Use of fused ring compound

Abstract

Disclosed is use of a fused ring compound. The present invention provides use of a substance A in preparing a medicament for treating classic chordoma. The substance A is a CDK4 / 6 inhibitor. Experimental data show that the CDK4 / 6 inhibitor has a significant effect in treating classic chordoma, but has no effects on differentiated chordoma. When the CDK4 / 6 inhibitor is used for treating classic chordoma, the experimental data demonstrate that the response is partial response or stable disease.

Description

Application of a cyclic compound

[0001] This application claims priority to Chinese patent application CN2023117728301, filed on December 21, 2023, and Chinese patent application CN2024101455262, filed on February 1, 2024. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to an application of a cyclic compound. Background Art

[0003] Among the CDK4 / 6 inhibitor drugs that have been marketed domestically and internationally, except for Trilaciclib (G1 Therapeutics) with a different commercial layout, which is approved for the prevention of bone marrow suppression caused by platinum / etoposide or topotecan chemotherapy in adult patients with extensive small cell lung cancer, other CDK4 / 6 inhibitor drugs have been approved as monotherapy or combination therapy for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer (such as Pfizer's Palbociclib, Eli Lilly's Abemaciclib, Novartis' Ribociclib and Hengrui Medicine's Darcillib).

[0004] The approved indications for these marketed CDK4 / 6 inhibitors are all concentrated in HR+ and HER2- breast cancer, indicating that these drug molecules that target CDK4 / 6 and exert an inhibitory effect have similar effectiveness in treating tumors. For example, the randomized phase 3 clinical trial PALOMA-2 (NCT01740427) of Palbociclib compared letrozole combined with the CDK4 / 6 inhibitor drug Palbociclib or combined with placebo in the initial endocrine therapy (ET) of HR+, HER2-, postmenopausal advanced or metastatic breast cancer patients. The results showed that the PFS of letrozole combined with Palbociclib and letrozole combined with placebo were 27.6 months and 14.5 months, respectively, and the objective response rate (ORR) was 47.5% and 38.7%, respectively. Alternatively, the US FDA approved Abemaciclib based on the randomized, double-blind, placebo-controlled multicenter clinical trial MONARCH 3 (NCT02246621). The trial results showed that patients receiving Abemaciclib combined with ET had an estimated PFS of 28.2 months (95% CI: 23.5, not yet reached), compared to 14.8 months for patients receiving placebo combined with ET, indicating significant efficacy in the experimental group. In addition, the results of the large-scale, international, multicenter Phase 3 clinical trial MONALEESA-7 (NCT02278120) of Ribociclib showed that compared with patients treated with placebo combined with an aromatase inhibitor (AI), patients treated with Ribociclib combined with an AI had a significantly prolonged PFS (27.5 months vs. 13.8 months). Therefore, the US FDA approved Ribociclib in combination with an AI as the initial endocrine-based treatment for postmenopausal women with HR+, HER2- advanced or metastatic cancer. Even the DAWNA-2 study (NCT03966898) of Dalcili is a multicenter phase 3 clinical study evaluating the efficacy and safety of Dalcili combined with letrozole or anastrozole versus placebo combined with letrozole or anastrozole as initial treatment for HR+, HER2- locally advanced or metastatic breast cancer; the results showed that the PFS of the experimental group and the control group were 30.6 and 18.2 months, respectively. Ultimately, Dalcili was approved in China for initial treatment in combination with an aromatase inhibitor (AI) for patients with HR+, HER2- locally advanced or metastatic breast cancer. The fact that these CDK4 / 6 inhibitors have achieved similar efficacy in patients with HR+, HER2- breast cancer indicates that these CDK4 / 6 inhibitors achieve their tumor treatment effects through the same mechanism; this means that these CDK4 / 6 inhibitors can also achieve similar efficacy in appropriate new indications.

[0005] Chordoma is a rare cancer. Based on the 2021 NCCN Clinical Practice Guidelines for Bone Tumors, chordoma is divided into three histological subtypes: conventional chordoma, chondroid chordoma, and dedifferentiated chordoma. Currently, chordoma is mostly treated with surgery.

[0006] Currently, the treatment of chordoma remains a challenge. Surgery is the primary treatment, while radiotherapy and chemotherapy have limited effectiveness. Although numerous clinical trials are underway for various drugs, such as cetuximab, lapatinib, and imatinib, the most advanced are currently only Phase II (see clinicaltrials.gov), and no drug has yet reached market approval.

[0007] Those skilled in the art know that deuterated molecules can achieve the same pharmacological effects. Specifically, deuterium (D) has a smaller molar volume and lower lipophilicity than hydrogen (H), and the CD bond is shorter than the CH bond. The physicochemical properties of hydrogen and deuterium are similar. The most critical difference between the two is that the mass of deuterium is twice that of hydrogen. Therefore, compared with the C-H bond, the vibration stretching frequency of the CD bond is lower and the ground state energy is lower, so the activation energy of the cleavage is greater, which makes the CD bond more stable than the C-H bond. Therefore, by utilizing the characteristics of deuterium replacing hydrogen, it is possible to improve the pharmacokinetic characteristics and metabolic spectrum of the drug without losing its activity, and ultimately achieve the purpose of reducing the frequency or dosage of administration, reducing adverse drug reactions, etc. [J.Am.Chem.Soc.1996,118,6,1511–1521]. In the past two decades, deuterium substitution has been increasingly used to improve the pharmacokinetic characteristics of marketed drugs [Nat Rev Drug Discov.2002Oct;1(10):753-68;J Med Chem.2019Jun 13;62(11):5276-5297]. The first deuterated drug, deutetrabenazine (deutetrabenazine, ) was approved by the US FDA in 2017; compared with undeuterated tetrabenazine (for the treatment of Huntington's disease and tardive dyskinesia-related chorea), deuterated drugs show superior PK characteristics, so deuterated tetrabenazine can reduce the dose and frequency of administration, and thus avoid the adverse reaction of tetrabenazine in reducing serotonin levels. In addition, donafenib is a deuterated derivative of the multikinase inhibitor sorafenib. Compared with sorafenib, it has better pharmacokinetic characteristics, higher efficacy and fewer adverse reactions. Therefore, in 2021, China approved donafenib for the treatment of unresectable hepatocellular carcinoma [Drugs. 2021 Nov; 81(16): 1915-1920]. Currently, there are at least 15 deuterated drug candidates undergoing clinical trials, 6 of which are in Phase III [Nat Rev Drug Discov. 2023 Jul; 22(7): 562-584]. These situations indicate that deuterated drugs can maintain drug activity and improve drug pharmacokinetics and toxicity, which is well known in the industry. Summary of the Invention

[0008] The present invention addresses the current lack of effective treatments for conventional chordoma. To address this issue, the present invention provides a method for treating conventional chordoma with a cyclic compound. The CDK4 / 6 inhibitor of the present invention has demonstrated promising therapeutic effects on conventional chordoma, with clinical trials demonstrating partial remission or disease stabilization.

[0009] The present invention provides an application of a substance A in preparing a drug for treating conventional chordoma, wherein the substance A is a CDK4 / 6 inhibitor.

[0010] In one embodiment, the substance A is substance AA, its stereoisomers, tautomers, isotopic derivatives, pharmaceutically acceptable salts, solvates, or solvates of pharmaceutically acceptable salts thereof; the substance AA is a compound of formula I, Abemaciclib, Trilaciclib, Ribociclib, Lerociclib, FCN-437c, or Birociclib;

[0011] Among them, R 1 C 1-6 alkyl;

[0012] R 2 H, halogen, -OR a 、-NR b R c 、-COOR d 、-COR e 、-(CH2) 0-6 -phenyl, -O(CH2) 0- 6-ORa 、C 1-6 Alkyl, or 1, 2 or 3 R f Substituted -OR a 、-NR b R c 、-COOR d 、-COR e 、-(CH2) 0-6 -phenyl, -O(CH2) 0-6 -OR a 、C 1-6 alkyl;

[0013] R is H, halogen, -OR a 、-NR b R c 、-COOR d 、-COR e 、C 1-6 Alkyl, C 3-7 Cycloalkyl, 5-7 membered heterocycloalkyl, or 1, 2 or 3 R f Substituted -OR a 、-NR b R c 、-COOR d 、-COR e 、C 1-6 Alkyl, C 3-7 Cycloalkyl, 5-7 membered heterocycloalkyl; the heteroatom species of the 5-7 membered heterocycloalkyl are independently selected from N, O or S, and the number of heteroatoms is 1, 2 or 3;

[0014] R a are independently H or C 1-6 alkyl;

[0015] R b and R c are independently H or C 1-6 alkyl;

[0016] R d and R e are independently H or C 1-6 alkyl;

[0017] R f are independently -OH, halogen or C 1-6 alkyl;

[0018] n is 0, 1, 2 or 3.

[0019] In one embodiment, the compound of formula I is

[0020] In one embodiment, the substance A is Palbociclib, its stereoisomers, its tautomers, its isotopic derivatives, its pharmaceutically acceptable salts, its solvates, and its solvates of pharmaceutically acceptable salts.

[0021] In one embodiment, the pharmaceutically acceptable salt of Palbociclib is Palbociclib isethionate, Palbociclib salicylate, Palbociclib p-toluenesulfonate, Palbociclib hydrochloric acid, Palbociclib sulfate, Palbociclib pyrosulfate, Palbociclib bisulfate, Palbociclib sulfite, Palbociclib bisulfite, Palbociclib nitrate, Palbociclib phosphate, Palbociclib monohydrogenphosphate, Palbociclib dihydrogensulfate ...nitrate, Palbociclib phosphate, Palbociclib monohydrogenphosphate, Palbociclib dihydrogensulfate, Palbociclib nitrate, Palbociclib nitrate, Palbociclib nitrate, Palbociclib nitrate, Palbociclib nitrate, Palbociclib nitrate, Palbociclib nitrate, Palbociclib nitrate, Palbociclib nitrate, Palbociclib nitrate, Palbociclib nitrate, Palbociclib nitrate, Palbociclib nitrate, Palbociclib nitrate, Palbociclib Palbociclib metaphosphate, Palbociclib pyrophosphate, Palbociclib nitrate, Palbociclib phosphate, Palbociclib hydrobromide, Palbociclib hydroiodide, Palbociclib oxalate, Palbociclib valerate, Palbociclib oleate, Palbociclib palmitate, Palbociclib stearate, Palbociclib laurate, Palbociclib borate, Palbociclib benzoate, Palbociclib lactate, Palbociclib citrate, Palbociclib Palbociclib maleate, Palbociclib fumarate, Palbociclib succinate, Palbociclib tartrate, Palbociclib naphthoate, Palbociclib methanesulfonate, Palbociclib glucoheptonate, Palbociclib lactobionate, Palbociclib lauryl sulfonate, Palbociclib acetate, Palbociclib propionate, Palbociclib octanoate, Palbociclib isobutyrate, Palbociclib oxalate, Palbociclib malonate, Palbociclib succinate Palbociclib suberate, Palbociclib sebacate, Palbociclib fumarate, Palbociclib maleate, Palbociclib mandelate, Palbociclib benzoate, Palbociclib chlorobenzoate, Palbociclib methylbenzoate, Palbociclib dinitrobenzoate, Palbociclib naphthoate, Palbociclib benzenesulfonate, Palbociclib phenylacetate, Palbociclib citrate, Palbociclib lactate, Palbociclib maleate,Palbociclib tartrate, Palbociclib mesylate.

[0022] In one embodiment, the substance A is Dalpiciclib, a stereoisomer thereof, a tautomer thereof, an isotopic derivative thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutically acceptable salt of Dalpiciclib is Dalpiciclib isethionate, Dalpiciclib salicylate, Dalpiciclib p-toluenesulfonate, Dalpiciclib hydrochloric acid, Dalpiciclib sulfate, Dalpiciclib pyrosulfate, Dalpiciclib bisulfate, Dalpiciclib sulfite, Dalpiciclib bisulfite, Dalpiciclib nitrate, Dalpiciclib phosphate, Dalpiciclib monohydrogen phosphate ... Dalpiciclib dihydrogen sulfate, Dalpiciclib metaphosphate, Dalpiciclib pyrophosphate, Dalpiciclib nitrate, Dalpiciclib phosphate, Dalpiciclib hydrobromide, Dalpiciclib hydroiodide, Dalpiciclib oxalate, Dalpiciclib valerate, Dalpiciclib oleate, Dalpiciclib palmitate, Dalpiciclib stearate, Dalpiciclib laurate, Dalpiciclib borate, Dalpiciclib benzoate Dalpiciclib lactate, Dalpiciclib citrate, Dalpiciclib maleate, Dalpiciclib fumarate, Dalpiciclib succinate, Dalpiciclib tartrate, Dalpiciclib naphthoate, Dalpiciclib methanesulfonate, Dalpiciclib glucoheptonate, Dalpiciclib lactobionate, Dalpiciclib laurylsulfonate, Dalpiciclib acetate, Dalpiciclib propionate, Dalpiciclib octanoate, D Dalpiciclib isobutyrate, Dalpiciclib oxalate, Dalpiciclib malonate, Dalpiciclib succinate, Dalpiciclib suberate, Dalpiciclib sebacate, Dalpiciclib fumarate, Dalpiciclib maleate, Dalpiciclib mandelate, Dalpiciclib benzoate, Dalpiciclib chlorobenzoate, Dalpiciclib methylbenzoate, Dalpiciclib dinitrobenzoate, Dalpiciclib naphthoate,Dalpiciclib benzenesulfonate, Dalpiciclib phenylacetate, Dalpiciclib citrate, Dalpiciclib lactate, Dalpiciclib maleate, Dalpiciclib tartrate, Dalpiciclib methanesulfonate.

[0023] In one embodiment, the pharmaceutically acceptable salt of Dalpiciclib is Dalpiciclib isethionate.

[0024] In one embodiment, the substance A is trilaciclib, a stereoisomer thereof, a tautomer thereof, an isotopic derivative thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0025] In one embodiment, the pharmaceutically acceptable salt of Trilaciclib is Trilaciclib isethionate, Trilaciclib salicylate, Trilaciclib toluenesulfonate, Trilaciclib hydrochloric acid, Trilaciclib sulfate, Trilaciclib pyrosulfate, Trilaciclib bisulfate, Trilaciclib sulfite, Trilaciclib bisulfite, Trilaciclib nitrate, Trilaciclib phosphate, Trilaciclib monohydrogen phosphate, Trilaciclib dihydrogen sulfate, Trilaciclib metaphosphate, Trilaciclib pyrophosphate, Trilaciclib nitrate, Trilaciclib phosphate, Trilaciclib hydrobromide, Trilaciclib hydroiodide, Trilaciclib oxalate, Trilaciclib valerate, Trilaciclib oleate, Trilaciclib palmitate, Trilaciclib stearate, Trilaciclib laurate, Trilaciclib borate, Trilaciclib benzoate, Trilaciclib lactate, Trilaciclib cit ...benzoate, Trilaciclib phosphate, Trilaciclib benzoate, Trilaciclib lactate, Trilaciclib citrate, Trilaciclib benzoate, Trilaciclib benzoate, Trilaciclib benzoate, Trilaciclib benzoate, Trilaciclib benzoate, Trilaciclib benzoate, Trilacic Trilaciclib Maleate, Trilaciclib Fumarate, Trilaciclib Succinate, Trilaciclib Tartrate, Trilaciclib Naphthoate, Trilaciclib Methanesulfonate, Trilaciclib Gluceptate, Trilaciclib Lactobionate, Trilaciclib Laurylsulfonate, Trilaciclib Acetate, Trilaciclib Propionate, Trilaciclib Octanoate, Trilaciclib Isobutyrate, Trilaciclib Oxalate, Trilaciclib Malonate, Trilaciclib Succinate Trilaciclib Suberate, Trilaciclib Sebacate, Trilaciclib Fumarate, Trilaciclib Maleate, Trilaciclib Mandelate, Trilaciclib Benzoate, Trilaciclib Chlorobenzoate, Trilaciclib Methylbenzoate, Trilaciclib Dinitrobenzoate, Trilaciclib Naphthoate, Trilaciclib Benzenesulfonate, Trilaciclib Phenylacetate, Trilaciclib Citrate, Trilaciclib Lactate, Trilaciclib Maleate,Trilaciclib tartrate, Trilaciclib mesylate.

[0026] In one embodiment, the pharmaceutically acceptable salt of Trilaciclib is Trilaciclib dihydrochloride.

[0027] In a certain embodiment, the substance A is Ribociclib, its stereoisomers, its tautomers, its isotopic derivatives, its pharmaceutically acceptable salts, its solvates, or its pharmaceutically acceptable salt solvates.In one embodiment, the pharmaceutically acceptable salt of Ribociclib is Ribociclib isethionate, Ribociclib salicylate, Ribociclib p-toluenesulfonate, Ribociclib hydrochloric acid, Ribociclib sulfate, Ribociclib pyrosulfate, Ribociclib bisulfate, Ribociclib sulfite, Ribociclib bisulfite, Ribociclib nitrate, Ribociclib phosphate, Ribociclib monohydrogen phosphate, Ribociclib dihydrogen sulfate, Ribociclib metaphosphate Salt, Ribociclib Pyrophosphate, Ribociclib Nitrate, Ribociclib Phosphate, Ribociclib Hydrobromide, Ribociclib Hydroiodide, Ribociclib Oxalate, Ribociclib Valerate, Ribociclib Oleate, Ribociclib Palmitate, Ribociclib Stearate, Ribociclib Laurate, Ribociclib Borate, Ribociclib Benzoate, Ribociclib Lactate, Ribociclib Citrate, Ribociclib Maleate, Ribociclib Ribociclib Fumarate, Ribociclib Succinate, Ribociclib Tartrate, Ribociclib Naphthoate, Ribociclib Methanesulfonate, Ribociclib Gluceptate, Ribociclib Lactobionate, Ribociclib Lauryl Sulfonate, Ribociclib Acetate, Ribociclib Propionate, Ribociclib Caprylate, Ribociclib Isobutyrate, Ribociclib Oxalate, Ribociclib Malonate, Ribociclib Succinate, Ribociclib Suberate, Ribociclib Ribociclib sebacate, Ribociclib fumarate, Ribociclib maleate, Ribociclib mandelate, Ribociclib benzoate, Ribociclib chlorobenzoate, Ribociclib methylbenzoate, Ribociclib dinitrobenzoate, Ribociclib naphthoate, Ribociclib benzenesulfonate, Ribociclib phenylacetate, Ribociclib citrate, Ribociclib lactate, Ribociclib maleate, Ribociclib tartrate, Ribociclib methanesulfonate.

[0028] In one embodiment, the pharmaceutically acceptable salt of Ribociclib is Ribociclib succinate.

[0029] In a certain embodiment, the substance A is Abemaciclib, its stereoisomers, its tautomers, its isotopic derivatives, its pharmaceutically acceptable salts, its solvates, or its pharmaceutically acceptable salt solvates.

[0030] In one embodiment, the pharmaceutically acceptable salt of Abemaciclib is Abemaciclib isethionate, Abemaciclib salicylate, Abemaciclib p-toluenesulfonate, Abemaciclib hydrochloric acid, Abemaciclib sulfate, Abemaciclib pyrosulfate, Abemaciclib bisulfate, Abemaciclib sulfite, Abemaciclib bisulfite, Abemaciclib nitrate, Abemaciclib phosphate, Abemaciclib monohydrogen phosphate, Abemaciclib dihydrogen sulfate ...nitrate, Abemaciclib phosphate, Abemaciclib monohydrogen phosphate, Abemaciclib dihydrogen sulfate, Abemaciclib nitrate, Abemaciclib nitrate, Abemaciclib nitrate, Abemaciclib nitrate, Abemaciclib nitrate, Abemaciclib nitrate, Abemaciclib nitrate, Abemaciclib nitrate, Abemaciclib nitrate, Abemaciclib nitrate, Abemaciclib nitrate, Abemaciclib nitrate, Abemaciclib nitrate, Abemaciclib nitrate, Abemaciclib Abemaciclib metaphosphate, Abemaciclib pyrophosphate, Abemaciclib nitrate, Abemaciclib phosphate, Abemaciclib hydrobromide, Abemaciclib hydroiodide, Abemaciclib oxalate, Abemaciclib valerate, Abemaciclib oleate, Abemaciclib palmitate, Abemaciclib stearate, Abemaciclib laurate, Abemaciclib borate, Abemaciclib benzoate, Abemaciclib lactate, Abemaciclib citrate, Abemaciclib oxalate, Abemaciclib valerate, Abemaciclib oleate, Abemaciclib palmitate, Abemaciclib stearate, Abemaciclib laurate, Abemaciclib borate, Abemaciclib benzoate, Abemaciclib lactate, Abemaciclib citrate, Abemaciclib benzoate Abemaciclib maleate, Abemaciclib fumarate, Abemaciclib succinate, Abemaciclib tartrate, Abemaciclib naphthoate, Abemaciclib methanesulfonate, Abemaciclib glucoheptonate, Abemaciclib lactobionate, Abemaciclib lauryl sulfonate, Abemaciclib acetate, Abemaciclib propionate, Abemaciclib octanoate, Abemaciclib isobutyrate, Abemaciclib oxalate, Abemaciclib malonate, Abemaciclib succinate Abemaciclib suberate, Abemaciclib sebacate, Abemaciclib fumarate, Abemaciclib maleate, Abemaciclib mandelate, Abemaciclib benzoate, Abemaciclib chlorobenzoate, Abemaciclib methylbenzoate, Abemaciclib dinitrobenzoate, Abemaciclib naphthoate, Abemaciclib benzenesulfonate, Abemaciclib phenylacetate, Abemaciclib citrate, Abemaciclib lactate, Abemaciclib maleate,Abemaciclib tartrate, Abemaciclib mesylate.

[0031] In a certain embodiment, the substance A is Birociclib, its stereoisomers, its tautomers, its isotopic derivatives, its pharmaceutically acceptable salts, its solvates, or its pharmaceutically acceptable salt solvates.In one embodiment, the pharmaceutically acceptable salt of Birociclib is Birociclib isethionate, Birociclib salicylate, Birociclib p-toluenesulfonate, Birociclib hydrochloric acid, Birociclib sulfate, Birociclib pyrosulfate, Birociclib bisulfate, Birociclib sulfite, Birociclib bisulfite, Birociclib nitrate, Birociclib phosphate, Birociclib monohydrogen phosphate, Birociclib dihydrogen sulfate, Birociclib metaphosphate, Salt, Birociclib Pyrophosphate, Birociclib Nitrate, Birociclib Phosphate, Birociclib Hydrobromide, Birociclib Hydroiodide, Birociclib Oxalate, Birociclib Valerate, Birociclib Oleate, Birociclib Palmitate, Birociclib Stearate, Birociclib Laurate, Birociclib Borate, Birociclib Benzoate, Birociclib Lactate, Birociclib Citrate, Birociclib Maleate, Birociclib Birociclib Fumarate, Birociclib Succinate, Birociclib Tartrate, Birociclib Naphthoate, Birociclib Methanesulfonate, Birociclib Gluceptate, Birociclib Lactobionate, Birociclib Laurylsulfonate, Birociclib Acetate, Birociclib Propionate, Birociclib Caprylate, Birociclib Isobutyrate, Birociclib Oxalate, Birociclib Malonate, Birociclib Succinate, Birociclib Suberate, Birociclib Birociclib sebacate, Birociclib fumarate, Birociclib maleate, Birociclib mandelate, Birociclib benzoate, Birociclib chlorobenzoate, Birociclib methylbenzoate, Birociclib dinitrobenzoate, Birociclib naphthoate, Birociclib benzenesulfonate, Birociclib phenylacetate, Birociclib citrate, Birociclib lactate, Birociclib maleate, Birociclib tartrate, Birociclib methanesulfonate.

[0032] In one embodiment, the substance A is TY-302, its stereoisomers, its tautomers, its isotopic derivatives, its pharmaceutically acceptable salts, its solvates, or its pharmaceutically acceptable salt solvates.

[0033] In one embodiment, the pharmaceutically acceptable salt of TY-302 is TY-302 isethionate, TY-302 salicylate, TY-302 p-toluenesulfonate, TY-302 hydrochloric acid, TY-302 sulfate, TY-302 pyrosulfate, TY-302 hydrogen sulfate, TY-302 sulfite, TY-302 hydrogensulfite, TY-302 nitrate, TY-302 phosphate, TY-302 monohydrogenphosphate, TY-302 dihydrogen sulfate, TY-302 Metaphosphate, TY-302 pyrophosphate, TY-302 nitrate, TY-302 phosphate, TY-302 hydrobromide, TY-302 hydroiodide, TY-302 oxalate, TY-302 valerate, TY-302 oleate, TY-302 palmitate, TY-302 stearate, TY-302 laurate, TY-302 borate, TY-302 benzoate, TY-302 lactate, TY-302 citrate, TY-302 maleate, TY- TY-302 fumarate, TY-302 succinate, TY-302 tartrate, TY-302 naphthoate, TY-302 methanesulfonate, TY-302 glucoheptonate, TY-302 lactobionate, TY-302 laurylsulfonate, TY-302 acetate, TY-302 propionate, TY-302 octanoate, TY-302 isobutyrate, TY-302 oxalate, TY-302 malonate, TY-302 succinate, TY-302 suberate, TY-302 oxalate ... TY-302 sebacate, TY-302 fumarate, TY-302 maleate, TY-302 mandelate, TY-302 benzoate, TY-302 chlorobenzoate, TY-302 methylbenzoate, TY-302 dinitrobenzoate, TY-302 naphthoate, TY-302 benzenesulfonate, TY-302 phenylacetate, TY-302 citrate, TY-302 lactate, TY-302 maleate, TY-302 tartrate, TY-302 methanesulfonate.

[0034] In one embodiment, the substance A is lerociclib, a stereoisomer thereof, a tautomer thereof, an isotopic derivative thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.In one embodiment, the pharmaceutically acceptable salt of lerociclib is lerociclib isethionate, lerociclib salicylate, lerociclib p-toluenesulfonate, lerociclib hydrochloric acid, lerociclib sulfate, lerociclib pyrosulfate, lerociclib bisulfate, lerociclib sulfite, lerociclib bisulfite, lerociclib nitrate, lerociclib phosphate, lerociclib monohydrogen phosphate, lerociclib dihydrogen sulfate, lerociclib metaphosphate Salt, Lerociclib pyrophosphate, Lerociclib nitrate, Lerociclib phosphate, Lerociclib hydrobromide, Lerociclib hydroiodide, Lerociclib oxalate, Lerociclib valerate, Lerociclib oleate, Lerociclib palmitate, Lerociclib stearate, Lerociclib laurate, Lerociclib borate, Lerociclib benzoate, Lerociclib lactate, Lerociclib citrate, Lerociclib maleate, Leroc Lerociclib fumarate, Lerociclib succinate, Lerociclib tartrate, Lerociclib naphthoate, Lerociclib methanesulfonate, Lerociclib glucoheptonate, Lerociclib lactobionate, Lerociclib laurylsulfonate, Lerociclib acetate, Lerociclib propionate, Lerociclib octanoate, Lerociclib isobutyrate, Lerociclib oxalate, Lerociclib malonate, Lerociclib succinate, Lerociclib suberate, Leroc Lerociclib sebacate, Lerociclib fumarate, Lerociclib maleate, Lerociclib mandelate, Lerociclib benzoate, Lerociclib chlorobenzoate, Lerociclib methylbenzoate, Lerociclib dinitrobenzoate, Lerociclib naphthoate, Lerociclib benzenesulfonate, Lerociclib phenylacetate, Lerociclib citrate, Lerociclib lactate, Lerociclib maleate, Lerociclib tartrate, Lerociclib methanesulfonate.

[0035] In one embodiment, the substance A is FCN-437c, its stereoisomers, its tautomers, its isotopic derivatives, its pharmaceutically acceptable salts, its solvates, or its pharmaceutically acceptable salt solvates.

[0036] In one embodiment, the pharmaceutically acceptable salt of FCN-437c is FCN-437c isethionate, FCN-437c salicylate, FCN-437c p-toluenesulfonate, FCN-437c hydrochloric acid, FCN-437c sulfate, FCN-437c pyrosulfate, FCN-437c bisulfate, FCN-437c sulfite, FCN-437c bisulfite, FCN-437c nitrate, FCN-437c phosphate, FCN-437c monohydrogen phosphate, FCN-437c dihydrogen sulfate, FCN-437c metaphosphate FCN-437c pyrophosphate, FCN-437c nitrate, FCN-437c phosphate, FCN-437c hydrobromide, FCN-437c hydroiodide, FCN-437c oxalate, FCN-437c valerate, FCN-437c oleate, FCN-437c palmitate, FCN-437c stearate, FCN-437c laurate, FCN-437c borate, FCN-437c benzoate, FCN-437c lactate, FCN-437c citrate, FCN-437c maleate, FCN- FCN-437c fumarate, FCN-437c succinate, FCN-437c tartrate, FCN-437c naphthoate, FCN-437c methanesulfonate, FCN-437c glucoheptonate, FCN-437c lactobionate, FCN-437c laurylsulfonate, FCN-437c acetate, FCN-437c propionate, FCN-437c octanoate, FCN-437c isobutyrate, FCN-437c oxalate, FCN-437c malonate, FCN-437c succinate, FCN-437c suberate ... FCN-437c sebacate, FCN-437c fumarate, FCN-437c maleate, FCN-437c mandelate, FCN-437c benzoate, FCN-437c chlorobenzoate, FCN-437c methylbenzoate, FCN-437c dinitrobenzoate, FCN-437c naphthoate, FCN-437c benzenesulfonate, FCN-437c phenylacetate, FCN-437c citrate, FCN-437c lactate, FCN-437c maleate, FCN-437c tartrate, and FCN-437c methanesulfonate.

[0037] In one embodiment, the substance A is a compound of formula IV, a stereoisomer thereof, a tautomer thereof, an isotopic derivative thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0038] In one embodiment, the pharmaceutically acceptable salt of the compound of formula IV is isethionate, salicylate, p-toluenesulfonate, hydrochloric acid, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogensulfate, metaphosphate, pyrophosphate, nitrate, phosphate, hydrobromide, hydroiodide, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, citrate, maleate, or thiazolyl salt. fumarate of the compound IV, succinate of the compound IV, tartrate of the compound IV, naphthoate of the compound IV, methanesulfonate of the compound IV, glucoheptonate of the compound IV, lactobionate of the compound IV, laurylsulfonate of the compound IV, acetate of the compound IV, propionate of the compound IV, octanoate of the compound IV, isobutyrate of the compound IV, oxalate of the compound IV, malonate of the compound IV, succinate of the compound IV, suberate of the compound IV, sebacate of the compound IV, fumarate of the compound IV, maleate of the compound IV, mandelate of the compound IV, benzoate of the compound IV, chlorobenzoate of the compound IV, methylbenzoate of the compound IV, dinitrobenzoate of the compound IV, naphthoate of the compound IV, benzenesulfonate of the compound IV, phenylacetate of the compound IV, citrate of the compound IV, lactate of the compound IV, maleate of the compound IV, tartrate of the compound IV, methanesulfonate of the compound IV.

[0039] In one embodiment, the isotopic derivative is a deuterated derivative.

[0040] In one embodiment, the substance A is used alone or in combination with other substances.

[0041] In a certain embodiment, the substance A is administered orally.

[0042] In one embodiment, the dosage of substance A is (75-500) mg / day, calculated based on the amount of its active ingredient, for example, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 1 70mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg; another example is 125mg / day, another example is calculated as (75-500)mg / day based on the amount of Palbociclib, another example is 125mg / day.

[0043] In one embodiment, the frequency of administration of substance A is (1-3) times / day, for example, once, twice or three times; and another example, once / day.

[0044] In one embodiment, the administration cycle of substance A is 14-42 days as a dosing cycle; for example, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, 42 days; for example, 28 days.

[0045] In one embodiment, the substance A is administered for the first 10-32 days (e.g., 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, and for example, 21 days) and then discontinued for 4-10 days (e.g., 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, and for example, 7 days).

[0046] In one embodiment, the substance A is administered for 1-12 cycles, for example, 1-4 cycles, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 cycles.

[0047] In one embodiment, the conventional chordomas do not have 9p (short arm of chromosome 9) genomic segment deletion (i.e., the 9p genomic segments of these patients are intact, i.e., no 9p genomic segments are deleted) and / or no CDKN2A / B gene deletion.

[0048] In one embodiment, the conventional chordoma patient is clinically diagnosed with PR (partial response) or SD (stable disease) after receiving the substance A.

[0049] In one embodiment, the conventional chordoma is a "conventional chordoma with activated NO and ROS production in macrophages signaling pathways in the tumor, such as APSP greater than or equal to 0."

[0050] The present invention provides a method for treating traditional chordoma, comprising administering a therapeutically effective amount of substance A to a patient; the substance A is as described in any of the previous schemes.

[0051] In one embodiment, the dosage, frequency, and cycle of administration of the substance A are as described in any of the previous schemes.

[0052] In one embodiment, the conventional chordoma is as described in any of the preceding embodiments.

[0053] The present invention provides a method for treating chordoma, comprising: determining whether to administer a therapeutically effective amount of substance A to the patient based on the specific subtype of chordoma suffered by the patient;

[0054] If the patient suffers from conventional chordoma, administering a therapeutically effective amount of the substance A to the patient;

[0055] If the patient has a dedifferentiated chordoma, a therapeutically effective amount of the substance A is not administered to the patient.

[0056] In one embodiment, the method comprises: determining whether to administer a therapeutically effective amount of the substance A to the patient based on the specific subtype of chordoma suffered by the patient;

[0057] If the patient suffers from conventional chordoma and the patient does not have 9p (short arm of chromosome 9) genomic segment deletion and / or CDKN2A / B gene deletion, administering a therapeutically effective amount of the substance A to the patient;

[0058] If the patient has dedifferentiated chordoma and does not have 9p (short arm of chromosome 9) genomic segment deletion and / or CDKN2A / B gene deletion, the patient is not administered a therapeutically effective amount of substance A.

[0059] The compounds listed in the present invention (Formula I compound, Abemaciclib, Trilaciclib, Ribociclib, Lerociclib, FCN-437c or Birociclib) are all common CDK4 / 6 inhibitors in the art. It is known to those skilled in the art that compounds with the same target usually have the same or similar biological activities. Therefore, based on the fact that Palbociclib has a good therapeutic effect on traditional chordoma, it can be known that the CDK4 / 6 inhibitors of the present application also have a good therapeutic effect on traditional chordoma.

[0060] In particular, compared with Palbociclib, the compounds of Formula I, Formula IV, and TY-302 of the present application are not only CDK4 / 6 inhibitors, but also have very similar structures. Those skilled in the art can fully expect that the compounds of Formula I, Formula IV, and TY-302 can have the same or similar therapeutic effects as Palbociclib.

[0061] In the present invention, the structure of the compound is as follows:

[0062] This invention is also based on Zheyuan Technology's original digital twin technology. By combining the data-driven algorithm DAGM (SCI journal: EBioMedicine.2021Jul;69:103446; China Authorized Patent No.: ZL201880003025.3) with the knowledge-driven algorithm TWIRLS (Drug Dev Res.2021May;82(3):465.), a scoring model for evaluating the sensitivity of subjects to CDK4 / 6 inhibitors was successfully constructed. Through systematic analysis of this scoring model, conventional chordoma was found to be a new potential indication for CDK4 / 6 inhibitors, providing a strong theoretical basis and practical guidance for precision treatment.

[0063] The DAGM algorithm is an artificial intelligence-based method for assessing genomic mutational damage. It uses eQTL (expression quantitative trait loci) analysis to establish associations between gene expression traits and gene mutations. The algorithm efficiently converts complex, discrete, and high-dimensional genomic variation information into lower-dimensional, highly correlated activity profiles of signaling pathways (APSPs). The DAGM algorithm takes genomic data as input and, leveraging multiple techniques including built-in data models, deep learning models, and knowledge models, ultimately outputs a comprehensive cellular signaling pathway functional profile for the subject, providing a comprehensive assessment of cellular biological function. The process first requires obtaining the subject's whole-exome sequencing (WES) data (Fast file). After rigorous quality control, rare variants (MAF < 0.01) are extracted from the data. After processing the DAGM algorithm, the VCF files representing the variant sites generate a set of continuous variables representing the functional characteristics of the subject's cells, known as the signaling pathway activity profile (APSP). The APSP is further transformed into a point in a high-dimensional space, where each dimension represents a cellular function. This process allows each biological individual to be transformed into a digital entity, forming a functional digital twin of the subject.

[0064] By integrating these digital entities to form a topological structure, a digital twin model representing groups with similar characteristics or diseases can be constructed. In this high-dimensional space composed of specific digital twins, the present invention continues to develop an artificial intelligence-driven mechanism model that can effectively distinguish between drug-responsive patients and non-responsive patients. This mechanism model realizes the function of computer simulation of clinical trials by encoding a generalizable hyperplane (scoring model), thereby discovering that traditional chordoma is a new indication for CDK4 / 6 inhibitors.

[0065] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings.

[0066] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. When the compound of the present invention contains both 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).

[0067] The term "solvate" refers to a compound of the present invention combined with a stoichiometric or non-stoichiometric amount of a solvent. The solvent molecules in the solvate may be present in an ordered or non-ordered arrangement.

[0068] The term "pharmaceutically acceptable salt" and "solvate" as used herein refer to substances prepared from the compounds of the present invention and relatively non-toxic, pharmaceutically acceptable acids or bases, in combination with stoichiometric or non-stoichiometric amounts of solvents.

[0069] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0070] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "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.

[0071] The term "patient" refers to any animal, preferably a mammal, and most preferably a human, that is about to be or has been administered a compound according to embodiments of the present invention. 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, and humans, with humans being the most preferred.

[0072] 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.

[0073] The reagents and raw materials used in the present invention are commercially available.

[0074] The present invention provides a positive advancement in the use of a paracyclic compound, particularly palbociclib, its stereoisomers, tautomers, isotopic derivatives, pharmaceutically acceptable salts, solvates, and solvates of its pharmaceutically acceptable salts, for the preparation of a medicament for treating conventional chordoma. Palbociclib has demonstrated promising results in clinical trials, with therapeutic effects including partial remission or stable disease. DETAILED DESCRIPTION

[0075] 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.

[0076] The conventional chordoma may be a single lesion or multiple lesions. For example, the conventional chordoma may include any of the following options:

[0077] (1) A single lesion located in the vertebra;

[0078] (2) multiple lesions are located in the vertebrae;

[0079] (3) Single lesion located at the skull base

[0080] (4) multiple lesions located at the skull base;

[0081] (5) Multiple lesions are located in the vertebrae and skull base.

[0082] Patients with conventional chordoma may have one or more of the following conditions:

[0083] (1) Untreated;

[0084] (2) recurrence after surgery and radiotherapy;

[0085] (3) taking apatinib but not achieving clinical remission or relapse;

[0086] (4) Using a PARP inhibitor-containing treatment regimen but failing to achieve clinical remission or relapse;

[0087] (5) Using immunotherapy regimen, but no clinical remission or relapse was achieved.

[0088] Example 1 Traditional Chordoma Subtype + Palbociclib

[0089] Based on the 2021 "Clinical Practice Guidelines for Bone Tumors" published by the National Comprehensive Cancer Network (NCCN), chordomas are divided into three histological subtypes: conventional, chondroid, and dedifferentiated. Conventional chordomas are the most common, typically characterized by loss of cartilage or mesenchymal tissue.

[0090] In a prospective clinical trial, from March 2019 to August 2023, five patients with conventional chordoma (two women and three men) were treated with Palbociclib. Based on RECIST 1.1 or CHOI criteria, two patients achieved a partial response (PR), three patients had stable disease (SD), and no patients had progressive disease (PD). Genomic analysis confirmed that none of these patients had 9p (short arm of chromosome 9) genomic fragment deletions (i.e., all patients had intact 9p genomic fragments, meaning no 9p genomic fragments were deleted) and / or CDKN2A / B gene deletions.

[0091] Compared with patients with conventional chordoma, another patient with dedifferentiated chordoma received Palbociclib treatment, and the patient's treatment outcome was PD (progressive disease) based on RECIST 1.1 or CHOI criteria.

[0092] The brief treatment details of all 6 patients are as follows:

[0093] Patient 1

[0094] A 48-year-old male patient with traditional chordoma had a single lesion located in the cervical spine. Between 2016 and 2018, the disease recurred after multiple surgeries and radiotherapy. The patient took Palbociclib from March to June 2019 for a total of 2 courses (125 mg once a day for 21 consecutive days, followed by a 7-day break; 28 days as a treatment cycle). During this period, the patient reported that his condition had improved, and after completing the first cycle of medication in April, an imaging examination was performed, and the long diameter of the tumor was reduced to 17.4%, which was a PR (partial response) to the drug based on RECIST 1.1 or CHOI standards. An imaging examination was performed in June 2019, and based on RECIST 1.1 or CHOI standards, compared with the situation before treatment in March, it was still judged to be a PR (partial response) to the drug.

[0095] Patient 2

[0096] A 60-year-old female patient with conventional chordoma had multiple lesions located in the cervical spine. She underwent multiple surgeries between 2005 and 2021 and relapsed. She also took apatinib in 2020 but did not achieve clinical remission. The patient took Palbociclib from January to May 2023 for a total of 4 courses (125 mg once a day for 21 consecutive days, followed by a 7-day break; 28-day treatment cycle). In April 2023 (after completing the third dosing cycle), an imaging examination was performed, and the long diameter of the tumor was reduced by 12.5% ​​(Table 1), which was a PR (partial remission) based on RECIST 1.1 or CHOI criteria.

[0097] Table 1

[0098] Patient 3

[0099] A 38-year-old male patient with conventional chordoma had multiple lesions located in the vertebrae and occipital bone. He had relapsed after multiple surgeries and radiotherapy between 2018 and 2021. He received two cycles of palbociclib (125 mg once daily for 21 consecutive days, followed by a 7-day break; each cycle consisted of 28 days) from March to April 2023. Radiographic imaging in May 2023 showed stable disease (SD) according to RECIST 1.1 or CHOI criteria.

[0100] Patient 4

[0101] A 28-year-old female patient with conventional chordoma presented with a single lesion in the cervical spine. She had relapsed after multiple surgeries and radiotherapy between 2019 and 2021. She received two cycles of palbociclib (125 mg once daily for 21 consecutive days, followed by a 7-day break; each cycle consisted of 28 days) from May to June 2023. Radiographic imaging in July 2023 confirmed stable disease (SD) based on either RECIST 1.1 or CHOI criteria.

[0102] Patient 5

[0103] A 19-year-old male patient with conventional chordoma presented with multiple lesions located in the occipital bone. He had previously received a PARP inhibitor combined with immunotherapy, but his tumor had recently progressed and was inoperable. He received two courses of palbociclib (125 mg once daily for 21 consecutive days, followed by a 7-day break; each cycle lasted 28 days) between June and July 2023. Radiographic imaging in August 2023 confirmed stable disease (SD) based on either RECIST 1.1 or CHOI criteria.

[0104] Patient 6

[0105] A 65-year-old male patient with dedifferentiated chordoma had a single lesion in the cervical spine and recurred after surgery. He received one course of palbociclib (125 mg once daily for 21 consecutive days, followed by a 7-day break; a 28-day treatment cycle) between July 2023 and August 2023. Imaging was performed, and the patient was classified as unresponsive to the drug, with progressive disease (PD) according to RECIST 1.1 or CHOI criteria.

Claims

1. Use of a substance A in the preparation of a drug for treating conventional chordoma, wherein the substance A is a CDK4 / 6 inhibitor.

2. The use according to claim 1, wherein the substance A is substance AA, its stereoisomer, its tautomer, its isotopic derivative, its pharmaceutically acceptable salt, its solvate, or its pharmaceutically acceptable salt solvate; the substance AA is a compound of formula I, Abemaciclib, Trilaciclib, Ribociclib, Lerociclib, FCN-437c or Birociclib; in, R 1 C 1-6 alkyl; R 2 H, halogen, -OR a 、-NR b R c 、-COOR d 、-COR e 、-(CH2) 0-6 -phenyl, -O(CH2) 0- 6-OR a , C 1-6 Alkyl, or 1, 2 or 3 R f Substituted-OR a 、-NR b R c 、-COOR d 、-COR e 、-(CH2) 0-6 -phenyl, -O(CH2) 0-6 -OR a , C 1-6 alkyl; R is H, halogen, -OR a 、-NR b R c 、-COOR d 、-COR e , C 1-6 Alkyl, C 3-7 Cycloalkyl, 5-7 membered heterocycloalkyl, or 1, 2 or 3 R f Substituted-OR a 、-NR b R c 、-COOR d 、-COR e , C 1-6 Alkyl, C 3-7 Cycloalkyl, 5-7 membered heterocycloalkyl; the heteroatom species of the 5-7 membered heterocycloalkyl are independently selected from N, O or S, and the number of heteroatoms is 1, 2 or 3; R a are independently H or C 1-6 alkyl; R b and R c are independently H or C 1-6 alkyl; R d and R e are independently H or C 1-6 alkyl; R f are independently -OH, halogen or C 1-6 alkyl; n is 0, 1, 2 or 3.

3. The use according to claim 2, wherein the compound of formula I is 4. The use according to claim 1, wherein the substance A is Palbociclib, its stereoisomers, its tautomers, its isotopic derivatives, its pharmaceutically acceptable salts, its solvates, and its solvates of pharmaceutically acceptable salts.

5. The use according to claim 4, wherein the pharmaceutically acceptable salt of Palbociclib comprises a pharmaceutically acceptable salt of Palbociclib is Palbociclib isethionate, Palbociclib salicylate, Palbociclib p-toluenesulfonate, Palbociclib hydrochloric acid, Palbociclib sulfate, Palbociclib pyrosulfate, Palbociclib hydrogen sulfate, Palbociclib sulfite, Palbociclib bisulfite, Palbociclib nitrate, Palbociclib phosphate, Palbociclib Palbociclib Monohydrogen Phosphate, Palbociclib Dihydrogen Sulfate, Palbociclib Metaphosphate, Palbociclib Pyrophosphate, Palbociclib Nitrate, Palbociclib Phosphate, Palbociclib Hydrobromide, Palbociclib Hydroiodide, Palbociclib Oxalate, Palbociclib Valerate, Palbociclib Oleate, Palbociclib Palmitate, Palbociclib Stearate, Palbociclib Laurate, Palbociclib Borate, Palbociclib Benzoate, Palbociclib Hydrogen Sulf ... Palbociclib lactate, Palbociclib citrate, Palbociclib maleate, Palbociclib fumarate, Palbociclib succinate, Palbociclib tartrate, Palbociclib naphthoate, Palbociclib mesylate, Palbociclib glucoheptonate, Palbociclib lactobionate, Palbociclib lauryl sulfonate, Palbociclib acetate, Palbociclib propionate, Palbociclib octanoate, Palbociclib isobutyrate, Palbociclib oxalate , Palbociclib malonate, Palbociclib succinate, Palbociclib suberate, Palbociclib sebacate, Palbociclib fumarate, Palbociclib maleate, Palbociclib mandelate, Palbociclib benzoate, Palbociclib chlorobenzoate, Palbociclib methylbenzoate, Palbociclib dinitrobenzoate, Palbociclib naphthoate, Palbociclib benzenesulfonate, Palbociclib phenylacetate, Palbociclib citrate,Palbociclib lactate, Palbociclib maleate, Palbociclib tartrate, Palbociclib mesylate.

6. The use according to claim 1, wherein the substance A is Dalpiciclib, its stereoisomers, its tautomers, its isotopic derivatives, its pharmaceutically acceptable salts, its solvates, and its solvates of pharmaceutically acceptable salts.

7. The use according to claim 6, wherein the pharmaceutically acceptable salt of Dalpiciclib is Dalpiciclib isethionate.

8. The use according to claim 2, wherein the substance AA is a compound of formula IV or TY-302; 9. The use according to claim 1, wherein the isotope derivative is a deuterated derivative.

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