WO2023104074A1 - New use of kinase inhibitor - Google Patents

Abstract

The present invention belongs to the technical field of medicines, and relates to a new use of a kinase inhibitor. Disclosed is the use of a compound of formula (I) or a pharmaceutically acceptable salt, a stereoisomer and a crystal form thereof in the preparation of a drug for treating and/or preventing an osteosarcoma, wherein each variable in the general formula is as defined in the description. Research shows that the compound of the general formula (I) in the present invention or the pharmaceutically acceptable salt, the stereoisomer and the crystal form thereof has a treatment effect on an osteosarcoma, and has the potential of treating an osteosarcoma clinically.

Description

New uses for kinase inhibitors technical field

The invention belongs to the technical field of medicine, and in particular relates to a new application of a kinase inhibitor.

Background technique

Osteosarcoma is a malignant tumor originating from mesenchymal tissue. The worldwide incidence is about 3/1 million. Primary osteosarcoma accounts for less than 0.2% of all malignant tumors. Osteosarcoma tends to occur in children and adolescents, with a median age of onset of 20 years. The second peak of incidence is over 50 years old.

Osteosarcoma has a high degree of malignancy, fast growth and strong invasiveness. It is highly destructive to local bone tissue and prone to early metastasis, among which lung metastasis is the most common. More than 1/2 of osteosarcoma patients will develop lung metastasis during the course of the disease, causing disability The morbidity and mortality are extremely high, and most osteosarcoma patients survive less than 1 year after diagnosis. Simple amputation was the standard treatment for osteosarcoma before the 1970s, but the 5-year survival rate after surgery was less than 20%. With the development of modern medical technology, the current clinical treatment methods for patients with osteosarcoma include surgery, chemotherapy, radiotherapy, ablation therapy, interventional therapy and various comprehensive treatment methods. Comprehensive treatment methods such as chemotherapy, limb salvage surgery, systemic therapy combined with local therapy have been widely used in clinical practice, especially systemic chemotherapy combined with local limb salvage therapy has achieved great success. The postoperative 5-year survival rate of osteosarcoma patients in my country has reached From the previous less than 20% to the current 55% -75%. There are other treatment methods, such as cellular immunotherapy, gene therapy, stem cell therapy, etc., the effectiveness of which is yet to be confirmed by further research.

At present, for patients with recurrent or unresectable osteosarcoma after surgery, the guidelines recommend a large amount of chemotherapy drugs such as methotrexate, ifosf adenamine, doxorubicin, and cisplatin to be given sequentially or in combination. treat. For patients with osteosarcoma who are resistant, unable to tolerate or unable to effectively control tumor metastasis and progression of the above chemotherapy drugs, the prognosis is extremely poor. Moreover, due to various unidentified factors such as the pathogenesis of osteosarcoma and insufficient genomics research, further breakthroughs in the treatment of osteosarcoma have not been achieved, and it has entered a treatment bottleneck, and there are still huge unmet clinical needs.

Contents of the invention

The compound of the general formula (I) of the present invention is a kinase inhibitor, and it is found through research that the kinase inhibitor of the present invention has a therapeutic effect on osteosarcoma.

To achieve the above object, the present invention at first provides the following scheme:

The present invention provides the use of a compound of general formula (I) or a pharmaceutically acceptable salt, stereoisomer, and crystal form thereof in the preparation of a medicine for treating and/or preventing osteosarcoma;

Wherein, Ar is phenyl optionally substituted by 1-3 R ₆ , each R ₆ is independently selected from hydrogen, amino, cyano, halogen, C _1-4 alkyl and trifluoromethyl;

Y is CR ₃ ;

P is _CR4 ;

W is N;

R ₃ is hydrogen or C _1-4 alkyl;

R ₄ is -(CH ₂ ) _n -(5-11) membered heterocyclic group, wherein n=0-6, and the ring-forming S atom in the heterocyclic group is optionally oxidized to S(O) or S (O) ₂ , the ring-forming C atom is optionally oxidized to C(O), and the heterocyclic group is optionally substituted by one or more independently selected from C _1-3 alkyl and C _3-6 cycloalkyl base substitution.

In some embodiments, Ar is phenyl optionally substituted with 1-3 R ₆ , each R ₆ independently selected from hydrogen and halogen;

Y is CR ₃ ;

P is _CR4 ;

W is N;

_R3 is hydrogen;

R ₄ is selected from -(CH ₂ ) _n -(5-6) membered monoheterocyclic group and -(CH ₂ ) _n -(7-11) membered condensed heterocyclic group, wherein, n=0-6, said The ring-forming S atom in the heterocyclic group is optionally oxidized to S(O) or S(O) ₂ , the ring-forming C atom is optionally oxidized to C(O), and the heterocyclic group is optionally oxidized by one or more Substituents independently selected from C _1-3 alkyl and C _3-6 cycloalkyl are substituted.

In a further embodiment, the (5-6) membered monoheterocyclic group is a (5-6) membered saturated monoheterocyclic group, and the (7-11) membered condensed heterocyclic group is a (7- 11) A membered saturated condensed heterocyclic group. In a preferred embodiment, the (7-11) membered saturated condensed heterocyclic group is (7-11) membered saturated heterocyclic group, (7-11) membered saturated spiroheterocyclic group or (7-11) membered saturated spiroheterocyclic group 11) A membered saturated bridged heterocyclic group.

In some embodiments, the R ₄ is

n=0-3, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from C _1-3 alkyl and C _3-6 cycloalkyl;

In a preferred embodiment, the R ₄ is

n=0-3, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from C _1-3 alkyl and C _3-6 cycloalkyl.

In one embodiment, the compound of general formula (I) is a compound shown in Table 1 or a pharmaceutically acceptable salt, stereoisomer, or crystal form thereof.

Table 1 Compounds of the present invention

In some embodiments, the compounds of the present invention may also include compounds other than compounds of general formula (I), for example, the specific compounds shown in the table below.

In some embodiments, the compound is

or a pharmaceutically acceptable salt, stereoisomer, or crystal form thereof.

The present invention also provides a pharmaceutical composition or a pharmaceutical combination product. The pharmaceutical composition or pharmaceutical combination product of the present invention comprises a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt, stereoisomer, A crystal form and one or more pharmaceutically acceptable carriers, diluents or excipients. Optionally, the pharmaceutical composition or pharmaceutical combination further comprises one or more other active agents. Wherein the definition of the compound of general formula (I) is as described above.

The present invention also provides a method for treating osteosarcoma, the method comprising administering a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt, stereoisomer, crystal form or The pharmaceutical composition or pharmaceutical combination product of the present invention, wherein the definition of the compound of general formula (I) is as described above.

The present invention also provides the use of the compound of general formula (I) or its pharmaceutically acceptable salt, stereoisomer, crystal form or the pharmaceutical composition or pharmaceutical combination product described in the present invention in the prevention and/or treatment of osteosarcoma , wherein the compound of general formula (I) is as defined above.

The present invention also provides the compound of general formula (I) or its pharmaceutically acceptable salt, stereoisomer, crystal form or the pharmaceutical composition or pharmaceutical combination product described in the present invention for the prevention and/or treatment of osteoarthritis The use in the medicine of tumor, wherein the definition of the compound of general formula (I) is as described above.

The present invention also provides the compound of general formula (I) or its pharmaceutically acceptable salt, stereoisomer, crystal form or the pharmaceutical composition or pharmaceutical combination product described in the present invention for preventing and/or treating osteosarcoma , wherein the compound of general formula (I) is as defined above.

In some embodiments, the osteosarcoma is primary osteosarcoma and/or secondary osteosarcoma.

In some embodiments, the osteosarcoma is osteoblastic osteosarcoma and/or osteolytic osteosarcoma.

In some embodiments, the osteosarcoma is osteoblastic osteosarcoma, chondrogenic osteosarcoma, and/or fibroblastic osteosarcoma.

In some embodiments, the osteosarcoma is locally advanced or advanced, relapsed, refractory and/or metastatic osteosarcoma.

In some embodiments, the osteosarcoma is refractory osteosarcoma.

In some embodiments, the osteosarcoma is locally advanced, recurrent, metastatic osteosarcoma.

In some embodiments, the osteosarcoma is osteosarcoma that has failed or has not received standard treatment.

In some embodiments, the osteosarcoma is osteosarcoma that has failed chemotherapy.

In some embodiments, the osteosarcoma is an osteosarcoma with an abnormal MYC gene.

In some embodiments, the osteosarcoma is a MYC gene amplified and/or MYC protein overexpressed osteosarcoma.

In some embodiments, the osteosarcoma is MYC gene amplified and/or MYC protein overexpressed, primary osteosarcoma and/or secondary osteosarcoma.

In some embodiments, the osteosarcoma is MYC gene amplified and/or MYC protein overexpressed, osteogenic osteosarcoma and/or osteolytic osteosarcoma.

In some embodiments, the osteosarcoma is MYC gene amplified and/or MYC protein overexpressed, osteoblastic osteosarcoma, chondrogenic osteosarcoma and/or fibroblast osteosarcoma.

In some embodiments, the osteosarcoma is locally advanced or advanced, relapsed, refractory and/or metastatic, MYC gene amplified and/or MYC protein overexpressed osteosarcoma.

In some embodiments, the osteosarcoma is MYC gene amplified and/or MYC protein overexpressed refractory osteosarcoma.

In some embodiments, the osteosarcoma is locally advanced, recurrent, metastatic, MYC gene amplified and/or MYC protein overexpressed osteosarcoma.

In some embodiments, the osteosarcoma is a MYC gene amplified and/or MYC protein overexpressed osteosarcoma that fails or has not undergone standard treatment.

In some embodiments, the osteosarcoma is chemotherapy failure, MYC gene amplification and/or MYC protein overexpression osteosarcoma.

In some embodiments, the MYC gene/protein refers to c-MYC, n-MYC, l-MYC gene/protein.

In some embodiments, the MYC gene refers to the c-MYC gene.

In some embodiments, the MYC protein refers to c-MYC protein.

In some embodiments, the osteosarcoma is a TP53-mutated and/or RB1-mutated osteosarcoma.

In some embodiments, the osteosarcoma is a RECQL4 mutated, RUNX2 mutated, GRM4 mutated, ALT mutated, ATRX mutated, DLG2 mutated, and/or IGF1R mutated osteosarcoma.

In some embodiments, the osteosarcoma described in the present invention is classified by WHO: classical osteosarcoma (chondrogenic osteosarcoma, fibroblastic osteosarcoma, osteoblastic osteosarcoma), telangiectatic osteosarcoma , small cell osteosarcoma, low-grade central osteosarcoma, periosteal osteosarcoma, secondary osteosarcoma, high-grade superficial osteosarcoma.

In some embodiments, the present invention also provides the dosage and regimen of the compound of general formula (I) or its pharmaceutically acceptable salt, stereoisomer, and crystal form for treating osteosarcoma patients, specifically as follows:

In some embodiments, the single administration dose of the compound of general formula (I) or its pharmaceutically acceptable salt, stereoisomer, and crystal form is 3 mg to 20 mg, for example: 3 mg, 4 mg, 5 mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg. The administration frequency is once a day, twice a day or once every two days, once every three days. The preferred frequency of dosing is once daily.

In some embodiments, the compound of general formula (I) or its pharmaceutically acceptable salt, stereoisomer, and crystal form can also be formulated with one or more pharmaceutically acceptable carriers. Any acceptable pharmaceutical formulation.

In some embodiments, the pharmaceutical preparation may contain one or more pharmaceutically acceptable carriers, and may be administered orally, parenterally, rectally, or pulmonary to patients or subjects in need of such treatment. By. When used for oral administration, the pharmaceutical composition can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions , syrup, etc. When making oral preparations, suitable fillers, binders, disintegrants, lubricants and the like can be added. For parenteral administration, the pharmaceutical composition can be made into injections, including injections, sterile powders for injections and concentrated solutions for injections. When making injections, conventional methods in the existing pharmaceutical field can be used for production. When preparing injections, no additives can be added, or appropriate additives can be added according to the properties of the medicine. For rectal administration, the pharmaceutical composition can be made into suppositories and the like. When used for pulmonary administration, the pharmaceutical composition can be made into inhalants or sprays and the like.

definition

The "halogen" in the present invention refers to fluorine, chlorine, bromine and iodine, etc., preferably fluorine and chlorine.

"Halo" in the present invention means that any hydrogen atom in the substituent can be replaced by one or more same or different halogens. "Halogen" is as defined above.

The "cyano group" mentioned in the present invention refers to the -CN group.

The "amino group" mentioned in the present invention refers to the -NH ₂ group.

The "C _1-4 alkyl" in the present invention refers to a straight-chain or branched-chain alkyl derived from a hydrocarbon part containing 1-4 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, iso Propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc. The "C _1-3 alkyl group" refers to the above-mentioned alkyl group containing 1-3 carbon atoms.

The "C _3-6 cycloalkyl" in the present invention refers to a monocyclic cycloalkyl, a bicyclic cycloalkyl system or a multicyclic cycloalkyl system containing 3-6 carbon atoms. These groups are saturated but not aromatic. Unless otherwise specified, single ring and condensed ring structures that can be formed are included. Examples include, but are not limited to: cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexane, bicyclo[2.2.2]hexane, bicyclo[3.2.1]hexane.

The "5-11 membered heterocyclic group" in the present invention refers to a non-aromatic cyclic group with 5-11 ring carbon atoms, wherein at least one ring carbon atom is selected from one of O, S, N or multiple heteroatoms, preferably 1-3 heteroatoms, and ring atoms including carbon atoms, nitrogen atoms and sulfur atoms can be oxidized.

The "heterocyclic group" refers to a monocyclic heterocyclic group, a bicyclic heterocyclic group system or a polycyclic heterocyclic group system, including saturated and partially saturated heterocyclic groups, but excluding aromatic rings. The "5-11 membered heterocyclic group" in the present invention includes the monocyclic and condensed ring structures that can be formed unless otherwise specified.

The single heterocyclic group can be 5-7 membered heterocyclic group, 5-6 membered heterocyclic group, 5-6 membered oxygen-containing heterocyclic group, 5-6 membered nitrogen-containing heterocyclic group, 5-6 membered saturated Heterocyclyl etc. Examples of the 5-6 membered monoheterocyclic group in the present invention include, but are not limited to, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazolidinyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl , morpholino, 1,4-dioxanyl, 1,4-oxathione, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, 3,4-dihydro-2H-pyrrolyl, 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro -1H-imidazolyl, 4,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-3H-pyrazolyl, 4,5-dihydro Thiazolyl, 2,5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4,5-tetrahydropyridyl, 1 , 2-isoxazinyl, 1,4-isoxazinyl or 6H-1,3-oxazinyl, etc.

The condensed heterocyclic ring includes a heterocyclic group, a spiro heterocyclic group, and a bridged heterocyclic group, which may be saturated, partially saturated or unsaturated, but not aromatic. The 7- to 11-membered condensed heterocyclic group in the present invention includes the possible formation of parallel, spiro and bridge structures unless otherwise specified.

The alkane ring group can be a 7-11 membered alkane group, preferably a 7-11 membered abheterocyclic group, examples of which include but are not limited to: 3,6-diazabicyclo[3.2.0]heptane, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrole And[3,4-b]pyrrole, octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridine, 2,3- Dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl , 2,3 dihydrobenzothiophen-2yl, octahydro-1H-indolyl, octahydrobenzofuranyl.

The spiroheterocyclyl can be a 7-11 membered spiroheterocyclyl, preferably a 7-11 membered saturated spiroheterocyclyl, examples of which include but are not limited to:

The bridged heterocyclic group can be a 7-11 membered bridged heterocyclic group, preferably a 7-11 membered bridged heterocyclic group, examples of which include but are not limited to:

The "pharmaceutically acceptable salt" in the present invention refers to the addition salts and solvates of pharmaceutically acceptable acids and bases. Such pharmaceutically acceptable salts include salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid , hydriodic acid, alkanoic acid (such as acetic acid, HOOC-(CH ₂ )n-COOH (where n=0-4)) and the like. Such pharmaceutically acceptable salts also include salts of bases such as sodium, potassium, calcium, ammonium and the like. A variety of non-toxic pharmaceutically acceptable addition salts are known to those skilled in the art.

All numerical ranges stated in the present invention include both endpoints of the range, all integers within the range, and subranges formed by these integers. For example, "5-11 yuan" includes 5, 6, 7, 8, 9, 10, 11 yuan, "5-6 yuan" includes 5, 6 yuan, "7-11 yuan" includes 7, 8, 9, 10, 11 yuan and so on.

The "one to more" mentioned in the present invention about substituents means that the number of substituents can be all chemically substituted positions of the substituted groups, preferably 1-6, more preferably 1-5, more preferably 1 - 3, more preferably 1-2.

The "crystal form" described in the present invention can be prepared from the compound of general formula (I) by conventional methods used in the art for preparation of crystal forms.

The "stereoisomer" of the compound of general formula (I) described in the present invention means that when there is an asymmetric carbon atom in the compound of general formula (I), enantiomers can be produced; when the compound has a carbon-carbon double bond or When the compound has a cyclic structure, cis-trans isomers will be produced; when the compound has a ketone or oxime, tautomers will be produced. Enantiomers, diastereoisomers, racemic isomers, cis-trans isomers, tautomers, geometric isomers, epimers and Their mixtures are included in the scope of the present invention.

"Treatment" as used herein refers to administering an effective amount of a drug to a patient to slow or cure an unwanted physiological change or condition, such as a hyperproliferative condition, such as the growth, formation or spread of cancer, in order to obtain a beneficial or desired Clinical outcomes, including, but not limited to: relief of symptoms, diminishment of extent of disease, stabilization of disease state (i.e., not worsening), delay or slowing of disease progression, amelioration or palliation of disease state, and regression (whether partial or complete), regardless of is detectable or undetectable.

The "treatment" mentioned in the present invention may include neoadjuvant therapy and adjuvant therapy.

"Neoadjuvant therapy" refers to the systemic treatment performed before the planned surgical treatment or local treatment of surgery plus radiotherapy for patients with initial tumors. According to different tumor types, neoadjuvant therapy may be chemotherapy, endocrine, targeted direction, immunization or radiotherapy. The goal of neoadjuvant therapy is to provide immediate systemic therapy, potentially eradicating micrometastases that would otherwise proliferate following the standard sequence of surgery followed by systemic therapy. Neoadjuvant therapy can also help reduce tumor size, allowing complete resection of initially unresectable tumors or preserving parts of the organ and its functions. Furthermore, neoadjuvant therapy allows in vivo assessment of drug efficacy, which can guide the choice of subsequent therapy.

"Adjuvant therapy" refers to therapy given after definitive surgery (where no evidence of residual disease can be detected) to destroy any remaining cancer cells in the body and to reduce the likelihood of tumor recurrence or spread to other sites. Treatment methods are roughly the same as neoadjuvant therapy. The goal of adjuvant therapy is to prevent cancer recurrence, and thus reduce the chance of cancer-related death. Adjuvant therapy explicitly excludes neoadjuvant therapy in this context.

The "refractory osteosarcoma" in the present invention refers to osteosarcoma that fails all existing treatments, for example: chemotherapy failure of methotrexate, ifosfamide, doxorubicin, and cisplatin.

The term "locally advanced osteosarcoma" in the present invention refers to osteosarcoma that is relatively extensive but still limited to one area. In some cases, it can refer to an osteosarcoma that has not spread but has invaded nearby organs or tissue, making it difficult to remove with surgery alone.

The term "advanced osteosarcoma" in the present invention refers to osteosarcoma that is difficult to obtain radical resection due to distant metastasis or severe local invasion.

The term "metastatic osteosarcoma" in the present invention refers to osteosarcoma that spreads to other parts of the body from its original body part (primary part).

"Relapsed osteosarcoma" in the present invention refers to osteosarcoma that regenerates at the original site or at a distant site after responding to initial treatment (eg, surgery).

The "standard treatment" mentioned in the present invention includes one or more of surgery, chemotherapy, radiotherapy, ablation therapy, interventional therapy and various comprehensive treatments, cellular immunotherapy, gene therapy, stem cell therapy, etc.

The "chemotherapy" mentioned in the present invention includes, but is not limited to, sequential or combined drug use of methotrexate, ifosfamide, doxorubicin, and cisplatin, as well as gemcitabine combined with docetaxel, etoposide combined with cyclic Chemotherapy regimens such as phosphoramide or ifosfamide.

"Failure", "treatment failure" or "chemotherapy failure" as described in the present invention refers to disease progression (PD) in the course of treatment or after the last treatment (according to tumor tissue evaluation RECIST1.1 curative effect evaluation standard is disease progression (PD) ), or intolerable due to toxic side effects during treatment.

The term "intolerable toxic and side effects" in the present invention refers to the inability to continue treatment due to adverse reactions caused by drugs.

Progression-free survival (PFS): Time from first dose of study drug to time of disease progression or death from any cause in the efficacy analysis.

Overall Survival (OS): Time from start of study drug treatment to death from any cause. Patients who had not died at the time of analysis were censored using the date when their survival was last known.

Objective Response Rate (ORR): The proportion of patients whose best response is CR or PR when the test drug is discontinued for each patient.

Duration of response (DOR): the time from the first PR or CR to the first PD or death.

Disease Control Rate (DCR): The proportion of patients whose best response was CR, PR, or SD.

According to the RECIST1.1 standard, the efficacy evaluation criteria were divided into complete remission (CR), partial remission (PR), stable (SD), and progressive (PD).

Complete remission (CR): all target lesions disappear (the short diameter of all pathological lymph nodes must be reduced to <10mm), non-target lesions disappear, and no new lesions appear.

Partial response (PR): the sum of the diameters of target lesions is reduced by at least 30% compared with the baseline level, non-target lesions disappear or stabilize, and no new lesions appear.

Progression of disease (PD): the relative increase of the sum of the diameters of target lesions is at least 20%, or the deterioration of non-target lesions, or the appearance of new lesions (one occurrence of the three is PD).

Stable disease (SD): The increase/decrease of target lesions is between PR and PD, and non-target lesions are stable or disappear, and there are no new lesions.

The "MYC gene/protein" in the present invention refers to c-MYC, n-MYC, l-MYC gene/protein, and all refer to c-MYC gene/protein unless otherwise specified.

"Clinically having a therapeutic effect" in the present invention means that the progression-free survival (PFS) of clinical patients is prolonged, the overall survival (OS) is prolonged, the objective response rate (ORR) is improved, and the disease control rate (DCR) is improved. Improvement, reduction in the number and/or degree of adverse reactions, reduction in distant metastasis rate and local control rate, etc. Specifically, in some specific embodiments of the present application, especially in the specific examples of the present application, the progression-free survival period of osteosarcoma patients in clinical trials reaches more than 3 months, preferably reaches about 5 months or more, more preferably about 7 months or more.

The "therapeutically effective amount" in the present invention refers to the amount of the aforementioned compound or its pharmaceutically acceptable salts, stereoisomers, and crystal forms that can at least alleviate the symptoms of the patient's disease when administered to the patient. The actual amount, including a "therapeutically effective amount," will vary depending on various circumstances including, but not limited to, the particular condition being treated, the severity of the condition, the size and health of the patient, and the route of administration. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may comprise single or multiple doses. For any given individual, the specific dosing regimen will be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.

A "subject" or "individual" for the prevention and/or treatment of osteosarcoma refers to any animal classified as a mammal, including humans, domesticated animals and farm animals, and zoo animals, sports animals or pet animals, such as dogs, horses, cats, cows, etc. Preferably, the mammal is a human. A subject or individual can be a patient.

Beneficial effects of the present invention

The compound of general formula (I) of the present invention or its pharmaceutically acceptable salts, stereoisomers, and crystal forms have therapeutic effects on osteosarcoma, and have good clinical application potential.

Description of drawings

Fig. 1 is a graph showing the inhibitory activity of compound 29 of the present invention on the formation of osteosarcoma cell clones.

Detailed ways

In order to make the purpose, technical solution, and advantages of the present invention clearer, the present invention is further described in detail below. Apparently, the described embodiments are only some, not all, embodiments of the present invention. Based on the implementations in the present invention, all other implementations obtained by persons of ordinary skill in the art without creative efforts fall within the protection scope of the present invention.

For the preparation of the compound of general formula (I) described in the present invention, please refer to the specific embodiments of WO2018108079A1.

Abbreviations and English expressions used in the present invention have the following meanings:

Abbreviation/English	meaning
DMSO	Dimethyl sulfoxide
MC	Methylcellulose
Q	once a day

Experimental Example 1 Compounds of the present invention are tested for the inhibitory activity of osteosarcoma cell clone formation

Test object: compound 29 in the present invention, its structure is shown above, and the preparation method can refer to the specific embodiment part of WO2018108079A1.

Test cells: Osteosarcoma cells 143B, MNNG/HOS and U2OS, from the American Type Culture Collection (ATCC)

experiment method:

Each strain of osteosarcoma cells (143B, MNNG/HOS, U2OS) was inoculated in a 6-well plate, 1000 cells/well, and after culturing for 24 hours, different concentrations of compound 29 were added to make the concentration 0, 10, 100 nM, and the final content of DMSO was the same as 0.1%, cultivated for 7 days. After washing the cells, the cells were fixed with paraformaldehyde, stained with crystal violet, and each well was photographed by a digital camera to evaluate the colony formation.

The test results are shown in Figure 1, the compound 29 of the present invention shows good antitumor activity to the osteosarcoma cell line, the compound 29 of 10nM can achieve obvious inhibition to the osteosarcoma cell line, the compound 29 of 100nM can almost suppress the osteosarcoma cell line Complete inhibition is achieved, and it has the potential to treat osteosarcoma clinically.

Experimental example 2 The compounds of the present invention are tested on the inhibition of osteosarcoma PDX model tumor growth

Test object: compound 29 in the present invention, its structure is shown above, and the preparation method can refer to the specific embodiment part of WO2018108079A1.

Tumors, mice and other materials: SGH-CZX is a xenograft model derived from an osteosarcoma patient, pathologically diagnosed as osteosarcoma, MYC amplification, c-MYC overexpression; Balb/c 4-week-old nude mice.

experiment method:

1. Construction and grouping of tumor-bearing mice

Tumor tissues were collected from the osteosarcoma xenograft model SGH-CZX tumor-bearing mice, cut into tumor pieces with a diameter of about 2 mm, and inoculated subcutaneously in Balb/c nude mice. After 2 weeks, they were randomly divided into two groups: vehicle group (0.5% MC) and compound 15 mg/kg administration group, 5 rats in each group. Vehicle or compound was orally administered once a day, and tumors were collected and measured after 42 days of continuous administration.

2. Dosing regimen

Administer according to the table below.

Note: vehicle control: 0.5% MC; compound 29 prescription: 0.5% MC.

3. Experimental observation indicators

The health status and death of the animals were monitored daily, body weight and tumor volume were measured twice a week, and samples were collected after the last administration. The curative effect of tumor volume is evaluated by TGI%, relative tumor inhibition rate TGI(%): TGI=1-T/C(%). T/C% is the relative tumor proliferation rate, that is, the percentage value of the relative tumor volume between the treatment group and the control group at a certain time point. T and C are the relative tumor volume (RTV) of the treatment group and the control group at a specific time point, respectively. The calculation formula is: T/C%=T _RTV /C _RTV ×100% (T _RTV : the average RTV of the treatment group; C _RTV : the average RTV of the vehicle control group; RTV=V _t /V ₀ , V ₀ is the average RTV of the animal at the time of grouping. The tumor volume of V _t is the tumor volume of this animal after treatment.The results are shown in table 2:

Table 2 Effect of compound 29 of the present invention on tumor growth of osteosarcoma PDX model

From the experimental results in Table 2, it can be seen that the tumor volume of the administered compound 29 is significantly reduced compared with the vehicle control group, and the TGI reaches 88%, indicating that the compound 29 of the present invention has a significant inhibitory effect on the growth of osteosarcoma and has good potential for clinical application .

Experimental example 3 Clinical research on the treatment of patients with osteosarcoma by the compound of the present invention

Tested drug: compound 29, whose structure is shown above, and the preparation method can refer to the specific implementation part of WO2018108079A1.

Inclusion criteria: Histopathologically or cytologically confirmed osteosarcoma patients without standard treatment options.

Dosing regimen: Compound 29 is administered orally according to the prescribed dose (such as 5 mg, 8 mg, 10 mg or 12 mg), once a day, and administered continuously, 28 days/cycle.

According to the clinical curative effect evaluation (such as: progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR) etc.), compound 29 of the present invention has clinically significant effects on osteosarcoma. Has a therapeutic effect.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the present invention. within the scope of protection.

Claims (13)

1. Use of a compound of general formula (I) or a pharmaceutically acceptable salt, stereoisomer, or crystal form thereof in the preparation of a medicament for treating and/or preventing osteosarcoma;

   

   Wherein, Ar is phenyl optionally substituted by 1-3 R ₆ , each R ₆ is independently selected from hydrogen, amino, cyano, halogen, C _1-4 alkyl and trifluoromethyl;

   Y is CR ₃ ;

   P is _CR4 ;

   W is N;

   R ₃ is hydrogen or C _1-4 alkyl;

   R ₄ is -(CH ₂ ) _n -(5-11) membered heterocyclic group, wherein n=0-6, and the ring-forming S atom in the heterocyclic group is optionally oxidized to S(O) or S (O) ₂ , the ring-forming C atom is optionally oxidized to C(O), and the heterocyclic group is optionally substituted by one or more independently selected from C _1-3 alkyl and C _3-6 cycloalkyl base substitution.
2. purposes as claimed in claim 1,

   Wherein, Ar is optionally phenyl substituted by 1-3 R ₆ , each R ₆ is independently selected from hydrogen and halogen;

   Y is CR ₃ ;

   P is _CR4 ;

   W is N;

   _R3 is hydrogen;

   R ₄ is selected from -(CH ₂ ) _n -(5-6) membered monoheterocyclic group and -(CH ₂ ) _n -(7-11) membered condensed heterocyclic group, wherein, n=0-6, said The ring-forming S atom in the heterocyclic group is optionally oxidized to S(O) or S(O) ₂ , the ring-forming C atom is optionally oxidized to C(O), and the heterocyclic group is optionally oxidized by one or more Substituents independently selected from C _1-3 alkyl and C _3-6 cycloalkyl are substituted.
3. Use as claimed in claim 2,

   in,

   _R4 is

   

   

   n=0-3, wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from C _1-3 alkyl and C _3-6 cycloalkyl.
4. The use as claimed in claim 3, wherein said compound is selected from compounds of the following structure or pharmaceutically acceptable salts, stereoisomers, and crystal forms thereof:

   

   
5. purposes as claimed in claim 4, wherein said compound is

   

   or a pharmaceutically acceptable salt, stereoisomer, or crystal form thereof.
6. Composition or combination product comprising the compound as described in any one of claims 1 to 5 or its pharmaceutically acceptable salt, stereoisomer, and crystal form in the preparation of medicines for treating and/or preventing osteosarcoma use.
7. The use according to any one of claims 1-6, wherein the osteosarcoma is primary osteosarcoma and/or secondary osteosarcoma.
8. The use according to any one of claims 1-6, wherein the osteosarcoma is osteogenic osteosarcoma and/or osteolytic osteosarcoma.
9. The use according to any one of claims 1-6, wherein the osteosarcoma is osteoblastic osteosarcoma, chondrogenic osteosarcoma and/or fibroblast osteosarcoma.
10. The use according to any one of claims 1-6, wherein the osteosarcoma is locally advanced or advanced, relapsed, refractory and/or metastatic osteosarcoma.
11. The use according to any one of claims 1-6, wherein the osteosarcoma is osteosarcoma that has failed standard treatment or has not received standard treatment.
12. The use according to any one of claims 1-6, wherein the osteosarcoma is an osteosarcoma with abnormal MYC gene.
13. The use according to claim 12, wherein said osteosarcoma is MYC gene amplified and/or MYC protein overexpressed osteosarcoma.

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