A method of treating breast cancer using tetrahydronaphthalene derivatives as estrogen receptor degraders.

Abstract

The present invention provides methods for treating and / or preventing breast cancer, including locally advanced or metastatic ER+ and HER2- breast cancers in patients requiring treatment, compounds for use in treatment, and combinations thereof. [Solution] Administer a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, isotope derivative thereof, or a prodrug thereof. JPEG2026136114000154.jpg65134

Description

[Technical Field]

[0001] Cross-reference of related applications This application is based on U.S. Provisional Patent Application No. 63 / 125,37, filed on December 14, 2020. This asserts the priority and interest of item 1, the contents of which are in their entirety as referenced herein. It will be incorporated into it.

[0002] Inclusion by referencing the sequence list This application was submitted via EFS-Web in ASCII format, and the entire application is available by reference. This specification includes sequence listings incorporated herein. The ASCII created on December 8, 2021. The first copy is named “ARVN-015-001WO_ST25.txt” and is approximately 6 This is the size in KB. [Background technology]

[0003] In the United States, breast cancer was the cause of death for approximately 41,000 women in 2018. It is the second leading cause of death from cancer in women, which was predicted to be fatal. Breast cancer is not as common in men. Although not common, men account for approximately 1% of all newly diagnosed cases, and in 2018... It is estimated that approximately 500 men will die from these diseases (Seigel R. L.et al.Cancer Statistics,CA Cancer J Cl in.2018, 68(1); 7-30.).

[0004] As of January 2017, approximately 155,000 women had metastatic breast cancer (mBC). It is estimated that they are in the United States. Also, mainly due to improved treatment and the aging of the US population, mBC and It has also been reported that the number of women living with mBC is increasing. The estimated number of women with mBC is It increased by 17% from 2000 to 2010, and by 3% from 2010 to 2020. It is predicted to increase by 1% (Mariotto Abe et al. “Estim ation of the Number of Women Living with Metastatic Breast Cancer in the United States” Cancer Epidemiol.Biomarkers Prev 2017, 26(6):809-815.).

[0005] Treatment options for advanced breast cancer or mBC include tumors that target hormone receptors, i.e., estrogen ER receptor and / or progesterone receptor, or human epidermal growth factor receptor 2 It depends on many different factors, including whether or not it expresses (HER2). Standard treatment for women is endocrine therapy, chemotherapy, and / or targeted therapy, either alone or in combination. Therefore, patients with ER-positive (ER+) and HER2-negative (HER2-) mBCs are It is treated with endocrine therapy, sometimes in combination with targeted drugs such as CDK4 / 6 inhibitors (CDKi). They are treated in combination. Patients with invasive diseases, or patients whose disease continues to progress despite endocrine therapy. In such cases, chemotherapy may be prescribed.

[0006] The current standard of care for women with ER+, HER2-, and mBC is endocrine therapy + / -CDKi or mTOR inhibitors. Endocrine therapy includes oophorectomy or suppression (premenopausal women). (Sexually oriented), tamoxifen (selective ER regulator), aromatase inhibitors, and fulvest It includes rant (SERD). Metastatic breast cancer remains incurable, and ER+ breast cancer Treatment involves the sequencing of endocrine therapies, with CDKi and mTO being the recommended approaches. Adding targeted drugs, including R inhibitors, to the backbone of endocrine therapy further improves patient outcomes. To do good.

[0007] Fulvestrant is a fundamental component of ER-targeted endocrine regimens in advanced disease settings. It is thought that this mechanism acts indirectly through protein degradation, leading to ER destabilization. The monotherapy drug fulvestrant is administered intramuscularly at a dose of 500 mg on days 1, 15, and 29. It is administered once a month thereafter. The effectiveness of fulvestrant is for locally progressive or In two randomized controlled clinical trials in postmenopausal women with mBC, selective aromatherapy This was established through comparison with the tase inhibitor anastrozole (Astra Zeneca F aslodex Full Prescribing Information,rev (Ised 03 / 2019). All patients in an adjuvant or progressive disease state. , progression after previous treatment with anti-estrogen or progestin for breast cancer In both trials, eligible patients with measurable and / or evaluable diseases were included. , receive fulvestrant 250 mg intramuscularly once a month (28 days + 3 days), or Patients were randomized to receive either anastrozole 1 mg orally once daily. Results from trials conducted after a minimum follow-up period of 14.6 months showed that fulvestrant was superior to anastrozole. The possibility of inferiority was ruled out. Overall survival between the two treatment groups after a follow-up period of more than 2 years ( There was no statistically significant difference in OS. In the third study, the dose of fulvestrant 500 mg This study compared the dose of fulvestrant 250 mg with that of fulvestrant 250 mg after a minimum follow-up period of 18 months. The results were fulvestrant 500mg vs fulvestrant 250mg (6.5 each). showed a statistically significant improvement in progression-free survival (PFS) at 5.4 months versus 1 month There was no statistically significant difference in OS between the two treatment groups (25.1 months with fulvestrant 500 mg and 22.8 months with fulvestrant 250 mg). The overall response rates were similar, with a response rate of 13.8% for the 500 mg dose (95% confidence interval [CI] 9.7- 18.8%) and 14.6% (CI 10.5-19.4%) for the 250 mg dose (Astra Zeneca Faslodex Full Prescribi ng Information, revised 03 / 2019).

SUMMARY OF THE INVENTION

[0008] In one aspect, the present application relates to a method of treating a subject who needs treatment for breast cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, isotope derivative, or prodru

Chemical formula

[0009] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Regarding the subject, the study includes at least one somatic ER tumor mutation, and the method involves formulating the therapeutically effective dose. The treatment involves administering the compound of formula (I) to the target, and the therapeutically effective dose of the compound of formula (I) is approximately 10 The amount is approximately 1000 mg. In some embodiments, breast cancer is diagnosed in at least one body. Includes cellular ER tumor mutations.

[0010] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Regarding breast cancer, if the patient has at least one somatic ER tumor mutation, the method is effective in providing a therapeutic dose. The treatment involves administering a compound of formula (I) to a target, and the therapeutically effective amount of the compound of formula (I) is approximately 1 The range is 0 mg to approximately 1000 mg.

[0011] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Regarding the compound of formula (I) for use, the subject is at least one somatic ER tumor Includes differences. In some embodiments, the subject is Y537X, D538X, E380X, L At least one selected from the group consisting of 379X, V422X, S463X, and L536X It also includes one somatic ER tumor mutation, where "X" is any residue other than the wild-type residue at that location. This refers to amino acid residues. In some embodiments, the target residues are Y537S, Y537N, and D5. 38G, E380Q, L379I, V422del, S463P, L536P and L53 Includes at least one somatic ER tumor mutation selected from the group consisting of 6_D538>P nothing.

[0012] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Regarding the compound of formula (I) for use, breast cancer is at least one somatic ER tumor. This includes mutations. In some embodiments, breast cancer is Y537X, D538X, E380X A small number of the group consisting of L379X, V422X, S463X, and L536X are selected. It contains at least one somatic ER tumor mutation, and "X" is a non-wild-type residue at that location. This refers to the amino acid residues of a certain type. In some embodiments, breast cancer is Y537S, Y537N , D538G, E380Q, L379I, V422del, S463P, L536P and At least one somatic ER tumor selected from the group consisting of L536_D538>P Includes differences.

[0013] In some embodiments, the breast cancer is ER+, HER2-. Therefore, breast cancer is either metastatic or locally advanced.

[0014] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs It is.

[0015] In some embodiments, the compound of formula (I) is the compound of formula (Ia). In that embodiment, the compound of formula (I) is the compound of formula (Ic). Several embodiments Morphologically, the compound of formula (I) is the same as the compound of formula (Ij).

[0016] In some embodiments, the compound of formula (I) is administered orally to the subject.

[0017] In some embodiments, a therapeutically effective amount of the compound of formula (I) is administered once daily, twice daily, or once daily. It is administered to the subject three or four times a day. In some embodiments, the formula for the therapeutically effective dose is ( The compounds in I) are administered to the subject all at once, or in units of two, three, or four doses. It is administered in a dose. In some embodiments, a therapeutically effective dose of the compound of formula (I) is about 3 mg Approximately 5 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, or approximately 4 It is 0 mg. In some embodiments, the therapeutically effective dose of the compound of formula (I) is about 10 mg The dosage is approximately 15 mg, 20 mg, 25 mg, 30 mg, or 40 mg.

[0018] In one aspect, the present application relates to a method for treating breast cancer in a subject, wherein the method is effective in treating the disease. The amount of the compound of formula (I) is administered to the target, and the amount of at least one additional therapeutically effective dose is also administered. This further includes administering anticancer drugs to patients in need of treatment.

[0019] In some embodiments, additional anticancer agents include FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors Drugs, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 6 inhibitors, anti-HG F antibody, PI3 kinase inhibitor, AKT inhibitor, mTORC1 / 2 inhibitor, JAK / ST AT inhibitors, checkpoint 1 inhibitors, checkpoint 2 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, B7-H3 inhibitors, CTLA4 inhibitors, LAG-3 inhibitors, OX40 Agonists, focal adhesion kinase inhibitors, MAP kinase kinase inhibitors, and VEGF traps Selected from the group consisting of antibodies. In some embodiments, additional anticancer agents are CDK It is a 4 / 6 inhibitor.

[0020] In some embodiments, additional anticancer agents include SHR6390, trilaciclib (tr ilaciclib, lerociclib, AT7519M, Gina dinaciclib, ribociclib, abemasi Crib, palbociclib, everolimus, venetoclax, inavolicib ISIB, Pazopanib, Carboplatin, Cisplatin, Oxaliplatin, Paclita Kiseru, Epithilone B, Fulvestrant, Acorbife acolbifene, rasofoxifen, idoxifen, topotecan, pemel Trexed, erlotinib, tisilimmab, ipilimumab, vorinostat, etoposide gemcitabine, doxorubicin, 5'-deoxy-5-fluorouridine, vincris Chin, temozolomide, capecitabine, camptothecin, PD0325901, Irinoteca Tamoxifen, toremifene, anastrazole, Trozole, bevacizumab, goserelin acetate, raloxifene, alpelisib (alpe lisib), trastuzumab, trastuzumab emtansine, pertuzumab, trast Zumab deruxtecan (recombinant) (fam-trastuzumab deru xtecan-nxki) (Enharts), or eribulin (Halaven). In some embodiments, the additional anticancer agent is palbociclib.

[0021] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Regarding the treatment, the treatment includes a therapeutically effective dose of the compound of formula (I) administered orally once daily, and the compound of formula (I) but, [ka] [ka] [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs The subject is a somatic ER tumor mutation, and the subject includes at least one somatic ER tumor mutation. Several embodiments Therefore, breast cancer contains at least one somatic ER mutation.

[0022] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Regarding the treatment, the treatment includes a therapeutically effective dose of the compound of formula (I) administered orally once daily, and the compound of formula (I) However, (Ia), (Ib), (Ic), (Id), (Ie), (If), (I -g), (Ih), (Ii), or (Ij), or their pharmaceutically acceptable salts. These are solvates, polymorphs, isotopic derivatives, or prodrugs, and breast cancer is at least It also includes another somatic ER tumor mutation.

[0023] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Regarding breast cancer, the method involves at least one somatic ER tumor mutation, (i) A therapeutically effective amount of the compound of formula (Ia) or its pharmaceutically acceptable salt, solvate, poly Oral administration of the form, isotope derivative, or prodrug once daily, (ii) an oral dose of palbociclib once daily, comprising:

[0024] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Regarding breast cancer, the method involves at least one somatic ER tumor mutation, (i) A therapeutically effective amount of the compound of formula (Ic) or a pharmaceutically acceptable salt, solvate, poly(Ic) thereof. Oral administration of the form, isotope derivative, or prodrug once daily, (ii) an oral dose of palbociclib once daily, comprising:

[0025] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Regarding breast cancer, the method involves at least one somatic ER tumor mutation, (i) A therapeutically effective amount of the compound of formula (Ij) or its pharmaceutically acceptable salt, solvate, poly Oral administration of the form, isotope derivative, or prodrug once daily, (ii) an oral dose of palbociclib once daily, comprising:

[0026] In one embodiment, the present application relates to a method for treating breast cancer in a subpopulation of breast cancer patients, Based on the somatic ER tumor biomarker status of the target patient, breast cancer patients are selected for treatment. Choosing, A compound of formula (I) in a therapeutically effective amount, [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs The administration of , and the formula includes, Each R 1 and each R 2 They are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, S O2(R 5 ), selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl , R 3 and R 4 Both are hydrogen, or together with the carbon they are bonded to. It either forms a carbonyl group or Each R 5 and each R 6 These independently contain hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl Selected from the group consisting of, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, or 4. The therapeutically effective dose of the compound in formula (I) is approximately 10 mg to 1000 mg, and this invention relates to a method for determining this.

[0027] In one embodiment, the present application relates to a method for treating breast cancer in a subpopulation of breast cancer patients, Based on the somatic ER tumor biomarker status of the target patient, breast cancer patients are selected for treatment. Choosing, A compound of formula (I) in a therapeutically effective amount, [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs The administration of , and the formula includes, Each R 1 and each R 2 They are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, S O2(R 5 ), selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl , R 3 and R 4 Both are hydrogen, or together with the carbon they are bonded to. It either forms a carbonyl group or Each R 5 and each R 6 These independently contain hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl Selected from the group consisting of, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, or 4. The therapeutically effective dose of the compound in formula (I) is approximately 10 mg to 1000 mg, according to the method. .

[0028] In some embodiments, the method further includes the administration of at least one additional anticancer agent. In some embodiments, additional anticancer agents include FLT-3 inhibitors and VEGFR inhibitors. EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors Harmful agents, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 6 inhibitors, anti-H GF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / S TAT inhibitors, checkpoint 1 inhibitors, checkpoint 2 inhibitors, PD-1 inhibitors PD-L1 inhibitors, B7-H3 inhibitors, CTLA4 inhibitors, LAG-3 inhibitors, OX4 0 agonists, focal adhesion kinase inhibitors, MAP kinase kinase inhibitors, and VEGF inhibitors Selected from the group consisting of cyanoacrylate antibodies. In some embodiments, additional anticancer agents are CD It is a K4 / 6 inhibitor. Additional anticancer drugs include SHR6390, trilaciclib, and relosiclib. Rib, AT7519M, Dinacicrib, Ribociclib, Abemaciclib, Palbociclib Everolimus, venetoclax, inavolisib, pazopanib, carboplatin, cisplatin Latin, oxaliplatin, paclitaxel, epithilone B ), fulvestrant, acorbifen, rasofoxifen, idoxifen, topote Can, pemetrexed, erlotinib, tisilimmab, ipilimumab, vorinostat, Etoposide, gemcitabine, doxorubicin, 5'-deoxy-5-fluorouridine, Vincristine, temozolomide, capecitabine, camptothecin, PD0325901, Irinotecan, tamoxifen, toremifene, anastrazole, letrozole, beba Cizumab, goserelin acetate, raloxifene, alpelisib, trastuzumab, trast Zumab emtansine, pertuzumab, trastuzumab, deruxtecan (recombinant) (fam-trastuzumab deruxtecan-nxki) (Enhertz) , or eribulin (halaven). In some embodiments, additional anticancer agents are It is palbociclib.

[0029] In some embodiments, the administration of an additional anticancer agent is performed prior to the administration of the compound of formula (I). In some embodiments, the administration of an additional anticancer agent is the administration of a compound of formula (I). This is done at least 30 minutes prior. In some embodiments, the administration of additional anticancer drugs is performed according to the formula. This is performed after the administration of compound (I). In some embodiments, additional anticancer drugs are administered. This is performed at least 30 minutes after administration of the compound of formula (I).

[0030] In one embodiment, this application is for use in the treatment of breast cancer in subjects requiring treatment. The compound of formula (I), [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs Regarding the formula, Each R 1 and each R 2 They are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, SO 2(R 5 ), selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl groups. , R 3 and R 4 Both are hydrogen, or together with the carbon they are bonded to It either forms a carbonyl group, Each R 5 and each R 6 These are independently hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl Selected from the group consisting of, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, or 4. The subjects include at least one somatic ER tumor mutation, The therapeutically effective dose of the compound in formula (I) is approximately 10 mg to 1000 mg. Several implementations Morphologically, breast cancer contains at least one somatic ER mutation.

[0031] In one embodiment, this application is for use in the treatment of breast cancer in subjects requiring treatment. The compound of formula (I), [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs Regarding the formula, Each R 1 and each R 2 They are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, SO 2(R 5 ), selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl groups. , R 3 and R 4 Both are hydrogen, or together with the carbon they are bonded to It either forms a carbonyl group, Each R 5 and each R 6 These are independently hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl Selected from the group consisting of, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, or 4. Breast cancer containing at least one somatic ER tumor mutation, The therapeutically effective dose of the compound in formula (I) is approximately 10 mg to 1000 mg.

[0032] In one embodiment, this application is for use in the treatment of breast cancer in subjects requiring treatment. The compound of formula (I), [ka] [ka] [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs Regarding the subject, the subject includes at least one somatic ER tumor mutation. Several embodiments Therefore, breast cancer contains at least one somatic ER tumor mutation.

[0033] In one embodiment, this application is for use in the treatment of breast cancer in subjects requiring treatment. The compound of formula (I), [ka] [ka] [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs Regarding breast cancer, it is defined as having at least one somatic ER tumor mutation.

[0034] In one embodiment, the present application further comprises at least one additional anticancer agent, as disclosed herein. Compounds of formula (I) are used in the treatment of breast cancer in patients requiring treatment. Regarding combinations for achieving this.

[0035] In one embodiment, the present application relates to (i) a compound of formula (Ia), or a pharmaceutically acceptable salt thereof. (ii) palbociclib and, including, a combination for use in the treatment of patients requiring treatment for breast cancer. Regarding this, breast cancer includes at least one somatic ER tumor mutation.

[0036] In one embodiment, the present application relates to (i) a compound of formula (Ic), or a pharmaceutically acceptable salt thereof. (ii) palbociclib and, including, a combination for use in the treatment of patients requiring treatment for breast cancer. Regarding this, breast cancer includes at least one somatic ER tumor mutation.

[0037] In one embodiment, the present application relates to (i) a compound of formula (Ij), or a pharmaceutically acceptable salt thereof. (ii) palbociclib and, including, a combination for use in the treatment of patients requiring treatment for breast cancer. Regarding this, breast cancer includes at least one somatic ER tumor mutation.

[0038] In one aspect, this application relates to a pharmaceutical product for the treatment of breast cancer in a person requiring treatment. Compounds of formula (I), or pharmaceutically acceptable salts thereof, solvated, for use in the manufacture of the product. With respect to substances, polymorphs, isotopic derivatives, or prodrugs, breast cancer is at least one The compound of formula (I), including somatic ER tumor mutations, is effective in therapeutic doses of approximately 10 mg to 100 mg. It is 0 mg.

[0039] In one aspect, this application relates to a pharmaceutical product for the treatment of breast cancer in a person in need of treatment. A compound of formula (I) for use in the manufacture of the product, [ka] [ka] [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs Regarding this, the subjects include at least one somatic ER tumor mutation and the therapeutically effective dose of formula (I) The compound is present in amounts ranging from approximately 10 mg to approximately 1000 mg. In some embodiments, breast cancer is present in small amounts. It includes at least one somatic ER tumor mutation.

[0040] In one aspect, this application relates to a pharmaceutical product for the treatment of breast cancer in a person in need of treatment. A compound of formula (I) for use in the manufacture of the product, [ka] [ka] [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs Regarding breast cancer, the effective dose is given by formula (I) for at least one somatic ER tumor mutation. The amount of the compound ranges from approximately 10 mg to approximately 1000 mg.

[0041] In one embodiment, the present application further comprises at least one additional anticancer agent, as disclosed herein. Compounds of formula (I) are included for the treatment of breast cancer in patients requiring treatment. Regarding combinations for use in the manufacture of pharmaceuticals.

[0042] In one embodiment, the present application relates to (i) a compound of formula (Ia), or a pharmaceutically acceptable salt thereof. (ii) palbociclib and, including, used in the manufacture of pharmaceuticals for the treatment of breast cancer in patients requiring treatment. Regarding combinations for use, breast cancer contains at least one somatic ER tumor mutation. nothing.

[0043] In one embodiment, the present application relates to (i) a compound of formula (Ic), or a pharmaceutically acceptable salt thereof. (ii) palbociclib and, including, used in the manufacture of pharmaceuticals for the treatment of breast cancer in patients requiring treatment. Regarding combinations for use, breast cancer contains at least one somatic ER tumor mutation. nothing.

[0044] In one embodiment, the present application relates to (i) a compound of formula (Ij), or a pharmaceutically acceptable salt thereof. (ii) palbociclib and, including, used in the manufacture of pharmaceuticals for the treatment of breast cancer in patients requiring treatment. Regarding combinations for use, breast cancer contains at least one somatic ER tumor mutation. nothing.

[0045] In one aspect, this application relates to a pharmaceutical product for the treatment of breast cancer in a person requiring treatment. Compounds of formula (I), or pharmaceutically acceptable salts thereof, solvated, for use in the manufacture of the product. With respect to substances, polymorphs, isotopic derivatives, or prodrugs, breast cancer is at least one The compound of formula (I), including somatic ER tumor mutations, is effective in therapeutic doses of approximately 10 mg to 100 mg. It is 0 mg. [Brief explanation of the drawing]

[0046] This patent or application document includes at least one color-coded drawing. Including copies of this patent or patent application publication, upon application and payment of the necessary fees, It will be provided by Xu Ting.

[0047] [Figure 1] The results of tumor growth inhibition experiments (mean tumor volume (mm3) vs. time) associated with once-daily oral administration of compound (Ic) at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg compared to the vehicle are shown. Tumor growth inhibition (TGI) of 85%, 98%, and 124% were observed at doses of compound (Ic) of 3 mg / kg, 10 mg / kg, and 30 mg / kg, respectively, compared to the control group in the MCF7 xenograft model. [Figure 2] This is a Western blot experiment showing a reduction in ER in MCF7 xenograft tumors in response to administration of compound (Ic) at 3 mg / kg, 10 mg / kg, and 30 mg / kg (oral, once daily). [Figure 3] These are a pair of line graphs showing the mean concentration (ng / mL) of compound (Ic) over 24 hours post-administration on both day 1 and day 15 of the Phase I clinical trial. [Figure 4] This line graph shows the average trough concentration (ng / mL) of compound (Ic) throughout the entire Phase I clinical trial. [Figure 5] This graph and Western blot show the ERα-degrading activity of compound (Ic) after oral administration of 10 mg / kg three times a day. [Figure 6] The results of tumor growth inhibition experiments (mean tumor volume (mm3) vs. time) associated with once-daily oral administration of compound (Ic) at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg over 28 days, compared to the vehicle, are shown. Tumor growth inhibition (TGI) of 85%, 98%, and 124% were observed at doses of compound (Ic) of 3 mg / kg, 10 mg / kg, and 30 mg / kg, respectively, compared to the control group in the MCF7 xenograft model. [Figure 7]Graph showing that daily oral administration of compound (I-c) at 3 mg / kg, 10 mg / kg, and 30 mg / kg for 28 days reduces ERα levels by >94% compared to mice administered only vehicle. [Figure 8] Results of tumor growth inhibition experiments (mean tumor volume (mm3) vs. time) related to once-daily oral administration of compound (I-c) at a dose of 30 mg / kg for 28 days, compound (I-c) (30 mg / kg, oral, once daily for 28 days) and palbociclib (oral, once daily at 60 mg / kg for 28 days), fulvestrant (200 mg / kg, subcutaneous, twice weekly for 2 weeks), and fulvestrant (200 mg / kg, subcutaneous, twice weekly for 2 weeks) and palbociclib (oral, once daily at 60 mg / kg for 28 days), compared to vehicle. The combination of compound (I-c) and palbociclib resulted in significant tumor regression (131% TGI), compared to the single-agent compound (I-c) activity (105% TGI) in this model. In contrast, single-agent fulvestrant administered subcutaneously resulted in only slight tumor growth inhibition (46% TGI), while the combination of fulvestrant and palbociclib resulted in improved inhibition of tumor growth (108% TGI), but did not reach the level achieved with compound (I-c) and palbociclib. [Figure 9] Results of tamoxifen-resistant MCF7 xenograft growth inhibition experiments (mean tumor volume (mm3) vs. time) related to once-daily oral administration of compound (I-c) at a dose of 30 mg / kg for 28 days, palbociclib (60 mg / kg, oral, once daily for 28 days), compound (I-c) (30 mg / kg, oral, once daily for 28 days) and palbociclib (60 mg / kg, oral, once daily for 28 days), compared to vehicle. When compound (I-c) was combined with 60 mg / kg / day palbociclib, the combination regimen caused greater inhibition of tumor growth (113% TGI) compared to the palbociclib monotherapy group (91% TGI). [Figure 10]Graph showing the effect of administration of compound (I-c) (30 mg / kg, orally, once daily for 28 days, Figure 10) on in vivo ERα levels in tamoxifen-resistant MCF7 xenograft experiments. [Figure 11] Graph showing the effect of administration of compound (I-c) (30 mg / kg, orally, once daily for 28 days) and palbociclib (60 mg / kg, orally, once daily for 28 days) (Figure 11) on in vivo ERα levels in tamoxifen-resistant MCF7 xenograft experiments. [Figure 12] Graph showing the effect of administration of palbociclib (60 mg / kg, orally, once daily for 28 days, Figure 12) on in vivo ERα levels in tamoxifen-resistant MCF7 xenograft experiments. [Figure 13] Provide the results of several Western blot experiments comparing the in vitro ERα degradation activities of fulvestrant and compound (I-c) at various concentrations in several ER-positive breast cancer cell lines. [Figure 14] Graph showing that the half-maximal degradation concentration (DC50) of compound (I-c) in MCF7 cells is 0.9 nM. [Figure 15] Provide the results of several Western blot experiments comparing the in vitro ERα degradation activities of fulvestrant and compound (I-c) at various concentrations in clinically relevant ESR1 cell line variants Y537S and D538G. [Figure 16] Graph showing the relative expression of GREB1 and PR in experiments using fulvestrant and compound (I-c) compared to vehicle (DMSO). [Figure 17] Graph showing the effect of fulvestrant (100 mg / kg, once daily, subcutaneous administration) and compound (I-c) (30 mg / kg, once daily, oral administration) on uterine weight compared to vehicle. [Figure 18]This is a Western blot comparing the in vivo ERα-degrading activity of compound (Ic) (oral administration at 10 mg / kg for 3 days) with that of the vehicle in an MCF7 / E2 xenograft model. [Figure 19] The results of tumor growth inhibition experiments (mean tumor volume (mm3) vs. time) associated with oral administration of compound (Ic) once daily for 28 days at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg, compared to the vehicle, are shown. At doses of compound (Ic) of 3 mg / kg, 10 mg / kg, and 30 mg / kg, tumor growth inhibition (TGI) of 85%, 98%, and 124% were observed in the MCF7 / estradiol xenograft model compared to the control group, respectively. [Figure 20] The results of tumor growth inhibition (mean tumor volume (mm3) vs. time) experiments in the MCF7 / estradiol model are presented, compared to the vehicle, with oral administration of compound (Ic) at a dose of 30 mg / kg once daily for 28 days, fulvestrant (200 mg / kg subcutaneously, twice weekly for 2 weeks), compound (Ic) (oral, 30 mg / kg once daily for 28 days) and palbociclib (oral, 60 mg / kg once daily for 28 days), and fulvestrant (200 mg / kg subcutaneously, twice weekly for 2 weeks) and palbociclib (oral, 60 mg / kg once daily for 28 days). Compared to the monotherapy activity of compound (Ic) in this model (105% TGI), the combination of compound (Ic) and palbociclib resulted in significant tumor regression (131% TGI). In contrast, subcutaneously administered fulvestrant alone resulted in only slight inhibition of tumor growth (46% TGI), while the combination of fulvestrant and palbociclib showed improved inhibition of tumor growth (108% TGI), but this was not as high as the level achieved with compound (Ic) and palbociclib alone (131% TGI). [Figure 21]The results of tumor growth inhibition (mean tumor volume (mm3) vs. time) experiments in a tamoxifen-resistant MCF7 model are presented, compared to oral administration of compound (Ic) at a dose of 30 mg / kg once daily for 28 days, palbociclib (oral, 60 mg / kg once daily for 28 days), and compound (Ic) (oral, 30 mg / kg once daily for 28 days) and palbociclib (oral, 60 mg / kg once daily for 28 days). Compound (Ic) alone reduced tumor growth, but the combination of compound (Ic) and palbociclib resulted in improved inhibition of tumor growth compared to compound (Ic) alone (113% vs. 65%). [Figure 22] The results of a tumor growth inhibition (mean tumor volume (mm3) vs. time) experiment in an ESR1(Y537S)PDX model are shown, associated with oral administration of compound (Ic) once daily for 28 days at doses of 10 mg / kg or 30 mg / kg, or administration of fulvestrant (200 mg / kg, subcutaneously, twice weekly for 2 weeks). At either the 10 mg / kg or 30 mg / kg dose, compound (Ic) reduced tumor ERα levels more significantly than fulvestrant (79 / 88% vs. 63%) and resulted in improved inhibition of tumor growth compared to fulvestrant (99 / 106% vs. 62%). [Figure 23A] Figure 23A shows the growth inhibitory effect observed when compound (Ic) is combined with the CDK4 / 6 inhibitor abemaciclib in a luminescence-based MCF7 cell proliferation assay. The dose-response analysis (percentage change) of compound (Ic) on cell proliferation compared to vehicle control (DMSO) treated cells. [Figure 23B] Figure 23B shows the dose-response analysis (percentage change) of the effect of abemaciclib on cell proliferation compared to vehicle control (DMSO) treated cells. [Figure 23C] Figure 23C shows the dose-response shift of compound (Ic) upon the addition of abemaciclib. [Figure 23D] Figure 23D shows the efficacy analysis of drug combinations using the Bliss independence model. [Figure 23E] Figure 23E shows the efficacy analysis of drug combinations using the Loewe additivity model. [Figure 23F] Figure 23F shows the efficacy analysis of drug combinations using the Highest Single Agent model. [Figure 24A] Live-cell imaging analysis demonstrates the enhanced growth inhibitory effect of the combination of compound (Ic) and abemaciclib on MCF7 cells compared to either monotherapy alone. Figure 24A shows the changes in cell proliferation of drug-treated cells compared to control cells over 120 hours. [Figure 24B] Figure 24B shows the changes in cell proliferation of drug-treated cells compared to control cells at 120 hours. [Figure 25A] This shows the growth inhibitory effect observed when compound (Ic) is combined with the mTOR inhibitor everolimus in a luminescence-based MCF7 cell proliferation assay. Figure 25A shows the dose-response analysis (percentage change) of the effect of compound (Ic) on cell proliferation compared to vehicle control (DMSO) treated cells. [Figure 25B] Figure 25B shows the dose-response analysis (percentage change) of the effect of everolimus on cell proliferation compared to vehicle control (DMSO) treated cells. [Figure 25C] Figure 25C shows the dose-response shift of compound (Ic) upon the addition of everolimus. [Figure 25D] Figure 25D shows the efficacy analysis of drug combinations using the Bliss independence model. [Figure 25E] Figure 25E shows the efficacy analysis of drug combinations using the Löwe additive model. [Figure 25F] Figure 25F shows the efficacy analysis of drug combinations using the best monotherapy model. [Figure 26A]Demonstrates live cell imaging analysis showing enhanced growth inhibitory effects of the combination of compound (I-c) and everolimus in MCF7 (Figure 26A, Figure 26B) or T47D cells (Figure 26C, Figure 26D) against cells treated with any drug alone. Figure 26A shows the change in cell proliferation of drug-treated MCF7 cells against control cells over time. [Figure 26B] Figure 26B shows the change in cell proliferation of drug-treated MCF7 cells against control cells. [Figure 26C] Figure 26C shows the change in cell proliferation of drug-treated T47D cells against control cells over time. [Figure 26D] Figure 26D shows the change in cell proliferation of drug-treated T47D cells against control cells. [Figure 27A] Demonstrates live cell imaging analysis showing enhanced growth inhibitory effects of the combination of compound (I-c) and everolimus in T47D cells harboring ESR1 Y537S (Figure 27A, Figure 27B) or D538G (Figure 27C, Figure 27D) against cells treated with any drug alone. Figure 27A shows the change in cell proliferation of drug-treated MCF7 cells against control cells over time. [Figure 27B] Figure 27B shows the change in cell proliferation of drug-treated MCF7 cells against control cells. [Figure 27C] Figure 27C shows the change in cell proliferation of drug-treated T47D cells against control cells over time. [Figure 27D] Figure 27D shows the change in cell proliferation of drug-treated T47D cells against control cells. [Figure 28] Shows the results of the tumor growth inhibition (TGI) experiment (mean tumor volume (mm3) vs. time) related to once-daily oral administration of compound (I-c), everolimus, and the combination of compound (I-c) and everolimus, compared to vehicle. [Figure 29A]Figure 29A shows the enhanced growth inhibitory effect observed when compound (Ic) is combined with the PI3 kinase inhibitor alpelisib in luminescence-based MCF7 cell proliferation. The dose-response analysis (percentage change) of compound (Ic) on cell proliferation compared to vehicle control (DMSO) treated cells. [Figure 29B] Figure 29B shows the dose-response analysis (percentage change) of alpelisib's effect on cell proliferation compared to vehicle control (DMSO) treated cells. [Figure 29C] Figure 29C shows the dose-response shift of compound (Ic) upon the addition of alperisib. [Figure 29D] Figure 29D shows the efficacy analysis of drug combinations using the Bliss independence model. [Figure 29E] Figure 29E shows the efficacy analysis of drug combinations using the Löwe additive model. [Figure 29F] Figure 29F shows the efficacy analysis of drug combinations using the best monotherapy model. [Figure 30A] Live-cell imaging analyses demonstrate the enhanced growth inhibitory effect of the combination of compound (Ic) and alpelisib in MCF7 (Figures 30A, 30B) or T47D cells (Figures 30C, 30D) compared to cells treated with either drug alone. Figure 30A shows the changes in cell proliferation of drug-treated MCF7 cells over time compared to control cells. [Figure 30B] Figure 30B shows the changes in cell proliferation of drug-treated MCF7 cells compared to control cells at 120 hours. [Figure 30C] Figure 30C shows the changes in cell proliferation of drug-treated T47D cells over time compared to control cells. [Figure 30D] Figure 30D shows the changes in cell proliferation of drug-treated T47D cells compared to control cells at 120 hours. [Figure 31] The results of tumor growth inhibition (TGI) associated with the administration of compound (Ic), alpelisib, and compound (Ic) plus, compared to the vehicle, are shown. [Figure 32A]This study demonstrates the enhanced growth inhibitory effect observed by combining the PI3 kinase inhibitor inavolicib (GDC-0077) with compound (Ic) in a luminescence-based MCF7 cell proliferation assay. Figure 32A shows the dose-response analysis (percentage change) of the effect of compound (Ic) on cell proliferation compared to vehicle control (DMSO) treated cells. [Figure 32B] Figure 32B shows the dose-response analysis (percentage change) of the effect of GDC-0077 on cell proliferation compared to vehicle control (DMSO) treated cells. [Figure 32C] Figure 32C shows the dose-response shift of compound (Ic) upon addition of GDC-0077. [Figure 32D] Figure 32D shows the efficacy analysis of drug combinations using the Bliss independence model. [Figure 32E] Figure 32E shows the efficacy analysis of drug combinations using the Löwe additive model. [Figure 32F] Figure 32F shows the efficacy analysis of drug combinations using the best monotherapy model. [Figure 33A] Live-cell imaging analyses demonstrate the enhanced growth inhibitory effect of the combination of compound (Ic) and GDC-0077 in MCF7 (Figures 33A, 33B) or T47D cells (Figures 33C, 33D) compared to cells treated with either drug alone. Figure 33A shows the changes in cell proliferation of drug-treated MCF7 cells over time compared to control cells. [Figure 33B] Figure 33B shows the changes in cell proliferation of drug-treated MCF7 cells compared to control cells. [Figure 33C] Figure 33C shows the changes in cell proliferation of drug-treated T47D cells over time compared to control cells. [Figure 33D] Figure 33D shows the changes in cell proliferation of drug-treated T47D cells compared to control cells. [Figure 34A]This study demonstrates the enhanced growth inhibitory effect observed by combining the BCL2 inhibitor venetoclax with compound (Ic) in a luminescence-based MCF7 cell proliferation assay. Figure 34A shows the dose-response analysis (percentage change) of compound (Ic) on cell proliferation compared to vehicle control (DMSO) treated cells. [Figure 34B] Figure 34B shows the dose-response analysis (percentage change) of the effect of venetoclax on cell proliferation compared to vehicle control (DMSO) treated cells. [Figure 34C] Figure 34C shows the dose-response shift of compound (Ic) upon the addition of venetoclax. [Figure 34D] Figure 34D shows the efficacy analysis of drug combinations using the Bliss independence model. [Figure 34E] Figure 34E shows the efficacy analysis of drug combinations using the Löwe additive model. [Figure 34F] Figure 34F shows the efficacy analysis of drug combinations using the best monotherapy model. [Figure 35A] This shows live-cell imaging analysis demonstrating the enhanced growth inhibitory effects of compound (Ic), venetoclax, and combinations on cell proliferation in DMSO-treated (control) cells over a 120-hour (5-day) period. Figure 35A shows the changes in cell proliferation of drug-treated cells compared to control cells over time. [Figure 35B] Figure 35B shows the changes in cell proliferation of drug-treated cells compared to control cells.

[0048] Sequence Listing: All references to amino acid mutations in the estrogen receptor are provided below. Numbering is assigned to column number 1. Sequence Listing 1 JPEG2026136114000025.jpg122145 [Modes for carrying out the invention]

[0049] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Regarding the method, the therapeutically effective amount of the compound of formula (I) is [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs The formula includes administering the substance to the target, Each R 1 and each R 2 They are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, S O2(R 5 ), selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl , R 3 and R 4 Both are hydrogen, or together with the carbon they are bonded to. It either forms a carbonyl group or Each R 5 and each R 6 These independently contain hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl Selected from the group consisting of, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, or 4.

[0050] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Regarding the subject, the study includes at least one somatic ER tumor mutation, and the method involves formulating the therapeutically effective dose. (I) Compound, [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs The formula includes administering the substance to the target, Each R 1and each R 2 They are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, S O2(R 5 ), selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl , R 3 and R 4 Both are hydrogen, or together with the carbon they are bonded to. It either forms a carbonyl group or Each R 5 and each R 6 These independently contain hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl Selected from the group consisting of, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, or 4. In some embodiments, breast cancer is at least It also includes another somatic ER mutation.

[0051] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Regarding breast cancer, the method involves at least one somatic ER tumor mutation, and the therapeutically effective dose Compound of formula (I), [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs The formula includes administering the substance to the target, Each R 1 and each R 2 They are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, S O2(R 5 ), selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl , R 3and R 4 Both are hydrogen, or together with the carbon they are bonded to. It either forms a carbonyl group or Each R 5 and each R 6 These independently contain hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl Selected from the group consisting of, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, or 4.

[0052] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Regarding breast cancer, if the patient has at least one somatic ER tumor mutation, the method is effective in providing a therapeutic dose. The treatment involves administering a compound of formula (I) to a target, and the therapeutically effective amount of the compound of formula (I) is approximately 1 The range is 0 mg to approximately 1000 mg.

[0053] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Regarding the compound of formula (I) for use, breast cancer is at least one somatic ER tumor. This includes mutations. In some embodiments, the method targets a therapeutically effective amount of the compound of formula (I). This includes administering the drug.

[0054] In one embodiment, this application is for use in the treatment of breast cancer in subjects requiring treatment. Regarding the compound of formula (I), breast cancer contains at least one somatic ER tumor mutation. .

[0055] In one embodiment, this application is for use in the treatment of breast cancer in subjects requiring treatment. Regarding the compound of formula (I), breast cancer contains at least one somatic ER tumor mutation. .

[0056] In some embodiments, the subjects are D538G, E380Q, V422del, and L It includes at least one somatic ER tumor mutation selected from the group consisting of 536P. In one embodiment, breast cancer is D538G, E380Q, V422del, and L53 It includes at least one somatic ER tumor mutation selected from the group consisting of 6P.

[0057] In some embodiments, the breast cancer is ER+ and HER2-.

[0058] In some embodiments, breast cancer is metastatic or locally advanced.

[0059] Several embodiments, each R 1 and each R 2 These are independently of the halo and OR 5 A group consisting of It will be selected.

[0060] In some embodiments, R 3 and R 4 Both are hydrogen.

[0061] In some embodiments, R 3 and R 4は , together with the carbons to which they are bonded It forms a carbonyl group.

[0062] In some embodiments, m and n are each 0. Each of the values ​​of m and n is 1. In some embodiments, one of m and n is 0, and the other is 0. The value of m is 1. For example, in some embodiments, m is 0 and n is 1. In the application form, m is 0 and n is 1.

[0063] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs It is.

[0064] In some embodiments, the method involves administering a therapeutically effective amount of a compound of formula (I) to a target, or the same This includes administering pharmaceutically acceptable salts, solvates, polymorphs, or isotopic derivatives. .

[0065] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Compounds of formula (I) for use, or pharmaceutically acceptable salts, solvates, polymorphs thereof, Alternatively, with respect to isotopic derivatives, the subject includes at least one somatic ER tumor mutation. In some embodiments, the method involves administering a therapeutically effective amount of a compound of formula (I) or a drug thereof to a target. This includes administering a scientifically acceptable salt, solvate, polymorph, or isotopic derivative. In some embodiments, the compound of formula (I) is administered orally to the subject. Morphologically, breast cancer contains at least one somatic ER mutation.

[0066] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Compounds of formula (I) for use, or pharmaceutically acceptable salts, solvates, polymorphs thereof, Alternatively, with respect to isotopic derivatives, breast cancer includes at least one somatic ER tumor mutation. In some embodiments, the method involves administering a therapeutically effective amount of a compound of formula (I) to a target, or the same This includes administering pharmaceutically acceptable salts, solvates, polymorphs, or isotopic derivatives. In some embodiments, the compound of formula (I) is administered orally to the subject.

[0067] In one embodiment, this application is for use in the treatment of breast cancer in subjects requiring treatment. Compounds of formula (I), or pharmaceutically acceptable salts, solvates, polymorphs thereof, or the same Regarding the topical derivatives, the subject includes at least one somatic ER tumor mutation. In some embodiments, the compound of formula (I) is administered orally to the subject. In some embodiments, Breast cancer contains at least one somatic ER mutation.

[0068] In one embodiment, this application is for use in the treatment of breast cancer in subjects requiring treatment. Compounds of formula (I), or pharmaceutically acceptable salts, solvates, polymorphs thereof, or the same Regarding the topological derivatives, breast cancer contains at least one somatic ER tumor mutation. In this embodiment, the compound of formula (I) is administered orally to the subject.

[0069] In some embodiments, a therapeutically effective amount of the compound of formula (I) is administered once daily, twice daily, or once daily. It is administered to the subject three or four times a day. In some embodiments, the formula for the therapeutically effective dose is ( Compound I) is administered to the subject once daily. In some embodiments, the formula for the therapeutically effective dose is used. The compound in (I) is administered to the subject all at once, or in units of two, three, or four doses. It is administered according to the prescribed dose.

[0070] In some embodiments, the therapeutically effective dose of the compound of formula (I) is approximately 3 mg, approximately 5 mg, approximately The dosage is 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, or approximately 40 mg.

[0071] In some embodiments, the therapeutically effective dose of the compound of formula (I) is approximately 10 mg, approximately 15 mg The dosage is approximately 20 mg, 25 mg, 30 mg, or 40 mg.

[0072] In some embodiments, the therapeutically effective dose of the compound of formula (I) is approximately 10 mg to approximately 1000 mg It is mg.

[0073] In some embodiments, the therapeutically effective dose of the compound of formula (I) is approximately 20 mg to approximately 700 mg. It is g.

[0074] In some embodiments, the therapeutically effective dose of the compound of formula (I) is approximately 30 mg to approximately 500 mg. It is g.

[0075] In some embodiments, the therapeutically effective dose of the compound of formula (I) is approximately 30 mg to approximately 120 mg. It is g.

[0076] In some embodiments, the therapeutically effective amount of the compound of formula (I) is about 10 to about 40 mg, about 20 to about 50 mg, about 30 to about 60 mg, about 40 to about 70 mg, about 50 to about 80 mg, about 60~90mg, 70~100mg, 80~110mg, 90~120m g, about 100 to about 130 mg, about 110 to about 140 mg, about 120 to about 150 mg, about 1 30~160mg, 140~170mg, 150~180mg, 160~170mg 190mg, about 170~200mg, about 180~210mg, about 190~220m g, about 200 to about 230 mg, about 210 to about 240 mg, about 220 to about 250 mg, about 2 30~260mg, 240~270mg, 250~280mg, 260~270mg 290mg, about 270~300mg, about 280~310mg, about 290~320m g, about 300 to about 330 mg, about 310 to about 340 mg, about 320 to about 350 mg, about 3 30 to about 360 mg, about 340 to about 370 mg, about 350 to about 380 mg, about 360 to about 390 mg, or about 370 to about 400 mg.

[0077] In some embodiments, a therapeutically effective amount of the compound of formula (I) is greater than about 3,500 ng·hour / mL, greater than about 3,600 ng·hour / mL, greater than about 3,700 ng·hour / mL, greater than about 3, 800 ng·hour / mL, greater than about 3,900 ng·hour / mL, greater than about 4,000 ng·hour / mL, greater than about 4,100 ng·hour / mL, greater than about 4,200 ng·hour / mL, greater than about 4, 300 ng·hour / mL, greater than about 4,400 ng·hour / mL, greater than about 4,500 ng·hour / mL, greater than about 4,600 ng·hour / mL, greater than about 4,700 ng·hour / mL, greater than about 4, 800 ng·hour / mL, greater than about 4,900 ng·hour / mL, or greater than about 5,000 ng· hour / mL of the average AUC on day 15 TAU to provide.

[0078] In some embodiments, a therapeutically effective amount of the compound of formula (I) is greater than about 3,500 ng·hour / mL and less than about 4,000 ng·hour / mL of the average AUC on day 15 TAU to provide . In some embodiments, a therapeutically effective amount of the compound of formula (I) is greater than about 3,600 ng·hour / mL and less than about 4,100 ng·hour / mL of the average AUC on day 15 TAU to provide . In some embodiments, a therapeutically effective amount of the compound of formula (I) is greater than about 3,700 ng·hour / mL and less than about 4,200 ng·hour / mL of the average AUC on day 15 TAU to provide 。In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a 15-day mean AUC greater than about 3,800 ng·hour / mL and less than about 4,300 ng·hour / mL TAU and 。In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a 15-day mean AUC greater than about 3,900 ng·hour / mL and less than about 4,400 ng·hour / mL TAU and 。In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a 15-day mean AUC greater than about 4,000 ng·hour / mL and less than about 4,500 ng·hour / mL TAU and 。In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a 15-day mean AUC greater than about 4,100 ng·hour / mL and less than about 4,600 ng·hour / mL TAU and 。In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a 15-day mean AUC greater than about 4,200 ng·hour / mL and less than about 4,700 ng·hour / mL TAU and 。In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a 15-day mean AUC greater than about 4,300 ng·hour / mL and less than about 4,800 ng·hour / mL TAU and 。In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a 15-day mean AUC greater than about 4,400 ng·hour / mL and less than about 4,900 ng·hour / mL TAU and 。In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a 15-day mean AUC greater than about 4,500 ng·hour / mL and less than about 5,000 ng·hour / mL TAU and 。In some embodiments, a therapeutically effective amount of a compound of formula (I) provides a 15-day mean AUC greater than about 4,600 ng·hour Average AUC on day 15 greater than / mL and less than approximately 5,100 ng·hour / mL TAU Bringing about In some embodiments, a therapeutically effective amount of the compound of formula (I) is approximately 4,700 ng·hour. Average AUC on day 15 greater than / mL and less than approximately 5,200 ng·hour / mL TAU Bringing about In some embodiments, a therapeutically effective amount of the compound of formula (I) is approximately 4,800 ng·hour. Average AUC on day 15 greater than / mL and less than approximately 5,300 ng·hour / mL TAU Bringing about In some embodiments, a therapeutically effective amount of the compound of formula (I) is approximately 4,900 ng·hour. Average AUC on day 15 greater than / mL and less than approximately 5,400 ng·hour / mL TAU Bringing about In some embodiments, a therapeutically effective amount of the compound of formula (I) is approximately 5,000 ng·hour. Average AUC on day 15 greater than / mL and less than approximately 5,500 ng·hour / mL TAU Bringing about .

[0079] In some embodiments, a therapeutically effective amount of the compound of formula (I) is approximately 4,000 ng·hour. Average AUC on day 15 greater than / mL and less than approximately 4,200 ng·hour / mL TAU Bringing about In some embodiments, a therapeutically effective amount of the compound of formula (I) is approximately 3,900 ng·hour. Average AUC on day 15 greater than / mL and less than approximately 4,300 ng·hour / mL TAU Bringing about In some embodiments, a therapeutically effective amount of the compound of formula (I) is approximately 3,800 ng·hour. Average AUC on day 15 greater than / mL and less than approximately 4,400 ng·hour / mL TAU Bringing about In some embodiments, a therapeutically effective amount of the compound of formula (I) is approximately 3,700 ng·hour. Average AUC on day 15 greater than / mL and less than approximately 4,500 ng·hour / mLTAU Bringing about In some embodiments, a therapeutically effective amount of the compound of formula (I) is approximately 3,600 ng·hour. Average AUC on day 15 greater than / mL and less than approximately 4,600 ng·hour / mL TAU Bringing about .

[0080] In some embodiments, the therapeutically effective amount of the compound of formula (I) is about 200 ng / mL, approximately 205ng / mL, approx. 210ng / mL, approx. 215ng / mL, approx. 220ng / mL, approx. 225ng / mL, approx. 230ng / mL, approx. 235ng / mL, approx. 240ng / mL, approx. Average C15 level of 245 ng / mL or over approximately 250 ng / mL max It brings about.

[0081] In some embodiments, the therapeutically effective amount of the compound of formula (I) is greater than approximately 200 ng / mL. Average C levels on day 15 were less than approximately 220 ng / mL max This brings about... In some embodiments... The therapeutically effective dose of the compound of formula (I) is greater than approximately 205 ng / mL and less than approximately 225 ng / mL. Day 15 average C max This results in a therapeutically effective amount of formula (I) The compound had an average C15 level greater than approximately 210 ng / mL and less than approximately 230 ng / mL. max of In some embodiments, a therapeutically effective amount of the compound of formula (I) is approximately 215 ng / Average C15 greater than mL and less than approximately 235 ng / mL max This brings about several implementations. In terms of morphology, the therapeutically effective dose of the compound of formula (I) is greater than approximately 220 ng / mL and approximately 240 ng / mL Less than mL of average C on day 15. max This brings about a therapeutic effective dose formula in some embodiments. (I) Compound (I) had an average C15-day concentration greater than approximately 225 ng / mL and less than approximately 245 ng / mL. max This results in a therapeutically effective amount of the compound of formula (I) of about 23 Average C on day 15: greater than 0 ng / mL and less than approximately 250 ng / mL max It brings about several. In that embodiment, the therapeutically effective amount of the compound of formula (I) is greater than about 235 ng / mL and about 25 Average C levels on day 15 were less than 5 ng / mL. max This brings about treatment. In some embodiments, treatment is For compounds with efficacy formula (I), the effective dose is greater than approximately 240 ng / mL and less than approximately 260 ng / mL for 15 days. eye average C max In some embodiments, a therapeutically effective amount of compound of formula (I) , average C15th day C15th day C15th day C14 max Bringing about In some embodiments, the therapeutically effective amount of the compound of formula (I) is greater than approximately 250 ng / mL. Average C15th day less than approximately 270 ng / mL max It brings about.

[0082] In some embodiments, the therapeutically effective amount of the compound of formula (I) is greater than approximately 214 ng / mL. Average C15th day less than approximately 236 ng / mL max This brings about... In some embodiments... The therapeutically effective dose of the compound of formula (I) is greater than approximately 213 ng / mL and less than approximately 237 ng / mL. Day 15 average C max This results in a therapeutically effective amount of formula (I) The compound had an average C15 level greater than approximately 212 ng / mL and less than approximately 238 ng / mL. max of In some embodiments, a therapeutically effective amount of the compound of formula (I) is approximately 211 ng / Average C on day 15 greater than mL and less than approximately 239 ng / mL max This brings about several implementations. In terms of morphology, the therapeutically effective dose of the compound of formula (I) is greater than approximately 210 ng / mL and approximately 240 ng / mL Less than mL of average C on day 15. max This brings about a therapeutic effective dose formula in some embodiments. Compound (I) had an average C15-day concentration greater than approximately 205 ng / mL and less than approximately 245 ng / mL. max This results in a therapeutically effective amount of the compound of formula (I) of about 20 Average C on day 15: greater than 0 ng / mL and less than approximately 250 ng / mL max It brings about.

[0083] In some embodiments, the therapeutically effective amount of the compound of formula (I) is greater than approximately 223 ng / mL. Average C15th day less than approximately 225 ng / mL max This brings about... In some embodiments... The therapeutically effective dose of the compound of formula (I) is greater than approximately 222 ng / mL and less than approximately 226 ng / mL. Day 15 average C max This results in a therapeutically effective amount of formula (I) The compound had an average C15 level greater than approximately 221 ng / mL and less than approximately 227 ng / mL. max of In some embodiments, a therapeutically effective amount of the compound of formula (I) is approximately 220 ng / Average C15 greater than mL and less than approximately 228 ng / mL max This brings about several implementations. In terms of morphology, the therapeutically effective dose of the compound of formula (I) is greater than approximately 219 ng / mL and approximately 229 ng / mL Less than mL of average C on day 15. max This brings about a therapeutic effective dose formula in some embodiments. Compound (I) had an average C15-day concentration greater than approximately 218 ng / mL and less than approximately 230 ng / mL. max This results in a therapeutically effective amount of the compound of formula (I) of about 21 Average C levels on day 15 greater than 7 ng / mL and less than approximately 231 ng / mL maxIt brings about several. In that embodiment, the therapeutically effective amount of the compound of formula (I) is greater than approximately 216 ng / mL and approximately 23 Average C levels on day 15 were less than 2 ng / mL. max This brings about treatment. In some embodiments, treatment is For compounds with efficacy formula (I), the effective dose is greater than approximately 215 ng / mL and less than approximately 233 ng / mL for 15 days. eye average C max In some embodiments, a therapeutically effective amount of compound of formula (I) , average C15 between approximately 214 ng / mL and approximately 234 ng / mL max Bringing about .

[0084] In some embodiments, the compound of formula (I) is formulated as a tablet. In this embodiment, the tablet contains a compound of formula (I), and optionally the following emulsifiers, surfactants. It contains one or more of the following: a property agent, a binder, a disintegrant, a flow enhancer, and a lubricant. In the application form, the emulsifier is hypromellose. In some embodiments, the surfactant is , vitamin E polyethylene glycol succinate. In some embodiments, The mixture is microcrystalline cellulose or lactose monohydrate. In some embodiments, The disintegrant is croscarmellose sodium. In some embodiments, a flow enhancer is used. It is silicon dioxide. In some embodiments, the lubricant is stearyl sodium fumarate. It is a lye. In some embodiments, the subject requiring treatment is in a feeding state. In some embodiments, the subject requiring treatment is in a fasting state.

[0085] In one embodiment, this application relates to a method for treating breast cancer in a person in need of treatment for breast cancer. The subject is to administer a therapeutically effective amount of the compound of formula (I) as defined herein. This includes administering a therapeutically effective dose of at least one additional anticancer drug to a subject in need of treatment. Regarding methods, which further include the following.

[0086] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. With respect to a therapeutically effective amount of a compound of formula (I) as defined herein for use, the method is to treat Further includes administering an effective dose of at least one additional anticancer drug to the subject in need of treatment. In some embodiments, the method involves administering a therapeutically effective amount of the compound of formula (I) to the target. This includes.

[0087] In one embodiment, this application is for use in the treatment of breast cancer in subjects requiring treatment. With respect to the compounds of formula (I) as defined herein in terms of therapeutic effective amounts, the treatment is performed in terms of the therapeutic effective amount of This further includes administering at least one additional anticancer drug to patients requiring treatment.

[0088] In one embodiment, this application relates to a compound of formula (I) as defined herein and to the treatment of breast cancer. A therapeutically effective dose of at least one additional anticancer drug for the treatment of the target subject and Regarding combinations that include ,

[0089] In some embodiments, at least one additional anticancer agent is an FLT-3 inhibitor, V EGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 6 inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors Drugs, JAK / STAT inhibitors, checkpoint 1 inhibitors, checkpoint 2 inhibitors, Focal adhesion kinase inhibitors, MAP kinase kinase inhibitors, or VEGF trap antibodies be.

[0090] In some embodiments, at least one additional anticancer agent is a CDK4 / 6 inhibitor. be.

[0091] In some embodiments, at least one additional anticancer agent is SHR6390, Tri Lasiclib, Lerocilib, AT7519M, Dinacilib, Ribociclib, Abemacic Rib, palbociclib, everolimus, pazopanib, carboplatin, cisplatin, O Xaliplatin, paclitaxel, epithilone B, fluvialisin Strand, acorbifen, rasofoxifen, idoxifen, topotecan, pemel Trexed, erlotinib, tisilimmab, ipilimumab, vorinostat, etoposide gemcitabine, doxorubicin, 5'-deoxy-5-fluorouridine, vincris Chin, temozolomide, capecitabine, camptothecin, PD0325901, Irinoteca N, tamoxifen, toremifene, anastrazole, letrozole, bevacizumab, Goserelin acetate, raloxifene, alpelisib, trastuzumab, trastuzumab M Tansine, pertuzumab, trastuzumab, deruxtecan (recombinant) (fam- trastuzumab deruxtecan-nxki) (Enharts), or Eli It is Brin (Halaven).

[0092] In some embodiments, at least one additional anticancer agent is SHR6390, Tri Lasiclib, Lerocilib, AT7519M, Dinacilib, Ribociclib, Abemacic Selected from rib and palbociclib.

[0093] In some embodiments, at least one additional anticancer agent is palbociclib. In some embodiments, at least one additional anticancer agent is abemaciclib. In some embodiments, at least one additional anticancer agent is everolimus. In some embodiments, at least one additional anticancer agent is an alpericib. In some embodiments, at least one additional anticancer agent is GDC-0077. In some embodiments, at least one additional anticancer agent is venetoclax.

[0094] In some embodiments, the administration of an additional anticancer agent is performed prior to the administration of the compound of formula (I). It breaks.

[0095] In some embodiments, the administration of additional anticancer agents is less than the administration of the compound of formula (I). Both take place 30 minutes prior.

[0096] In some embodiments, the administration of an additional anticancer agent is carried out after the administration of the compound of formula (I). It breaks.

[0097] In some embodiments, the administration of additional anticancer agents is less than the administration of the compound of formula (I). Both will take place in 30 minutes.

[0098] In some embodiments, this includes administering a therapeutically effective amount of the compound of formula (I) to the target. Treatment for breast cancer requiring treatment, further comprising administering a therapeutically effective dose of palbociclib. In the method used to administer the treatment to the subject, a therapeutically effective dose of palbociclib is administered once daily to the subject. In some embodiments, the therapeutically effective dose of palbociclib is 60 mg, 75 mg The dose is 100 mg or 125 mg. In some embodiments, palbociclib is 1 It is administered once a day for a maximum of 21 consecutive days, after which treatment is discontinued for a maximum of 7 consecutive days. The cycle of treatment with rubociclib and subsequent discontinuation of treatment is 1, 2, 3, 4, 5 The process is repeated a certain number of times or more. In some embodiments, the compound of formula (I) It is administered once a day for a maximum of 21 consecutive days, and then treatment is discontinued for a maximum of 7 consecutive days. The cycle of treatment with the compound of formula (I) followed by discontinuation of treatment was 1, 2, or 3 times. This is repeated four, five, or more times. In some embodiments, formula (I) The administration of the compound and palbociclib to patients requiring treatment should be performed when the patient is able to feed. This is done when... In some embodiments, the compound of formula (I) and palbociclib, Administration to patients requiring treatment should be done while the patient is fasting.

[0099] In one aspect, the present application relates to a method for treating breast cancer in subjects requiring treatment. The subject has at least one somatic ER tumor mutation, and the effective therapeutic dose is given by formula (I) Compounds, or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs thereof. Regarding methods comprising once-daily oral administration of a body, isotope derivative, or prodrug, the formula (I) The compound is selected from the group consisting of the following: [ka] [ka] [ka] In some embodiments, breast cancer includes at least one somatic ER tumor mutation.

[0100] In one embodiment, this application relates to treating metastatic breast cancer in subjects requiring treatment. A method wherein breast cancer includes at least one somatic ER tumor mutation and a therapeutically effective dose Compounds of formula (I), or pharmaceutically acceptable salts, enantiomers, stereoisomers, or solvents thereof. A method comprising once-daily oral administration of a dimethyl product, polymorph, isotopic derivative, or prodrug. Regarding this, the compound of formula (I) is selected from the group consisting of the following: [ka] [ka] [ka]

[0101] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Compounds of formula (I), or pharmaceutically acceptable salts, enantiomers thereof, for use. Regarding stereoisomers, solvates, polymorphs, isotopic derivatives, or prodrugs, breast cancer The method includes at least one somatic ER tumor mutation, and the combination of formula (I) in a therapeutically effective amount A substance, or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, The compound comprises an isotope derivative or prodrug administered orally once daily, and is a compound of formula (I). However, (Ia), (Ib), (Ic), (Id), (Ie), (If), (I Selected from the group consisting of (g), (Ih), and (Ii).

[0102] In one embodiment, this application is for use in the treatment of breast cancer in subjects requiring treatment. The compound of formula (I), or its pharmaceutically acceptable salts, enantiomers, or stereoisomers. Regarding solvates, polymorphs, isotopic derivatives, or prodrugs, breast cancer is at least It also includes one somatic ER tumor mutation, and the treatment involves a therapeutically effective dose of a compound of formula (I), or Pharmacologically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, and isotope derivatives of [the substance]. The body or prodrug is administered orally once daily, and the compound of formula (I) is (I- a), (Ib), (Ic), (Id), (Ie), (If), (Ig), ( Selected from the group consisting of (Ih) and (Ii).

[0103] In some embodiments, the compound of formula (I) is the compound of formula (Ic).

[0104] In some embodiments, the subjects are D538G, E380Q, V422del, and L It includes at least one somatic ER tumor mutation selected from the group consisting of 536P. In one embodiment, breast cancer is D538G, E380Q, V422del, and L53 It includes at least one somatic ER tumor mutation selected from the group consisting of 6P.

[0105] In some embodiments, the breast cancer is ER+ and HER2-.

[0106] In some embodiments, breast cancer is metastatic or locally advanced.

[0107] In some embodiments, a therapeutically effective amount of the compound of formula (I) is administered to the subject all at once. It is administered either in one dose or in two, three, or four unit doses.

[0108] In some embodiments, the therapeutically effective dose of the compound of formula (I) is approximately 30 mg to approximately 1000 mg. It is mg.

[0109] In some embodiments, the therapeutically effective amount of the compound of formula (I) is about 10 to about 40 mg, about 20 to about 50 mg, about 30 to about 60 mg, about 40 to about 70 mg, about 50 to about 80 mg, about 60~90mg, 70~100mg, 80~110mg, 90~120m g, about 100 to about 130 mg, about 110 to about 140 mg, about 120 to about 150 mg, about 1 30~160mg, 140~170mg, 150~180mg, 160~170mg 190mg, about 170~200mg, about 180~210mg, about 190~220m g, about 200 to about 230 mg, about 210 to about 240 mg, about 220 to about 250 mg, about 2 30~260mg, 240~270mg, 250~280mg, 260~270mg 290mg, about 270~300mg, about 280~310mg, about 290~320m g, about 300 to about 330 mg, about 310 to about 340 mg, about 320 to about 350 mg, about 3 30 to about 360 mg, about 340 to about 370 mg, about 350 to about 380 mg, about 360 to about It is 390 mg, or approximately 370 to 400 mg.

[0110] In some embodiments, the compound of formula (I) is formulated as a tablet.

[0111] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. The method involves administering a therapeutically effective amount of the compound of formula (I) to the target, and the compound of formula (I) The compound is represented by formulas (Ia), (Ib), (Ic), (Id), and (Ie). Compounds of formula (If), formula (Ig), formula (Ih), formula (Ii), or their pharmaceutically appropriate Acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopic derivatives, or It is a prodrug, and the method involves administering at least one additional anticancer drug in a therapeutically effective dose. Furthermore, the anticancer drugs include FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c - Met inhibitors, PARP inhibitors, CDK4 / 6 inhibitors, anti-HGF antibodies, PI3 kinases Inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, checkpot Int1 inhibitors, checkpoint 2 inhibitors, focal adhesion kinase inhibitors, MAP kinases Kinase inhibitors, VEGF trap antibodies, SHR6390, trilaciclib, rerocycliclib B, AT7519M, ginaciclib, ribociclib, abemaciclib, palbociclib, Everolimus, venetoclax, inavolicib (GDC-0077), pazopanib, kale Voplatin, cisplatin, oxaliplatin, paclitaxel, epithilon B (epi thilone B), fulvestrant, acorbifen, rasofoxifen, id Xiphen, Topotecan, Pemetrexed, Erlotinib, Tisilimumab, Ipilimumab , vorinostat, etoposide, gemcitabine, doxorubicin, 5'-deoxy-5- Fluorouridine, vincristine, temozolomide, capecitabine, camptothecin, P D0325901, Irinotecan, Tamoxifen, Toremifene, Anastrazole, Letrozole, bevacizumab, goserelin acetate, raloxifene, alpelisib, tras Tuzumab, trastuzumab emtansine, pertuzumab, trastuzumab derxteca (Genetically modified) (fam-trastuzumab deruxtecan-nxk i) Enhertz, or Eribulin (Halaven).

[0112] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Regarding the compound of formula (I) for use, the method targets a therapeutically effective amount of the compound of formula (I). This includes administering a compound of formula (I) to formula (Ia), formula (Ib), and formula (Ic ), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih), formula (I -i) Compounds, or pharmaceutically acceptable salts, enantiomers, stereoisomers, and solvations thereof The substance, polymorph, isotope derivative, or prodrug is a substance, polymorph, isotope derivative, or prodrug, and the method involves a small therapeutically effective dose. Both also include the administration of one additional anticancer drug, the anticancer drug being an FLT-3 inhibitor, VEGF R inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bc L-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 6 inhibitors Drugs, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, J AK / STAT inhibitors, checkpoint 1 inhibitors, checkpoint 2 inhibitors, focal point MAP kinase inhibitors, MAP kinase kinase inhibitors, VEGF trap antibodies, SHR63 90, Trilaciclib, Lerocilib, AT7519M, Dinacilib, Ribociclib, Abemaciclib, palbociclib, everolimus, venetoclax, inavolicib (GD C-0077), Pazopanib, Carboplatin, Cisplatin, Oxaliplatin, Pa Ritaxel, Epithilone B, Fulvestrant, Acorbi Fen, rasofoxifen, idoxifen, topotecan, pemetrexed, erroci Nib, tisilimmab, ipilimumab, vorinostat, etoposide, gemcitabine, dox Sorbicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, Capecitabine, Camptothecin, PD0325901, Irinotecan, Tamoxifen, Toremifene, anastrazole, letrozole, bevacizumab, goserelin acetate, laro Xiphen, alpericib, trastuzumab, trastuzumab emtansine, pertuzumab Trastuzumab deruxtecan (recombinant) (fam-trastuzuma b deruxtecan-nxki) (Enharts), or Eribulin (Halaven) That is the case.

[0113] In one embodiment, this application is for use in the treatment of breast cancer in subjects requiring treatment. Regarding the compound of formula (I), the treatment involves administering a therapeutically effective amount of the compound of formula (I) to the target. This includes the compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (I -d), formula(Ie), formula(If), formula(Ig), formula(Ih), formula(Ii) Compounds, or pharmaceutically acceptable salts thereof, enantiomers, stereoisomers, solvates, polymorphs The treatment is an isotopic derivative or prodrug, and the treatment is administered in a therapeutically effective amount of at least one of the following: Further administration of additional anticancer drugs, including FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors Drugs, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 6 inhibitors, anti-HG F antibody, PI3 kinase inhibitor, AKT inhibitor, mTORC1 / 2 inhibitor, JAK / ST AT inhibitors, checkpoint 1 inhibitors, checkpoint 2 inhibitors, focal adhesion kinases Inhibitors, MAP kinase kinase inhibitors, VEGF trap antibodies, SHR6390, Tri Lasiclib, Lerocilib, AT7519M, Dinacilib, Ribociclib, Abemacic Rib, palbociclib, everolimus, venetoclax, inabolisib (GDC-007) 7) Pazopanib, carboplatin, cisplatin, oxaliplatin, paclitaxel Epithilone B, fulvestrant, acorbifen, ra Sofoxifen, Idoxifen, Topotecan, Pemetrexed, Erlotinib, Tisi Limumab, ipilimumab, vorinostat, etoposide, gemcitabine, doxorubicin 5'-deoxy-5-fluorouridine, vincristine, temozolomide, capecitabine Camptothecin, PD0325901, Irinotecan, Tamoxifen, Toremife N, anastrazole, letrozole, bevacizumab, goserelin acetate, raloxifene Alpericib, trastuzumab, trastuzumab emtansine, pertuzumab, trast Tuzumab deruxtecan (recombinant) (fam-trastuzumab der It is uxtecan-nxki) (Enharts), or eribulin (Halaven).

[0114] In one embodiment, this application is for use in the treatment of breast cancer in subjects requiring treatment. The combination of the compound of formula (I) and at least one additional anticancer drug in a therapeutically effective dose. Regarding this, the compound of formula (I) is, formula (Ia), formula (Ib), formula (Ic), formula (Id Compounds of formula (Ie), formula (If), formula (Ig), formula (Ih), and formula (Ii) , or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, and the same A tectonic derivative or prodrug, wherein at least one additional anticancer agent is FLT -3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PI K-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors Drugs, CDK4 / 6 inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTO RC1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint 1 inhibitors, checkpoint ENT2 inhibitors, focal adhesion kinase inhibitors, MAP kinase kinase inhibitors, VEGF inhibitors Top antibody, SHR6390, trilaciclib, relociclib, AT7519M, dinacic Ribociclib, abemaciclib, palbociclib, everolimus, venetoclax Inavolicib (GDC-0077), pazopanib, carboplatin, cisplatin, o Xaliplatin, paclitaxel, epithilone B, fluvialisin Strand, acorbifen, rasofoxifen, idoxifen, topotecan, pemel Trexed, erlotinib, tisilimmab, ipilimumab, vorinostat, etoposide gemcitabine, doxorubicin, 5'-deoxy-5-fluorouridine, vincris Chin, temozolomide, capecitabine, camptothecin, PD0325901, Irinoteca N, tamoxifen, toremifene, anastrazole, letrozole, bevacizumab, Goserelin acetate, raloxifene, alpelisib, trastuzumab, trastuzumab M Tansine, pertuzumab, trastuzumab, deruxtecan (recombinant) (fam- trastuzumab deruxtecan-nxki) (Enharts), or Eli It is Brin (Halaven).

[0115] In some embodiments, at least one additional anticancer agent is a CDK4 / 6 inhibitor. be.

[0116] In some embodiments, at least one additional anticancer agent is SHR6390, Tri Lasiclib, Lerocilib, AT7519M, Dinacilib, Ribociclib, Abemacic Rib, everolimus, venetoclax, inavolicib (GDC-0077), or parvovirus It is a cyclib.

[0117] In some embodiments, at least one additional anticancer agent is palbociclib. In some embodiments, at least one additional anticancer agent is abemaciclib. In some embodiments, at least one additional anticancer agent is an alpericib. In some embodiments, at least one additional anticancer agent is GDC-0077. In some embodiments, at least one additional anticancer agent is everolimus. In some embodiments, at least one additional anticancer agent is venetoclax.

[0118] In some embodiments, the administration of an additional anticancer agent is performed prior to the administration of the compound of formula (I). It breaks.

[0119] In some embodiments, the administration of additional anticancer agents is less than the administration of the compound of formula (I). Both take place 30 minutes prior.

[0120] In some embodiments, the administration of an additional anticancer agent is carried out after the administration of the compound of formula (I). It breaks.

[0121] In some embodiments, the administration of additional anticancer agents is less than the administration of the compound of formula (I). Both will take place in 30 minutes.

[0122] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Regarding this, the subjects include at least one somatic ER tumor mutation, and the method is as follows: (i) Compounds of formula (Ic) in therapeutically effective amounts, [ka] , or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs The medication is administered orally once a day, (ii) an oral dose of palbociclib once daily. In some embodiments, Breast cancer contains at least one somatic ER tumor mutation.

[0123] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Regarding breast cancer, the method involves at least one somatic ER tumor mutation, (i) Compounds of formula (Ic) in therapeutically effective amounts, [ka] , or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs The medication is administered orally once a day, (ii) an oral dose of palbociclib once daily, comprising:

[0124] In one aspect, this application relates to a method for treating breast cancer in a person requiring treatment. Regarding the compound of formula (Ic) for use, breast cancer is at least one somatic ER The method includes tumor mutations, (i) A therapeutically effective amount of the compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, Oral administration of polymorphs, isotope derivatives, or prodrugs once daily, (ii) an oral dose of palbociclib once daily, comprising:

[0125] In one embodiment, this application is for use in the treatment of breast cancer in subjects requiring treatment. Regarding the compound of formula (Ic), breast cancer has at least one somatic ER tumor mutation. Including treatment, (i) A therapeutically effective amount of the compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, Oral administration of polymorphs, isotope derivatives, or prodrugs once daily, (ii) an oral dose of palbociclib once daily, comprising:

[0126] In some embodiments, the subjects are D538G, E380Q, V422del, and L It includes at least one somatic ER tumor mutation selected from the group consisting of 536P. In one embodiment, breast cancer is D538G, E380Q, V422del, and L53 It includes at least one somatic ER tumor mutation selected from the group consisting of 6P.

[0127] In some embodiments, the breast cancer is ER+ and HER2-.

[0128] In some embodiments, breast cancer is metastatic or locally advanced.

[0129] In some embodiments, the therapeutically effective dose of the compound of formula (Ic) is approximately 30 mg to approximately 10 mg It is 00mg.

[0130] In some embodiments, therapeutically effective doses of palbociclib are 60 mg, 75 mg, and 10 mg. The dose is 0 mg or 125 mg. In some embodiments, palbociclib is administered once daily. It is administered for a maximum of 21 consecutive days, followed by a maximum of 7 consecutive days of discontinuation of treatment, and then parboshi The cycle of treatment with crib and subsequent discontinuation of treatment is 1, 2, 3, 4, 5 times, or It is repeated more times than that.

[0131] In some embodiments, the compound of formula (Ic) is administered once daily for a maximum of 21 consecutive days. The drug is administered, and then treatment is discontinued for up to 7 consecutive days, followed by treatment with a compound of formula (Ic). And the subsequent cycle of discontinuing treatment may occur once, twice, three times, four times, five times, or more. It is repeated a certain number of times.

[0132] In some embodiments, the subject is in a feeding state.

[0133] In some embodiments, the subject is in a fasting state.

[0134] In some embodiments, palbociclib is administered before administration of the compound of formula (Ic). It will be observed.

[0135] In some embodiments, administration of palbociclib is less than administration of the compound of formula (Ic). At the very least, it will be held 30 minutes prior.

[0136] In some embodiments, palbociclib is administered after administration of the compound of formula (Ic). It will be observed.

[0137] In some embodiments, administration of palbociclib is less than administration of the compound of formula (Ic). Check at least 30 minutes later

[0138] In one embodiment, the present application relates to a method for treating breast cancer in a subpopulation of breast cancer patients, Based on the somatic ER tumor biomarker status of the target patient, breast cancer patients are selected for treatment. Choosing, A compound of formula (I) in a therapeutically effective amount, [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs The administration of , and the formula includes, Each R 1 and each R 2 They are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, S O2(R 5 ), selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl , R 3 and R 4 Both are hydrogen, or together with the carbon they are bonded to. It either forms a carbonyl group or Each R 5 and each R 6 These independently contain hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl Selected from the group consisting of, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, or 4. The therapeutically effective dose of the compound in formula (I) is approximately 10 mg to 1000 mg, according to the method. .

[0139] In one embodiment, this application is used for a method of treating breast cancer in a subpopulation of breast cancer patients. For the purpose of, a compound of formula (I), or its pharmaceutically acceptable salts, solvates, polymorphs, isotopes With respect to derivatives or prodrugs, in the formula, Each R 1 and each R 2 They are independent, halo, OR 5 , N(R5 )(R 6 ), NO2, CN, S O2(R 5 ), selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl , R 3 and R 4 Both are hydrogen, or together with the carbon they are bonded to. It either forms a carbonyl group or Each R 5 and each R 6 These independently contain hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl Selected from the group consisting of, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, or 4. The method is, Based on the somatic ER tumor biomarker status of the target patient, breast cancer patients are selected for treatment. Choosing, This includes administering a therapeutically effective dose of the compound of formula (I), The therapeutically effective dose of the compound in formula (I) is approximately 10 mg to 1000 mg.

[0140] In one embodiment, this application is for use in the treatment of breast cancer in a subpopulation of breast cancer patients. Compounds of formula (I), or pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives thereof, Or, with respect to prodrugs, in the formula, Each R 1 and each R 2 They are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, S O2(R 5 ), selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl , R 3 and R 4 Both are hydrogen, or together with the carbon they are bonded to. It either forms a carbonyl group or Each R 5 and each R 6 These independently contain hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl Selected from the group consisting of, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, or 4. The treatment is, Based on the somatic ER tumor biomarker status of the target patient, breast cancer patients are selected for treatment. Choosing, This includes administering a therapeutically effective dose of the compound of formula (I), The therapeutically effective dose of the compound in formula (I) is approximately 10 mg to 1000 mg.

[0141] In some embodiments, the target somatic ER tumor biomarker status is D538G at least one somatic cell selected from E380Q, V422del, and L536P Includes sexual ER tumor mutations.

[0142] In some embodiments, the target ER biomarker status is determined by ctDNA analysis, fluorescence For situ hybridization, immunohistochemistry, PCR analysis, or sequencing Therefore, it is determined.

[0143] In some embodiments, the ER biomarker status of the subject is determined from a blood sample derived from the subject. It will be determined by [the method used].

[0144] In some embodiments, the target ER biomarker status is derived from the target tumor. This is determined by a physical biopsy.

[0145] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs Selected from the group consisting of G.

[0146] In some embodiments, the compound of formula (I) is [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs It is.

[0147] In some embodiments, the breast cancer is ER+ and HER2-.

[0148] In some embodiments, breast cancer is metastatic or locally advanced.

[0149] In some embodiments, the method further includes the administration of at least one additional anticancer agent. nothing.

[0150] In some embodiments, additional anticancer agents include FLT-3 inhibitors, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors Drugs, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 6 inhibitors, anti-HG F antibody, PI3 kinase inhibitor, AKT inhibitor, mTORC1 / 2 inhibitor, JAK / ST AT inhibitors, checkpoint 1 inhibitors, checkpoint 2 inhibitors, focal adhesion kinases Select from the group consisting of inhibitors, MAP kinase kinase inhibitors, and VEGF trap antibodies. It will be done.

[0151] In some embodiments, at least one additional anticancer agent is a CDK4 / 6 inhibitor. be.

[0152] In some embodiments, additional anticancer agents include SHR6390, trilaciclib, and lero. Ciclib, AT7519M, Dina Ciclib, Ribociclib, Abemaciclib, Palbosiclib Rib, everolimus, pazopanib, venetoclax, inavolicib (GDC-0077) Carboplatin, cisplatin, oxaliplatin, paclitaxel, epithiron B ( epithilone B), fulvestrant, acorbifen, rasofoxifen , doxifen, topotecan, pemetrexed, erlotinib, tisilinumab, ipirin Mumab, vorinostat, etoposide, gemcitabine, doxorubicin, 5'-deoxy -5-Fluorouridine, Vincristine, Temozolomide, Capecitabine, Camptothecin N, PD0325901, Irinotecan, Tamoxifen, Toremifene, Anastrazo Letrozole, bevacizumab, goserelin acetate, raloxifene, alpelisib, Trastuzumab, trastuzumab emtansine, pertuzumab, trastuzumab deruk Stecan (genetically modified) (fam-trastuzumab deruxtecan- It is nxki (Enhertz) or eribulin (Halaven).

[0153] In some embodiments, at least one additional anticancer agent is SHR6390, Tri Lasiclib, Lerocilib, AT7519M, Dinacilib, Ribociclib, Alpericib Abemaciclib, everolimus, venetoclax, inavolicib (GDC-0077) ), or palbociclib.

[0154] In some embodiments, at least one additional anticancer agent is palbociclib. In some embodiments, at least one additional anticancer agent is abemaciclib. In some embodiments, at least one additional anticancer agent is an alpericib. In some embodiments, at least one additional anticancer agent is GDC-0077. In some embodiments, at least one additional anticancer agent is everolimus. In some embodiments, at least one additional anticancer agent is venetoclax.

[0155] In some embodiments, the administration of an additional anticancer agent is performed prior to the administration of the compound of formula (I). It breaks.

[0156] In some embodiments, the administration of additional anticancer agents is less than the administration of the compound of formula (I). Both take place 30 minutes prior.

[0157] In some embodiments, the administration of an additional anticancer agent is carried out after the administration of the compound of formula (I). It breaks. In some embodiments, the administration of an additional anticancer agent is less than the administration of the compound of formula (I). It will take place in 30 minutes.

[0158] definition "H" stands for hydrogen.

[0159] Halogen or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine ( I) refers to

[0160] "C1-C6 alkyl" refers to a saturated carbonized linear or branched chain containing 1 to 6 carbon atoms. This refers to hydrogen. Examples of (C1-C6) alkyl groups include methyl, ethyl, propyl, and butyric. Isopropyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl Examples include, but are not limited to, isopentyl, neopentyl, and isohexyl. stomach.

[0161] "C3-C6 cycloalkyl" is a monocyclic saturated carbon ring containing 3 to 6 carbon atoms. In other words, the cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl portion It tastes good.

[0162] When used herein with respect to the compound of formula (I), “pharmaceutically acceptable salt” means This refers to the salt form of the compound of formula (I), and the hydrate form of the salt in which one or more water molecules are present. It tastes good. Such salt and hydrated forms retain the biological activity of the compound of formula (I), and biological Not scientifically or otherwise undesirable, that is, even if there are toxicological effects, This shows the minimum acceptable levels. Typical "pharmaceutically acceptable salts" include, for example, acetates and amsonates. (amsonate)(4,4-diaminostilbene-2,2-disulfonate), ben Zensulfonates, benzoates, bicarbonates, bisulfates, bicarbonates, tartarates, borates, bromides , butyrate, calcium, calcium edetate, camsylate, charcoal Salts, chlorides, citrates, clavulariates, dihydrochloride edetate, edisylate, estrate, esylate, fumarate, gluceptate , gluconate, glutamate, glycolyl arsanilate, hexafluorophosphate hexylresorcinate, hydravamin, bromide Hydrogenates, hydrochlorides, hydroxynaphthoates, iodides, isothionates (isothi (onate), lactate, lactobionate, laurate, magnesium, malate, Maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, muco Salts, napsylates, nitrates, N-methylglucamine ammonium salts, 3-hydroxy- 2-Naphthoate, Oleate, Oxalate, Palmitate, Pamoate (1,1-Me Ten-bis-2-hydroxy-3-naphthoate, einbonate )) Pantothenate, phosphate / diphosphate, picrate, polygalacturonate, Propionate, p-toluenesulfonate, salicylate, stearate, basic vinegar Salts, succinates, sulfates, sulfosalicylates, suramates, Examples include nitrates, tartrates, theoclates, tosylates, triethiozides, and valersates. It contains both water-soluble and water-insoluble salts.

[0163] The term "isomer" refers to a compound having the same composition and molecular weight, but possessing different physical and / or chemical characteristics. This refers to salts and / or compounds with different properties. Structural differences are represented by their composition (geometric isomers) or polarization plane. This could be due to the ability to rotate the surface (stereoisomerism). Regarding stereoisomerism, the compound of formula (I) The salt may have one or more chiral carbon atoms, and as a racemate or racemic mixture, They may also occur as individual enantiomers or diastereomers.

[0164] The compound of formula (I) can exist in both a non-solvated form and a solvated form, such as a hydrate. ru.

[0165] A "solvate" is a solvent that contains either a stoichiometric or non-stoichiometric amount of the solvent. This refers to the addition form. Some compounds capture solvent molecules in a fixed molar ratio while in a crystalline solid state. It tends to form a solvate. When the solvent is water, the solvate that is formed is It is a hydrate, and when the solvent is an alcohol, the solvate formed is an alkoxide. A hydrate is a molecule containing one or more water molecules, within which the water molecules retain their molecular state as H2O. It is formed by a combination with one of the substances, and such a combination is one The above hydrate can be formed. In the hydrate, water molecules are subjected to intermolecular forces, especially hydrogen bridging. Therefore, they are bonded via secondary valence. The solid hydrate, in stoichiometric ratio, is composed of so-called crystal water and It contains water, and the water molecules do not need to be equivalent in terms of their bonding state. Examples of hydrates and Examples include sesquihydrate, monohydrate, dihydrate, or trihydrate. Similarly, this invention Hydrates of the salts of the compounds from the Ming Dynasty are also appropriate.

[0166] When a compound is crystallized from a solution or slurry, it crystallizes in a space lattice with a different arrangement. (This property is called "polymorphism"), which means forming crystals with different crystalline forms. These can be formed, and each of them is known as a "polymorph." As used herein, "polymorph" This refers to the crystalline form of the compound of formula (I), in which the molecules are localized at three-dimensional lattice sites. Different polymorphs of compound (I) have different solubility and dissolution rates, true specific gravity, crystal morphology, and accumulation modes. , differing from one or more other physical properties such as fluidity and / or solid-state stability. It's okay to be there.

[0167] As used herein, “isotope derivative” means (with respect to one or more atoms of a compound) (t) Regarding compounds of formula (I) that are isotope enriched or labeled with one or more stable isotopes. Therefore, in this application, the compound of formula (I) is, for example, deuterium ( 2 H or D) or Carbon-13 13 This includes compounds that are isotope-enriched or labeled with one or more atoms, such as C).

[0168] As used herein, the term "pharmaceutically acceptable prodrug" is based on sound medical judgment. Within the range of excessive toxicity, irritation, allergic reactions, etc., humans and lower-level beings Suitable for use in contact with animal tissues, with a reasonable benefit / risk ratio, and with respect to the intent The formula of the compound of the present invention, which is effective for use as shown in the illustration and, if possible, is in an amphoteric form. (I) refers to a prodrug of the compound.

[0169] As used herein, "prodrug" means a drug that is metabolized by means of (e.g., by hydrolysis). (By decomposition) it is convertible in vivo to any compound detailed by the formula of the present invention It refers to a compound that drips or oozes. Various forms of prodrugs are known in the art, For example, Bundgaard, (ed.), Design of Prodrugs, E lsevier (1985), Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985) ), Krogsgaard-Larsen,et al.,(ed).”Design and Application of Prodrugs,Textbook of Drug Design and Development,Chapter5,1 1 3-191 (1991), Bundgaard, et al., Journal of Drug Delivery Reviews, 8:1-38 (1992), Bundg aard, J. of Pharmaceutical Sciences, 77:285 et seq.(1988), Higuchi and Stella(eds.)P rodrugs as Novel Drug Delivery Systems,A American Chemical Society (1975), and Bernard Testa & Joachim Mayer,”Hydrolysis In Dr. ug And Prodrug Metabolism:Chemistry,Bioc hemistry And Enzymology,”John Wiley and This is discussed in Sons, Ltd. (2002).

[0170] The present invention also relates to pharmaceutical compositions containing pharmaceutically acceptable prodrugs of the compounds of the present invention. Impairment by administering the substance and a pharmaceutically acceptable prodrug of the compound of the present invention. This includes methods for treating free amino groups, amide groups, hydroxyl groups, or carbo groups. The compounds of the present invention having an acidic group can be converted into prodrugs. It contains an amino acid residue, or two or more (for example, two, three, or four) amino acid residues. The polypeptide chain, via an amide or ester bond, contains the free amino group of the compound of the present invention. It contains compounds covalently bonded to a hydroxyl group or a carboxylic acid group. The amino acid residues are It contains 20 natural amino acids, which are generally specified by three letter symbols, and also 4-hydroxy Cyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, nor Valine, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homocysteine Includes, but is not limited to, phosphorus, ornithine, and methionine sulfone. Additional species This also includes prodrugs of the same type. For example, the free carboxyl group is an amide or alkyl group. It can be derivatized as a ruester. The free hydroxyl group is an Advanced Drug As outlined in Delivery Reviews, 1996, 19, 1 15, While not limited to these, hemisuccinate, phosphate ester, dimethylaminoacetate It can be derivatized using groups containing phosphoryloxymethyloxycarbonyl and phosphoryloxymethyloxycarbonyl. Carbamate prodrugs of hydroxyl and amino groups include carbonate prodrugs. This also includes hydroxyl group sulfonic acid esters and sulfate esters. (Acylo Derivatization of the hydroxyl group as hydroxy(xy)methyl and (acyloxy)ethyl ethers is also included. In this case, the acyl group includes ether, amine, and carboxylic acid functional groups, but these The alkyl ester may be optionally substituted with any group, or the acyl group may be These are amino acid esters as described above. This type of prodrug is classified as such by J.Med. It is described in Chem., 1996, 39:10. Free amines are also amides, sul These prodrug portions can be derivatized as phonamide or phosphonamide. All but not limited to, groups incorporating ether, amine, and carboxylic acid functional groups This is also acceptable. The combinations of substituents and variables envisioned by the present invention are stable compound forms. Only those who bring about success.

[0171] Metastatic breast cancer, or metastasis, is a condition where the cancer spreads beyond the breast and nearby lymph nodes to other organs such as the bones, liver, and lungs. This refers to breast cancer that has spread to other parts of the body, such as the brain (https: / / www.canc (er.org / cancer / breast-cancer.)

[0172] Locally advanced breast cancer (LABC) is classified as a disease in the United States National Comprehensive Medical Center. According to the e Cancer Network, the most advanced breast tumors without distant metastases. Defined as a subset of breast cancer characterized by the presence of regional lymph node swelling. If it is more than 5 cm and regardless of regional lymph node swelling, it is located in the chest wall or skin, or both (ulcerated). A tumor of any size with direct expansion (including ulcers or satellite nodules), and the stage of the tumor Regardless, the presence of regional lymph node swelling (clinically fixed or matted axillary lymph nodes) (or swelling of the subclavian, supraclavicular, or internal mammary lymph nodes). (Garg et al.Curr Oncol.2015 Oct;22(5):e409-e41 0, National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Onc ology:Breast Cancer.Fort Washington,PA:N CCN; 2015.Ver.2.2015.)

[0173] ER+, estrogen receptor positive, as used herein, refers to the hormone estrogen This refers to breast cancer cells that possess receptor proteins that bind to the gene. Cancer cells that are ER+ are It may require estrogen for proliferation, and it may block estrogen binding and action. When treated with a substance that inhibits growth, proliferation may stop or the organism may die. (ht tps: / / www.cancer.gov / publications / dictio naries / cancer-terms / def / 44404.)

[0174] HER2-, human epidermal growth factor receptor 2, when used herein, on its surface This refers to breast cancer cells that do not have a large amount of a protein called HER2. In normal cells, HE R2 helps regulate cell proliferation. HER2- cancer cells have a large amount of HER2 on their surface. Cancer cells with a higher proliferative capacity than those with a higher proliferative capacity, and are less likely to recur or metastasize to other parts of the body. It is unlikely. (https: / / www.cancer.gov / publicat ions / dictionaries / cancer-terms / def / her2- (negative.)

[0175] As used herein, “to treat” means to combat a disease, condition or disorder. This refers to the management and care of the affected person, reducing or alleviating symptoms or complications, or the disease. , including removing a condition or defect.

[0176] As used herein, “prevent” means the symptoms or complications of a disease, condition, or disorder. This refers to stopping the onset of the condition.

[0177] "Administration" refers to the process of introducing a drug, such as the compound in formula (I), into the target area. Related terms include The verbs "administer" and "administer" (and their grammatical equivalents) are used by or for medical professionals. Direct administration, which may involve self-administration to the subject, and / or the act of prescribing a drug. This refers to both possible indirect administrations. For example, instructing a patient to self-administer a drug, and / Alternatively, a physician who provides a patient with a prescription for medication is administering the medication to the patient.

[0178] As used herein, the term “anticancer agent” means an anticancer agent, or an anticancer agent administered concurrently with an anticancer agent. It is used to describe the therapeutic drugs (e.g., palonosetron), which are used for cancer, and Co-administration and / or concurrent administration with the compound of formula (I) to treat side effects associated with cancer treatment. It may be prescribed.

[0179] In some embodiments, the anticancer agent is selected from one of the following: FLT-3 inhibitors Harmful agents, VEGFR inhibitors, EGFR TK inhibitors, Aurora kinase inhibitors, PIK-1 Regulatory factors, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, C DK4 / 6 inhibitors, anti-HGF antibodies, PI3 kinase inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, checkpoint 1 inhibitors, checkpoint 2 Inhibitors, PD-1 inhibitors, PD-L1 inhibitors, B7-H3 inhibitors, CTLA4 inhibitors, L AG-3 inhibitors, OX40 agonists, focal adhesion kinase inhibitors, MAP kinase kinase inhibitors Harmful agents and VEGF trap antibodies.

[0180] In some embodiments, the anticancer agent is selected from one of the following: SHR639 0, Trilaciclib, Lerocilib, AT7519M, Dinacilib, Ribociclib, A Bemaciclib, palbociclib, everolimus, venetoclax, inavolicib (GDC) -0077), Pazopanib, Carboplatin, Cisplatin, Oxaliplatin, Pacri Taxel, Epithilone B, Fulvestrant, Acorbif En, rasofoxifen, idoxifen, topotecan, pemetrexed, erlotin Bu, tisilimmab, ipilimumab, vorinostat, etoposide, gemcitabine, doxo Rubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, Pecitabine, Camptothecin, PD0325901, Irinotecan, Tamoxifen, Remifene, Anastrazole, Letrozole, Bevacizumab, Goserelin Acetate, Laroxine Ciphen, alpericib, trastuzumab, trastuzumab emtansine, pertuzumab , trastuzumab deruxtecan (recombinant) (fam-trastuzumab deruxtecan-nxki) (Enharts), and eribulin (Halaven). In some embodiments, the anticancer agent is palbociclib, in some embodiments The anticancer drug is abemaciclib. In some embodiments, the anticancer drug is everoli It is mus. In some embodiments, the anticancer agent is alpericib. In the application form, the anticancer agent is GDC-0077. In some embodiments, the anticancer agent This is Venetocracy.

[0181] As used herein, “therapeutic dose” refers to a specific disease (e.g., breast cancer), disease To treat, improve, or prevent the symptoms, disorders, or conditions of, or to treat or detect the symptoms, disorders, or conditions of This refers to the amount of free base of the compound of formula (I) that is sufficient to exhibit an inhibitory effect. The effect can be detected by any analytical method known in the art. The effective dose depends on the subject's weight, size and health condition, the nature and extent of the condition, and any additional therapeutic agents. It may depend on whether it is administered to the target. The effective therapeutic dose for a given situation is determined by the clinician. It can be determined through routine experiments within the scope of skills and judgment.

[0182] When used herein, "C max "After administering a specific dose of a compound to the subject This refers to the peak plasma concentration of the compound observed in the subject.

[0183] As used herein, "AUC" refers to the total area under the plasma concentration-time curve. This is a measure of exposure to the compound of interest, and represents the concentration-time ratio after a single dose or at steady state. This is the integral of a curve. AUC is expressed in units of ng·time / mL (ng×time / mL). .

[0184] When used herein, "AUC" tau " is from 0 hours until the end of the dosing interval. This refers to UC.

[0185] As used herein with respect to oral dosage forms of this disclosure, “sustained release” or “CR” means formula ( This means that the compound in I) is released from the dosage form according to a predetermined profile, The profile indicates when, where, and / or where release occurs after oral administration. This may include a specified release rate over a period of time. Slow release is uncontrolled release or immediate release. This can be in contrast to the outward appearance.

[0186] As used herein with respect to oral dosage forms of this disclosure, “sustained-release agent” is derived from the formula ( I) refers to one or more substances or materials that regulate the release of the compound. Sustained-release agents are organic or inorganic. , naturally derived or synthetic materials, such as polymer materials, triglycerides, and triglyceride inducers The materials may be conductors, fatty acids and salts of fatty acids, talc, boric acid, and colloidal silica.

[0187] As used herein, “oral dosage form” means a specific amount (dose) of the active ingredient. Compounds of formula (I), or pharmaceutically acceptable salts and / or solvates thereof, and inert compounds Contains excipients and is used for oral administration and drug delivery in the form of tablets, capsules, or liquid oral formulations. This refers to a pharmaceutical product formulated to a specific configuration suitable for certain purposes. In some embodiments, the composition is It is a tablet form that can be scored.

[0188] As used in this disclosure, the term "carrier" encompasses carriers, excipients, and diluents, and refers to a single vessel. Involved in the transport or delivery of pharmaceuticals from one organ or part of the body to another organ or part of the body, Materials, compositions, or vinyl such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. It means to hikuru.

[0189] The term "approximately" as part of a quantitative expression such as "approximately X" means 10% higher or lower than X. It includes any value, and also any number between X-10% and X+10%. Therefore, For example, a weight of approximately 40g includes a weight of 36-44g. When used herein, E To indicate amino acid residues in R, the term "approximately" refers to 5 amino acids of a specified amino acid residue. This refers to any amino acid residue within a given residue. For example, approximately 181 amino acid residues in ER. When referring to a continuous stretch of amino acid residues extending up to approximately 263 amino acid residues, this This refers to amino acid residues 176, 177, 178, 179, 180, and 181 of the ER of SEQ ID NO: 1. , 182, 183, 184, 185, or 186, amino acid residues 258, 259, 26 A extending to 0, 261, 262, 263, 264, 265, 266, 267 or 268 Refers to a continuous stretch of amino acid residues. In some embodiments, the term "about" is used to specify This refers to any amino acid residue within 3 amino acid residues of the amino acid residue being targeted. In that embodiment, the term "about" means within one amino acid residue of the specified amino acid residue. This refers to any amino acid residue.

[0190] As used herein, the term "del" refers to an inversion of an amino acid residue compared to the wild type. It shows a Rehm deletion. For example, "V422del" is at position 422 in the wild-type ER protein. This shows a mutant lacking valine.

[0191] Where used herein, an underline between two amino acid notations means the remainder including both endpoints. This indicates that the base sequence has been changed. For example, "L536_D538>P" means 536 The amino acid residues that begin with lysine at position 538 and end with aspartic acid at position 538 are single proline This shows a mutant resulting from an in-frame deletion that is replaced by [a specific character].

[0192] The specific dosage forms, compositions, uses, methods, or patents described or claimed herein The term "comprising" or "comprising" applies to the process. "es)" means that the dosage form, composition, use, method, or process is not specified in the detailed description or patent application. This means that the search includes all the elements listed within the scope of the request, but does not exclude other elements. . "consists essentially of" and "ka "Consisting essentially of" means, A composition, dosage form, method, use, or process described or claimed by the patent is Listed physical, pharmacological, and pharmacokinetic aspects of compositions, dosage forms, methods, uses, or processes. This means not excluding other materials or processes that do not substantially affect the properties or therapeutic effect. "consists of" and "consisting" "of)" refers to trace elements of other components, and those that exceed substantial methods or process steps. It means exclusion.

[0193] The term "fasted condition" is used to describe the subject. Alternatively, "fasted state" refers to the time period during which the compound of formula (I) is administered. This means that the subject has not eaten for at least four hours prior to the point in time of interest. In one embodiment, a fasted subject is subjected to at least 6,8 prior to administration of the compound of formula (I). You have not eaten within the last 10 or 12 hours.

[0194] In this specification, the term "feeding condition" is used to describe the subject. "ion)" or "fed state" refers to the state when administering the compound of formula (I). This means that the subject ate a meal less than four hours before the point in time of interest. Morphologically, the feeding state of the subjects was at most 4, 3, 2, 1 before administration of the compound of formula (I). Or, they have not eaten for any of the following periods: 0.5 hours or longer.

[0195] As used herein, "Tween 80" refers to polyoxyethylene monooleate. Len(20) sorbitan, and sorbitan, mono-9-octadecenoate, poly(Oxy Polysorbate 80, also known as the (Z)- derivative (C-1,2-ethanediyl), refers to polysorbate 80. vinegar.

[0196] When used herein, "low molecular weight polyethylene glycol" or "low molecular weight PE "G" generally refers to 1500, 1400, 1300, 1200, 1100, 1000, and 900. , having a molecular weight of less than 800, 700, 600, 500, 400, or 300 Daltons This refers to polyethylene glycol (PEG) polymer. An example of low molecular weight PEG is PE Examples include G-200, PEG-400, and PEG-600.

[0197] As used herein, the term “CDK4 / 6 inhibitor” means cyclin-dependent This refers to compounds that inhibit enzymes in humans called kinases (CDK) 4 and 6. Examples of K4 / 6 inhibitors, though not limited to them, include SHR6390 and Trilasic. Rib, lerocicrib, AT7519M, dinacicrib, ribociclib, abemaciclib, Examples include palbociclib, or any pharmaceutically acceptable salt thereof. In terms of administration, the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof. ru.

[0198] The articles "a" and "an" in this disclosure refer to one or more (i.e., less) articles. Both are used to refer to the grammatical object of the article (one). For example, "element" is one. It means one element or two or more elements.

[0199] Unless otherwise suggested, the terms “and / or” in this disclosure mean “and” or “ It is used to mean either "or".

[0200] The terms "patient" and "subject" are used interchangeably in this specification and refer to mammals, e.g., humans. Mice, rats, guinea pigs, dogs, cats, horses, cattle, pigs, or non-human primates, for example This refers to monkeys such as macaques, chimpanzees, baboons, or rhesus macaques.

[0201] In some embodiments, the subject is a human.

[0202] In some embodiments, the subjects are individuals diagnosed with breast cancer.

[0203] In some embodiments, the subjects are humans diagnosed with metastatic breast cancer.

[0204] In some embodiments, the subjects are humans diagnosed with ER-+, HER2- breast cancer. .

[0205] In some embodiments, the subjects are patients diagnosed with metastatic, ER-+, HER2- breast cancer. It is.

[0206] Compound of formula (I) In one embodiment, the present application relates to the formulation of formula (I) for subjects requiring treatment and / or prevention of cancer. Methods for treating and / or preventing cancer, including the administration of a compound.

[0207] In one embodiment, this application relates to the use of compounds of formula (I) in the treatment and / or prevention of breast cancer. Regarding.

[0208] In one embodiment, the present application relates to a formula in the manufacture of pharmaceuticals for the treatment and / or prevention of breast cancer. Regarding the use of compound (I).

[0209] As referred to herein, the compound of formula (I) is a compound having the following structure: [ka] or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopes This refers to a derivative or prodrug, and in the formula, Each R 1 and each R 2 They are independent, halo, OR 5 , N(R 5 )(R 6), NO2, CN, S O2(R 5 Selected from the group consisting of ), C1-C6 alkyl, and C3-C6 cycloalkyl. And so, R 3 and R 4 Both are hydrogen, or together with the carbon they are bonded to. It either forms a carbonyl group or Each R 5 and each R 6 These are independently hydrogen, C1-C6 alkyl, and C3-C6 cycloal Selected from a group consisting of kills, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, or 4.

[0210] Several embodiments, each R 1 and each R 2 They are independent, halo, OR 5 , and C1-C Selected from the group consisting of 6 alkyl groups.

[0211] In some embodiments, R 1 is hydrogen, halo, OR 5 , N(R 5 )(R 6 ), or C It is a 1-C6 alkyl group. In some embodiments, R 1 It is hydrogen. In terms of application form, R 1 is a halo. In some embodiments, R 1 is OR 5 That is. In some embodiments, R 1 N(R) 5 )(R 6 ) In some embodiments, R 1 It is a C1-C6 alkyl group.

[0212] In some embodiments, R 2 is hydrogen, halo, OR5 , N(R 5 )(R 6 ), or C It is a 1-C6 alkyl group. In some embodiments, R 2 It is hydrogen. In terms of application form, R 2 is a halo. In some embodiments, R 2 is OR 5 That is. In some embodiments, R 2 N(R) 5 )(R 6 ) In some embodiments, R 2 It is a C1-C6 alkyl group.

[0213] In some embodiments, R 3 and R 4 Both are hydrogen.

[0214] In some embodiments, R 3 and R 4は , together with the carbons to which they are bonded It forms a carbonyl group.

[0215] Several embodiments, each R 5 and each R 6 These are independently hydrogen and C1-C6 alkyl Selected from the group consisting of R 5 and R 6 Each of them uses hydrogen be.

[0216] In some embodiments, m is 0.

[0217] In some embodiments, m is 1.

[0218] In some embodiments, m is 2.

[0219] In some embodiments, m is 3.

[0220] In some embodiments, m is 4.

[0221] In some embodiments, m is 5.

[0222] In some embodiments, n is 0.

[0223] In some embodiments, n is 1.

[0224] In some embodiments, n is 2.

[0225] In some embodiments, n is 3.

[0226] In some embodiments, n is 4.

[0227] In some embodiments, m and n are each 0.

[0228] In some embodiments, m is 0 and n is 1.

[0229] In some embodiments, m is 1 and n is 0.

[0230] In some embodiments, m is 1 and n is 1.

[0231] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopes Selected from the group consisting of isomer derivatives or prodrugs.

[0232] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] It is selected from the group consisting of the following.

[0233] In some embodiments, the compound of formula (I) is the compound of formula (Ia), [ka] or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopes It is a derivative or prodrug.

[0234] In some embodiments, the compound of formula (I) is the compound of formula (Ia), [ka]

[0235] In some embodiments, the compound of formula (I) is the compound of formula (Ib), [ka] or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopes It is a derivative or prodrug.

[0236] In some embodiments, the compound of formula (I) is the compound of formula (Ic), i.e., Compound (Ic) or Cmp (Ic), [ka] or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopes It is a derivative or prodrug.

[0237] In some embodiments, the compound of formula (I) is the compound of formula (Ic), i.e., It is a compound (Ic) or Cmp(Ic). [ka]

[0238] In some embodiments, the compound of formula (I) is the compound of formula (Id), [ka] or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopes It is a derivative or prodrug.

[0239] In some embodiments, the compound of formula (I) is the compound of formula (Ie), [ka] or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopes It is a derivative or prodrug.

[0240] In some embodiments, the compound of formula (I) is the compound of formula (If), [ka] or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopes It is a derivative or prodrug.

[0241] In some embodiments, the compound of formula (I) is the compound of formula (Ig), [ka] or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopes It is a derivative or prodrug.

[0242] In some embodiments, the compound of formula (I) is the compound of formula (Ih), [ka] or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopes It is a derivative or prodrug.

[0243] In some embodiments, the compound of formula (I) is the compound of formula (Ii), [ka] or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopes It is a derivative or prodrug.

[0244] In some embodiments, the compound of formula (I) is the compound of formula (Ij), [ka] or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopes It is a derivative or prodrug.

[0245] In some embodiments, the compound of formula (I) is the compound of formula (Ij), [ka]

[0246] The compound of formula (I) is, in the art of this disclosure, in the relevant scientific literature or in the standard of the art Preparation of organic molecules, including the use of protecting groups, and functional groups, as can be obtained from reference textbooks. It can be synthesized using standard synthesis methods and procedures for the conversion and manipulation of any one or, not limited to, several sources, but recognized as reference textbooks for organic synthesis This includes Smith, MB; March, J. March's Advanced Organic Chemistry:Reactions,Mechanisms,a nd Structure, 5 th ed.; John Wiley & Sons: N New York, 2001, and Greene, TWWuts, PGMPro Tective Groups in Organic Synthesis,3 rd ; John Wiley & Sons: New York, 1999 is cited. Formula ( A method for preparing the compound in (I) is described in U.S. Patent Application Publication No. 2018 / 0155322. This has been done, and this has been issued as U.S. Patent No. 10,647,698, and its contents The entirety of it is incorporated herein.

[0247] For example, compounds (Ib) and (Ic) are prepared according to the procedure described below. It is possible: 3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-the Tralin-1-yl]phenyl]-4-piperidyl]methyl]piperazine-1-yl]- 1-Oxo-isoindorin-2-yl]piperidine-2,6-dione (compound (Ib )) synthesis:

[0248] Step 1: Preparation of 6-tert-butoxytetralin-1-one [ka]

[0249] 6-Hydroxytetralin-1-one (50g, 308.29 mmol, 1 equivalent) Add 2,2,2-trichloroethane to a stirred solution of anhydrous dichloromethane (2000 mL) at °C. tert-butyl imidate (67.36g, 308.29mmol, 55mL, 1 equivalent) And, pyridinium para-toluenesulfonate (7.75g, 30.83mmol, 0.1 An equivalent amount was added. The reaction mixture was stirred at 10°C for 3 hours. 2,2,2-Trichloroethane tert-butyl imidate (67.36g, 308.29mmol, 55mL, 1 equivalent) And, pyridinium para-toluenesulfonate (7.75g, 30.83mmol, 0.1 An additional (equivalent) was added, and the reaction mixture was stirred at 10°C for 15 hours. This process was repeated three times. Thin-layer chromatography (petroleum ether:ethyl acetate = 3:1, R f =0.8) is the opposite The reaction mixture was stirred at 10°C for 72 hours, indicating that most of the responding material remained. The reaction mixture is prepared by adding sodium bicarbonate solution (1500 mL) at 15°C. The mixture was entrenched, then extracted with dichloromethane (300 mL x 3). The resulting organic solution was then combined into one. Wash the layers with brine (300 mL x 2), dry with anhydrous sodium sulfate, filter, and reduce The solution was concentrated under pressure. The residue was subjected to silica gel chromatography (petroleum ether:ethyl acetate = Purified by (100:1~50:1), 6-tert-butoxytetralin-1-one (21 g, 96.20 mmol, yield 31%) was obtained as a yellow oily substance. 1 H NMR ( 400MHz, CDCl3)δ7.97(d,J=8.8Hz,1H),6.91(dd ,J=2.4,8.8Hz,1H),6.82(d,J=2.0Hz,1H),2.93 -3.90(t,J=6.0Hz,2H),2.63-2.60(m,t,J=6.0H z,2H),2.13(m,2H),1.43(s,9H).

[0250] Step 2: (6-tert-butoxy-3,4-dihydronaphthalene-1-yl) Preparation of trifluoromethanesulfonate [ka]

[0251] 6-tert-butoxytetralin-1-one (40g, 183.24mmol, 1 dose) In a 500 mL solution of tetrahydrofuran (amount), add 2 M diisopropylamide lithium (2M). (137 mL, 1.5 equivalents) was added at -70°C. The mixture was stirred at -70°C for 1 hour, and then... 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl) Tetrahyaluronic acid of methanesulfonamide (72.01 g, 201.56 mmol, 1.1 equivalents) A 200 mL solution of Drofuran was added dropwise to the mixture. The reaction mixture was left at 20°C for 2 hours. The mixture was stirred. Thin-layer chromatography (petroleum ether:ethyl acetate = 5:1) was performed to confirm the complete reaction. This indicated completion. Saturated ammonium chloride (300 mL) was added to the mixture, and the organic layer was separated. They were separated. Ethyl acetate (500 mL x 3) was added to the mixture, and the resulting mixture was brined ( Washed with 1000 mL x 2. The combined organic layer was dried with sodium sulfate. The residue was filtered and concentrated in a vacuum. The residue was subjected to silica gel chromatography (petroleum ether). Purified with ethyl acetate (1:0~50:1), (6-tert-butoxy-3,4 -Dihydronaphthalene-1-yl)trifluoromethanesulfonate (52g, 144. 64 mmol, yield 78%, purity 97% was obtained as a yellow oily substance. LC-MS (ESI )m / z:294.9[M+1-56] + . 1 H-NMR (400MHz, CDCl3) δ:7.30(d,J=6.4Hz,1H),6.91(d,J=8.4Hz,1H), 6.84(s,1H),5.95(s,1H),2.93-2.78(m,2H),2. 59-2.46 (m, 2H), 1.42 (s, 9H).

[0252] Step 3: 4-(6-tert-butoxy-3,4-dihydronaphthalene-1-yl) Preparation of phenols [ka]

[0253] (6-tert-butoxy-3,4-dihydronaphthalene-1-yl)trifluorometh (52g, 148.42 mmol, 1 equivalent), (4-hydroxyphenyl ) Boronic acid (24.57g, 178.11 mmol, 1.2 equivalents) dioxane (800 A solution of potassium carbonate (41.03 g, 296.84 ml) in water (150 mL) (ol, 2 equivalents) and (1,1'-bis(diphenylphosphin)ferrocene)palladium (II) Add dichloride (10.86 g, 14.84 mmol, 0.1 equivalent) under nitrogen. The reaction mixture was stirred at 100°C for 10 hours. Thin-layer chromatography (petroleum ether) was performed. The reaction was completed using ethyl acetate (5:1). The residue was diluted with water (500 mL). Diluted and extracted with ethyl acetate (500 mL x 2). The combined organic layer was then brined ( Wash with 1000mL x 2, dry with anhydrous sodium sulfate, filter, and concentrate in vacuum. The residue was subjected to silica gel chromatography (petroleum ether:tetrahydrofuran = 50). Purified by :1~20:1, 4-(6-tert-butoxy-3,4-dihydrona Phthalen-1-yl)phenol (43g, 131.46 mmol, yield 88%, purity 9%) 0% was obtained as a yellow oily substance. LCMS(ESI)m / z:239.1[M+1-56 ] + , 1 H-NMR(400MHz,CDCl3)δ7.23(d,J=7.6Hz,2 H),6.91(d,J=8.0Hz,1H),6.87-6.79(m,3H),6. 73(d,J=8.4Hz,1H),5.95(s,1H),4.83-4.75(m, 1H),2.87-2.73(m,2H),2.44-2.31(m,2H),1.37 (s,9H).

[0254] Step 4: 4-(2-bromo-6-tert-butoxy-3,4-dihydronaphthalene- Preparation of 1-yl)phenol [ka]

[0255] 4-(6-tert-butoxy-3,4-dihydronaphthalene-1-yl)phenol In a solution of (1g, 3.06 mmol, 1 equivalent) of acetonitrile (20 mL), N-bromide is added. Moscuscinimide (489 mg, 2.75 mmol, 0.9 equivalents) was added in three divided doses. The reaction mixture was stirred at 20°C for 1.5 hours. LC-MS indicated that the reaction was complete. The residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). Wash the combined organic layer with brine (20 mL x 2), dry with anhydrous sodium sulfate, The solution was filtered and concentrated in a vacuum. The residue was subjected to silica gel chromatography (petroleum ether:vinegar). Purified with ethyl acid (1:0~20:1), 4-(2-bromo-6-tert-butyrate) Xy-3,4-dihydronaphthalene-1-yl)phenol (1g, 2.46 mmol, A yellow oily substance was obtained with a yield of 80% and a purity of 91%. LC-MS (ESI) m / z: 31 6.9 [M+1-56] + , 1 H-NMR (400 MHz, CDCl3) δ 7.12 (d ,J=8.4Hz,2H),6.90(d,J=8.0Hz,2H),6.77(s,1 H),6.69-6.62(m,1H),6.60-6.53(m,1H),4.86( s, 1H), 2.96 (s, 4H), 1.35 (s, 9H).

[0256] Step 5: 4-(6-tert-butoxy-2-phenyl-3,4-dihydronaphthalene) Preparation of -1-yl)phenol [ka]

[0257] 4-(2-bromo-6-tert-butoxy-3,4-dihydronaphthalene-1-yl) ) Phenol (1g, 2.46 mmol, 1 equivalent), Phenylboronic acid (314mg, 2 A solution of 0.58 mmol (1.05 equivalent) of dioxane (10 mL) and water (2 mL) is prepared. Potassium carbonate (678 mg, 4.91 mmol, 2 equivalents) and (1,1'-bis(diphenyl) Nylphosphino(ferrocene)palladium(II) dichloride (179mg, 0.24mg) (0.1 equivalents per mole) was added under nitrogen. The reaction mixture was stirred at 100°C for 12 hours. LC-MS indicated that the reaction was complete. Dilute the residue with water (20 mL) and extract acetate. Extraction was performed using chill (20 mL x 2). The combined organic layer was then treated with brine (20 mL x 3). Washed, dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was siliceous. Purified by chromatography (petroleum ether:ethyl acetate = 1:0 to 10:1) , 4-(6-tert-butoxy-2-phenyl-3,4-dihydronaphthalene-1- Phenol (930 mg, 2.35 mmol, yield 95%, purity 93%) is an orange oil. Obtained as a physical object. LCMS(ESI)m / z:314.1[M+1-56] + , 1 H-NM R(400MHz,CDCl3)δ7.16-7.09(m,2H),7.08-6.9 9(m,3H),6.97-6.89(m,2H),6.86-6.82(m,1H), 6.74-6.66(m,4H),4.70(s,1H),2.99-2.89(m,2 H), 2.84-2.75(m, 2H), 1.37(s, 9H).

[0258] Step 6: 4-(6-tert-butoxy-2-phenyltetralin-1-yl) Preparation of Knoll [ka]

[0259] 4-(6-tert-butoxy-2-phenyl-3,4-dihydronaphthalene-1-i) (Lu) Phenol (930 mg, 2.35 mmol, 1 equivalent) Tetrahydrofuran (20 A solution of (mL) and methanol (4mL) is prepared by adding palladium activated carbon catalyst (100mg, purity 1) 0%) was added under nitrogen. The suspension was degassed under vacuum and purged three times with hydrogen. The mixture was then... The mixture was stirred at 30°C for 36 hours under hydrogen (50 psi). LC-MS confirmed that the reaction was complete. The reaction mixture was filtered and the solution was concentrated. The resulting substance was subjected to further purification. It is used directly in the next step without any need for further processing, and is cis-4-(6-tert-butoxy-2-phenyl -Tetralin-1-yl)phenol (870 mg, 2.14 mmol, yield 91%, pure A concentration of 91% was obtained as a white solid. LC-MS (ESI) m / z: 317.0 [M+1 -56] + , 1 H-NMR(400MHz,CDCl3)δ7.22-7.12(m,3 H),6.89-6.78(m,4H),6.74(dd,J=2.0,8.4Hz,1 H),6.45(d,J=8.4Hz,2H),6.27(d,J=8.4Hz,2H) ,4.51(s,1H),4.25(d,J=4.8Hz,1H),3.38(dd,J =3.2,12.8Hz,1H),3.08-2.99(m,2H),2.27-2.0 8(m,1H),1.87-1.76(m,1H),1.37(s,9H).

[0260] Step 7: 4-[(1S,2R)-6-tert-butoxy-2-phenyltetraline Preparation of -1-yl]phenol [ka]

[0261] 4-(6-tert-butoxy-2-phenyltetralin-1-yl)phenol (870 mg, 2.13 mmol, 1 equivalent) supercritical liquid chromatography for chiral separation - (Column: AD, 250mm x 30mm, 5um; Mobile phase: 0.1% ammonium hydroxide) Prepare a methanol solution of 20% to 20%, perform 4.2 minutes for each run, and then 4-[(1S ,2R)-6-tert-butoxy-2-phenyltetralin-1-yl]phenol (420 mg, 1.04 mmol, yield 97%, purity 92%) was used as the first fraction, and 4-[(1R,2S)-6-tert-butoxy-2-phenyltetralin-1-yl ]フェノール (420mg, 1.04mmol, yield 97%, purity 92%) 2nd drawing points として got た. Drawing points 1:[α] D =+336.9(C=0.50g / 100mL Ethyl anhydride Medium, 25℃), LC-MS(ESI)m / z:395.1[M+23] + , 1 H NMR (400MHz, DMSO-d6)δ9.02(s,1H),7.20-7.07(m, 3H),6.87-6.79(m,3H),6.79-6.72(m,1H),6.71 -6.64(m,1H),6.36(d,J=8.4Hz,2H),6.15(d,J= 8.4Hz,2H),4.19(d,J=4.8Hz,1H),3.31-3.26(m ,1H),3.09-2.89(m,2H),2.17-2.04(m,1H),1.7 9-1.65(m,1H),1.29(s,9H). Drawing points 2:[α] D =-334.1( C=0.50g / 100mL ethanol (at 25℃), LC-MS (ESI) m / z: 3 95.2[M+23] + , 1 H-NMR (400MHz, DMSO-d6) δ: 9.02 (s,1H),7.21-7.06(m,3H),6.88-6.78(m,3H),6 .78-6.72(m,1H),6.71-6.64(m,1H),6.36(d,J= 8.4Hz,2H),6.15(d,J=8.4Hz,2H),4.19(d,J=4. 8Hz,1H),3.30-3.27(m,1H),3.08-2.90(m,2H), 2.16-2.04(m,1H),1.79-1.65(m,1H),1.29(s,9 H).

[0262] Step 8: 4-(6-benzyloxy-2-phenyl-3,4-dihydronaphthalene-1 -yl)phenyl]1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfate Preparation of sulfonate [ka]

[0263] 4-[(1R,2S)-6-tert-butoxy-2-phenyltetralin-1-i [Lu]phenol (1g, 2.68 mmol, 1 equivalent) and 1,1,2,2,3,3,4, 4,4-Nonafluorobutane-1-sulfonylfluoride (811 mg, 2.68 mmol) In a solution of 1 / 1 equivalent of tetrahydrofuran (5 mL) and acetonitrile (5 mL), Potassium carbonate (557 mg, 4.03 mmol, 1.5 equivalents) was added. Reaction mixture 2 The mixture was stirred at 5°C for 16 hours. TLC (petroleum ether:ethyl acetate = 10:1) was used as the starting material. This indicated that the material was completely consumed and a new spot had formed. The reaction mixture was then reduced in pressure. The solution was concentrated below. The residue was subjected to silica gel chromatography (petroleum ether:ethyl acetate = It was purified by (1:0~50:1). The desired product was [4-[(1R,2S)-6 -tert-butoxy-2-phenyl-tetralin-1-yl]phenyl]1,1,2, 2,3,3,4,4,4-Nonafluorobutane-1-sulfonate (1.6g, 2.44 mmol (91% yield) was obtained as a colorless oil. 1 1H NMR (400MHz, CDC) l3)δ7.21-7.11(m,3H),6.94-6.86(m,3H),6.84 -6.73(m,4H),6.46(d,J=8.8Hz,2H),4.33(d,J= 5.2Hz, 1H), 3.50-3.40(m, 1H), 3.16-2.95(m, 2H) ),2.20-2.02(m,1H),1.91-1.79(m,1H),1.38(s ,9H).

[0264] Step 9: 1-[4-(6-benzyloxy-2-phenyl-3,4-dihydronaphthalate Preparation of 1-1-yl)phenyl]-4-(dimethoxymethyl)piperidine [ka]

[0265] [4-[(1R,2S)-6-tert-butoxy-2-phenyltetralin-1- [yl]phenyl]1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfur Honate (1.6g, 2.44mmol, 1 equivalent), 4-(dimethoxymethyl)piperidi (584 mg, 3.67 mmol, 1.5 equivalents), sodium tert-butoxide ( (705 mg, 7.33 mmol, 3 equivalents), palladium acetate (82 mg, 0.37 mmol) (1, 0.15 equivalents), and dicyclohexylphosphino-2',4',6'-triisopropyl alcohol Ropirbiphenyl (233 mg, 0.49 mmol, 0.2 equivalents) in toluene (30 mL) The mixture was degassed, purged three times with nitrogen, and then the mixture was left in a nitrogen atmosphere for 16 hours. The mixture was stirred at 90°C. LC-MS detected one main peak with the desired MS. This demonstrated that TLC (petroleum ether:ethyl acetate = 10:1) completely eliminates the starting material. It was consumed and showed that one new spot had formed. The mixture was cooled and ethyl acetate was added. Dilute with (50 mL), filter through a diatomaceous earth plug, and remove the filter cake from ethyl acetate (30 Washed with (mL). The filtrate was concentrated. The residue was subjected to silica gel chromatography (petroleum ethylene oxide). The solution was purified using ethyl acetate (100:1~10:1). The desired product was 1- [4-[(1R,2S)-6-tert-butoxy-2-phenyltetralin-1-i Phenyl-4-(dimethoxymethyl)piperidine (1.1g, 2.14 mmol, 87% yield was obtained as a white solid. LC-MS(ESI) m / z: 514.3[M+ 1] + , 1 H NMR(400MHz,CDCl3)δ7.21-7.11(m,3H) ,6.88-6.78(m,4H),6.73(dd,J=2.4,8.0Hz,1H) ,6.57(d,J=8.4Hz,2H),6.27(d,J=8.8Hz,2H),4 .23(d,J=4.8Hz,1H),4.06(d,J=7.2Hz,1H),3.6 3-3.52(m,2H),3.41-3.30(m,7H),3.13-2.96(m ,2H),2.54(d,J=2.0,12.0Hz,2H),2.28-2.10(m ,1H),1.85-1.63(m,4H),1.49-1.31(m,11H).

[0266] Step 10: 1-[4-[(1R,2S)-6-hydroxy-2-phenyltetraline Preparation of -1-yl]phenyl]piperidine-4-carbaldehyde [ka]

[0267] 1-[4-[(1R,2S)-6-tert-butoxy-2-phenyl-tetralin- 1-Il]phenyl]-4-(dimethoxymethyl)piperidine (1.1g, 2.14mm) A solution of tetrahydrofuran (45 mL) (1 ol, 1 equivalent) is mixed with sulfuric acid (2 M, 43 mL, 4 (0 equivalents) was added. The reaction mixture was stirred at 70°C for 1 hour. LC(petroleum ether: acetate) Chill (3:1) means that the starting material has been completely consumed and one new spot has been formed. The reaction mixture was prepared by adding saturated sodium bicarbonate solution to adjust the pH to approximately 7-8. The mixture was quenched and extracted with ethyl acetate (20 mL x 2). The combined organic layer was then collected. Wash with brine (20 mL), dry with sodium sulfate, filter, and concentrate under reduced pressure. The residue was used in the next step without further purification. The desired product was 1- [4-[(1R,2S)-6-hydroxy-2-phenyltetralin-1-yl]phenyl [Nyl]piperidine-4-carbaldehyde (900 mg, 2.14 mmol, yield 99%) A 97% purity solution was obtained as a pale yellow solid. LC / MS (MS(ESI) m / z: 412. 1[M+1] +

[0268] Step 11: 3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2- Phenyltetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazine- 1-yl]-1-oxoisoindoline-2-yl]piperidine-2,6-dione (chemical Preparation of compound (Ib) [ka]

[0269] 3-(1-oxo-5-piperazine-1-yl-isoindoline-2-yl)piperidine n-2,6-dione hydrochloride (319 mg, 0.87 mmol, compared to exemplary compound 62) Methanol (4 mL) and dichloromethane (4 mL) prepared in step 17 as described above. Sodium acetate (120 mg, 1.46 mmol, 2 equivalents) was added to the solution of ). Mix The mixture is stirred at 20°C for 0.5 hours, and then 1-[4-[(1R,2S)- 6-Hydroxy-2-phenyltetralin-1-yl]phenyl]piperidine-4-ca Rubaldehyde (300 mg, 0.73 mmol, 1 equivalent) and sodium cyanoborhydride Um (137 mg, 2.19 mmol, 3 equivalents) was added. The mixture was stirred at 20°C for 12 hours. Mixed. LC-MS was performed to ensure that the starting material was completely consumed and that one main phase had the desired MW. The detection of the substance indicated that the reaction mixture was concentrated under reduced pressure. The residue was then prepared using prep- HPLC (Phenomenex Luna C18 column, 250x50mm, 10u) m; Mobile phase: [Water (0.05% HCl)-Acetonitrile]; B%: Acetonitrile 1 The solution was purified by (0%~40%, 30 minutes). The desired product was 3-[5-[4-[[1 -[4-[(1R,2S)-6-hydroxy-2-phenyltetralin-1-yl]f [enyl]-4-piperidyl]methyl]piperazine-1-yl]-1-oxo-isoindo Phosphate-2-yl]piperidine-2,6-dione (288.4 mg, 0.37 mmol, lysate A concentration of 51% was obtained as a white solid of hydrochloride. LC-MS (ESI) m / z: 724. 4 [M+1] + , 1 H NMR(400MHz,DMSO-d6)δ10.97(s, 1H),10.83(s,0.9H,HCl),7.60(d,J=8.5Hz,1H) ,7.40(br s,2H),7.22-7.11(m,5H),6.83(d,J= 6.0Hz,2H),6.69-6.63(m,2H),6.58-6.47(m,3H ),5.07(dd,J=5.2,13.2Hz,1H),4.41-4.30(m,2 H),4.28-4.21(m,1H),4.00(d,J=12.7Hz,2H),3 .61(d,J=11.0Hz,2H),3.54-3.36(m,6H),3.16( br s,4H),3.06-2.84(m,3H),2.76-2.53(m,1H) ,2.43-2.33(m,1H),2.27(br s,1H),2.16-2.04 (m,3H), 2.02-1.69 (m,5H).

[0270] (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydroxy-2- Phenyltetralin-1-yl]phenyl]-4-piperidyl]methyl]piperazine- 1-yl]-1-oxoisoindoline-2-yl]piperidine-2,6-dione (chemical Synthesis of compound (Ic)

[0271] Step 1: (4S)-5-amino-4-(benzyloxycarbonylamino)-5-oxy Preparation of tert-butyl sopentanoate [ka] (2S)-2-(benzyloxycarbonylamino)-5-tert-butoxy-5- Oxopentanoic acid (20g, 59.28 mmol, 1.00 equivalent), dicarboxylic acid tert-butyl (94.85 mmol, 21.79 mL, 1.60 equivalents) and pyridine (9.38g, 118.57mmol, 9.57mL, 2.00 equivalents) 1,4-Dioxy The mixture of Sun (200 mL) was degassed at 0°C, purged three times with nitrogen, and then the mixture was degassed at 0°C. The mixture was stirred under a nitrogen atmosphere for 0.5 hours. Ammonium bicarbonate (14.06 g, 177.8 5 mmol (14.65 mL, 3.00 equivalents) was added at 0°C. The mixture was heated at 25°C for 16 minutes. The mixture was stirred for a specified time. LC-MS showed the desired mass. Volatile components were removed under reduced pressure. Residual The substance was diluted with water (300 mL) and extracted with ethyl acetate (300 mL x 1). The mixture was then combined into one solution. The organic phase was then mixed with hydrochloric acid solution (0.5 M, 200 mL x 2) and saturated sodium bicarbonate (300 mL). Wash with (3 mL x 3) and brine (500 mL x 3), then dry with anhydrous sodium sulfate. The mixture was filtered and concentrated in a vacuum to obtain the crude product. The crude product was then ground (petroleum ether: acetate ether). Chill = 10:1, 300mL) and (4S)-5-amino-4-(benzyloxycal Bonylamino)-5-oxopentanoate tert-butyl (19g, 56.08mmo) 1 was obtained as a white solid with a yield of 94% and a purity of 99%. LC-MS (ESI) m / z: 359.0 [M+23] + . 1 H-NMR (400 MHz, CDCl3) δ7.39-7 .29(m,5H),6.38(s,1H),5.74(d,J=7.2Hz,1H), 5.58(s,1H),5.11(s,2H),4.25(d,J=5.6Hz,1H) ,2.55-2.41(m,1H),2.39-2.27(m,1H),2.18-2. 04(m,1H),2.02-1.85(m,1H),1.45(s,9H).

[0272] Step 2: Preparation of (4S)-4,5-diamino-5-oxopentanoate tert-butyl Made [ka]

[0273] (4S)-5-amino-4-(benzyloxycarbonylamino)-5-oxopene tert-butyl tanate (19g, 56.48 mmol, 1.00 equivalent) in methanol ( To a 200 mL solution, palladium-carbon (2 g, 10%) was added under a nitrogen atmosphere. The mixture was degassed and purged three times with hydrogen. The mixture was then incubated at 25°C under H2 (50 psi) for 16 hours. The mixture was stirred. Thin-layer chromatography (petroleum ether:ethyl acetate = 1:2) showed that the reaction was The process was completed. The reaction mixture was filtered, and the filtrate was concentrated. The compound (4S)-4, 5-Diamino-5-oxopentanoate tert-butyl (11g, 54.39mmol) The result was obtained as a pale green oily substance with a yield of 96%. 1 1H NMR (400MHz, CDCl3) )δ7.03(br s,1H),5.55(br s,1H),3.44(br s, 1H),2.49-2.31(m,2H),2.11(dd,J=6.0,12.8Hz ,1H),1.92-1.76(m,1H),1.66(s,2H),1.45(s,9 H).

[0274] Step 3: 4-[2-[(1S)-4-tert-butoxy-1-carbamoyl-4-o [xo-butyl]-1-oxo-isoindolin-5-yl]piperazine-1-carboxylic acid Preparation of tert-butyl [ka] 4-[3-(bromomethyl)-4-methoxycarbonylphenyl]piperazine-1- Tert-butyl carboxylate (1.5g, 3.63 mmol, 1 equivalent, published US patent application) Exemplary compound 62 of No. 2018 / 0155322, prepared in step 15) (4S)-4,5-diamino-5-oxo-penta tert-butyl nitrate (1.10 g, 5.44 mmol, 1.5 equivalents) and diisopropyl nitrate Ethylamine (1.41 g, 10.89 mmol, 1.90 mL, 3 equivalents) was added. The mixture was stirred at 80°C for 12 hours. LC-MS indicated that the reaction was complete. The substance was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The mixture was then combined into one. The organic layer was washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was subjected to preparative reverse-phase HPLC (column: Phenomenex). Synergi Max-RP 250x50mm, 10 microns, mobile phase: [Water (0 .225% formic acid)-acetonitrile], B%:acetonitrile 40%~acetonitrile 7 Purified by 0% (30 minutes), 4-[2-[(1S)-4-tert-butoxy-1- Carbamoyl-4-oxo-butyl]-1-oxo-isoindoline-5-yl]pipera tert-butyl din-1-carboxylate (1.6g, 2.94 mmol, yield 81.05%) A %, 92% purity product was obtained as an off-white solid. LC-MS(ESI)m / z: 503.2[M+1] + .

[0275] Step 4: (3S)-3-(1-oxo-5-piperazine-1-yl-isoindoline- Preparation of 2-yl)piperidine-2,6-dione [ka] 4-[2-[(1S)-4-tert-butoxy-1-carbamoyl-4-oxo-bu [Tyl]-1-oxo-isoindoline-5-yl]piperazine-1-carboxylic acid -Butyl (700 mg, 1.39 mmol, 1 equivalent) dissolved in acetonitrile (15 mL) Benzenesulfonic acid (440 mg, 2.79 mmol, 2 equivalents) was added to the solution. The mixture was stirred at 85°C for 12 hours. LC-MS indicated that the reaction was complete. The solution was concentrated in the air. The residue was pulverized with ethyl acetate (30 mL x 3) and (3S)-3-(1 -Oxo-5-piperazine-1-yl-isoindoline-2-yl)piperidine-2,6 - Zion (630 mg, crude product) was obtained as a gray solid. LC-MS (ESI) m / z :329.1 [M+1] + ; Chiral SFC analysis shows 100% ee.

[0276] Process 5: (3S)-3-[5-[4-[[1-[4-[(1R,2S)-6-hydrox C-2-phenyltetralin-1-yl]phenyl]-4-piperidyl]methyl]piper [Radin-1-yl]-1-oxoisoindolin-2-yl]piperidine-2,6-di Preparation of ON (compound (Ic)) [ka] (3S)-3-(1-oxo-5-piperazine-1-yl-isoindoline-2-yl) ) Piperidine-2,6-dione (1.30g, 3.47mmol, 1 equivalent, benzenesulfur A mixture of dichloromethane (8 mL) and methanol (32 mL) of fonate, containing sodium acetate. 854 mg of lium (10.41 mmol, 3 equivalents) was added all at once at 20°C. Stirred at 20°C for 10 minutes. Then, 1-[4-[(1R,2S)-6-hydroxy- 2-phenyl-tetralin-1-yl]phenyl]piperidine-4-carbaldehyde (1 g, 2.43 mmol, 0.7 equivalents, in the synthesis of compound (Ib) as described above The prepared solution was added. The mixture was stirred at 20°C for 10 minutes. Then, acetic acid (0.2 mL) was added. ) and sodium cyanoborohydride (436 mg, 6.94 mmol, 2 equivalents) once It was added to the mixture. The mixture was stirred at 20°C for 40 minutes. The mixture was concentrated in a vacuum and 50 mL of tape was added. Add trahydrofuran and 20 mL of water. Stir the mixture for 20 minutes. Saturated sodium bicarbonate Thorium solution was added to adjust the pH to 8-9. The aqueous phase was mixed with ethyl acetate and tetrahydrofoam. Extraction was performed using ran (v:v=2:1, 60mL x 3). The combined organic phase was then treated with brine ( The solution was washed with 60 mL x 1), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was separated and subjected to reverse-phase HPLC (column: Phenomenex Luna C18 250). x50mm, 10 microns; Mobile phase: [Water (0.225% formic acid)-acetonitrile]; B The product was purified by (20%~50%, 30 minutes). The product is (3S)-3-[5-[ 4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-tetralin-1 -yl]phenyl]-4-piperidyl]methyl]piperazine-1-yl]-1-oxo- Isoindoline-2-yl]piperidine-2,6-dione (964 mg, 1.23 mmol) (1, yield 35%, purity 98%, formate) was obtained as a white solid of formate after freeze-drying. The chiral purity is determined by the chiral SFC (Chiralcel OJ-3 50×4.6 mm). 3 microns; mobile phase: 50% ethanol (0.05% DEA) in CO2; flow rate: 3 mL Analysis was performed using ( / min, wavelength: 220nm), t p = 2.89 minutes, observed over 95% of de I did. [α D =-267.5(c=0.2 in DMF, 25°C). LC-MS(ESI) m / z:724.2[M+1] + . 1 1H NMR (400MHz, DMSO-d6) δ1 0.94 (s, 1H), 8.16 (s, 1H, formate), 7.51 (d, J=8.8Hz) ,1H),7.21-6.98(m,5H),6.83(d,J=6.4Hz,2H), 6.68-6.57(m,2H),6.56-6.44(m,3H),6.20(d,J =8.8Hz,2H),5.04(dd,J=5.2,13.2Hz,1H),4.32 (d,J=16.8Hz,1H),4.19(d,J=17.2Hz,1H),4.12 (d,J=4.8Hz,1H),3.51(br d,J=10.0Hz,4H),3. 27(br s,8H),3.03-2.82(m,3H),2.63-2.54(m, 1H),2.43-2.28(m,2H),2.19(d,J=6.8Hz,2H),2 .15-2.02(m,1H),2.01-1.89(m,1H),1.83-1.51 (m,4H), 1.28-1.04(m,2H).

[0277] Free, non-salt type 1 H-NMR:(400MHz,DMSO-d6)δ10.93(s,1 H),9.09(s,1H),7.51(d,J=8.8Hz,1H),7.18-7. 09(m,3H),7.08-7.02(m,2H),6.83(d,J=6.4Hz, 2H),6.64(d,J=8.4Hz,1H),6.60(d,J=2.0Hz,1H ),6.53(d,J=8.8Hz,2H),6.48(dd,J=2.4,8.4Hz ,1H),6.20(d,J=8.8Hz,2H),5.04(dd,J=5.2,13 .2Hz,1H),4.39-4.27(m,1H),4.24-4.15(m,1H) ,4.12(d,J=4.8Hz,1H),3.51(d,J=9.6Hz,2H),3 .29-3.24(m,5H),3.03-2.83(m,3H),2.62-2.54 (m,4H),2.52(s,3H),2.41-2.36(m,1H),2.19(d ,J=7.2Hz,2H),2.15-2.08(m,1H),2.00-1.89(m ,1H),1.81-1.58(m,4H),1.22-1.06(m,2H).

[0278] Palbocicilb 6-Acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazine-1-I [Pyridine-2-yl]amino]pyrido[2,3-d]pyrimidine-7(8H)-one Palbociclib, also known as palbociclib, has the following structural formula: [ka] .

[0279] Palbociclib is an inhibitor of cyclin-dependent kinases (CDKs) 4 and 6. Ikurin D1 and CDK4 / 6 are located downstream of signaling pathways that lead to cell proliferation. In vitro, palbociclib blocks the progression of cells from the G1 to the S phase of the cell cycle. This reduced the cell proliferation of estrogen receptor (ER)-positive breast cancer cell lines. Treatment of breast cancer cell lines with a combination of rubociclib and anti-estrogen is more effective than treating each drug alone. Compared to treatment, it results in a decrease in the phosphorylation of retinoblastoma (Rb) protein, and This results in decreased E2F expression and signaling, and increased growth arrest. ER-positive milk Cancer cell lines were treated in vitro with a combination of palbociclib and anti-estrogen. As a result, cellular senescence increased compared to each drug alone, and this was up to 6% after palbociclib withdrawal. The levels were higher when they lasted for several days and when anti-estrogen treatment was continued. Patient-derived ER-positive breast milk In an in vivo trial using a cancer xenograft model, the combination of palbociclib and letrozole The combination, compared to each drug alone, affects Rb phosphorylation, downstream signaling, and tumor growth. It was demonstrated that inhibition was increased.

[0280] Human bone treated with palbociclib in vitro, with or without anti-estrogen. Medullary mononuclear cells did not age and resumed proliferation after discontinuation of palbociclib.

[0281] In some embodiments, this application relates to the treatment and / or prevention of breast cancer as disclosed herein. Regarding any method for prevention, this method provides a therapeutically effective amount to the target that needs it. A compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a CDK4 / 6 inhibitor or This includes administering the pharmaceutically acceptable salt concurrently with the substance, or to subjects requiring it. , a therapeutically effective dose of the compound of formula (Ic) or a pharmaceutically acceptable salt thereof and CDK4 / 6 inhibitor This includes the simultaneous administration of a harmful agent or a combination of a pharmaceutically acceptable salt thereof. In the embodiment, the compound of formula (Ic) is a free base or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 / 6 inhibitor is a free base or its pharmaceutically acceptable form. It is a salt. In some embodiments, the CDK4 / 6 inhibitor is palbociclib or so It is a pharmaceutically acceptable salt of [the substance]. In some embodiments, the CDK4 / 6 inhibitor is [the substance]. It is palbociclib dihydrochloride. Palbociclib dihydrochloride is, for example, a hydrogen chloride ether. It can be prepared by the reaction of palbociclib free base in solution. The product was developed by Pfizer and sold under the brand name Ibrance (registered trademark). It is an over-the-counter medication used to treat breast cancer.

[0282] Methods for ubiquitinating / degrading target proteins within cells This invention relates to the ubiquitination of intracellular target proteins (e.g., intracellular target proteins). / Provides a method for disassembly. This method preferably involves E, which is connected via a linker portion. 3. Administer a bifunctional compound containing a ubiquitin ligase binding site and a protein targeting site. This includes, in this case, the E3 ubiquitin ligase binding site is located in the ubiquitin pathway. It recognizes proteins (e.g., ubiquitin ligase, preferably E3 ubiquitin ligase). The protein targeting portion recognizes the target protein (e.g., intracellular target protein). As a result, when the target protein is positioned in close proximity to the E3 ubiquitin ligase, the target Protein ubiquitination occurs, resulting in target protein ubiquitination via the proteasome pathway. This leads to the breakdown of the protein, resulting in the regulation (e.g., reduction) of the target protein level. Morphologically, the protein-targeting moiety binds to nuclear hormone receptors. In certain embodiments, The protein-targeting portion binds to estrogen receptors or estrogen-related receptors. In one embodiment, the intracellular target protein is an estrogen receptor or estrogen-related protein. It is a receptor. In one embodiment, the linker portion is the protein targeting portion, E3 ubiquitous It is a bond or chemical group that covalently bonds to the linkage bond portion. In a particular embodiment, the linker - may contain one or more alkanes and one or more heterocyclic moieties. Specific implementation Morphologically, alkanes are C1-C6 alkyl groups, and the heterocyclic portion is pyrrolidine, imida The substance is zolidine, piperidine, or piperazine. In one embodiment, it is an E3 ubiquitin rigger. Ze is cereblon. In certain embodiments, the cereblon-binding portion is thalidomide. Lenalidomide, pomalidomide, their analogues, their counterparts, or their derivatives. The control (e.g., reduction) of protein levels brought about by the present invention is a pathological or state. This treatment provides a reduction in the level of that protein in the patient's cells. It is regulated via target proteins.

[0283] In one embodiment, the present application relates to a method for degrading estrogen receptor (ER) proteins, formula (I) Compounds of the same, or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates thereof, poly The present invention provides a form, an isotopic derivative, or a prodrug thereof. In some embodiments, the formula ( The ER that is degraded by compound I) is wild-type ER. In some embodiments, The ER that is degraded by the compound of formula (I) is a variant form of ER.

[0284] In some embodiments, the mutant form of ER that is degraded by the compound of formula (I) is Contains at least one ER somatic tumor mutation.

[0285] In some embodiments, at least one somatic ER tumor mutation is Y537X, D Choose from 538X, E380X, L379X, V422X, S463X, and L536X. And "X" refers to any amino acid residue other than the wild-type residue at that position. In this embodiment, at least one somatic ER tumor mutation is Y537X, D538X, E Choose from 380X, L379X, V422X, S463X, and L536X, and select "X". refers to any amino acid residue other than the wild-type residue at that position, such as alanine (A) and valine. (V), leucine (L), isoleucine (I), phenylalanine (F), methionine ( M), tryptophan (W), proline (P), glycine (G), serine (S), threo Nin (T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y) ), lysine (K), arginine (R), histidine (H), aspartic acid (D), and Selected from glutamic acid (E).

[0286] In some embodiments, the mutant form of ER that is degraded by the compound of formula (I) is It includes at least the Y537X ER somatic tumor mutation.

[0287] In some embodiments, the mutant form of ER that is degraded by the compound of formula (I) is It includes at least the D538X ER somatic tumor mutation.

[0288] In some embodiments, the mutant form of ER that is degraded by the compound of formula (I) is It includes at least the E380X ER somatic tumor mutation.

[0289] In some embodiments, the mutant form of ER that is degraded by the compound of formula (I) is It includes at least the L379X ER somatic tumor mutation.

[0290] In some embodiments, the mutant form of ER that is degraded by the compound of formula (I) is It includes at least the V422X ER somatic tumor mutation.

[0291] In some embodiments, the mutant form of ER that is degraded by the compound of formula (I) is It includes at least the S463X ER somatic tumor mutation.

[0292] In some embodiments, the mutant form of ER that is degraded by the compound of formula (I) is It includes at least the L536X ER somatic tumor mutation.

[0293] In some embodiments, at least one somatic ER tumor mutation is Y537S, Y 537N, D538G, E380Q, L379I, V422del, S463P, L53 Selected from 6P and L536_D538>P.

[0294] In some embodiments, the mutant form of ER that is degraded by the compound of formula (I) is It includes at least the Y537S ER somatic tumor mutation.

[0295] In some embodiments, the mutant form of ER that is degraded by the compound of formula (I) is It includes at least the Y537N ER somatic tumor mutation.

[0296] In some embodiments, the mutant form of ER that is degraded by the compound of formula (I) is It includes at least the D538G ER somatic tumor mutation.

[0297] In some embodiments, the mutant form of ER that is degraded by the compound of formula (I) is It includes at least the E380Q ER somatic tumor mutation.

[0298] In some embodiments, the mutant form of ER that is degraded by the compound of formula (I) is It includes at least the L379I ER somatic tumor mutation.

[0299] In some embodiments, the mutant form of ER that is degraded by the compound of formula (I) is It includes at least the V422del ER somatic tumor mutation.

[0300] In some embodiments, the mutant form of ER that is degraded by the compound of formula (I) is It includes at least the S463P ER somatic tumor mutation.

[0301] In some embodiments, the mutant form of ER that is degraded by the compound of formula (I) is It includes at least the L536P ER somatic tumor mutation.

[0302] In some embodiments, the mutant form of ER that is degraded by the compound of formula (I) is It includes at least the ER somatic tumor mutation L536_D538>P.

[0303] In some embodiments, the present disclosure treats a pathological condition or state that is causally related to a protein. The aim is to provide a method for treating patients who need to break down the protein in question. This method produces a therapeutic effect, and the method involves selecting an effective amount of the compound of formula (I) as needed. The alternative is to administer it to patients who need it, in combination with another bioactive agent, such as an anticancer drug. This includes the following: The pathological condition or state is a pathological condition or condition that is causally related to the expression or overexpression of the protein. It can be in any condition.

[0304] Treatment method In one embodiment, the present application relates to a method for treating and / or preventing cancer, which requires To the target, a therapeutically effective dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, enant Administer omers, stereoisomers, solvates, polymorphs, isotopic derivatives, or prodrugs. Regarding methods, including the act of doing so.

[0305] In one embodiment, the present application relates to a formula (I) for use in a method of treating and / or preventing cancer. ) compounds, or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates thereof, The present invention relates to polymorphs, isotopic derivatives, or prodrugs. In some embodiments, the method This refers to a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer. , stereoisomers, solvates, polymorphs, isotopic derivatives, or prodrugs, as needed This includes administering the drug to the target population.

[0306] In one embodiment, the present application relates to a method for treating and / or preventing cancer, which requires For the target, a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, enantio Mer, stereoisomer, solvate, polymorph, isotopic derivative, or prodrug, one or more The present invention relates to a method, including administration in combination with the additional anticancer drugs mentioned above.

[0307] In one embodiment, this application describes a method for treating cancer and / or in combination with one or more additional anticancer agents. A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of prevention. enantiomers, stereoisomers, solvates, polymorphs, isotopic derivatives, or prodrugs Regarding the method, in some embodiments, the method involves a therapeutically effective amount of the compound of formula (I), or Its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, and isotopes This includes administering a conductor or prodrug to a subject who requires it.

[0308] In one embodiment, this application relates to the treatment of cancer and / Alternatively, for use in prevention, a compound of formula (I), or a pharmaceutically acceptable salt thereof, enan Regarding thiomers, stereoisomers, solvates, polymorphs, isotopic derivatives, or prodrugs ru.

[0309] The methods for treating cancer described herein include reducing tumor size, or, Alternatively, the cancer may be metastatic, and this treatment method may include inhibiting the invasion of metastatic cancer cells.

[0310] In some embodiments, the cancer is breast cancer.

[0311] In some embodiments, the breast cancer is metastatic breast cancer.

[0312] In some embodiments, the breast cancer is locally advanced breast cancer.

[0313] In some embodiments, the breast cancer is ER+, HER2- breast cancer.

[0314] In some embodiments, the breast cancer is metastatic, ER-+, and HER2- breast cancer.

[0315] In some embodiments, breast cancer is locally advanced, metastatic, ER-positive, and HER2-positive. I have breast cancer.

[0316] In some embodiments, subjects with breast cancer have ER biomarkers Depending on the state, that is, whether the subject has one or more somatic tumor mutations against ER , the compound of formula (I), or its pharmaceutically acceptable salts, enantiomers, stereoisomers, and solutions Different responses to treatment with mediators, polymorphs, isotopic derivatives, or prodrugs They may have it.

[0317] In one embodiment, the disclosure relates to a breast cancer having at least one somatic ER tumor mutation. This invention provides a method for treating breast cancer in the target population.

[0318] As used herein, "ER" refers to the human ESR1 gene that encodes the human ESR1 gene. This refers to toestrogen receptor alpha (ERα). Somatic ER tumor mutations are treated with endocrine therapy. This is observed with increased frequency in patients with breast cancer who have acquired resistance to (T oy et al(2013)Nature Genetics 45:1439-14 45, Merenbakh-Lamin et al (2013) Cancer Res search 73:6856-6864, Robinson et al(2013)N ature Genetics 45:1446-1451, Li et al (201 3) Cell Reports 4:1116-1130. Somatic ER mutations are E It forms a hydrophobic pocket for binding to an R hormone ligand (e.g., estrogen). This frequently occurs in the ER ligand-binding domain, which is a functional domain of the human ER. Hamadeh et al(2018)Cancer Treat Rev 70:4 7-55, Jeselsohn, et al (2015) Nat Rev Clin O (ncol 12:573-583). Furthermore, somatic properties in the ER ligand-binding domain. ER tumor mutations can be treated with endocrine therapy that creates a low-estrogen environment (e.g., aromatase inhibition). It has been demonstrated that it is acquired in response to selective pressure of the agent (Jeselsohn e t al(2014)Clinical Cancer Research 20:17 57-1767, Schiavon, et al (2015) Sci Transl M (ed 7:313ra182). Although not bound by theory, ER ligand binding Mutations in the main lead to decreased ligand specificity, thereby causing the ER to estrogen It functions independently of gen. These ER tumor mutations proliferate in estrogen-depleted environments. Endocrine endocrine systems provide tumor cells with the ability to block or reduce estrogen levels. It is selected in response to the therapy.

[0319] As will be understood by those skilled in the art, ER is a 525-amino acid residue in length and has three functions. Action domains: N-terminal transcriptional regulatory domain, DNA binding domain, and ligand binding domain This polypeptide contains (Kumar, et al. 2011) J. Amino Ac (ids Article ID 812540). The DNA-binding domain is via a hinge. It is then linked to the ligand-binding domain. The reference sequence suitable for ER is indicated by Sequence ID No. 1. It is stated that in the UniProt database, P03372(ESR1_HUMAN) It has been identified as such.

[0320] As used herein, “N-terminal transcriptional regulatory domain” refers to amino acid residue 1 of the ER or A continuous stretch of amino acid residues extending up to approximately 180 amino acid residues (for example, sequence number This refers to amino acid residues 1-180 of No. 1. In some embodiments, "N-terminal transcriptional regulatory The "main" refers to a sequence of amino acid residues from amino acid residue 1 to amino acid residue 180 of the ER. This refers to a continuous stretch (for example, amino acid residues 1-180 of sequence number 1).

[0321] As used herein, the "DNA-binding domain" refers to approximately 181 amino acid residues of the ER. A continuous stretch of amino acid residues extending from approximately 263 amino acid residues (for example, sequence This refers to amino acid residues 181-263 of number 1. In some embodiments, it refers to "DNA binding". The "domain" refers to the amino acid residues from amino acid residue 181 to amino acid residue 263 of the ER. This refers to a continuous stretch of a base (for example, amino acid residues 181-263 of sequence number 1).

[0322] As used herein, “hinge” refers to approximately amino acid residues 264 to ER. A continuous stretch of amino acid residues extending up to acid residue 302 (for example, the amino acid in SEQ ID NO: 1) This refers to acid residues 264-302). In some embodiments, the "hinge" is the endothelial matrix of the ER. A continuous stretch of amino acid residues from amino acid residue 264 to amino acid residue 302 ( For example, it refers to amino acid residues 264-302 of sequence number 1.

[0323] As used herein, the "ligand-binding domain" is defined as starting from approximately amino acid residue 303. A continuous stretch of amino acid residues extending up to approximately 552 amino acid residues (for example, sequence number This refers to amino acid residues 303-552. In some embodiments, it refers to "ligand-bound The "main" is a sequence of amino acid residues from amino acid residue 303 to amino acid residue 552. This refers to the stretched section (for example, amino acid residues 303-552 of sequence number 1).

[0324] In some embodiments, the subject is at least one body located in the functional domain of the ER. She has breast cancer, including a cellular ER tumor mutation.

[0325] In some embodiments, at least one somatic ER tumor mutation is present in the ER reference sequence ( For example, compared to SEQ ID NO: 1), one or more amino acid residues in the functional domain of the ER This is an insertion, deletion, or substitution.

[0326] In some embodiments, at least one somatic ER tumor mutation is present in the ER reference sequence ( For example, compared to SEQ ID NO: 1), one or more amino acid residues in the functional domain of the ER This is a substitution.

[0327] In some embodiments, at least one somatic ER tumor mutation is associated with ER ligand binding. It exists in the combined domain.

[0328] In some embodiments, at least one somatic ER tumor mutation is present in the ER reference sequence ( For example, compared to SEQ ID NO: 1), one or more amino acids in the ligand-binding domain of ER This involves the insertion, deletion, or substitution of an acid residue.

[0329] In some embodiments, at least one somatic ER tumor mutation is associated with the ER reference sequence and In comparison, insertion of one or more amino acid residues selected from amino acid residues 303-552, This is a deletion or substitution, and the ER reference sequence is described by sequence number 1.

[0330] In some embodiments, at least one somatic cell in the ER ligand-binding domain Sexual ER tumor mutations exhibit reduced ligand specificity and / or enhanced cofactor recruitment. Provides ER. Not bound by theory, but with reduced ligand specificity and / or ER with enhanced cofactor recruitment has an increased ability to trigger ER signaling pathways. This thereby confers a proliferative advantage to tumor cells containing the mutated ER.

[0331] In some embodiments, at least one somatic ER tumor mutation is Y537X, D Of the 538X, E380X, L379X, V422X, S463X, and L536X models... Selected from any one or any combination, "X" is a wild-type residue at that position. Refers to any amino acid residue outside. In some embodiments, at least one somatic E The R tumor mutations are Y537X, D538X, E380X, L379X, V422X, and S46. Select one or any combination of 3X and L536X, and "X" This refers to an amino acid residue other than the wild-type residue at that position, such as alanine (A) and valine (V). , leucine (L), isoleucine (I), phenylalanine (F), methionine (M), Tryptophan (W), Proline (P), Glycine (G), Serine (S), Threonine ( T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), ri Din (K), arginine (R), histidine (H), aspartic acid (D), and gluta It is selected from mic acid (E).

[0332] In some embodiments, at least one somatic ER tumor mutation is Y537X ru.

[0333] In some embodiments, at least one somatic ER tumor mutation is D538X ru.

[0334] In some embodiments, at least one somatic ER tumor mutation is E380X. ru.

[0335] In some embodiments, at least one somatic ER tumor mutation is L379X ru.

[0336] In some embodiments, at least one somatic ER tumor mutation is V422X. ru.

[0337] In some embodiments, at least one somatic ER tumor mutation is S463X ru.

[0338] In some embodiments, at least one somatic ER tumor mutation is L536X ru.

[0339] In some embodiments, at least one somatic ER tumor mutation is Y537S, Y 537N, D538G, E380Q, L379I, V422del, S463P, L53 Includes one or any combination of 6P and L536_D538>P.

[0340] In some embodiments, at least one somatic ER tumor mutation is Y537S. ru.

[0341] In some embodiments, at least one somatic ER tumor mutation is Y537N. ru.

[0342] In some embodiments, at least one somatic ER tumor mutation is D538G. ru.

[0343] In some embodiments, at least one somatic ER tumor mutation is E380Q. ru.

[0344] In some embodiments, at least one somatic ER tumor mutation is L379I. ru.

[0345] In some embodiments, at least one somatic ER tumor mutation is V422del That is the case.

[0346] In some embodiments, at least one somatic ER tumor mutation is S463P. ru.

[0347] In some embodiments, at least one somatic ER tumor mutation is L536P. ru.

[0348] In some embodiments, at least one somatic ER tumor mutation is L536_D5 38>P.

[0349] In some embodiments, breast cancer is at least one somatic cancer as described herein. Includes cancer cells characterized by the expression of ER tumor mutations. Cancers characterized by the expression of somatic mutations. The method of identification is publicly known in the art, for example, by obtaining a biological sample from the subject, This involves collecting biological samples to obtain genetic material (e.g., genomic DNA or RNA), and sequencing analysis, RNA sequencing analysis, or real-time polymerase chain reaction This includes performing (RT-PCR). For example, in some embodiments, first the target is From the cancer tissue obtained, genomic DNA was obtained (using any standard technique), and cDNA Prepare the cDNA and perform amplification to provide a sufficient amount of cDNA for sequence analysis (e.g., poly Using a melanase chain reaction, for example, next-generation sequencing, Perform a single procedure. Genomic DNA or RNA is usually obtained, for example, by tissue biopsy. It is extracted from biological samples such as tissues that have been removed. In some embodiments, biological The sample is a tissue biopsy sample (e.g., a breast tumor biopsy sample) containing genomic DNA or RNA. Sequence analysis reveals somatic mutations in the ER (for example, somatic mutations present in the ER ligand-binding domain). This is performed to identify the presence of cellular ER tumor mutations. In some embodiments, Biological samples containing plasma obtained from elephants can be used, for example, for PCR-based amplification and gene sequencing. Using quenching, we detect somatic ER tumor mutations present in circulating tumor DNA. It is used for [purpose].

[0350] In one embodiment, this application relates to a method for treating breast cancer in a subpopulation of breast cancer patients, Based on the somatic ER tumor biomarker status of the target patient, breast cancer patients are selected for treatment. Choosing, A compound of formula (I) in a therapeutically effective amount, [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs The administration of , and the formula includes, Each R 1 and each R 2 They are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, S O2(R 5 ), selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl , R 3 and R 4 Both are hydrogen, or together with the carbon they are bonded to. It either forms a carbonyl group or Each R 5 and each R 6 These independently contain hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl Selected from the group consisting of, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, or 4. The therapeutically effective dose of the compound in formula (I) is approximately 10 mg to 1000 mg.

[0351] In one embodiment, the present application is used for a method of treating breast cancer in a subpopulation of breast cancer patients. For the purpose of, a compound of formula (I), or its pharmaceutically acceptable salts, solvates, polymorphs, isotopes With respect to derivatives or prodrugs, in the formula, Each R 1 and each R 2 They are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, S O2(R 5 ), selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl , R 3 and R 4 Both are hydrogen, or together with the carbon they are bonded to. It either forms a carbonyl group or Each R 5 and each R 6 These independently contain hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl Selected from the group consisting of, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, or 4. The method is, Based on the somatic ER tumor biomarker status of the target patient, breast cancer patients are selected for treatment. Choosing, This includes administering a therapeutically effective dose of the compound of formula (I), The therapeutically effective dose of the compound in formula (I) is approximately 10 mg to 1000 mg.

[0352] In one embodiment, this application is for use in the treatment of breast cancer in a subpopulation of breast cancer patients. Compounds of formula (I), or pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives thereof, Or, with respect to prodrugs, in the formula, Each R 1 and each R 2 They are independent, halo, OR 5 , N(R 5 )(R 6 ), NO2, CN, S O2(R 5 ), selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl , R 3 and R 4 Both are hydrogen, or together with the carbon they are bonded to. It either forms a carbonyl group or Each R 5 and each R 6 These independently contain hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl Selected from the group consisting of, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, or 4. The treatment is, Based on the somatic ER tumor biomarker status of the target patient, breast cancer patients are selected for treatment. Choosing, This includes administering a therapeutically effective dose of the compound of formula (I), The therapeutically effective dose of the compound in formula (I) is approximately 10 mg to 1000 mg.

[0353] In some embodiments, the ER biomarker status of a subject with breast cancer is the subject This can be determined through the analysis of circulating tumor DNA (ctDNA). Alternative methods for determining the target ER biomarker status include fluorescence in situ testing. This includes bridization, immunohistochemistry, PCR analysis, or sequencing, but These are not the only options.

[0354] In some embodiments, the ER biomarker status of the subject is determined by blood sample derived from the subject. It is determined by the pull.

[0355] In some embodiments, the ER biomarker status of a subject with breast cancer is compared to It is determined by a solid biopsy derived from an elephant tumor.

[0356] In some embodiments, breast cancer patients have at least one somatic ER tumor mutation. Treatment is selected based on the current condition.

[0357] In some embodiments, breast cancer patients are Y537X, D538X, E380X, L3 At least one selected from the group consisting of 79X, V422X, S463X, and L536X Selected for treatment based on the presence of one somatic ER tumor mutation, "X" is in that position This refers to any amino acid residue other than the wild-type residue in the given location.

[0358] In some embodiments, breast cancer patients are Y537X, D538X, E380X, L3 At least one selected from the group consisting of 79X, V422X, S463X, and L536X Selected for treatment based on the presence of one somatic ER tumor mutation, "X" is in that position This refers to amino acid residues other than wild-type residues in the given location, such as alanine (A), valine (V), and leucine. (L), isoleucine (I), phenylalanine (F), methionine (M), tryptophthol Fan (W), proline (P), glycine (G), serine (S), threonine (T), cis Thein (C), asparagine (N), glutamine (Q), tyrosine (Y), lysine (K) Arginine (R), histidine (H), aspartic acid (D), and glutamic acid (E) ) will be selected from.

[0359] In some embodiments, breast cancer patients are classified as Y537S, Y537N, D538G, E3 80Q, L379I, V422del, S463P, L536P and L536_D538 Based on the presence of at least one somatic ER tumor mutation selected from the group consisting of >P It is selected for treatment.

[0360] In some embodiments, breast cancer patients have the presence of the Y537S somatic ER tumor mutation. Treatment is selected based on the following criteria.

[0361] In some embodiments, breast cancer patients with the presence of the Y537N somatic ER tumor mutation Treatment is selected based on the following criteria.

[0362] In some embodiments, breast cancer patients have the presence of the D538G somatic ER tumor mutation. Treatment is selected based on the following criteria.

[0363] In some embodiments, breast cancer patients have the presence of the E380Q somatic ER tumor mutation. Treatment is selected based on the following criteria.

[0364] In some embodiments, breast cancer patients have the presence of the L379I somatic ER tumor mutation. Treatment is selected based on the following criteria.

[0365] In some embodiments, breast cancer patients have a somatic ER tumor mutation of V422del. Treatment is selected based on the current condition.

[0366] In some embodiments, breast cancer patients have the presence of the somatic ER tumor mutation S463P. Treatment is selected based on the following criteria.

[0367] In some embodiments, breast cancer patients have the presence of the L536P somatic ER tumor mutation. Treatment is selected based on the following criteria.

[0368] In some embodiments, breast cancer patients have somatic ER tumors of type L536_D538>P. Treatment is selected based on the presence of the mutation.

[0369] In one aspect, the present application relates to treating breast cancer in subjects who require treatment. The present invention relates to administering a therapeutically effective amount of the compound of formula (I) to the subject, wherein the compound of formula (I) is , compounds having the following structure: [ka] or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopes This refers to a derivative or prodrug, where R is used in the formula. 1 , R 2 , R 3 , R 4 m, and n are , as defined herein. In some embodiments, breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, breast cancer is ER+, HER2-. , ER+, HER2- breast cancer. In some embodiments, the breast cancer is locally advanced This is a metastatic, ER-positive, HER2-negative breast cancer.

[0370] In one aspect, the present application relates to treating breast cancer in subjects who require treatment. The present invention relates to administering a therapeutically effective amount of the compound of formula (I) to the subject, wherein the compound of formula (I) is , [ka] [ka] [ka] or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopes Selected from the group consisting of isomer derivatives or prodrugs. In some embodiments, The compound of formula (I) is the compound of formula (Ia). In some embodiments, formula (I) The compound is the compound of formula (Ic). In some embodiments, the compound of formula (I) is a compound of formula (Ij). In some embodiments, breast cancer is metastatic breast cancer. Yes. In some embodiments, breast cancer is locally advanced breast cancer. In this state, breast cancer is ER+, HER2-. In some embodiments, breast cancer metastasizes. This is metastatic, ER-+, HER2-positive breast cancer. In some embodiments, the breast cancer is locally advanced. It is a metastatic, ER-positive, HER2-negative breast cancer.

[0371] In one aspect, the present application relates to treating breast cancer in subjects who require treatment. The present invention relates to administering a therapeutically effective amount of the compound of formula (I) to the subject, wherein the compound of formula (I) is , [ka] It is selected from the group consisting of the following. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, The breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HE It is R2-. In some embodiments, breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, breast cancer is locally advanced, metastatic, ER+, HER+. 2. It is breast cancer.

[0372] In one aspect, the present application relates to treating breast cancer in subjects who require treatment. Regarding breast cancer, the formula for effective treatment of the target includes at least one somatic ER tumor mutation. The procedure involves administering compound (I), wherein compound (I) is a compound having the following structure. : [ka] or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopes This refers to a derivative or prodrug, where R is used in the formula. 1 , R 2 , R 3 , R 4 m, and n are , as defined herein. In some embodiments, breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, breast cancer is ER+, HER2-. , ER+, HER2- breast cancer. In some embodiments, the breast cancer is locally advanced This is a metastatic, ER-positive, HER2-negative breast cancer.

[0373] In some embodiments, at least one somatic ER tumor mutation is Y537X, D Of the 538X, E380X, L379X, V422X, S463X, and L536X models... Selected from any one or any combination, "X" is a wild-type residue at that position. Refers to any amino acid residue outside. In some embodiments, at least one somatic E The R tumor mutations are Y537X, D538X, E380X, L379X, V422X, and S46. Select one or any combination of 3X and L536X, and "X" This refers to an amino acid residue other than the wild-type residue at that position, such as alanine (A) and valine (V). , leucine (L), isoleucine (I), phenylalanine (F), methionine (M), Tryptophan (W), Proline (P), Glycine (G), Serine (S), Threonine ( T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), ri Din (K), arginine (R), histidine (H), aspartic acid (D), and gluta It is selected from mic acid (E).

[0374] In some embodiments, at least one somatic ER tumor mutation is Y537X ru.

[0375] In some embodiments, at least one somatic ER tumor mutation is D538X ru.

[0376] In some embodiments, at least one somatic ER tumor mutation is E380X. ru.

[0377] In some embodiments, at least one somatic ER tumor mutation is L379X ru.

[0378] In some embodiments, at least one somatic ER tumor mutation is V422X. ru.

[0379] In some embodiments, at least one somatic ER tumor mutation is S463X ru.

[0380] In some embodiments, at least one somatic ER tumor mutation is L536X ru.

[0381] In some embodiments, at least one somatic ER tumor mutation is Y537S, Y 537N, D538G, E380Q, L379I, V422del, S463P, L53 Includes one or any combination of 6P and L536_D538>P.

[0382] In some embodiments, at least one somatic ER tumor mutation is Y537S. ru.

[0383] In some embodiments, at least one somatic ER tumor mutation is Y537N. ru.

[0384] In some embodiments, at least one somatic ER tumor mutation is D538G. ru.

[0385] In some embodiments, at least one somatic ER tumor mutation is E380Q. ru.

[0386] In some embodiments, at least one somatic ER tumor mutation is L379I. ru.

[0387] In some embodiments, at least one somatic ER tumor mutation is V422del That is the case.

[0388] In some embodiments, at least one somatic ER tumor mutation is S463P. ru.

[0389] In some embodiments, at least one somatic ER tumor mutation is L536P. ru.

[0390] In some embodiments, at least one somatic ER tumor mutation is L536_D5 38>P.

[0391] In one aspect, the present application relates to treating breast cancer in subjects who require treatment. Regarding breast cancer, the formula for effective treatment of the target includes at least one somatic ER tumor mutation. The procedure includes administering compound (I), wherein compound (I) is [ka] [ka] [ka] or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopes Selected from the group consisting of isomer derivatives or prodrugs. In some embodiments, The compound of formula (I) is the compound of formula (Ia). In some embodiments, formula (I) The compound is the compound of formula (Ic). In some embodiments, the compound of formula (I) is a compound of formula (Ic). In some embodiments, breast cancer is metastatic breast cancer. Yes. In some embodiments, breast cancer is locally advanced breast cancer. In this state, breast cancer is ER+, HER2-. In some embodiments, breast cancer metastasizes. This is metastatic, ER-+, HER2-positive breast cancer. In some embodiments, the breast cancer is locally advanced. It is a metastatic, ER-positive, HER2-negative breast cancer.

[0392] In some embodiments, at least one somatic ER tumor mutation is Y537X, D Of the 538X, E380X, L379X, V422X, S463X, and L536X models... Selected from any one or any combination, "X" is a wild-type residue at that position. Refers to any amino acid residue outside. In some embodiments, at least one somatic E The R tumor mutations are Y537X, D538X, E380X, L379X, V422X, and S46. Select one or any combination of 3X and L536X, and "X" This refers to an amino acid residue other than the wild-type residue at that position, such as alanine (A) and valine (V). , leucine (L), isoleucine (I), phenylalanine (F), methionine (M), Tryptophan (W), Proline (P), Glycine (G), Serine (S), Threonine ( T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), ri Din (K), arginine (R), histidine (H), aspartic acid (D), and gluta It is selected from mic acid (E).

[0393] In some embodiments, at least one somatic ER tumor mutation is Y537X ru.

[0394] In some embodiments, at least one somatic ER tumor mutation is D538X ru.

[0395] In some embodiments, at least one somatic ER tumor mutation is E380X. ru.

[0396] In some embodiments, at least one somatic ER tumor mutation is L379X ru.

[0397] In some embodiments, at least one somatic ER tumor mutation is V422X. ru.

[0398] In some embodiments, at least one somatic ER tumor mutation is S463X ru.

[0399] In some embodiments, at least one somatic ER tumor mutation is L536X ru.

[0400] In some embodiments, at least one somatic ER tumor mutation is Y537S, Y 537N, D538G, E380Q, L379I, V422del, S463P, L53 Includes one or any combination of 6P and L536_D538>P.

[0401] In some embodiments, at least one somatic ER tumor mutation is Y537S. ru.

[0402] In some embodiments, at least one somatic ER tumor mutation is Y537N. ru.

[0403] In some embodiments, at least one somatic ER tumor mutation is D538G. ru.

[0404] In some embodiments, at least one somatic ER tumor mutation is E380Q. ru.

[0405] In some embodiments, at least one somatic ER tumor mutation is L379I. ru.

[0406] In some embodiments, at least one somatic ER tumor mutation is V422del That is the case.

[0407] In some embodiments, at least one somatic ER tumor mutation is S463P. ru.

[0408] In some embodiments, at least one somatic ER tumor mutation is L536P. ru.

[0409] In some embodiments, at least one somatic ER tumor mutation is L536_D5 38>P.

[0410] In one aspect, the present application relates to treating breast cancer in subjects who require treatment. Regarding breast cancer, the formula for effective treatment of the target includes at least one somatic ER tumor mutation. The procedure includes administering compound (I), wherein compound (I) is [ka] It is selected from the group consisting of the following. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, The breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HE It is R2-. In some embodiments, breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, breast cancer is locally advanced, metastatic, ER+, HER+. 2. It is breast cancer.

[0411] In some embodiments, at least one somatic ER tumor mutation is Y537X, D Of the 538X, E380X, L379X, V422X, S463X, and L536X models... Selected from any one or any combination, "X" is a wild-type residue at that position. Refers to any amino acid residue outside. In some embodiments, at least one somatic E The R tumor mutations are Y537X, D538X, E380X, L379X, V422X, and S46. Select one or any combination of 3X and L536X, and "X" This refers to an amino acid residue other than the wild-type residue at that position, such as alanine (A) and valine (V). , leucine (L), isoleucine (I), phenylalanine (F), methionine (M), Tryptophan (W), Proline (P), Glycine (G), Serine (S), Threonine ( T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), ri Din (K), arginine (R), histidine (H), aspartic acid (D), and gluta It is selected from mic acid (E).

[0412] In some embodiments, at least one somatic ER tumor mutation is Y537X ru.

[0413] In some embodiments, at least one somatic ER tumor mutation is D538X ru.

[0414] In some embodiments, at least one somatic ER tumor mutation is E380X. ru.

[0415] In some embodiments, at least one somatic ER tumor mutation is L379X ru.

[0416] In some embodiments, at least one somatic ER tumor mutation is V422X. ru.

[0417] In some embodiments, at least one somatic ER tumor mutation is S463X ru.

[0418] In some embodiments, at least one somatic ER tumor mutation is L536X ru.

[0419] In some embodiments, at least one somatic ER tumor mutation is Y537S, Y 537N, D538G, E380Q, L379I, V422del, S463P, L53 Includes one or any combination of 6P and L536_D538>P.

[0420] In some embodiments, at least one somatic ER tumor mutation is Y537S. ru.

[0421] In some embodiments, at least one somatic ER tumor mutation is Y537N. ru.

[0422] In some embodiments, at least one somatic ER tumor mutation is D538G. ru.

[0423] In some embodiments, at least one somatic ER tumor mutation is E380Q. ru.

[0424] In some embodiments, at least one somatic ER tumor mutation is L379I. ru.

[0425] In some embodiments, at least one somatic ER tumor mutation is V422del That is the case.

[0426] In some embodiments, at least one somatic ER tumor mutation is S463P. ru.

[0427] In some embodiments, at least one somatic ER tumor mutation is L536P. ru.

[0428] In some embodiments, at least one somatic ER tumor mutation is L536_D5 38>P.

[0429] In one aspect, cancer treatment results in a reduction in tumor size. This can also be called "tumor regression." Preferably, after treatment, the tumor size is smaller than before treatment. It reduces the size by 5% or more, and more preferably reduces the tumor size by 10% or more. More preferably, it is reduced by 20% or more, more preferably by 30% or more, and more preferably by 40% A decrease of % or more, more preferably a decrease of 50% or more, and most preferably a decrease of 75% or more. The size of the tumor may be measured by any reproducible measuring means. In one embodiment, the size of the tumor may be measured as the diameter of the tumor.

[0430] In another aspect, cancer treatment results in a reduction in tumor volume. Preferably, after treatment, the tumor The volume is reduced by more than 5% compared to its size before treatment, and more preferably, the tumor volume is reduced by 10%. A decrease of % or more, more preferably a decrease of 20% or more, and more preferably a decrease of 30% or more. More preferably reduced by 40% or more, even more preferably reduced by 50% or more, most preferably The tumor volume decreases by more than 75%. Tumor volume is measured by any reproducible measurement method. That's fine.

[0431] In another aspect, cancer treatment results in a reduction in the number of tumors. Preferably, after treatment, the tumors The number decreased by more than 5% compared to the number before treatment, and more preferably, the number of tumors decreased by more than 10%. A slight, more preferably 20% or more reduction, more preferably 30% or more reduction, and even better The amount is reduced by 40% or more, more preferably by 50% or more, and most preferably by 7 The number of tumors decreases by more than 5%. The number of tumors may be measured by any reproducible measurement method. In a preferred embodiment, the number of tumors is determined by the number of tumors that can be seen with the naked eye or at a specified magnification. It can be measured by counting. In a preferred embodiment, the specified magnification is 2x, 3x These are 4 times, 5 times, 10 times, or 50 times.

[0432] In another aspect, cancer treatment involves treating metastases in other tissues or organs distant from the primary tumor site. This results in a reduction in the number of metastatic lesions. Preferably, after treatment, the number of metastatic lesions is equal to the number before treatment. It is reduced by 5% or more, and more preferably the number of metastatic lesions is reduced by 10% or more. More preferably, it is reduced by 20% or more, more preferably by 30% or more, and more preferably by 40% A decrease of % or more, more preferably a decrease of 50% or more, and most preferably a decrease of 75% or more. The number of metastatic lesions may be measured by any reproducible measurement method. In a specific configuration, the number of metastatic lesions can be seen with the naked eye or at a specified magnification. It can be measured by counting lesions. In a preferred embodiment, the specified magnification is 2x These are 3 times, 4 times, 5 times, 10 times, or 50 times.

[0433] In another aspect, cancer treatment is more effective in the treated group compared to the group that received the carrier alone. This results in an increase in the average survival time of the elephant population. Preferably, the average survival time is more than 30 days. Preferably, the increase is more than 60 days, more preferably more than 90 days, and most preferably more than 120 days. The increase in the average survival time of the group may be measured by any reproducible means. In one embodiment, the increase in the average survival time of the population is, for example, due to the development of treatment using active drugs or compounds. The average length of post-initiation survival may be measured by calculating it for the population. In a preferred embodiment, the increase in the average survival time of the population is achieved, for example, by using an active agent or compound. By calculating the average length of survival after the completion of the first round of treatment for the population, It is also used for measurement.

[0434] In another aspect, cancer treatment is more effective in the treated population compared to the untreated population. This results in an increase in the average survival time of the group. Preferably, the average survival time is more than 30 days, more preferably... The average of the group increases by more than 60 days, more preferably more than 90 days, and most preferably more than 120 days. The increase in mean survival time may be measured by any reproducible means. Preferred embodiment So, is the increase in the average survival time of the population due to, for example, the initiation of treatment with an active drug or compound? The average length of survival may be measured by calculating it for the population. Another preference In one embodiment, the increase in the average survival time of the population is achieved, for example, by using the compound of formula (I) in the first Laurel The average length of survival after the completion of treatment is measured by calculating it for the population. That's fine.

[0435] In another aspect, cancer treatment results in a reduction in the rate of tumor growth. Preferably, after treatment, The tumor growth rate is reduced by at least 5% compared to the pre-treatment number, and more preferably, the tumor growth rate is reduced by at least 5% compared to the pre-treatment number. The speed is reduced by at least 10%, more preferably by at least 20%, and even more preferably Or, a reduction of at least 30%, more preferably a reduction of at least 40%, and even more preferably Or, at least a 50% reduction, more preferably at least a 50% reduction, and most Preferably, it is reduced by at least 75%. The tumor growth rate is measured by any reproducible means. It may be measured by a method. In a preferred embodiment, the tumor growth rate is the tumor growth rate per unit time. It is measured according to the change in diameter.

[0436] In another aspect, cancer treatment results in a reduction of tumor regrowth. Preferably, after treatment, the tumor Scar regrowth was less than 5%, more preferably tumor regrowth was less than 10%, and more preferably less than 20%. Full, more preferably less than 30%, more preferably less than 40%, more preferably less than 50% More preferably less than 50%, and most preferably less than 75%. Tumor regrowth is left to the discretion of the individual. It may be measured by a reproducible measurement method. In a preferred embodiment, tumor regrowth is For example, it can be measured by measuring the increase in tumor diameter after the tumor has shrunk following treatment. In another preferred embodiment, the reduction in tumor regrowth means that the tumor does not recur after treatment is discontinued. This is demonstrated by [the following].

[0437] The dose of the compound of formula (I) for any of the methods and uses described herein is the drug The agent may affect the recipient's age, weight, and clinical condition, as well as the selected dose. Among other factors, the most significant is the variation depending on the experience and judgment of the clinician or practitioner administering the therapy. .

[0438] A therapeutically effective dose of the compound of formula (I) is administered once, twice, three times, four times, five times a day, or otherwise. The number of times exceeding 5 days, 10 days, 15 days, 30 days, 60 days, 90 days, 120 days It is administered for days, 150 days, 180 days or more, followed by 1 day, 2 days 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 1 2 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 2 0 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 2 8 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 3 For 6 days, 37 days, 38 days, 39 days, 40 days or more, the formula (I) The compound may be omitted. This type of treatment schedule, i.e., formula ( Administration of compound (I) followed by non-administration of compound (I) on consecutive days constitutes a treatment cycle and You can call them.

[0439] In some embodiments, a therapeutically effective amount of the compound of formula (I) is administered once or twice daily, up to It is administered for 5, 10, 15, 20, 25, or 30 days, followed by 1, 2, 3, 4, 5, 6, The compound of formula (I) may be withheld for 7, 8, 9, or 10 days.

[0440] In some embodiments, a therapeutically effective dose of the compound of formula (I) is administered once daily, up to 5 or 10 times. It is administered for 15, 20, 25, or 30 days, followed by 1, 2, 3, 4, 5, 6, 7, 8, The compound of formula (I) may be withheld for 9 or 10 days.

[0441] In some embodiments, a therapeutic cycle involving a compound of formula (I) produces the intended effect. It can be repeated as many times as necessary to achieve the goal.

[0442] In some embodiments, a therapeutically effective amount of the compound of formula (I) is administered once, twice, or three times a day. , four times, or more times, for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days Between, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 1 For 5 days, 30 consecutive days, or for 2 months, 3 months, 4 months, 5 months, or 6 months. Or more, administered as a single dose or in divided doses, 0.01, 0.05, 0.1, 0.2 , 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9 .5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 2 2, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 ,36,37,38,39,40,41,42,43,44,45,46,47,48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 6 2, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 , 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105 , 110, 115, 120, 125, 130, 135, 140, 145, 150, 155 , 160, 165, 170, 175, 180, 185, 190, 195, 200, 205 , 210, 215, 220, 225, 230, 235, 240, 245, 250, 255 , 260, 265, 270, 275, 280, 285, 290, 295, 300, 305 , 310, 315, 320, 325, 330, 335, 340, 345, 350, 355 , 360, 365, 370, 375, 380, 385, 390, 395, 400, 405 , 410, 415, 420, 425, 430, 435, 440, 445, 450, 455 , 460, 465, 470, 475, 480, 485, 490, 495, 500, 505 , 510, 515, 520, 525, 530, 535, 540, 545, 550, 555 , 560, 565, 570, 575, 580, 585, 590, 595, 600, 605 , 610, 615, 620, 625, 630, 635, 640, 645, 650, 655 , 660, 665, 670, 675, 680, 685, 690, 695, 700, 705 , 710, 715, 720, 725, 730, 735, 740, 745, 750, 755 , 760, 765, 770, 775, 780, 785, 790, 795, 800, 805 , 810, 815, 820, 825, 830, 835, 840, 845, 850, 855 , 860, 865, 870, 875, 880, 885, 890, 895, 900, 905 , 910, 915, 920, 925, 930, 935, 940, 945, 950, 955 , 960, 965, 970, 975, 980, 985, 990, 995, or 1,000 It is mg.

[0443] In some embodiments, a therapeutically effective amount of the compound of formula (I) is administered once, twice, or three times a day. Approximately 30 mg, approximately 60 ml, administered as a single dose or in divided doses, four or more times. g, approx. 90mg, approx. 120mg, approx. 150mg, approx. 180mg, approx. 210mg, approx. 240 mg, approx. 270 mg, approx. 300 mg, approx. 330 mg, approx. 360 mg approx. 390 mg, approx. 4 20mg, about 450mg, about 480mg, about 510mg, about 540mg, about 570mg, Approx. 600mg, approx. 630mg, approx. 660mg, approx. 690mg, approx. 720mg, approx. 750m g, about 780mg, about 810mg, about 840mg, about 870mg, about 900mg, about 93 The dosage is 0 mg, approximately 960 mg, or approximately 990 mg (this dosage depends on the patient's body weight (kg) and body weight). Surface area (m 2 ), and may be adjusted for age (years).

[0444] In some embodiments, a therapeutically effective amount of the compound of formula (I) is administered once, twice, or three times a day. It is administered in single doses or divided doses, in four or more doses, ranging from approximately 30 mg to approximately 100 mg. 0 mg (This dose is calculated based on the patient's body weight (kg) and body surface area (m²). 2 ), and age (years) (This can be adjusted.)

[0445] In some embodiments, a therapeutically effective amount of the compound of formula (I) is administered once, twice, or three times a day. Approximately 10-40 mg, administered as a single dose or in divided doses, four or more times. about 20 to about 50 mg, about 30 to about 60 mg, about 40 to about 70 mg, about 50 to about 80 mg, Approx. 60~90mg, approx. 70~100mg, approx. 80~110mg, approx. 90~120 mg, about 100 to about 130 mg, about 110 to about 140 mg, about 120 to about 150 mg, about 130~160mg, 140~170mg, 150~180mg, 160~ Approximately 190mg, approximately 170~200mg, approximately 180~210mg, approximately 190~220 mg, about 200 to about 230 mg, about 210 to about 240 mg, about 220 to about 250 mg, about 230~260mg, 240~270mg, 250~280mg, 260~ Approximately 290mg, approximately 270~300mg, approximately 280~310mg, approximately 290~320 mg, approximately 300~330mg, approximately 310~340mg, approximately 320~350mg, approximately 330~approx. 360mg, approx. 340~approx. 370mg, approx. 350~approx. 380mg, approx. 360~ Approximately 390mg, approximately 370~400mg, approximately 380~410mg, approximately 390~420mg mg, approximately 400~430mg, approximately 410~440mg, approximately 420~450mg, approximately 430~approx. 460mg, approx. 440~approx. 470mg, approx. 450~approx. 480mg, approx. 460~ Approximately 490mg, approximately 470~500mg, approximately 480~510mg, approximately 490~520mg mg, approximately 500~530mg, approximately 510~540mg, approximately 520~550mg, approximately 530~approx. 560mg, approx. 540~approx. 570mg, approx. 550~approx. 580mg, approx. 560~ Approximately 590mg, approximately 570~600mg, approximately 580~610mg, approximately 590~620mg mg, approximately 600~630mg, approximately 610~640mg, approximately 620~650mg, approximately 630~approx. 660mg, approx. 640~approx. 670mg, approx. 650~approx. 680mg, approx. 660~ Approximately 690mg, approximately 670~700mg, approximately 680~710mg, approximately 690~720mg mg, approximately 700~730mg, approximately 710~740mg, approximately 720~750mg, approximately 730~approx. 760mg, approx. 740~approx. 770mg, approx. 750~approx. 780mg, approx. 760~ Approximately 790mg, approximately 770~800mg, approximately 780~810mg, approximately 790~820mg mg, approximately 800~830mg, approximately 810~840mg, approximately 820~850mg, approximately 830~approx. 860mg, approx. 840~approx. 870mg, approx. 850~approx. 880mg, approx. 860~ Approximately 890mg, approximately 870~900mg, approximately 880~910mg, approximately 890~920mg mg, approximately 900~930mg, approximately 910~940mg, approximately 920~950mg, approximately 930~960mg, 940~970mg, 950~980mg, 960~ The dosage is approximately 990 mg, or approximately 970 to 1,000 mg (the dosage depends on the patient's body weight (kg) and body weight). Surface area (m 2 (and may be adjusted for age (years)).

[0446] The therapeutically effective dose of the compound of formula (I) is also approximately 0.01 mg / kg per day. The range may be approximately 100 mg / kg. In one embodiment, the therapeutically effective dose of the compound of formula (I) This may be in the range of approximately 0.05 mg / kg to approximately 10 mg / kg per day. In one embodiment, the therapeutically effective dose of the compound of formula (I) is approximately 0.075 mg / kg per day. The range may be approximately 5 mg / kg per day. In one embodiment, the therapeutic effective dose is given by formula (I) The compound was present in a range of approximately 0.10 mg / kg to approximately 1 mg / kg per day. This may also be the case. In one embodiment, the therapeutically effective dose of the compound of formula (I) is approximately 0.20 mg / day The range may be approximately 0.70 mg / kg per day.

[0447] In some embodiments, a therapeutically effective dose of the compound of formula (I) is approximately 0.10 ml per day. g / kg, approximately 0.15 mg / kg per day, approximately 0.20 mg / kg per day, per day Approximately 0.25 mg / kg per day, approximately 0.30 mg / kg per day, approximately 0.35 mg per day g / kg, approximately 0.40 mg / kg per day, approximately 0.45 mg / kg per day, per day Approximately 0.50 mg / kg per day, approximately 0.55 mg / kg per day, approximately 0.60 mg per day g / kg, approximately 0.65 mg / kg per day, approximately 0.70 mg / kg per day, per day Approximately 0.75 mg / kg per day, approximately 0.80 mg / kg per day, approximately 0.85 mg per day g / kg, approximately 0.90 mg / kg per day, approximately 0.95 mg / kg per day, or 1 The daily average is approximately 1.00 mg / kg.

[0448] In some embodiments, a therapeutically effective dose of the compound of formula (I) is approximately 1.05 ml per day. g / kg, approximately 1.10 mg / kg per day, approximately 1.15 mg / kg per day, per day Approximately 1.20 mg / kg per day, approximately 1.25 mg / kg per day, approximately 1.30 mg per day g / kg, approximately 1.35 mg / kg per day, approximately 1.40 mg / kg per day, per day Approximately 1.45 mg / kg per day, approximately 1.50 mg / kg per day, approximately 1.55 mg per day g / kg, approximately 1.60 mg / kg per day, approximately 1.65 mg / kg per day, per day Approximately 1.70 mg / kg per day, approximately 1.75 mg / kg per day, approximately 1.80 mg per day g / kg, approximately 1.85 mg / kg per day, approximately 1.90 mg / kg per day, per day This is approximately 1.95 mg / kg, or approximately 2.00 mg / kg per day.

[0449] In some embodiments, a therapeutically effective dose of the compound of formula (I) is approximately 2 mg / kJ per day. g, approximately 2.5 mg / kg per day, approximately 3 mg / kg per day, approximately 3.5 mg per day g / kg, approximately 4 mg / kg per day, approximately 4.5 mg / kg per day, approximately 5 mg / kg, approximately 5.5 mg / kg per day, approximately 6 mg / kg per day, approximately per day 6.5 mg / kg, approximately 7 mg / kg per day, approximately 7.5 mg / kg per day, per day Approximately 8.0 mg / kg per day, approximately 8.5 mg / kg per day, approximately 9.0 mg / kg per day This is approximately 9.5 mg / kg per day, or approximately 10 mg / kg per day.

[0450] In some embodiments, a therapeutically effective dose of the compound of formula (I) is administered to the subject once daily. In some embodiments, this daily dose of the compound of formula (I) is administered to the subject all at once. It is administered. In some embodiments, this daily dose of the compound of formula (I) is administered twice to the subject. It is administered in unit doses (divided doses). In some embodiments, the compound of formula (I) The daily dose is administered to the subject in three unit doses. In some embodiments, formula (I) This daily dose of the compound is administered to the subject in four unit doses. In some embodiments The daily dose of the compound of formula (I) is administered to the subject in units of five or more doses. In some embodiments, these unit doses are administered at regular intervals throughout the day, for example, every 12 hours. It is administered to the target individual at intervals such as every 8 hours, every 6 hours, every 5 hours, or every 4 hours.

[0451] In some embodiments, a therapeutically effective amount of the compound of formula (I) is approximately 3,500 ng·hour. / mL, approximately 3,550ng·hr / mL, approximately 3,600ng·hr / mL, approximately 3, More than 650ng·hr / mL, approximately 3,700ng·hr / mL, approximately 3,750ng·hr / mL, approximately 3,800ng·hr / mL, approximately 3,850ng·hr / mL, approximately 3, More than 900ng·hr / mL, about 3,950ng·hr / mL, about 4,000ng·hr / mL, approximately 4,050ng·hr / mL, approximately 4,100ng·hr / mL, approximately 4, More than 150 ng·hr / mL, approximately 4,200 ng·hr / mL, approximately 4,250 ng·hr >4,300 ng·hr / mL, approximately 4,350 ng·hr / mL, 4,4 More than 00ng·hr / mL, about 4,450ng·hr / mL, about 4,500ng·hr / More than mL, about 4,550 ng·hr / mL, about 4,600 ng·hr / mL, about 4,6 More than 50ng·hr / mL, approximately more than 4,700ng·hr / mL, approximately 4,750ng·hr / More than mL, about 4,800 ng·hr / mL, about 4,850 ng·hr / mL, about 4,9 Over 00 ng·hour / mL, over approximately 4,950 ng·hour / mL, or approximately 5,000 ng·hour Average AUC on day 15 with a value greater than 1 / mL TAU It brings about.

[0452] In some embodiments, the therapeutically effective amount of the compound of formula (I) is greater than approximately 150 ng / mL. More than about 155ng / mL, more than about 160ng / mL, more than about 165ng / mL, about 170ng / More than mL, more than about 175 ng / mL, more than about 180 ng / mL, more than about 185 ng / mL, about 19 More than 0ng / mL, more than about 195ng / mL, more than about 200ng / mL, more than about 205ng / mL , more than about 210ng / mL, more than about 215ng / mL, more than about 220ng / mL, about 225ng / mL, approximately 230ng / mL, approximately 235ng / mL, approximately 240ng / mL, approximately 2 More than 45ng / mL. More than 250ng / mL, more than about 255ng / mL, more than about 260ng / mL , more than about 265ng / mL, more than about 270ng / mL, more than about 275ng / mL, about 280ng / mL, approximately 285ng / mL, approximately 290ng / mL, approximately 295ng / mL, approximately 3 More than 00ng / mL, more than about 305ng / mL, more than about 310ng / mL, about 315ng / mL Ultra, more than about 320ng / mL, more than about 325ng / mL, more than about 330ng / mL, about 335n Greater than g / mL, greater than approximately 340 ng / mL, greater than approximately 345 ng / mL, or greater than approximately 350 ng / mL Day 15 average C max It brings about.

[0453] The therapeutically effective dose of the compound of formula (I) can be used in cell culture assays or animal models, usually rats. It can be initially estimated using one of the following animals: mouse, rabbit, dog, or pig. This information may be used to determine the appropriate concentration range and route of administration. This allows for the determination of useful doses and routes for administration in humans. The prophylactic effects and toxicity can be assessed using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED5 0 (effective therapeutic dose in 50% of the population) and LD 50 (A dose that would kill 50% of the population) This can be determined by the dose ratio between toxicity and therapeutic effect, which is an indicator of treatment, and the LD5 0 / ED 50 It can be expressed as a ratio. Pharmaceutical compositions exhibiting a large therapeutic index are preferred. The dose is This range may vary depending on the dosage form used, the patient's sensitivity, and the route of administration.

[0454] The dosage and administration should be such as to provide a sufficient level of the compound of formula (I), or the desired level. The treatment is adjusted to maintain its effectiveness. Factors to consider include the severity of the condition and the individual of the patient. General health status, age, weight, and sex of the subject, diet, time and frequency of administration, concomitant drug use, response This includes response sensitivity and tolerance / response to therapy. Long-acting pharmaceutical compositions are specific Depending on the half-life and clearance rate of the formulation, the drug is administered every 3-4 days, weekly, or every 2 weeks. It may be permitted.

[0455] A treatment method comprising administering the compound of formula (I) and additional anticancer agents. In one aspect, this application relates to a subject in need of treatment and / or prevention of breast cancer. A method of treatment and / or prevention, comprising a therapeutically effective amount of a compound of formula (I) and a therapeutically effective amount The present invention relates to a method that includes the simultaneous administration of additional anticancer drugs.

[0456] In one aspect, this application relates to a subject in need of treatment and / or prevention of breast cancer. The present invention relates to a compound of formula (I) for use in methods of treatment and / or prevention, wherein the treatment The target is to administer an effective amount of the compound of formula (I) and an effective therapeutic amount of an additional anticancer agent simultaneously. include.

[0457] In one embodiment, this application relates to the treatment of breast cancer in subjects who require treatment and / or prevention. With respect to compounds of formula (I) for use in treatment and / or prevention, treatment and / or prevention are The target is to administer a therapeutically effective dose of the compound of formula (I) and a therapeutically effective dose of an additional anticancer agent simultaneously. This includes.

[0458] These methods include reducing tumor size. Alternatively, or in addition, breast cancer can be treated with This is metastatic breast cancer, and this treatment method involves inhibiting the invasion of metastatic cancer cells. In some embodiments, breast cancer is metastatic breast cancer. In some embodiments, breast cancer is local This is advanced breast cancer. In some embodiments, the breast cancer is ER-+ and HER2-. In some embodiments, the breast cancer is metastatic, ER-+, HER2- breast cancer. In that embodiment, the breast cancer is locally advanced, metastatic, ER+, HER2- breast cancer. ru.

[0459] In some embodiments, a therapeutically effective amount of the compound of formula (I) and a therapeutically effective amount of additional antibodies are used. The medications are administered simultaneously (either as the same formulation or as separate formulations).

[0460] In some embodiments, a therapeutically effective amount of the compound of formula (I) and a therapeutically effective amount of additional antibodies are used. The anticancer drugs are administered sequentially, that is, first the compound of formula (I), followed by additional anticancer drugs. The following are administered: or initially an additional anticancer drug, followed by the compound of formula (I). In this embodiment, the additional anticancer agent is first administered, followed by the compound of formula (I) 1 hour later. A substance is administered.

[0461] In some embodiments, a therapeutically effective amount of the compound of formula (I) and a therapeutically effective amount of additional antibodies are used. The medications are administered in close proximity in time.

[0462] In some embodiments, "temporal proximity" means that the therapeutic effect of the compound of formula (I) is added. To overlap with the therapeutic effect of the anticancer drug, the compound of formula (I) is administered as an additional anticancer drug. This means that it is performed within a certain period before or after administration. In some embodiments, formula (I) The therapeutic effect of the compound completely overlaps with the therapeutic effect of additional anticancer drugs. In terms of application methods, "temporal proximity" refers to the synergistic effect between the compound of formula (I) and the additional anticancer agent. As shown in the results, administering the compound of formula (I) for a period of time before or after the administration of additional anticancer drugs. It means to do it within the time frame.

[0463] "Temporal proximity" is not limited to the age, sex, and weight of the person receiving the drug. Genetic background, medical condition, medical history and treatment history, disease or condition being treated or alleviated, achieved Treatment outcomes, dosage, frequency and duration of administration of therapeutic drugs, pharmacokinetics and pharmacodynamics of therapeutic drugs, and This can vary depending on various factors, including the route through which the therapeutic agent is administered. So, what is "temporal proximity"? Within 15 minutes, within 30 minutes, within 1 hour, within 2 hours, 4 hours Within hours, within 6 hours, within 8 hours, within 12 hours, within 18 hours, within 24 hours, 36 hours Within a week, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 1 week, within 2 weeks This means within 3 weeks, 4 weeks, 6 weeks, or 8 weeks. Several implementation forms In this situation, multiple administrations of one therapeutic agent can be performed in temporal proximity to a single administration of another therapeutic agent. In some embodiments, temporal proximity is between treatment cycles or within a dosing regimen. It can change.

[0464] In one aspect, this application relates to a subject in need of treatment and / or prevention of breast cancer. Regarding methods of treatment and / or prevention, breast cancer is characterized by at least one somatic ER tumor mutation. The regimen includes administering the compound of formula (I) and additional anticancer agents to the target of formula (I) The compound is a compound having the following structure: [ka] or its pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, polymorphs, isotopes This refers to a derivative or prodrug, where R is used in the formula. 1 , R 2 , R 3 , R 4 m, and n are , as defined herein.

[0465] In one aspect, this application relates to a subject in need of treatment and / or prevention of breast cancer. Compounds of formula (I), or pharmaceutically acceptable thereof, for use in methods of treatment and / or prevention. Accepted salts, enantiomers, stereoisomers, solvates, polymorphs, isotopic derivatives, or Regarding prodrugs, breast cancer includes at least one somatic ER tumor mutation, and the method This includes administering the compound of formula (I) and additional anticancer agents to the target.

[0466] In one embodiment, this application relates to the treatment of breast cancer in subjects who require treatment and / or prevention. Compounds of formula (I), or pharmaceutically acceptable salts thereof, for use in the treatment and / or prevention of disease. enantiomers, stereoisomers, solvates, polymorphs, isotopic derivatives, or prodrugs Regarding breast cancer, it includes at least one somatic ER tumor mutation and is treated and / or prognostic. The prevention includes administering the compound of formula (I) and additional anticancer agents to the target.

[0467] In one embodiment, this application relates to the treatment of breast cancer in subjects who require treatment and / or prevention. Pharmacopoecially acceptable salts, enantiomers, and stereoisomers for use in the treatment and / or prevention of disease. The compound, solvate, polymorph, isotope derivative, or prodrug thereof, along with additional anticancer agents. Regarding combinations, breast cancer includes at least one somatic ER tumor mutation.

[0468] In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, The breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HE It is R2-. In some embodiments, breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, breast cancer is locally advanced, metastatic, ER+, HER+. 2. It is breast cancer.

[0469] In some embodiments, at least one somatic ER tumor mutation is Y537X, D Of the 538X, E380X, L379X, V422X, S463X, and L536X models... Selected from any one or any combination, "X" is a wild-type residue at that position. Refers to any amino acid residue outside. In some embodiments, at least one somatic E The R tumor mutations are Y537X, D538X, E380X, L379X, V422X, and S46. Select one or any combination of 3X and L536X, and "X" This refers to an amino acid residue other than the wild-type residue at that position, such as alanine (A) and valine (V). , leucine (L), isoleucine (I), phenylalanine (F), methionine (M), Tryptophan (W), Proline (P), Glycine (G), Serine (S), Threonine ( T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), ri Din (K), arginine (R), histidine (H), aspartic acid (D), and gluta It is selected from mic acid (E).

[0470] In some embodiments, at least one somatic ER tumor mutation is Y537X ru.

[0471] In some embodiments, at least one somatic ER tumor mutation is D538X ru.

[0472] In some embodiments, at least one somatic ER tumor mutation is E380X. ru.

[0473] In some embodiments, at least one somatic ER tumor mutation is L379X ru.

[0474] In some embodiments, at least one somatic ER tumor mutation is V422X. ru.

[0475] In some embodiments, at least one somatic ER tumor mutation is S463X ru.

[0476] In some embodiments, at least one somatic ER tumor mutation is L536X ru.

[0477] In some embodiments, at least one somatic ER tumor mutation is Y537S, Y 537N, D538G, E380Q, L379I, V422del, S463P, L53 Includes one or any combination of 6P and L536_D538>P.

[0478] In some embodiments, at least one somatic ER tumor mutation is Y537S. ru.

[0479] In some embodiments, at least one somatic ER tumor mutation is Y537N. ru.

[0480] In some embodiments, at least one somatic ER tumor mutation is D538G. ru.

[0481] In some embodiments, at least one somatic ER tumor mutation is E380Q. ru.

[0482] In some embodiments, at least one somatic ER tumor mutation is L379I. ru.

[0483] In some embodiments, at least one somatic ER tumor mutation is V422del That is the case.

[0484] In some embodiments, at least one somatic ER tumor mutation is S463P. ru.

[0485] In some embodiments, at least one somatic ER tumor mutation is L536P. ru.

[0486] In some embodiments, at least one somatic ER tumor mutation is L536_D5 38>P.

[0487] In one aspect, this application relates to a subject in need of treatment and / or prevention of breast cancer. Regarding methods of treatment and / or prevention, breast cancer is characterized by at least one somatic ER tumor mutation. The method includes a therapeutically effective amount of the compound of formula (I) and a therapeutically effective amount of an additional anticancer agent. The compound of formula (I) is administered to the following: [ka] [ka] [ka] or its pharmaceutically acceptable salts, solvates, polymorphs, isotopic derivatives, or prodrugs Selected from the group consisting of G.

[0488] In one aspect, this application relates to a subject in need of treatment and / or prevention of breast cancer. Regarding compounds of formula (I) for use in methods of treatment and / or prevention, breast cancer is less common. The method involves including at least one somatic ER tumor mutation, and a therapeutically effective amount of the compound of formula (I) and This includes administering additional anticancer drugs to the target, and the compound of formula (I) is (Ia), (I- b), (Ic), (Id), (Ie), (If), (Ig), (Ih), ( Selected from the group consisting of (i) and (j).

[0489] In one embodiment, this application relates to the treatment of breast cancer in subjects who require treatment and / or prevention. With respect to compounds of formula (I) for use in the treatment and / or prevention of breast cancer, at least one The treatment and / or prevention of somatic ER tumor mutations is carried out by a therapeutically effective amount of the compound of formula (I). and administer additional anticancer agents, wherein the compound of formula (I) is (Ia), ( Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) Selected from the group consisting of (Ii) and (Ij).

[0490] In one embodiment, this application relates to the treatment of breast cancer in subjects who require treatment and / or prevention. A combination comprising a compound of formula (I) for use in the treatment and / or prevention of cancer, and an additional anticancer agent. Regarding breast cancer, it contains at least one somatic ER tumor mutation and the compound of formula (I). The object is (Ia), (Ib), (Ic), (Id), (Ie), (If), ( Selected from the group consisting of (Ig), (Ih), (Ii), and (Ij).

[0491] In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, The breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HE It is R2-. In some embodiments, breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, breast cancer is locally advanced, metastatic, ER+, HER+. 2. It is breast cancer.

[0492] In some embodiments, at least one somatic ER tumor mutation is Y537X, D Of the 538X, E380X, L379X, V422X, S463X, and L536X models... Selected from any one or any combination, "X" is a wild-type residue at that position. Refers to any amino acid residue outside. In some embodiments, at least one somatic E The R tumor mutations are Y537X, D538X, E380X, L379X, V422X, and S46. Select one or any combination of 3X and L536X, and "X" This refers to an amino acid residue other than the wild-type residue at that position, such as alanine (A) and valine (V). , leucine (L), isoleucine (I), phenylalanine (F), methionine (M), Tryptophan (W), Proline (P), Glycine (G), Serine (S), Threonine ( T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), ri Din (K), arginine (R), histidine (H), aspartic acid (D), and gluta It is selected from mic acid (E).

[0493] In some embodiments, at least one somatic ER tumor mutation is Y537X ru.

[0494] In some embodiments, at least one somatic ER tumor mutation is D538X ru.

[0495] In some embodiments, at least one somatic ER tumor mutation is E380X. ru.

[0496] In some embodiments, at least one somatic ER tumor mutation is L379X ru.

[0497] In some embodiments, at least one somatic ER tumor mutation is V422X. ru.

[0498] In some embodiments, at least one somatic ER tumor mutation is S463X ru.

[0499] In some embodiments, at least one somatic ER tumor mutation is L536X ru.

[0500] In some embodiments, at least one somatic ER tumor mutation is Y537S, Y 537N, D538G, E380Q, L379I, V422del, S463P, L53 Includes one or any combination of 6P and L536_D538>P.

[0501] In some embodiments, at least one somatic ER tumor mutation is Y537S. ru.

[0502] In some embodiments, at least one somatic ER tumor mutation is Y537N. ru.

[0503] In some embodiments, at least one somatic ER tumor mutation is D538G. ru.

[0504] In some embodiments, at least one somatic ER tumor mutation is E380Q. ru.

[0505] In some embodiments, at least one somatic ER tumor mutation is L379I. ru.

[0506] In some embodiments, at least one somatic ER tumor mutation is V422del That is the case.

[0507] In some embodiments, at least one somatic ER tumor mutation is S463P. ru.

[0508] In some embodiments, at least one somatic ER tumor mutation is L536P. ru.

[0509] In some embodiments, at least one somatic ER tumor mutation is L536_D5 38>P.

[0510] In one aspect, this application relates to a subject in need of treatment and / or prevention of breast cancer. Regarding methods of treatment and / or prevention, breast cancer is characterized by at least one somatic ER tumor mutation. The method includes a therapeutically effective amount of the compound of formula (I) and a therapeutically effective amount of an additional anticancer agent. The compound of formula (I) is administered to the following: [ka] It is selected from the group consisting of the following.

[0511] In one aspect, this application relates to a subject in need of treatment and / or prevention of breast cancer. Regarding compounds of formula (I) for use in methods of treatment and / or prevention, breast cancer is less common. The method involves including at least one somatic ER tumor mutation, and a therapeutically effective amount of the compound of formula (I) and This includes administering additional anticancer drugs to the target, and the compound of formula (I) is (Ia), (I- The group is selected from (c) and (Ij).

[0512] In one embodiment, this application relates to the treatment of breast cancer in subjects who require treatment and / or prevention. With respect to compounds of formula (I) for use in the treatment and / or prevention of breast cancer, at least one The treatment and / or prevention of somatic ER tumor mutations is carried out by a therapeutically effective amount of the compound of formula (I). and administer additional anticancer agents, wherein the compound of formula (I) is (Ia), ( Selected from the group consisting of (Ic) and (Ij).

[0513] In one embodiment, this application relates to the treatment of breast cancer in subjects who require treatment and / or prevention. A combination comprising a compound of formula (I) for use in the treatment and / or prevention of cancer, and an additional anticancer agent. Regarding breast cancer, it contains at least one somatic ER tumor mutation and the compound of formula (I). The object is selected from the group consisting of (Ia), (Ic), and (Ij).

[0514] In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, The breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HE It is R2-. In some embodiments, breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, breast cancer is locally advanced, metastatic, ER+, HER+. 2. It is breast cancer.

[0515] In some embodiments, at least one somatic ER tumor mutation is Y537X, D Of the 538X, E380X, L379X, V422X, S463X, and L536X models... Selected from any one or any combination, "X" is a wild-type residue at that position. Refers to any amino acid residue outside. In some embodiments, at least one somatic E The R tumor mutations are Y537X, D538X, E380X, L379X, V422X, and S46. Select one or any combination of 3X and L536X, and "X" This refers to an amino acid residue other than the wild-type residue at that position, such as alanine (A) and valine (V). , leucine (L), isoleucine (I), phenylalanine (F), methionine (M), Tryptophan (W), Proline (P), Glycine (G), Serine (S), Threonine ( T), cysteine ​​(C), asparagine (N), glutamine (Q), tyrosine (Y), ri Din (K), arginine (R), histidine (H), aspartic acid (D), and gluta It is selected from mic acid (E).

[0516] In some embodiments, at least one somatic ER tumor mutation is Y537X ru.

[0517] In some embodiments, at least one somatic ER tumor mutation is D538X ru.

[0518] In some embodiments, at least one somatic ER tumor mutation is E380X. ru.

[0519] In some embodiments, at least one somatic ER tumor mutation is L379X ru.

[0520] In some embodiments, at least one somatic ER tumor mutation is V422X. ru.

[0521] In some embodiments, at least one somatic ER tumor mutation is S463X ru.

[0522] In some embodiments, at least one somatic ER tumor mutation is L536X ru.

[0523] In some embodiments, at least one somatic ER tumor mutation is Y537S, Y 537N, D538G, E380Q, L379I, V422del, S463P, L53 Includes one or any combination of 6P and L536_D538>P.

[0524] In some embodiments, at least one somatic ER tumor mutation is Y537S. ru.

[0525] In some embodiments, at least one somatic ER tumor mutation is Y537N. ru.

[0526] In some embodiments, at least one somatic ER tumor mutation is D538G. ru.

[0527] In some embodiments, at least one somatic ER tumor mutation is E380Q. ru.

[0528] In some embodiments, at least one somatic ER tumor mutation is L379I. ru.

[0529] In some embodiments, at least one somatic ER tumor mutation is V422del That is the case.

[0530] In some embodiments, at least one somatic ER tumor mutation is S463P. ru.

[0531] In some embodiments, at least one somatic ER tumor mutation is L536P. ru.

[0532] In some embodiments, at least one somatic ER tumor mutation is L536_D5 38>P.

[0533] In one embodiment, this application relates to simultaneous, separate, or sequential treatment and / or prevention of breast cancer. For use, the compound of formula (I) as defined herein and additional antimicrobial agents as defined herein. This relates to combination preparations with cancer drugs. In some embodiments, breast cancer is metastatic breast cancer. In some embodiments, breast cancer is locally advanced breast cancer. In terms of morphology, breast cancer is ER+, HER2-. In some embodiments, breast cancer is It is metastatic, ER+, and HER2- breast cancer. In some embodiments, breast cancer is local This is progressive, metastatic, ER-positive, HER2-negative breast cancer.

[0534] In one embodiment, this application relates to simultaneous, separate, or sequential treatment and / or prevention of breast cancer. For use, compounds of formula (Ic) as defined herein and additional compounds as defined herein. This relates to combination preparations with anticancer drugs. In some embodiments, breast cancer is metastatic It is breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, the breast This is metastatic, ER-+, HER2- breast cancer. In some embodiments, breast cancer is, This is locally advanced, metastatic breast cancer with ER+ and HER2-negative profiles.

[0535] In one embodiment, this application relates to simultaneous, separate, or sequential treatment and / or prevention of breast cancer. For use, the compound of formula (I) as defined herein and the palboshi as defined herein. This relates to combination preparations with crib inhibitors. In some embodiments, breast cancer is metastatic. It is breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In one embodiment, the breast cancer is ER+, HER2-. In some embodiments, breast The cancer is metastatic, ER-+, HER2- breast cancer. In some embodiments, the breast cancer is It is locally advanced, metastatic, ER-positive, and HER2-negative breast cancer.

[0536] In one embodiment, this application relates to simultaneous, separate, or sequential treatment and / or prevention of breast cancer. For use, the compound of formula (Ic) as defined herein and the pal as defined herein. This relates to combination preparations with bosiclib inhibitors. In some embodiments, breast cancer is treated with It is metastatic breast cancer. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is ER+, HER2-. In some embodiments, Breast cancer is metastatic, ER+, HER2- breast cancer. In some embodiments, breast It is locally advanced, metastatic, ER-positive, HER2-negative breast cancer.

[0537] In one embodiment, treating cancer with the compound of formula (I) and additional anticancer agents is possible. This results in a reduction in the size of the ulcer. A reduction in tumor size can also be called "tumor regression." Preferably, after treatment, the tumor size decreases by 5% or more compared to its size before treatment. Preferably, the tumor size is reduced by 10% or more, more preferably by 20% or more. More preferably, it is reduced by 30% or more, more preferably by 40% or more, and even more preferably The tumor size is reduced by more than 50%, and most preferably by more than 75%. It may be measured by a readily available measuring means. In a preferred embodiment, the size of the tumor is measured by a readily available measuring means. It may also be measured as the diameter of the ulcer.

[0538] In another embodiment, treating cancer with the compound of formula (I) and additional anticancer agents is: This results in a reduction in tumor volume. Preferably, after treatment, the tumor volume is equal to its size before treatment. The tumor volume is reduced by 5% or more, more preferably by 10% or more, A reduction of 20% or more, more preferably a reduction of 30% or more, and more preferably a reduction of 40% or more. Furthermore, it is reduced by 50% or more, and most preferably by 75% or more. Tumor The volume may be measured by any reproducible measuring means.

[0539] In another embodiment, treating cancer with the compound of formula (I) and additional anticancer agents is: This results in a reduction in the number of tumors. Preferably, after treatment, the number of tumors is 5 times the number before treatment. A decrease of % or more, more preferably a decrease of 10% or more in the number of tumors, more preferably a decrease of 20% or more. It decreases by more than 30%, more preferably by more than 40%, and further More preferably, the number of tumors is reduced by 50% or more, and most preferably, by 75% or more. The number of tumors may be measured by any reproducible measurement method. In a preferred embodiment, the number of tumors It can be measured by counting tumors that can be seen with the naked eye or at a specified magnification. In a preferred embodiment, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x. It is double.

[0540] In another embodiment, treating cancer with the compound of formula (I) and additional anticancer agents is: This results in a reduction in the number of metastatic lesions in other tissues or organs distant from the primary tumor site. Furthermore, after treatment, the number of metastatic lesions decreased by more than 5% compared to the number before treatment, and improved More preferably, the number of metastatic lesions decreases by 10% or more, and more preferably by 20% or more. More preferably, it is reduced by 30% or more, more preferably by 40% or more, and even more preferably The number of metastatic lesions decreases by more than 50%, and most preferably by more than 75%. The number of metastatic lesions may be measured by a reproducible measurement method. In a preferred embodiment, the number of metastatic lesions Measured by counting metastatic lesions that can be seen with the naked eye or at a specified magnification. It is possible. In a preferred embodiment, the specified magnification is 2x, 3x, 4x, 5x, 10x, or It is 50 times.

[0541] In another embodiment, treating cancer with the compound of formula (I) and additional anticancer agents is: Compared to the group administered the carrier alone, the mean survival time of the treated group was increased. It brings about. Preferably, the average survival period is more than 30 days, more preferably more than 60 days, even better. The increase is over 90 days, most preferably over 120 days. The increase in the average survival period of the population is arbitrary. It may be measured by a reproducible means. In a preferred embodiment, the mean survival period of the population. An increase in, for example, the mean length of survival after the initiation of treatment with an active drug or compound, in a population It may be measured by calculating the mean of the population. In another preferred embodiment, the mean of the population The increase in survival time is, for example, the survival time after the completion of the first round of treatment with the active drug or compound. The average length of the structure may be measured by calculating it over the group.

[0542] In another embodiment, treating cancer with the compound of formula (I) and additional anticancer agents is: Compared to the untreated group, the treated group showed an increase in average survival time. Preferably, the average survival period is more than 30 days, more preferably more than 60 days, and more preferably 9 The increase is greater than 0 days, most preferably greater than 120 days. The increase in the mean survival period of the population is any reproduction. It may be measured by a specific means. In a preferred embodiment, the increase in the mean survival time of the population. For example, the average length of survival after the start of treatment with an active drug or compound is used for a population. It may be measured by calculation. In another preferred embodiment, the average survival period of the population. The increase is, for example, in the first round of treatment using the compound of formula (I) and additional anticancer agents. The average length of survival after completion may be measured by calculating it for the population.

[0543] In another embodiment, treating cancer with the compound of formula (I) and additional anticancer agents is: This results in a decrease in the tumor growth rate. Preferably, after treatment, the tumor growth rate is equal to the number before treatment. The tumor growth rate is reduced by at least 5%, and more preferably by at least 10%. , more preferably reduced by at least 20%, and more preferably reduced by at least 30% More preferably, reduced by at least 40%, and more preferably, reduced by at least 50%. More preferably, a reduction of at least 50%, and most preferably, a reduction of at least 75%. The tumor growth rate may be measured by any reproducible measurement method. In a more accurate representation, the tumor growth rate is measured according to the change in tumor diameter per unit time.

[0544] In another embodiment, treating cancer with the compound of formula (I) and additional anticancer agents is: This results in a reduction in tumor regrowth. Preferably, tumor regrowth after treatment is less than 5%, more preferably... Tumor regrowth is less than 10%, more preferably less than 20%, more preferably less than 30%. More preferably less than 40%, more preferably less than 50%, and even more preferably less than 50% , most preferably less than 75%. Tumor regrowth can be measured by any reproducible means. It may be measured by, for example, tumor regrowth after tumor reduction following previous treatment. In a preferred embodiment, tumor regrowth may be measured by, for example, tumor reduction after previous treatment. It is measured by measuring the increase in the diameter or volume of the tumor. In another preferred embodiment, The reduction in tumor regrowth is indicated by the absence of tumor recurrence after discontinuation of treatment.

[0545] Compounds of formula (I) and additional antimicrobial agents for any of the methods and uses described herein. The dosage of cancer drugs depends on the drug, the recipient's age, weight, and clinical condition, as well as the selection of the drug. Among other factors that influence the dosage, the experience and judgment of the clinician or practitioner administering the therapy are particularly important. It changes depending on the interruption.

[0546] An effective dose of additional anticancer drugs may be administered once, twice, three times, four times, or five times per day. The number of times you exceed this limit is 5 days, 10 days, 15 days, 30 days, 60 days, 90 days, and 120 days. It is administered for 150 days, 180 days or more, and then for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days Additional anticancer treatment for days, 37 days, 38 days, 39 days, 40 days or more. The drug may not be administered. This type of treatment schedule, i.e., additional antimicrobial therapy on consecutive days The administration of cancer drugs, followed by the non-administration of additional anticancer drugs on consecutive days, is called a treatment cycle. It is possible.

[0547] In some embodiments, an effective dose of an additional anticancer drug is administered once or twice daily, up to 5 times a day. It is administered for 10, 15, 20, 25, or 30 days, followed by 1, 2, 3, 4, 5, 6, 7 Additional anticancer drugs may be withheld for 8, 9, or 10 days.

[0548] In some embodiments, an effective dose of an additional anticancer drug is administered once daily, up to 5, 10 times. It is administered for 15, 20, 25, or 30 days, followed by 1, 2, 3, 4, 5, 6, 7, 8, 9 Alternatively, the patient may be exempted from additional anticancer drugs for 10 days.

[0549] In some embodiments, a treatment cycle with additional anticancer drugs achieves the intended effect. It can be repeated as many times as necessary to achieve the goal.

[0550] In some embodiments, a treatment cycle using an additional anticancer agent is performed using a compound of formula (I). This is the same treatment cycle as using [the specified method].

[0551] In some embodiments, a treatment cycle using an additional anticancer agent is performed using a compound of formula (I). This differs from the treatment cycle using [the other method].

[0552] A therapeutically effective dose of the compound of formula (I) and additional anticancer agents is administered once or multiple times daily, up to a maximum of 3 times. Administered for 0 days or more, followed by 1 day or more of compound (I) and / or This may involve the non-administration of additional anticancer drugs. This type of treatment schedule, i.e., consecutive Administration of the compound of formula (I) and / or additional anticancer agents on days, followed by administration of formula (I) on consecutive days. The absence of the compound and / or additional anticancer agents can be called a treatment cycle. In some embodiments, the treatment cycle is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 times. Or it may be repeated more times. In some embodiments, additional anticancer agents The treatment cycle may be repeated as many times as necessary to achieve the intended effect.

[0553] In some embodiments, the administration includes a compound of formula (I) and additional anticancer agents. In the method disclosed herein, a therapeutically effective amount of the compound of formula (I) is administered once or twice daily. , 3 times, 4 times, or more times, for 1 day, 2 days, 3 days, 4 days, 5 days 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days For periods of 15, 30 consecutive days, or 2 months, 3 months, 4 months, 5 months, or 6 months Monthly or longer, administered as a single or divided dose, 0.01, 0.05, 0.1 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 2 1, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 ,35,36,37,38,39,40,41,42,43,44,45,46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 6 1, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74 , 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1, It is 000mg.

[0554] In some embodiments, the administration includes a compound of formula (I) and additional anticancer agents. In the method disclosed herein, a therapeutically effective amount of the compound of formula (I) is administered once or twice daily. Approximately 30 mg, administered as a single dose or in divided doses, in 3, 4, or more doses. 60mg, about 90mg, about 120mg, about 150mg, about 180mg, about 210mg, about 240mg, approx. 270mg, approx. 300mg, approx. 330mg, approx. 360mg approx. 390mg Approximately 420mg, 450mg, 480mg, 510mg, 540mg, 570mg mg, about 600mg, about 630mg, about 660mg, about 690mg, about 720mg, about 7 50mg, approximately 780mg, approximately 810mg, approximately 840mg, approximately 870mg, approximately 900mg, The dosage is approximately 930 mg, 960 mg, or 990 mg (this dose is calculated based on the patient's body weight (kg)). ), body surface area (m 2 ), and may be adjusted for age (years).

[0555] In some embodiments, the administration includes a compound of formula (I) and additional anticancer agents. In the method disclosed herein, a therapeutically effective amount of the compound of formula (I) is administered once or twice daily. Approximately 30 mg to approximately 30 mg is administered in single doses or divided doses, in 3, 4, or more doses. The dose is 1000 mg (this dose is calculated based on the patient's weight (kg) and body surface area (m²). 2 ), and age ( (May be adjusted for age)

[0556] In some embodiments, the administration includes a compound of formula (I) and additional anticancer agents. In the method disclosed herein, a therapeutically effective amount of the compound of formula (I) is administered once or twice daily. It is administered in single doses or divided doses in 3, 4, or more doses, for approximately 10 to 40 doses. mg, about 20 to about 50 mg, about 30 to about 60 mg, about 40 to about 70 mg, about 50 to about 80 mg, about 60 to about 90 mg, about 70 to about 100 mg, about 80 to about 110 mg, about 90 to about 120mg, about 100~130mg, about 110~140mg, about 120~150m g, about 130 to about 160 mg, about 140 to about 170 mg, about 150 to about 180 mg, about 1 60~approx. 190mg, approx. 170~approx. 200mg, approx. 180~approx. 210mg, approx. 190~approx. 220mg, approximately 200~230mg, approximately 210~240mg, approximately 220~250mg g, approximately 230~260mg, approximately 240~270mg, approximately 250~280mg, approximately 2 60~approx. 290mg, approx. 270~approx. 300mg, approx. 280~approx. 310mg, approx. 290~approx. 320mg, approximately 300~330mg, approximately 310~340mg, approximately 320~350mg g, approximately 330~360mg, approximately 340~370mg, approximately 350~380mg, approximately 3 60~approx. 390mg, approx. 370~approx. 400mg, approx. 380~approx. 410mg, approx. 390~approx. 420mg, approximately 400~430mg, approximately 410~440mg, approximately 420~450mg g, approximately 430~460mg, approximately 440~470mg, approximately 450~480mg, approximately 4 60~approx. 490mg, approx. 470~approx. 500mg, approx. 480~approx. 510mg, approx. 490~approx. 520mg, approximately 500~530mg, approximately 510~540mg, approximately 520~550mg g, approximately 530~560mg, approximately 540~570mg, approximately 550~580mg, approximately 5 60~approx. 590mg, approx. 570~approx. 600mg, approx. 580~approx. 610mg, approx. 590~approx. 620mg, approximately 600~630mg, approximately 610~640mg, approximately 620~650mg g, approximately 630~660mg, approximately 640~670mg, approximately 650~680mg, approximately 6 60~approx. 690mg, approx. 670~approx. 700mg, approx. 680~approx. 710mg, approx. 690~approx. 720mg, approximately 700~730mg, approximately 710~740mg, approximately 720~750mg g, approximately 730~760mg, approximately 740~770mg, approximately 750~780mg, approximately 7 60~approximately 790mg, approximately 770~approximately 800mg, approximately 780~approximately 810mg, approximately 790~approximately 820mg, approximately 800-830mg, approximately 810-840mg, approximately 820-850mg g, about 830 to about 860 mg, about 840 to about 870 mg, about 850 to about 880 mg, about 8 60-approximately 890mg, approximately 870-approximately 900mg, approximately 880-approximately 910mg, approximately 890-approximately 920mg, about 900 to about 930mg, about 910 to about 940mg, about 920 to about 950m g, about 930 to about 960 mg, about 940 to about 970 mg, about 950 to about 980 mg, about 9 The dosage is 60 to approximately 990 mg, or approximately 970 to approximately 1,000 mg (the dosage is based on the patient's body weight (kg)). ), body surface area (m 2 (and may be adjusted for age (years)).

[0557] In some embodiments, the administration includes a compound of formula (I) and additional anticancer agents. In the case of the method disclosed herein, a therapeutically effective amount of the compound of formula (I) is also approximately per day 0.01 mg / kg to approximately 100 mg / kg per day, approximately 0.05 mg / kg per day ~Approximately 10 mg / kg per day, approximately 0.075 mg / kg per day ~Approximately 5 mg / kg per day g / kg, approximately 0.10 mg / kg to approximately 1 mg / kg per day, or per day The dosage may be in the range of approximately 0.20 mg / kg to approximately 0.70 mg / kg per day.

[0558] In some embodiments, the administration includes a compound of formula (I) and additional anticancer agents. In the method disclosed herein, a therapeutically effective amount of the compound of formula (I) is approximately 0 per day. 10 mg / kg, approximately 0.15 mg / kg per day, approximately 0.20 mg / kg per day, Approximately 0.25 mg / kg per day, approximately 0.30 mg / kg per day, approximately 0. 35 mg / kg, approximately 0.40 mg / kg per day, approximately 0.45 mg / kg per day, Approximately 0.50 mg / kg per day, approximately 0.55 mg / kg per day, approximately 0. 60 mg / kg, approximately 0.65 mg / kg per day, approximately 0.70 mg / kg per day, Approximately 0.75 mg / kg per day, approximately 0.80 mg / kg per day, approximately 0. 85 mg / kg, approximately 0.90 mg / kg per day, approximately 0.95 mg / kg per day, Alternatively, it is approximately 1.00 mg / kg per day.

[0559] In some embodiments, the administration includes a compound of formula (I) and additional anticancer agents. In the method disclosed herein, a therapeutically effective dose of the compound of formula (I) is approximately 1 per day. 0.5 mg / kg, approximately 1.10 mg / kg per day, approximately 1.15 mg / kg per day, Approximately 1.20 mg / kg per day, approximately 1.25 mg / kg per day, approximately 1. 30 mg / kg, approximately 1.35 mg / kg per day, approximately 1.40 mg / kg per day, Approximately 1.45 mg / kg per day, approximately 1.50 mg / kg per day, approximately 1. 55 mg / kg, approximately 1.60 mg / kg per day, approximately 1.65 mg / kg per day, Approximately 1.70 mg / kg per day, approximately 1.75 mg / kg per day, approximately 1. 80 mg / kg, approximately 1.85 mg / kg per day, approximately 1.90 mg / kg per day, This is approximately 1.95 mg / kg per day, or approximately 2.00 mg / kg per day.

[0560] In some embodiments, the administration includes a compound of formula (I) and additional anticancer agents. In the method disclosed herein, a therapeutically effective dose of the compound of formula (I) is approximately 2 ml per day. g / kg, approximately 2.5 mg / kg per day, approximately 3 mg / kg per day, approximately 3 0.5 mg / kg, approximately 4 mg / kg per day, approximately 4.5 mg / kg per day, per day Approximately 5 mg / kg, approximately 5.5 mg / kg per day, approximately 6 mg / kg per day, per day Approximately 6.5 mg / kg per day, approximately 7 mg / kg per day, approximately 7.5 mg / kg per day, Approximately 8.0 mg / kg per day, approximately 8.5 mg / kg per day, approximately 9.0 mg / kg per day This is approximately 9.5 mg / kg per day, or approximately 10 mg / kg per day, depending on the g / kg.

[0561] In some embodiments, the administration includes a compound of formula (I) and additional anticancer agents. In the method disclosed herein, an effective therapeutic dose of an additional anticancer agent is administered once or twice daily. Three, four, or more times, for one day, two days, three days, four days, five days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days , for 15 days, 30 consecutive days, or once, twice, three times, four times, or more than that per day The number of times you can do it, or for 2 months, 3 months, 4 months, 5 months, 6 months, or more Above, administered in single or divided doses, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3. 5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 3 7, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 , 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64、65、66、67、68、69、70、71、72、73、74、75、76、7 7、78、79、80、81、82、83、84、85、86、87、88、89、90 、91、92、93、94、95、96、97、98、99、100、105、110、 115、120、125、130、135、140、145、150、155、160、 165、170、175、180、185、190、195、200、205、210、 215、220、225、230、235、240、245、250、255、260、 265、270、275、280、285、290、295、300、305、310、 315、320、325、330、335、340、345、350、355、360、 365、370、375、380、385、390、395、400、405、410、 415、420、425、430、435、440、445、450、455、460、 465、470、475、480、485、490、495、500、505、510、 515、520、525、530、535、540、545、550、555、560、 565、570、575、580、585、590、595、600、605、610、 615、620、625、630、635、640、645、650、655、660、 665、670、675、680、685、690、695、700、705、710、 715、720、725、730、735、740、745、750、755、760、 765、770、775、780、785、790、795、800、805、810、 815、820、825、830、835、840、845、850、855、860、 865、870、875、880、885、890、895、900、905、910、 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, The dosage is 965, 970, 975, 980, 985, 990, 995, or 1,000 mg. In some embodiments, the additional anticancer agent is palbociclib.

[0562] In some embodiments, the compound of formula (I) and palbociclib are administered simultaneously. It is also good. In some embodiments, the compound of formula (I) is administered first, and palbociclib It is administered second. In some embodiments, palbociclib is administered first, and formula Compound (I) is administered secondly. For example, in some embodiments, the compound of formula (I) The combination is administered and palbociclib is administered simultaneously. In some embodiments, the formula The administration of compound (I) and palbociclib are performed consecutively.

[0563] In some embodiments, palbociclib is administered before administration of the compound of formula (I). As a result, the two compounds and their respective excipients do not mix in the stomach of the subject. In this embodiment, the maximum time between the administration of palbociclib and the administration of the compound of formula (I) is This is the time at which the advantages of the combination are achieved. In some embodiments, Parbosik Rib is administered with the compound of formula (I) for at least 5 minutes, at least 10 minutes, and at least It is administered 15 minutes, at least 20 minutes, at least 25 minutes, or at least 30 minutes prior to the procedure. In some embodiments, palbociclib is administered 5 to 35 minutes after the compound of formula (I) is administered. , 10-40 minutes, 15-25 minutes, 20-50 minutes, 25-55 minutes, or 30-60 minutes before In some embodiments, palbociclib is administered as a compound of formula (I). 30-60 minutes, 30-70 minutes, 30-80 minutes, 30-90 minutes, 30-120 minutes, 30-1 80 minutes, 30-240 minutes, 30-300 minutes, 30-360 minutes, 30-480 minutes, 30-6 It is administered 00 minutes before or 30 to 720 minutes before the scheduled time.

[0564] In some embodiments, palbociclib is administered after administration of the compound of formula (I). As a result, the two compounds and their respective excipients (if present) mix in the stomach of the subject. No. In some embodiments, the administration of palbociclib and the administration of the compound of formula (I) The maximum time between is the time at which the benefits of the combination are achieved. Several embodiments Therefore, palbociclib is administered at least 5 minutes after the compound of formula (I) is administered, at least 1 0 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, or at least 30 minutes It is administered later. In some embodiments, palbociclib is administered by a compound of formula (I). The duration is 5-35 minutes, 10-40 minutes, 15-25 minutes, 20-50 minutes, 25-55 minutes, or 3 It is administered 0 to 60 minutes later. In some embodiments, palbociclib is chemically compounded by formula (I). The combined substance is administered at 30-60 minutes, 30-70 minutes, 30-80 minutes, 30-90 minutes, and 30-1 20 minutes, 30-180 minutes, 30-240 minutes, 30-300 minutes, 30-360 minutes, 30-4 It is administered after 80 minutes, 30-600 minutes, or 30-720 minutes.

[0565] In some embodiments, the administration includes a compound of formula (I) and additional anticancer agents. In the case of the methods disclosed herein, an effective amount of additional anticancer agent is administered once daily, as a single dose, or The dosage is 60 mg, 75 mg, 100 mg, or 125 mg, administered in divided doses. In that embodiment, a therapeutically effective dose of an additional anticancer drug is administered once daily for 21 consecutive days. Then, treatment is discontinued for 7 days. In some embodiments, additional anticancer drugs are administered. It is bosiclib.

[0566] This specification specifies a 21-day consecutive treatment with additional anticancer drugs followed by a 7-day discontinuation of treatment. This is called a treatment cycle or cycle. In some embodiments, additional anticancer drugs are used in the treatment cycle. Ikuru is repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 times, or more times. It may be. In some embodiments, an additional anticancer drug treatment cycle is intended. It may be repeated as many times as necessary to achieve the effect. In some embodiments, additional The anticancer drug is palbociclib.

[0567] In some embodiments, the administration includes a compound of formula (I) and additional anticancer agents. In the case of the method disclosed herein, the therapeutically effective amount of additional anticancer agent is approximately 0.1 per day. mg / kg, approximately 0.2 mg / kg per day, approximately 0.3 mg / kg per day, per day Approximately 0.4 mg / kg, approximately 0.5 mg / kg per day, 0.6 mg / kg per day, Approximately 0.7 mg / kg per day, approximately 0.8 mg / kg per day, approximately 0.9 mg / kg per day g / kg, approximately 1 mg / kg per day, approximately 1.1 mg / kg per day, approximately 1 0.2 mg / kg, approximately 1.3 mg / kg per day, approximately 1.4 mg / kg per day, 1 day Approximately 1.5 mg / kg per serving, 1.6 mg / kg per day, and approximately 1.7 mg / kg per day. g, approximately 1.8 mg / kg per day, approximately 1.9 mg / kg per day, approximately 2 m per day g / kg, approximately 2.5 mg / kg per day, approximately 3 mg / kg per day, approximately 3 0.5 mg / kg, approximately 4 mg / kg per day, approximately 4.5 mg / kg per day, per day Approximately 5 mg / kg, approximately 5.5 mg / kg per day, approximately 6 mg / kg per day, per day Approximately 6.5 mg / kg per day, approximately 7 mg / kg per day, approximately 7.5 mg / kg per day, Approximately 8.0 mg / kg per day, approximately 8.5 mg / kg per day, approximately 9.0 mg / kg per day This is approximately 9.5 mg / kg per day, or approximately 10 mg / kg per day. In some embodiments, the additional anticancer agent is palbociclib.

[0568] In some embodiments, the administration includes a compound of formula (I) and additional anticancer agents. In the case of the method disclosed herein, the therapeutically effective amount of additional anticancer agent is approximately 0.5 per day. mg / kg is approximately 3.0 mg / kg per day.

[0569] In some embodiments, the administration includes a compound of formula (I) and additional anticancer agents. In the method disclosed herein, a therapeutically effective dose of the compound of formula (I) is administered to the subject once daily. In some embodiments, this daily dose of the compound of formula (I) is given to all subjects. It is administered at a time. In some embodiments, this daily dose of the compound of formula (I) is administered to the subject It is administered in two unit doses (divided doses). In some embodiments, the compound of formula (I) This daily dose is administered to the subject in three unit doses. In some embodiments, the formula ( The daily dose of compound I) is administered to the subject in four unit doses. Several implementations In this scenario, the daily dose of the compound of formula (I) is administered to the subject in units of five or more doses. In some embodiments, these unit doses are taken at regular intervals throughout the day, for example, 12 It is administered to the target individual at intervals of hours, every 8 hours, every 6 hours, every 5 hours, every 4 hours, etc.

[0570] In some embodiments, the administration includes a compound of formula (I) and additional anticancer agents. In the method disclosed herein, a therapeutically effective amount of additional anticancer agent is administered to the subject once daily. In some embodiments, this daily dose of the additional anticancer drug is administered to the target all at once. It is administered. In some embodiments, this daily dose of the additional anticancer agent is administered twice to the subject. It is administered in unit doses (divided doses). In some embodiments, additional anticancer agents are used. The daily dose is administered to the subject in three unit doses. In some embodiments, additional antimicrobial agents are used. This daily dose of the cancer drug is administered to the subject in four unit doses. In some embodiments, This daily dose of additional anticancer drugs is administered to the subject in units of five or more doses. In this embodiment, these unit doses are administered at regular intervals throughout the day, for example, every 12 hours. It is administered to the target individual every 8 hours, 6 hours, 5 hours, 4 hours, etc.

[0571] A therapeutically effective dose of the compound of formula (I) and additional anticancer agents can be used in cell culture assays or animal models. The first estimated species is usually a rat, mouse, rabbit, dog, or pig. Furthermore, animal models may be used to determine appropriate concentration ranges and administration routes. Then, This information is used to determine useful doses and routes for administration in humans. This can be done. Therapeutic / preventive effects and toxicity are determined by standard pharmaceutical studies in cell culture or experimental animals. Procedure, for example ED 50 (Effective therapeutic dose in 50% of the population) and LD 50 (50 in the group) The dose ratio between toxicity and therapeutic effect can be determined by the dose at which % of the dose is lethal. It is an indicator, LD 50 / ED 50 It can be expressed as a ratio. Pharmaceutical compositions exhibiting a large therapeutic index. This is preferable. The dose is within this range, depending on the dosage form used, the patient's sensitivity, and the route of administration. It can change internally.

[0572] The dosage and administration shall provide a sufficient level of the compound of formula (I) and / or additional anticancer agents. It is adjusted to achieve or maintain the desired effect. Possible factors to consider include: , severity of the condition, general health status of the subject, age, weight, and sex of the subject, diet, administration Factors include duration and frequency, drug combinations, response sensitivity, and tolerance / response to therapy. The active pharmaceutical composition is administered every 3 to 4 days, depending on the half-life and clearance rate of the specific formulation. It may be administered weekly or every two weeks.

[0573] Pharmaceutical composition Compounds of formula (I) and additional anticancer agents are administered orally, parenterally (subcutaneously, intramuscularly, intravenously (Borne). (Lass or infusion), depot, intraperitoneal, subarachnoid, intranasal, vaginal, sublingual, buccal, intraocular It can be administered in accordance with the present invention by any suitable route, including the rectum.

[0574] In some embodiments, the compound of formula (I) and additional anticancer agents are formulated into separate dosage forms. These may be formulated as follows: These distinct dosage forms may be, for example, oral, parenteral (subcutaneous, intramuscular, intravenous). Any method including (depot), subarachnoid space, nasal cavity, vagina, sublingual, buccal, intraocular, or rectal. It may be suitable for administration via the appropriate route.

[0575] In some embodiments, the compound of formula (I) and an additional anticancer agent are combined together. It may be formulated into a single dosage form. This single dosage form may be, for example, administered orally, parenterally (subcutaneously, Intramuscular, intravenous, depot, subarachnoid, intranasal, vaginal, sublingual, buccal, intraocular, or direct It may be suitable for administration via any appropriate route, including the intestines.

[0576] In some embodiments, the compound of formula (I) and additional anticancer agents are formulated into separate dosage forms. It may be modified, each suitable for oral administration. In some embodiments, additional antimicrobial agents are used. The cancer drugs are SHR6390, trilaciclib, lerocyclib, AT7519M, and dinasic. Ribociclib, alpelicib, abemaciclib, everolimus, venetoclax, Inavolicib (GDC-0077), palbociclib, or any of the following pharmaceutically acceptable alternatives It is a salt. In some embodiments, additional anticancer agents include palbociclib, palbociclib. Bunicillin hydrochloride, or any other pharmaceutically acceptable salt of palbociclib.

[0577] In some embodiments, the compound of formula (I) and additional anticancer agents are suitable for oral administration. It may be formulated into a single dosage form. In some embodiments, additional anticancer agents are SH R6390, Trilaciclib, Lerocilib, AT7519M, Dinacilib, Ribociclib Rib, alpericib, abemaciclib, everolimus, venetoclax, inavolicib ( GDC-0077), palbociclib, or pharmaceutically acceptable salts thereof. In some embodiments, additional anticancer agents include palbociclib, palbociclib dihydrochloride, and It is a pharmaceutically acceptable salt of any other palbociclib.

[0578] In some embodiments, the compound of formula (I) and additional anticancer agents are used separately or together. Each is formulated for oral administration in one of the following ways. For example, in some embodiments, The compound of formula (I) and the additional anticancer agent can be used either separately or together as follows: Zero of each of the emulsifiers, surfactants, binders, disintegrants, flow promoters, and lubricants. It is formulated as a tablet containing one, two or more, or alternatively, formula ( I) The compounds and additional anticancer agents may be taken separately, together in a capsule, or in an oral liquid. They can be formulated as, or in combination thereof.

[0579] In some embodiments, the emulsifier is hypromellose.

[0580] In some embodiments, the surfactant is vitamin E polyethylene glycol succinate. It is.

[0581] In some embodiments, the binder (also referred to herein as the filler) is a microcrystalline cellulose From the group consisting of sucrose, lactose monohydrate, sucrose, glucose, and sorbitol Selected.

[0582] In some embodiments, the disintegrant is croscarmellose sodium.

[0583] In some embodiments, the flow enhancer improves the flow of the powder by reducing interparticle aggregation. This refers to a substance used to promote this. In some embodiments, the dosage form of the present disclosure The fluidity enhancers consist of silicon dioxide, anhydrous silica colloid, starch, and talc. Selected from.

[0584] In some embodiments, the lubricant is used in a machine used to prepare the dosage forms of the present disclosure. This refers to a substance that prevents components from adhering and / or agglomerating. In some embodiments, this disclosure In this dosage form, the lubricant is magnesium stearate, sodium stearyl fumarate. Selected from the group consisting of stearic acid and plant-derived stearin.

[0585] A medical device containing the compound of formula (I) and additional anticancer agents (either separately or together) Pharmaceutical compositions are, for example, manufactured using conventional mixing, dissolving, granulation, and sugar production (dragee-making). ), wet grinding (levigating), emulsification, encapsulation, filling, or freeze-drying process It can be manufactured by means of a commonly known method. The pharmaceutical composition is of formula (I) Excipients and Using one or more pharmaceutically acceptable carriers containing a syrup and / or adjuvants, in a conventional manner It can be formulated into a pharmaceutical product. Naturally, the appropriate formulation depends on the chosen route of administration.

[0586] Compounds of formula (I) suitable for injection and additional anticancer agents (either separately or together) A pharmaceutical composition containing ) is a sterile aqueous solution for the immediate preparation of a sterile injection solution or dispersion. (In the case of water solubility) or includes a dispersion and sterile powder. For intravenous administration, a suitable carrier is used. And, physiological saline, bacteriostatic water, Cremophor EL (registered trademark) (BASF, Pars Examples include ippany, NJ, or phosphate-buffered saline (PBS). All In such cases, the composition must be sterile and fluid enough to be easily injected. It must be stable under manufacturing and storage conditions, and must be free of bacteria and It must be protected from contamination by microorganisms such as fungi. The carrier is, for example, water. Ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyols) A solvent or dispersion medium containing ethylene glycol, etc., and suitable mixtures thereof. This can be achieved by using a coating such as lecithin. , maintained by the particle size required in the case of dispersion, and by the use of surfactants. It is possible to prevent the action of microorganisms using various antibacterial and antifungal agents, such as parabens. This is achieved by chlorobutanol, phenol, ascorbic acid, thimerosal, etc. Obtain. Often, isotonic agents, such as sugars, mannitol, sorbitol, and other polyhydric compounds. It is preferable to include kohl and sodium chloride in the composition. Sustained action of the injectable composition Absorption is slowed by drugs such as aluminum monostearate and gelatin. This can be achieved by including it in the composition.

[0587] The sterile injection solution may require, if necessary, the compound of formula (I) and / or additional anticancer agents. In appropriate quantities, incorporate one or a combination of the components listed above into a suitable solvent, It can be prepared by sterilizing by filtration afterwards. Generally, the dispersion contains the active agent or The compound contains a basic dispersion medium and other necessary components from those listed above. Prepared by incorporating into a bacterial vehicle. Sterile powder for the preparation of sterile injection solutions. In this case, the preparation method is vacuum drying and freeze-drying, and the active ingredients are extracted from the solution that has been previously sterile filtered. Powders of the active ingredient and any additional desired ingredients are obtained.

[0588] Oral compositions generally contain inert diluents or edible, pharmaceutically acceptable carriers. It may be encapsulated in gelatin capsules or compressed into tablets. Oral therapeutic administration For the purpose of this, the compound of formula (I) and / or additional anticancer agents are used in combination with excipients in tablets, etc. It can be used in the form of roaches or capsules. The oral composition can also be used as a mouthwash. It can be prepared using a fluid carrier for use as a fluid, and the drug or in the fluid carrier The compound is applied orally, and the mouth is rinsed and spat out, or swallowed. Pharmacologically A suitable binder and / or adjuvant can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. contain the following ingredients: microcrystalline cellulose, traga. Cant gum or gelatin as a binder, starch or lactose as an excipient , disintegrants such as alginic acid, Primogel, or corn starch, stearic acid Lubricants such as magnesium, flow promoters such as colloidal silicon dioxide, sucrose, etc. The sweeteners used are saccharin, peppermint, methyl salicylate, or orange. It contains either a flavoring agent such as a spice, or a compound with similar properties. It is possible.

[0589] For administration by inhalation, the compound of formula (I) and / or additional anticancer agents should be administered appropriately. A pressurized container or dispenser containing an adjuvant, such as a gas like carbon dioxide, or It is delivered from a nebulizer in the form of an aerosol spray.

[0590] Systemic administration of the compound of formula (I) and / or additional anticancer agents may also be performed via mucosal means or percutaneous means. In some cases, the method may vary. For transmucosal or transdermal administration, appropriate immersion in the barrier to penetration is necessary. Penetrating agents are used in the formulation. These penetrating agents are generally known in the art, For example, for transmucosal administration, this includes detergents, bile salts, and fusidic acid derivatives. Administration can be achieved by using a nasal spray or suppository. For transdermal administration, active The agent or compound is an ointment, salve, or gel commonly known in the art. Alternatively, it may be formulated into a cream.

[0591] In one embodiment, the compound of formula (I) and / or additional anticancer agents are, for example, implants and Rapid elimination from the body, including controlled-release formulations such as microencapsulated delivery systems. It is prepared with a pharmaceutically acceptable carrier that protects the drug or compound from exposure. For example, Ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoester Biodegradable and biocompatible polymers such as polylactic acid can be used. The method for preparing the eel preparation will be obvious to those skilled in the art. The materials are Alza Corpora. Products commercially available from tion and Nova Pharmaceuticals are included. It can also be done by hand. Liposome suspension (a monoclonal antibody against the viral antigen) Liposomes that target stained cells can also be used as pharmaceutically acceptable carriers. These are, for example, those described in U.S. Patent No. 4,522,811, and are for those skilled in the art. It can be prepared according to known methods.

[0592] For ease of administration and dose uniformity, the compound of formula (I) and / or additional anticancer agents It is particularly advantageous to formulate the oral or parenteral composition into unit dosage forms. When used, the dosage unit form or "unit dose" refers to the unit dose for the subject being treated. This refers to physically distinct units suitable as such, each unit being a desired pharmaceutical carrier in relation to the required pharmaceutical carrier. It contains a predetermined amount of an active agent or compound calculated to produce a therapeutic effect. The specifications of the dosage unit form are based on the inherent properties of the compound of f...

Claims

1. A method for treating breast cancer in a person who requires treatment for breast cancer, wherein the breast cancer is It contains at least one somatic estrogen receptor (ER) tumor mutation, The above method provides a therapeutically effective amount of the compound of formula (I), 【Chemistry 1】 or administering a pharmaceutically acceptable salt thereof to the subject, in the formula, Each R １ and each R ２ They are independent, halo, OR ５ , N(R ５ ) (Caution ６ ), NO ２ , CN, S O ２ (R ５ ), C １ -C ６ alkyl and C ３ -C[[ID=|1]] ６ selected from the group consisting of cycloalkyl Re, R ３ and R ４ Both are hydrogen, or together with the carbon they are bonded to. It either forms a carbonyl group or Each R ５ and each R ６ These are independently hydrogen and C １ -C ６ Alkyl and C ３ -C ６ Cycloalkyl Selected from the group consisting of, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, or 4. The therapeutically effective amount of the compound of formula (I) is approximately 10 mg to approximately 1000 mg. 。

2. The aforementioned at least one somatic ER tumor mutation is Y537X, D538X, E380X Selected from the group consisting of L379X, V422X, S463X, and L536X, "X The method according to claim 1, wherein "" refers to any amino acid residue other than the wild-type residue at that position. 。

3. The aforementioned at least one somatic ER tumor mutation is Y537S, Y537N, D538G E380Q, L379I, V422del, S463P, L536P and L536_D The method according to claim 1 or 2, selected from the group consisting of 538>P.

4. The aforementioned breast cancer is estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative. The method according to any one of claims 1 to 3, wherein the method is HER2-.

5. The person according to any one of claims 1 to 4, wherein the breast cancer is metastatic or locally advanced. Law.

6. R １ and R ２ Each of them independently, Halo and OR ５ Selected from the group consisting of claims 1 to The method described in any one of item 5.

7. R ３ and R ４ The method according to any one of claims 1 to 6, wherein both are hydrogen.

8. R ３ and R ４ However, together with the carbon atoms to which they are bonded, they form a carbonyl group. The method described in any one of the requests 1 to 6.

9. The method according to any one of claims 1 to 5, 7, or 8, wherein m and n are each 0.

10. The method according to any one of claims 1 to 8, wherein m and n are each 1.

11. One of m and n is 0 and the other is 1, any of claims 1 to 5, 7, or 8 The method described in any one of the items.

12. The compound of formula (I) above, 【Chemistry 2-1】 【Chemistry 2-2】 [Chemistry 2-3] The method according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

13. Any one of claims 1 to 5, wherein the compound of formula (I) is the compound of formula (I-a). Methods used. 【Transformation 3】

14. Any one of claims 1 to 5, wherein the compound of formula (I) is the compound of formula (I-c). Methods used. 【Chemistry 4】

15. Any one of claims 1 to 5, wherein the compound of formula (I) is the compound of formula (I-j). Methods used. 【Transformation 5】

16. The compound of formula (I) is administered orally to the subject, any one of claims 1 to 15. Methods used.

17. The therapeutically effective amount of the compound of formula (I) is administered once a day, twice a day, three times a day, or once a day. The method according to any one of claims 1 to 16, wherein the subject is administered four times.

18. Claim that the therapeutically effective amount of the compound of formula (I) is administered to the subject once a day. The method described in any one of items 1 to 17.

19. The therapeutically effective amount of the compound of formula (I) is administered to the subject all at once, or The method according to claims 1 to 16, administered in two, three, or four unit doses.

20. The therapeutically effective amount of the compound of formula (I) is approximately 10 mg, approximately 15 mg, approximately 20 mg, and approximately The present invention according to any one of claims 1 to 19, wherein the present invention is 25 mg, approximately 30 mg, or approximately 40 mg. method.

21. Claim that the therapeutically effective amount of the compound of formula (I) is about 20 mg to about 750 mg. The method described in any one of items 1 to 19.

22. Claim that the therapeutically effective amount of the compound of formula (I) is about 30 mg to about 500 mg. The method described in any one of items 1 to 19.

23. Claim that the therapeutically effective amount of the compound of formula (I) is about 30 mg to about 120 mg. The method described in any one of items 1 to 19.

24. The therapeutically effective amount of the compound of formula (I) is greater than approximately 3,500 ng·hour / mL, approximately 3, More than 600ng・hour / mL, more than about 3,700ng・hour / mL, about 3,800ng・hour / mL, more than about 3,900 ng・hour / mL, more than about 4,000 ng・hour / mL, about 4, More than 100ng・hour / mL, about 4,200ng・hour / mL or more, about 4,300ng・hour / mL, more than about 4,400 ng・hour / mL, more than about 4,500 ng・hour / mL, about 4, More than 600 ng・hour / mL, about 4,700 ng・hour / mL or more, about 4,800 ng・hour One of the following: over 1 / mL, over approximately 4,900 ng·hour / mL, or over approximately 5,000 ng·hour / mL Average AUC on day 5 ＴＡＵ The method according to any one of claims 1 to 23, which brings about the following:

25. The therapeutically effective amount of the compound of formula (I) is greater than approximately 4,000 ng·hours / mL and approximately 4 , mean AUC on day 15 less than 500 ng-hour / mL ＴＡＵ Claims 1 to 23 bring about the following: The method described in any one of the items.

26. The therapeutically effective amount of the compound of formula (I) is greater than approximately 200 ng / mL and approximately 205 ng / mL. More than L, more than about 210 ng / mL, more than about 215 ng / mL, more than about 220 ng / mL, about 225 More than ng / mL, more than about 230 ng / mL, more than about 235 ng / mL, more than about 240 ng / mL, Average C levels on day 15 exceeding approximately 245 ng / mL or approximately 250 ng / mL ｍａｘ to bring about The method according to any one of claims 1 to 25.

27. The therapeutically effective amount of the compound of formula (I) is greater than approximately 215 ng / mL and greater than approximately 235 ng / mL Average C levels on day 15 less than mL ｍａｘ The method according to any one of claims 1 to 25, which brings about Law.

28. The compound of formula (I) is formulated as a tablet, according to any one of claims 1 to 27. Method of description.

29. The aforementioned tablets contain the compound of formula (I) and the following emulsifiers, surfactants, binders, disintegrants, and fluids. A claim comprising one or more excipients selected from the group consisting of accelerators and lubricants. The method described in item 28.

30. The method according to claim 29, wherein the emulsifier is hypromellose.

31. Claim 2, wherein the surfactant is vitamin E polyethylene glycol succinate. The method described in 9 or 30.

32. Claims 29, 30, wherein the binder is microcrystalline cellulose or lactose monohydrate. , or the method described in 31.

33. The disintegrant is croscarmellose sodium, any one of claims 29 to 32. The method described in section [section number].

34. The method according to any one of claims 29 to 33, wherein the flow promoter is silicon dioxide. Law.

35. The lubricant is sodium stearyl fumarate, any one of claims 29 to 34. The method described in section [section number].

36. Administer a therapeutically effective dose of at least one additional anticancer drug to the subject requiring the treatment. The method according to any one of claims 1 to 35, further comprising:

37. The aforementioned additional anticancer agents include FLT-3 inhibitors, VEGFR inhibitors, and EGFR TK inhibitors. Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 6 inhibitors, anti-HGF antibodies, PI3 kinase ZE inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, check Point 1 inhibitors, checkpoint 2 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, B 7-H3 inhibitors, CTLA4 inhibitors, LAG-3 inhibitors, OX40 agonists, focal adhesion kinase From the group consisting of enzyme inhibitors, Map kinase kinase inhibitors, and VEGF trap antibodies The method according to claim 36, which is selected.

38. The method according to claim 36 or 37, wherein the additional anticancer agent is a CDK4 / 6 inhibitor. 。

39. The aforementioned additional anticancer drugs are SHR6390 and trilaciclib. , lerocilib, AT7519M, dinaciclib iClib, ribociclib, abemaciclib, palbociclib B, Everolimus, Venetocracus, Inavolisib, Pazopani Carboplatin, cisplatin, oxaliplatin, paclitaxel, epithilon B (epitis B), fulvestrant, acolbifen ne), rasofoxifen, idoxifen, topotecan, pemetrexed, erloci Nib, tisilimmab, ipilimumab, vorinostat, etoposide, gemcitabine, dox Sorbicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, Capecitabine, Camptothecin, PD0325901, Irinotecan, Tamoxifen, Toremifene, anastrazole, letrozole, bevaciz Mab, goserelin acetate, raloxifene, alpelisib, tras Tuzumab, trastuzumab emtansine, pertuzumab, trastuzumab derxteca (Genetically modified) (fam-trastuzumab deruxtecan-nxk) i) The method according to claim 36, wherein the substance is (Enhertz) or eribulin (Halaven).

40. The method according to claim 39, wherein the additional anticancer agent is palbociclib.

41. Claim 40 states that the therapeutically effective dose of palbociclib is administered to the subject once daily. Method of loading.

42. The therapeutically effective dose of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg. The method according to claim 40 or 41, wherein g is g.

43. The aforementioned palbociclib is administered once daily for a maximum of 21 consecutive days, followed by a maximum of 7 days. The treatment was discontinued for several consecutive periods, and the cycle of palbociclib treatment and subsequent discontinuation of treatment was as follows: Claims 40-42, which are repeated one, two, three, four, five, or more times. The method described in any one of the items.

44. The compound of formula (I) is administered once daily for a maximum of 21 consecutive days, followed by a maximum of 7 Treatment was discontinued for several consecutive days, and the period between treatment with the compound of formula (I) and subsequent discontinuation of treatment was measured. Claim 1, where the rotation is repeated one, two, three, four, five, or more times. The method described in any one of items ~43.

45. The method according to any one of claims 1 to 44, wherein the subject is in a feeding state.

46. The method according to any one of claims 1 to 44, wherein the subject is in a fasting state.

47. The administration of the additional anticancer agent is performed before the administration of the compound of formula (I). The method according to any one of claims 36 to 46.

48. The administration of the additional anticancer agent is at least 30 times the administration of the compound of formula (I). The method according to claim 47, which is performed minutes earlier.

49. The administration of the additional anticancer agent is performed after the administration of the compound of formula (I). The method according to any one of claims 36 to 46.

50. The administration of the additional anticancer agent is at least 30 times the administration of the compound of formula (I). The method according to claim 49, which is performed after minutes.

51. A method for treating breast cancer in patients who require treatment, and the formula for the effective amount of treatment. The regimen includes oral administration of the compound of formula (I) once daily, wherein the compound of formula (I) is 【Chemistry 6-1】 【Chemistry 6-2】 【Transformation 6-3】 or a pharmaceutically acceptable salt thereof, wherein the breast cancer is at least one somatic cell e A method involving strogen receptor (ER) tumor mutations.

52. The aforementioned at least one somatic ER tumor mutation is Y537X, D538X, E380X Selected from the group consisting of L379X, V422X, S463X, and L536X, "X The method according to claim 51, wherein "" refers to any amino acid residue other than the wild-type residue at that position. Law.

53. The aforementioned at least one somatic ER tumor mutation is Y537S, Y537N, D538G E380Q, L379I, V422del, S463P, L536P and L536_D The method according to claim 51 or 52, selected from the group consisting of 538>P.

54. The aforementioned breast cancer is estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative. The method according to any one of claims 51 to 53, wherein the method is HER2-.

55. The breast cancer is metastatic or locally advanced, as described in any one of claims 51 to 54. The method.

56. The compound of formula (I) above, 【Transformation 7】 The method according to any one of claims 51 to 55.

57. The compound of formula (I) is the compound of formula (I-c), according to any of claims 51 to 56. The method described in any one of the items. 【Transformation 8】

58. The therapeutically effective amount of the compound of formula (I) is administered to the subject all at once, or The following is a description of a drug administered in two, three, or four unit doses, according to any one of claims 51 to 57. Method of description.

59. The claim states that the therapeutically effective amount of the compound of formula (I) is approximately 30 mg to approximately 1000 mg. The method described in any one of paragraphs 51 to 58.

60. Any one of claims 51 to 59, wherein the compound of formula (I) is formulated as a tablet. Methods used.

61. Administer a therapeutically effective dose of at least one additional anticancer drug to the subject requiring the treatment. The method according to any one of claims 51 to 60, further comprising:

62. The aforementioned additional anticancer agents include FLT-3 inhibitors, VEGFR inhibitors, and EGFR TK inhibitors. Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 6 inhibitors, anti-HGF antibodies, PI3 kinase ZE inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, check Point 1 inhibitors, checkpoint 2 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, B 7-H3 inhibitors, CTLA4 inhibitors, LAG-3 inhibitors, OX40 agonists, focal adhesion kinase From the group consisting of enzyme inhibitors, Map kinase kinase inhibitors, and VEGF trap antibodies The method according to claim 61, which is selected.

63. The method according to claim 61, wherein the additional anticancer agent is a CDK4 / 6 inhibitor.

64. The aforementioned additional anticancer drugs are SHR6390, trilaciclib, rerocyclib, and AT751. 9M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, Venetoclax, inavolicib, pazopanib, carboplatin, cisplatin, oxali Platin, paclitaxel, epithilone B, fulvestla Acorbifen, Rasofoxifen, Idoxifen, Topotecan, Pemetrex Ced, erlotinib, tisilimmab, ipilimumab, vorinostat, etoposide, gem Cytabine, doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, Temozolomide, capecitabine, camptothecin, PD0325901, irinotecan, Ta Moxifen, toremifene, anastrazole, letrozole, bevacizumab, gall acetate Sererin, raloxifene, alpelisib, trastuzumab, Trastuzumab emtansine, pertuzumab, trastuzumab deruxtecan (genetic compound) The method according to claim 61, wherein the substitute is (Enhertz) or eribulin (Halaven). 。

65. The method according to claim 64, wherein the additional anticancer agent is palbociclib.

66. Claim 65 states that the therapeutically effective dose of palbociclib is administered to the subject once daily. Method of loading.

67. The therapeutically effective dose of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg. The method according to claim 65 or 66, wherein g is g.

68. The aforementioned palbociclib is administered once daily for a maximum of 21 consecutive days, followed by a maximum of 7 days. The treatment was discontinued for several consecutive periods, and the cycle of palbociclib treatment and subsequent discontinuation of treatment was as follows: Claims 65-67, which are repeated one, two, three, four, five, or more times. The method described in any one of the items.

69. The compound of formula (I) is administered once daily for a maximum of 21 consecutive days, followed by a maximum of 7 Treatment was discontinued for several consecutive days, and the period between treatment with the compound of formula (I) and subsequent discontinuation of treatment was measured. Claim 5, where the rotation is repeated one, two, three, four, five, or more times. The method described in any one of items 1 to 68.

70. The method according to any one of claims 51 to 69, wherein the subject is in a feeding state.

71. The method according to any one of claims 51 to 69, wherein the subject is in a fasting state.

72. The administration of the additional anticancer agent is performed before the administration of the compound of formula (I). The method according to any one of claims 51 to 71.

73. The administration of the additional anticancer agent is at least 30 times the administration of the compound of formula (I). The method according to claim 72, which is performed a few minutes earlier.

74. The administration of the additional anticancer agent is performed after the administration of the compound of formula (I). The method according to any one of claims 51 to 71.

75. The administration of the additional anticancer agent is at least 30 times the administration of the compound of formula (I). The method according to claim 74, which is performed a few minutes later.

76. A method for treating breast cancer in a person who requires treatment for breast cancer, wherein the breast cancer is The method comprises at least one somatic estrogen receptor (ER) tumor mutation, and the method is (i) Once daily doses of the compound of formula (I-a) or a pharmaceutically acceptable salt thereof Oral administration and 【Chemistry 9】 (ii) A method comprising administering palbociclib orally once daily.

77. A method for treating breast cancer in a person who requires treatment for breast cancer, wherein the breast cancer is The method comprises at least one somatic estrogen receptor (ER) tumor mutation, and the method is (i) Once daily an effective dose of the compound of formula (I-c), or a pharmaceutically acceptable salt thereof. Oral administration and 【Chemistry 10】 (ii) A method comprising administering palbociclib orally once daily.

78. A method for treating breast cancer in a person who requires treatment for breast cancer, wherein the breast cancer is The method comprises at least one somatic estrogen receptor (ER) tumor mutation, and the method is (i) Once daily doses of a therapeutically effective amount of the compound of formula (I-j), or a pharmaceutically acceptable salt thereof. Oral administration and 【Chemistry 11】 (ii) A method comprising administering palbociclib orally once daily.

79. The aforementioned at least one somatic ER tumor mutation is Y537X, D538X, E380X Selected from the group consisting of L379X, V422X, S463X, and L536X, "X " refers to any amino acid residue other than the wild-type residue at that position, according to claims 76 to 78. The method described in either of the above terms.

80. The aforementioned at least one somatic ER tumor mutation is Y537S, Y537N, D538G E380Q, L379I, V422del, S463P, L536P and L536_D The method according to any one of claims 76 to 79, selected from the group consisting of 538>P.

81. The aforementioned breast cancer is estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative. The method according to any one of claims 76 to 80, wherein the method is HER2-.

82. The breast cancer is metastatic or locally advanced, as described in any one of claims 76 to 81. The method.

83. The therapeutically effective amount of the compound of formula (I-a), (I-c), or (I-j) is approximately 30 The method according to any one of claims 76 to 82, wherein the amount is between mg and approximately 1000 mg.

84. The therapeutically effective dose of palbociclib is 60 mg, 75 mg, 100 mg, or 125 mg. The method according to any one of claims 76 to 83, wherein g.

85. The aforementioned palbociclib is administered once daily for a maximum of 21 consecutive days, followed by a maximum of 7 days. The treatment was discontinued for several consecutive periods, and the cycle of palbociclib treatment and subsequent discontinuation of treatment was as follows: Claims 76-84, which are repeated one, two, three, four, five, or more times. The method described in any one of the items.

86. The compound of formula (I-a), (I-c), or (I-j) is administered once a day for a maximum of 21 days. The drug is administered continuously, and then treatment is discontinued for a maximum of 7 consecutive days, and the compound of formula (I-c) is administered. The cycle of treatment with a substance and subsequent discontinuation of treatment is 1, 2, 3, 4, 5 times, or The method according to any one of claims 76 to 85, which is repeated more than the number of times specified.

87. The method according to any one of claims 76 to 86, wherein the subject is in a feeding state.

88. The method according to any one of claims 76 to 86, wherein the subject is in a fasting state.

89. The aforementioned administration of palbociclib is a combination of the compounds of formula (I-a), (I-c), or (I-j). The method according to any one of claims 76 to 88, which is performed before the administration of the substance.

90. The aforementioned administration of palbociclib is a combination of the compounds of formula (I-a), (I-c), or (I-j). The method according to claim 89, wherein the procedure is performed at least 30 minutes before the administration of the substance.

91. The aforementioned administration of palbociclib is a combination of the compounds of formula (I-a), (I-c), or (I-j). The method according to any one of claims 76 to 90, which is performed after the administration of the substance.

92. The aforementioned administration of palbociclib is a combination of the compounds of formula (I-a), (I-c), or (I-j). The method according to claim 91, wherein the procedure is carried out at least 30 minutes after the administration of the substance.

93. A method for treating breast cancer in a subpopulation of breast cancer patients, Based on the target somatic estrogen receptor (ER) tumor biomarker status, treatment To select breast cancer patients for this purpose, The therapeutically effective amount of the compound of formula (I), 【Chemistry 12】 or administering a pharmaceutically acceptable salt thereof, comprising, Each R １ and each R ２ They are independent, halo, OR ５ , N(R ５ ) (Caution ６ ), NO ２ , CN, S O ２ (R ５ ), C １ -C ６ Alkyl and C ３ -C ６ Selected from the group consisting of cycloalkyl groups Re, R ３ and R ４ Both are hydrogen, or together with the carbon they are bonded to. It either forms a carbonyl group or Each R ５ and each R ６ These are independently hydrogen and C １ -C ６ Alkyl and C ３ -C ６ Cycloalkyl Selected from the group consisting of, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, or 4. The therapeutically effective amount of the compound of formula (I) is approximately 10 mg to approximately 1000 mg. 。

94. The somatic ER tumor biomarker status of the subject was Y537X, D538X, E38 Selected from the group consisting of 0X, L379X, V422X, S463X, and L536X. It contains at least one somatic ER tumor mutation, where "X" is a residue other than the wild-type residue at that position. The method according to claim 93, which refers to any amino acid residue of

95. The somatic ER tumor biomarker status of the subject is Y537S, Y537N, D53 8G, E380Q, L379I, V422del, S463P, L536P and L536 Claim 9, comprising at least one somatic ER tumor mutation selected from _D538>P The method described in 3 or 94.

96. The ER biomarker status of the subject was determined by ctDNA analysis, fluorescence in situ hive Determined by rediization, immunohistochemistry, PCR analysis, or sequencing. The method according to any one of claims 93 to 95.

97. The ER biomarker status of the subject is determined by a blood sample derived from the subject. The method according to any one of claims 93 to 95.

98. The ER biomarker status of the subject is determined by a solid biopsy derived from the tumor of the subject. The method according to any one of claims 93 to 95, as determined.

99. The compound of formula (I) above, 【Chemistry 13-1】 【Chemistry 13-2】 【Chemistry 13-3】 or any one of claims 93 to 98, selected from the group consisting of pharmaceutically acceptable salts thereof. The method described in item 1.

100. The compound of formula (I) above, 【Chemistry 14】 The method according to any one of claims 93 to 99.

101. The compound of formula (I) above, 【Chemistry 15】 or the person according to any one of claims 93 to 100, which is a pharmaceutically acceptable salt thereof. Law.

102. The compound of formula (I) above, 【Chemistry 16】 The method according to any one of claims 93 to 100.

103. The aforementioned breast cancer is estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative. The method according to any one of claims 93 to 102, wherein the method is HER2-.

104. The breast cancer is metastatic or locally advanced, as described in any one of claims 93 to 103. Method of loading.

105. Claims 93 to 104 further include administering at least one additional anticancer agent. The method described in either of the above terms.

106. The aforementioned additional anticancer agents include FLT-3 inhibitors, VEGFR inhibitors, and EGFR TK inhibitors. Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 6 inhibitors, anti-HGF antibodies, PI3 kinase ZE inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, check Point 1 inhibitors, checkpoint 2 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, B 7-H3 inhibitors, CTLA4 inhibitors, LAG-3 inhibitors, OX40 agonists, focal adhesion kinase From the group consisting of enzyme inhibitors, Map kinase kinase inhibitors, and VEGF trap antibodies The method according to claim 105, which is selected.

107. The method according to claim 105, wherein the additional anticancer agent is a CDK4 / 6 inhibitor.

108. The aforementioned additional anticancer drugs are SHR6390, trilaciclib, rerocyclib, and AT751. 9M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, Venetoclax, inavolicib, pazopanib, carboplatin, cisplatin, oxali Platin, paclitaxel, epithilone B, fulvestla Acorbifen, Rasofoxifen, Idoxifen, Topotecan, Pemetrex Ced, erlotinib, tisilimmab, ipilimumab, vorinostat, etoposide, gem Cytabine, doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, Temozolomide, capecitabine, camptothecin, PD0325901, irinotecan, Ta Moxifen, toremifene, anastrazole, letrozole, bevacizumab, gall acetate Sererin, raloxifene, alpelisib, trastuzumab, Trastuzumab emtansine, pertuzumab, trastuzumab deruxtecan (genetic compound) The alternative (Enhertz) or eribulin (Halaven) as described in claim 105. Law.

109. The method according to claim 108, wherein the additional anticancer agent is palbociclib.

110. The administration of the additional anticancer agent is performed before the administration of the compound of formula (I). The method according to any one of claims 105 to 109.

111. The administration of the additional anticancer agent is at least 30 times the administration of the compound of formula (I). The method according to claim 110, which is performed a few minutes earlier.

112. The administration of the additional anticancer agent is performed after the administration of the compound of formula (I). The method according to any one of claims 105 to 109.

113. The administration of the additional anticancer agent is at least 30 times the administration of the compound of formula (I). The method according to claim 112, which is performed a few minutes later.

114. A compound of formula (I) for use in the treatment of patients requiring treatment for breast cancer. 、 【Chemistry 17】 or a pharmaceutically acceptable salt thereof, in the formula, Each R １ and each R ２ They are independent, halo, OR ５ , N(R ５ ) (Caution ６ ), NO ２ , CN, S O ２ (R ５ ), C １ -C ６ Alkyl and C ３ -C ６ Selected from the group consisting of cycloalkyl groups Re, R ３ and R ４ Both are hydrogen, or together with the carbon they are bonded to. It either forms a carbonyl group or Each R ５ and each R ６ These are independently hydrogen and C １ -C ６ Alkyl and C ３ -C ６ Cycloalkyl Selected from the group consisting of, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, or 4. The breast cancer comprises at least one somatic estrogen receptor (ER) tumor mutation. 、 The therapeutically effective amount of the compound of formula (I) is approximately 10 mg to approximately 1000 mg. A substance or its pharmaceutically acceptable salt.

115. A compound of formula (I) for use in the treatment of patients requiring treatment for breast cancer. 【Chemistry 18-1】 【Chemistry 18-2】 【Chemistry 18-3】 or a pharmaceutically acceptable salt thereof, wherein the breast cancer is at least one somatic cell e Compounds or pharmaceutically acceptable salts thereof containing strogen receptor (ER) tumor mutations.

116. The compound for use described in claim 114 or 115 comprises at least one additional This further includes anticancer drugs, for use in the treatment of patients requiring treatment for breast cancer. A combination.

117. The aforementioned additional anticancer agents include FLT-3 inhibitors, VEGFR inhibitors, and EGFR TK inhibitors. Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 6 inhibitors, anti-HGF antibodies, PI3 kinase ZE inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, check Point 1 inhibitors, checkpoint 2 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, B 7-H3 inhibitors, CTLA4 inhibitors, LAG-3 inhibitors, OX40 agonists, focal adhesion kinase From the group consisting of enzyme inhibitors, Map kinase kinase inhibitors, and VEGF trap antibodies A combination for use as described in claim 116, which is selected.

118. The use of the additional anticancer agent described in claim 116 is a CDK4 / 6 inhibitor. A good combination.

119. The aforementioned additional anticancer drugs are SHR6390, trilaciclib, rerocyclib, and AT751. 9M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, Venetoclax, inavolicib, pazopanib, carboplatin, cisplatin, oxali Platin, paclitaxel, epithilone B, fulvestla Acorbifen, Rasofoxifen, Idoxifen, Topotecan, Pemetrex Ced, erlotinib, tisilimmab, ipilimumab, vorinostat, etoposide, gem Cytabine, doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, Temozolomide, capecitabine, camptothecin, PD0325901, irinotecan, Ta Moxifen, toremifene, anastrazole, letrozole, bevacizumab, gall acetate Sererin, raloxifene, alpelisib, trastuzumab, Trastuzumab emtansine, pertuzumab, trastuzumab deruxtecan (genetic compound) The use according to claim 116, which is (Enhertz) or eribulin (Halaven). A combination for use.

120. The additional anticancer agent is palbociclib, as described in claim 119. combination.

121. A combination of drugs for use in the treatment of patients requiring treatment for breast cancer. hand, (i) Compound of formula (I-a), 【Chemistry 19】 、 or a pharmaceutically acceptable salt thereof, (ii) Palbociclib, The breast cancer comprises at least one somatic estrogen receptor (ER) tumor mutation. ,combination.

122. A combination of drugs for use in the treatment of patients requiring treatment for breast cancer. hand, (i) Compound of formula (I-c), 【Chemistry 20】 、 or a pharmaceutically acceptable salt thereof, (ii) Palbociclib, The breast cancer comprises at least one somatic estrogen receptor (ER) tumor mutation. ,combination.

123. A combination of drugs for use in the treatment of patients requiring treatment for breast cancer. hand, (i) Compound of formula (I-j), 【Chemistry 21】 、 or a pharmaceutically acceptable salt thereof, (ii) Palbociclib, The breast cancer comprises at least one somatic estrogen receptor (ER) tumor mutation. ,combination.

124. The aforementioned at least one somatic ER tumor mutation is Y537X, D538X, E380X Selected from the group consisting of L379X, V422X, S463X, and L536X, "X Claims 114-123, where "" refers to any amino acid residue other than the wild-type residue at that position. Any combination for use as described in one of the items.

125. The aforementioned at least one somatic ER tumor mutation is Y537S, Y537N, D538G E380Q, L379I, V422del, S463P, L536P and L536_D A use according to any one of claims 114 to 124, selected from the group consisting of 538 > P. A combination for use.

126. For use in the manufacture of pharmaceuticals for the treatment of breast cancer in patients who require such treatment. The compound of formula (I), 【Chemistry 22】 or a pharmaceutically acceptable salt thereof, in the formula, Each R １ and each R ２ They are independent, halo, OR ５ , N(R ５ ) (Caution ６ ), NO ２ , CN, S O ２ (R ５ ), C １ -C ６ Alkyl and C ３ -C ６ Selected from the group consisting of cycloalkyl groups Re, R ３ and R ４ Both are hydrogen, or together with the carbon they are bonded to. It either forms a carbonyl group or Each R ５ and each R ６ are independently hydrogen, C １ -C ６ alkyl and C ３ -C ６ cycloalkyl Selected from the group consisting of, m is 0, 1, 2, 3, 4, or 5. n is 0, 1, 2, 3, or 4. The breast cancer comprises at least one somatic estrogen receptor (ER) tumor mutation. 、 The therapeutically effective amount of the compound of formula (I) is approximately 10 mg to approximately 1000 mg. A substance or its pharmaceutically acceptable salt.

127. For use in the manufacture of pharmaceuticals for the treatment of breast cancer in patients who require such treatment. The compound of formula (I) 【Chemistry 23-1】 【Chemistry 23-2】 【Chemistry 23-3】 or a pharmaceutically acceptable salt thereof, wherein the breast cancer is at least one somatic cell e Compounds or pharmaceutically acceptable salts thereof containing strogen receptor (ER) tumor mutations.

128. Claim 126 or 127 further comprises administering at least one additional anticancer agent. Compounds for use as described above.

129. The aforementioned additional anticancer agents include FLT-3 inhibitors, VEGFR inhibitors, and EGFR TK inhibitors. Aurora kinase inhibitors, PIK-1 regulators, Bcl-2 inhibitors, HDAC inhibitors, c-Met inhibitors, PARP inhibitors, CDK4 / 6 inhibitors, anti-HGF antibodies, PI3 kinase ZE inhibitors, AKT inhibitors, mTORC1 / 2 inhibitors, JAK / STAT inhibitors, check Point 1 inhibitors, checkpoint 2 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, B 7-H3 inhibitors, CTLA4 inhibitors, LAG-3 inhibitors, OX40 agonists, focal adhesion kinase From the group consisting of enzyme inhibitors, Map kinase kinase inhibitors, and VEGF trap antibodies A compound for use as described in claim 128, selected.

130. The use of the additional anticancer agent described in claim 128 is a CDK4 / 6 inhibitor. A compound related to eye.

131. The aforementioned additional anticancer drugs are SHR6390, trilaciclib, rerocyclib, and AT751. 9M, dinaciclib, ribociclib, abemaciclib, palbociclib, everolimus, Venetoclax, inavolicib, pazopanib, carboplatin, cisplatin, oxali Platin, paclitaxel, epithilone B, fulvestran To, Acorbifen, Lasofoxifen, Idoxifen, Topotecan, Pemetrexate D, erlotinib, tisilimmab, ipilimumab, vorinostat, etoposide, gemus Tabin, doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, te Mozolomid, capecitabine, camptothecin, PD0325901, irinotecan, tammo Xyzifene, Toremifene, Anastrazole, Letrozole, Bevacizumab, Gose acetate Relin, raloxifene, alpelisib, trastuzumab, tra Stuzumab emtansine, pertuzumab, trastuzumab deruxtecan (genetically modified) The use according to claim 128, e) Enhertz, or eribulin (Halaven) A compound for that purpose.

132. The additional anticancer agent is palbociclib, as described in claim 131. compound.

133. For use in the manufacture of pharmaceuticals for the treatment of breast cancer in patients who require such treatment. It is a combination of, (i) Compound of formula (I-a), 【Chemistry 24】 or a pharmaceutically acceptable salt thereof, (ii) Palbociclib, The breast cancer comprises at least one somatic estrogen receptor (ER) tumor mutation. ,combination.

134. For use in the manufacture of pharmaceuticals for the treatment of breast cancer in patients who require such treatment. It is a combination of, (i) Compound of formula (I-c), 【Chemistry 25】 or a pharmaceutically acceptable salt thereof, (ii) Palbociclib, The breast cancer comprises at least one somatic estrogen receptor (ER) tumor mutation. ,combination.

135. For use in the manufacture of pharmaceuticals for the treatment of breast cancer in patients who require such treatment. It is a combination of, (i) Compound of formula (I-j), 【Chemistry 26】 or a pharmaceutically acceptable salt thereof, (ii) Palbociclib, The breast cancer comprises at least one somatic estrogen receptor (ER) tumor mutation. ,combination.

136. The aforementioned at least one somatic ER tumor mutation is Y537X, D538X, E380X Selected from the group consisting of L379X, V422X, S463X, and L536X, "X Claims 126-135, where "" refers to any amino acid residue other than the wild-type residue at that position. The compound or combination for use described in any one of the items.

137. The aforementioned at least one somatic ER tumor mutation is Y537S, Y537N, D538G E380Q, L379I, V422del, S463P, L536P and L536_D A use according to any one of claims 126 to 136, selected from the group consisting of 538 > P. A compound or combination intended for use.

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