Pharmaceutical composition and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to a pharmaceutical composition and application thereof. The invention specifically relates to a novel endocrine therapeutic drug comprising (a) a compound of general formula (I) or a pharmaceutically acceptable salt, isomer or crystal form thereof, and (b) a novel endocrine therapeutic drug, each variable in the general formula being as defined in the specification. Research finds that the compound shown in the general formula (I) or the pharmaceutically acceptable salt, isomer or crystal form of the compound and a novel endocrine therapeutic drug have a synergistic effect in treatment of prostatic cancer; # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a pharmaceutical composition and use thereof. Background Art

[0002] Prostate cancer (PCa) is one of the most common malignant tumors in men. Worldwide, the incidence of PCa ranks second among male tumors, and ranks first among male malignant tumors in the United States, with a mortality rate second only to lung cancer.

[0003] Treatment options vary according to the stage and risk level of prostate cancer. For patients with early low-risk prostate cancer, active monitoring is the main approach. Due to the lack of obvious symptoms in early prostate cancer or the limitations of detection methods, most prostate cancers are already in the late stage when diagnosed, and more than half of them have already metastasized to distant sites. The 5-year relative survival rate of patients with distant metastases is only 30%. For patients with advanced and metastatic prostate cancer, medical castration or surgical castration is the main treatment, namely androgen deprivation therapy (ADT). Since the growth of normal prostate cells and prostate cancer cells depends on androgens, surgical castration or medical castration can minimize the concentration of androgens in the patient's body, thereby inhibiting the androgen signaling pathway and ultimately inhibiting the growth of tumor cells. Currently, the therapeutic drugs used for ADT include gonadotropin-releasing hormone agonists (GnRH agonists), gonadotropin-releasing hormone antagonists (GnRH antagonists), androgen secretion inhibitors, etc. Most patients are sensitive to ADT at the beginning of treatment and have castration sensitive prostate cancer (CSPC). However, due to genetic or drug-induced reasons, almost all patients will progress to castration resistant prostate cancer (CRPC) after 2 years and become drug-resistant. Once progressing to CRPC, the median survival time of patients is only 9-12 months.

[0004] CRPC is mainly divided into two independent stages: metastatic castration resistant prostate cancer (mCRPC) with distant metastasis and non metastatic castration resistant prostate cancer (nmCRPC) without distant metastasis. When nmCRPC patients develop distant metastasis or disease progression after failure of novel endocrine therapy, they will enter the mCRPC stage, so mCRPC can be regarded as the final stage of PCa patients. The main therapies currently used for mCRPC include chemotherapy (docetaxel), novel endocrine therapy (enzalutamide, abiraterone acetate, etc.), immunotherapy (Sipuleucel-T) and radiotherapy for bone metastasis (radium-223). Doxetaxel is the first FDA-approved chemotherapy drug for the treatment of mCRPC. It can effectively prolong the patient's overall survival (OS) by about 19.2 months, but the drug can cause a series of side effects, such as nausea, vomiting, neurological diseases, anemia, etc. 17α-hydroxylase / C17,20-lyase (CPY17 enzyme) plays a key role in the synthesis of androgens. Abiraterone acetate is a prodrug that is converted into abiraterone in the body. Abiraterone is an androgen synthesis inhibitor that can reduce androgen levels by inhibiting the CYP17 enzyme. The drug was approved by the FDA for CRPC patients in 2011. Enzalutamide is a second-generation AR (androgen receptor) inhibitor. After binding to enzalutamide, AR cannot be normally transported to the cell nucleus or recruit co-activators, and AR transcriptional activity is reduced. Compared with the first-generation AR inhibitors, enzalutamide has a stronger affinity for AR. Although the approval of abiraterone acetate, enzalutamide, etc. is of great significance for the treatment of mCRPC, most patients will eventually develop drug resistance after a period of treatment.

[0005] Due to drug resistance and safety issues, the treatment of prostate cancer remains a difficult clinical problem, and it is urgent to explore effective treatment methods. Summary of the invention

[0006] In order to solve the above problems, the present invention provides the following solutions:

[0007] In a first aspect, the present invention provides a pharmaceutical composition comprising component (a) and component (b):

[0008] (a) a compound of formula (I) or a pharmaceutically acceptable salt, isomer or crystalline form thereof, and

[0009] (b) New endocrine therapy drugs;

[0010]

[0011] Wherein Ar is optionally replaced by 1 to 3 R 6 Substituted phenyl, each R 6 are independently selected from hydrogen, amino, cyano, halogen, C 1-4 Alkyl and trifluoromethyl;

[0012] Y1 is CR 3 ;

[0013] P1 is CR 4 ;

[0014] W1 is N;

[0015] R 3 is hydrogen or C 1-4 alkyl;

[0016] R 4 -(CH2) n -(5-11) membered heterocyclic group, wherein n=an integer of 0-6, the ring-forming S atom (if any) in the heterocyclic group is optionally oxidized to S(O) or S(O)2, the ring-forming C atom (if any) is optionally oxidized to C(O), the heterocyclic group is optionally oxidized by one or more independently selected C 1-3 Alkyl and C 3-6 Substitution of cycloalkyl groups;

[0017] In some embodiments, Ar is optionally replaced by 1-3 R 6 Substituted phenyl, each R 6 are independently selected from hydrogen and halogen;

[0018] Y1 is CR 3 , R 3 is hydrogen;

[0019] P1 is CR 4 , R 4 Selected from -(CH2) n -(5-6) membered monoheterocyclic group and -(CH2) n -(7-11) membered fused heterocyclic group, wherein n=an integer of 0-6, the ring-forming S atoms (if any) in the heterocyclic group are optionally oxidized to S(O) or S(O)2, the ring-forming C atoms (if any) are optionally oxidized to C(O), the heterocyclic group is optionally oxidized by one or more independently selected C 1-3 Alkyl and C 3-6Substitution of cycloalkyl groups;

[0020] W1 is N;

[0021] Preferably, the weight ratio of component (a) to component (b) is 1:2000 to 1000:2000, such as 10:2000-1000:2000, or 100:2000-1000:2000, including but not limited to: 10:2000, 12:2000, 13.3:2000, 16:2000, 20:2000, 21.3:2 000, 24: 2000, 26.7: 2000, 32: 2000, 40: 2000, 62.5: 2000, 75: 2000, 83.3: 2000, 100: 2000, 125: 2000, 133.3: 2000, 150: 2000, 166.7: 2000, 200: 2000, 250: 2000.

[0022] In a second aspect, the present invention provides a pharmaceutical combination, comprising component (a) and component (b), wherein the component (a) and component (b) are active ingredients; or the combination consists of component (a) and component (b):

[0023] (a) a compound of formula (I) or a pharmaceutically acceptable salt, isomer or crystalline form thereof, and

[0024] (b) New endocrine therapy drugs;

[0025]

[0026] Wherein Ar is optionally replaced by 1 to 3 R 6 Substituted phenyl, each R 6 are independently selected from hydrogen, amino, cyano, halogen, C 1-4 Alkyl and trifluoromethyl;

[0027] Y1 is CR 3 ;

[0028] P1 is CR 4 ;

[0029] W1 is N;

[0030] R 3 is hydrogen or C 1-4 alkyl;

[0031] R 4 -(CH2) n-(5-11) membered heterocyclic group, wherein n=an integer of 0-6, the ring-forming S atom (if any) in the heterocyclic group is optionally oxidized to S(O) or S(O)2, the ring-forming C atom (if any) is optionally oxidized to C(O), the heterocyclic group is optionally oxidized by one or more independently selected C 1-3 Alkyl and C 3-6 Substitution of cycloalkyl groups;

[0032] In some embodiments, Ar is optionally replaced by 1-3 R 6 Substituted phenyl, each R 6 are independently selected from hydrogen and halogen;

[0033] Y1 is CR 3 , R 3 is hydrogen;

[0034] P1 is CR 4 , R 4 Selected from -(CH2) n -(5-6) membered monoheterocyclic group and -(CH2) n -(7-11) membered fused heterocyclic group, wherein n=an integer of 0-6, the ring-forming S atoms (if any) in the heterocyclic group are optionally oxidized to S(O) or S(O)2, the ring-forming C atoms (if any) are optionally oxidized to C(O), the heterocyclic group is optionally oxidized by one or more independently selected C 1-3 Alkyl and C 3-6 Substitution of cycloalkyl groups;

[0035] W1 is N;

[0036] Preferably, the weight ratio of component (a) to component (b) is 1:2000 to 1000:2000, such as 10:2000-1000:2000, or 100:2000-1000:2000, including but not limited to: 10:2000, 12:2000, 13.3:2000, 16:2000, 20:2000, 21.3:2 000, 24: 2000, 26.7: 2000, 32: 2000, 40: 2000, 62.5: 2000, 75: 2000, 83.3: 2000, 100: 2000, 125: 2000, 133.3: 2000, 150: 2000, 166.7: 2000, 200: 2000, 250: 2000.

[0037] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, the (5-6)-membered monoheterocyclic group is a (5-6)-membered saturated monoheterocyclic group, and the (7-11)-membered fused heterocyclic group is a (7-11)-membered saturated fused heterocyclic group. In a preferred embodiment, the (7-11)-membered saturated fused heterocyclic group is a (7-11)-membered saturated fused heterocyclic group, a (7-11)-membered saturated fused heterocyclic group, a (7-11)-membered saturated fused heterocyclic group, or a (7-11)-membered saturated bridged heterocyclic group.

[0038] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, the R 4 for n=an integer of 0-3, wherein the heterocyclic group in R4 is optionally substituted by one or more independently selected from C 1-3 Alkyl and C 3-6 Cycloalkyl (e.g., 1, 2 or 3 independently selected from C 1-2 alkyl and C3 cycloalkyl) substituents;

[0039] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, the R4 is n=an integer of 0-3, wherein the heterocyclic group in R4 is optionally substituted by one or more independently selected from C 1-3 Alkyl and C 3-6 Cycloalkyl (e.g., 1, 2 or 3 independently selected from C 1-2 alkyl and C3 cycloalkyl) substituents;

[0040] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, the R4 is n=an integer of 0-3, wherein the heterocyclic group in R4 is optionally substituted by one or more independently selected from C 1-3 Alkyl and C 3-6 Cycloalkyl (e.g., 1, 2 or 3 independently selected from C 1-2 alkyl and C3 cycloalkyl) substituents;

[0041] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, the R 4 for n=an integer from 0 to 3, wherein R 4 The heterocyclic group is optionally substituted by one or more independently selected from C 1-3 Alkyl and C 3-6 The cycloalkyl group is substituted with a substituent.

[0042] In any embodiment of the above-mentioned pharmaceutical combination and pharmaceutical composition, the compound of general formula (I) includes the compounds shown in Table 1.

[0043] Table 1: Examples of compounds of general formula (I)

[0044]

[0045]

[0046]

[0047] The preparation examples of the compounds in the above table and the examples for verifying the biological activities of these compounds can be found in patent application WO2018108079A1, the entire content of which is incorporated herein.

[0048] In any embodiment of the above-mentioned pharmaceutical combination and pharmaceutical composition, the compound of the present invention may also include compounds other than the compound of general formula (I), for example, the specific compounds shown in the following table.

[0049]

[0050]

[0051]

[0052]

[0053] The preparation examples of the compounds in the above table and the examples for verifying the biological activities of these compounds can be found in patent application WO2018108079A1, the entire content of which is incorporated herein.

[0054] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, the novel endocrine therapeutic drug is an androgen receptor inhibitor.

[0055] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, the androgen receptor inhibitor is enzalutamide, apalutamide, darolamide, or bicalutamide.

[0056] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, the androgen receptor inhibitor is reviluamide.

[0057] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, the androgen receptor inhibitor is enzalutamide.

[0058] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, said (a) is Or a pharmaceutically acceptable salt, isomer or crystal form thereof; the (b) novel endocrine therapeutic drug is enzalutamide.

[0059] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, the novel endocrine therapeutic drug is an androgen synthesis inhibitor.

[0060] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, the androgen synthesis inhibitor is abiraterone or abiraterone acetate.

[0061] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, said (a) is or a pharmaceutically acceptable salt, isomer or crystal form thereof; the (b) novel endocrine therapeutic drug is abiraterone or abiraterone acetate.

[0062] In any of the above embodiments of the pharmaceutical combination and pharmaceutical composition, the component (a) and the component (b) are provided in the form of one inseparable entity, or the component (a) and the component (b) are provided in separate entities.

[0063] In a third aspect, the present invention also provides a pharmaceutical kit comprising the pharmaceutical combination or pharmaceutical composition according to any one of the preceding embodiments, and instructions for administration.

[0064] Furthermore, the medicine kit of the present invention comprises:

[0065] a) one or more unit preparations of a compound described in the first or second aspect of the present invention or a pharmaceutically acceptable salt, isomer or crystalline form thereof, i.e. component (a);

[0066] b) one or more unit preparations of the novel endocrine therapeutic agent described in the first or second aspect of the present invention, namely component (b); and

[0067] c) Instructions for use.

[0068] Preferably, a) one or more unit preparations of the compound described in the first or second aspect of the present invention or a pharmaceutically acceptable salt, isomer or crystalline form thereof and b) one or more unit preparations of the novel endocrine therapeutic drug described in the first or second aspect of the present invention are provided in the form of an inseparable entity, or are provided separately in different entities.

[0069] In a fourth aspect, the present invention also provides a method for combined treatment of prostate cancer, comprising administering to a prostate cancer patient in need thereof an effective amount of a drug combination, or a pharmaceutical composition, or a drug kit comprising the compound described in the first or second aspect of the present invention or a pharmaceutically acceptable salt, isomer or crystalline form thereof, and the novel endocrine therapy drug described in the first or second aspect of the present invention.

[0070] In the fifth aspect, the present invention also provides a drug combination, or a pharmaceutical composition, or a drug kit comprising the compound described in the first or second aspect of the present invention or a pharmaceutically acceptable salt, isomer or crystal form thereof, and the new endocrine therapy drug described in the first or second aspect of the present invention, which is used for preventing and / or treating prostate cancer.

[0071] In a sixth aspect, the present invention also provides use of the drug combination, or drug composition, or drug kit described in any one of the first, second and third aspects in the preparation of a drug for preventing and / or treating prostate cancer.

[0072] In any embodiment of the sixth aspect, the use also includes that the compound or pharmaceutically acceptable salt, isomer or crystalline form described in the first or second aspect of the present invention in the drug combination, pharmaceutical composition or medicine kit, and the novel endocrine therapy drug described in the first or second aspect of the present invention are provided in different entities respectively, and are administered in combination in a therapeutically effective amount to a prostate cancer patient simultaneously, separately or sequentially; or the compound or pharmaceutically acceptable salt, isomer or crystalline form described in the first or second aspect of the present invention in the drug combination, pharmaceutical composition or medicine kit, and the novel endocrine therapy drug described in the first or second aspect of the present invention are provided in the form of an inseparable entity and administered simultaneously in a therapeutically effective amount to a prostate cancer patient.

[0073] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is metastatic prostate cancer.

[0074] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is non-metastatic prostate cancer.

[0075] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is early prostate cancer.

[0076] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is advanced prostate cancer.

[0077] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer includes prostate cancer that has been previously treated or has not received any treatment; the treatment includes standard treatment and / or non-standard treatment.

[0078] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is prostate cancer that has not received standard treatment in the past.

[0079] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is prostate cancer for which standard treatment has failed in the past.

[0080] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is prostate cancer for which chemotherapy has failed in the past.

[0081] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is prostate cancer for which endocrine therapy has failed in the past.

[0082] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is prostate cancer that has previously failed androgen deprivation therapy.

[0083] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is prostate cancer that has previously failed to be treated with androgen synthesis inhibitors and / or androgen receptor inhibitors.

[0084] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is prostate cancer that has previously failed to be treated with abiraterone or abiraterone acetate.

[0085] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is prostate cancer that has previously failed to be treated with enzalutamide, apalutamide, darolutamide and / or bicalutamide.

[0086] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is prostate cancer that has previously failed treatment with revilutamide.

[0087] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is early-stage and / or non-metastatic prostate cancer, for example, the early-stage and / or non-metastatic prostate cancer has not received standard treatment in the past.

[0088] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is advanced and / or metastatic prostate cancer, for example, the advanced and / or metastatic prostate cancer has not been previously treated with standard treatment, or the advanced and / or metastatic prostate cancer has previously failed standard treatment.

[0089] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is castration-sensitive prostate cancer. In one embodiment, the castration-sensitive prostate cancer has not been previously treated with standard treatment. In one embodiment, the castration-sensitive prostate cancer has previously failed standard treatment. In one embodiment, the castration-sensitive prostate cancer has previously failed chemotherapy. In one embodiment, the castration-sensitive prostate cancer has previously failed endocrine therapy. In one embodiment, the castration-sensitive prostate cancer has previously failed androgen deprivation therapy. In one embodiment, the castration-sensitive prostate cancer has previously failed androgen synthesis inhibitors and / or androgen receptor inhibitors. In one embodiment, the castration-sensitive prostate cancer has previously failed abiraterone or abiraterone acetate. In one embodiment, the castration-sensitive prostate cancer has previously failed enzalutamide, apalutamide, darolamide and / or bicalutamide. In one embodiment, the castration-sensitive prostate cancer has been previously treated with revilutamide but has failed.

[0090] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is castration-resistant prostate cancer. In one embodiment, the castration-resistant prostate cancer has previously failed standard treatment. In one embodiment, the castration-resistant prostate cancer has previously failed chemotherapy. In one embodiment, the castration-resistant prostate cancer has previously failed endocrine therapy. In one embodiment, the castration-resistant prostate cancer has previously failed androgen deprivation therapy. In one embodiment, the castration-resistant prostate cancer has previously failed androgen synthesis inhibitors and / or androgen receptor inhibitors. In one embodiment, the castration-resistant prostate cancer has previously failed abiraterone or abiraterone acetate. In one embodiment, the castration-resistant prostate cancer has previously failed enzalutamide, apalutamide, darolamide and / or bicalutamide. In one embodiment, the castration-resistant prostate cancer has previously failed reviluamide.

[0091] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is metastatic castration-sensitive prostate cancer, for example, the metastatic castration-sensitive prostate cancer has not been previously treated with standard treatment or has previously failed standard treatment.

[0092] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is localized prostate cancer, for example, the localized prostate cancer has not been previously treated with standard treatment or has previously failed standard treatment.

[0093] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is metastatic castration-resistant prostate cancer. In one embodiment, the metastatic castration-resistant prostate cancer has previously failed standard treatment. In one embodiment, the metastatic castration-resistant prostate cancer has previously failed chemotherapy. In one embodiment, the metastatic castration-resistant prostate cancer has previously failed endocrine therapy. In one embodiment, the metastatic castration-resistant prostate cancer has previously failed androgen deprivation therapy. In one embodiment, the metastatic castration-resistant prostate cancer has previously failed androgen synthesis inhibitors and / or androgen receptor inhibitors. In one embodiment, the metastatic castration-resistant prostate cancer has previously failed abiraterone or abiraterone acetate. In one embodiment, the metastatic castration-resistant prostate cancer has previously failed enzalutamide, apalutamide, darolamide and / or bicalutamide. In one embodiment, the metastatic castration-resistant prostate cancer has previously failed treatment with reviluamide. In one embodiment, the metastatic castration-resistant prostate cancer is confirmed by histopathology or cytology, has failed after initial continuous androgen deprivation therapy, and has clear bone or soft tissue metastatic lesions confirmed by imaging. In one embodiment, the metastatic castration-resistant prostate cancer is confirmed by histopathology or cytology, and has no standard treatment options.

[0094] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is non-metastatic castration-resistant prostate cancer. In one embodiment, the non-metastatic castration-resistant prostate cancer has previously failed standard treatment. In one embodiment, the non-metastatic castration-resistant prostate cancer has previously failed chemotherapy. In one embodiment, the non-metastatic castration-resistant prostate cancer has previously failed endocrine therapy. In one embodiment, the non-metastatic castration-resistant prostate cancer has previously failed androgen deprivation therapy. In one embodiment, the non-metastatic castration-resistant prostate cancer has previously failed androgen synthesis inhibitors and / or androgen receptor inhibitors. In one embodiment, the non-metastatic castration-resistant prostate cancer has previously failed abiraterone or abiraterone acetate. In one embodiment, the non-metastatic castration-resistant prostate cancer has previously failed enzalutamide, apalutamide, darolamide and / or bicalutamide. In one embodiment, the non-metastatic castration-resistant prostate cancer has previously failed treatment with revilutamide.

[0095] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is metastatic high-risk castration-sensitive prostate cancer.

[0096] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is non-metastatic castration-sensitive prostate cancer with biochemical recurrence and high risk of metastasis.

[0097] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is a high-risk metastatic endocrine therapy-sensitive prostate cancer. In one embodiment, the high-risk metastatic endocrine therapy-sensitive prostate cancer has not been previously treated with standard treatment. In one embodiment, the high-risk metastatic endocrine therapy-sensitive prostate cancer has not been previously treated with endocrine therapy or has been treated with endocrine therapy for no longer than 3 months. In one embodiment, the high-risk metastatic endocrine therapy-sensitive prostate cancer has previously failed chemotherapy.

[0098] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the chemotherapy comprises docetaxel chemotherapy, docetaxel combined with corticosteroids, cabazitaxel chemotherapy, platinum-based single-agent chemotherapy or combined chemotherapy.

[0099] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the abiraterone or abiraterone acetate treatment includes abiraterone or abiraterone acetate treatment, and abiraterone or abiraterone acetate combined with corticosteroid treatment.

[0100] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the endocrine therapy includes androgen deprivation therapy and novel endocrine therapy. For example, the androgen deprivation therapy includes surgical castration therapy (orchiectomy, etc.) and drug castration therapy (including but not limited to goserelin, leuprorelin, triptorelin, degarelix, etc.).

[0101] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the compound or its pharmaceutically acceptable salt, isomer or crystal form described in the first or second aspect of the present invention, i.e., component (a), has a single dosage (based on the compound) of 3 mg to 20 mg, for example: 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg. The frequency of administration is once a day, twice a day, once every two days, or once every three days.

[0102] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the dosage of the novel endocrine therapeutic drug described in the first or second aspect of the present invention, namely component (b), is 10 mg to 2000 mg per day.

[0103] In any embodiment of the fourth, fifth and sixth aspects of the present invention, component (b) is abiraterone or abiraterone acetate, and its dosage (calculated as abiraterone) is 500 mg to 1500 mg per day, for example, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg.

[0104] In any embodiment of the fourth, fifth and sixth aspects of the present invention, component (b) is abiraterone or abiraterone acetate, and the dosage thereof (calculated as abiraterone) is 900 mg to 1100 mg per day.

[0105] In any embodiment of the fourth, fifth and sixth aspects of the present invention, component (b) is enzalutamide, and its dosage is 140 mg to 180 mg per day, for example, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg.

[0106] In any embodiment of the fourth, fifth and sixth aspects of the present invention, component (b) is enzalutamide, and its dosage is 150 mg to 170 mg per day.

[0107] In some embodiments of the fourth, fifth and sixth aspects of the present invention, component (a) and component (b) may be provided in the form of an inseparable entity, or provided in different entities. When component (a) and component (b) are provided in the form of an inseparable entity, each entity may contain 3 mg to 20 mg (e.g., 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg) of component (a) and 10 mg to 2000 mg of component (b) (e.g., 500 mg to 1500 mg, 900 mg to 1100 mg, such as 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 20 ... 00mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg of abiraterone or abiraterone acetate (calculated as abiraterone), or 140mg-180mg, 150mg-170mg, such as 140mg, 150mg, 160mg, 170mg, 180mg of enzalutamide), or each entity may contain 1 / n or p times the amount of the above-mentioned component (a) and 1 / m or q times the amount of component (b), wherein n and m are independently integers of 1-6, and p and q are independently integers of 2-6; when component ( When component (a) and component (b) are provided in different entities, the entity containing component (a) may contain 3 mg to 20 mg (e.g., 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg) of component (a) or 1 / n or p times the above amount of component (a); and the entity containing component (b) may contain 10 mg to 2000 mg of component (b) (e.g., 500 mg to 1500 mg, 900 mg to 110 0 mg, such as 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of abiraterone or abiraterone acetate (calculated as abiraterone), or 140 mg to 180 mg, 150 mg to 170 mg, such as 140 mg, 150 mg, 160 mg, 170 mg, 180 mg of enzalutamide) or 1 / m or q times the above amount of component (b), wherein n and m are independently integers of 1 to 6, and p and q are independently integers of 2 to 6.

[0108] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the drug combination or drug composition or drug kit can also be administered to a prostate cancer patient in combination with a corticosteroid. In one embodiment, the corticosteroid is prednisone or dexamethasone. For example, the dosage of prednisone is 5 mg to 20 mg per day, such as 5 mg per day or 10 mg per day, and the dosage of dexamethasone is 0.2 mg to 2 mg per day, such as 0.5 mg per day.

[0109] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the compound described in the first or second aspect of the present invention or its pharmaceutically acceptable salt, isomer or crystal form, i.e. component (a), and / or the novel endocrine therapeutic drug described in the first or second aspect of the present invention, i.e. component (b), can also be prepared into any pharmaceutically acceptable pharmaceutical preparation with one or more pharmaceutically acceptable carriers. The components (a) and (b) can be provided in the form of an inseparable entity, or provided in different entities respectively. The pharmaceutical preparation can contain one or more pharmaceutically acceptable carriers, and can be administered to a patient or subject in need of such treatment by oral, parenteral, rectal or pulmonary administration. The term "pharmaceutically acceptable carrier" used herein refers to a carrier (or excipient) that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound administered. Any commonly used pharmaceutically acceptable carrier can be used, and its selection depends on factors such as the specific mode of administration, the effect of the carrier on solubility and stability, and the properties of the dosage form and is within the ordinary skills of those skilled in the art. Examples of pharmaceutically acceptable carriers include, but are not limited to, fillers (e.g., lactose, sucrose, mannitol or sorbitol, cellulose derivatives and / or calcium phosphate); binders (e.g., corn, wheat or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and / or polyvinyl pyrrolidone); disintegrants (e.g., starch, carboxymethyl starch, cross-linked polyvinyl pyrrolidone, alginic acid or its salts); lubricants (e.g., silicic acid, talc, stearic acid or its salts, and / or polyethylene glycol or its derivatives, etc.); diluents, wetting agents, colorants (dyes or pigments such as titanium dioxide, lacquer solutions), flavors, absorption promoters, surfactants, adsorption carriers, etc., such as gelatin, gum tragacanth, gum arabic, carbopol gel, glycerol, sorbitol, liquid paraffin, liquid polyethylene glycol, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes.

[0110] In any embodiment of the above-mentioned second aspect of the present invention, component (a) and component (b) in the pharmaceutical composition can be provided in the form of an inseparable entity, or provided in different entities respectively. In any embodiment of the above-mentioned third aspect of the present invention, a) and b) in the medicine box can also be provided in the form of an inseparable entity, or provided in different entities respectively. Each of the above-mentioned entities can contain about 0.1% by weight-99.5% by weight of active ingredients, such as about 0.1% by weight-95% by weight, about 0.1% by weight-50% by weight, or about 1% by weight-40% by weight, such as about 1% by weight, about 1.5% by weight, about 2% by weight, about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 40% by weight or about 50% by weight of active ingredients, and the remainder is a pharmaceutically acceptable carrier. The entity can contain one, two, three or more pharmaceutically acceptable carriers. When used for oral administration, the entity 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, syrups, etc. When made into oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. can be added. When used for parenteral administration, the entity can be made into injections, including injections, sterile powders for injection, and concentrated solutions for injection. When making injections, conventional methods in the existing pharmaceutical field can be used for production. When preparing injections, additives may not be added, or suitable additives may be added according to the properties of the drug (for example, physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer). When used for rectal administration, the entity can be made into suppositories, etc. (for example, containing conventional suppository base materials such as cocoa butter or other glycerides). For pulmonary administration, the entity may be formulated as an inhaler or spray or the like (e.g. delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer, with the aid of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas).

[0111] Beneficial Effects of the Invention

[0112] Through research, it is found that the compound of the general formula (I) of the present invention or its pharmaceutically acceptable salt, isomer or crystal form, and the new endocrine therapy drug have a synergistic effect in the combined treatment of prostate cancer. Further, the compound 29 of the present invention and a specific new endocrine therapy drug have a synergistic effect in the combined treatment of prostate cancer. Further, the compound 29 of the present invention and enzalutamide or abiraterone acetate have a significant synergistic effect in the combined treatment of prostate cancer, especially metastatic castration-resistant prostate cancer (mCRPC) with distant metastasis. DETAILED DESCRIPTION OF THE INVENTION

[0114] The "halogen" described in the present invention refers to fluorine, chlorine, bromine and iodine, etc., preferably fluorine and chlorine.

[0115] The term "halogenated" as used herein means that any hydrogen atom in a substituent group may be replaced by one or more identical or different halogens. "Halogen" is as defined above.

[0116] The "cyano group" described in the present invention refers to a -CN group.

[0117] The "amino group" described in the present invention refers to the -NH2 group.

[0118] The present invention's "C 1-4 "Alkyl" refers to a straight or branched chain alkyl derived from an alkane portion containing 1 to 4 carbon atoms by removing a hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc. The "C 1-3 The term "alkyl group" refers to an alkyl group as described above having 1 to 3 carbon atoms.

[0119] The "C 3-6 "Cycloalkyl" refers to a monocyclic cycloalkyl, a bicyclic cycloalkyl system or a polycyclic cycloalkyl system containing 3-6 carbon atoms. These groups are saturated but not aromatic. Unless otherwise specified, they include single and condensed ring structures that can be formed. Examples include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

[0120] The "5-11 membered heterocyclic group" described in the present invention refers to a non-aromatic cyclic group having 5-11 ring carbon atoms, wherein at least one ring carbon atom is replaced by one or more heteroatoms selected from O, S, and N, preferably 1-3 heteroatoms, and the ring atoms including carbon atoms, nitrogen atoms and sulfur atoms can be oxidized.

[0121] 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" described in the present invention includes the monocyclic and condensed ring structures that can be formed unless otherwise specified.

[0122] The monoheterocyclic group may be a 5-7 membered heterocyclic group, a 5-6 membered heterocyclic group, a 5-6 membered oxygen-containing heterocyclic group, a 5-6 membered nitrogen-containing heterocyclic group, a 5-6 membered saturated heterocyclic group, etc. Examples of the 5-6 membered monoheterocyclic group of the present invention include, but are not limited to, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazolidinyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxane, 1,4-oxathiacyclohexane, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2,3-dihydro oxazolyl, 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-dihydrothiazolyl, 2,5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4,5-tetrahydropyridinyl, 1,2-isoxazinyl, 1,4-isoxazinyl or 6H-1,3-oxazinyl, and the like.

[0123] The fused heterocyclic ring includes a para-heterocyclic ring, a spiro-heterocyclic ring, and a bridged heterocyclic ring, which may be saturated, partially saturated, or unsaturated, but not aromatic. The 7-11-membered fused heterocyclic ring described in the present invention includes the para-, spiro-, and bridged structures that can be formed unless otherwise specified.

[0124] The heterocyclic group may be a 7-11-membered heterocyclic group, preferably a 7-11-membered saturated heterocyclic group, examples of which include but are not limited to: 3,6-diazabicyclo[3.2.0]heptane, 3,8-diazabicyclo[4.2.0]octanyl, 3,7-diazabicyclo[4.2.0]octanyl, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[3,4-b]pyrrole oxazine, 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-2-yl, octahydro-1H-indolyl, octahydrobenzofuranyl.

[0125] The spiro heterocyclic group may be a 7-11 membered spiro heterocyclic group, preferably a 7-11 membered saturated spiro heterocyclic group, examples of which include but are not limited to:

[0126] The bridged heterocyclic group may be a 7-11-membered bridged heterocyclic group, preferably a 7-11-membered saturated bridged heterocyclic group, examples of which include but are not limited to:

[0127] The "pharmaceutically acceptable salts" of the present invention refer to 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, hydroiodic acid, alkanoic acids (such as acetic acid, HOOC-(CH2) n -COOH (wherein n = integer from 0 to 4)) and the like. Such pharmaceutically acceptable salts also include salts of bases such as sodium, potassium, calcium, ammonium, and the like. Those skilled in the art are aware of a wide variety of non-toxic pharmaceutically acceptable addition salts.

[0128] All numerical ranges described in the present invention are meant to 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, and 11 yuan, "5-6 yuan" includes 5 and 6 yuan, "7-11 yuan" includes 7, 8, 9, 10, and 11 yuan, and so on.

[0129] The "one to more" in the present invention regarding substituents means that the number of substituents can be all chemically substitutable positions of the substituted group, preferably 1-6, more preferably 1-5, more preferably 1-3, and more preferably 1-2.

[0130] The "crystalline form" described in the present invention can be prepared from the compound of general formula (I) by conventional methods for preparing crystalline forms in the art.

[0131] The "isomers" of the compounds of general formula (I) described in the present invention include stereoisomers and tautomers.

[0132] The term "stereoisomer" refers to isomers that are produced by the different spatial arrangements of atoms in a molecule. When a compound has an asymmetric carbon atom, enantiomers are produced; when a compound has a carbon-carbon double bond or a ring structure, cis-trans isomers are produced.

[0133] The term "tautomer" refers to different functional group isomers in dynamic equilibrium, which can quickly transform into each other and are a special functional group isomer. For example, when ketones or oximes are present, tautomers will be produced, representative examples of which are: keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc.

[0134] All enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of the compounds are included within the scope of the present invention.

[0135] The preparation of the compound of general formula (I) described in the present invention can be found in the specific implementation method section of WO2018108079A1.

[0136] The term "treatment" as used herein refers to administering an effective amount of a drug to a patient to slow down or cure the patient's unwanted physiological changes or conditions, such as hyperproliferative conditions, such as the growth, formation or spread of cancer, to obtain beneficial or desired clinical results, including but not limited to: relieving symptoms, weakening the extent of the disease, stabilizing the disease state (i.e., not worsening), delaying or slowing disease progression, improving or alleviating the disease state, and regression (whether partial or complete), whether detectable or undetectable.

[0137] The "treatment" described in the present invention may include neoadjuvant therapy and adjuvant therapy.

[0138] "Neoadjuvant therapy" refers to systemic treatment for patients with initial tumors before planned surgical treatment or local treatment with surgery plus radiotherapy. Depending on the type of tumor, neoadjuvant therapy may be chemotherapy, endocrine, targeted, immune or radiotherapy. The purpose of neoadjuvant therapy is to provide immediate systemic treatment, thereby potentially curing micrometastases, which in other cases will proliferate when following the standard sequence of surgery followed by systemic therapy. Neoadjuvant therapy can also help reduce tumor size, allowing complete resection of tumors that were initially inoperable or preserving parts of organs and their functions. In addition, neoadjuvant therapy allows in vivo evaluation of drug efficacy, which can guide the selection of subsequent treatments.

[0139] "Adjuvant therapy" refers to therapy given after radical surgery (in which no evidence of residual disease can be detected) to destroy any remaining cancer cells in the body to reduce the likelihood that the tumor will return or spread to other parts of the body. The treatment approach is generally the same as neoadjuvant therapy. The goal of adjuvant therapy is to prevent the cancer from coming back and, therefore, reduce the chance of cancer-related death. Adjuvant therapy is specifically excluded in this article from neoadjuvant therapy.

[0140] The "combination", "combined use", "combined administration" or "combination therapy" mentioned in the present invention refers to the administration of at least one dose of the compound of the aforementioned general formula (I) or its pharmaceutically acceptable salt, isomer or crystal form and the aforementioned novel endocrine therapeutic drug within a certain period of time, which can be prepared together as a compound preparation or each can be prepared as an independent preparation for simultaneous, separate or sequential administration to the patient; or on the basis of the above-mentioned combination, corticosteroids can be administered to the patient simultaneously, separately or sequentially.

[0141] The term "failed", "treatment failure" or "chemotherapy failure" as used herein refers to disease progression during treatment or after the last treatment (progressive disease (PD) according to the RECIST 1.1 efficacy evaluation standard for tumor tissue assessment or progressive disease (PD) according to the PCWG3 bone lesion evaluation standard for prostate cancer), or intolerable toxic side effects during treatment.

[0142] The "drug resistance" mentioned in the present invention refers to the reduced sensitivity of pathogens, tumor cells or individuals to drugs, resulting in the failure of the drugs to exert the expected therapeutic effect, which meets the situation of "treatment failure" mentioned in the present invention.

[0143] The "intolerable side effects" mentioned in the present invention means that the patient cannot continue to receive treatment due to adverse reactions caused by the drug.

[0144] The "standard treatment" described in the present invention includes androgen deprivation therapy (surgical castration and medical castration therapy including but not limited to goserelin, leuprorelin, triptorelin, degarelix, etc.), chemotherapy, systemic radiotherapy and / or new endocrine therapy. Of course, the "standard treatment" is not limited to this. With the update of the standard treatment plan, the "standard treatment" described in the present invention will also be included.

[0145] The "non-standard treatment" mentioned in the present invention refers to treatment performed by means other than standard treatment.

[0146] The "chemotherapy" mentioned in the present invention includes but is not limited to docetaxel, docetaxel combined with corticosteroids (such as prednisone), cabazitaxel, platinum-based single-agent or combined chemotherapy regimens, etc.

[0147] The "abiraterone acetate treatment" described in the present invention includes but is not limited to abiraterone acetate, abiraterone acetate combined with corticosteroids (such as prednisone), etc.

[0148] The "endocrine therapy" described in the present invention is a method for treating prostate cancer by reducing androgen levels, inhibiting or reducing androgen receptor activity, which includes traditional androgen deprivation therapy (ADT) and novel endocrine therapy (NHT). Among them, ADT treatment includes surgical castration therapy (orchiectomy, etc.) and medical castration therapy (including but not limited to goserelin, leuprorelin, triptorelin, degarelix, etc.).

[0149] The "therapeutically effective amount" of the present invention refers to the amount of the aforementioned compound or its pharmaceutically acceptable salt, isomer or crystal form and the aforementioned novel endocrine therapeutic drug that can at least alleviate the symptoms of the patient's condition when administered to the patient. The actual amount comprising the "therapeutically effective amount" will vary according to a variety of circumstances, including but not limited to the specific condition being treated, the severity of the condition, the patient's physique and health condition, 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 urgency of the treatment situation. It should be noted that the dosage value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. For any particular individual, the specific dosing regimen should be adjusted over time according to individual needs and the professional judgment of the person administering the composition or supervising the administration of the composition.

[0150] The "unit dosage form" of the present invention refers to a physically discrete unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules, lozenges, etc. In such compositions, the active substance is usually a small component (e.g., about 0.1% to about 50% by weight or preferably about 1% to about 40% by weight), and the rest are various vehicles or carriers and processing aids that help form the desired dosage form. The unit dosage formulation is preferably about 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg or 1000 mg per unit, etc. In a specific embodiment, the unit dosage form is packaged in a multi-pack for sequential use, such as a blister pack containing at least 6, 9 or 12 unit dosage tablets.

[0151] "Subject" or "individual" for preventing and / or treating prostate cancer 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. The subject or individual can be a patient.

[0152] The "synergistic effect" of the present invention refers to the effect produced by two active ingredients (e.g., the compound of general formula (I) and the novel endocrine therapeutic drug), and its positive effects include: an effect greater than the sum of the two, additional beneficial effects (such as other therapeutic effects not found in any of the ingredients), reduced side effects, a combined therapeutic effect can be obtained when one or both of the first and second active ingredients are in non-effective doses, and the two active ingredients have a stronger synergistic effect. The positive effects of synergy are not limited to this, and may also include other positive effects.

[0153] “Abiraterone acetate” is sometimes also referred to as “abiraterone” in the art. DETAILED DESCRIPTION

[0154] In order to make the purpose, technical scheme, and advantages of the present invention more clearly understood, the present invention is further described in detail below. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0155] The abbreviations and English expressions used in the present invention have the following meanings:

[0156] Abbreviation / English meaning DMSO Dimethyl sulfoxide MC Methylcellulose QD Once a day mCRPC Metastatic castration-resistant prostate cancer PEG300 Polyethylene glycol 300 PR Partial remission CR Complete remission SD Stable condition PD Disease progression

[0157] Example

[0158] The DMSO, MC and PEG300 used in the examples are all commercially available.

[0159] Experimental Example 1 In vivo pharmacodynamic study of the compound of the present invention combined with enzalutamide on subcutaneous xenograft tumor model of human prostate cancer cell line

[0160] Test substance: Compound 29 of the present invention, the structure of which is shown above, and the preparation method can refer to the specific implementation method of WO2018108079A1. Enzalutamide is commercially available.

[0161] Animal and cell line source information and other materials:

[0162] The cell line used in the human prostate cancer model in this experiment was 22Rv1, which was purchased from ATCC.

[0163] Male BALB / c nude mice, 6-8 weeks old, were obtained from Sibeifu (Beijing) Biotechnology Co., Ltd.

[0164] Test method:

[0165] 1. Construction and grouping of tumor-bearing mice

[0166] All mice were castrated by scrotal orifice removal 14 days before tumor cell inoculation. 22Rv1 tumor cells were subcutaneously injected into the right flank of each mouse with 0.1 ml of serum-free RPMI-1640 medium and Matrigel (supplier: Corning) in a 1:1 ratio to culture tumors. Animals were weighed before administration, tumor volumes were measured, and groups were divided according to tumor volumes using a block design.

[0167] 2. Dosage regimen

[0168] Dosing is carried out according to the following table.

[0169]

[0170] Note:

[0171] Vehicle control: DMSO / PEG300 / Tween 80 / normal saline (%): 5 / 40 / 5 / 50;

[0172] Compound 29 prescription: 0.5% MC;

[0173] Enzalutamide prescription: DMSO / PEG300 / Tween 80 / normal saline (%): 5 / 40 / 5 / 50.

[0174] 3. Experimental observation indicators

[0175] The health status and mortality 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 efficacy was evaluated according to the clinical efficacy evaluation index for solid tumors (RECIST1.1). After two consecutive measurements of tumor volume, mice with a tumor volume reduction greater than or equal to 30% of the value measured on day 0 were considered to have partial remission (PR). No palpable tumors (two consecutive measurements were 0.00 mm 3 ) will be classified as complete remission (CR); if the tumor volume increases by less than 20% of the volume on day 0 or decreases by less than 30% of the volume on day 0, it will be classified as stable disease (SD); if the tumor volume increases by more than 20% of the measured value on day 0, it will be classified as progressive disease (PD). The results are shown in Table 2:

[0176] Table 2 Effects of compound 29 of the present invention combined with enzalutamide on tumor growth in human prostate cancer 22Rv1 CDX subcutaneous xenograft tumor model

[0177]

[0178] It can be seen from the experimental results in Table 2 that the cell line is insensitive to the treatment of enzalutamide, while the combination of compound 29 and enzalutamide has a significant inhibitory effect on the castration subcutaneous xenograft tumor model of human prostate cancer 22Rv1, indicating that the compound of the present invention combined with enzalutamide has good clinical application potential for the treatment of prostate cancer, especially prostate cancer that is insensitive to enzalutamide treatment.

[0179] Experimental Example 2 In vivo pharmacodynamic study of the compound of the present invention combined with enzalutamide on castrated subcutaneous xenograft tumor model of human prostate cancer cell line

[0180] Test substance: Compound 29 of the present invention, the structure of which is shown above, and the preparation method can refer to the specific implementation method of WO2018108079A1. Enzalutamide is commercially available.

[0181] Animal and cell line source information and other materials:

[0182] The cell line used in the human prostate cancer model in this experiment is an enzalutamide-resistant strain (derived from the laboratory after long-term administration of enzalutamide to commercially available human prostate cancer cell lines)

[0183] Male BALB / c nude mice, 6-8 weeks old, were obtained from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.

[0184] Test method:

[0185] 1. Construction and grouping of tumor-bearing mice

[0186] All mice were castrated by scrotal orchiectomy 14 days before tumor cell inoculation. Enzalutamide-resistant tumor cells were subcutaneously injected into the right flank of each mouse together with 0.1 ml of serum-free RPMI-1640 medium and a 1:1 mixture of Matrigel to culture tumors. Animals were weighed before administration, tumor volumes were measured, and groups were divided according to tumor volumes using a block design.

[0187] 2. Dosage regimen

[0188] Dosing is carried out according to the following table.

[0189]

[0190]

[0191] Note: Vehicle control: DMSO / PEG300 / Tween 80 / normal saline (%): 5 / 40 / 5 / 50; Compound 29 prescription: 0.5% MC; Enzalutamide prescription: DMSO / PEG300 / Tween 80 / normal saline (%): 5 / 40 / 5 / 50.

[0192] 3. Experimental observation indicators

[0193] The health status and mortality of the animals were monitored daily, body weight and tumor volume (TV) were measured twice a week, and samples were collected after the last administration. At the end of the study, the tumor growth inhibition rate (TGI%) of each group was calculated based on the tumor volume: TGI% = (1-T / C) × 100%; T / C% = TRTV / CRTV × 100%. TRTV: average RTV of the treatment group; CRTV: average RTV of the control group; RTV = Vf / Vi, Vi: TV at the initial treatment; Vf: TV after treatment; The results are shown in Table 3:

[0194] Table 3 Effect of compound 29 of the present invention combined with enzalutamide on tumor growth in subcutaneous xenograft tumor model of human prostate cancer enzalutamide-resistant strain CDX

[0195]

[0196] # When compound 29 was used alone, the tumor volume was statistically significantly different from that of the vehicle control group, P<0.01

[0197] ## When compound 29 was used alone, the tumor volume was statistically significantly different from that of the enzalutamide group, P = 0.028

[0198] * When compound 29 was used in combination with enzalutamide, the tumor volume was statistically significantly different from that of the vehicle control group, P < 0.01

[0199] ** When compound 29 was used in combination with enzalutamide, the tumor volume was statistically significantly different from that in the enzalutamide group, P < 0.01

[0200] ***When compound 29 was used in combination with enzalutamide, the tumor volume was statistically significantly different from that of the compound 29 alone group, P = 0.01

[0201] From the experimental results in Table 3, it can be seen that the combination of compound 29 and enzalutamide has a significant inhibitory effect on the castrated subcutaneous xenograft tumor model of human prostate cancer enzalutamide-resistant strains, with significant statistical differences (**, P < 0.01), indicating that the compound of the present invention combined with enzalutamide has good clinical application potential for the treatment of enzalutamide-resistant prostate cancer.

[0202] Experimental Example 3 Clinical study of the compound of the present invention combined with abiraterone acetate or enzalutamide in the treatment of prostate cancer patients

[0203] Drugs tested:

[0204] Compound 29, whose structure is shown above, and the preparation method can refer to the specific implementation method of WO2018108079A1;

[0205] Abiraterone acetate and enzalutamide were commercially available.

[0206] Inclusion criteria: patients with histologically or cytologically confirmed prostate cancer (including patients with metastatic castration-resistant prostate cancer with no standard treatment options).

[0207] Dosage regimen:

[0208] Treatment group A: Compound 29 was orally administered at a prescribed dose (eg, 5 mg, 6 mg, 8 mg, 10 mg) once a day; abiraterone acetate was orally administered at a prescribed dose (eg, 500 mg, 750 mg, 1000 mg) once a day.

[0209] Treatment group B: Compound 29 was orally administered at a prescribed dose (eg, 5 mg, 6 mg, 8 mg, 10 mg) once a day; enzalutamide was orally administered at a prescribed dose (eg, 80 mg, 120 mg, 160 mg) once a day.

[0210] Efficacy expectation evaluation: Compound 29 combined with abiraterone acetate or enzalutamide is expected to have a therapeutic effect in the treatment of prostate cancer in the clinic.

[0211] Experimental Example 4: In vivo pharmacodynamic study of the compounds of the present invention on a human castration-resistant prostate cancer subcutaneous xenograft PDX (patient-derived xenograft) tumor model

[0212] Test substance: Compound 29 in the present invention, the structure of which is shown above, and the preparation method can refer to the specific implementation method of WO2018108079A1. Abiraterone is commercially available.

[0213] Animals, patient information of tumor masses, etc.: Human prostate cancer tumor sample LD1-0034-361929 was derived from a male patient. Clinical diagnosis: castration-resistant prostate cancer with bladder metastasis; pathological diagnosis: prostate cancer-poorly differentiated adenocarcinoma;

[0214] Male Nu / Nu nude mice, 6-8 weeks.

[0215] Test method:

[0216] 1. Construction and grouping of tumor-bearing mice

[0217] The tumor was inoculated on the right back of the mice. The animals were weighed and the tumor volume was measured before administration. The mice were divided into groups according to the tumor volume using a block design.

[0218] 2. Dosage regimen

[0219] Dosing is carried out according to the following table.

[0220]

[0221] Note: Solvent control: 0.5% MC; Compound 29 prescription: 0.5% MC; Abiraterone prescription: 10% DMSO + 90% vegetable oil

[0222] 3. Experimental observation indicators

[0223] The health status and mortality 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 therapeutic effect of tumor volume was evaluated by TGI%, and the relative tumor inhibition rate TGI (%) was: TGI = 1-T / C (%). T / C% is the relative tumor growth rate, that is, the percentage value of the relative tumor volume of 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% = TRTV / CRTV × 100% (TRTV: average RTV of the treatment group; CRTV: average RTV of the vehicle control group; RTV = Vt / V0, V0 is the tumor volume of the animal when grouping, and Vt is the tumor volume of the animal after treatment.

[0224] The results are shown in the following table:

[0225] Table: Effect of Compound 29 of the present invention combined with abiraterone on tumor growth in human prostate cancer LD1-0034-361929 subcutaneous xenograft tumor model

[0226] Group Number of animals <![CDATA[Tumor volume (mm 3 )]]> TGI (%) Solvent control 5 1404.87±483.33 -- Abiraterone <![CDATA[ 5 ]]> <![CDATA[ 1549 . 43±533 . 15 ]]> <![CDATA[- 8 . 97 ]]> Compound 29 5 622.23±247.3 58.07 Compound 29 + Abiraterone 5 203.85±66.15 85.15

[0227] It can be seen from the experimental results in the above table that compared with single drugs (compound 29 alone or abiraterone alone), the combination of compound 29 and abiraterone has a significant inhibitory effect on the human castration-resistant prostate cancer PDX subcutaneous xenograft tumor model LD1-0034-361929, indicating that the combination of compound 29 of the present invention and abiraterone in the treatment of mCRPC has good clinical application potential.

[0228] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A drug combination, characterized in that Comprising (a) a compound of general formula (I) or a pharmaceutically acceptable salt, isomer or crystal form thereof, and (b) a novel endocrine therapeutic drug; Wherein Ar is optionally replaced by 1 to 3 R 6 Substituted phenyl, each R 6 are independently selected from hydrogen, amino, cyano, halogen, C 1-4 Alkyl and trifluoromethyl; Y1 is CR 3 ; P1 is CR 4 ; W1 is N; R 3 is hydrogen or C 1-4 alkyl; R 4 -(CH2) n -(5-11) membered heterocyclic group, wherein n=an integer of 0-6, the ring-forming S atom (if any) in the heterocyclic group is optionally oxidized to S(O) or S(O)2, the ring-forming C atom (if any) is optionally oxidized to C(O), the heterocyclic group is optionally oxidized by one or more independently selected C 1-3 Alkyl and C 3-6 Substitution of cycloalkyl groups; Further, Ar is optionally replaced by 1-3 R 6 Substituted phenyl, each R 6 are independently selected from hydrogen and halogen; Y1 is CR 3 , R 3 is hydrogen; P1 is CR 4 , R 4 Selected from -(CH2) n -(5-6) membered monoheterocyclic group and -(CH2) n -(7-11) membered fused heterocyclic group, wherein n=an integer of 0-6, the ring-forming S atoms (if any) in the heterocyclic group are optionally oxidized to S(O) or S(O)2, the ring-forming C atoms (if any) are optionally oxidized to C(O), the heterocyclic group is optionally oxidized by one or more independently selected C 1-3 Alkyl and C 3-6 Substitution of cycloalkyl groups; W1 is N.

2. A pharmaceutical composition, characterized in that Comprising (a) a compound of general formula (I) or a pharmaceutically acceptable salt, isomer or crystal form thereof, and (b) a novel endocrine therapeutic drug; Wherein Ar is optionally replaced by 1 to 3 R 6 Substituted phenyl, each R 6 are independently selected from hydrogen, amino, cyano, halogen, C 1-4 Alkyl and trifluoromethyl; Y1 is CR 3 ; P1 is CR 4 ; W1 is N; R 3 is hydrogen or C 1-4 alkyl; R 4 -(CH2) n -(5-11) membered heterocyclic group, wherein n=an integer of 0-6, the ring-forming S atom (if any) in the heterocyclic group is optionally oxidized to S(O) or S(O)2, the ring-forming C atom (if any) is optionally oxidized to C(O), the heterocyclic group is optionally oxidized by one or more independently selected C 1-3 Alkyl and C 3-6 Substitution of cycloalkyl groups; Further, Ar is optionally replaced by 1-3 R 6 Substituted phenyl, each R 6 are independently selected from hydrogen and halogen; Y1 is CR 3 , R 3 is hydrogen; P1 is CR 4 , R 4 Selected from -(CH2) n -(5-6) membered monoheterocyclic group and -(CH2) n -(7-11) membered fused heterocyclic group, wherein n=an integer of 0-6, the ring-forming S atoms (if any) in the heterocyclic group are optionally oxidized to S(O) or S(O)2, the ring-forming C atoms (if any) are optionally oxidized to C(O), the heterocyclic group is optionally oxidized by one or more independently selected C 1-3 Alkyl and C 3-6 Substitution of cycloalkyl groups; W1 is N.

3. The pharmaceutical combination according to claim 1 or the pharmaceutical composition according to claim 2, characterized in that: The R 4 for n=an integer from 0 to 3, wherein R 4 The heterocyclic group is optionally substituted by one or more independently selected from C 1-3 Alkyl and C 3-6 Cycloalkyl (e.g., 1, 2 or 3 independently selected from C 1-2 alkyl and C3 cycloalkyl) are substituted; for example, the R 4 for n=an integer from 0 to 3, wherein R 4 The heterocyclic group is optionally substituted by one or more independently selected from C 1-3 Alkyl and C 3-6 Cycloalkyl (e.g., 1, 2 or 3 independently selected from C 1-2 alkyl and C3 cycloalkyl), Furthermore, the R 4 for n=an integer from 0 to 3, wherein R 4 The heterocyclic group is optionally substituted by one or more independently selected from C 1-3 Alkyl and C 3-6 Cycloalkyl (e.g., 1, 2 or 3 independently selected from C 1-2 alkyl and C3 cycloalkyl) substituents; For example, the R 4 for n=an integer from 0 to 3, wherein R 4 The heterocyclic group is optionally substituted by one or more independently selected from C 1-3 Alkyl and C 3-6 The cycloalkyl group is substituted with a substituent.

4. The pharmaceutical combination according to claim 1 or the pharmaceutical composition according to claim 2, characterized in that: Wherein component (a) is one or more of the following compounds, or a pharmaceutically acceptable salt, isomer or crystal form thereof:

5. The pharmaceutical combination according to any one of claims 1 and 3-4 or the pharmaceutical composition according to any one of claims 2-4, characterized in that: The novel endocrine therapeutic drug is an androgen synthesis inhibitor and / or an androgen receptor inhibitor; preferably, the androgen receptor inhibitor is enzalutamide, apalutamide, darolutamide, bicalutamide, or reviluamide, and the androgen synthesis inhibitor is abiraterone or abiraterone acetate.

6. The pharmaceutical combination according to any one of claims 1 and 3-4 or the pharmaceutical composition according to any one of claims 2-4, characterized in that: The (a) is or a pharmaceutically acceptable salt, isomer or crystal form thereof; the (b) novel endocrine therapeutic drug is enzalutamide, apalutamide, darolamide, bicalutamide, revilutamide, abiraterone or abiraterone acetate; for example, the (b) novel endocrine therapeutic drug is enzalutamide, or abiraterone or abiraterone acetate.

7. A medicine box, characterized in that: Comprising the pharmaceutical composition according to any one of claims 2 to 6, and instructions for administration.

8. Use of the pharmaceutical combination according to any one of claims 1 and 3-6, or the pharmaceutical composition according to any one of claims 2-6, or the medicine kit according to claim 7 in the preparation of a medicament for preventing and / or treating prostate cancer.

9. The use according to claim 8, characterized in that The prostate cancer is Castration-resistant prostate cancer or castration-sensitive prostate cancer; preferably, metastatic castration-resistant prostate cancer, non-metastatic castration-resistant prostate cancer, or metastatic castration-sensitive prostate cancer, high-risk metastatic endocrine-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer with biochemical recurrence and high risk of metastasis, or Prostate cancer that has failed standard treatment in the past, or prostate cancer that has not received standard treatment in the past; preferably, prostate cancer that has failed previous treatment with androgen synthesis inhibitors and / or androgen receptor inhibitors; preferably, prostate cancer that has failed previous treatment with enzalutamide, apalutamide, darolutamide, bicalutamide, revilutamide and / or abiraterone acetate.

10. The pharmaceutical combination according to any one of claims 1 and 3-6, or the pharmaceutical composition according to any one of claims 2-6, or the pharmaceutical kit according to claim 7, for use in medicine.

11. The pharmaceutical combination according to any one of claims 1 and 3-6, or the pharmaceutical composition according to any one of claims 2-6, or the drug kit according to claim 7, for preventing and / or treating prostate cancer, preferably the prostate cancer is: Castration-resistant prostate cancer or castration-sensitive prostate cancer; preferably, metastatic castration-resistant prostate cancer, non-metastatic castration-resistant prostate cancer, or metastatic castration-sensitive prostate cancer, high-risk metastatic endocrine-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer with biochemical recurrence and high risk of metastasis, or Prostate cancer that has failed standard treatment in the past, or prostate cancer that has not received standard treatment in the past; preferably, prostate cancer that has failed previous treatment with androgen synthesis inhibitors and / or androgen receptor inhibitors; preferably, prostate cancer that has failed previous treatment with enzalutamide, apalutamide, darolutamide, bicalutamide, revilutamide and / or abiraterone acetate.

12. A method for preventing and / or treating prostate cancer, the method comprising administering a therapeutically effective amount of the pharmaceutical combination according to any one of claims 1 and 3-6, or the pharmaceutical composition according to any one of claims 2-6, or the kit according to claim 7 to a patient in need thereof, Preferably, the prostate cancer is: Castration-resistant prostate cancer or castration-sensitive prostate cancer; preferably, metastatic castration-resistant prostate cancer, non-metastatic castration-resistant prostate cancer, or metastatic castration-sensitive prostate cancer, high-risk metastatic endocrine-sensitive prostate cancer, non-metastatic castration-sensitive prostate cancer with biochemical recurrence and high risk of metastasis, or Prostate cancer that has failed standard treatment in the past, or prostate cancer that has not received standard treatment in the past; preferably, prostate cancer that has failed previous treatment with androgen synthesis inhibitors and / or androgen receptor inhibitors; preferably, prostate cancer that has failed previous treatment with enzalutamide, apalutamide, darolutamide, bicalutamide, reviluamide and / or abiraterone or abiraterone acetate.

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