Pharmaceutical composition and use thereof

Abstract

A pharmaceutical composition and a use thereof, specifically relating to (a) a compound of general formula (I) or a pharmaceutically acceptable salt, isomer or crystal form thereof, and (b) a novel endocrine therapy drug, variables in the general formula each being as defined in the description. It has been found by means of research that the compound of general formula (I) or the pharmaceutically acceptable salt, isomer or crystal form thereof, and the novel endocrine therapy drug, have a synergistic effect in combined treatment of prostate cancer.

Description

Pharmaceutical composition and use thereof 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 depending on the stage and risk level of prostate cancer. For patients with early-stage, low-risk prostate cancer, active surveillance is the primary approach. Because early prostate cancer lacks obvious symptoms or is limited by detection methods, most cases are diagnosed at an advanced stage, with more than half already having distant metastases. The 5-year relative survival rate for patients with distant metastases is only 30%. For patients with advanced, metastatic prostate cancer, medical or surgical castration, also known as androgen deprivation therapy (ADT), is the primary treatment. Because both normal prostate cells and prostate cancer cells depend on androgens for growth, surgical or medical castration can minimize androgen levels in the patient's system, thereby inhibiting androgen signaling and ultimately suppressing tumor cell growth. Currently used ADT medications include gonadotropin-releasing hormone agonists (GnRH agonists), gonadotropin-releasing hormone antagonists (GnRH antagonists), and androgen secretion inhibitors. Most patients initially develop castration-sensitive prostate cancer (CSPC) that is sensitive to ADT. However, due to genetic or drug-induced factors, almost all patients will progress to castration-resistant prostate cancer (CRPC) after two years, becoming resistant to treatment. Once CRPC develops, the median survival is only 9-12 months.

[0004] CRPC is primarily divided into two distinct stages: metastatic castration-resistant prostate cancer (mCRPC), which develops distant metastases, and non-metastatic castration-resistant prostate cancer (nmCRPC), which does not. When patients with nmCRPC develop distant metastases or disease progression after failure of novel endocrine therapy, they transition to the mCRPC stage. Therefore, mCRPC can be considered the final stage of prostate cancer. Currently, the main treatments for mCRPC include chemotherapy (docetaxel), novel endocrine therapy (enzalutamide, abiraterone acetate, etc.), immunotherapy (Sipuleucel-T), and radiation therapy (radium-223) for bone metastases. Doxetaxel was the first FDA-approved chemotherapy drug for the treatment of mCRPC, effectively extending overall survival (OS) by approximately 19.2 months. However, it is associated with a range of side effects, including nausea, vomiting, neurological problems, and anemia. 17α-hydroxylase / C17,20-lyase (CPY17) plays a key role in androgen synthesis. Abiraterone acetate, a prodrug that is converted to abiraterone in vivo, is an androgen synthesis inhibitor that reduces 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. Binding to enzalutamide prevents normal AR translocation to the nucleus and recruitment of coactivators, resulting in reduced AR transcriptional activity. Compared to 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 clinical challenge, and it is urgent to explore effective treatment methods.

[0006] Summary of the Invention

[0007] In order to solve the above problems, the present invention provides the following solutions:

[0008] In a first aspect, the present invention provides a pharmaceutical composition comprising component (a) and component (b):

[0009] (a) a compound of formula (I) or a pharmaceutically acceptable salt, isomer or crystalline form thereof, and

[0010] (b) New endocrine therapy drugs;

[0011] Wherein, Ar is optionally replaced by 1-3 R 6 Substituted phenyl, each R 6 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 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;

[0017] In some embodiments, Ar is optionally replaced by 1-3 R 6 Substituted phenyl, each R 6 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 3-6 Substitution 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 components (a) and (b) serve as 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] Wherein, Ar is optionally replaced by 1-3 R 6 Substituted phenyl, each R 6 are independently selected from hydrogen, amino, cyano, halogen, C 1-4 alkyl and trifluoromethyl;

[0026] Y1 is CR 3 ;

[0027] P1 is CR 4 ;

[0028] W1 is N;

[0029] R 3 is hydrogen or C 1-4 alkyl;

[0030] R 4 -(CH2) n -(5-11) membered 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 C1-3 Alkyl and C 3-6 Substitution of cycloalkyl groups;

[0031] In some embodiments, Ar is optionally replaced by 1-3 R 6 Substituted phenyl, each R 6 independently selected from hydrogen and halogen;

[0032] Y1 is CR 3 , R 3 is hydrogen;

[0033] 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;

[0034] W1 is N;

[0035] 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.

[0036] 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, or a (7-11)-membered saturated bridged heterocyclic group.

[0037] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, the R4 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;

[0038] 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 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 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;

[0040] 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.

[0041] 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.

[0042] Table 1: Examples of compounds of formula (I)

[0043] Preparation examples of the compounds in the above table, as well as examples verifying the biological activities of these compounds, can be found in patent application WO2018108079A1, the entire content of which is incorporated herein.

[0044] 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.

[0045] Preparation examples of the compounds in the above table, as well as examples verifying the biological activities of these compounds, can be found in patent application WO2018108079A1, the entire content of which is incorporated herein.

[0046] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, the novel endocrine therapeutic drug is an androgen receptor inhibitor.

[0047] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, the androgen receptor inhibitor is enzalutamide, apalutamide, darolamide, or bicalutamide.

[0048] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, the androgen receptor inhibitor is reviluamide.

[0049] In any embodiment of the above-mentioned pharmaceutical combination and pharmaceutical composition, the androgen receptor inhibitor is enzalutamide.

[0050] 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.

[0051] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, the novel endocrine therapeutic drug is an androgen synthesis inhibitor.

[0052] In any embodiment of the above-mentioned drug combination and pharmaceutical composition, the androgen synthesis inhibitor is abiraterone or abiraterone acetate.

[0053] 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.

[0054] In any of the above embodiments of the pharmaceutical combination and pharmaceutical composition, said component (a) and said component (b) are provided in the form of one inseparable entity, or said component (a) and said component (b) are provided in separate entities.

[0055] In a third aspect, the present invention also provides a kit comprising the pharmaceutical combination or pharmaceutical composition according to any one of the preceding embodiments and instructions for administration.

[0056] Furthermore, the kit of the present invention comprises:

[0057] a) one or more unit dosage forms of a compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt, isomer or crystalline form thereof, i.e. component (a);

[0058] b) one or more unit dosage forms of the novel endocrine therapeutic agent described in the first or second aspect of the present invention, i.e. component (b); and

[0059] c) Instructions for use.

[0060] 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.

[0061] 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.

[0062] In a 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 therapeutic drug described in the first or second aspect of the present invention, which is used for preventing and / or treating prostate cancer.

[0063] In a sixth aspect, the present invention further provides use of the drug combination, or drug composition, or drug kit according to any one of the first, second and third aspects above in the preparation of a drug for preventing and / or treating prostate cancer.

[0064] In any embodiment of the sixth aspect, the use also includes the compound or pharmaceutically acceptable salt, isomer or crystal 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 simultaneously, separately or sequentially to the prostate cancer patient; or the compound or pharmaceutically acceptable salt, isomer or crystal 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 to the prostate cancer patient in a therapeutically effective amount.

[0065] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is metastatic prostate cancer.

[0066] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is non-metastatic prostate cancer.

[0067] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is early-stage prostate cancer.

[0068] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is advanced prostate cancer.

[0069] 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.

[0070] 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 before.

[0071] 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.

[0072] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is prostate cancer that has failed chemotherapy in the past.

[0073] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is prostate cancer that has previously failed endocrine therapy.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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, darolamide and / or bicalutamide.

[0078] 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 revilutamide.

[0079] 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.

[0080] 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.

[0081] 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 previously received 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, darolutamide and / or bicalutamide. In one embodiment, the castration-sensitive prostate cancer has been previously treated with revilutamide but has failed treatment.

[0082] 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, darolutamide and / or bicalutamide. In one embodiment, the castration-resistant prostate cancer has previously failed reviluamide.

[0083] 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 received standard treatment in the past, or has failed standard treatment in the past.

[0084] 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 failed standard treatment in the past.

[0085] 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 is a patient who has previously failed treatment with revilutamide. In one embodiment, the metastatic castration-resistant prostate cancer is a patient who has failed initial continuous androgen deprivation therapy and has clear bone or soft tissue metastases as confirmed by imaging. In one embodiment, the metastatic castration-resistant prostate cancer is a patient who has previously failed initial continuous androgen deprivation therapy as confirmed by histopathology or cytology and has no standard treatment options.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the prostate cancer is high-risk metastatic endocrine therapy-sensitive prostate cancer. In one embodiment, the high-risk metastatic endocrine therapy-sensitive prostate cancer has not previously received standard treatment. In one embodiment, the high-risk metastatic endocrine therapy-sensitive prostate cancer has not previously received endocrine therapy or has received endocrine therapy for no longer than 3 months. In one embodiment, the high-risk metastatic endocrine therapy-sensitive prostate cancer has previously failed chemotherapy.

[0090] 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.

[0091] 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.

[0092] 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 medical castration therapy (including but not limited to goserelin, leuprorelin, triptorelin, degarelix, etc.).

[0093] In any embodiment of the fourth, fifth, and sixth aspects of the present invention, the single dose of the compound or pharmaceutically acceptable salt, isomer, or crystalline form thereof described in the first or second aspect of the present invention, i.e., component (a), (calculated on the basis of the compound) is 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.

[0094] 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.

[0095] 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.

[0096] 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 900 mg to 1100 mg per day.

[0097] 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.

[0098] 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.

[0099] In some embodiments of the fourth, fifth and sixth aspects of the present invention, component (a) and component (b) may be provided as one inseparable entity, or provided in separate entities. When component (a) and component (b) are provided as one 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, 200 mg). 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 mg, 1200 mg to 1300 mg, 1400 mg to 1500 mg, 1500 mg to 1300 mg, 1400 mg to 1300 mg, 15 ... 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 an integer of 1 to 6, and p and q are independently an integer of 2 to 6.

[0100] In any embodiment of the fourth, fifth, and sixth aspects of the present invention, the pharmaceutical combination, pharmaceutical composition, or drug kit may 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 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.

[0101] In any embodiment of the fourth, fifth and sixth aspects of the present invention, the compound or pharmaceutically acceptable salt, isomer or crystalline form thereof described in the first or second aspect of the present invention, 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. 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" as 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 administered compound. 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 nature of the dosage form and is within the ordinary skill 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); diluents, wetting agents, colorants (dyes or pigments such as titanium dioxide, lacquer solutions), flavors, absorption promoters, surfactants, adsorption carriers, and the like, for example, 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.

[0102] 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 ingredient, for example, about 0.1% by weight -95% by weight, about 0.1% by weight -50% by weight, or about 1% by weight -40% by weight, for example, 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 ingredient, 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 can be omitted, or suitable additives can 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 (e.g., delivered as an aerosol spray from a pressurized pack or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas).

[0103] Beneficial effects of the present invention

[0104] Through research, it was 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 combined treatment of prostate cancer have a synergistic effect. Further, the present compound 29 and a specific new endocrine therapy drug combined treatment of prostate cancer have a synergistic effect. Furthermore, the present compound 29 and enzalutamide or abiraterone acetate combined treatment of prostate cancer, especially metastatic castration-resistant prostate cancer (mCRPC) with distant metastasis has a significant synergistic effect.

[0105] Detailed Description of the Invention

[0106] The "halogen" described in the present invention refers to fluorine, chlorine, bromine and iodine, etc., preferably fluorine and chlorine.

[0107] The term "halo" as used herein means that any hydrogen atom in a substituent group may be replaced by one or more halogens, which may be the same or different. "Halogen" is as defined above.

[0108] The "cyano group" described in the present invention refers to a -CN group.

[0109] The "amino group" described in the present invention refers to the -NH2 group.

[0110] 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" refers to an alkyl group as defined above having 1 to 3 carbon atoms.

[0111] The "C 3-6 "Cycloalkyl" refers to a monocyclic cycloalkyl group, 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 fused ring structures that can be formed. Examples include, but are not limited to, cyclopropane, cyclobutane, cyclopentane and cyclohexane.

[0112] 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 may be oxidized.

[0113] The term "heterocyclyl" refers to a monocyclic, bicyclic, or polycyclic heterocyclyl system, including saturated and partially saturated heterocyclyls, but excluding aromatic rings. The term "5- to 11-membered heterocyclyl" as used herein includes any monocyclic or fused ring structures that can be formed, unless otherwise specified.

[0114] The monocyclic heterocyclic group can 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, and the like. Examples of the 5-6 membered monoheterocyclic group of 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, morpholinyl, 1,4-dioxane, 1,4-oxathiacyclohexane, 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-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, etc.

[0115] 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 any para-, spiro-, or bridged structures that can be formed, unless otherwise specified.

[0116] The heterocyclic group can 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]octane, 3,7-diazabicyclo[4.2.0]octane, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[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, dihydroindole-1-yl, dihydroindole-2-yl, dihydroindole-3-yl, 2,3-dihydrobenzothiophene-2-yl, octahydro-1H-indolyl, octahydrobenzofuranyl.

[0117] 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:

[0118] 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:

[0119] The "pharmaceutically acceptable salts" of the present invention refer to pharmaceutically acceptable acid and base addition salts and solvates. Such pharmaceutically acceptable salts include salts of the following acids: 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 acid (such as acetic acid, HOOC-(CH2) n -COOH (wherein n = an integer from 0 to 4)) and the like. Such pharmaceutically acceptable salts also include salts with 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.

[0120] All numerical ranges described herein are intended 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.

[0121] The term "one to more" used in the present invention with respect to 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.

[0122] The "crystalline form" of the present invention can be prepared from the compound of general formula (I) by conventional methods for preparing crystalline forms in the art.

[0123] The "isomers" of the compounds of general formula (I) described in the present invention include stereoisomers and tautomers.

[0124] The term "stereoisomer" refers to isomers that arise from differences in the spatial arrangement of atoms in a molecule. Enantiomers are formed when a compound has an asymmetric carbon atom; cis- and trans-isomers are formed when a compound has a carbon-carbon double bond or a ring structure.

[0125] The term "tautomer" refers to a special type of functional group isomerism in which different functional group isomers are in dynamic equilibrium and can rapidly interconvert. For example, tautomers can occur in the presence of ketones or oximes. Representative examples include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, and imine-enamine tautomers.

[0126] 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.

[0127] The preparation of the compound of general formula (I) described in the present invention can be found in the specific implementation section of WO2018108079A1.

[0128] The term "treatment" as used herein refers to administering to a patient an effective amount of a drug 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 the progression of the disease, improving or alleviating the disease state, and regression (whether partial or complete), whether detectable or undetectable.

[0129] The "treatment" described in the present invention may include neoadjuvant therapy and adjuvant therapy.

[0130] "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, immunotherapy or radiotherapy. The purpose of neoadjuvant therapy is to provide immediate systemic treatment, thereby potentially eradicating micrometastases that would otherwise proliferate when 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 organs and their functions. In addition, neoadjuvant therapy allows in vivo evaluation of drug efficacy, which can guide the selection of subsequent treatments.

[0131] "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 of the tumor returning or spreading 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, to reduce the chance of cancer-related death. Adjuvant therapy is specifically excluded in this context from neoadjuvant therapy.

[0132] The "combination", "joint use", "combined administration" or "combination therapy" described in the present invention refers to the administration of at least one dose of the aforementioned compound of general formula (I) or its pharmaceutically acceptable salt, isomer or crystalline form and the aforementioned novel endocrine therapeutic drug within a certain period of time. They can be prepared together as a compound preparation or prepared separately as preparations for simultaneous, separate or sequential administration to the patient; or, on the basis of the above-mentioned combination, a corticosteroid can be administered to the patient simultaneously, separately or sequentially.

[0133] 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 criteria for tumor tissue assessment or progressive disease (PD) according to the PCWG3 bone lesion evaluation criteria for prostate cancer), or intolerable toxic side effects during treatment.

[0134] The "drug resistance" mentioned in the present invention refers to the reduced sensitivity of pathogens, tumor cells or individuals to drugs, resulting in the inability of drugs to exert the expected therapeutic effect, which meets the situation of "treatment failure" mentioned in the present invention.

[0135] The "intolerable toxic and side effects" mentioned in the present invention means that the patient cannot continue to receive treatment due to adverse reactions caused by the drug.

[0136] The "standard treatment" referred to in the present invention includes androgen deprivation therapy (surgical castration and medical castration therapy including but not limited to goserelin, leuprorelin, triptorelin, and degarelix), chemotherapy, systemic radiotherapy, and / or novel endocrine therapy. Of course, "standard treatment" is not limited to these. As standard treatment regimens are updated, the "standard treatment" referred to in the present invention will also be included.

[0137] The "non-standard treatment" mentioned in the present invention refers to treatment performed in a manner other than standard treatment.

[0138] 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.

[0139] 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.

[0140] "Endocrine therapy" as used in this invention is a method for treating prostate cancer by lowering androgen levels and inhibiting or reducing androgen receptor activity. It encompasses traditional androgen deprivation therapy (ADT) and novel hormone therapy (NHT). ADT includes surgical castration (such as orchiectomy) and medical castration (including but not limited to goserelin, leuprorelin, triptorelin, degarelix, etc.).

[0141] The "therapeutically effective amount" of the present invention refers to the amount of the aforementioned compound or its pharmaceutically acceptable salt, isomer or crystalline form and the aforementioned new endocrine therapy drug that can at least alleviate the symptoms of the patient's condition when administered to a 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 physical 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. 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 the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0142] As used herein, a "unit dosage form" 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 minor component (e.g., about 0.1% to about 50% by weight or preferably about 1% to about 40% by weight), with the remainder being various vehicles or carriers and processing aids that help form the desired dosage form. Unit dosage forms are 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 forms are packaged in a multipack for sequential use, such as a blister pack containing at least 6, 9 or 12 unit dosage tablets.

[0143] A "subject" or "individual" for the prevention and / or treatment of prostate cancer refers to any animal classified as a mammal, including humans, domesticated and farm animals, and zoo, sport, or pet animals, such as dogs, horses, cats, and cows. Preferably, the mammal is a human. The subject or individual can be a patient.

[0144] The "synergistic effect" described in the present invention refers to the effect produced by two active ingredients (e.g., the compound of formula (I) and the novel endocrine therapeutic agent). Positive effects include: an effect greater than additive, additional beneficial effects (e.g., other therapeutic effects not previously observed with either ingredient), reduced side effects, the ability to achieve a combined therapeutic effect when one or both of the first and second active ingredients are at non-effective doses, and a stronger synergistic effect between the two active ingredients. The positive effects of synergy are not limited to these and may also include other positive effects.

[0145] “Abiraterone acetate” is sometimes also referred to as “abiraterone” in the art. DETAILED DESCRIPTION

[0146] To make the objectives, technical solutions, and advantages of the present invention more clearly understood, the present invention is described in further detail below. It is apparent that the embodiments described herein are merely a portion of the embodiments of the present invention, and not all of them. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort are intended to fall within the scope of protection of the present invention.

[0147] The abbreviations and English expressions used in this invention have the following meanings:

[0148] Example

[0149] DMSO, MC and PEG300 used in the examples were all commercially available.

[0150] Experimental Example 1 In vivo pharmacodynamic study of the compound of the present invention combined with enzalutamide on a subcutaneous xenograft tumor model of a human prostate cancer cell line

[0151] Test substance: Compound 29 of the present invention, whose structure is shown above. The preparation method can be found in the detailed description of WO2018108079A1. Enzalutamide was commercially available.

[0152] Materials such as animal and cell line source information:

[0153] The cell line used in the human prostate cancer model in this experiment was 22Rv1, which was purchased from ATCC.

[0154] Male BALB / c nude mice, 6-8 weeks old, were obtained from Spefox (Beijing) Biotechnology Co., Ltd.

[0155] Test method:

[0156] 1. Construction and grouping of tumor-bearing mice

[0157] Fourteen days prior to tumor cell inoculation, all mice were castrated by scrotal orchiectomy. 22Rv1 tumor cells were subcutaneously injected into the right flank of each mouse along with 0.1 ml of a 1:1 mixture of serum-free RPMI-1640 medium and Matrigel (Corning) to establish tumors. Prior to dosing, animals were weighed, tumor volumes were measured, and mice were divided into groups based on tumor volume using a block design.

[0158] 2. Dosage regimen

[0159] Dosing is carried out according to the following table.

[0160] Note:

[0161] Vehicle control: DMSO / PEG300 / Tween 80 / normal saline (%): 5 / 40 / 5 / 50;

[0162] Compound 29 prescription: 0.5% MC;

[0163] Enzalutamide prescription: DMSO / PEG300 / Tween 80 / normal saline (%): 5 / 40 / 5 / 50.

[0164] 3. Experimental observation indicators

[0165] 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 dose. The efficacy was evaluated according to the clinical efficacy evaluation index for solid tumors (RECIST1.1). After two consecutive tumor volume measurements, 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). There was no palpable tumor (two consecutive measurements were 0.00 mm 3 Mice with a tumor volume increase of less than 20% of the volume on day 0 or a tumor volume decrease of less than 30% of the volume on day 0 were classified as having stable disease (SD); and mice with tumors that increased by more than 20% of the volume measured on day 0 were classified as having progressive disease (PD). The results are shown in Table 2:

[0166] 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

[0167] As can be seen from the experimental results in Table 2, this cell line is insensitive to enzalutamide treatment, while compound 29 combined with enzalutamide has a significant inhibitory effect on the castration-resistant 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.

[0168] Experimental Example 2 In vivo pharmacodynamic study of the compound of the present invention combined with enzalutamide on castration-induced subcutaneous xenograft tumor models of human prostate cancer cells

[0169] Test substance: Compound 29 of the present invention, whose structure is shown above. The preparation method can be found in the detailed description of WO2018108079A1. Enzalutamide was commercially available.

[0170] Materials such as animal and cell line source information:

[0171] The cell line used in this experiment for the human prostate cancer model is an enzalutamide-resistant strain (derived from the laboratory after long-term administration of enzalutamide to a commercially available human prostate cancer cell line).

[0172] Male BALB / c nude mice, 6-8 weeks old, were obtained from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0173] Test method:

[0174] 1. Construction and grouping of tumor-bearing mice

[0175] Fourteen days prior to tumor cell inoculation, all mice were castrated by scrotal orchiectomy. Enzalutamide-resistant tumor cells were subcutaneously injected into the right flank of each mouse along with 0.1 ml of a 1:1 mixture of serum-free RPMI-1640 medium and Matrigel to establish tumors. Before dosing, animals were weighed and tumor volumes were measured. Groups were assigned according to tumor volume using a block design.

[0176] 2. Dosage regimen

[0177] Dosing is carried out according to the following table.

[0178] Note: Vehicle control: DMSO / PEG300 / Tween 80 / normal saline (%): 5 / 40 / 5 / 50; Compound 29 formulation: 0.5% MC; Enzalutamide formulation: DMSO / PEG300 / Tween 80 / normal saline (%): 5 / 40 / 5 / 50.

[0179] 3. Experimental observation indicators

[0180] Animal health and mortality were monitored daily. Body weight and tumor volume (TV) were measured twice weekly, and samples were collected after the final dose. At the end of the study, the tumor growth inhibition rate (TGI%) was calculated for each group based on tumor volume: TGI% = (1-T / C) × 100%; T / C% = TRTV / CRTV × 100%. TRTV: mean RTV of the treatment group; CRTV: mean RTV of the control group; RTV = Vf / Vi, where Vi is the TV at the time of initial treatment; Vf is the TV after treatment. The results are shown in Table 3.

[0181] Table 3 Effects of compound 29 of the present invention combined with enzalutamide on tumor growth in a subcutaneous xenograft tumor model of human prostate cancer enzalutamide-resistant strain CDX

[0182] # When compound 29 was used alone, the tumor volume showed a statistically significant difference compared with the vehicle control group, P < 0.01

[0183] ## When compound 29 was used alone, the tumor volume showed a statistically significant difference compared with the enzalutamide group, P = 0.028

[0184] * When compound 29 was combined with enzalutamide, the tumor volume showed a statistically significant difference compared with the vehicle control group, P < 0.01

[0185] **When compound 29 was combined with enzalutamide, the tumor volume showed a statistically significant difference compared with the enzalutamide group, P < 0.01

[0186] ***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

[0187] As shown in the experimental results in Table 3, the combination of compound 29 and enzalutamide has a significant inhibitory effect on the castration subcutaneous xenograft tumor model of human prostate cancer enzalutamide-resistant strains, with a significant statistical difference (**, P < 0.01). This indicates that the compound of the present invention combined with enzalutamide has good clinical application potential for the treatment of enzalutamide-resistant prostate cancer.

[0188] 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

[0189] Test drug:

[0190] Compound 29, whose structure is shown above, and the preparation method can refer to the detailed description of WO2018108079A1;

[0191] Abiraterone acetate and enzalutamide were commercially available.

[0192] Inclusion criteria: Patients with histologically or cytologically confirmed prostate cancer (including patients with metastatic castration-resistant prostate cancer who have no standard treatment options).

[0193] Dosage regimen:

[0194] Treatment group A: Compound 29 was orally administered at a prescribed dose (e.g., 5 mg, 6 mg, 8 mg, 10 mg) once daily; abiraterone acetate was orally administered at a prescribed dose (e.g., 500 mg, 750 mg, 1000 mg) once daily.

[0195] Treatment Group B: Compound 29 was orally administered at a prescribed dose (e.g., 5 mg, 6 mg, 8 mg, 10 mg) once daily; Enzalutamide was orally administered at a prescribed dose (e.g., 80 mg, 120 mg, 160 mg) once daily.

[0196] Efficacy 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.

[0197] Experimental Example 4: In vivo pharmacodynamic study of the compound of the present invention on a human castration-resistant prostate cancer subcutaneous xenograft PDX (patient-derived xenograft) tumor model

[0198] Test substance: Compound 29 of the present invention, whose structure is shown above. The preparation method can be found in the detailed description of WO2018108079A1. Abiraterone was commercially available.

[0199] Animal and tumor source patient information and other materials: Human prostate cancer tumor sample LD1-0034-361929 was obtained from a male patient. Clinical diagnosis: castration-resistant prostate cancer with bladder metastases; pathological diagnosis: prostate cancer-poorly differentiated adenocarcinoma.

[0200] Male Nu / Nu nude mice, 6-8 weeks old.

[0201] Test method:

[0202] 1. Construction and grouping of tumor-bearing mice

[0203] 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.

[0204] 2. Dosage regimen

[0205] Dosing is carried out according to the following table.

[0206] Note: Vehicle control: 0.5% MC; Compound 29 formulation: 0.5% MC; Abiraterone formulation: 10% DMSO + 90% vegetable oil

[0207] 3. Experimental observation indicators

[0208] 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 volumes (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 at the time of grouping, and Vt is the tumor volume of the animal after treatment.

[0209] The results are shown in the following table:

[0210] Table: Effects of Compound 29 of the present invention combined with Abiraterone on tumor growth in human prostate cancer LD1-0034-361929 subcutaneous xenograft tumor model

[0211] As can be seen from the experimental results in the above table, 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.

[0212] 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, Medium 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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