Application of quinolin compound in treatment of small cell lung cancer

Abstract

The invention relates to an application of a quinolin compound in treatment of small cell lung cancer, in particular to an application and a method of N-(4-((7-((1-(cyclopentyl amino) cyclopropyl) methoxy)-6-methoxyquinolin-4-yl) oxy)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1, 1-dicarboxamide in treatment of wide-period small cell lung cancer. # imgabs0 #

Description

Use of quinoline compounds in treating small cell lung cancer

[0001] Citation of Related Applications

[0002] This application claims priority and benefits from Chinese patent application No. 202211582933.7 filed with the State Intellectual Property Office of the People's Republic of China on December 9, 2022, the entire contents of which are hereby incorporated by reference into the text in their entirety. Technical Field

[0003] The present disclosure belongs to the field of medical technology and relates to the use of quinoline compounds in treating small cell lung cancer, and specifically to the use and method of N-(4-((7-((1-(cyclopentylamino)cyclopropanyl)methoxy)-6-methoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide in treating extensive-stage small cell lung cancer. Background Art

[0004] Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy that accounts for approximately 13% to 17% of lung cancers. SCLC grows rapidly, metastasizes extensively in the early stages, and is extremely malignant. More than 70% of SCLC patients have entered the extensive stage (ES) at the time of diagnosis. Chemotherapy is the main treatment for extensive stage small cell lung cancer (ES-SCLC), but most patients experience relapse and drug resistance after chemotherapy, with a poor prognosis and an extremely low 5-year survival rate. Currently, there are limited drugs approved for second-line treatment, and molecular targeted therapy may provide more options for clinical treatment.

[0005] WO2012034055 discloses N-(4-((7-((1-(cyclopentylamino)cyclopropanyl)methoxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (hereinafter referred to as the compound of formula (I)) as a c-Met kinase inhibitor and its use in inhibiting tyrosine kinase activity. The compound of formula (I) is a new class of compounds with excellent pharmacological properties. The compound can inhibit the activity of multiple protein tyrosine kinases, such as c-Met, VEGFr, EGFr, c-kit, PDGF, FGF, SRC, Ron, Tie2, etc.

[0006] Summary of the Invention

[0007] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating extensive small cell lung cancer.

[0008] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating extensive-stage small cell lung cancer.

[0009] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in treating extensive-stage small cell lung cancer.

[0010] In another aspect, the present disclosure provides a method for treating extensive-stage small cell lung cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0011] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating extensive-stage small cell lung cancer. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0012] In another aspect, the present disclosure provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating extensive-stage small cell lung cancer. In some embodiments, the pharmaceutical composition is a single-dose pharmaceutical composition or a multi-dose pharmaceutical composition. In some embodiments, the pharmaceutical composition further contains a pharmaceutically acceptable excipient.

[0013] In another aspect, the present disclosure provides use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of extensive-stage small cell lung cancer. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0014] In another aspect, the present disclosure provides a method for treating extensive-stage small cell lung cancer, comprising administering to a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0015] In another aspect, the present disclosure provides a kit for treating extensive-stage small cell lung cancer, the kit comprising: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof; and b) instructions for use in treating extensive-stage small cell lung cancer.

[0016] In some embodiments, the kit may contain a single dose or multiple doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0017] Extensive-stage small cell lung cancer

[0018] In some embodiments, the patient with extensive-stage small cell lung cancer meets at least one of the following conditions:

[0019] 1) The lesion involves more than one side of the chest cavity and includes malignant pleural and pericardial effusion or hematogenous metastasis;

[0020] 2) American Joint Committee on Cancer (AJCC) 8th edition stage IV (any T, any N, M1a / b / c), or T3-4 cannot be included in a tolerable radiation therapy plan due to multiple lung nodules or the tumor / nodule volume is too large.

[0021] In some embodiments, the extensive-stage small cell lung cancer is advanced extensive-stage small cell lung cancer.

[0022] In some embodiments, the extensive-stage small cell lung cancer is recurrent extensive-stage small cell lung cancer.

[0023] In some embodiments, the extensive-stage small cell lung cancer is inoperable extensive-stage small cell lung cancer.

[0024] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has been previously treated with radiation therapy.

[0025] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least one systemic therapy.

[0026] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least one systemic therapy and has failed treatment (eg, progressed or relapsed after treatment).

[0027] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received one or two systemic therapies.

[0028] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received one or two systemic therapies and has failed treatment (eg, progressed or relapsed after treatment).

[0029] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least two systemic therapies.

[0030] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least two systemic therapies and has failed treatment (eg, progressed or relapsed after treatment).

[0031] In some embodiments, the systemic therapy is selected from a combination of one or more of systemic chemotherapy or targeted therapy.

[0032] In some embodiments, the targeted therapy is selected from immunotherapy.

[0033] In some embodiments, the systemic therapy is selected from systemic chemotherapy, or systemic chemotherapy plus immunotherapy.

[0034] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least one first-line systemic treatment.

[0035] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received or is equal to first-line systemic therapy and has failed treatment (eg, progressed or relapsed after treatment).

[0036] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received first-line, second-line, third-line, fourth-line, or fifth-line systemic treatment.

[0037] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received first-line, second-line, third-line, fourth-line, or fifth-line systemic therapy and has failed treatment (eg, progressed or relapsed after treatment).

[0038] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received first-line systemic treatment.

[0039] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least one line of systemic therapy and has failed treatment (eg, progressed or relapsed after treatment).

[0040] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received second-line systemic treatment.

[0041] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least two lines of systemic therapy and has failed treatment (eg, progressed or relapsed after treatment).

[0042] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received three lines of systemic treatment.

[0043] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least three lines of systemic therapy and has failed treatment (eg, progressed or relapsed after treatment).

[0044] In some embodiments, the first-line systemic treatment is selected from a combination of one or more of systemic chemotherapy or targeted therapy.

[0045] In some embodiments, the targeted therapy is selected from immunotherapy.

[0046] In some embodiments, the first-line systemic treatment is selected from systemic chemotherapy, or systemic chemotherapy plus immunotherapy.

[0047] In some embodiments, the second-line systemic treatment is selected from a combination of one or more of systemic chemotherapy or immunotherapy.

[0048] In some embodiments, the second-line systemic treatment is selected from systemic chemotherapy, or systemic chemotherapy plus immunotherapy.

[0049] In some embodiments, the third-line systemic treatment is selected from a combination of one or more of systemic chemotherapy or immunotherapy.

[0050] In some embodiments, the third-line systemic treatment is selected from systemic chemotherapy, or systemic chemotherapy plus immunotherapy.

[0051] In the present disclosure, the systemic chemotherapy drugs include but are not limited to one or more of the following: alkylating agents (including but not limited to bendamustine, carmustine, chlorambucil, mechlorethamine, lomustine, carboplatin, cisplatin, lobaplatin, oxaliplatin, cyclophosphamide, ifosfamide, dacarbazine, temozolomide, rubicatin); antimetabolites (including but not limited to azacitidine, cytarabine, 5-fluorouracil, 6-mercaptopurine, capecitabine, decitabine, gemcitabine, floxuridine, fludarabine, nelarabine, hydroxyurea, methotrexate, pralatrexate, pemetrexed, pentostatin, hexamethylmeline, trifluridine / dipifrine combination); plant alkaloids (including but not limited to camptothecin and vinorelbine); antitumor antibiotics (including but not limited to vinorelbine); antibiotics, including but not limited to daunorubicin, doxorubicin, epirubicin, doxorubicin, idarubicin, valrubicin, bleomycin, and mitoxantrone); topoisomerase inhibitors (including but not limited to irinotecan, topotecan, etoposide, and teniposide); mitotic inhibitors (including but not limited to paclitaxel, albumin-bound paclitaxel, docetaxel, and cabazitaxel).

[0052] In some embodiments, the systemic chemotherapy drugs include but are not limited to one or more of platinum drugs, fluoropyrimidine derivatives, camptothecins, taxanes, vinca alkaloids, anthracyclines, antibiotics, podophyllums, other anti-tumor drugs, and antimetabolites. Examples include, but are not limited to, one or more of the following: platinum drugs (e.g., oxaliplatin, miplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, lobaplatin, triplatin tetranitrate, phenaplatin, picoplatin, satraplatin, lobaplatin), fluoropyrimidine derivatives (e.g., gemcitabine, capecitabine, ancitabine, fluorouracil, fufurouracil, doxifluridine, tegafur, carmofur, trifluridine), taxanes (e.g., paclitaxel, albumin-bound paclitaxel, and docetaxel), camptothecins (e.g., camptothecin, hydroxycamptothecin, 9-aminocamptothecin, 7-ethylcamptothecin, irinotecan, topotecan), vinca alkaloids (vinorelbine, vinblastine, vincristine, vindesine, vinflunine, norvinblastine), anthracyclines (epirubicin, doxorubicin),

[00135] Examples of the present invention include, but are not limited to, cytarabine, adriamycin, daunorubicin, pirarubicin, amrubicin, idarubicin, mitoxantrone, aclarubicin, valrubicin, daunorubicin, pixantrone, pirarubicin), cytarabine, mercaptoguanine, pemetrexed, carmustine, melphalan, etoposide (etoposide), teniposide, mitomycin, ifosfamide, cyclophosphamide, azacitidine, methotrexate, bendamustine, liposomal doxorubicin, actinomycin D (dactinomycin), bleomycin, bleomycin, temozolomide, decamidine, peplomycin, eribulin, plinabulin, sapacitabine, treosulfan, 153Sm-EDTMP, S-1, L-asparaginase, pegaspargase, hexamethylmeline, lurbinectedin, and encequidar.

[0053] In some embodiments, the systemic chemotherapy drug is selected from one or more of carboplatin, cisplatin, lobaplatin, doxorubicin, cyclophosphamide, etoposide, irinotecan (including polyethylene glycol irinotecan), topotecan, paclitaxel, docetaxel, gemcitabine, vinorelbine, temozolomide, rubicatin, and bendamustine.

[0054] In some embodiments, the systemic chemotherapy drug is selected from one or more of carboplatin, cisplatin, lobaplatin, etoposide, irinotecan (including polyethylene glycol irinotecan), topotecan, paclitaxel, docetaxel, gemcitabine, vinorelbine, temozolomide, rubicatin, and bendamustine.

[0055] In some embodiments, the systemic chemotherapy drug is selected from one or more of carboplatin, cisplatin, lobaplatin, doxorubicin + cyclophosphamide, etoposide, irinotecan (including polyethylene glycol irinotecan), topotecan, paclitaxel, docetaxel, gemcitabine, vinorelbine, temozolomide, rubicatin, and bendamustine.

[0056] In some embodiments, the systemic chemotherapy drug is selected from a combination of platinum drugs and other chemotherapy drugs.

[0057] In some embodiments, the platinum drug includes but is not limited to one or more of cisplatin, carboplatin, nedaplatin, oxaliplatin, milaplatin, dicycloplatin, picoplatin, satraplatin, phenaplatin, tetranitrotriplaplatin, or lobaplatin.

[0058] In some embodiments, the platinum drug is selected from cisplatin, carboplatin, or lobaplatin.

[0059] In some embodiments, the additional chemotherapy drugs include but are not limited to one or more of doxorubicin, cyclophosphamide, etoposide, irinotecan (including polyethylene glycol irinotecan), topotecan, paclitaxel, docetaxel, gemcitabine, vinorelbine, temozolomide, rubicatin, and bendamustine.

[0060] In some embodiments, the additional chemotherapy drugs include but are not limited to one or more of etoposide, irinotecan, topotecan, paclitaxel, docetaxel, gemcitabine, vinorelbine, temozolomide, rubicatin, and bendamustine.

[0061] In some embodiments, the additional chemotherapy drug is selected from doxorubicin, cyclophosphamide, lubicatin, etoposide, and / or irinotecan.

[0062] In some embodiments, the additional chemotherapy drug is selected from doxorubicin, cyclophosphamide, rubicatin, etoposide, or irinotecan.

[0063] In some embodiments, the systemic chemotherapy drug is selected from doxorubicin + cyclophosphamide, doxorubicin + platinum drugs, cyclophosphamide + platinum drugs, paclitaxel + platinum drugs, paclitaxel + platinum drugs + rubicatin, etoposide + platinum drugs, irinotecan + platinum drugs, topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, rubicatin, or bendamustine.

[0064] In some embodiments, the systemic chemotherapy drug is selected from etoposide + platinum drug, irinotecan + platinum drug, topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, rubicatin, or bendamustine.

[0065] In some embodiments, the systemic chemotherapy drug is selected from etoposide + carboplatin, etoposide + cisplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, rubicatin, or bendamustine.

[0066] In the present disclosure, the immunotherapy drugs include but are not limited to immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors).

[0067] In some embodiments, the immunotherapy drugs include but are not limited to anti-CTLA-4 antibodies (e.g., ipilimumab), anti-PD-1 antibodies (e.g., candurizumab, serotonin, sepalizumab, penampalimumab, dotalizumab, tislelizumab, carrelizumab, toripalimab, sintilimab, cemiplizumab, pembrolizumab, nivolumab, BMS-986213, palolizumab, gelotrimazole, rivalizumab, HX-008), anti-PD-L1 antibodies (e.g., sugemalimab, envolimab, durvalumab, avelumab, atezolizumab, sukemalimab, adebelimumab, TQB2450).

[0068] In some embodiments, the immunotherapy drug is selected from atezolizumab, durvalumab, serotonin, adebelimumab, TQB2450, toripalimab, tislelizumab, camrelizumab, nivolumab, or pembrolizumab.

[0069] In some embodiments, the systemic therapy is selected from topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, bendamustine, durvalumab + paclitaxel + carboplatin or cisplatin, atezolizumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin + sintilimab, doxorubicin + cyclophosphamide + durvalumab, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + carboplatin, etoposide Imfinzi plus lobaplatin, durvalumab plus irinotecan plus carboplatin or cisplatin, irinotecan plus cisplatin, irinotecan plus carboplatin, serotonin plus etoposide plus carboplatin, adebelimumab plus etoposide plus carboplatin, tislelizumab plus etoposide plus carboplatin, tislelizumab plus etoposide plus cisplatin, toripalizumab plus etoposide plus carboplatin, toripalizumab plus etoposide plus cisplatin, rubicatin, nivolumab, pembrolizumab, atezolizumab, or imfinzi.

[0070] In some embodiments, the systemic therapy is selected from topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, bendamustine, atezolizumab + etoposide + carboplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, serotonin + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin, tislelizumab + etoposide + cisplatin, toripalizumab + etoposide + carboplatin, toripalizumab + etoposide + cisplatin, rubicatin, nivolumab, or pembrolizumab.

[0071] In some embodiments, the first-line systemic treatment is selected from atezolizumab + etoposide + carboplatin or cisplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + cisplatin + sintilimab, doxorubicin + cyclophosphamide + durvalumab, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, serotonin + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin, tislelizumab + etoposide + cisplatin, toripalizumab + etoposide + carboplatin, toripalizumab + etoposide + cisplatin, atezolizumab, or durvalumab.

[0072] In some embodiments, the first-line systemic treatment is selected from atezolizumab + etoposide + carboplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, serotonin + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin, tislelizumab + etoposide + cisplatin, toripalimab + etoposide + carboplatin, or toripalimab + etoposide + cisplatin.

[0073] In some embodiments, the second-line systemic treatment is selected from topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, bendamustine, irinotecan + atezolizumab, atezolizumab + docetaxel, atezolizumab + paclitaxel, atezolizumab + etoposide + carboplatin, durvalumab + etoposide + carboplatin or cisplatin, carboplatin or cisplatin + irinotecan + durvalumab Ulcetumab, etoposide + cisplatin, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, serotonin + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin, tislelizumab + etoposide + cisplatin, toripalimab + etoposide + carboplatin, toripalimab + etoposide + cisplatin, atezolizumab, or rubicatin.

[0074] In some embodiments, the second-line systemic treatment is selected from topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, bendamustine, atezolizumab + etoposide + carboplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, serotonin + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin, tislelizumab + etoposide + cisplatin, toripalimab + etoposide + carboplatin, toripalimab + etoposide + cisplatin, or rubicatin.

[0075] In some embodiments, the third-line systemic treatment is selected from one or more of the following: alkylating agents (including but not limited to bendamustine, carmustine, chlorambucil, mechlorethamine, lomustine, carboplatin, cisplatin, lobaplatin, oxaliplatin, cyclophosphamide, ifosfamide, dacarbazine, temozolomide, rubicatin), mitotic inhibitors (including but not limited to paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel), anti-PD-L1 antibodies (such as sugemalimab, envolimab, durvalumab, avelumab, atezolizumab, sugemalimab, adebelimumab, TQB2450), etc.

[0076] In some embodiments, the third-line systemic therapy is selected from one or more of the following drugs: bendamustine, carmustine, chlorambucil, mechlorethamine, lomustine, carboplatin, cisplatin, lobaplatin, oxaliplatin, cyclophosphamide, ifosfamide, dacarbazine, temozolomide, rubicatin, paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel, sugemalimab, envoralizumab, durvalumab, avelumab, atezolizumab, cefixime, adebelimumab, or TQB2450.

[0077] In some embodiments, the third-line systemic treatment is selected from durvalumab + paclitaxel + cisplatin or carboplatin, and / or rubicatin.

[0078] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received and failed at least one systemic therapy, wherein the systemic therapy is selected from topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, bendamustine, atezolizumab + etoposide + carboplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, serotonin + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin, tislelizumab + etoposide + cisplatin, toripalimab + etoposide + carboplatin, toripalimab + etoposide + cisplatin, or rubicatin.

[0079] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received and failed one or two systemic therapies, wherein the systemic therapies are selected from topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, bendamustine, atezolizumab + etoposide + carboplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, slulizumab + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin, tislelizumab + etoposide + cisplatin, toripalimab + etoposide + carboplatin, toripalimab + etoposide + cisplatin, or rubicatin.

[0080] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received and failed at least two systemic therapies, wherein the systemic therapies are selected from topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, bendamustine, atezolizumab + etoposide + carboplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, serotonin + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin, tislelizumab + etoposide + cisplatin, toripalimab + etoposide + carboplatin, toripalimab + etoposide + cisplatin, or rubicatin.

[0081] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least one first-line systemic therapy and has failed treatment, and the first-line systemic therapy is selected from atezolizumab + etoposide + carboplatin or cisplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + cisplatin + sintilimab, doxorubicin + cyclophosphamide + durvalumab, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, slulizumab + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin, tislelizumab + etoposide + cisplatin, toripalimab + etoposide + carboplatin, toripalimab + etoposide + cisplatin, atezolizumab, or durvalumab.

[0082] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least one first-line systemic treatment and has failed treatment, and the first-line systemic treatment is selected from doxorubicin + cyclophosphamide + durvalumab, etoposide + cisplatin + sintilimab, etoposide + cisplatin, atezolizumab + etoposide + carboplatin or cisplatin, durvalumab, or atezolizumab.

[0083] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least one line of systemic treatment and failed treatment, and the first-line systemic treatment is doxorubicin + cyclophosphamide + durvalumab, and durvalumab maintenance treatment.

[0084] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least two lines of systemic therapy and failed treatment, and the second-line systemic therapy is selected from topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, bendamustine, irinotecan + atezolizumab, atezolizumab + docetaxel, atezolizumab + paclitaxel, atezolizumab + etoposide + carboplatin, durvalumab + etoposide + Carboplatin or cisplatin, carboplatin or cisplatin + irinotecan + durvalumab, etoposide + cisplatin, etoposide + carboplatin, etoposide + lovaplatin, irinotecan + cisplatin, irinotecan + carboplatin, serotonin + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin, tislelizumab + etoposide + cisplatin, toripalizumab + etoposide + carboplatin, toripalizumab + etoposide + cisplatin, atezolizumab, or rubicatin.

[0085] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least two lines of systemic therapy and has failed treatment, and the second-line systemic therapy is selected from irinotecan + atezolizumab, cisplatin + irinotecan + durvalumab, atezolizumab + docetaxel, atezolizumab + paclitaxel, atezolizumab, or irinotecan (including polyethylene glycol irinotecan).

[0086] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least two-line systemic treatments and failed treatment, and the second-line systemic treatment is selected from atezolizumab + docetaxel, atezolizumab + paclitaxel, or atezolizumab.

[0087] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least three lines of systemic therapy and has failed treatment.

[0088] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least three lines of systemic treatment and failed treatment, and the third-line systemic treatment is selected from alkylating agents (including but not limited to bendamustine, carmustine, chlorambucil, mechlorethamine, lomustine, carboplatin, cisplatin, lobaplatin, oxaliplatin, cyclophosphamide, ifosfamide, dacarbazine, temozolomide, rubicatin), mitotic inhibitors (including but not limited to paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel), anti-PD-L1 antibodies (such as sugemalimab, envolimab, durvalumab, avelumab, atezolizumab, sugemalimab, adebelimumab, TQB2450), etc.

[0089] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least three lines of systemic therapy and has failed treatment, and the third-line systemic therapy is selected from one or more of the following drugs: bendamustine, carmustine, chlorambucil, mechlorethamine, lomustine, carboplatin, cisplatin, lobaplatin, oxaliplatin, cyclophosphamide, ifosfamide, dacarbazine, temozolomide, rubicatin, paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel, sugemalimab, envoralizumab, durvalumab, avelumab, atezolizumab, cefixime, adebelimumab, or TQB2450.

[0090] In some embodiments, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least three lines of systemic therapy and failed treatment, and the third-line systemic therapy is selected from durvalumab + paclitaxel + cisplatin or carboplatin, or rubicatin.

[0091] In some embodiments, the patient with extensive-stage small cell lung cancer has not received prior anti-angiogenic drug treatment.

[0092] In some embodiments, the anti-angiogenic drug comprises pazopanib, sorafenib, erlotinib, apatinib, cabozantinib, anlotinib, recombinant human endostatin, or bevacizumab.

[0093] In some embodiments, the patient with extensive-stage small cell lung cancer has not received anti-angiogenic drug treatment, and the anti-angiogenic drug includes cabozantinib, anlotinib, recombinant human endostatin, or bevacizumab.

[0094] In some embodiments, the anti-angiogenic drug comprises apatinib or anlotinib.

[0095] In some embodiments, the patient with extensive-stage small cell lung cancer has undergone surgery.

[0096] In some embodiments, the patient with extensive-stage small cell lung cancer has received radiation therapy.

[0097] In some embodiments, the radiation therapy includes but is not limited to chest radiation therapy and head radiation therapy.

[0098] In some embodiments, the patient with extensive-stage small cell lung cancer has previously received at least one systemic treatment but failed treatment, and optionally has received treatment with an immune checkpoint inhibitor (such as a PD-1 inhibitor, a PD-L1 inhibitor, etc.) in the previous treatment.

[0099] In some embodiments, the patient with extensive-stage small cell lung cancer has previously received at least one systemic treatment but failed treatment, has not received anti-angiogenic drug treatment, and optionally has received treatment with immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment.

[0100] In some embodiments, the patient with extensive-stage small cell lung cancer has previously received one or two systemic therapies but failed treatment, and optionally has received treatment with immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment.

[0101] In some embodiments, the patient with extensive-stage small cell lung cancer has previously received one or two systemic therapies but failed treatment, has not received anti-angiogenic drug treatment, and optionally has received treatment with immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment.

[0102] In some embodiments, the patient with extensive-stage small cell lung cancer has previously received at least two systemic therapies but failed treatment, and optionally has received treatment with immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment.

[0103] In some embodiments, the patient with extensive-stage small cell lung cancer has previously received at least two systemic therapies but failed treatment, has not received anti-angiogenic drug treatment, and optionally has received immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment.

[0104] In some embodiments, the patient with extensive-stage small cell lung cancer has previously received at least one first-line systemic treatment but failed treatment (e.g., progression or recurrence after treatment), and optionally has received treatment with immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment.

[0105] In some embodiments, the patient with extensive-stage small cell lung cancer has previously received at least one first-line systemic treatment but failed treatment (e.g., progression or recurrence after treatment), has not received anti-angiogenic drug treatment, and optionally has received treatment with immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment.

[0106] In some embodiments, the patient with extensive-stage small cell lung cancer has previously received at least two lines of systemic treatment but failed treatment (e.g., progression or recurrence after treatment), and optionally has received treatment with immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment.

[0107] In some embodiments, the patient with extensive-stage small cell lung cancer has previously received at least two lines of systemic treatment but failed treatment (e.g., progression or recurrence after treatment), has not received anti-angiogenic drug treatment, and optionally has received immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment.

[0108] In some embodiments, the patient with extensive-stage small cell lung cancer has undergone three consecutive chemotherapy treatments combined with immune checkpoint inhibitors but has failed all treatments.

[0109] In some specific embodiments, the patient with extensive-stage small cell lung cancer has undergone treatment with doxorubicin + cyclophosphamide + durvalumab but failed, followed by treatment with cisplatin + irinotecan + durvalumab but failed, followed by treatment with durvalumab + paclitaxel + cisplatin but failed.

[0110] In some specific embodiments, the patient with extensive-stage small cell lung cancer has failed two prior systemic chemotherapy treatments.

[0111] In some specific embodiments, the patient with extensive-stage small cell lung cancer has undergone etoposide + cisplatin treatment but failed, followed by polyethylene glycol irinotecan treatment but failed.

[0112] In some embodiments, the patient with extensive-stage small cell lung cancer meets all of the following conditions:

[0113] 1) Subjects with extensive-stage small cell lung cancer confirmed by histopathological or cytological examination, who have received at least two lines of systemic therapy and failed treatment;

[0114] 2) Patients with at least one measurable lesion according to RECIST 1.1 criteria.

[0115] In some embodiments, the patient with extensive-stage small cell lung cancer meets all of the following conditions:

[0116] 1) Subjects with extensive-stage small cell lung cancer confirmed by histopathological or cytological examination are required to have received at least two lines of systemic treatment and failed treatment. Previous treatment with immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) is allowed;

[0117] 2) Patients with at least one measurable lesion according to RECIST 1.1 criteria.

[0118] In some embodiments, the patient with extensive-stage small cell lung cancer has previously received at least two lines of systemic treatment and has failed treatment (e.g., progression or recurrence after treatment), and optionally has received treatment with immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment, and has not received anti-angiogenic drug treatment.

[0119] In some embodiments, the patient with extensive-stage small cell lung cancer meets all of the following conditions:

[0120] 1) Subjects with extensive-stage small cell lung cancer confirmed by histopathological or cytological examination are required to have received at least two lines of systemic treatment and failed treatment. Previous treatment with immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) is allowed;

[0121] 2) having at least one measurable lesion according to RECIST 1.1 criteria;

[0122] 3) Not received anti-angiogenic drug treatment, including cabozantinib, anlotinib, recombinant human endostatin or bevacizumab.

[0123] Dosage regimen

[0124] In some embodiments, the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt is 2-6 weeks. In some embodiments, the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt is 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks or the range formed by any of the above values. In some embodiments, the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt is 3 weeks or 4 weeks.

[0125] In some embodiments, the administration cycle of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be more than 1 cycle, including 1, 2, 3, 4, 5, 6 or more cycles. In some embodiments, the administration cycle of the compound of formula (I) or a pharmaceutically acceptable salt thereof may preferably be 1-6 administration cycles.

[0126] In some embodiments, the frequency of administration of the compound of formula (I) or its pharmaceutically acceptable salt can be 3 times a day, 2 times a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, 3 times a week, 2 times a week, once a week, once every two weeks, or once every three weeks. In some embodiments, the frequency of administration of the compound of formula (I) or its pharmaceutically acceptable salt is 3 times a day, 2 times a day, or once a day. In some embodiments, the frequency of administration of the compound of formula (I) or its pharmaceutically acceptable salt is once a day.

[0127] In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, or a range formed by any of the above values.

[0128] In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 20-180 mg. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 20-40 mg, 20-60 mg, 20-90 mg, 20-120 mg, 20-150 mg, 40-60 mg, 40-90 mg, 40-120 mg, 40-150 mg, 40-180 mg, 60-90 mg, 60-120 mg, 60-150 mg, 60-180 mg, 90-120 mg, 90-150 mg, 90-180 mg, 120-150 mg, 120-180 mg or 150-180 mg. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 60-120 mg, 60-150 mg, 60-180 mg, 90-120 mg, 90-150 mg, 90-180 mg, 120-150 mg, 120-180 mg or 150-180 mg.

[0129] In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 60 mg, 90 mg, 120 mg, 150 mg or 180 mg. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 90 mg or 120 mg.

[0130] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered in a single dose or multiple doses. In some embodiments, the compound is administered in multiple doses.

[0132] In some embodiments, the pharmaceutical composition is a pharmaceutical composition with a single dose of 30-60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is a pharmaceutical composition with a single dose of 30 mg or 60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, the pharmaceutical composition is a multiple-dose pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the multiple doses may consist of a single dose of 30 mg or 60 mg of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, the pharmaceutical composition is a pharmaceutical composition of multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the multiple doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 60 mg, 90 mg, 120 mg, 150 mg or 180 mg. In some embodiments, the multiple doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof are 90 mg or 120 mg.

[0135] In some embodiments, the multiple doses of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof may consist of a single dose of 30 mg or 60 mg of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered as follows: a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered for one or more dosing cycles.

[0137] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered as follows: a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered for one or more dosing cycles, and the dosing frequency may be 3 times a day, 2 times a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, 3 times a week, 2 times a week, once a week, once every two weeks, or once every three weeks, preferably 3 times a day, 2 times a day or once a day.

[0138] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered to the subject by administering a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof for one or more dosing cycles, continuously daily (e.g., 3 times a day, 2 times a day or once a day).

[0139] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered as follows: a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject continuously every day (e.g., 3 times a day, 2 times a day or once a day).

[0140] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or pharmaceutical composition thereof is administered as follows: with a 28-day administration cycle, a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg, administered once a day.

[0141] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered as follows: one or more administration cycles are administered with a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg, administered once a day, with a 28-day administration cycle.

[0142] In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 60 mg, 90 mg, 120 mg, 150 mg or 180 mg. Optionally, the daily dose can be adjusted after administration (including but not limited to adjusting the daily dose upward or downward).

[0143] In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 90 mg or 120 mg, and optionally, the daily dose is adjusted after administration (including but not limited to upward or downward adjustment of the daily dose).

[0144] In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 90 mg or 120 mg, optionally, the daily dose is adjusted upward after administration. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be 90 mg or 120 mg, optionally, the daily dose is adjusted upward after administration to a daily dose selected from 120 mg, 150 mg or 180 mg.

[0145] In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 90 mg or 120 mg, and optionally, the daily dose is adjusted downward after administration. In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 90 mg, and optionally, the daily dose is adjusted downward after administration to 60 mg or less. In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 120 mg, and optionally, the daily dose is adjusted downward after administration to 90 mg or 60 mg or less.

[0146] In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 90 mg, and optionally, the daily dose is adjusted downward to 60 mg after administration. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 120 mg, and optionally, the daily dose is adjusted downward to 90 mg or 60 mg after administration.

[0147] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition can be administered by various routes, including but not limited to oral administration. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition can be taken orally on an empty stomach (e.g., in the morning on an empty stomach).

[0148] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or pharmaceutical composition thereof is administered orally in the morning on an empty stomach, once a day, for one or more dosing cycles (for example, 28 days can be one dosing cycle).

[0149] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or pharmaceutical composition thereof is administered orally in the morning on an empty stomach, once a day, for one or more dosing cycles, wherein 28 days constitutes one dosing cycle.

[0150] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered as follows: oral administration on an empty stomach every day (e.g., once a day), with a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg, for one or more consecutive administration cycles (e.g., 28 days as one administration cycle).

[0151] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered as follows: with a 28-day administration cycle, it is orally administered once a day on an empty stomach, with a daily dosage of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg, for 28 consecutive days (i.e., one administration cycle).

[0152] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered as follows: with a 28-day administration cycle, it is orally administered once a day on an empty stomach, with each dose being 60 mg, 90 mg, 120 mg, 150 mg or 180 mg, for 28 consecutive days (i.e., one administration cycle).

[0153] In embodiments of the present disclosure, the above-described dosing cycles are repeated as long as the disease remains under control and the regimen is clinically tolerated.

[0154] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is prepared as a single dose or multiple dose form suitable for administration of 60mg-180mg, or 60mg-150mg, or 60mg-120mg, or 90mg-180mg, or 90mg-150mg, or 90mg-120mg, or 120mg-150mg, or 120mg-180mg, or 150mg-180mg, or 60mg, or 90mg, or 120mg, or 150mg, or 180mg of the compound of formula (I) or its pharmaceutically acceptable salt per dose.

[0155] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is prepared as a single dose or multiple dose form suitable for once a day and administering 60mg-180mg, or 60mg-150mg, or 60mg-120mg, or 90mg-180mg, or 90mg-150mg, or 90mg-120mg, or 120mg-150mg, or 120mg-180mg, or 150mg-180mg, or 60mg, or 90mg, or 120mg, or 150mg, or 180mg of the compound of formula (I) or its pharmaceutically acceptable salt to the patient each time.

[0156] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is prepared as a single dose or multiple dose form suitable for administering 60 mg-180 mg, or 60 mg-150 mg, or 60 mg-120 mg, or 90 mg-180 mg, or 90 mg-150 mg, or 90 mg-120 mg, or 120 mg-150 mg, or 120 mg-180 mg, or 150 mg-180 mg, or 60 mg, or 90 mg, or 120 mg, or 150 mg, or 180 mg of the compound of formula (I) or its pharmaceutically acceptable salt to the patient once a day for 28 consecutive days.

[0157] In some embodiments, the disclosed compound of formula (I) or a pharmaceutically acceptable salt thereof is used as the sole active agent.

[0158] Compound of formula (I) or a pharmaceutically acceptable salt thereof

[0159] The compounds of formula (I) disclosed herein can be administered in the form of their free base or in the form of their pharmaceutically acceptable salts. For example, pharmaceutically acceptable salts of the compounds of formula (I) are within the scope of the present disclosure and can be produced from various organic and inorganic acids according to methods known in the art, such as inorganic acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, and organic acids selected from succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, or naphthalenesulfonic acid.

[0160] In some embodiments, the compound of formula (I) is administered as its free base.

[0161] Pharmaceutical composition

[0162] The "compound of formula (I) or a pharmaceutically acceptable salt thereof" described in the present disclosure may be in the form of a "pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof".

[0163] In some embodiments, the strength of the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is 30-60 mg (calculated as the compound of formula (I)). In some embodiments, the strength of the pharmaceutical composition may be 30 mg or 60 mg (calculated as the compound of formula (I)).

[0164] The method of administration can be determined comprehensively based on the activity, toxicity and patient tolerance of the drug.

[0165] In some embodiments, the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof further contains a pharmaceutically acceptable excipient.

[0166] In some embodiments, a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be suitable for oral administration.

[0167] In some embodiments, the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition is a capsule.

[0168] In some embodiments, the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule formulation with strengths of 30 mg and 60 mg.

[0169] In some embodiments, the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule preparation, which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

[0170] In some embodiments, the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule formulation comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, corn starch, carboxymethylcellulose calcium, hypromellose, and magnesium stearate.

[0171] In other embodiments, the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule preparation comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, lactose, microcrystalline cellulose, sodium starch glycolate and magnesium stearate.

[0172] Technical Effects

[0173] The compound of formula (I) disclosed herein, or its pharmaceutically acceptable salt, or its pharmaceutical composition has good safety and anti-tumor activity, exhibits good inhibitory activity against small cell lung cancer cells, and exhibits good tumor inhibitory activity in a human small cell lung cancer subcutaneous transplant tumor model in nude mice.

[0174] The treatment regimen disclosed herein has good efficacy and good safety in the treatment of extensive-stage small cell lung cancer. Wherein, the compound of formula (I) or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising the compound of formula (I) or its pharmaceutically acceptable salt, at least in survival efficacy evaluation, such as overall survival (OS), median survival; in tumor response efficacy evaluation, such as disease-free survival (DFS), median DFS, progression-free survival (PFS), 6-month PFS rate, time to disease progression (TTP), objective response rate (ORR), disease control rate (DCR), duration of remission (DOR); and tolerability or safety evaluation, such as the incidence and severity of adverse events, etc., at least one aspect has excellent effect.

[0175] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof has a good objective response rate and / or disease control rate in the treatment of extensive-stage small cell lung cancer.

[0176] Definition and Description

[0177] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this disclosure, it is intended to refer to the corresponding commercial product or its active ingredient.

[0178] In the present disclosure, unless otherwise stated, the dosages and ranges thereof provided herein for the compound of formula (I) or its pharmaceutically acceptable salt are calculated based on the molecular weight of the free base of the compound of formula (I).

[0179] In the present disclosure, “+” indicates combined use, for example, “etoposide + carboplatin” indicates combined use of etoposide and carboplatin.

[0180] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0181] Unless otherwise specifically stated, singular terms encompass plural terms and plural terms encompass the singular. Unless otherwise specifically stated, the words "a" or "an" mean "at least one" or "at least one." Unless otherwise specified, the use of "or" means "and / or."

[0182] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0183] The term "pharmaceutically acceptable salts" includes salts formed between an alkali ion and a free acid or a salt between an acid ion and a free base.

[0184] The term "treat" generally refers to obtaining a desired pharmacological and / or physiological effect, including partial or complete stabilization or cure of a disease and / or effects resulting from a disease. As used herein, "treat" encompasses any treatment of a patient's disease that: (a) inhibits the symptoms of the disease, i.e., arrests its progression; or (b) alleviates the symptoms of the disease, i.e., causes regression of the disease or its symptoms.

[0185] In the context of cancer, the term "first-line systemic therapy" refers to the first treatment given to the disease. It's usually part of a standard treatment plan, such as surgery followed by chemotherapy and radiation therapy. First-line therapy, when used alone, is generally considered the best treatment. If it doesn't cure the disease or causes severe side effects, other treatments may be added or used.

[0186] In the context of cancer, the term "second-line systemic therapy" refers to treatment given when the initial treatment (first-line treatment) is ineffective or stops working. The same applies to third-line treatment or multiple-line treatment.

[0187] The term "treatment failure" refers to disease progression, recurrence, or intolerable side effects during or after treatment (e.g., within 3 months, 6 months, or 12 months after treatment).

[0188] The term "recurrent" cancer is a cancer that regenerates at the original site or at a distant site after responding to initial treatment (e.g., surgery). The term "effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, or (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder. The amount of active substance (e.g., a compound of the present disclosure) that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the subject to be treated (e.g., a mammal), but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0189] The term "administering" or "dosing" or "giving" means physically introducing a composition comprising an active compound into a host or patient or subject using any of a variety of methods and delivery systems known to those skilled in the art. In certain embodiments, administration is oral.

[0190] The term "daily dose" refers to the dose administered to a patient on a single day.

[0191] The terms "patient" or "subject" or "subject" are used interchangeably herein to refer to mammals, such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In some embodiments, the patient, subject, or subject is a human.

[0192] The term "single dose" refers to the smallest packaging unit containing a certain amount of medicine. For example, if a box of medicine contains seven capsules, each capsule is a single dose; for example, if a box of medicine contains seven tablets, each tablet is a single dose.

[0193] The term "multiple doses" consists of a plurality of single doses.

[0194] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present disclosure and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to a subject.

[0195] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0196] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, they can be formulated into solid preparations (e.g., granules, tablets, pills, capsules, etc.) or liquid preparations (e.g., injections).

[0197] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0198] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to form a core for a capsule, tablet, or dragee. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0199] When referring to a dosing regimen, the terms "day," "daily," and the like refer to times within a calendar day, starting at midnight and ending at the following midnight.

[0200] All patents, patent applications and other identified publications are expressly incorporated herein by reference for the purposes of description and disclosure. Any citation of these publications herein does not constitute an admission that the publications become part of the common general knowledge in the art. DETAILED DESCRIPTION

[0201] The purpose of the following specific embodiments is to enable those skilled in the art to more clearly understand and implement the present disclosure. They should not be considered as limiting the scope of the present disclosure, but are merely exemplary descriptions and typical representatives of the present disclosure.

[0202] Example 1 Determination of NCI-H526 Cell Proliferation Inhibitory Activity

[0203] Take NCI-H526 cells that are in good growth condition, collect them into a centrifuge tube, and adjust the cell density to 3×10 4 Cells were plated at 100 μL / well in a 96-well plate and incubated overnight in a cell culture incubator. Compounds were added using a nanoliter pipette to a final concentration of 10,000 nM to 4.57 nM in duplicate wells. A control was also set up. After 72 hours of incubation in a cell culture incubator, the detection reagent CCK-8 (manufacturer: Tongren Chemical, 10 μL / well) was added. After incubation in a cell culture incubator for 4 hours, the absorbance was measured at 450 nm using an Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 .

[0204] The compounds of formula (I) disclosed herein exhibit good inhibitory activity against small cell lung cancer cells.

[0205] Example 2 Pharmacodynamic Evaluation in NCI-H526 Human Small Cell Lung Cancer Subcutaneous Transplantation Model in Nude Mice

[0206] NCI-H526 cells were subcutaneously inoculated in the right axilla of SPF female nude mice (source: Jiangsu Huachuang Xinnuo Pharmaceutical Technology Co., Ltd.) at a rate of 5 × 10 6 When the average tumor volume reaches 200mm 3 When about 30 seconds, divide the animals into groups.

[0207] The day of grouping was designated Day 0. Starting from Day 0, drugs were administered by gavage daily. Tumor volume was measured 2-3 times per week, and mice were weighed and recorded. The general condition of the mice was observed and recorded daily. At the end of the experiment, tumors were removed, weighed, and photographed.

[0208] The detection indicators and calculation formulas are as follows:

[0209] Tumor volume, TV (mm 3 )=1 / 2×(a×b 2 ), where a is the long diameter of the tumor and b is the short diameter of the tumor.

[0210] Relative tumor volume, RTV = TV t / TV0; TV0 is the tumor volume on day 0, TV t is the tumor volume at each measurement.

[0211] Relative tumor growth rate, T / C (%) = T RTV / C RTV ×100%; where T RTV RTV for the treatment group; C RTV The vehicle control group was RTV.

[0212] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) × 100%; wherein, TW is the tumor weight of the treatment group, and TW0 is the tumor weight of the vehicle control group.

[0213] Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0×100%; where Wt0 is the weight of mice on day 0, Wt t is the weight of the mice at each measurement.

[0214] The compound of formula (I) disclosed herein exhibits good tumor-suppressing activity in a nude mouse subcutaneous transplant tumor model of human small cell lung cancer.

[0215] Example 3 Clinical Trial

[0216] 1.1 Main inclusion criteria

[0217] (1) Subjects with extensive-stage small cell lung cancer confirmed by histopathological or cytological examination are required to have received at least two lines of systemic treatment and failed treatment. Previous treatment with immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) is allowed;

[0218] (2) Age ranged from 18 to 75 years; ECOG PS score was 0 to 1;

[0219] (3) having at least one measurable lesion according to RECIST 1.1 criteria;

[0220] (4) normal function of major organs;

[0221] (5) Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study and within 6 months after the end of the study; the serum pregnancy test should be negative within 7 days before study enrollment, and the subjects must be non-breastfeeding; male subjects should agree to use contraceptive measures during the study and within 6 months after the end of the study.

[0222] 1.2 Dosage regimen

[0223] Test drug: capsules of the compound of formula (I), specifications: 30 mg or 60 mg.

[0224] Dosage: Oral administration on an empty stomach in the morning, once a day, for 28 consecutive days as a dosing cycle, until the study termination criteria are met.

[0225] Dosage: 90mg or 120mg.

[0226] 1.3 Evaluation Criteria

[0227] Safety evaluation: The severity of adverse events was evaluated using the NCI CTC AE 5.0 standard;

[0228] Effectiveness evaluation: RECIST 1.1 standard was used for evaluation.

[0229] 1.4 Safety Assessment

[0230] The time of occurrence, severity, relevance to study treatment, duration, measures taken and outcome of the adverse event, etc.

[0231] Adverse reaction incidence: the occurrence of all adverse events (AEs), serious adverse events (SAEs), and treatment-emergent adverse events (TEAEs).

[0232] 1.5 Efficacy evaluation

[0233] Objective response rate (ORR) refers to the proportion of subjects whose tumor volume has been confirmed to have decreased to a predetermined value and maintained for the minimum required time according to the RECIST 1.1 standard, that is, the proportion of subjects with complete remission (CR) and partial remission (PR).

[0234] Progression-free survival (PFS): refers to the time from the first treatment to the first disease progression or death due to any cause, whichever occurs first, regardless of whether the subject stopped the study treatment before the disease progressed, but re-acceptance of other approved systemic anti-cancer treatments is not included. If the subject has not been observed to have disease progression and has not died, lost to follow-up, or received other systemic anti-cancer treatments by the data analysis cutoff date, the data will be treated as censored, and the censoring date will be the date of the last imaging examination of the measurable lesions. If the subject has missed more than 3 RECIST assessment visits before disease progression or death, the censoring date will be the date of the last imaging examination of the previous measurable lesions. PFS time is always based on the imaging examination date, not the assessment date or visit date.

[0235] Disease control rate (DCR) refers to the percentage of subjects with complete response, partial response, or stable disease for ≥4-6 weeks as determined by RECIST 1.1.

[0236] Duration of response (DOR) refers to the time from the first complete or partial response of the tumor to the first disease progression or death from any cause. If the tumor response is not confirmed, it will not be used. If the patient does not experience disease progression or death from any cause before the data analysis cutoff date, the data will be treated as censored, and the PFS censoring time will be used to determine the duration of response.

[0237] Overall survival (OS) is the time from the first dose of treatment to death from any cause. If a subject was still receiving study treatment or had not died and was not lost to follow-up at the data analysis cutoff date, the data were considered censored, with the censoring date being the last date of study treatment or the last follow-up visit confirming survival. If the subject was lost to follow-up, the censoring date was the last survival follow-up visit (this visit confirmed the subject was still alive) before the loss of follow-up.

[0238] 1.6 Pharmacokinetic Assessment

[0239] Peak concentration (C max ), peak time (T max ), elimination half-life (t 1 / 2 ), area under the plasma concentration-time curve (AUC), elimination half-life at steady state (t 1 / 2,ss ), steady-state peak concentration (Css-max ), steady-state valley concentration (C ss-min ), mean steady-state plasma concentration (C ss-av ), the area under the plasma concentration-time curve at steady state (AUC ss ) or coefficient of fluctuation (DF), etc.

[0240] 1.7 Test results

[0241] The test results show that the compound of formula (I) disclosed herein has good safety, can effectively control disease progression, and exhibits certain clinical benefits. For example, in a patient with extensive-stage small cell lung cancer whose disease progressed after treatment with doxorubicin + cyclophosphamide + durvalumab, then after treatment with cisplatin + irinotecan + durvalumab, then after treatment with durvalumab + paclitaxel + cisplatin and then lurbinectedin, the disease was effectively controlled using the treatment regimen of the compound of formula (I) disclosed herein. In a patient with extensive-stage small cell lung cancer whose disease progressed after treatment with etoposide + cisplatin and then with polyethylene glycol irinotecan, the disease was effectively controlled using the treatment regimen of the compound of formula (I) disclosed herein.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof for treating extensive small cell lung cancer, 2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of a compound of formula (I) or a pharmaceutically acceptable pharmaceutical composition thereof; optionally, the pharmaceutical composition further contains a pharmaceutically acceptable excipient.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein The extensive-stage small cell lung cancer is recurrent extensive-stage small cell lung cancer; Alternatively, the extensive-stage small cell lung cancer is advanced extensive-stage small cell lung cancer; Alternatively, the extensive-stage small cell lung cancer is inoperable extensive-stage small cell lung cancer; Alternatively, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received radiotherapy.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein The extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least one systemic treatment; Alternatively, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least one systemic treatment and has failed treatment; Alternatively, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least two systemic therapies; Alternatively, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least two systemic therapies and has failed treatment; Alternatively, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received first-line systemic treatment; Alternatively, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least one line of systemic therapy and has failed treatment; Alternatively, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received second-line systemic treatment; Alternatively, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least two lines of systemic therapy and has failed treatment; Alternatively, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received third-line systemic treatment; Alternatively, the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least three lines of systemic treatment and has failed treatment.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4, wherein The systemic treatment, first-line systemic treatment and second-line systemic treatment are selected from a combination of one or more of systemic chemotherapy or targeted therapy; Alternatively, the systemic therapy, first-line systemic therapy and second-line systemic therapy are selected from a combination of one or more of systemic chemotherapy or targeted therapy, and the targeted therapy is selected from immunotherapy; Alternatively, the systemic therapy, first-line systemic therapy and second-line systemic therapy are selected from systemic chemotherapy, or systemic chemotherapy plus immunotherapy; Alternatively, the systemic therapy, first-line systemic therapy, second-line systemic therapy or third-line systemic therapy is selected from systemic chemotherapy, or systemic chemotherapy plus immunotherapy.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 5, wherein The systemic chemotherapy drugs include one or more of alkylating agents, antimetabolites, plant alkaloids, antitumor antibiotics, topoisomerase inhibitors, and mitotic inhibitors; Alternatively, the systemic chemotherapy drugs include one or more of platinum drugs, fluoropyrimidine derivatives, camptothecins, taxanes, vinblastines, anthracyclines, antibiotics, podophyllums, other anti-tumor drugs, and antimetabolites; Alternatively, the systemic chemotherapy drug is selected from one or more of carboplatin, cisplatin, lobaplatin, etoposide, irinotecan, topotecan, doxorubicin, cyclophosphamide, paclitaxel, docetaxel, gemcitabine, vinorelbine, temozolomide, rubicatin, and bendamustine; Alternatively, the systemic chemotherapy drug is selected from etoposide + carboplatin, etoposide + cisplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, topotecan, doxorubicin + cyclophosphamide, paclitaxel + carboplatin, paclitaxel + cisplatin, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, rubicatin, or bendamustine; Alternatively, the immunotherapy drug includes an immune checkpoint inhibitor; Alternatively, the immunotherapy drug includes anti-CTLA-4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody; Alternatively, the immunotherapy drug is selected from atezolizumab, durvalumab, serotonin, adebelimumab, TQB2450, Toripalimab, tislelizumab, camrelizumab, nivolumab, or pembrolizumab.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 6, wherein The systemic therapy is selected from topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, doxorubicin, cyclophosphamide, etoposide, vinorelbine, temozolomide, bendamustine, doxorubicin + cyclophosphamide, paclitaxel + carboplatin, paclitaxel + cisplatin, atezolizumab + etoposide + carboplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, serotonin + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin, tislelizumab + etoposide + cisplatin, toripalizumab + etoposide + carboplatin, toripalizumab + etoposide + cisplatin, rubicatin, nivolumab or pembrolizumab; Alternatively, the first-line systemic therapy is selected from atezolizumab + etoposide + carboplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, serotonin + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin, tislelizumab + etoposide + cisplatin, toripalimab + etoposide + carboplatin, or toripalimab + etoposide + cisplatin; Alternatively, the second-line systemic treatment is selected from topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, bendamustine, atezolizumab + etoposide + carboplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, serotonin + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin, tislelizumab + etoposide + cisplatin, toripalimab + etoposide + carboplatin, toripalimab + etoposide + cisplatin, or rubicatin; Alternatively, the third-line systemic treatment is selected from durvalumab + paclitaxel + cisplatin or carboplatin, or rubicatin.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein The patients with extensive-stage small cell lung cancer had not received anti-angiogenic drug treatment; Alternatively, the patient with extensive-stage small cell lung cancer has not received anti-angiogenic drug treatment, and the anti-angiogenic drug includes pazopanib, sorafenib, erlotinib, apatinib, cabozantinib, anlotinib, recombinant human endostatin, or bevacizumab; Alternatively, the patient with extensive-stage small cell lung cancer has received surgical treatment; Alternatively, the patient with extensive-stage small cell lung cancer has received radiation therapy.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein The patient with extensive-stage small cell lung cancer has previously received at least one systemic therapy and has failed treatment, and optionally has received treatment with an immune checkpoint inhibitor in the previous treatment; Alternatively, the patient with extensive-stage small cell lung cancer has previously received at least one systemic therapy and has failed treatment, has not received anti-angiogenic drug treatment, and optionally has received immune checkpoint inhibitor treatment in previous treatment; Alternatively, the patient with extensive-stage small cell lung cancer has previously received one or two systemic therapies and has failed treatment, and optionally has received immune checkpoint inhibitors in the previous treatment; Alternatively, the patient with extensive-stage small cell lung cancer has previously received one or two systemic therapies and has failed treatment, has not received anti-angiogenic drugs, and optionally has received immune checkpoint inhibitors in previous treatment; Alternatively, the patient with extensive-stage small cell lung cancer has previously received at least two systemic therapies and has failed treatment, and optionally has received immune checkpoint inhibitors in the previous treatment; Alternatively, the patient with extensive-stage small cell lung cancer has previously received at least two systemic therapies and has failed treatment, has not received anti-angiogenic drugs, and optionally has received immune checkpoint inhibitors in previous treatment; Alternatively, the patient with extensive-stage small cell lung cancer has previously received at least two lines of systemic therapy and has failed treatment, and optionally has received treatment with an immune checkpoint inhibitor in the previous treatment, preferably the immune checkpoint inhibitor is selected from PD-1 inhibitors and PD-L1 inhibitors; Alternatively, the patient with extensive-stage small cell lung cancer has previously received at least two lines of systemic treatment and has failed treatment, and optionally has received immune checkpoint inhibitors in previous treatment, and has not received anti-angiogenic drug treatment, preferably the immune checkpoint inhibitors are selected from PD-1 inhibitors and PD-L1 inhibitors.

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein The daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, or a range formed by any of the above values; Alternatively, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 20-180 mg; Alternatively, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 20-40 mg, 20-60 mg, 20-90 mg, 20-120 mg, 20-150 mg, 40-60 mg, 40-90 mg, 40-120 mg, 40-150 mg, 40-180 mg, 60-90 mg, 60-120 mg, 60-150 mg, 60-180 mg, 90-120 mg, 90-150 mg, 90-180 mg, 120-150 mg, 120-180 mg or 150-180 mg.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein The compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered for one or more administration cycles; Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: administering to the subject a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, continuously every day; Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: with a 28-day administration cycle, a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg, administered once a day; Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally once a day on an empty stomach, with a dosage of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg per administration, for 28 consecutive days, with a dosing cycle of 28 days.

12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 11, wherein The pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition; optionally, the solid pharmaceutical composition is a capsule.

13. A kit for treating extensive-stage small cell lung cancer, comprising: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and b) instructions for use in the treatment of extensive-stage small cell lung cancer.

14. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating extensive-stage small cell lung cancer, 15. A method for treating extensive small cell lung cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof,

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