═O)OC １～６ Alkyl or C １～６ The alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium; R ２ａ and R ２ｂ are each independently H, C １～６ alkyl or 3- to 5-membered cycloalkyl, １～６ Alkyl is OH, D, halogen, C １～６ Alkyl and C １～６ optionally further substituted with one or more substituents selected from alkoxy; Alternatively, R ２ａ and R ２ｂ together with the atoms to which they are attached form a 5- to 6-membered heterocyclyl, which contains 1, 2, or 3 heteroatoms selected from N, O, and S, and C １～６ optionally further substituted with one or more substituents selected from alkyl, OH, and halogen; R ３ is a halogen or C １～６ alkyl, １～６ the alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2; x and y are each independently 1, 2, or 3; however, 【Chemistry 7】 , R ０ , R ２ and R ３ If the following conditions are satisfied simultaneously, R １ teeth, 【Chemistry 8】 isn't it: 【Chemistry 9】 but, 【Chemistry 10】 where n is 1 and R ０ is H or methyl, and R ２ is methoxy or -S(=O) ２ Me and R ３ is methyl).

2. 2. The use according to claim 1, wherein the active ingredient is a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein: R １ teeth, 【Chemistry 11】 and R １ａ is H or C １～６ is alkyl, R ２ is H, cyano, -C(=O)NR ２ａ R ２ｂ , C １～６ Alkoxy, halogen, -S(=O) ２ R ２ａ or -C(=O)OC １～６ alkyl, and the —C(═O)OC １～６ Alkyl or C １～６ The alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium; R ２ａ and R ２ｂ are each independently H, C １～６ alkyl or 3- to 5-membered cycloalkyl, １～６ the alkyl is optionally further substituted with one or more substituents selected from OH, D or halogen; Alternatively, R ２ａ and R ２ｂ together with the atoms to which they are attached form a 5-6 membered heterocyclyl, which contains 1-3 heteroatoms selected from N, O and S, and is optionally further substituted with one or more substituents selected from OH and halogen; R ３ is a halogen or C １～６ alkyl, １～６ the alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2; however, 【Chemistry 12】 , R ０ , R ２ and R ３ If the following conditions are satisfied simultaneously, R １ teeth, 【Chemistry 13】 isn't it: 【Chemistry 14】 but, 【Chemistry 15】 where n is 1 and R ０ is H or methyl, and R ２ is methoxy or -S(=O) ２ Me and R ３ is methyl).

3. 2. The use according to claim 1, wherein the active ingredient is a compound of formula (I) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein: 【Chemistry 16】 teeth, 【Chemistry 17】 and R ０ is H, C １～４ alkyl or cyclopropyl, １～４ The alkyl is optionally further substituted with one or more substituents selected from halogen and D; R １ teeth, 【Chemistry 18】 and R １ａ is H, C １～６ Alkyl or -C(=O)C １～６ is alkyl, R ２ is H, cyano, -C(=O)NR ２ａ R ２ｂ , C １～６ Alkoxy, halogen, -S(=O) ２ R ２ａ or -C(=O)OC １～６ alkyl, and the —C(═O)OC １～６ Alkyl or C １～６ The alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium; R ２ａ and R ２ｂ are each independently H, C １～６ alkyl or 3- to 5-membered cycloalkyl, １～６ the alkyl is optionally further substituted with one or more substituents selected from OH, D and halogen; Alternatively, R ２ａ and R ２ｂ together with the atoms to which they are attached form a 5-6 membered heterocyclyl, which contains 1-3 heteroatoms selected from N, O and S, and which is also optionally further substituted with one or more substituents selected from OH and halogen; R ３ is a halogen or C １～６ alkyl, １～６ the alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2; however, 【Chemistry 19】 , R ０ , R ２ and R ３ If the following conditions are satisfied simultaneously, R １ teeth, 【Chemistry 20】 isn't it: 【Chemical 21】 but, 【Chemical 22】 When n is 1, R ０ is H or methyl, and R ２ is methoxy or -S(=O) ２ Me and R ３ is methyl).

4. 2. The use according to claim 1, wherein the active ingredient is selected from a compound of formula (II) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof: 【Chemical 23】 (In the formula, R ０ is H, C １～６ alkyl or cyclopropyl, １～６ the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R １ teeth, 【Chemistry 24】 or pyridyl, and R １ is D, halogen, cyano, hydroxyl, C １～６ Alkyl and C １～６ optionally further substituted with 1 to 2 substituents selected from alkoxy; R １ａ is H or C １～６ is alkyl, R １ｂ is H, OH, cyano or hydroxyl substituted C １～６ is alkyl, R ２ｃ is H, cyano, halogen or C １～６ is an alkoxy, R ２ｄ is H, cyano, carboxyl, -C(=O)NR ２ａ R ２ｂ , C １～６ Alkyl, halogen, -S(=O) ２ R ２ａ or -C(=O)OC １～６ alkyl, １～６ Alkyl and —C(═O)OC １～６ the alkyl is optionally substituted with one or more substituents selected from halogen and deuterium; R ２ａ and R ２ｂ is H, C １～６ alkyl or 3- to 5-membered cycloalkyl, １～６ Alkyl is OH, D, halogen, C １～６ Alkyl and C １～６ optionally further substituted with one or more substituents selected from alkoxy; Alternatively, R ２ａ and R ２ｂ together with the atoms to which they are attached form a 5-6 membered heterocyclyl, which contains 1-3 heteroatoms selected from N, O and S, and C １～６ optionally further substituted with one or more substituents selected from alkyl, OH, and halogen; R ３ is a halogen or C １～６ alkyl, １～６ the alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1; n is 0, 1 or 2; x and y are each independently 1, 2, or 3; however, 【Chemistry 25】 , R ０ , R ２ and R ３ If the following conditions are satisfied simultaneously, R １ teeth, 【Chemical 26】 isn't it: 【Chemical 27】 but, 【Chemical Formula 28】 n is 1; and R ０ is H or methyl, and R ２ is methoxy or -S(=O) ２ Me and R ３ is methyl).

5. 5. The use according to claim 4, wherein the active ingredient is selected from a compound of formula (III) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof: 【Chemical Formula 29】 (In the formula, R ０ is H, C １～６ alkyl or cyclopropyl, １～６ the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R １ teeth, 【Chemistry 30】 or pyridyl, and R １ is D, halogen, cyano, hydroxyl, C １～６ Alkyl and C １～６ optionally further substituted with 1 to 2 substituents selected from alkoxy; R １ｂ is H, OH, cyano or hydroxyl substituted C １～６ is alkyl, R ２ａ and R ２ｂ are each independently H, C １～６ alkyl or 3- to 5-membered cycloalkyl, １～６ The alkyl is optionally further substituted with one or more substituents selected from D or halogen; Alternatively, R ２ａ and R ２ｂ together with the atoms to which they are attached form a 5-6 membered heterocyclyl, which contains 1-3 heteroatoms selected from N, O and S, and C １～６ optionally further substituted with one or more substituents selected from alkyl, OH, and halogen; R ２ｃ is H, cyano, halogen or C １～６ is an alkoxy, １～６ the alkoxy is optionally substituted with one or more deuterium atoms; R ３ is a halogen or C １～６ alkyl, １～６ the alkyl is optionally further substituted with 1 to 3 substituents selected from D or halogen; m is 0 or 1; n is 0, 1 or 2; x and y are each independently 1, 2, or 3.

6. 2. The use according to claim 1, wherein the active ingredient is selected from a compound of formula (IV) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof: 【Chemical 31】 (In the formula, R ０ is H, C １～６ alkyl or cyclopropyl, １～６ the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R １ is -(CH) ｍ -4 to 7-membered carbocyclyl, -(CH) ｍ -4 to 7-membered heterocyclyl, -(CH) ｍ -8 to 12-membered bridged ring, -(CH) ｍ -7 to 12-membered spiro ring, wherein the -(CH) ｍ -4 to 7-membered carbocyclyl, -(CH) ｍ -4 to 7-membered heterocyclyl, -(CH) ｍ -8 to 12-membered bridged ring or -(CH) ｍ - 7 to 12 membered spiro rings are hydroxy, cyano, halogen, ═O, C １～６ Alkyl, C １～６ Alkoxy and hydroxy substituted C １～６ and optionally further substituted with one or more substituents selected from alkyl.

7. the active ingredient is selected from a compound of formula (IV) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof; R ０ But H, C １～６ alkyl or cyclopropyl, １～６ the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R １ but, 【Chemical 32】 or pyridyl, and R １ D, halogen, cyano, hydroxyl, C １～６ Alkyl and C １～６ optionally further substituted with 1 to 2 substituents selected from alkoxy; R １ａ is H or C １～６ is alkyl, R １ｂ is H, OH, cyano or hydroxyl substituted C １～６ is alkyl, m is 0 or 1; x and y are each independently 1, 2, or 3; 7. The use according to claim 6.

8. the active ingredient is a compound of formula (IV) or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof; R ０ But C １～４ alkyl, １～４ the alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; R １ but, 【Chemical 33】 That is, 8. The use according to claim 7.

9. The active ingredient is 【Chemical 34】 【change】 【change】 【change】 【change】 The use according to any one of claims 1 to 8, wherein the compound is selected from the group consisting of:

10. The use according to any one of claims 1 to 9, wherein the tumor is selected from solid tumors.

11. 10. The use according to any one of claims 1 to 9, wherein the daily dose of the active ingredient is 25 to 500 mg, preferably 50 to 400 mg, more preferably 100 to 300 mg, and the administered dose of the doxorubicin or pharmaceutically acceptable salt thereof is 0.02 to 10 mg / kg.

12. The administered dose of doxorubicin or a pharmaceutically acceptable salt thereof is measured over a body surface area m of a subject. ２ The use according to claim 11, wherein the amount is 50 mg or less per dose.

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