TW201215610A - Combinational compositions and methods for treatment of cancer - Google Patents

Abstract

The present invention provides methods of treating a cell proliferative disorder, such as a cancer, by administering to a subject in need thereof a therapeutically effective amount of a pyrroloquinolinyl-pyrrole-2, 5-dione compound or a pyrroloquinolinyl-pyrrolidine-2, 5-dione compound in combination with a therapeutically effective amount of a second anti-proliferative agent.

Description

201215610 VI. INSTRUCTIONS: Cross-references to related applications This application claims US Provisional Application No. 61 / 3 60, 758, filed on July 1, 2010, and US application filed on April 15, 2011 Priority and benefit of 61/4 75, 9 95. The contents of these applications are incorporated herein by reference in their entirety. TECHNICAL FIELD OF THE INVENTION The present invention relates to methods, compositions and kits for treating cell proliferative diseases, such as cancer, wherein a therapeutically effective amount of pyrroloquinolinyl-pyrrole-2,5-dione compound is utilized. Or a pyrroloquinolinyl-pyrrolidine-2,5-dione compound in combination with a therapeutically effective amount of a second anti-proliferative agent. [Prior Art] Background of the Invention 癌症 Cancer is the second leading cause of death in the United States, second only to heart disease. (Cancer

Facts^J Figures 2004, American Cancer Society, Inc.) Although recent advances in cancer diagnosis and treatment have enabled surgery and radiation therapy to cure early-stage cancers, current drug treatments for metastatic disease are mostly palliative Treatment, rarely provides long-term cure. Even as new chemotherapy continues to enter the market, there is a continuing need to be effective as a first-line therapy in anti-tumor therapy, as well as a novel drug for second- and third-line therapy, in monotherapy or in combination with existing agents. Cancer cells are defined as heterogeneous. For example, 'multiple mutations' mechanisms in a single tissue or cell type -5 - 201215610 can lead to cancer development. Therefore, heterogeneity often occurs between cancer cells derived from the same tissue originating from different individuals and tumors of the same histiotype. Frequently observed mutational 'mechanisms' associated with some cancers may differ between one tissue type and another (eg, the often observed mutation "cause" that causes colon cancer may be associated with the often observed 'leukemia' The mechanism 'different'. It is therefore often difficult to predict whether a particular cancer will respond to a particular chemotherapeutic agent. (Cancer Medicine, 5th ed., Bast et al., BC Decker Inc., Hamilton, Ontario) 成分 A component of the cellular signaling pathway that regulates normal cell growth and differentiation, when dysregulated, can lead to cell proliferative diseases and cancer. occur. Mutations in cell signaling proteins may cause such proteins to become manifested or activated in an inappropriate amount or at inappropriate times during the cell cycle, which in turn may result in uncontrolled cell growth or changes in cell-cell attachment properties. . For example, receptor tyrosine kinase dysregulation due to mutation, gene rearrangement, gene amplification, and excessive expression of both receptors and ligands has been implicated in the development and progression of human cancer. The c-Met receptor tyrosine kinase is the only known high affinity receptor for hepatocyte growth factor (HGF), also known as the dispersing factor. Binding of HGF to the c-Met extracellular ligand binding domain results in receptor multimerization and phosphorylation of multiple tyrosine residues in the internal fraction of c-Met cells. Activation of c_Met leads to the binding of adaptor proteins such as Gab-1, Grb-2, She and c-Cbl and phosphorylation, and subsequent activation of messenger such as PI3K, PLC1, STAT, ERK1 and 2 and FAK . c-Met and HGF are dysregulated in human cancers and -6-201215610 can contribute to cell growth disorders, tumor cell dissemination, and tumor invasion during disease progression and metastasis (see, for example, Journal of Clinical Investigation 1 09: 863-867 (2002) ) and Cancer Cell pp 5-6

July 2004). c-Met and HGF are highly expressed in many cancers relative to surrounding tissues, and their performance is associated with poor prognosis of patients (see, for example, Journal of Cellular Biochemistry 86: 665-677 (2002); Int. J. Cancer (Pred. Oncol.) 74 : 3 0 1 -3 09 ( 1 997); 〇 Clinical Cancer Research 9 : 1480-1488 (2003);

Cancer Research 62: 589-596 (2002)). Without wishing to be bound by theory, c-Met and HGF prevent tumors from being killed by DNA-damaging agents and thus contribute to the chemical and radio-radiation of tumors. Without wishing to be bound by any theory, inhibitors of c-Met may be used as therapeutic agents for the treatment of proliferative diseases, including breast cancer (see 'For example, Cancer and Metastasis Reviews 22: 309-325 (2003)) ° References cited herein It is not considered to be the prior art of the patent application. SUMMARY OF THE INVENTION The present invention provides a method of treating a cell proliferative disorder comprising administering a therapeutically effective amount of a compound of formula 111, IIIa, IVa, IVb, Va or Vb, or a pharmaceutically acceptable salt thereof, Or a prodrug or metabolite thereof, in combination with a therapeutically effective amount of a second antiproliferative agent, wherein the compound of formula III, Ilia, IVa, IVb, Va or Vb or a pharmaceutically acceptable salt thereof is 201215610, Or its drug or metabolite' and the second anti-proliferative agent are not administered at the same time. The invention also provides a method of treating a cell proliferative disorder, the method comprising administering a therapeutically effective amount of a compound of Formula III, Ilia, IVa, IVb, Va or Vb, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolism thereof And administering to the subject a therapeutically effective amount of a second antiproliferative agent, wherein the compound of formula I, Ilia, IVa, IVb, Va or ¥1), or a pharmaceutically acceptable salt thereof, or a prodrug thereof Metabolites are administered after administration of a second anti-proliferative agent. The invention also provides a method of treating a cell proliferative disorder comprising administering a therapeutically effective amount of Formula III, Ilia, IVa, IVb, Va or Vb. A compound, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof, is administered to a subject in combination with a therapeutically effective amount of a second antiproliferative agent, wherein the second antiproliferative agent is administered Formula III, Ilia, A compound of IVa, IVb, Va or Vb, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof, is administered. The compound of formula III, Ilia, IVa, IVb, Va or Vb may be ( + )-cis-3-(5,6-dihydro-4^1-pyrrolo[3,2,1-indenyl]quinoline. -1-yl)-4-(111-indol-3-yl)pyrene is slightly steeper -2,5 - one 嗣, (-) - cis - 3 (5,6 - qi - 4H-shame And [3,2,1 - ij ]quinolin-1 -yl)-4 - (1 Η -吲哚-3 -yl)pyrrolidine-2,5-dione, (+)-trans-3-( 5,6-dihydro-411-pyrrolo[3,2,1-indolyl]quinolin-1-yl)-4-(111-indol-3-yl)pyrrolidine-2,5-dione Or (-)-trans-3-(5,6-dihydro-4Η-pyrrolo[3,2,1 - ij ]quinolin-1-yl)-4 - (1 Η -吲哚-3 - Pyrrolidine-2,5-dione. Preferably, the compound is (-)-trans-3-(5,6-dihydro-4Η-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1Η-吲) Indole-3-yl)pyrrolidine-2,5-dione. The second antiproliferative agent can be a kinase inhibitor, an alkylating agent, an antibiotic, an anti-metabolite of -8 - 201215610, an antidote, an interferon, a multi- or monoclonal antibody, a HER2 inhibitor, and a histone deacetylase inhibitor. 'hormone, mitotic inhibitor, MTOR inhibitor, taxane or taxane derivative, aromatase inhibitor, anthracycline, microtubule target drug, topoisomerase poison, adenosine analog drug, A guanosine analog drug, a methyl uridine analog drug, or a cytidine analog drug. Preferably, the cytidine analog is gemcitabine. Preferably, the kinase inhibitor is a serine/threonine kinase inhibitor or a tyrosine kinase Q inhibitor. Preferred kinase inhibitors include, but are not limited to, sorafenib, sunitinib, erlotinib, imatinib or gefitinib. Preferred alkylating agents include, but are not limited to, cisplatin or carboplatin. Preferred anti-metabolites include, but are not limited to, gemcitabine, flu〇rouracil (5-FU), TS-1 or capecitabine. Preferred mitotic inhibitors include, but are not limited to, camptothecin or irino tec an. Preferred taxane or taxane derivatives include, but are not limited to, paclitaxel or docetaxel. The cell proliferative disorder can be a pre-cancerous state or cancer. The cell proliferative disease may be a blood tumor or a malignant tumor, or a solid tumor (or a tumor, etc.). The method of treating cancer involves reducing tumor size. Alternatively or additionally, the cancer is a metastatic cancer and the method of treatment comprises inhibiting metastatic cancer cell invasion. The method may additionally comprise radiation therapy. The cancer can be lung cancer, small cell lung cancer, non-small cell lung cancer (NSCLC), colon cancer, breast cancer, pancreatic cancer, prostate cancer, kidney cancer, cervical cancer, brain cancer, stomach cancer, uterine cancer, small intestine cancer, liver cancer, chronic Myeloid leukemia, melanoma, ovarian cancer, metastasis-related -9- 201215610 Renal cell carcinoma (RCC), vesicular soft tissue sarcoma (ASPS), clear cell sarcoma (CCS) or hepatocellular carcinoma (HCC). A cell having a proliferative disease may comprise DNA encoding c-Met. Alternatively or additionally, cells having a proliferative disease have constitutively enhanced c-Met activity. Preferably, the cell proliferative disorder is cancer, and particularly preferably, the cancer exhibiting c-Met or exhibiting active c-Met. Accordingly, the present invention provides a method of treating a cell proliferative disorder, wherein the cells exhibit a high degree of c-Met or an active c-Met. The invention further provides a method of treating a cell proliferative disorder comprising selectively modulating the activity of c-Met but not significantly inhibiting the activity of protein kinase C. Preferably, the subject is a mammal. More preferably, the object is a human. Preferably, the compound of formula III, Ilia, IVa, IVb, Va or Vb of the process described herein is (-)-trans-3-(5,6-dihydro-41^-pyrho[3, 2,1-1]] quinoline-bu)-4-(1 H-indol-3-yl)pyrrolidine-2,5-dione and administered at a dose of 3 60 mg, one for two Times. Alternatively, the composition is administered at a maximum daily dose of 720 mg. Preferably, the compound of formula III, nia, IVa, IVb, Va or Vb and the second antiproliferative agent are administered intravenously, orally or intraperitoneally. The second anti-proliferative agent can be administered prior to or after administration of a composition comprising a compound of formula III, Ilia, IVa, IVb, Va or Vb. Preferably, the compound of formula III, Ilia, IVa, IVb, Va or Vb is (_)_trans-3-(5,6-dihydro-4H-pyrido[3,2,l-ij]quina Phenyl-l-yl)-4-(lH-indol-3-yl)pyrrolidine-2,5-dione and a second antiproliferative agent are gemcitabine and (-)-trans-3 - (5,6 -Dihydro-4 Η-pyrrolo[3,2,1 - ij ]quinolin-1 -yl)-4- -10- 201215610 (1H_indol-3-yl)pyrrolidine-2,5- The diketone is administered for at least 12 hours after administration of gemcitabine. (-)_反·3·(5,6--hydrogen succinyl[3,2,l-ij] sputum_1_yl)_4-(111-11 晩-3-yl) 卩 咯 11 The _2,5-dione can also be administered for at least 24 hours, at least 48 hours, at least 72 hours, or at least 9.6 hours after administration of gemcitabine. Preferably, the subject is not administered any medication for at least 12 hours, at least 24 hours, or at least 48 hours prior to administration of the gemcitabine. 0 Preferably, the subject is not administered any drug for at least 24 hours 'then and then is given gemcitabine for no more than 24 hours' and then administered (-)-trans-3-(5,6-dichloro-4?-la- [3,2,1-ϋ]Salantaline-I-yl)_4-(1Η-Β引-3-yl)pyridinium-2,5-dione is at least 7 hours. Preferably, the gemcitabine is administered in a single dose at no more than 30 minutes, no more than 1 hour, no more than 12 hours, or no more than 24 hours. Preferably '(-)·anti_3_(5,6-dihydro-4Η-pyrrolo[3,2,l-ij]quinolin-1-yl)-4-(1Η-吲哚-3 - The pyrrolidine-2,5-diketone is administered for at least 24 hours, at least 48 hours, or at least 72 hours. Preferably, the compound of formula III, Ilia, IVa, IVb, Va or Vb is (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinoline -1-yl)-4-(1Η-indol-3-yl)pyrrolidine-2,5-dione, which is about 90% of the concentration or amount of gemcitabine in the subject being less than its initial concentration or amount Administration after %, less than about 50%, less than about 20%, less than about 10%, less than about 5%, or less than about 1%. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by persons of ordinary skill in the art to which the invention pertains. -11 - 201215610 In the present specification 'unless the context clearly dictates otherwise, Otherwise, the singular form also includes the plural. Although equivalent to the method and material _#$ described herein can be measured, the appropriate method and material are described below. All publications, patent applications, patents and other references mentioned herein are hereby incorporated by reference. The references cited herein are not to be considered as prior art to the patent application. In the event of a conflict, this specification will be defined as the main. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. Other features and advantages of the invention will be apparent from the description and appended claims. DETAILED DESCRIPTION OF THE INVENTION 1. Methods of Treatment The present invention provides a method of treating a cell proliferative disorder comprising a therapeutically effective amount of a compound of Formula III, Ilia, iVa, IVb, Va or Vb' or a pharmaceutically acceptable compound thereof a salt, or a prodrug or metabolite thereof, in combination with one or more pharmaceutically acceptable carriers or excipients, in combination with a therapeutically effective amount of a second antiproliferative agent, together with one or more pharmaceutically acceptable carriers or The excipient is administered to a subject in need thereof, wherein the cell proliferative disorder is treated. The present invention provides a pharmaceutical composition for treating a cell proliferative disease comprising: (a) a therapeutically effective amount of a compound of the formula m, IIIa, IVa, IVb, Va or Vb' or a pharmaceutically acceptable salt thereof, or Its prodrug or metabolite 'combines (b) a therapeutically effective amount of a second anti-proliferative agent. One or more -12-201215610 A pharmaceutically acceptable carrier or excipient is optionally included in the composition. The second anti-proliferative agent is preferably a second chemotherapeutic agent. The cell proliferative disorder can be a pre-cancerous state or cancer. The cell proliferative disease may be a hematological tumor or a malignant tumor, or a solid tumor (or a tumor or the like). This method of treating cancer involves a reduction in tumor volume. Alternatively or additionally, the cancer is a metastatic cancer and the method of treatment comprises inhibiting the invasion of metastatic cancer cells into 〇O m κ匕, and the therapeutic agent (also known as an anti-tumor agent or anti-proliferative agent) may be an alkylating agent; Antibiotics; antimetabolites; antidote; interferon; multi- or monoclonal antibodies; EGFR inhibitors; HER2 inhibitors; tissue protein deacetylase inhibitors; hormones; mitotic inhibitors; MTOR inhibitors; ; a serine/threonine kinase inhibitor; a tyrosine kinase inhibitor; a VEGF/VEGFR inhibitor; a taxane or a taxane derivative, an aromatase inhibitor, an anthracycline, a microtubule target drug, Topoisomerase poisons, molecular targets or inhibitors of enzymes (eg kinase inhibitors), cytidines, or any of the drugs listed at www.cancer.org/docroot/cdg/cdgO.asp a chemotherapeutic agent, an antitumor agent or an anti-proliferative agent. Typical alkylating agents include, but are not limited to, cyclophosphamide (Cytoxan; Neosar); chlorambucil (Leukeran); melphalan (Alkeran); carmustine (BiCNU) ); Busulfan (Busulfex); lomustine (CeeNU); dacarbazine (DTIC-Dome); oxaliplatin (Eloxatin); carmustine (carmustine) (Gliadel); ifosfamide (Ifex); nitrogen mustard-13- 201215610 (mechlorethamine) (Mustargen); busulfan (Myleran); carboplatin (Paraplatin); Lead (cisplatin) (CDDP; Platinol); temozolomide (Temodar); thiotepa (Thioplex); bendamustine (Treanda); or streptozotocin ( Streptozocin) (Zanosar). Typical antibiotics include, but are not limited to, doxorubicin (adriamycin); doxorubicin liposomes (Doxil); mitoxantrone (Novantrone); bleomycin (Blenoxane); daunorubicin (Cerubidine); daunomycin liposome (DaunoXome); dactinomycin (Cosmegen): epirubicin (Ellence); Idamycin (Idamycin); plicamycin (Mithracin); mit〇mycin (Mutamycin); pentostatin (Nipent); or valrubicin (Valstar). Typical antimetabolites include, but are not limited to, fluorouracil (Adrucil); capecitabine (Xeloda); ureea (Hydrea); thiophene (Purinethol); pemetrexed (pemetrexed) (Alimta); fludarabine (Fludara); nelarabine (Arranon); cladribine (Cladribine Novaplus); clofarabine (Clolar); Cytarabine (Cytosar-U); decitabine (Dacogen); cytarabine liposome (DepoCyt); transurea (Droxia ); pralatrexate (Folotyn); fluorouridine (fl〇XUridine) (FUDR); gemcitabine-14- 201215610 (Gemzar); clasmin (Leustatin); gas dalabin (Oforta); Methretrexate (ΜTX; Rheumatrex); Trexall; thioguanine (Tabloid); TS-1 or cytarabine (Tarabine PFS). Typical antidote includes but Not limited to amifostine (Ethyol) or mesna (Mesnex).

Typical interferons include, but are not limited to, interferon a-2b ((Intr〇n) A) or interferon a-2a (Roferon-A). Typical multi-strain or monoclonal antibodies include, but are not limited to, trastuzumab (Herceptin); ofatumumab (Arzerra); bevacizumab (Avastin); Rituximab (Rituxan); cetuximab (Erbitux): panitumumab (V ectibi X ); tositumomab/iodine; tosimo (Bexxar); alemtuzumab (Campath); ibritumomab (In-111 Zevalin); gemtuzumab (Mylotarg); eculizumab KSoliris ); Y-90 Zevalin; denosumab or Zevalin. Typical EGFR inhibitors include, but are not limited to, gefitinib (Iressa); lapatinib (Tykerb); cetuximab (Erbitux); erlotinib (Tarceva); panitumumab (Vectibix) PKI-166: canertinib (CI-1 033); matuzumab (Emd7200) or EKB-569. -15- 201215610 Typical HER2 inhibitors include, but are not limited to, trastuzumab (Herceptin); lapatinib (Tykerb) or AC-480. Histone deacetylase inhibitors include, but are not limited to, vorinostat (Zolinza). Typical hormones include, but are not limited to, tamoxifen (Soltamox; Nolvadex); raloxifene (raloxifene) Evista); megestrol (Megace); leuprolide (1 e up r ο 1 ide) (L upr ο η; Lupron Depot; Eligard; Viadur); fulvestrant (fulvestrant) Faslodex); Letrozole (Femara); Triptorelin (Trelstar LA; Trelstar Depot); exemestane (Aromasin); Goserelin (Z〇dex) ); bicalutamide (Casodex); anastrozole (Arimidex); fluoxymesterone (Androxy; Halotestin); medroxyprogesterone (Provera; Depo-Provera) ; estramustine (Emcyt); flutamide (Eulexin); toremifene (Fareston); degarelix (Firmagon); nilutamide (Nilandron); abarelix (Plenaxis) or testolactone (Teslac). Typical mitotic inhibitors include, but are not limited to, paclitaxel (Taxol; Onxol; Abraxane); docetaxel (vintexine); vincristine (Oncovin; Vincasar PFS); vinblastine (Velban); Etoposide (Toposar; -16- 201215610

Etopophos; VePesid); teniposide (Vumon); ixabepilone (Ixempra); nocodazole; epothilone; vinorelbine Navelbine); camptothecin (CPT); irinotecan (Camptosar); topotecan (Hycamtin); amsacrine or mellatin D (LAM-D) ). Typical mTOR inhibitors include, but are not limited to, everolimus (Afinitor) or temsirolimus (Torisel), rapamune, ridafromos (ridaf 〇r ο 1 imus) or AP 2 3 5 7 3.

Typical kinase inhibitors include, but are not limited to, Bevacizumab (target VEGF), BIB W2 9 9 2 (target E GF R and Er b2), Cetuximab/Erbitux (standard)耙Erbl), Imatinib/Gleevic (IE Bcr-Abl, PDGFRs and c-Kit), Trastuzumab (Erb2), Gefitinib/Iressa (target EGFR), ranibizumab (RanibizumabK target VEGF), pegaptanib (target VEGF), erlotinib (Erlotinib)/Tarceva (standard Erbl), nilotinib ( Nilotinib) (Bcr-Abl), lapatinib (standards Erbl and Erb2/Her2), GW-572016/Lapatinib ditosylate (standard HER2/ Erb2), Panitumumab/Vectibix (labeled EGFR), Vandetinib (labeled RET/VEGFR), E7080 (including multiple targets of RET and VEGFR), Herceptin ) (target HER2/Erb2), PKI-16 6 (target EGFR), -17- 201215610 Cannitinib/CI-1 03 3 (target EGFR), sunitinib (Sunitinib)/ SU-11464/Sutent (targets EGFR and FLT3), Matuzumab/Emd7200 (target EGFR), EKB-569 (target EGFR), Zd6474 (target EGFR and VEGFR), PKC-412 (target VEGR and FLT3), Vatalanib / Ptk78 7/ZK2225 84 (target VEGR), CEP - 7 0 1 (target FLT 3 ), SU5614 (target FLT3), M LN 5 1 8 (target FLT 3), XL999 (target FLT3), VX-322 (target FLT3), Azd 0 5 3 0 (target S RC ), BMS-354825 (standard SRC), SKI-606 (target SRC), CP -690 (target JAK), AG-490 (target JAK), WHI-P154 (target JAK), WHI-P131 (standard JAK), sorafenib (Sorafenib) / Resava (Nexavar) ( Standard RAF kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, KIT, FLT-3 and RET), Dasatinib/Sprycel (BCR/Abl and Src), AC-220 (target Flt3), AC-4 80 (all target HER proteins, "pan-HER"), Motesanib bisphosphate (target VEGF1-3 'PDGFR and c-kit), Denosumab (standard RANKL, inhibition of SRC), AMG888 (marker HER3) and AP24534 (including multiple targets of Flt3). Exemplary multi-kinase inhibitors include, but are not limited to, Sexapini (Nexavar), Sunitinib (Sutent), BIBW 29 92, E7080, Zd6474, PKC-412, motetanil or AP24534. Typical serine/threonine kinase inhibitors include, but are not limited to, eril/easudil hydrochloride; rapamune (target mTOR/FRAPl); Deforolimus (target mTOR); -18- 201215610 Certican/Everolimus (standard MTOR/FRAPl); AP23 5 73 (target mTOH/FRAPl); Illulu ( Eril) / Fasudil hydrochloride (target RHO); Flavopiridol (target CDK); Seliciclib / CYC202 / Roscovitrine Target CDK); SNS-032/BMS-3 87032 (target CDK); Ruboxistaurin (standard $EPKC); Pkc412 (target PKC); Byrytin (Byostatin) PKC); KAI-9803C target PKC); SF1126 (target PI3K); VX-6 8 0 (target aurora (human 1!1: 〇1^) kinase); 八 2 (11152 (target aurora kinase) Arry- 1 42886/AZD-6244 (target MAP/MEK); SCIO-469 (target MAP/MEK); GW6 8 1 3 23 (target MAP/MEK); CC-401 (target JNK); CEP-1347 (target JNK); and PD332991 (target CDK). Typical tyrosine kinase inhibitors include, but are not limited to, Ero Tarceva; Iressa; Gleevec; Nexavar; Sutent; Herceptin; Bevacizum Antibiotic (Avastin); Rituxan: ractatinib (Tykerb); cetuximab (Erbitux); panitumumab (Vectibix); everimox (Afinitor); Antibiotic (Campath); jitozumab (Mylotarg); temsirolimus (Torisel); pazopanib (Votrient); dasatinib (Sprycel); nilotinib ( Nilotinib) (Tasigna); vatalanib (Ptk787 ZK2225 84); CEP-70 1 ; SU5614; MLN518; XL999; VX-3 2 2 ; Azd05 3 0 ; BMS-3 54825 ; SKI-606 CP- 690 ; AG-490 ; WHI-P154 ; WHI-P1 3 1 ; AC-220 ; or AMG888. -19- 201215610 Typical VEGF/VEGFR inhibitors include, but are not limited to, bevacizumab (Avastin): Sorafenib (Nexavar); Sunitinib (Sutent): ranibizumab, pegaptanib; or Vandetinib (vandetinib). Typical aromatase inhibitors include, but are not limited to, aminoglutethimide, Teslac, Arimidex, Letrozole (Femara), Exemestane (Aromasin), Vorozole (Rivizor), Formestane (Lentaron), Fadrozole (Afema), 4-androstene-3,6,17-trione (6-OXO), 1,4,6-androstene-3,17-dione (ATD) and 4-hydroxyandrostenedione. Typical anthracyclines include, but are not limited to, daunorubicin (Daunomycin), doxorubicin ((addrimycin), epirubicin, idarubicin, and valrubicin. Glycoside analogs include, but are not limited to, gemcitabine, aza-cytidine (eg, 5-azacytidine), and cytosine arabinose (cytarabine, araC, Cytosar). Typical microtubule targets include but not Limited to paclitaxel, docetaxel, vincristine, vinblastine, norcodazole, epothilone, and velopene (navelbine). Typical topoisomerase poisons include, but are not limited to, teniposide, relying on Bovine, adrimycin, camptothecin, daunorubicin, dactinomycin, mitoxantrone; guanidine, ampicillin, epirubicin and idarubicin. typical taxane or taxane derived Materials include, but are not limited to, paclitaxel and docetaxel. -20- 201215610 Typical general chemotherapeutic, antitumor, and antiproliferative agents including, but not limited to, altretamine (Hexalen); isotretinoin (isotretinoin) ) (Accutane ; Amnesteem ; Claravis ; Sotret ) ; Vitamin A acid (tretinoin) ( Vesanoid); azacitidine (V idaza ); bortezomib (V e 1 cade) asparaginase (Elspar); levamisole (Ergamisol) ); mitotane (Lysodren); ◎ procarbazine (Matulane); pegaspargase (Oncaspar); denileukin diftitox (Ontak); (p〇rfimer) (Photofrin); aldesleukin (Proleukin); lenalidomide (Revlimid); bexarotene (Targretin); thalidomide (Thalomid) ); Torisel; Trisenox; verteporfin (Visudyne); mimosine (Leucenol); (1M tegafur (tegafur)-0. 4M 5-indole chloride-2,4-dihydroxypyrimidine-1M potassium oxonate) or statins (eg lovastatin, atorvastatin, cerivastatin, fluvastatin) Fluvastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin 〇 The present invention also provides a treatment for cell proliferation. A method of treating a therapeutically effective amount of a compound of formula III, Ilia, IVa, ivb, Va or Vb, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof, in combination - 21 - 201215610 An effective amount of a second anti-proliferative agent, which is administered to a subject, wherein the compound of formula III, Ilia, IVa, IVb, Va or Vb, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof, and the same The two antiproliferative agents are not administered at the same time. In some preferred systems, the compound of formula III, Ilia, IVa, IVb, Va or Vb is (-)-trans-3-(5,6-dihydro-4H). -pyrrolo[3,2,l-ij]salostino-pyl)-4-(lH-indol-3-yl)pyrrolidine-2,5-dione. In a preferred system, the second antiproliferative agent is a cytidine analog, including but not limited to gemcitabine, aza-cytidine (eg, 5-azacytidine), and chewing steep arabinose (cytarabine, araC Preferably, the cytidine analog is gemcitabine. In another system, the second anti-proliferative agent is an inhibitor of the G1/S phase of the cell cycle. In certain preferred systems, Formula III, A compound of Ilia, IVa, IVb, Va or Vb, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof, is administered after administration of the second anti-proliferative agent. In a system, A compound of Ilia' IVa, IVb, Va or Vb, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof, is administered in a single dose for 12 hours, 24 hours, 36 after administration of the second anti-proliferative agent. Hour, 48 hours, 60 hours, 72 hours, 4 days, 5 days, 6 days, 7 days, 10 days, 2 weeks, 3 weeks, or 4 weeks. Preferably, the second anti-proliferative agent is administered without a compound of formula III, Ilia, IVa, IVb, Va or Vb or a pharmaceutically acceptable salt thereof, or a prodrug or metabolism thereof, in excess of 12 or 24 hours The administration is carried out for 24 hours after administration of the second anti-proliferative agent -22-201215610. Preferably, no drug is administered at least 12 hours or 24 hours before administration of the second anti-proliferative agent. More preferably, A compound of Formula III, Ilia, IVa, IVb, Va or Vb, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof, is administered to a second antiproliferative agent when the compound or agent is administered to a subject The concentration or amount in the object is less than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or 10% of its starting concentration or starting amount. Vote for 2 4 hours. Preferably, the concentration or amount of the compound or agent is less than 50% of its initial concentration. More preferably, the concentration or amount of the compound or agent is less than the initial concentration or the initial amount of 10%, 9%, 8%, 7%, 6%, 5%, 5%, 3%, 3%, 2%, 1 %. In one system, the subject is administered to a subject in the form of a compound of formula III, Ilia, IVa, IVb, Va or Vb, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof, 12 hours, 24 hours, 36 hours before administration to a subject. , 48 hours, 60 hours, 72 hours, 4 days, 5 days, 6 days, 7 days, 10 days, 2 weeks, 3 weeks, or 4 weeks ❹ "None" (no administration) second anti-proliferative agent Medicine. Preferably, the subject is administered at least 24 hours, at least 48 hours or at least 72 hours prior to administration of the compound of Formula III, Ilia, IVa, IVb, Va or Vb, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof thereof. A drug that is "none" a second anti-proliferative agent. In certain preferred systems, the second anti-proliferative agent is administered after administration of a compound of Formula III, Ilia, IVa, IVb, Va or Vb, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof Give. In one system, the second antiproliferative agent is administered a compound of formula III, Ilia, IVa, IVb, Va or Vb or a pharmaceutically acceptable salt thereof, or -23-201215610, a prodrug or metabolite thereof After administration to a subject, a single dose is administered for 30 minutes, 1 hour, 12 hours, 24 hours '36 hours, 48 hours, 60 hours, 72 hours, 4 days, 5 days, 6 days, 7 Days, 1 day, 2 weeks, 3 weeks, or 4 weeks. Preferably, the compound of formula III, Ilia, IVa, IVb, Va or Vb, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof, is administered for at least 24 hours or 48 hours and a second anti-proliferative agent The compound is administered for 48 hours after administration of a compound of formula III, Illa, IVa, IVb, Va or Vb, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof. Most preferably, no drug is administered at least 12 hours or at least 24 hours prior to administration of the second anti-proliferative agent. More preferably, when the compound or agent is administered to a subject, the second antiproliferative agent is a compound of Formula III, Ilia, IVa, IVb, Va or Vb or a pharmaceutically acceptable salt thereof, or a prodrug thereof or The concentration or amount of the metabolite in the subject is less than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or 1 of its starting concentration or starting amount. After 〇%, it was administered for 48 hours. Preferably, the concentration or amount of the compound or agent is less than 50% of its initial concentration. More preferably, the concentration or amount of the compound or agent is less than the initial concentration or the initial amount of 10%, 9%, 8%, 7%, 6%, 5%, 5%, 3%, 3%, 2%, 1 %. In one system, the subject is administered 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 4 days, 5 days, 6 days before the second anti-proliferative agent is administered to the subject. , 7 days, 1 day, 2 weeks, 3 weeks, or 4 weeks, is a compound of the formula III, Ilia, IVa, IVb, Va or Vb or a pharmaceutically acceptable salt thereof, or a prodrug thereof or Metabolite drug. Preferably, the subject is at least 24 hours, at least 48 hours or at least 72 hours prior to administration of the second anti-proliferative agent as "no" compounds of formula III, Ilia, IVa, IVb, Va or Vb or It is a medicine of the acceptable salt, or its prodrug or metabolite. As used herein, "unmedicated" means that no drug is administered to the subject. It can also mean that the subject does not receive any medication. Preferably, the drug-free representation of the subject is not administered any anti-proliferative or anti-cancer agent. Preferred combination therapies include, but are not limited to, (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1-indolyl]quinolin-1-yl)-4-(111 -Ind-3-yl)pyrrolidine-2,5-dione was administered in combination with gemcitabine. In some systems, the subject or patient receives gemcitabine and is administered from about 25 mg/m2 to about 50 mg/m2 once daily. In some systems, gemcitabine is administered at a reduced dose to reduce toxicity. For example, gemcitabine is administered at 100 mg/m2, 750 mg/m2, 500 mg/m2, 250 mg/m2, 100 mg/m2, or 50 mg/m2 once daily. In some systems, the subject or patient receives twice a day (360 mg) of (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1- ij]quinoline- 1-yl)-4-(1Η-indol-3-yl)pyrrolidine-2,5-dione. (_)_反_ 3-(5,6-Dihydro-411-pyrrolo[3,2,1-indolyl]quinolin-1-yl)-4-(111-indole-3-indenyl) Preferred dosage forms of pyrrolidine-2,5-dione include, but are not limited to, capsules and lozenges. This example demonstrates that (-)-trans-3-(5,6-dihydro-411-pyrrolo[3] , 2,1-ij]quinolin-1 -yl)-4 - (1 Η -吲哚·3 -yl)pyrrolidine-2,5-dione in combination with gemcitabine, has synergistic effects on various cancers Or at least add anti-proliferative effects in vitro and in vivo. Such cancers include, but are not limited to, lung cancer, small cell lung cancer, non-small cell lung cancer, colon cancer, breast cancer, pancreatic cancer, prostate cancer, kidney cancer, cervical cancer, brain cancer, stomach cancer, uterine cancer, small intestine cancer, liver cancer, chronic Myeloid leukemia, melanoma, ovarian cancer, metastasis-related renal cells-25- 201215610 cancer (RCC), vesicular soft tissue sarcoma (ASPS), clear cell sarcoma (CCS), and hepatocellular carcinoma. The anti-proliferative effects of such combination therapies are increased/enhanced in cell proliferative diseases in which the affected cells are constitutively characterized or overexpressed c-Met. (-)-trans-3-(5,6-dihydro-41 pyrrolo[3,2,1-indolyl]quinolin-1-yl)-4-(1H-indol-3-yl)pyridinium L-pyridine-2,5-dione is a non-ATP competitive small molecule that selectively targets the receptor tyrosine kinase of c-Met. Exposure of the c-Met cancer cell line to (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinoline-l-yl)-4-( lH-Indol-3-yl)pyrrolidine-2,5-dione causes a decrease in phosphorylation-c-Met content and eventual apoptosis of cells. In the multi-mouse allograft efficacy study (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-buyl)-4-(1Η -Indole-3-yl)pyrrolidine-2,5-dione also inhibits the growth of human tumors (Munshi N, et al.) ARQ 197, a Novel and Selective Inhibitor of the Human c-Met receptor Tyrosine Kinase with Antitumor Activity ".  Mol Cancer Ther (2010 May 18)) o Gemcitabine is an anti-cancer chemotherapy drug used to treat pancreatic cancer, non-small cell lung cancer, bladder cancer, soft tissue sarcoma, and metastatic breast cancer. Gemcitabine is classified as an antimetabolite. Gemcitabine triphosphate analogues replace cytidine during DN A replication, resulting in inhibition of DN A synthesis and induction of apoptosis. The gemcitabine bisphosphonate analog inactivates the ribonucleotide reductase enzyme (RNR) and inhibits the production of deoxynucleotides required for DNA replication and repair, and induces apoptosis. Gemcitabine has been shown to arrest cancer cells in the G 1 / S phase (Cerqueira, P.  A.  Fernandes, M.  J.  Ramos (2 007),  -26- 201215610 " Understanding ribonucleotide reductase inactivation by gemcitabine" ,  Chemistry,  a European Journal 13 (30):  8507-15)° Formula III of the present invention, Ilia, IVa, IVb, a compound of Va or Vb, Or its pharmaceutically acceptable salt, Prodrug, Metabolites, The analog or derivative can be incorporated into a pharmaceutical composition suitable for administration. Such compositions typically comprise the compound (i.e., including the active compound) and a pharmaceutically acceptable excipient or carrier. As used in this article, "Pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" is intended to include any and all solvents which are compatible with pharmaceutical administration, Dispersing medium, coating, Antibacterial and antifungal agents, Isotonic agent, Absorption delay agent, and many more. Suitable carriers are described in the latest edition of Remington’s Pharmaceutical Sciences. This is the standard bibliography for this field. Preferred examples of such carriers or diluents include, but are not limited to, water, brine, Ringer's solution, Glucose solution and 5% human serum albumin.  Pharmaceutically acceptable carriers include solid carriers such as lactose, White clay,  蔗糖 sucrose, talc, gelatin, agar, Pectin, Gum arabic, Magnesium stearate,  Stearic acid, and many more. Typical liquid carriers include syrup, Peanut oil, Olive oil, water, and many more. Similarly, The carrier or diluent may comprise a time delay material as is known in the art. Such as glyceryl monostearate or glyceryl distearate, alone or together with a wax, Ethyl cellulose, Hydroxypropylmethylcellulose, Methyl methacrylate or the like. Other sputum, excipient, Flavors and other additives such as those known in the art can also be included in the pharmaceutical compositions according to the present invention. Liposomes and water-insoluble vehicle fluids such as fixed oils can also be used. The use of such media and reagents in pharmaceutically active substances is well known in the art. -27-201215610. Except where any conventional media or reagents are incompatible, They are used in the composition system. The active compound can also be incorporated into the composition.  on the one hand, Formula III, Ilia, IVa, IVb, Va, its pharmaceutically acceptable salt, Prodrug, Metabolites, In the appropriate dosage form, The dosage form is effective according to conventional steps (for example, sufficient to inhibit tumor growth, Formula III for killing or preventing cell proliferative diseases, etc. Ilia, IVa, IVb, An acceptable salt of Va or Vb, Prodrug, Metabolites, The analog component is prepared in accordance with a standard pharmaceutical carrier or diluent (i.e., by means of a pharmaceutical composition). These steps may, as appropriate, include compressing or dissolving the ingredients to obtain the desired formulation.  As used in this article, "Object" can be any human, Primates, Mouse, Rat, dog, Cat, sheep, goat, camel. Preferably, The object is human, as used in this article, "The object that needs it, ‘for the object of disease, Or an object that increases the risk of disease relative to the general population. on the one hand, a preferred aspect of the object The subject in need of it has cancer.  As used in this article, The term "cell proliferative g is regulated or abnormally grown or the condition of the cells of both or does not develop as an undesired symptom or disease of cancer.  Cytoproliferative diseases encompassing each of the active compounds in which cell division is dysregulated. Supplemental or Vb compounds or analogs or derivatives are used to treat dead tumor cells by combination, An effective therapeutic effect of a compound or a pharmaceutical g derivative thereof (as a living preparation of the present invention, Granulation and dairy animals, E.g , Cattle, horse, pig,  〇 Has cell proliferative cell proliferative disease with a pre-cancerous state.  "rickets" refers to typical fine symptoms in which the present invention is not caused to cause cancer. Typical fine -28- 201215610 Cytoproliferative diseases include but are not limited to tumors, Benign tumor, Malignant tumor,  Precancerous state, In situ tumor, Membrane tumor, Metastatic tumor, Liquid tumor, Solid tumor, Immune tumor, Blood tumor, cancer, cancer, Leukemia, Lymphoma, Sarcoma and rapidly dividing cells. The term "rapidly dividing cells" as used herein is defined as any cell that divides at a rate that exceeds or is greater than the rate expected or observed between adjacent or juxtaposed cells within the same tissue. Cell proliferative disorders include primary cancer or pre-cancerous conditions. Cell proliferative diseases 〇 include cancer. Preferably, The methods provided herein are used to treat or alleviate cancer signs. The term "cancer" includes solid tumors as well as hematological and/or malignant tumors. The "primary cancer cell" or "pre-cancerous cell" is a cell which exhibits a cell proliferative disease in a primary cancer or a pre-cancerous state. A "cancer cell" or a "cancerous cell" is a cell which exhibits a cell proliferative disease of cancer. Any reproducible measurement can be used to identify cancer cells or pre-cancerous cells.  Cancer cells or pre-cancerous cells can be sampled by tissue (for example, Histological or grading identification of biological samples. Cancer cells or pre-cancerous cells can be identified by using appropriate molecular markers.  Typical non-cancer conditions or conditions include, but are not limited to, rheumatoid arthritis;  inflammation; Autoimmune disease Lymphatic hyperplasia symptoms; Acromegaly; Rheumatoid spondylitis; Osteoarthritis; gout, Other joint symptoms; Sepsis ; Septic shock Endotoxic shock; Gram-negative sepsis; Toxic shock syndrome; asthma; Adult respiratory distress syndrome; Chronic obstructive pulmonary disease; Chronic pulmonary inflammation; Inflammatory bowel disease; Crohn's disease;  Psoriasis; eczema; Ulcerative colitis; Pancreatic fibrosis; Liver Fibrosis; Acute and chronic kidney disease; Intestinal fistula; Pyresis ; Vascular restenosis; Brain -29- 201215610 malaria; Stroke and ischemic injury; Neurological trauma Alzheimer’s disease; Huntington’s disease: Parkinson’s disease; Acute and chronic pain;  Allergic rhinitis; Allergic conjunctivitis; Chronic heart failure; Acute coronary artery syndrome; Physique malaria; Leprosy Leishmaniasis; Lyme disease; Reiter syndrome: Acute synovitis; Muscle regression Bursitis; Tendinitis Tenosynovitis Intervertebral plate cartilage prolapse, Rupture or prominent syndrome; Osteosclerosis; thrombus; Vascular restenosis; Silicosis  Pulmonary sarcoma; Bone resorption disease (such as osteoporosis); Transplantation to the host; Multiple sclerosis: lupus; Fibromyalgia; AIDS and other viral diseases (such as herpes zoster; Herpes simplex I or II; Influenza virus and huge cell virus); And diabetes.  Typical cancers include, but are not limited to, adrenocortical carcinoma, AID S related cancer, AIDS-related lymphoma, Rectal cancer, Anal cancer, Anal cancer, Appendix cancer, Child cerebellar stellate cell tumor, Children's brain astrocytoma, Basal cell carcinoma, Skin cancer (non-melanoma), Cholangiocarcinoma, Extrahepatic cholangiocarcinoma, Intrahepatic cholangiocarcinoma, Breast cancer, Urinary bladder cancer, Bone and joint cancer, Osteosarcoma and malignant fibrous tissue tumors, Brain cancer, Brain tumor, Brain stem glioblastoma, Cerebellar stellate cell tumor, Cerebral stellate cell tumor/malignant glioma, Ependymoma, Neural tube blastoma, Primitive neuroectodermal tumor on the sky, Visual pathway and pituitary gland glioma, Breast cancer, Bronchial adenoma/carcinoid, Carcinoid tumor, Gastrointestinal tract Nervous system cancer, Nervous system lymphoma, Central nervous system cancer, Central nervous system lymphoma, Cervical cancer, Childhood cancer, Chronic lymphocytic leukemia Chronic myelogenous white blood -30- 201215610 Chronic myeloproliferative disorder, Colon cancer, Colorectal cancer, Skin T cell lymphoma, Lymphoma, Sickle granuloma, Seziary syndrome, Endometrial cancer' esophageal cancer, Extracranial germ cell tumor, Extragonadal germ cell tumor, Extrahepatic cholangiocarcinoma, Eye cancer, Intraocular melanoma, Retinoblastoma,  Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid, Gastrointestinal stromal tumor (GIST), Germ cell tumor, Ovarian germ cell tumor, Pregnancy trophoblastic tumor, Glioma, Head and neck cancer, Hepatocyte (liver) cancer,  〇 Hodgkin's lymphoma 'in swallow cancer, Intraocular melanoma, Eye cancer, Pancreatic islet cell tumor (endocrine pancreatic tumor), Kaposi sarcoma, Kidney cancer, Renal cancer, Throat cancer,  Acute lymphocytic leukemia, Acute myeloid leukemia, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Hairy cell leukemia, Lip and oral cancer, Liver cancer, Lung cancer, Non-small cell lung cancer, Small Cell Lung Cancer, AIDS-related lymphoma, Non-Hodgkin's lymphoma, Primary central nervous system lymphoma,  Waldenstram macroglobulinemia, Neural tube blastoma 〇 , Melanoma, Intraocular (eye) melanoma, Merkel cell carcinoma, Malignant mesothelioma, Mesothelioma, Metastatic squamous neck cancer, Oral Cancer,  Tongue cancer, Multiple endocrine neoplasia syndrome, Sickle granuloma, Myelodysplastic syndrome, Myelodysplastic/myeloablative, Chronic myelopathic leukemia, Acute myeloid leukemia, Multiple myeloma, Chronic myeloproliferative disorder, Nasopharyngeal carcinoma, Neuroblastoma, Oral cancer, Oral Cancer, Oropharyngeal cancer, Ovarian cancer, Ovarian epithelial cancer, Low-grade ovarian tumors, Pancreatic cancer, Pancreatic islet cells, pancreatic cancer, Sinus and nasal cancer, Parathyroid carcinoma, Penile cancer, Pharyngeal cancer, Trophoblastoma, Pineal mesoblastoma and opioid primitive neuroectodermal tumor,  -31 - 201215610 Pituitary tumor, Paddle cell tumor/multiple myeloma, Pleural pulmonary blastoma, Prostate cancer, Rectal cancer, Renal pelvis and ureter, Transitional cell carcinoma,  Retinoblastoma, Rhabdomyosarcoma, Salivary gland cancer, Ew i n g family tumors, Kaposi's sarcoma, Uterine cancer, Uterine sarcoma, Skin cancer (non-melanoma), Skin cancer (melanoma), Merkel cell skin cancer, Small intestine cancer, Soft tissue sarcoma, Squamous cell carcinoma, Stomach (stomach) cancer, Primitive ectodermal tumors on the sky, 睪9 cancer, Laryngeal cancer, Thymoma, Thymoma and thymic cancer, Thyroid cancer, Transitional cell carcinoma of the renal pelvis and ureters and other urinary organs, Gestational trophoblastic tumor, Urethral cancer, Endometrial cancer, Uterine sarcoma, Uterine body cancer, Vaginal cancer, Vulvar cancer and Wilm's tumors.  "Cellular proliferative disease of the blood system" is a cell proliferative disease involving cells of the blood system. on the one hand, Cell proliferative diseases of the blood system include lymphoma, leukemia, Bone marrow tumor, Obese cell tumor, Osteomyelopathy, Benign monogenic globulin, Lymphomatoid granuloma, Lymphoma-like papules, True erythrocytosis, Chronic myeloid leukemia, Causes of unexplained myelosynthesis and essential thrombocytosis. on the other hand, Cell proliferative diseases of the blood system include excessive cell proliferation of the blood system,  Dysplasia and metaplasia. a preferred aspect, The composition of the present invention can be used to treat a cancer selected from the group consisting of the blood cancer of the present invention or the blood cell proliferative disease of the present invention. on the one hand, The blood cancer of the present invention includes multiple myeloma, Lymphoma (including Hodgkin's lymphoma, Non-Hodgkin's lymphoma, Children with lymphoma and lymphocytes and lymphoma of skin origin), White blood disease (including childhood leukemia, Hairy cell leukemia, Acute lymphocytic leukemia, Acute myeloid leukemia, Chronic lymphocytic leukemia, Chronic myeloid -32- 201215610 Cytogenous leukemia, Chronic myelogenous leukemia, And obese cell leukemia), Myeloma, And obese cell tumor "cell proliferative disease of the lung" is a cell proliferative disease involving lung cells. on the one hand, Cell proliferative disorders of the lung include all forms of cell proliferative disorders affecting lung cells. on the one hand, Cellular proliferative diseases of the lung include lung cancer, Primary or precancerous condition of the lung, Benign growth or lesions of the lungs, Malignant growth or lesions of the lungs, And metastatic lesions of sputum in tissues and organs other than the lungs. a preferred aspect, The composition of the present invention can be used to treat cell proliferative diseases of lung cancer or lung. on the one hand, Lung cancer includes all forms of lung cancer. on the other hand, Lung cancer includes malignant lung tumors, Carcinoma in situ, Typical carcinoid tumors and atypical carcinoid tumors. on the other hand, Lung cancer includes small cell lung cancer (" SCLC"), Non-small cell lung cancer ("NSCLC" ), Squamous cell carcinoma, Adenocarcinoma, Small cell carcinoma, Large cell carcinoma, Adenoid squamous cell carcinoma and mesothelioma. on the other hand, Lung cancer includes "scar cancer", Bronchoalveolar carcinoma, Giant cell carcinoma, Spindle cell carcinoma and large cell neuroendocrine carcinoma. on the other hand, Lung cancer includes 肺 lung tumors with tissue and ultrastructural heterogeneity (eg mixed cell types) 一方面 Cell proliferative disorders of the lung include all forms of cell proliferative disorders affecting lung cells. on the one hand, Cell proliferative diseases of the lung include lung cancer, The precancerous state of the lungs. on the one hand, Cell proliferative diseases of the lung include hyperplasia of the lungs, Metaplasia and dysplasia. on the other hand, Cell proliferative diseases of the lung include asbestos-induced hyperplasia, Squamous metaplasia and benign reactive mesothelial metaplasia. on the other hand, Cell proliferative disorders of the lung include replacement of columnar epithelium with stratified squamous epithelium and mucosal dysplasia. on the other hand, Exposure to inhalation -33- 201215610 Individuals with harmful environmental agents such as cigarettes and asbestos may increase the risk of developing cell proliferative diseases of the lung. on the other hand, Previous lung diseases that cause individuals to develop cell proliferative diseases of the lungs include chronic interstitial lung disease, Bad lung disease, scleroderma, Rheumatoid disease, Sarcoidosis, Interstitial pneumonia,  tuberculosis, Repetitive pneumonia, Idiopathic pulmonary fibrosis, Granuloma, Silicosis, Fibrous sclerosis and Hodgkin's disease.  "Cellular proliferative disease of the colon" is a cell proliferative disease involving colon cells. a preferred aspect, The cell proliferative disorder of the colon is colon cancer. a preferred aspect, The composition of the present invention can be used to treat cell proliferative diseases of colon cancer or colon. on the one hand, Colon cancer includes all forms of colon cancer. on the other hand, Colon cancer includes sporadic and hereditary colon cancer. on the other hand, Colon cancer includes malignant colon tumors, Carcinoma in situ, Typical carcinoid tumors and atypical carcinoid tumors. on the other hand, Colon cancer includes adenocarcinoma, Squamous cell carcinoma and adenosquamous cell carcinoma. on the other hand, Colon cancer line and selected from hereditary nonpolyposis colorectal cancer, Familial adenomatous polyposis, Gardner syndrome, Peutz-Jeghers syndrome, It is related to the hereditary syndrome of the group consisting of Turcot syndrome and juvenile polyposis. on the other hand, Colon cancer can be selected from hereditary non-polyposis colorectal cancer, Family adenomatous polyposis, Jiashi syndrome, Pijie syndrome, Induced by hereditary syndromes in a group consisting of diarrhea syndrome and juvenile polyposis.  on the one hand, Cell proliferative disorders of the colon include all forms of cell proliferative disorders affecting colon cells. On the one hand, cell proliferative diseases of the colon include colon cancer, Precancerous state of the colon, Adenomatous polyps of the colon and metachronous lesions of the colon. on the one hand, Cell proliferative disorders of the colon include -34- 201215610 adenomas. on the one hand, Colonic cell proliferative disease is caused by colonic hyperplasia,  Metaplasia and dysplasia are characteristic. on the other hand, Pro-colon diseases that allow individuals to develop cell proliferative diseases of the colon, including pre-colon cancer. on the other hand, Current diseases that make individuals susceptible to cell proliferative diseases of the colon include Crohn's disease and ulcerative colitis. on the one hand, The cell proliferative disorder of the colon is selected from p53, Ras, The mutations in the genes of the FAP and DCC groups are related. on the other hand, Due to being selected from p53, Ras,  () Mutations in the genes of the group consisting of FAP and DCC exist, Therefore, individuals will have an increased risk of developing cell proliferative diseases of the colon.  "Cellular proliferative disease of the prostate" is a cell proliferative disease involving prostate cells. on the one hand, Cell proliferative diseases of the prostate include all forms of cell proliferative diseases affecting prostate cells. on the one hand,  Proliferative diseases of the prostate include prostate cancer, Primary or precancerous condition of the prostate, Benign growth or lesions of the prostate, And the malignant growth or lesions of the prostate, And metastatic sputum in tissues and organs other than the prostate. on the other hand, Proliferative diseases of the prostate include prostate hyperplasia, Metaplasia, And dysplasia.  "Cellular proliferative disease of the skin" is a cell proliferative disease involving skin cells. on the one hand, Cell proliferative diseases of the skin include all forms of cell proliferative diseases affecting the skin cells. on the one hand, Cell proliferative diseases of the skin include the initial or precancerous condition of the skin, Benign growth or lesions of the skin, Melanoma, Malignant melanoma and other malignant growth or lesions of the skin, And metastatic lesions in tissues and organs in the body other than the skin. on the other hand, Cell proliferative diseases of the skin include hyperplasia of the skin -35 - 201215610 Metaplasia, Psoriasis and dysplasia.  "Cellular proliferative disease of the ovary" is a cell proliferative disease involving ovarian cells. on the one hand, Cell proliferative diseases of the ovary include all forms of cell proliferative diseases affecting the ovarian cells. on the one hand, Cytoproliferative diseases of the ovary include primary or precancerous conditions of the ovary, Benign growth or lesions of the ovary, Ovarian cancer, Malignant growth or lesions of the ovaries, And metastatic lesions in tissues and organs other than the ovaries. on the other hand, Cell proliferative diseases of the ovary include proliferation of ovarian cells, Metaplasia and dysplasia 〇 “Cellular proliferative disease of the breast” is a cell proliferative disease involving breast cells. on the one hand, Cell proliferative disorders of the breast include all forms of cell proliferative disorders affecting the cells of the breast. on the one hand, Cellular proliferative diseases of the breast include breast cancer, Primary or precancerous condition of the breast, Benign growth or lesions of the breast, And the malignant growth or lesions of the breast, And metastatic lesions in tissues and organs in the body other than the breast. on the other hand, Cell proliferative diseases of the breast include breast hyperplasia, Metaplasia and dysplasia.  on the one hand, The cell proliferative disease of the breast is the precancerous state of the breast.  on the one hand, The compositions of the invention can be used to treat the pre-cancerous condition of the breast. on the one hand, The precancerous state of the breast includes atypical hyperplasia of the breast, In situ ductal carcinoma (DCIS), Intraductal cancer, Lobular carcinoma in situ (LCIS), Lobular tumor, Growth or lesions of the 0 or 0 grade of the breast (eg stage 0 or grade 0 breast cancer, Or carcinoma in situ).  on the other hand, The pre-cancerous status of the breast can be staged according to the TNM classification scheme accepted by the American Joint Committee on Cancer (AJCC). The primary tumor (T) has been designated as T0 or Tis; And its regional lymph node (N) has been designated as -36- 201215610 NO phase; And its medium-distance transfer (Μ) is designated as the MO period.  a preferred aspect, The cell proliferative disease of the breast may be breast cancer. a better aspect, The compositions of the invention may be used to treat breast cancer. on the one hand, Breast cancer includes all forms of breast cancer. Breast cancer includes primary epithelial breast cancer. on the other hand , Breast cancer includes breasts involving other tumors such as lymphoma, A cancer of sarcoma or melanoma. on the other hand, Breast cancer, including cancer of the breast, Breast cancer, Lobular carcinoma of the breast, Undifferentiated carcinoma of the breast, The lobular sac of the breast is a tumor, Angiosarcoma of the breast and primary lymphoma of the breast. on the one hand, Breast cancer includes the first, II, Oh, IIIB, Stage IIIC and IV breast cancer. on the one hand,  Breast ductal cancer includes invasive cancer, Invasive carcinoma in situ, which is mainly composed of intraductal components, Inflammatory breast cancer and having an acne selected from Mucin (colloid), Medulla, With the medulla of lymphatic infusion, Papillary, A ductal carcinoma of the breast in the form of a group consisting of a hard and a tubular group. on the one hand, Lobular lobular carcinoma of the breast includes invasive lobular carcinoma, which is predominantly in situ. Invasive lobular carcinoma and invasive lobular carcinoma. on the one hand, Breast cancer includes Paget’s O disease, Paget's disease with intraductal carcinoma and Paget's disease with invasive ductal carcinoma. on the other hand, Breast cancer includes breast tumors that have both tissue and ultrastructural heterogeneity (e.g., mixed cell forms).  a preferred aspect, Formula III, Ilia, IVa, IVb, Compounds of Va or Vb can be used to treat breast cancer. on the one hand, Breast cancer to be treated includes familial breast cancer. on the other hand, Breast cancer to be treated includes sporadic breast cancer. on the one hand,  Breast cancer to be treated can occur in male subjects. on the one hand, Breast cancer to be treated can occur in female subjects. on the one hand, The breast cancer to be treated can occur in a female subject before menopause or in a female subject after menopause. on the one hand, To treat -37- 201215610 Breast cancer can occur in subjects equal to or greater than 30 years old. Or less than 3 years old. on the one hand, Breast cancer to be treated can occur in an object equal to or greater than 50 years old. Or in an object younger than 50 years old. on the one hand, Breast cancer to be treated can occur in subjects equal to or greater than 70 years old. Or less than 70 years old.  on the one hand, Breast cancer to be treated has been classified, To confirm in BRCA 1,  BRCA2 Or a familial or spontaneous mutation in p53. on the one hand, Breast cancer to be treated has been classified as having HER2/neu gene amplification, Excessive performance HER2/neu or low, Medium or high HER2/neu performance. on the other hand , The breast cancer to be treated has been selected from the estrogen receptor (ER), Lutein receptor (PR), Human epidermal growth factor receptor-2, Ki-67, CA15-3, Group markers consisting of CA 27-29 and c-Met were classified. on the one hand, Breast cancer to be treated has been classified as ER-unknown, ER-rich or ER-starved. on the other hand, Breast cancer to be treated has been classified as ER-negative or ER-positive. The ER-classification of breast cancer can be performed in any reproducible manner. A preferred aspect 'The ER classification of breast cancer can be as good as Onkologie 27:  Performed as described in 175-179 (2004). on the one hand, Breast cancer to be treated has been classified as PR-unknown, PR-rich or PR-deficient. On the other hand, breast cancer to be treated has been classified as PR-negative or PR-positive. On the other hand, breast cancer to be treated has been classified as receptor-positive or receptor-negative. On the one hand, breast cancer to be treated has been classified as being associated with an increase in blood levels of CA 15-3 or CA 27-29 or both.  on the one hand, Breast cancer to be treated includes a localized breast tumor. on the one hand , Breast cancer to be treated includes breast tumors associated with negative sentinel lymph node (SLN) biopsies. On the one hand, breast cancer to be treated includes breast tumors associated with positive pre-B sputum (S L N) biopsies. On the other hand, breast cancer to be treated -38-201215610 includes breast tumors associated with one or more positive axillary lymph nodes,  The axillary lymph nodes have been staged by any applicable method. on the other hand,  Breast cancer to be treated includes a condition that has been classified as having a negative lymph node (eg,  Nitrate negative) or lymph node positive status (for example, Breast tumors with positive lymph nodes. on the other hand, Breast cancer to be treated includes breast tumors that have been transferred to other areas of the body. on the one hand, The breast cancer to be treated can be classified as having been transferred to be selected from bones, lung, The area of the group consisting of the liver or brain. Another aspect is that the breast cancer to be treated can be selected according to the transferability, Locality, Regional, Localized, Partial period, remote, Multi-center, On both sides, One side, Opposite side, New diagnosis, Classification of features of groups of relapsed and inoperable patients.  on the one hand, Formula III, Ilia, IVa, IVb, The compound of Va or Vb can be used to treat or prevent cell proliferative diseases of the breast relative to a general population having a risk of increasing the risk of breast cancer. Or to treat or prevent breast cancer.  on the one hand, The target of increasing the risk of breast cancer relative to the general population is 女性 a female subject with a family history of breast cancer or a personal medical history. on the other hand, The subject who has an increased risk of breast cancer relative to the general population is a female subject having a reproductive series mutation or a spontaneous mutation in BRCA1 or BRCA2 or both. on the one hand, An object that increases the risk of breast cancer relative to the general population is a female subject with a family history of breast cancer and a germline mutation or spontaneous mutation in BRCA1 or BRCA2 or both. on the other hand, Relative to the general population, the risk of increasing the risk of breast cancer is greater than 30 years old. More than 40 years old, More than 50 years old, More than 60 years old, More than 70 years old, Women older than 80 or older than 90. on the one hand, Relative to the general population with increased risk of breast cancer -39- 201215610 The risk is for atypical breast hyperplasia, In situ ductal carcinoma (DCIS),  Intraductal cancer, Lobular carcinoma in situ (LCIS), Growth or lesions of the lobular tumor or breast stage 0 (for example, Subjects of sputum or graded breast cancer or carcinoma in situ).  on the other hand, The breast cancer to be treated can be graded according to histology according to the Scarf-Bloom-Richardson system. Among them, the breast tumor has been designated 1. a mitotic count score of 2 or 3; 1, a nuclear polymorphism score of 2 or 3; 1, 2, Or a thin tube of 3 to form a score; And the total score of Skov-Bom-Richardson between 3 and 9. on the other hand, The International Consensus Panel on the Treatment of Breast Cancer may be selected to be selected from Level 1, Level 1-2, level 2, Tumor grade of a group consisting of 2-3 or 3 grades.  on the one hand, The cancer to be treated has been staged according to the American Joint Committee on Cancer (AJCC) TNM classification system. Where the tumor (T) has been designated as TX, T1, Tlmic, T1 a ' Tib, Tic, T2 T3, Τ4, T4a, T4b, T4c or T4d period; And its regional lymph nodes (N) have been designated as NX, NO, N1  N2 N2a, N2b, N3, N3a, N3b or N3c period; And its central remote transfer (M) has been designated as MX, MO or Ml period. on the other hand, The cancer to be treated has been classified as stage I according to the American Joint Committee on Cancer (AJCC).  Phase IIA, Phase IIB, Phase IIIA, Phase IIIB, Stage IIIC or IV. on the other hand, The cancer to be treated can be designated as GX grade according to the AJCC classification (for example,  Level that cannot be evaluated), Level 1, level 2, Level 3 or Level 4. on the other hand , The cancer to be treated has been based on ρΝΧ, ΝΟ, ΝΟΝΟ(Ι-), ΡΝ0(Ι + ),  PNO (mol-), PN0 (mol + ), PN1 PNl(mi), PNla, PNlb,  -40- 201215610 PNlc, pN2 pN2a, pN2b, pN3, pN3a, AJCC pathological classification (pN) staging of pN3b or pN3c.  on the one hand, The cancer to be treated includes tumors that have been determined to be less than or equal to about 2 cm in diameter. on the other hand, Cancers to be treated include tumors that have been determined to be from about 2 to about 5 centimeters in diameter. on the other hand, The cancer to be treated includes tumors that have been determined to be greater than or equal to about 3 cm in diameter. on the other hand,  Cancers to be treated include tumors that have been determined to be greater than 5 cm in diameter. Another 0 aspect, The cancer to be treated can be classified as well differentiated by microscopic appearance. Moderately differentiated, Poorly differentiated or undifferentiated. on the other hand, The cancer to be treated can be counted by mitosis (for example, Number of cell divisions) or nuclear polymorphism (for example, Classification of microscopic appearance of cell changes). on the other hand, The cancer to be treated can be treated with a necrotic area (for example, Classification of microscopic appearance related to the area of sudden or degraded cells. on the one hand, The cancer to be treated is classified as having an abnormal karyotype, A chromosome with an abnormal number of chromosomes or one or more abnormalities in appearance. on the one hand, The cancer to be treated is classified as aneuploid, Triple scorpion, Tetraploid or a chromosome with altered ploidy. on the one hand, The cancer to be treated is classified as having a chromosomal translocation or an entire chromosome deletion or doubling, Or the deletion of a part of the chromosome, Multiplied or enlarged area.  On the one hand, the cancer to be treated can be diagnosed by DNA cytometry, Flow cytometry or image cytometry evaluation. on the one hand, The cancer to be treated has been classified as having 10%, 20%, 30%, 40%, 50%, 60%,  70%, 80% or 90% of cells are in the synthesis phase of cell division (for example, In the S phase of cell division). on the one hand, The cancer to be treated has been classified as having a low s_phase cell fraction or a high S-phase cell fraction.  -41 - 201215610 As used in this article, "Normal cells" are cells that are not classified as "cell-proliferating diseases". on the one hand, Lack of normal cells can lead to dysregulation or abnormal growth of both unwanted symptoms or diseases or both. Preferably, Normal cells have a normal functioning cell cycle checkpoint control mechanism.  As used in this article, "Contacting a cell" refers to a condition in which a composition of a compound or other substance is in direct contact with the cell or is sufficiently close to induce a desired biological effect in the cell.  As used in this article, "Candidate compound" means Formula III that has been or will be tested in one or more in vitro or in vivo bioassays, Ilia,  IVa, IVb, Va or Vb compound, To determine if the compound is likely to be in the cell, organization, whole body, The desired biological or medical response sought by the researcher or clinician in the animal or human body. on the one hand, The candidate compound is a compound of formula III or Ilia; on the other hand, The candidate compound is of formula IVa, IVb, A compound of Va or Vb. a preferred aspect, Biological or medical reactions are treatments for cancer. on the other hand, Biological or medical reactions are the treatment or prevention of cell proliferative diseases. on the one hand, In vitro or in vivo bioassays including, but not limited to, enzyme activity assays, Electrophoretic displacement analysis, Reporting genetic analysis, In vitro cell viability assay and various assays.  As used in this article, "Monotherapy" means the administration of a single active compound or therapeutic compound to a subject in need thereof. Preferably, Monotherapy comprises administering a therapeutically effective amount of the active compound. E.g, Use (±)-cis-3 - (5, 6-dihydro-411-pyrrolo[3, 2, 1-^]quinoline-; 1-yl)-4-(111-indol-3-yl)pyrrolidine-2, 5-diketone cancer monotherapy comprises a therapeutically effective amount of (±)-cis-3 - (5, 6-dihydro-4 Η-pyrrolo[3, 2 ,  1 - ij ] quinoline-1-yl)-4 - ( 1 Η - -42- 201215610 ind-3-yl)pyrrolidine-2, 5-diketone, Or a pharmaceutically acceptable salt thereof, Prodrug, Metabolites, The analog or derivative is administered to a subject in need of treatment for cancer. Monotherapy can be compared to combination therapy, Wherein combination therapy is administered in combination with a plurality of active compounds, Each component that is preferably combined is present in a therapeutically effective amount. on the one hand, Formula III, Ilia, IVa, IVb, Monotherapy of a compound of Va or Vb is more effective than a combination therapy in inducing a desired biological effect. Formula III, Ilia, IVa, IVb, The effectiveness of the single treatment of compounds of Va or Vb is shown in PCT Publication No. WO 2006/0 86484.  As used in this article, "Treatment" is described in order to fight disease, Symptoms or illnesses for the purpose of managing and caring for patients, And include including reducing or alleviating symptoms or complications or eliminating disease, Symptom or condition.  As used in this article, "Prevention" describes stopping the disease, The onset of signs or symptoms of symptoms or conditions.  on the one hand, Treating cancer results in a reduction in tumor size. A reduction in tumor size can also be referred to as "tumor regression." Preferably, After treatment, Relative to the size of the 前 before treatment, Tumor size is reduced by 5% or more; More preferably, Tumor size is reduced by 10% or more; More preferably, Reduce by 20% or more; More preferably, Reduce by 30% or more; More preferably, Reduce by 40% or more; Even better, Reduce by 50% or more; And optimally reduce by more than 7 5 % or more. Tumor size can be measured by any reproducible measurement. a preferred aspect,  Tumor size can be measured as the diameter of the tumor.  on the other hand, Treating cancer results in a reduction in tumor volume. Preferably,  After treatment, Relative to its pre-treatment volume, Tumor volume is reduced by 5% or more; More preferably, Tumor volume is reduced by 1% or more; More preferably, Decrease -43- 201215610 2 〇 % or greater ‘More preferably, Reduced by 30% or more, More preferably, Reduce 40% or more' or even better, Reduce by 50% or more, And optimally reduce by more than 75% or more. Tumor volume can be measured by any reproducible measurement.  on the other hand, Treating cancer results in a reduction in the number of tumors. Preferably,  After treatment, Relative to the number before treatment, The number of tumors is reduced by 5% or more; More preferably, The number of tumors is reduced by 10% or more; More preferably, Reduce by 2 〇 % or more; More preferably, Reduce by 30% or more; More preferably, Reduce by 4 〇 % or more; Even better, Reduce by 50% or more; And optimally reduce by more than 75 percent. The number of tumors can be measured by any reproducible measurement. a preferred aspect, The number of tumors can be measured by visual inspection by naked eye or by counting tumors at a specific magnification. a preferred aspect, The specific magnification is 2χ, 3χ, 4χ, 5χ, 1 Οχ or 5 Οχ 0 On the other hand, Treating cancer results in a reduction in the number of metastatic lesions in other tissues or organs that are remote from the location of the primary tumor. Preferably, After treatment, Relative to the number before treatment, The number of metastatic lesions is reduced by 5% or more; More preferably, The number of metastatic lesions is reduced by 10% or more; More preferably,  Reduce by 20% or more; More preferably, Reduce by 30% or more: More preferably, Reduce by 40% or more; Even better by 50% or more; And optimally reduce by more than 75%. The number of metastatic lesions can be measured by any reproducible measurement. a preferred aspect, The number of metastatic lesions can be measured by visual inspection by naked eye or by counting metastatic lesions at a specific magnification. a preferred aspect, Specific magnification is 2χ, 3χ, 4χ, 5χ, 10χ or 50χ.  on the other hand, Treatment of cancer resulted in an increase in the average survival time of the population of the treated subject compared to the group receiving the single agent. Preferably, The increase in the floor is more than 30 days; More preferably, More than 60 days; More preferably,  : And optimally, More than 120 days. The average survival time of the population is measured by any reproducible method. a preferred aspect, The increase in the live time of the population can be measured, for example, by the average length of survival of the ethnic group starting with the active compound. Another preferred aspect, An increase in the survival time of the family can also be measured, for example, by calculating the average survival length of the population after completion of treatment with the active compound.  on the other hand, Compared to the untreated target group, Treatment increases the average survival time of the subject population. Preferably, the live time is increased by more than 30 days; More preferably, More than 60 days; Better 90 days; And optimally, More than 120 days. The average survival of the population can be measured by any reproducible method. a preferred aspect,  An increase in the mean survival time can be measured, for example, by calculating the average length of survival of the population in terms of active compound opening. Another preferred aspect 增加 an increase in the mean survival time can also be measured, for example, by calculating the average survival length of the population after completion of treatment with the active compound.  on the other hand, Compared to accepting, instead of using Formula III, Ilia,  , a compound of Va or Vb or a pharmaceutically acceptable salt thereof, Precursor a monotherapy group of drugs or analogues of drugs,  This results in an increase in the average survival time of the population of the subject. The average survival time increased by more than 30 days; More preferably, More than 60 days;  More than 90 days; And optimally, More than 120 days. The average increase in ethnicity can be measured in any reproducible manner. A better party. The average first-pass treatment of cancer after the average survival of the surviving group was more than 90 days. The average deposit* exceeded the time of the group. The first group of IVa medicines of the group after the initial treatment group. Preferably, the increase in mean survival time of the population-45-201215610 can be measured, for example, by calculating the average survival length of the population after starting treatment with the active compound. In another preferred aspect, the increase in the average survival time of the population can also be measured, for example, by calculating the average survival length of the population after completion of the first round of treatment with the active compound. On the other hand, treating cancer results in a reduction in mortality in the population of the subject compared to a group receiving a separate carrier. On the other hand, treating cancer results in a reduction in the mortality rate of the population of the subject compared to the untreated subject population. In another aspect, a monotherapy of a drug that accepts a compound that is not a compound of Formula III, Ilia, IVa, IVb, Va, or Vb, or a pharmaceutically acceptable salt, prodrug, metabolite, analog, or derivative thereof Ethnicity, treatment of cancer produces a reduction in mortality in the population of the subject. Preferably, the mortality rate is reduced by more than 2%; more preferably, more than 5%; more preferably, more than 1%; and optimally, more than 25%. In a preferred aspect, the reduction in mortality of the subject of the subject can be measured by any reproducible means. In another preferred aspect, the reduction in mortality of the ethnic group can be measured, for example, by calculating the average number of disease-related deaths per unit time of the population after initiation of treatment with the active compound. Another preferred aspect' reduction in mortality of the population can also be measured, for example, by calculating the average number of populations associated with disease-related death per unit time after completion of the first round of treatment with the active compound. On the other hand, the treatment of cancer results in a reduction in the rate of tumor growth. Preferably, the tumor growth rate is reduced by at least 5% relative to the pre-treatment tumor growth rate after treatment; more preferably, the tumor growth rate is reduced by at least 10%, and more preferably by at least 20%. , reduce by at least 30%, more preferably, by at least 40% 'better' by at least 50% 'even -46- 201215610 better by at least 5 Ο %, and optimally reduce by at least 7 5 % . The tumor growth rate can be measured by any reproducible measurement. In a preferred aspect, the tumor growth rate can be measured based on changes in tumor diameter per unit time. On the other hand, treating cancer leads to a reduction in tumor regrowth. Preferably, after treatment, the tumor regrowth is less than 5%; more preferably, the 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%; even more preferably less than 0 50%; and optimally, less than 75%. Tumor regrowth can be measured by any reproducible measurement. In a preferred aspect, tumor regrowth can be measured, for example, by measuring an increase in tumor diameter after previous tumor shrinkage after treatment. A decrease in tumor regrowth indicates that the tumor cannot relapse after treatment has stopped. On the other hand, treatment or prevention of cell proliferative diseases results in a decrease in the rate of cell proliferation. Preferably, after treatment, cell proliferation is reduced by at least 5%; more preferably, at least 1%; more preferably, at least 20%; more preferably, at least 30%; more preferably, at least 40%; Good, at least 50%; even better Q, at least 50%; and optimally at least 75%. The rate of cell proliferation can be measured by any reproducible measurement. In a preferred aspect, the rate of cell proliferation can be measured, for example, by measuring the number of dividing cells in a tissue sample per unit time. On the other hand, the treatment or prevention of cell proliferative diseases results in a decrease in the proportion of proliferating cells. Preferably, after treatment, the proportion of proliferating cells is reduced by at least 5%; more preferably, at least 1%; more preferably, at least 20%; more preferably, at least 30%; more preferably, at least 40 °/〇; more preferably, at least 50%; even more preferably at least 50%; and optimally at least 75%. The proportion of proliferating cells can be measured by any reproducible measurement method -47- 201215610. A greater ratio is measured, for example, by quantifying the number of undivided cells in a tissue sample. Another preferred aspect may be equal to the mitotic index. On the other hand, the number of areas or regions for treating or preventing cell proliferation is reduced. Preferably, the size of the area or region of birth is 5% compared to its treatment; more preferably, at least 1% reduction; more preferably, preferably, at least 30% reduction; more preferably, reduction to at least reduction 50%; even better, reduce at least 75% less. The measurement of the area of cell proliferation or the size of the area is measured. In a preferred aspect, the cell can increase the diameter or width of the area or region of cell proliferation. On the other hand, the number or proportion of cells that treat or prevent the appearance or morphology of the cell proliferative is reduced. The number of cells having an abnormal morphology is 5% less than that of the treatment; more preferably, at least 10%; more preferably, at least 30%; more preferably, less, less than 50%; Even better, reduce to at least 75%. Measurement of abnormal cell appearance or morphology. On the one hand, abnormal cells (for example using a reverse phase tissue culture microscope) are measured. The cell morphology can take the form of nuclear polymorphism. As used herein, the term "selectively" is preferred in that the number of proliferating cell fissure cells is relative to that of proliferating cells. After the disease causes cell proliferation therapy, the size of the cell growth is reduced by at least 20%; less 40%. More preferably, 50%; and the best reduction can be measured by any reproducible area or area size. The disease results in an abnormally better, the number of pre-treatment treatments is reduced to at least 20%; at least 40%; more preferably 50%; and optimally by any reproducible form Microscopy On the one hand, the anomalous fine representation tends to occur more frequently in one population -48-201215610 than in another group. On the one hand, the compared population is the cell population. In a preferred aspect, the compound of Formula III, Ilia, IVa, IVb, Va or Vb or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof selectively acts on cancer cells or pre-cancerous cells But does not act on normal cells. In another preferred aspect, the compound of Formula 111, 111 a, IV a, IV b , Va or Vb, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, selectively acts to modulate one Molecular targets (eg, 'c-Met), but do not significantly modulate another molecular target (eg, protein kinase C). In a preferred aspect, the invention provides a method of selectively inhibiting the activity of an enzyme, such as a kinase. Preferably, if an event occurs more than twice as frequently in population A than in group B, then preferably the event occurs selectively in population A relative to group B. More preferably, if an event occurs more than five times more frequently in ethnic group A, then the event occurs selectively. More preferably, an event occurs more than ten times more frequently in ethnic group A than in ethnic group B; more preferably greater than 50 times more frequently in ethnic group a than in ethnic group B; even more preferably greater than 100 The event occurs selectively when it is optimally greater than 1,000 times. For example, if cell death in cancer cells occurs more than twice as frequently as normal cells, cell death can occur selectively in cancer cells. In a preferred aspect, a compound of formula III, Ilia, IVa, IVb, Va or Vb or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof modulating a molecular target (eg, c-Met) Activity. In one aspect, regulation refers to stimulating or inhibiting the activity of a molecular target. Preferably, a compound of the formula -49-201215610 III, Ilia, IVa, IVb, Va or Vb stimulates or inhibits the molecular target relative to the activity of the molecular target in the absence of the compound under the same conditions. When the activity is at least 2 fold, the compound preferably modulates the molecular target activity. More preferably, a compound of formula I, Ilia, IVa, IVb, Va or Vb stimulates or inhibits the activity of the molecular target at least 5 times for the activity of the molecular target in the absence of the compound under the same conditions. At least 10 times, at least 20 times, at least 50 times, at least 100 times, the compound modulates the activity of the molecular target. The activity of the molecular target can be measured by any reproducible method. The activity of the molecular target can be measured in vitro or in vivo. For example, the activity of a molecular target can be measured in vitro by enzyme activity assay or DN A binding assay, or the activity of a molecular target can be measured in vivo by analyzing the expression of the reporter gene. In one aspect, Formula III, Ilia, IVa, IVb, if the addition of the compound does not stimulate or inhibit the activity of the molecular target by more than 1% relative to the activity of the molecular target in the absence of the compound under the same conditions. The compound of Va or Vb or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof does not significantly modulate the activity of the molecular target. In a preferred aspect, the compound of formula III, Ilia, IVa, IVb, Va or Vb does not significantly modulate the activity of protein kinase C. As used herein, the term "synergy enzyme selectivity" means that the first isoform of the enzyme is preferentially inhibited or stimulated compared to the second isoform of the enzyme (eg, compared to the kinase isozyme beta, which is preferred). Inhibiting or stimulating the kinase isozyme 〇〇. Preferably, the compound of formula III, Ilia, IVa, IVb, Va or Vb demonstrates a minimum of 4 fold difference in the dose required to achieve a biological effect, preferably 10 The difference is more preferably 50 times different. Preferably, the compound of the formula -50 - 201215610 III, Ilia, IVa, IVb, Va or Vb demonstrates this difference in the range of inhibition and the molecular label of interest The difference in target is exemplified by IC5Q (i.e., 50% inhibition). In a preferred system, a compound of formula III, Ilia, IVa, IVb, Va or Vb or a pharmaceutically acceptable salt thereof, Administration of a drug, metabolite, analog or derivative to a cell or subject in need thereof results in modulation (i.e., stimulation or inhibition) of the activity of c-Met. As used herein, the activity of c-Met 0 Refers to any biological function or activity performed by c-Met. For example, c- The function of Met includes phosphorylation of downstream target proteins. Other functions of c-Met include autophosphorylation, adaptor proteins (such as Gab-1, Grb-2, She, SHP2, and c-Cbl). Activation of binding and signal transductions (such as Ras, Src, PI3K, PLC-γ, STATs, ERK 1 and 2, and FAK). The c-Met knockout has been shown to inhibit cancer cells in a cell type-specific manner. Growth. 1^108-\18-231, :^(:1-11661::^(:1-H441, MIA PaCa-2, HT29, and MKN-45 human cancer cells. c-Met base cause knockout Caspase-dependent apoptosis is induced in a cell type-specific manner. Accordingly, the present invention relates to the treatment of cell proliferative diseases in which the cells exhibit high amounts of c-Met or exhibit active c-Met. In a preferred system, a compound of formula III, Ilia, IVa, IVb, Va or Vb, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, is administered to a cell or subject in need thereof A modulatory effect (ie, stimulation or inhibition) that results in the activity of ERK 1 or ERK 2 or both. As used herein, E The activity of RK 1 or ERK 2 refers to any biological function or activity by ERK 1 or ERK 2. For example, the functional package of ERK 1 or ERK 2 -51 - 201215610 includes phosphorylation of a downstream target protein. Activation refers to the state in which a composition of a substance (eg, a protein or nucleic acid) is in a state suitable for performing the desired biological function. On the one hand, the composition of the substance that can be activated also has an unactivated state. In one aspect, the activating composition of the substance can have a biological function that inhibits or stimulates or both. In one aspect, elevated refers to increasing the desired biological activity of a composition of a substance (e.g., a protein or nucleic acid). Elevation can occur by increasing the concentration of the constituents of the substance. As used herein, "cell cycle checkpoint pathway" refers to a biochemical pathway involved in the regulation of a cell cycle checkpoint. The cell cycle checkpoint pathway can have a stimulatory or inhibitory effect or both on one or more functions comprising cell cycle checkpoints. The cell cycle checkpoint pathway consists of a composition of at least two substances, preferably proteins, which contribute to the regulation of cell cycle checkpoints. The cell cycle checkpoint pathway can be activated by activation of one or more members of the cell cycle checkpoint pathway. Preferably, the cell cycle checkpoint path is preferably a biochemical communication pathway. As used herein, "cell cycle checkpoint modulator" refers to a composition of a substance that has at least a portion of the function of regulating cell cycle checkpoints. The cell cycle checkpoint modulator can have a stimulatory or inhibitory effect or both on one or more functions comprising a cell cycle checkpoint. In one aspect, the cell cycle checkpoint modulator can be a protein. On the other hand, cell cycle checkpoint modulators are not proteins. In one aspect, treating cancer or a cell proliferative disorder results in cell death, and preferably, cell death results in a reduction in the number of cells in the population by at least 10% -52 - 201215610. More preferably, cell death means a reduction of at least 20%; a better reduction of at least 30%; a better reduction of at least 40%; and a reduction of at least 50°/. ; optimally reduce by at least 75%. The number of cells in the population can be measured by any reproducible method. The number of cells in the population is measured by fluorescence activated cell sorting (FACS). On the other hand, the number of cells in the ethnic group is measured by immunofluorescence microscopy. On the other hand, the number of cells in the population is measured by optical microscopy. On the other hand, a method for measuring cell death f) is shown in Li et al. (2003) Proc Natl Acad Sci USA · 1 00(5): 2674-8. On the one hand, cell death occurs through apoptosis. In a preferred aspect, an effective amount of a compound of formula III, Ilia, IVa, IVb, Va or Vb or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof is not significantly cytotoxic to normal cells. A compound that is therapeutically effective will not be significantly cytotoxic to normal cells if the compound is administered in a therapeutically effective amount without inducing cell death of greater than 10% of normal cells. A therapeutically effective amount of a compound does not significantly affect the viability of normal cells if the compound is administered in a therapeutically effective amount without inducing cell death of greater than 10% of normal cells. On the one hand, cell death occurs through apoptosis. In one aspect, the cell is contacted with a compound of Formula III, Ilia, IVa, IVb, Va or Vb or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, selectively induced in cancer cells Or activate cell death. Preferably, a compound of the formula III, Ilia, IVa, IVb, Va or Vb or a pharmaceutically acceptable salt, prodrug, metabolite, analogue or derivative thereof is administered to a subject in need thereof, in a cancer cell Selectively induce or activate cell death. In another aspect, contacting the cell with a compound of Formula III, Ilia, IVa, IVb, Va or Vb-53-201215610, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, in one or A variety of cells affected by cell proliferative diseases selectively induce cell death. Preferably, a compound of the formula III, Ilia, IVa, IVb, Va or Vb or a pharmaceutically acceptable salt, prodrug, metabolite, analogue or derivative thereof is administered to a subject in need thereof, in one or A variety of cells affected by cell proliferative diseases selectively induce cell death. In a preferred aspect, the invention relates to a method of administering a compound of formula III, Ilia, IVa, IVb, Va or Vb or a pharmaceutically acceptable salt, prodrug, metabolite, analogue or derivative thereof to A method of treating or preventing cancer in need thereof, wherein administration of a compound of Formula III, Ilia, IVa, IVb, Va or Vb results in one or more of the following: cells accumulate in the G1 phase and/or S phase of the cell cycle, There is no significant amount of cell death cytotoxicity in normal cells, anti-tumor activity in animals with a therapeutic index of at least 2, and activation of cell cycle checkpoints via cell death in cancer cells. As used herein, "therapeutic index" is the maximum tolerated dose divided by the effective dose. Those skilled in the art can refer to the general reference text for a detailed description of known techniques or equivalent techniques discussed herein. The texts include A m u s a b 1 e et al., C u r r e n t P r o t 〇 c ο 1 s i η ο ο 1 e c u 1 a r B i ο 1 〇 g y, John Wiley and Sons, Inc.  (2005); Sam brook et al.

Molecular Cloning, A Laboratory Manual (3rd Edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Collagen et al, Current Protocols in Immunology, John Wiley & Sons, NY I Anna et al., Current Protocols In Pharmacology, John Wiley & Sons, NY ; Final et al, -54- 201215610

The Pharmacological Basis of The rapeutics (1 975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18 (1990). Of course, these texts are also referred to when conducting or using the ideas of the present invention. 2. Pyrroloquinolinyl-pyrrole-2,5-dione and pyrroloquinolinyl-pyrrolidine-2,5-dione Q Formula III and Ilia pyrroloquinolinyl-pyrrole 2,5- Diketone compound

Wherein: Ο 111, 112 and 113 are independently selected from the group consisting of hydrogen, 1?, <^1, 81', 1, -NR5R6, -(Ci-C6)alkyl, -(Ci-C6) , -(C3-C9)cycloalkyl, -(C3-C9) substituted ring, -〇-(ci_c6)alkyl, -〇-(Ci-Cd substituted alkyl, -〇_ (C3-C9) ring group and - 〇-(c3_c9) group of substituted cycloalkyl, aryl, heteroaryl, heterocyclic groups; R4 is independently selected from hydrogen, _(Cl_C6) Group of _CH2R7; R5 and R6 are independently selected from the group consisting of hydrogen and _(Cl_C6) yards; -55- 201215610 R7 is independently selected from -0-Ρ (= 0) (0Η2), -0-Ρ( = 0)(-0Η)(-0-(Ci-C6) ^ S ) ' -O-PpOK-O-iCi-Ce)alkyl)2 ' -O- p( = o) (-oh)(-o-(ch2)-phenyl), -op(=o)(-o-(ch2)-phenyl)2, a carboxylic acid group, an aminocarboxylic acid group and a group consisting of peptides; the Q group is selected from the group consisting of a aryl group, a heteroaryl group, a -〇-square group, an -S-aryl group, an -0-heteroaryl group, and a -S-heteroaryl group; Is selected from the group consisting of -(CH2)-, -(NR8)-, S and 0; R8 is independently selected from hydrogen, -(CrCfi)alkyl, -(c^-Cs) Alkyl, -(C3-C9)cycloalkyl, -(C3-C9) substituted cycloalkyl, and -0-(Ci-C6), -C(=0)-0-(Ci- C6) a group consisting of -C(=0)-0_(CrCd substituted alkyl group; Y system selected from the group consisting of -(ch2)- or a bond; wherein the aryl group, heteroaryl The group, -〇-aryl, -S-aryl, _〇_heteroaryl or -S-heteroaryl group may be substituted by one or more substituents independently selected from F, Cl, Br, I, -NR5R6, -(CpCe), -(Ci-C6) substituted, -(C3-C9) ring, -(c3-C9) substituted cycloalkyl, - 〇-(<^-(:6)alkyl,-0-(Κ6) substituted substituted, · o-(c3-c9)cycloalkyl, -o-(c3-c9) substituted ring Alkyl, aryl, _aryl-(Ci-C6), aryl-O-C(Ci-C6), aryl, (C1-C4), aryl, quaternary a group consisting of a heterocyclic group, a terpenyl ring, and a -(SbOhhiCi-C6)alkyl group; and m is 1 or 2. For a compound of the formula Ilia, the Q system is selected from the group consisting of an aryl group, a heteroaryl group, and a group consisting of 〇_aryl, _S-aryl, -0-heteroaryl and -S_heteroaryl-56-201215610, the prerequisite of which is when R4 is hydrogen or In the case of a CrCd alkyl group, Q is not a 3-indenyl group or a substituted 3-indenyl group. The pyrroloquinolinyl-pyrrolidine-2,5-dione compound of the formula 1 ¥3, 1 ¥1?, ¥& or ¥1) is:

among them:

R1, R2 and R3 are independently selected from the group consisting of hydrogen, F, cl, Br, _NR5R6, -(Ci-C6) alkyl, -(Ci-C6) substituted, -(C3-C9) ring Alkyl, -(c3-c9) substituted cycloalkyl, -〇-(Ci-c6)alkyl, -oxime-(CrCd substituted alkyl,-0-(C3-C9)cycloalkyl and a group consisting of a substituted cycloalkyl, aryl, heteroaryl, heterocyclic group; R4 is independently selected from hydrogen, -(Ci-C6)alkyl, -CH2R7 a group consisting of; R5, R6 are independently selected from hydrogen or - (Ci_C6) group consisting of 201215610 R7 are independently selected from -0-Ρ(= 〇)(〇η2;), -0 -p( = 0)(-OH)(-CMq-Cd alkyl),-0-P(=0)(-0-(Cl-C6)alkyl)2,-0-P( = 〇)( -oh)(-o-(ch2)-phenyl), -op(=o)(-〇_(CH2)-phenyl)2, a carboxylic acid group, an aminocarboxylic acid group and a peptide Group; Q is selected from the group consisting of aryl, heteroaryl, -O-aryl, -S-aryl, -〇-heteroaryl, and -S-heteroaryl; X is selected from - a group consisting of (CH2)-, -(NR8)-, s and oxime; R8 is independently selected from hydrogen, -(CrCd alkyl, -(Ci-CJ substituted alkyl, -(C3-C9 ) cycloalkyl, - (C3-C9) substituted cycloalkyl, and -0-(Ci-C6) yard, -(^( = 0)-0-((^-(^6)) and -C( = 〇 a group consisting of -C-(:6) substituted alkyl bond; Y group selected from the group consisting of -(ch2)- or a bond; wherein the aryl group, heteroaryl group, - The 0-aryl, -S-aryl, -fluorene-heteroaryl or -S-heteroaryl group may be substituted by one or more substituents independently selected from F, Cl, Br, I , -NR5R6, -(C!-C6)alkyl, -substituted alkyl, -(C3-C9)cycloalkyl, -(C3-C9) substituted cycloalkyl, alkyl, -CMQ- Cd substituted alkyl, -〇-(C3-C9)cycloalkyl, -〇-(C3-C9) substituted cycloalkyl, -aryl, _aryl-(Ci-Cd alkyl, - Aryl-0-((^-(^6)alkyl, -〇-aryl,-0-(d-CU)alkyl-aryl, heteroaryl, heterocyclyl, alkyl-heterocyclic and a group consisting of -(spcoo^Ci-C6)alkyl; and m is 1 or 2. The preparation of a compound of formula III, Ilia, IVa, IVb, Va or Vb is described in International Application PCT/US20 1 0 /023 8 93, the entire contents of which are incorporated herein by reference. 2.1 Definitions The term "alkyl" refers to a group containing carbon and hydrogen and having no unsaturation. The alkyl group can be straight or branched. Typical alkyl groups include, but are not limited to, decyl, ethyl 'propyl, isopropyl, hexyl, tert-butyl, secondary butyl, and the like. The thiol group may be represented by a range, and thus, for example, the (Ci-C6) fluorene group means an alkyl group having 1 to 6 carbon atoms in a linear or branched alkyl skeleton. The substituted and unsubstituted alkyl group may independently be (C!-c5)alkyl, (C丨-C6)alkyl, (C丨-Cio)alkyl, (c3-c丨〇) alkane. Or a (C5-C1Q) alkyl group. The term "alkyl" does not include "cycloalkyl" unless explicitly stated. "Cycloalkyl" group refers to a cyclic alkyl group having the indicated number of carbon atoms in the "ring moiety", wherein the "ring moiety" may be composed of one or more fused, spiro or bridged rings composition. For example, a C3 to C6 cycloalkyl group (e.g., (C3-O Ce)cycloalkyl) refers to a ring structure having from 3 to 6 carbon atoms in the ring. When no range is specified, the cycloalkyl group has from 3 to 9 carbon atoms ((C3-C9) cycloalkyl group) in the ring portion. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl. Preferably, the cycloalkyl group has three, four, five, six, seven, eight, nine or from three to nine carbon atoms in the ring structure. The term substituted alkyl and substituted cycloalkyl refers to alkyl and cycloalkyl groups as defined above substituted by one or more substituents independently selected from fluoro, aryl, heteroaryl. a group consisting of -CMCi-Cs)alkyl or -NR5R6 -59- 201215610, wherein R5 and R6 are independently selected from the group consisting of hydrogen and -(q-Cd alkyl. The term "aryl" "" refers to an aromatic carbocyclic group having one, two or three aromatic rings. Typical aryl groups include, but are not limited to, phenyl, naphthyl, and the like. The aryl group includes one or more An additional non-aromatic carbocyclic or heterocyclic fused, one or two or three aromatic ring structures of 4 to 9 members. Examples of fused aryl groups include benzocyclobutenyl, indanyl, and tetra Hydronylnaphthyl, 1,2,3,4-tetrahydrophenanthryl, tetrahydroindenyl, 1,4-dihydro-1,4-methylnaphthyl, benzodioxolyl. "Heteroaryl" refers to a heteroaromatic (heteroaryl) group having one, two or three aromatic rings containing from 1 to 4 heteroatoms (such as nitrogen, sulfur or oxygen). Heteroaryl groups include one or more having 4-9 members An additional non-aromatic ring is fused to one, two or three aromatic ring structures containing from 1 to 4 heteroatoms. Heteroaryl groups containing a single type of heteroatom in the aromatic ring are included The hetero atom type indicates that the nitrogen-containing heteroaryl group, the oxygen-containing heteroaryl group, and the sulfur-containing heteroaryl group respectively represent a heteroaromatic group containing one or more nitrogen, oxygen or sulfur atoms. Typical heteroaryl groups These include, but are not limited to, pyridyl, pyridinyl, triazolyl, quinolyl, quinoxalinyl, thiazolyl, benzo[b]phenylthio, furanyl, imidazolyl, fluorenyl, and the like. "Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated, stable non-aromatic ring structure which can be fused, fused or bridged to form an additional ring. Each heterocyclic ring system consists of one or more a carbon atom and consisting of 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur. "Heterocyclyl" or "heterocycle" includes a stable non-aromatic 3 to 7 membered monocyclic heterocyclic ring structure and 8 to 11 Bicyclic heterocyclic ring structure. Heterocyclyl-60-201215610 Groups can be attached to any internal ring carbon or nitrogen atom which results in a stable structure. Heterocycles include 3-7 membered monocyclic heterocycles (more preferably 5 to 7 membered monocyclic heterocycles) and 8 to 10 membered bicyclic heterocycles. Examples of such groups include piperidinyl, piperidinyl, pyran. Base, pyrrolidinyl, morpholinyl, thiomorpholinyl, oxetoxypiperidinyl, oxoperyrrolidinyl, oxoxime, oxime, isoxazolyl, tetraterpenoid

Hydropyranyl, tetrahydrofuranyl, bisoxazolyl, dioxin, oxathiolyl, dithiolyl, cyclobutenyl, dioxo, dioxolane Base, tetrahydrofuro-dihydrofuranyl, tetrahydrofuran dihydro-furanyl, indanylpyranyl, tetrahydrofurofuranyl, tetrahydropyranopylfuran, quinuclidinyl (1-azabicyclo[ 2.2.2] 辛院基) and tropyl (8-methyl-8-azabicyclo[3.2.1]octyl). For the purposes of a Q substituent, the term "substituted 3 - fluorenyl" refers to a 3-indenyl group substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, -NR5R6, -(C 丨-C6)alkyl, -(Cl_c6) substituted fluorenyl, -(c3-c9) ring-based, -(c3-c9) substituted ring-based, 〇(c C6) alkyl, substituted alkyl, -0(C3_c9)cyclodecyl, fluorene-(C3-C9) substituted cycloalkyl, -aryl, -aryl_(Ci_C6), _ 芳a group consisting of -O-aryl, heterocyclyl, -(MCrCU)alkyl-heterocycle and =alkyl; wherein R5, R6 are independently selected from nitrogen and 6-(Ci-Ce) alkane Group of groups. For the purpose of R7 substituents, the term 'carboxylic acid group' means _〇_CpOHCi-Ce), 〇-C( = 〇)-(C3-C9) Base, _〇cBu aryl, _〇-C(= 〇)-heteroaryl, -0_C(= 0)_heterocycle, _〇cbu-61 - 201215610 c6)alkyl-aryl, = alkane a group of a hetero-heteroaryl or _〇_(:( = 〇)_(C^C:6)alkyl-heterocyclic ring group, including a "carboxylic acid group," which is one or more substituted The base is substituted by -04( = 0)-((^-(:6)alkyl,-0-c( = 0)-(C3-C9)cycloalkyl, _〇_c(=0)_aryl,-0_(:(= 〇)_heteroaryl, -〇·c(=o)-heterocycle,- 〇_c( = 0)_(Cl_c6)alkyl-aryl, -〇-C( = 0)_(Cl·C6), ortho-aryl or _0_c( = 0)_(Cl_c6)alkyl a heterocyclic form of the group 'The substituent is independently selected from the group consisting of F, Cl, Br, fluorene, -OH, -SH, -NR5R6, fluorenyl-(:6)alkyl, -(C,-.) Substituted alkyl, -(C3-C9)cycloalkyl, -(C3-C9) substituted cycloalkyl, -O-CC^-Ce)alkyl,-0-(CrCd substituted alkyl, _s_(Cl-c6)alkyl, -〇_(C3_C9)cycloalkyl,-0-(C3-C9) substituted cycloalkyl, -aryl, -〇-aryl, -〇-(Ci- C4) alkyl-aryl, heteroaryl, heterocyclic, -〇-(Cl_C4)alkyl-heterocycle, -(S(= 〇)2)_(Cl_c6)alkyl, -NH-C( = a group of NH)-NH2 (eg, fluorenyl), -COOH, or -c(= 〇)-NR5R6, wherein R5 and R6 are independently selected from the group consisting of hydrogen and -(G-Ce)alkyl Further, for the purposes of the R7 substituent, the term "amino carboxylic acid group" refers to a carboxylic acid group, including a carboxylic acid group substituted with one or more substituents described above, the carboxylic acid group having a Or more An independently selected amino group of the form -NR5R6 wherein R5 and R6 are independently selected from the group consisting of hydrogen and (C^-Cs)alkyl. In one system of the invention, R7 is a- Amino acid or imido acid, including but not limited to alanine, arginine, aspartic acid, aspartic acid, cysteine, glutamic acid, glutamic acid, glycine, group Aminic acid, isoleucine, leucine, lysine, methionine, phenylalanine, valine, silk-62-201215610 acid, sulphate, tryptophan, tyrosine, guanamine An acid or a stereoisomer or a racemic mixture thereof. In another system of the invention, R7 is selected from the group consisting of L-alanine, L-arginine, L-aspartic acid, L-aspartic acid, L-cysteine, L-bran Amine acid, L-glutamic acid, L-glycine, L-histamine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-amphetamine Alpha-amino acid or imine consisting of acid, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine or L-proline Base acid. For the purposes of the R7 substituent, the term "peptide" refers to a dipeptide, tripeptide, tetrapeptide or pentapeptide which, when hydrolyzed, releases two, three, four or five amino acids or imido acids, respectively (eg Proline). For the purpose of R7, the peptide is linked to other parts of the molecule via an ester linkage. In one system, the peptide of R7 consists of an alpha-amino acid or an imido acid, including but not limited to alanine, arginine, aspartic acid, aspartic acid, cysteine, bran Proline, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, valine, serine, threonine, color Aminic acid, guanyl tyrosine, valine or a stereoisomer or racemic mixture thereof; and in preferred versions of the system, the carboxyl group participating in the ester bond is the carboxyl terminal COOH group of the peptide Not a side chain carboxyl group. In another system of the invention, R7 is selected from the group consisting of L-alanine, L-arginine, L-aspartic acid, L-aspartic acid, L-cysteine, L-bran Amine acid, L-glutamic acid, L-glycine, L-histamine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-amphetamine Α-amino acid or imine consisting of acid, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine or L-proline The base acid; and in a more preferred version of this preferred system, the carboxyl group participating in the ester bond is the carboxyl group-terminal COOH group of the peptide-63-201215610. 2.2 Preferred Compounds Included in the preferred system are Formula III, Ilia, IVa, IVb, Va or

a compound of Vb wherein Q is selected from the group consisting of aryl, heteroaryl, -〇-aryl, -S-aryl, -〇-heteroaryl and -S-heteroaryl, preconditions thereof Q is not a 3-mercapto group or a substituted 3 吲哚 group. In other preferred systems, Q is selected from the group consisting of aryl, heteroaryl, -〇-aryl, -S-aryl,-0-heteroaryl and -S-heteroaryl, the prerequisite The condition is that when R 4 is hydrogen 'cycloalkyl or alkyl, 'Q is not a 3-indenyl group or a substituted 3-indenyl group. In other still preferred systems, the Q system is selected from the group consisting of aryl, heteroaryl, -O-aryl, -S-aryl,-0-heteroaryl, and -S-heteroaryl. The prerequisite is that when R4 is hydrogen, (C3-C4)cycloalkyl or (CrCO alkyl, then Q is not 3-indenyl or substituted 3-indolyl. In another preferred system And Q is a 3-indenyl or substituted 3-indenyl group, the prerequisite of which is that R4 is not hydrogen, a cycloalkyl or an alkyl group. In another still preferred system, Q is a 3-indenyl group. Or a substituted 3-indenyl group, the prerequisite is that R4 is not hydrogen, (C3-C4)cycloalkyl or (Ch-Cd alkyl. Other preferred systems include formula III, Ilia, IVa, IVb, Va Or a compound of Vb wherein R4 is ·CH2R7. These compounds can be used as prodrug forms of the compound wherein R4 is 对应 of the corresponding oxime, Ilia, IVa 'IVb, Va or Vb. The prodrug form is hydrolyzed by hydrolysis And releasing the corresponding compound wherein R4 is oxime. The hydrolysis can be carried out by preparing an enzyme-catalyzed or non-enzymatic pathway corresponding to the hydroxymethylene derivative, which in the subsequent hydrolysis causes -64 - 201215610 to release R4 a compound of hydrazine. In the preferred system, 'thinks -CH2R7, where R7 is -〇-ρ( = 〇)(οη)2, -〇-Ρ( = 〇)(_ΟΗ)(-〇-(c丨-c6)alkyl) or - 〇-p( = 〇)(-〇-(Ci_C6) yard base) 2 ° in which " is -0-P( = 0)〇0-(Ci-C6) yard base) In the system of 2, the radical group is independently selected. In another preferred system, 'R4 is _CH2R7, wherein R7 is a carboxylic acid group or an aminocarboxylic acid group. In another preferred system Wherein R7 is in the form; wherein in a better system the peptide is linked to the remainder of the compound via an ester bond formed with the hydroxyl end C00H0 group of the peptide chain. In Formula 111, Ilia, IVa, Other preferred individual and independent systems of compounds of IVb, Va or Vb, wherein R4 is -CH2R7 and R7 is a peptide'. The peptide may be a dipeptide, a tripeptide, a tetrapeptide or a pentapeptide. The R7 functional peptide Preferred amino acid compositions are described above. Systems of compounds of formula III, Ilia, IVa, IVb, Va or Vb include those wherein X is selected from the group consisting of -(NR8)-, S or hydrazine, Wherein R8 is independently selected from the group consisting of hydrogen, -(G-C6)alkyl, -(Mountain-(:6) substituted ϋ a group consisting of alkyl, -(C3-C9)cycloalkyl, -(c3-c9) substituted cycloalkyl and -0-(Q-C6)alkyl. Formula III, Ilia, IVa, IVb Other systems of compounds of Va or Vb include those wherein - is -CH2-. In the system of compounds of formula III, Ilia, IVa, IVb, Va or Vb, 'X is oxygen (oxime). In other systems of other compounds of formula III, Ilia, IVa, IVb, Va or Vb, 'X is sulfur (S). In other systems of compounds of formula III, Ilia, IVa, IVb, Va or Vb, further _^118)-, wherein R8 is independently selected from hydrogen, -(Κ6)alkyl, _(Cl_c6) a group consisting of an alkyl group, a (c3-c9) ring-based group, a -(c3-c9) substituted cycloalkyl group or a _0_(Cl_C6)alkane-65 - 201215610 group. Other preferred systems of the invention include compounds of formula III or Ilia wherein Q is a heteroaryl or optionally substituted heteroaryl group. In four individual preferred preferred systems of the compound of formula III or 111a, Q is an optionally substituted monocyclic heteroaryl group, optionally substituted bicyclic heteroaryl group, with the proviso that The bicyclic heteroaryl group is not a fluorenyl or substituted fluorenyl group or a optionally substituted tricyclic heteroaryl group. Random substituents, when present, are independently selected from the group consisting of such aryl, heteroaryl, -fluorene-aryl, -s-aryl,-0-heteroaryl or -S-heteroaryl. Compounds of formula IVa, IVb, Va or Vb are included in the preferred embodiment of the invention wherein Q is a heteroaryl or optionally substituted heteroaryl group. In four individual preferred embodiments of the compound of Formula IVa, IVb, Va or Vb, Q is an optionally substituted monocyclic heteroaryl group, optionally substituted bicyclic heteroaryl group, It is a prerequisite that the bicyclic heteroaryl group is not a fluorenyl group or a tricyclic heteroaryl group which is optionally substituted. In a preferred system, Q is an optionally substituted nitrogen-containing heteroaryl group. In the related system, q is an optionally substituted thiol group. The optional substituents, when present, are independently selected from the aryl, heteroaryl, -indolyl, -S-aryl,-0-heteroaryl or -S-heteroaryl groups. Preferred systems of the invention include mixtures of the compounds of formula IVa and IVb, including racemic mixtures. In another preferred embodiment, the compound of Formula 1 V a and 1 V b is (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinoline _ Individual mirror image isomers of 4-(1-indole-3-yl)pyrrolidine-2,5-dione. In this system, (士)-cis-3-(5,6-dihydro-4Η-pyrrolo[3,2,l-ij]quino-66 - 201215610 phenyl-1-yl)-4-(1Η -Indole-3-yl)pyrrolidine-2,5-dione is prepared as a mixture starting from the starting materials 1,2,3,4-tetrahydroquinoline and indole-3-ethylamine. . 'H 3,4·tetrahydroquinoline was converted to 5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinolin-1-yl as described in Steps 1-5 of Example 1. Methyl glyoxylate. The methyl 5,6-dihydro-4H-pyrrolo[3,2,1-U]quinolin-1-yl)glyoxylate is as described in Step 6 of Example 1 with 吲哚-3-B Indoleamine reaction to produce 3-(5,6-dihydro-4H-pyrrolo[3,2,1-indolyl]quinolin-1-yl)-4-(1Η-吲0 哚-3-yl) Pyrrole-2,5-dione. The (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinine was prepared by catalytic hydrogenation using Step B as described in Example 2. Mixture of -1-yl)-4-(1Η-indol-3-yl)pyrrolidine-2,5-dione. Preferred systems of the invention also include mixtures of compounds of formula Va and Vb, including racemic mixtures. In another preferred embodiment, the compound of formula Va and Vb is (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinoline-l-yl ) Individual image isomers of -4-(lH-indol-3-yl)pyrrolidine-2,5-dione. In this system, the compounds are prepared by first preparing (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinolin-1- A mixture of 4-(1Η-indol-3-yl)pyrrolidin-2,5-dione is prepared. The mixture of cis compounds was then treated as a mixture of potassium tert-butoxide in tertiary butanol to give (±)-trans-3-(5,6-dihydro-4H- as described in Example 3. Mixture of pyrrolo[3,2,l-ij]quinolin-1-yl)-4-(1Η-indol-3-yl)pyrrolidine-2,5-dione. All stereoisomers of the compounds of the present invention are contemplated, whether in mixed or pure or substantially pure form, including the crystalline form of the racemic mixture of -67-201215610 and the crystalline form of the individual isomers. The definition of a compound according to the invention includes all possible stereoisomers (e.g., the R and S configurations of each asymmetric center) and mixtures thereof. This definition specifically includes racemic forms and the isolated optical isomers having a particular activity. The racemic form can be resolved by physical methods such as, for example, fractional crystallization, separation or crystallization of a non-imagewise derivative, separation by palm column chromatography or supercritical fluid chromatography. The individual optical isomers can be obtained from the racemate by conventional methods, such as, for example, the formation of a salt with an optically active acid followed by crystallization. Additionally, all geometric isomers, such as the E- and Z-configurations of the double bonds, are included within the scope of the invention unless otherwise indicated. Certain compounds of the invention may exist in tautomeric forms. All such tautomeric forms of the compounds are considered to be within the scope of the invention unless otherwise indicated. The invention also includes a regioisomeric mixture of one or more analogs or derivatives. As used herein, the term "salt" is a pharmaceutically acceptable salt and may include acid addition salts, including hydrochlorides, hydrobromides, phosphates, sulfates, hydrogen sulfate, Alkyl sulfonates, aryl sulfonates, acetates, benzoates, citrates, maleates, fumarates, succinates, lactic acid Salts, and tartrates; alkali metal cations such as Na+, K+, Li+, alkaline earth metal salts such as Mg2+ or Ca2+, or organic amine salts. As used herein, the term "metabolite" means a metabolite of a compound of formula 111, 111 a, IVa, IVb, Va or Vb, or a pharmaceutically acceptable salt, analog or derivative thereof, which is shown and A similar in vivo activity of a compound of Formula III, Ilia, IVa-68-201215610, IVb, Va or Vb. As used herein, the term "prodrug" means covalently attached to one or more anterior moieties (such as a compound of the formula, Ilia, IVa, IVb, Va or Vb of an amino acid moiety or other water soluble moiety. Compounds of formula III, Ilia, IVa, IVb, Va or Vb may be hydrolyzed, oxidized and/or enzymatically released The mechanism is released from the previous part. In a system, the prodrug composition of the present invention exhibits an added benefit of increased water solubility, improved stability, and improved pharmacokinetic C) distribution. Pharmaceutical properties. For example, the anterior moiety (e.g., an amino acid moiety or other water soluble moiety such as a phosphate in R4) can be selected based on solubility, stability, bioavailability, and/or in vivo delivery or absorption. 3. Pharmaceutical Compositions and Formulations The pharmaceutical compositions of the present invention are formulated to be compatible with the route of administration desired. Examples of routes of administration include parenteral (e.g., intravenous, intradermal, subcutaneous), menstrual Oral (eg inhalation), transdermal (topical) and transmucosal administration. Solutions or suspensions for parenteral, intradermal or subcutaneous use may include the following ingredients: Sterile diluents such as water for injection, saline solution, fixed oils , polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl benzoate; antioxidants such as ascorbic acid or sodium hydrogen sulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as Acetate, citrate or disc acid salt and reagents for adjusting tension such as sodium chloride or glucose. The pH can be adjusted with an acid or a base such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be encapsulated in ampoules, Disposable syringes or multiple doses made of glass or plastic - 69 - 201215610 vials. The compounds or pharmaceutical compositions of the invention may utilize many of the current public therapeutic uses The method of the present invention is administered to a subject. For example, in order to treat cancer, the compound of the present invention can be directly injected into a tumor, injected into a bloodstream or a body cavity, or administered orally or applied to the skin with a patch. It should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects. The state of the disease (eg, cancer, pre-cancerous, etc.) and the patient should be closely monitored during the treatment period and during the reasonable period after treatment. The health condition. The term "therapeutically effective amount", as used herein, refers to an amount of an agent that is used to treat, ameliorate or prevent an identified disease or condition or to exhibit a detectable therapeutic or inhibitory effect. Detection is detected by any analytical method known in the art. The precise effective amount for the subject will depend on the subject's weight, body and health; the nature and extent of the symptoms; and the combination of treatments or treatments selected for administration. The therapeutically effective amount for a given condition can be determined by routine experience within the skill and judgment of the clinician. In a preferred aspect, the disease or condition to be treated is cancer. On the other hand, the disease or symptom to be treated is cell hyperplasia. For any compound, a therapeutically effective amount can be initially assessed, for example, by cell culture assays of tumor cells or often in animal models of rats, mice, rabbits, dogs or pigs. Animal models can also be used to determine the appropriate concentration range and route of administration. This information can then be used to determine the effective dose and route of administration to humans. Therapeutic/prophylactic efficacy and toxicity can be determined in standard cell procedures in cell culture or laboratory animals, such as ED5D (dose in 50% of the population - 70-201215610) and LD5G (lethal dose to 50% of the population) ). The dose ratio between toxicity and efficacy is the therapeutic index and can be expressed as the ratio LD5〇/ED5(). A pharmaceutical composition exhibiting a large therapeutic index is preferred. The dosage may vary within this range depending on the dosage form employed, the sensitivity of the patient, and the route of administration. Dosage and administration are adjusted to provide sufficient active agent level or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the general health of the subject, the age, weight and sex of the subject, foraging, time and frequency of administration, drug combination, response sensitivity, and tolerance to treatment/ reaction. The long-acting pharmaceutical composition can be administered once every three to four days, every week, or every two weeks, depending on the half-life and clearance rate of the particular formulation. The pharmaceutical composition comprising the active compound of the present invention can be produced in a generally known manner, for example, by conventional mixing, dissolving, granulating, dragee-making, buffing, emulsifying, encapsulating, capturing or lyophilizing methods. The pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, which comprise excipients and/or adjuvants which facilitate the processing of the active compound into pharmaceutically acceptable elixirs. Of course, the appropriate formulation will depend on the route of administration chosen. The pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (water-soluble) or dispersions and sterile powders for the preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating film (such as lecithin), by the maintenance of the required particle size in the case of dispersions, and by the use of an surfactant. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc.). In many cases, it is preferred to include an isotonic agent (e.g., a sugar), a polyhydric alcohol (such as mannitol, sorbitol), sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by the inclusion of agents which delay absorption in the compositions, such as aluminum monostearate and gelatin. The sterile injectable solution can be prepared by incorporating the active compound in the required amount with one or a combination of the above-mentioned ingredients in a suitable solvent, if necessary, followed by filtration sterilization. Generally, the dispersion is prepared by incorporating the active compound into a sterile vehicle containing the base dispersion medium and the other ingredients enumerated above. In the case of sterile powders for the manufacture of sterile injectable solutions, the methods of manufacture are vacuum drying and lyophilization which yields the active ingredient plus a powder of any additional desired ingredient from the previously sterile filtered solution thereof. Oral compositions typically include an inert diluent or an edible, pharmaceutically acceptable carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound may be combined with excipients and used in the form of lozenges, lozenges or capsules. Oral compositions can also be prepared using a fluid carrier as a mouthwash, wherein the compound in the fluid carrier is administered orally and rinsed and spit or swallowed. Pharmaceutically compatible adhesives and/or adjuvant materials can be included as part of the composition. Tablets, nine doses, capsules, diamond ingots and the like may contain any of the following ingredients or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth or gelatin; excipients such as starch or lactose; disintegrating agents such as alginic acid 'Primo gel, or corn starch; lubricants such as magnesium stearate or Strotes; slip agents such as colloidal cerium oxide; sweeteners such as sucrose or saccharin; or flavoring agents Such as mint, methyl salicylate or orange flavor. For administration via inhalation, the compound is delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant (e.g., a gas such as carbon dioxide), or a nebulizer. Systemic administration can also be achieved by penetrating the mucosa or penetrating the skin. For penetrating the mucosa or penetrating the skin, penetrants suitable for penetrating the barrier are used in this formulation. Such penetrants are generally known in the art and include, for example, for penetrating mucosal administration, detergents, bile salts, and fusidic acid derivatives. Penetrating mucosal administration can be accomplished via the use of nasal sprays or suppositories. For penetration through the skin, the active compound is formulated as an ointment, salve, gel or cream as is conventional in the art. In one aspect, the active compound is formulated with a pharmaceutically acceptable carrier that prevents rapid elimination of the compound from the body' such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable and biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods of preparing such formulations are apparent to those skilled in the art. Materials are also commercially available from Alza-73-201215610 and Nova Pharmaceuticals. The liposome suspension (including the liposome of the cells infected with the monoclonal antibody against the viral antigen) can also be used as a pharmaceutically acceptable carrier. These can be made in accordance with methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,81. It is especially advantageous to formulate oral or parenteral compositions in unit dosage form for ease of administration and uniformity of the dosage. Dosage unit form, as used herein, refers to a physically discrete unit that is suitable as a single dose for the subject to be treated; each unit comprises a predetermined amount of the activity in association with the desired pharmaceutical carrier calculated to produce the desired therapeutic effect. Compound. The specifications of the unit dosage form of the present invention are determined by the unique characteristics of the active compound and the particular therapeutic effect desired. In therapeutic applications, the dosage of the pharmaceutical composition used in accordance with the present invention is selected based on the agent, the age, weight and clinical symptoms of the patient being treated, and the experience and judgment of the clinician or practitioner who is being treated, and other effects. The dosage factor changes. Generally, the dose should be sufficient to cause tumor growth to slow down, and preferably resolve, and preferably also cause complete regression of the cancer. The dosage may range from about 1 mg/kg per day to about 3000 mg/kg per day. In a preferred aspect, the dosage can range from about 1 mg/kg per day to about 1000 mg/kg per day. In one aspect, the dosage will be from about 0.1 mg/day to about 50 g/day; from about 0.1 mg/day to about 25 g/day; from about 0.1 mg/day to about 1 g/day; about 〇, 1 mg/day Up to about 3 g/day; or about 0 = 1 mg/day to about 1 g/day, which is a single, divided or continuous dose (the patient's body weight in kilograms, in square meters) The surface area of the body and the age of the age are adjusted). An effective amount of the agent provides an objectively identifiable improvement as noted by the clinician or other qualified observer. For example, tumor regression in a patient can be referred to tumor diameter measurement. A decrease in tumor diameter indicates regression. Regression is also indicated by the fact that the tumor does not recur after stopping treatment. As used herein, the term "dose effective means" refers to the amount of active compound that produces the desired biological effect in an object or cell. Preferably, (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinolin-1-yl)-4-( 1H-indole-3 The pyridyl-2,5-dione is administered at a dose of 0 360 mg twice daily for a maximum daily dose of 720 mg. (-)-trans-3-(5,6-dihydro-411-pyrolo[3,2,1-indol]]quinolin-1-yl)-4-(111-indol-3-yl) The pyrrolidine-2,5-dione is optionally administered to the subject or patient twice a day at an initial dose of 1 mg, with a maximum daily dose of 20 mg, and the dose is gradually increased to a dose of 360 mg twice a day. The maximum daily dose is 720 mg. (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1-7]quinolin-1-yl)-4-(1^1-indol-3-yl) Preferred dosage forms of pyrrolidine-2,5-dione include, but are not limited to, caplets, lozenges, nine doses, and lyophilized powders. For example, a capsule of 3 60 mg of bismuth is administered to a subject or patient twice a day, or two 180 mg capsules are administered twice a day to achieve a maximum daily dose of 720 mg. (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinolin-1-yl)-4-(1Η-indol-3-yl)pyrrole The pyridine-2,5-dione capsules or lozenges can also be formulated to a 60 mg dose. The pharmaceutical composition can include a co-formulation of any of the compounds described herein. The pharmaceutical composition can be included with the administration instructions in a container, package or dispenser. -75-201215610 [Embodiment] EXAMPLES Examples are provided below to further illustrate the different features of the present invention. These examples also illustrate useful methods of practicing the invention. These examples do not limit the invention of the patent application. Preparation of compounds of formula III, Ilia, IVa, IVb, Va or Vb (including ( + )-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinoline-l -yl)-4-(lH-indol-3-yl) batch D-but-2,5-dione, (-)_cis_3-(5,6-dihydro-4H-indole [3,2,l-ij]quinolin-1-yl)-4-(1Η-indol-3-yl)pyrrolidine-2,5-dione, (+)-trans-3-(5, 6-Dihydro-411-pyrrolo[3,2,1-indole]quinolin-1-yl)-4-(111-卩 哄-3-yl) 卩比略11定-2,5- Diketone, and (-)-trans-3-(5,6-diamino-4 Η-pyrrolo[3,2,1 - ij ]quinolin-1-yl)-4 - (1 Η -吲哚-3 -ylpyrrolidine-2,5-dione) and its use 'Examples of a therapeutically effective amount of a second anti-proliferative agent, alone or in combination, are described in International Patent Application PCT/US20 1 0/023 8 93 'For all purposes, it is incorporated herein by reference in its entirety. EXAMPLES Materials and Methods The following materials and methods are applicable to the biological assays described herein unless otherwise stated. Cell culture and reagents: ΑΝ3 CA, ASPC-1, MDA-MB-231, NCI-H 1 229, SK-OV-3 and Panc-Ι cancer cell lines (American Type Culture Collection) are cultured in 10% fetal Bovine serum, 100 units/ml penicillin, -76-201215610 100 μg/ml streptomycin and 2 mmoles of L-glutamic acid in Dulbecco's modified Eagle's medium ο etc. Line graph analysis: For each cell line and drug combination, 72 hours of 1C 5() 每种 for each individual drug and a combination of equivalent fixed ratios was determined by ΜΤΤ hyperplasia endpoint analysis or by colony formation analysis. For example, in the case of sputum and sputum, 1C 5 . The 値 is 1 μΜ and 5 μΜ, respectively, and the equivalent ratio is 1:5. Thus, serial dilutions of the highest combined concentrations (8 X to 0.12 5 Χ, where the X-line IC5Q specific concentration) were used to generate a dose response curve. The degree of inhibition of cell proliferation in this assay is referred to as the "effect" compared to the unexposed control group, which is from 〇.〇 (no inhibition) to 1.0 (cell transformation without MTT or MTS reagent, indicating complete cell death) The scope of). Two independent experiments were performed for each cell line/drug combination. Data analysis was then performed using CalcusynTM (Cambridge Biosoft, UK) data analysis software. Combination index. Two independent experiments were performed in parallel. The Chou algorithm was used to calculate the combination index (c) as shown in Table 1. Table 1 ___________ -------- Standard CK0.3 of the Matching Index (CI) Strong synergy 0.3<CI<0.85 Synergies 0.85<CI<1.2 Additive 1,2<CI< 3.3 Antagonistic Cl >3.3 ----__— -.-----1 Strong antagonistic combination index is determined according to Zhou's method (C h 0 u, T · _ C. 1 9 9 1 · - 77- 201215610

The median-effect principle and the combination index for quantitation of synergism and antagonism, p. 6 1-10 2. In T . - C Chou and D. C · Ri deout (ed . ) Synergism and antagonism in chemotherapy. Press, S an Diego, Calif). Figure 2, Block A, shows the individual concentrations of d and d for the A and B drugs, respectively, when the same effect as the mixture of drug A and drug B is achieved. Equivalent line graph analysis classifies drug combinations as synergistic, additive, or antagonistic. Specifically, Figure 2, Block B, shows an isobologram analysis of a particular effect (e.g., 50% of the maximum 値), where the single dose of drug A is A = 20 and the dose of drug B alone is B = 100. The line connecting these intercept points is the addition line, which should produce the same effect depending on these effects. The actual dose achieves this effect in a small amount such as the Q point, and is superadditive or synergistic, while the dose pair represented by the R point requires a higher amount and is therefore a sub-additive. Points that appear below the line, such as P, should be purely additive. Cell viability analysis. In some experiments, cell viability was detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Briefly, 5 - 10,000 cells per well were seeded in 96-well plates' for 24 hours in complete growth medium and then treated with various drugs and drug combinations for 72 hours. MTT was added to a final concentration of 0.5 mg/ml and cultured for 1 hour, and then cell viability was evaluated at a wavelength of 5 70 nm using a microplate reader. Data were normalized to the untreated control' and analyzed by Microsoft Exc e1. Cell proliferation analysis. The exponentially growing cells were seeded in a 6-well cell culture plate at 2,000 per well, and the cells were attached for 24 hours. The individual drugs at increasing concentrations of -78-201215610 and their combinations are then added to the medium for an additional 24 hours. After 24 hours of exposure, the drug was removed and fresh media was added over the next 14 to 21 days to allow colony formation. The cells were fixed and stained with GIEMSA (Gibc® BRL). Colonies of more than 50 cells were recorded as viable and plotted against cell viability as a percentage to determine IC5Q値. Gemcitabine and (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1-indolizine-1-yl)-4-(1Η-indol-3-yl) Both pyrrolidine-2,5-dione induce cell cycle arrest in cancer cells, but at different stages. Gemcitabine induced G1/S phase arrest, leading to a basic synchronization and accumulation of cell populations in the G1/S phase. (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1-^]quinolin-1-yl)-4-(111-indol-3-yl)pyrrole The pyridine-2,5-dione stagnates the cells in the G2/M phase of the cell cycle. The standard anchor-dependent MTS cytotoxicity assay was modified and extended to seven days to test (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1-"]quinoline- The anti-proliferative activity of 1-methyl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione in combination with gemcitabine.修改 The modified MTS analysis is shown in Figure 3. Plaped fine in the day

Cell. In the plans A and C, two agents were placed on the second day (ie, (-)-trans-3-(5,6-dihydro-41^pyrrolo[3,2,1-丨_]] Quinoline-1-yl)-4-(111-indol-3-yl) zizalidine-2,5-dione, identified as A drug, and gemcitabine, the first introduced cell for 24 hours, followed by The first agent was washed out on the third day. On day 5, the cells were cultured for 48 hours without the first agent prior to introduction of the second agent. Cells were incubated with the second agent for 24 hours before washing out the second agent on day 6. The cells were further cultured on day 8 or 9 without the second agent until MTS analysis was performed. In Plan B and D-79-201215610, the first or second agent was not washed out. Example 1. Combination of a c-Met inhibitor and gemcitabine for the treatment of various anti-proliferative diseases and cancer - giving gemcitabine and (-)-trans-3-(5,6) in various pulsed schemes as shown in Figure 3. -Dihydro-411-pyrrolo[3,2,1-7-quinolin-1-yl)-4-(11^-indol-3-yl)pyrrolidine-2,5-dione. If the cancer cells are not exposed to the two agents, that is, when no two agents are washed out, the cancer cells are more sensitive to the anti-proliferative effects of the two agents. In various formats, gemcitabine and (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,l-ij]quinolin-1-yl)-4-(1Η-吲) Both indole-3-yl)pyrrolidine-2,5-dione are combined at the same time, or when not washed out, the two agents are often resistant to cockroaches. The present invention converts this antagonism to a minimum, additive effect, and in many cases, a synergistic effect. (-)-trans-3-(5,6-dihydro-411-shame and [3,2,1-丨]]卩奎咐-1_yl)-4-(1 Η -吲哚-3 The combined data of piramiridin-2,5-dione and gemcitabine under continuous dosage conditions are shown in Table 2. -80- 201215610 Table 2. Human cancer cell line source tissue combination index classification RT4 bladder 1.10 additive HCI-H526 lung 1.11 additive SNU3 98 liver 1.15 additive SNU-1 6 stomach 1.16 additive LO VO colon 1.19 Additive U93 7 Blood 1.2 1 掊 Resistant SK-HEP1 Liver 1.23 Antagonistic HCT-1 1 6 Colon 1.26 Antagonist ASPC-1 Pancreas 1.27 Antagonistic KG-1 a Blood 1.28 Antagonist 786-0 Kidney 1.29 Antagonistic THP - 1 blood 1.31 antagonistic KG-1 blood 1.32 掊 resistance NCI-H 1 299 lung 1.33 antagonistic RT1 1 2 bladder 1.39 antagonistic DU 1 45 prostate 1.4 1 antagonist DU4475 breast 1.42 antagonist CAKI-1 kidney 1.42 antagonistic CCS-292 soft tissue 1.46 antagonistic A549 lung 1.47 掊 resistance SK-LMS- 1 vulva 1.50 掊 resistance DLD-1 colon 1.51 antagonist NCI-H520 lung 1.5 1 antagonist HT29 colon 1.57 antagonist WM-266.4 skin 1.63 掊 抗U266 blood 1.64 antagonistic COLO-205 colon 1.67 antagonistic K562 blood 1.67 antagonistic HEP-3B liver 1.68 antagonistic BX-PC3 pancreas 1.72 Antagonistic LS41 IN Colon 1.74 掊 Resistant HL-60 Blood 1.76 Antagonistic NCI-H460 Lung 1.87 Antagonistic BDCM Blood 1.9 1 Antagonistic NCI-H1 993 Lung 1.93 Antagonistic J urkat Blood 1.99 Antagonistic MDA MB-23 1 Breast 2.3 1 antagonistic SNU-387 liver 3.90 antagonistic NCI-H66 1 lung 4.08 antagonistic PANC-1 pancreas 5.20 antagonistic -81 - 201215610 Tables 3 and 4 show the continuous dose and the pulsed dose with no drug phase Comparison. In these tables the compound (-)-trans-3-(5,6-dihydro-4H-pyrido[3,2,l-ij]quinolin-1-yl)-4-(1Η-吲哚) The -3-yl)pyrrolidine-2,5,-dione is identified as "A Agent". Indicates the characteristics of the cancer cell line and the source of the tissue. "Gemcitabine-A agent" means that the A drug system was administered after gemcitabine and "A drug - gemcitabine" showed that the gemcitabine was administered after the A agent. Table 3 · Cancer cell line tissue type Gemcitabine - A drug A agent - Gemcitabine occurred during the washout without washing out occurred in the washout without washing out CI effect CI effect CI effect CI effect NCI-H1299 NSCLC (non-small Lung) 0.87 additive 1.25 antagonistic 1.05 additive 1.25 antagonistic AsPC-1 pancreas 0.43 synergistic 1.47 antagonistic 1.68 antagonistic 1.27 antagonistic MDA MB-231 breast 0.41 synergistic 1.52 antagonistic 1..01 phase Additive 2.04 Antagonistic AN3CA Uterine 0.66 Synergistic 1.36 Antagonist 0.79 Synergist 1.96 Antagonist is shown in Table 4; ^0.8 score is an indication of synergy, > 0.85- $1.2 score is an indication of additive effect And the score of > 1.2- $3.3 is an indication of antagonism. In a "parallel" dosing regimen, cell lines were treated simultaneously with gemcitabine and A agents for 72 hours prior to MTS cell proliferation assay. In a "sequential-continuous" dosage regimen, the cell line is treated with the first agent (gemcitabine or A agent) alone for the indicated time interval, followed by a second agent treatment without removing the first agent (and A different agent). The cells were incubated with the compound for the indicated time interval prior to performing MTS cell proliferation assay. Specifically, continuous I indicates that the administration of the first agent lasted for 24 hours, followed by administration of the second agent (no -82-201215610 removal of the first agent) for 48 hours. Continuous II indicates that the administration of the first agent lasted for 48 hours, followed by administration of the second agent (without removal of the first agent) for 48 hours. Succession III indicates that the first agent was administered for 72 hours, followed by administration of the second agent (without removing the first agent) for a period of 96 hours. In a "sequential-pulsed" dosing regimen, the cell line was treated with the first agent (gemcitabine or A agent) alone for 24 hours, followed by continued culture in the drug-free culture Q-base. The cells were then given a sputum, 24 or 48 hour drug-free period 24 hours prior to treatment with the second agent (different from the first agent). The cells were then given an additional 24 or 72 hours of drug-free culture prior to MTS cell proliferation assay. Specifically, Pulse Formula I indicates that the administration of the first agent lasts for 24 hours, followed by the 0 hour drug-free period, followed by the administration of the second agent for 24 hours, followed by the 24-hour drug-free period. Pulsed Formula I indicates that the administration of the first agent is administered for 24 hours 'and then 24 hours of drug-free period' followed by the administration of the second agent for 24 hours' followed by 24 hours of drug-free period. Pulsed t) III indicates that the first agent is administered for 24 hours, followed by a 48 hour drug-free period, followed by administration of the second agent over a 24 hour' followed by a 72 hour drug-free period. Figure 4-7 shows gemcitabine and (-)·trans-3_(5,6-dihydro_4H_lao[3,2,1-丨]]quinolin-1-yl)-4-(111- 1] Noisy _3-base) [1 ratio slightly 11 -2, 5-ketone treatment in AN3 CA (block A), ASPC-1 (block B), MDA-MB-231 (block C And isobologram analysis in NCI-H1299 (block D) cells. Specifically, Figure 4 shows that gemcitabine treatment followed by (-)-trans-3_(5,6-dihydro-4H-prado[3,2,1-ij]quinolin-1-yl)-4-( 1Η-吲哚-3-yl)pyrrolidine_2,5_di-83- 201215610 Ketone treatment and washing out the equivalent line diagram of gemcitabine. Figure 5 shows gemcitabine treatment followed by (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1-4]quinolin-1-yl)-4 - (1 Η-吲The 哚-3-ylpyrrolidine-2,5-dione treatment did not elute the equivalent line diagram of gemcitabine. Figure 6 shows (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1-indolyl]quinolin-1-yl)-4-(111-吲哚-3 -based) pyrrolidine-2,5-dione treatment followed by gemcitabine treatment and washing out (-)-trans-3_(5,6-dihydro-4Η_® succinyl[3,2,1-丨]]quinoline An isobologram of -1-yl)-4-(111-indol-3-yl)pyrrolidine-2,5-dione. Figure 7 shows (-)-trans-3-(5,6-dihydro-4Η-indolebi[3,2,1-ij]quinolin-1-yl)-4-(1 H-oxime Treatment with -3-yl)pyrrolidine·2,5-dione followed by gemcitabine did not wash out (-)-trans-3_(5,6-dihydro-4H-lao[3,2,1 - ij An equivalent diagram of quinoline-1-yl)-4-(1 Η-indol-3-yl)pyrrolidine-2,5-dione. Figure 8 is a cell cycle analysis of the dosage regimen set forth in Figure 3 'showing S-phase arrest and reaction (-)-trans-3-(5,6·dihydro-4 Η-pyrrolo[ 3,2,1 - ij ]quinoline-:1 -yl)-4 - (1 Η-吲哚-3 base) 11 G2/M arrested with pyridin-2,5-dione. Figure 9 shows the activation of the cell cycle checkpoint by gemcitabine during the dosing regimen presented in Figure 3. Figure 10 shows gemcitabine and (-)-anti-3_(5,6-dihydro-_ as shown) MDA - Μ B - 2 after treatment with 4H_pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(lH-indol-3-yl)pyrrolidine-2,5-dione Cell cycle analysis of 3 1 cells (A and B) 〇 Specifically, the MDA-MB-231 cell line uses the indicated dosage regimen with 0.4 mM gemcitabine and 3.3 mM (-) _ anti_3_ (5, 6 -Dihydro·4Η_ -84 - 201215610 Pyrrolo[3,2,1"-menistrin-1-yl)-4-(111-indol-3-yl)pyrrolidine-2,5-dione treatment. Samples were collected and flow cytometric analysis was performed at the indicated time points. The study was also performed using A5 49 cells with the same results. A portion of MDA-MB-23 1 cells were collected and dissolved in experiments performed in blocks A and B. Immunoblot analysis was performed using anti-phosphorylation _Chkl, phosphorylated histone H3 (SerlO) and β-actin antibodies, as shown in panels 10 and D, respectively.

-85- 201215610 Table 4. Cell Line A549 NCK- H1299 RT4 RT112 ASPC -1 PANC -1 MDA- MB-231 MDA- MB- 468 sv· OV-3 A2780 AN3 CA NOZ Tissue Source Lung, Lung, Bladder, Pancreas, Pancreas, Pancreas, Breast Ovarian ovary uterine gallbladder GEM+ A agent parallel 1.3 1.8 1.3 2.0 4.7 6.5 ND 2.2 2.2 1.7 4.0 2.5 GEM—A pharmaceutical continuous I 1.2 1.8 1.7 1.9 5.1 1.7 0.4 1.6 2.2 1.4 2.2 0.3 GEM-> A pharmaceutical continuous II 1.3 1.7 ND 1.4 1.6 ND 1.1 1.8 1.6 1.5 1.3 0.5 GEM—A pharmaceutical continuous in 1.1 ί.3 1.9 1.2 1.2 1.4 1.2 1.7 1.4 1.2 1.3 U GEM—A pharmaceutical pulse I 1.0 1.5 1.1 2.1 4.1 ND 9.1 0.1 2.2 1.3 10.3 2.0 GEM— A Pharmacy pulse type π 1.3 1.0 1.2 1.3 0.5 ND 1.6 1.3 1.6 1.5 0.7 0.6 GEM— A drug pulse type πι 0.7 1,0 1.2 1.0 0.6 1.1 0.6 1.2 0.8 1.1 0.9 0.7 A drug — GEM continuous I 2.0 4.4 3.8 ND 1.4 0.8 0.5 1.5 2.2 1.7 2.8 0.3 —1— Pharmaceutical Qi IJA — GEM Continuous 1.9 ND ND ND ND 1.3 ND 1.3 ND 1.6 ND 0.1 ____—1 Example 2. In vivo study in a one-week plan, after the drug-free period , gemcitabine at 1,000 mg / m 2 per day The amount administered to the patient. Gemcitabine treatment followed by another -86- 201215610 a drug-free period. The A agent was then administered to the patient twice a day for 360 days for 4 days. Close attention was paid to the cytotoxic gain between gemcitabine and A agents in vitro and in vivo and confirmed by appropriate xenograft models. [Simple description of the diagram] Figure 1 illustrates (±)-cis-3-(5,6-dihydro-411-pyrrolo[3,2,1 s]quinoline·1_yl)_4-(11€- Indole-3-yl)pyrrolidine-2,5-dione and (±)-trans-3-(5,6-0 dihydro-4H-pyrrolo[3,2,1-ij]quinoline- The chemical structure of 1-yl)-4-(1 H-indol-3-yl)pyrrolidine-2,5-dione. Figure 2 A-B is a plot of a calculation tool for assessing pharmacological synergy. FIG. 2A shows the calculation of the combination index (CI) and FIG. 2B shows the equivalent line analysis diagram. Figure 3 shows (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1-indolyl]]quinoline-i-yl)_4-(lH-indole-3) Dosage regimen of pyridinium-2,5-dione/gemcitabine combination. Figure 4 shows the treatment of gemcitabine followed by (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1Η- The equivalent line diagram of gemcitabine was treated with indole-3-yl)pyrrolidine-2,5-dione. Figure 5 shows the treatment of gemcitabine followed by (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinoline-l-yl)-4-(lH-indole) The indole-3-yl)pyrrolidine-2,5-dione treatment did not elute the equivalent line diagram of gemcitabine. Figure 6 shows (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1-indolyl]]quinolin-1-yl)-4-(1 H-oxime) Indole-3-yl)pyrrolidine-2,5-dione treatment followed by gemcitabine treatment and washing out (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1 -" 』] Quinoline-1-yl)-4-(1Η-indol-3-yl)pyrrolidine-2,5-dione equivalent line diagram. -87- 201215610 Figure 7 shows (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinoline-1-yl)-4-(1 H- Treatment with indole-3-yl)pyrrolidine-2,5-dione followed by gemcitabine did not wash out (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2, An equivalent line diagram of ij ij quinolin-1-yl)-4-(1Η-indol-3-yl)pyrrolidine-2,5-dione. Figure 8 is a cell cycle analysis of the dose regimen A presented in Figure 3, showing S-phase arrest and reaction (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3] in response to gemcitabine treatment. , 2,l-ij]quinolin-1-yl)-4-(1Η-indol-3-yl)pyrrolidine-2,5-dione treatment 02/:\1 stagnant. Figure 9 shows the activation of cell cycle checkpoints by gemcitabine during the dose regimen A presented in Figure 3. Figure 10 shows gemcitabine and (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinolin-1-yl)-4-(as shown). Cell cycle analysis of MDA-MB-231 cells treated with pyridinium-2,5-dione (blocks A and B). Blocks C and D show immunoblots of MDA-MB-231 cells using anti-phospho-Chkl, phosphorylated histone H3 (SerlO) and β-actin antibodies (respectively from blocks and sputum) Study).

Claims (1)

201215610 VII. Scope of Application: 1. A method for treating cell proliferative diseases. The method comprises treating a therapeutically effective amount of (-)-trans-3-(5,6--hydro- 4H-卩 略 并 [ [ , 2,l-ij]salin-1-yl)-4-(1Η-indol-3-yl)pyrrolidine-2,5·dione, or a pharmaceutically acceptable salt, prodrug or metabolism thereof And administering a therapeutically effective amount of a second anti-proliferative agent to the subject, wherein the (-)-trans-3-(5,6-dihydro- 4Η-pyrrolo[3,2,1-7]quinoline 1-yl)-4-(111-indol-3-yl)pyrrolidine-2,5-dione, hydrazine or a pharmaceutically acceptable salt, prodrug or metabolite thereof and the second anti-proliferation The agents are not administered at the same time. 2. The method of claim 1, wherein the (-)-trans-3-(5,6-diamino-411-la-do[3,2,1-丨_]] salin-1 -yl)-4-(111-indole-3-yl)pyrrolidine-2,5-dione, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, administered the second antibody The proliferative agent is administered later. 3. The method of claim 2, wherein the second anti-proliferator is an inhibitor of the G1/S phase of the cell cycle. 4. The method of claim 2, wherein the second anti-proliferative agent is an adenosine analog, a guanosine analog, a methyl uridine analog or a cytidine analog. 5- The method of claim 2, wherein the second anti-proliferation agent is gemcitabine. 6- The method of claim 5, wherein the gemcitabine is administered for no more than 30 minutes. 7. The method of claim 5, wherein the gemcitabine is administered for no more than one hour. -89-201215610 8 • The method of claim 5, wherein the gemcitabine is administered for no more than 12 hours. 9. The method of claim 5, wherein the gemcitabine is administered for no more than 24 hours. 10. The method of claim 1, wherein the (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl) 4-(1Η-indol-3-yl)pyrrolidine-2,5-dione is administered for at least 24 hours. 11. The method of claim 1, wherein the (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1 quinolin-1-yl)- 4-(111-Indol-3-yl)pyrrolidine-2,5-dione is administered for at least 48 hours. 12- The method of claim 1, wherein the (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,14-)]quinolin-1-yl)- 4-(111-Indol-3-yl)pyrrolidine-2,5-dione is administered for at least 72 hours. 13. The method of claim 1, wherein the (-)-trans-3-(5,6-dihydro-4 Η-pyrrolo[3,2,1 - ij ]quinolin-1 -yl group ) -4 - (1 Η -吲哚-3 -yl) Rabbi U--2,5 - One-line is administered for at least 9 6 hours. 14. The method of claim 5, wherein the (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1-indol]]quinolin-1- The 4-(111-indol-3-yl)pyrrolidine-2,5-dione is administered for at least 12 hours after administration of gemcitabine. The method of claim 5, wherein the method of claim 5, wherein (-)-trans-3 -(5,6-dihydro-411-pyrrolo[3,2,1-indolyl]quinolin-1-yl)-4-(111-indol-3-yl) Pyrrolidine-2,5-dione is administered for at least 24 hours after administration of gemcitabine - 90 - 201215610 16. The method of claim 5, wherein at least 12 hours prior to administration of gemcitabine is not administered drug. 17. The method of claim 5, wherein no drug is administered for at least 24 hours prior to administration of gemcitabine. 1 8 The method of claim 5, wherein no drug is administered for at least 48 hours prior to administration of gemcitabine. 19. The method of claim 5, wherein the (_)-trans_3_ 〇(5,6-dihydro-411-pyrrolo[3,2,1-indenyl]quinolin-1-yl The -4-(111-indol-3-yl)pyrrolidine-2,5-diketone is administered after the concentration or amount of gemcitabine in the subject is less than about 50% of its initial concentration or amount. 20. The method of claim 5, wherein the (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1""]quinolin-1-yl) The -4-(111-indol-3-yl)pyrrolidine-2,5-dione is administered after the concentration or amount of gemcitabine in the subject is less than about 10% of its initial concentration or amount. 21. The method of claim 5, wherein the (-)-trans-3_ oxime (5,6-dihydro-411-pyrrolo[3,2,1-indol]]quinolin-1-yl The -4-(111-indol-3-yl)pyrrolidine-2,5-dione is administered after gemcitabine has a concentration or amount in the subject that is less than about 5% of its initial concentration or amount. 22. The method of claim 5, wherein the (-)-trans-3_(5,6-dihydro-411-pyrrolo[3,2,1"]quinolin-1-yl)- 4-(111-Indol-3-yl)pyrrolidine-2,5-dione is administered after gemcitabine has a concentration or amount in the subject that is less than about 1% of its initial concentration or amount. A composition for treating a proliferative disease in a subject, the composition comprising a therapeutically effective amount of (-)-trans-3-(5,6-dihydro-4 H-pyrrolo-91 - 201215610 [3] , 2,l-ij]quinolin-1-yl)-4-(1Η-卩)-3-yl) schizophrenia _2,5-dione, or a pharmaceutically acceptable salt or prodrug thereof Or a metabolite, and combined with a therapeutically effective amount of a second anti-proliferative agent, wherein the (-)-trans-3-(5,6-digas-411-[] is more than [3,2,1-唾 』] sialolin-1-yl)-4-(111-[1 γ -3-yl) lysole|1 determinate-2,5-dione' or its pharmaceutically acceptable salt, prodrug or The metabolite is administered at the same time as the second anti-proliferative agent. 24. The composition of claim 23, wherein the (_)-trans-3-(5,6-dihydro-41{-pyrrolo[3,2,1"]]quinoline-1_ a _4_(111_吲哚-3-yl)pyrrolidole-2,5-dione, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, administered to the second anti-proliferative agent 2. The composition of claim 24, wherein the second anti-proliferative agent is an inhibitor of the G1/S phase of the cell cycle. 26. The combination of claim 24 And the second anti-proliferation agent is an adenosine analog, a guanosine analog, a methyl uridine analog or a cytidine analog. 2 7. The composition of claim 24, wherein the The two anti-proliferative agents are gemcitabine. 28. The composition of claim 27, wherein the gemcitabine is administered for no more than 30 minutes. 29. The composition of claim 27, wherein the gemcitabine is administered For a period of not more than one hour. 3 0. The composition of claim 27, wherein the gemcitabine is administered for no more than 12 hours. 3 1 . A composition of 7th, wherein the gemcitabine-92-201215610 is administered in a period of no more than 24 hours. 32. The composition of claim 23, wherein the (-)-trans-3-(5, 6-Dihydro-411-pyrrolo[3,2,1-1_1]quinolin-1-yl)-4-(111-indol-3-yl)pyrrolidine-2,5-dione At least 24 hours. 3 3. The composition of claim 23, wherein the (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1-丨] Quinoline-1-yl)-4-(1 -indol-3-yl)pyrrolidine-2,5-dione is administered for at least 48 hours. Ο 34. The composition of claim 23 Wherein (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1-indolyl]quinolin-1-yl)-4-(111-indole-3) · Pyridinyl-2,5-dione is administered for at least 72 hours. 35. The composition of claim 23, wherein the (-)-trans-3-(5,6-dihydro- 41 pyrrolo[3,2,1-indolyl]]quinolin-1-yl)-4-(111-indol-3-yl)pyrrolidine-2,5-dione is administered for at least 96 hours. 3. The composition of claim 27, wherein the (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1-indol]]quinoline- 1-base)- The 4-(111-indol-3-yl)pyrrolidine-2,5-dione is administered for at least 12 hours after administration of gemcitabine. 37. The composition of claim 27, wherein -)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1 quinolin-1-yl)-4-(111-indol-3-yl)pyrrolidine- The 2,5-diketone is administered for at least 24 hours after administration of gemcitabine. 3 8. The composition of claim 27, wherein no drug is administered for at least 12 hours prior to administration of gemcitabine. 39. The composition of claim 2.7, wherein no drug is administered for at least 24 hours prior to administration of ji-93-201215610 citabine. 40. The composition of claim 27, wherein no drug is administered for at least 48 hours prior to administration of gemcitabine. 41. The composition of claim 27, wherein the (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinolin-1-yl group -4-(1Η-吲哚-3-yl)pyrrolidine-2,5-dione is administered after gemcitabine has a concentration or amount in the subject that is less than about 50% of its initial concentration or amount. . 42. The composition of claim 27, wherein the (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1-4]quinolin-1-yl group -4-(111-Indol-3-yl)pyrrolidine-2,5-dione is administered after gemcitabine has a concentration or amount in the subject that is less than about 10% of its initial concentration or amount. . 43. The composition of claim 27, wherein the (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1-[ quinolin-1-yl) The -4-(111-indol-3-yl)pyrrolidine-2,5-dione is administered after the concentration or amount of gemcitabine in the subject is less than about 5% of its initial concentration or amount. 44. The composition of claim 27, wherein the (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1-7]quinolin-1-yl) The -4-(11^-indol-3-yl)pyrrolidine-2,5-diketone is administered after the concentration or amount of gemcitabine in the subject is less than about 1% of its initial concentration or amount. 4 5 · A kit for the treatment of cell proliferative diseases, the kit comprising a therapeutically effective amount of (-)-trans-3-(5,6-dihydro-4H-pyro[3,2, L-ij] quinoline-1-yl)-4-(1 Η-indol-3-yl)pyrrolidine-2,5-dione, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, And combining a therapeutically effective amount of a second anti-proliferative agent, wherein the (_)-trans-3-(5,6-dihydro-4?-pyrrolo-94-201215610 [3,2,1-丨"] Quinolin-1-yl)-4-(11 €-indol-3-yl)pyrrolidine-2,5-dione, or a pharmaceutically acceptable salt, prodrug or metabolite thereof and the second Anti-proliferative agents are administered at different times. 46. The kit of claim 45, wherein the (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinolin-1-yl group -4-(1Η-吲哚-3_yl)pyrrolidine-2,5-dione, or a pharmaceutically acceptable salt, prodrug or metabolite thereof, administered by the second anti-proliferative agent Then voted. 0 47. The kit of claim 46, wherein the second anti-proliferative agent is an inhibitor of the G 1 /S phase of the cell cycle. 48. The kit of claim 46, wherein The second anti-proliferative agent is an adenosine analog, a guanosine analog, a methyl uridine analog or a cytidine analog. 4 9. The kit of claim 46, wherein the second anti-proliferative agent is gemcitabine. 50. If the kit of claim 49 is applied, the gemcitabine is administered for no more than 30 minutes. 5 1. A kit of claim 49, wherein the gemcitabine is administered for no more than one hour. 52. The kit of claim 49, wherein the gemcitabine is administered for no more than 12 hours. 5 3. For the kit of claim 49, the gemcitabine is administered for no more than 24 hours. 54. The kit of claim 45, wherein the (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1-indenyl]quinoline-1- The base -4-(111-indol-3-yl-95-201215610) pirolidin-2,5-dione is administered for at least 24 hours. 55. The kit of claim 45, wherein the (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinolin-1-yl group -4-(1Η-indol-3-yl)pyrrolidine-2,5-dione is administered for at least 48 hours. 5 6. For the kit of claim 45, where the (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-indolyl]quinoline-1 -yl)-4-(11吲哚-3-yl)pyrrolidine-2,5-dione is administered for at least 72 hours. 5 7. The kit of claim 45, wherein the (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1""]quinoline-1- The base 4-(1^吲哚-3-yl)pyrrolidine-2,5-dione is administered for at least 96 hours. 58. As in the kit of claim 49, wherein the (-)- Trans-3-(5,6-dihydro-411-pyrrolo[3,2,1-1]]quinolin-1-yl)-4-(1^1-indol-3-yl)pyrrolidine The -2,5-diketone is administered for at least 12 hours after administration of gemcitabine. 59. For the kit of claim 49, wherein the (-)-trans-3-(5,6-dihydro- 411-pyrrolo[3,2,1-7-quinolin-1-yl)-4-(111-indol-3-yl)pyrrolidine-2,5-dione is administered at least after administration of gemcitabine 24 hours 〇 6 0. If the kit of claim 49 is applied, no drug is administered at least 12 hours before the administration of gemcitabine. 6 1. If the kit of claim 49 is applied, No drug was administered for at least 24 hours prior to gemcitabine. 62. For the kit of claim 49, no drug was administered at least 48 hours prior to administration of gemcitabine. -96- 201215610 63. The kit of claim 49, wherein the (-)-trans-3-(5,6-dihydro-4^1-pyrrolo[3,2,1-indenyl]quinolin-1-yl group -4-(1^1-indol-3-yl)pyrrolidine-2,5-dione is administered after gemcitabine has a concentration or amount in the subject that is less than about 50% of its initial concentration or amount. 64. For example, in the case of claim 49, the (-)-trans-3-(5,6-diaza-4H-卩j^; slightly [3,2,l-ij] The concentration or amount of gemcitabine-2,5-diketone in gemcitabine in this subject is lower than its initial concentration or amount. After about 1%, it is administered. 65. For the kit of claim 49, where (-)-trans-3-(5,6-dihydro-411-pyrrolo[3,2,1 -丨_|]quinolin-1-yl)-4-(111-indol-3-yl)pyrrolidine-2,5-dione is present in gemcitabine at a concentration or amount lower than its origin After about 5% of the concentration or amount is administered. 66. For the kit of claim 49, where (-)-anti_3_(5,6-dihydro-4H-pyrrolo[3,2 ,l-ij]quinolin-1-yl)-4-(1Η-indol-3-yl)pyrrolidine-2,5-dione is in gemcitabine The concentration or amount Q in the subject is administered after about 1% of its initial concentration or amount. -97-