Tetracyclic quinolone analogue combination therapy for treatment of cancer

Abstract

The present invention provides methods, compositions and combinations for treating cancer by the combined use of a compound of Formula I, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, wherein A, Q, n, m, R7, R8, V, X1, X2, X3, X4, X5, X6 and X7 are as defined herein, and at least one therapeutically active agent selected from the group consisting of immunotherapeutic agents, anti-cancer agents and anti-angiogenic agents. # imgabs0 #

Description

[0001] This application is a divisional application of the invention patent application with application date of November 9, 2016, application number 201680075438.3 (international application number PCT / US2016 / 061176), and name “Tetracyclic quinolone analog combination therapy for treating cancer”.

[0002] Cross-references to Related Patent Applications

[0003] This patent application claims priority to and the benefit of U.S. Provisional Patent Application Serial No. 62 / 258,211, filed November 20, 2015, which is incorporated herein by reference in its entirety for all purposes. Technical Field

[0004] The present invention generally relates to combination therapies for the treatment of cancer and tumors. Background of the Invention

[0006] A variety of tetracyclic quinolone compounds have been proposed to work by interacting with the quadruplex-forming region of nucleic acids and regulating ribosomal RNA transcription. See, for example, U.S. Patent Nos. 7,928,100 and 8,853,234. Specifically, tetracyclic quinolone compounds can stabilize DNA G-quadruplexes (G4s) in cancer cells, thereby inducing synthetic lethality of cancer cells. Since treating cells with G4 stabilizers can lead to DNA double-strand breaks (DSBs) formation, the DSB formation induced by treatment with G4 stabilizing ligands / agents (e.g., tetracyclic quinolone) is more significant in cells with genetic defects or chemical inhibition of repair pathways, including non-homologous end joining (NHEJ) and homologous recombination repair (HRR). In addition, tetracyclic quinolone compounds selectively inhibit rRNA synthesis by Pol I in the nucleolus, but do not inhibit mRNA synthesis by RNA polymerase II (Pol II), and do not inhibit DNA replication or protein synthesis. For example, it has been pointed out that targeting RNA polymerase I (Pol I) to activate p53 through the nucleolar stress pathway can cause the selective activation of p53 in tumor cells. The p53 protein usually acts as a tumor suppressor by causing cancer cells to self-destruct. Activating p53 to kill cancer cells is a well-proven anti-cancer strategy, and many methods are being used to develop this approach. Selective activation of the p53 in tumor cells would be an attractive method for treating, controlling, reducing tumor cells without affecting normal healthy cells. The above-mentioned tetracyclic quinolones are disclosed in U.S. Patents 7,928,100 and 8,853,234, and the contents of this publication are incorporated herein by reference in their entirety for all intended purposes.

[0007] Despite recent advances in anticancer agents, there remains a strong need to develop effective new cancer therapies. Summary of the Invention

[0008] In one embodiment, the present invention provides a pharmaceutical combination comprising a tetracyclic quinolone compound having the structure of formula (I);

[0009]

[0010] or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof;

[0011] in:

[0012] X 1 is CH or N;

[0013] X 2 、X 3 、X 4 、X 5 、X 6 and X 7 Independently NR 4 , CH2, CHQ or C(Q)2, provided that X 2 、X 3 、X 4 、X 5 、X 6 and X 7 Zero, one or two of them are NR 4 ;

[0014] A and V are independently H, halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 or -R 3 ;

[0015] Q is independently halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 or -R 3 ;

[0016] In each-NR 1 R 2 In, R 1 and R 2 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains one additional heteroatom selected from N, O and S as a ring member;

[0017] R 1 is H, or C1-C6 alkyl optionally substituted by one or more halogens, or ═O;

[0018] R 2 is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0019] R 3 is optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring, each of which is optionally substituted with one or more halogens;

[0020] R 4 are independently H, or C1-C6 alkyl;

[0021] R 7 is H, and R 8 is C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens; or in the case of –NR 7 R 8 In, R 7 and R 8 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains additional heteroatoms selected from N, O and S as ring members;

[0022] m is 0, 1, 2, 3 or 4; and

[0023] n is 0, 1, 2, 3, 4 or 5;

[0024] and at least one additional therapeutically active agent selected from the group consisting of an immunotherapeutic agent, an anticancer agent, and an angiogenic agent.

[0025] In another embodiment, a pharmaceutical combination is provided, comprising a therapeutically effective amount of a compound of formula (II);

[0026]

[0027] or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof;

[0028] in:

[0029] A and V are independently H, halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ;

[0030] Q is independently halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ;

[0031] In each-NR 1 R 2 In, R 1 and R 2 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains additional heteroatoms selected from N, O and S as ring members;

[0032] R 1 is H, or C1-C6 alkyl optionally substituted by one or more halogens, or ═O;

[0033] R 2 is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0034] R 3 is optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0035] Each R 4 are independently H, or C1-C6 alkyl;

[0036] m is 0, 1, 2, 3 or 4;

[0037] n is 0, 1, 2, 3, 4 or 5; and

[0038] p is 0, 1, 2, or 3;

[0039] and at least one additional therapeutically active agent selected from the group consisting of an immunotherapeutic agent, an anticancer agent, and an angiogenic agent.

[0040] In one embodiment, a pharmaceutical combination is provided, comprising a therapeutically effective amount of a compound of formula (III);

[0041]

[0042] or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof;

[0043] in:

[0044] A and V are independently H, halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ;

[0045] Each Q is independently halogen, azide, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ;

[0046] In each-NR 1 R 2 In, R 1 and R 2 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains additional heteroatoms selected from N, O and S as ring members;

[0047] R 1 is H, or C1-C6 alkyl optionally substituted by one or more halogens, or ═O;

[0048] R 2is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0049] R 3 is optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0050] Each R 4 are independently H, or C1-C6 alkyl;

[0051] R 7 is H, and R 8 is C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0052] m is 0, 1, 2, 3 or 4; and

[0053] n is 0, 1, 2, 3, 4 or 5;

[0054] and at least one additional therapeutically active agent selected from the group consisting of an immunotherapeutic agent, an anticancer agent, and an angiogenic agent.

[0055] In one embodiment, a pharmaceutical combination is provided, comprising Compound A and at least one additional therapeutically active agent.

[0056]

[0057] In one embodiment, a pharmaceutical combination is provided, comprising a compound of formula (I) and at least one additional therapeutic agent in a single dosage form or in separate dosage forms. In another embodiment, the pharmaceutical combination wherein the compound of formula (I) and at least one additional therapeutic agent are in separate dosage forms is administered by the same route of administration or by different routes of administration. In one embodiment, the separate dosage forms of the pharmaceutical combination provided herein are co-administered by simultaneous administration, sequential administration, administration, intermittent administration, continuous administration, or a combination thereof.

[0058] In one embodiment of the present invention, a pharmaceutical combination is provided, comprising a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a salt, solvate, ester and / or prodrug thereof, and at least one additional therapeutically active agent. In some embodiments, the additional therapeutically active agent is an immunotherapeutic agent, an anticancer agent and / or an anti-angiogenic agent.

[0059] In one embodiment, the at least one additional therapeutically active agent is an immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is selected from the group consisting of: a monoclonal antibody, an immune effector cell, an adoptive cell transfer, an immunotoxin, a vaccine, or a cytokine.

[0060] In other embodiments, the immunotherapeutic agent is an agent that can modulate the physiological levels of one or more cytokines in the tumor microenvironment of a cancer. In some embodiments, the immunotherapeutic agent induces local production of at least one endogenous cytokine that has a cytotoxic effect on tumor cells, such as TNF-α or IFN-γ. In some embodiments, the immunotherapeutic agent inhibits the production of endogenous cytokines that interfere with T cell recognition and destruction of cancer cells, such as IL-10, TGFβ, or VEGF.

[0061] In other embodiments, immunotherapeutic agents are agents that can induce tumor cells to produce one or more chemokines that lure immune cells to tumor cells, such as dendritic cells, effector T cells (e.g., CD8+ lymphocytes), and natural killer (NK) cells. In some embodiments, chemokines include but are not limited to CCL19, CCL20, CCL21, CX3CL1, CXCL9, and CXCL10.

[0062] In other embodiments, the immunotherapeutic agent is an agent that induces immune checkpoint blockade (e.g., PD-1 blockade and CTLA-4 blockade).

[0063] In some embodiments, the immunotherapeutic agent is an antibody or antigen binding portion thereof that disrupts the interaction between programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1). In one embodiment, the immunotherapeutic agent is selected from the group consisting of an anti-PD-1 antibody, a PD-1 antagonist, an anti-PD-L1 antibody, an siRNA targeting PD-1 expression, an siRNA targeting PD-L1 expression, and a peptide, fragment, positive negative form, or soluble form of PD-1 or PD-L1.

[0064] In one embodiment, the immunotherapeutic agent is a monoclonal antibody. In one embodiment, the monoclonal antibody is selected from the group consisting of anti-PD-1 antibody, nivolumab, pembrolizumab, alemtuzumab, bevacizumab, brentuximab vedotin, cetuximab, gemtuzumab ozogamicin, ibritumomab tiuxetan In some embodiments, the immunotherapeutic agent is an anti-PD-1 antibody. In other embodiments, the anti-PD-1 antibody is a humanized antibody. In one embodiment, the monoclonal antibody is selected from the group consisting of nivolumab and pembrolizumab. In a specific embodiment, the monoclonal antibody is nivolumab.

[0065] In one embodiment, the immunotherapeutic agent is selected from the group consisting of a CTLA-4 antagonist, an anti-CTLA-4 antibody, an siRNA targeting CTLA-4 expression, and / or a peptide, fragment, dominant negative, or soluble form of CTLA-4. In one embodiment, the anti-CTLA-4 antibody is ipilimumab.

[0066] In some embodiments, a pharmaceutical combination is provided, comprising a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a salt, solvate, ester and / or prodrug thereof, and at least one anticancer agent. In one embodiment, the anticancer agent is selected from the group consisting of an alkylating agent, an antimetabolite, a vinca alkaloid, a taxane, a topoisomerase inhibitor, an antitumor antibiotic, a tyrosine kinase inhibitor, an immunosuppressive macrolide, an Akt inhibitor, an HDAC inhibitor, an Hsp90 inhibitor, an mTOR inhibitor, a PI3K / mTOR inhibitor, a PI3K inhibitor, a CDK (cyclin-dependent kinase) inhibitor, a CHK (checkpoint kinase) inhibitor, a PARP (poly (DP-ribose) polymerase) inhibitor, and a combination thereof.

[0067] In one embodiment, at least one anticancer agent is a PI3K inhibitor. In another embodiment, the PI3K inhibitor is Idelalisib.

[0068] In one embodiment, at least one anticancer agent is a PARP inhibitor. In another embodiment, the PARP inhibitor is Olaparib.

[0069] In other embodiments, a pharmaceutical combination is provided, comprising a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenus thereof, or Compound A, or a salt, solvate, ester and / or prodrug thereof, and at least one anti-angiogenic agent. In one embodiment, the anti-angiogenic agent is selected from the group consisting of 2-methoxyestradiol, AG3340, pumastat, batimastat, BAY 12-9566, carboxyamidotriazole, CC-1088, dextromethorphan acetic acid, dimethylxanthenone acetic acid, EMD 121974, endostatin, IM-862, marimastat, matrix metalloproteinases, penicillamine, PTK787 / ZK 222584, RPI.4610, squalamine, squalamine lactate, 3-[2,4-dimethylpyrrol-5-yl-methyl-indenyl]-2-indolinone (SU5416), (±)-thalidomide, S-thalidomide, R-thalidomide, O-(chloroacetylcarbamoyl)fumagillol (TNP-470), cobricosides, paclitaxel, tamoxifen, COL-3, neovastat, BMS-275291, SU6668, 2-ME, interferon-α, anti-VEGF antibody, Medi-522 (Vitaxin II), CAI (calcium influx inhibitor), celecoxib, interleukin-12, IM862, amiloride, Protein, angiostatin K1-3, angiostatin K1-5, captopril, DL-α-difluoromethylornithine, DL-α-difluoromethylornithine HCl, Endostatin TM protein, fumagillin, herbimycin A, 4-hydroxyphenylretinamide, gamma-interferon, juglone, laminin, laminin hexapeptide, laminin pentapeptide, fumonisin A, medroxyprogesterone, medroxyprogesterone acetate, minocycline, minocycline HCl, placental ribonuclease inhibitor, suramin, suramin sodium salt, human thrombospondin, tissue inhibitor of metalloproteinase-1, neutrophil tissue inhibitor of metalloproteinase-1, rheumatoid synovial fibroblast tissue inhibitor of metalloproteinase-2, and combinations thereof.

[0070] In some embodiments, a pharmaceutical combination is provided, comprising a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenus thereof, or Compound A, or a salt, solvate, ester and / or prodrug thereof, at least one additional therapeutically active agent, and a pharmaceutically acceptable excipient or a pharmaceutically acceptable carrier.

[0071] In one embodiment, a pharmaceutical combination is provided, comprising a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a salt, solvate, ester and / or prodrug thereof, present in an amount of about 1 mg to about 500 mg.

[0072] In another embodiment, a pharmaceutical combination is provided, wherein the compound is Compound A and wherein the at least one additional therapeutically active agent is one or more selected from the group consisting of a PARP inhibitor and an anti-PD-1 antibody. In a specific embodiment, the PARP inhibitor is olaparib. In another specific embodiment, the anti-PD-1 antibody is nivolumab.

[0073] In one embodiment, a method for stabilizing G-quadruplexes (G4s) in a subject is provided, wherein the method comprises administering to the subject a therapeutically effective amount of a drug combination comprising a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a salt, solvate, ester and / or prodrug thereof, and at least one additional therapeutically active agent, as described herein. In some embodiments, a method for stabilizing G-quadruplexes (G4s) in a subject is provided, wherein the method comprises administering to the subject a therapeutically effective amount of a drug combination comprising a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a salt, solvate, ester and / or prodrug thereof, and administering to the subject radiation therapy or at least one additional therapeutically active agent before, during, or after the subject is administered the foregoing compounds.

[0074] In one embodiment, a method for modulating p53 activity in a subject is provided, wherein the method comprises administering to the subject a therapeutically effective amount of a drug combination comprising a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a salt, solvate, ester, and / or prodrug thereof, and at least one additional therapeutically active agent, as described herein. In some embodiments, a method for modulating p53 activity in a subject is provided, wherein the method comprises administering to the subject a therapeutically effective amount of a drug combination comprising a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a salt, solvate, ester, and / or prodrug thereof, and administering radiation therapy or at least one additional therapeutically active agent before, during, or after the subject is administered the foregoing compounds.

[0075] In one embodiment, a method for treating or ameliorating a cell proliferative disorder in a subject is provided, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical combination comprising a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a salt, solvate, ester and / or prodrug thereof, and at least one additional therapeutically active agent, as described herein. In some embodiments, a method for treating or ameliorating a cell proliferative disorder in a subject is provided, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a salt, solvate, ester and / or prodrug thereof, and administering radiation therapy or at least one additional therapeutically active agent before, during, or after the subject is administered the foregoing compounds.

[0076] In one embodiment, the methods described herein provide for administering a therapeutically effective amount of a pharmaceutical combination comprising a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a salt, solvate, ester and / or prodrug thereof, and at least one additional therapeutically active agent, wherein the at least one additional therapeutically active agent is selected from the group consisting of an immunotherapeutic agent, an anticancer agent, and an angiogenic agent.

[0077] In one embodiment, the methods described herein are useful for treating cancer. In one embodiment, the cancer is selected from the group consisting of heme cancer, colorectal cancer, ovarian cancer, breast cancer, cervical cancer, lung cancer, liver cancer, pancreatic cancer, lymph node cancer, colon cancer, prostate cancer, brain cancer, head and neck cancer, bone cancer, Ewing's sarcoma, skin cancer, kidney cancer, and heart cancer. In another embodiment, the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, Ewing's sarcoma, head and neck cancer, and cervical cancer.

[0078] In one embodiment, the methods described herein are suitable for treating a heme cancer. In some embodiments, the heme cancer is selected from the group consisting of: leukemia, lymphoma, myeloma, and multiple myeloma.

[0079] In some embodiments, the cancer that the method described herein is applicable to treat is homologous recombination dependency DNA double-strand break repair defective cancer.In another embodiment, the method described herein is applicable to treating cancer cells with defects in other members of breast cancer 1 (BRCA1), breast cancer 2 (BRCA2) and / or homologous recombination pathways.In one embodiment, the cancer cell has a phenotype selected from the group consisting of: ataxia telangiectasia mutation (ATM) defect phenotype, ataxia telangiectasia and Rad3 related (ATR) defect phenotype, CHK1 checkpoint homologue (fission yeast (S.pombe)) (CHK1) defect phenotype, CHK2 checkpoint homologue (fission yeast) (CHK2) defect phenotype, RAD51 homologue (RecA homologue, Escherichia coli) (Saccharomyces cerevisiae) (Rad51) defect phenotype, replication protein A (RPA) defect phenotype and Chinese hamster cell 3 (XRCC3) defect phenotype X-ray repair complement defect repair. In one embodiment, the cancer cells lack a gene selected from the group consisting of: ATM, ATR, CHK1, CHK2, Rad51, RPA, and XRCC3. In another embodiment, the cancer cells lack a gene selected from the group consisting of: Fanconi anemia complement group A (FANCA), Fanconi anemia complement group (FANCC), Fanconi anemia complement group D2 (FANCD2), Fanconi anemia complement group F (FANCF), Fanconi anemia complement group G (FANCG), and Fanconi anemia complement group M (FANCM). In another embodiment, the cancer cells are homozygous for a mutation in a gene selected from the group consisting of: FANCA, FANCC, FANCD2, FANCF, FANCG, and FANCM. In some embodiments, the cancer cells lack BRCA1 and / or BRCA2. In one embodiment, the cancer cells are homozygous for a mutation in BRCA1 and / or BRCA2. In another embodiment, the cancer cells are heterozygous for a mutation in BRCA1 and / or BRCA2.

[0080] In one embodiment, the methods described herein are suitable for treating human subjects.

[0081] In another embodiment, the methods described herein further comprise administering one or more additional therapeutic agents. In one embodiment, the one or more additional therapeutic agents are anti-cancer agents.

[0082] In one embodiment, a method for reducing or inhibiting cell proliferation is provided, wherein the method comprises contacting the cell with a therapeutically effective amount of a drug combination comprising a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a salt, solvate, ester and / or prodrug thereof, and at least one additional therapeutically active agent, as described herein. In some embodiments, a method for reducing or inhibiting cell proliferation is provided, wherein the method comprises contacting the cell with a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a salt, solvate, ester and / or prodrug thereof, and administering radiation therapy before, during, or after contacting the cell with a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A.

[0083] In one embodiment, the method for reducing or inhibiting cell proliferation as described herein is in a cancer cell line or in a tumor of a subject. In one embodiment, the cancer cell is a cancer cell line selected from the group consisting of heme cancer, colorectal cancer, ovarian cancer, breast cancer, cervical cancer, lung cancer, liver cancer, pancreatic cancer, lymph node cancer, colon cancer, prostate cancer, brain cancer, head and neck cancer, bone cancer, Ewing's sarcoma, skin cancer, kidney cancer and heart cancer. In another embodiment, the cancer cell is selected from the group consisting of: wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, Ewing's sarcoma, head and neck cancer, and cervical cancer.

[0084] In one embodiment, the method for reducing or inhibiting cell proliferation as described herein is in a cancer cell line or in a tumor in a subject, is a heme cancer cell line selected from the group consisting of leukemia, lymphoma, myeloma, and multiple myeloma.

[0085] In one embodiment, the method for reducing or inhibiting cell proliferation as described herein is in breast cancer 1 (BRCA1), breast cancer 2 (BRCA2) and / or other members of the homologous recombination pathway with defects in cancer cells. In one embodiment, the cancer cell has a phenotype selected from the group consisting of: ataxia telangiectasia mutation (ATM) defect phenotype, ataxia telangiectasia and Rad3 related (ATR) defect phenotype, CHK1 checkpoint homologue (fission yeast) (CHK1) defect phenotype, CHK2 checkpoint homologue (fission yeast) (CHK2) defect phenotype, RAD51 homologue (RecA homologue, Escherichia coli) (Saccharomyces cerevisiae) (Rad51) defect phenotype, replication protein A (RPA) defect phenotype and Chinese hamster cell 3 (XRCC3) defect phenotype X-ray repair complement defect repair. In one embodiment, the cancer cell lacks a gene selected from the group consisting of: ATM, ATR, CHK1, CHK2, Rad51, RPA and XRCC3. In another embodiment, the cancer cells lack a gene selected from the group consisting of Fanconi anemia complement group A (FANCA), Fanconi anemia complement group (FANCC), Fanconi anemia complement group D2 (FANCD2), Fanconi anemia complement group F (FANCF), Fanconi anemia complement group G (FANCG), and Fanconi anemia complement group M (FANCM). In another embodiment, the cancer cells are homozygous for a mutation in a gene selected from the group consisting of FANCA, FANCC, FANCD2, FANCF, FANCG, and FANCM. In some embodiments, the cancer cells lack BRCA1 and / or BRCA2. In one embodiment, the cancer cells are homozygous for a mutation in BRCA1 and / or BRCA2. In another embodiment, the cancer cells are heterozygous for a mutation in BRCA1 and / or BRCA2.

[0086] In one embodiment, the methods described herein are suitable for administering the drug combination 1-4 times per day, 1-6 times per week, 1-4 times per month, once per week, once every two weeks, once every three weeks, or once per month. BRIEF DESCRIPTION OF THE DRAWINGS

[0088] Figures 1A-1D The combination of Compound A and Olaparib is shown to inhibit growth and Loewe excess at 48 hours. Figure 1A The dose matrix shown shows the inhibition (%) of the combinations in the DLD1 parental cell line. Figure 1B Showing the combination in Figure 1A The Loewe in the middle is overdone. Figure 1CThe dose matrix shown shows the inhibition (%) of the combination in the DLD1-BRCA2(- / -) isogenic cell line. Figure 1D Showing the combination in Figure 1C The Loewe in the middle is overdone.

[0089] Figures 2A-2D The combination of Compound A and Olaparib was shown to inhibit growth and Loewe excess for 144 hours. Figure 2A The dose matrix shown shows the inhibition (%) of the combinations in the DLD1 parental cell line. Figure 2B Showing the combination in Figure 2A The Loewe in the middle is overdone. Figure 2C The dose matrix shown shows the inhibition (%) of the combination in the DLD1-BRCA2(- / -) isogenic cell line. Figure 2D Showing the combination in Figure 2C The Loewe in the middle is overdone.

[0090] Figures 3A-3C Combination therapy of Compound A with the PARP inhibitor Olaparib is shown to demonstrate in vivo synergy in a PDX model of BRCA2-deficient TNBC. Figure 3A Treatments of olaparib (50 mg, qd x 7) and olaparib (50 mg, qd x 7) in combination with Compound A (50 mg qwk x 2) are shown. Figure 3B Treatments of olaparib (50 mg, qd x 28) and olaparib (50 mg, qd x 28) in combination with Compound A (50 mg qwk x 2) are shown. Figure 3C Shown are treatments of olaparib (50 mg, qd x 28) and compound A (50 mg qwk x 2) in combination with olaparib (50 mg, qd x 7).

[0091] Figure 4A Shown is the dose-response curve of TNF-α on the viability of BRCA-positive (UWB1.289) cells after treatment with different concentrations of Compound A. Figure 4B Shown is the dose-response curve of INF-γ on the viability of BRCA-positive cells after treatment with different concentrations of Compound A. % inhibition values ​​of luminescent cell viability assay.

[0092] Figure 5A Shown is the dose-response curve of TNF-α on the viability of BRCA1 negative (UWB1.289-2945) cells after treatment with different concentrations of Compound A. Figure 5BShown is the dose-response curve of INF-γ on the viability of BRCA1-negative cells after treatment with different concentrations of Compound A. % inhibition values ​​of luminescent cell viability assay. Each data point is the mean ± SD from three independent determinations.

[0093] Figure 6A Shown is a student t-test of TNF-α on the viability of BRCA1 negative (UWB1.289-2945) cells after treatment with different concentrations of Compound A. Figure 6B Shown is a student t-test comparing INF-γ to BRCA1-negative cell viability after treatment with various concentrations of Compound A. Each data point is the mean ± SD from three independent determinations. **p < 0.01, *p < 0.05.

[0094] Figure 7 In vitro induction of IFN-γ by nivolumab or isotype control antibody (hIgG4 control) is shown. 4 Allogeneic monocyte-derived dendritic cells (DCs) were cultured for 10 5 Purified CD4 + T cells were cultured in triplicate for 6 days. Supernatants were collected on day 5 and IFN-γ production was measured by ELISA. Representative data from multiple donor DC / T cell pairs are shown. Left panel: IFN-γ concentrations induced in the presence of titrated nivolumab or isotype control antibody. Right panel: IFN-γ concentrations measured by counts per minute (CPM).

[0095] Figures 8A-8C Shown are the effects of Compound A treatment on chemokine expression in BRCA2 wild-type (WT) and mutant (Mut) PDX-derived breast cancer cells. Figure 8A Shown are the fold changes of CCL19 in WT (left panel) and Mut (right panel) cancer cells at day 14 and day 28 with treatment of titrated Compound A. Figure 8B Shown are the fold changes of CCL21 in WT (left panel) and Mut (right panel) cancer cells at day 14 and day 28 with treatment of titrated Compound A. Figure 8C Shown are the fold changes of CXCL9 in WT (left panel) and Mut (right panel) cancer cells at day 14 and day 28 with treatment of titrated Compound A.

[0096] Figure 9A hypothetical mechanism of a drug combination comprising a compound of the present invention (e.g., Compound A) and an immunotherapeutic agent (e.g., an agent that can induce the production of endogenous cytotoxic cytokines (e.g., TNF-α and IFN-γ), such as an anti-PD-1 antibody) for the treatment of cancer is shown. The combination can exert an effective anti-tumor effect by increasing the immunogenicity of cancer cells. Compound A involves the production of chemokines such as CCL19, CCL20, CCL21, CXCL9, CXCL10, and CXCL12 in tumor cells. These chemokines, in turn, attract active immune cells such as DC, NK, and TCD8. These immune cells release cytotoxic compounds such as cytokines TNF-α and IFN-γ. Compound A therefore enhances the cytotoxicity of TNF-α and IFN-γ, which leads to tumor cell death. DC: dendritic cell; NL: natural killer cell; TCD8: CD8 + T cells. Detailed Description of the Invention

[0098] In patients with disorders associated with cell proliferation (e.g., cancer), activation of the p53 protein can inhibit, alter, or reduce cell proliferation and / or induce apoptosis. Therefore, by providing patients with such disorders with pharmaceutically active Pol I inhibitors that selectively activate the p53 protein of cancer and / or tumor cells, the progression of the disorder or disorder can be alleviated or prevented. The present invention provides methods, combinations, and compositions for treating cancer or tumors, comprising the use of Compound A, or a pharmaceutically acceptable salt, ester, solvate, and / or prodrug thereof, in combination with at least one additional therapeutic agent or therapy. In one embodiment, the present disclosure provides a combination therapy for the use of Compound A with another therapy, such as radiotherapy. In another embodiment, the present invention relates to a combination therapy of Compound A with at least one additional therapeutic agent, wherein the at least one additional therapeutic agent comprises an immunotherapeutic agent, a targeted therapeutic agent (including a kinase inhibitor), and an anti-angiogenic agent.

[0099] definition

[0100] It should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0101] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of this application, representative methods and materials are still described herein.

[0102] Following long-standing patent law convention, the terms "a," "an," and "the," when used in this application (including the claims), mean "one or more." Thus, for example, reference to "a vector" includes mixtures of one or more vectors, two or more vectors, etc.

[0103] Unless otherwise indicated, all numbers used in the specification and claims expressing amounts of ingredients, reaction conditions, and the like are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximate values ​​that may vary depending on the desired properties sought to be obtained by the present application. In general, when referring to a measurable value of an amount such as weight, time, dosage, etc., the term "about" as used herein is meant to encompass variations of ±15% or ±10% of the specified amount in one example, ±5% of the specified amount in another example, ±1% of the specified amount in another example, and ±0.1% of the specified amount in yet another example, as such variations are appropriate for carrying out the disclosed methods.

[0104] The term "compound of the present invention" or "the present compound" refers to a compound of formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or 2-(4-methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-sulfa-1,11b-diazo-benzo[c]fluorene-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide (Compound A) or an isomer, N-oxide, salt, ester, solvate, or prodrug thereof. Alternatively, the above terms may refer to a compound of formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or a salt form of Compound A or a solvate thereof. The compounds of formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A described throughout this application may include any single isomer or a mixture of any number of isomers.

[0105]

[0106] The term "isomer" refers to compounds that have the same chemical formula but may have different stereochemical formulas, structural formulas, or specific atomic arrangements. Examples of isomers include stereoisomers, diastereomers, enantiomers, conformers, rotational isomers, geometric isomers, and atropisomers.

[0107] The term "N-oxide" (also known as amine oxide or amine-N-oxide) refers to a compound derived from a compound of the present invention by oxidation of the amine group of the compound of the present invention. N-oxides generally contain the functional group R3N + -O - (Sometimes written as R3N=O or R3N→O).

[0108] The term "ester" refers to any ester of a compound of the present invention wherein any -COOH functional group of the molecule is replaced by a -COOR functional group, wherein the R portion of the ester is any carbon-containing group that forms a stable ester moiety, including but not limited to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, and substituted derivatives thereof. The term "ester" includes but is not limited to pharmaceutically acceptable esters thereof. Pharmaceutically acceptable esters include but are not limited to alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, and heterocyclyl esters of acidic groups including but not limited to carboxylic acids, phosphoric acids, hypophosphorous acids, sulfonic acids, sulfinic acids, and boric acids.

[0109] The term "composition" or "formulation" refers to one or more substances in a physical form, such as a solid, liquid, gas, or mixtures thereof. An example of a composition is a pharmaceutical composition, i.e., a composition related to, prepared for, or used in a medical therapy.

[0110] The term "carboxylic acid" refers to an organic acid characterized by one or more carboxyl groups, such as acetic acid and oxalic acid. "Sulfonic acid" refers to an organic acid having the general formula R-(S(O)2-OH) n An organic acid wherein R is an organic moiety and n is an integer greater than zero, such as 1, 2, and 3. The term "polyhydroxy acid" refers to a carboxylic acid containing two or more hydroxyl groups. Examples of polyhydroxy acids include, but are not limited to, lactobionic acid, gluconic acid, and galactose.

[0111] As used herein, "pharmaceutically acceptable" means suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use within the scope of sound medical judgment.

[0112] "Salts" include derivatives of the active agent wherein the active agent has been modified by preparing an acid or base addition salt thereof. Preferably, the salt is a pharmaceutically acceptable salt. Such salts include, but are not limited to, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylene salicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaphthoates, glycerophosphates, ketoglutarate, and the like. Base addition salts include, but are not limited to, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietinamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine dicyclohexylamine, etc. Examples of metal salts include lithium, sodium, potassium, magnesium salts, etc. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts, etc. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline, etc. Standard methods for preparing pharmaceutically acceptable salts and their formulations are well known in the art and are disclosed in various references, including, for example, "Remington: The Science and Practice of Pharmacy," edited by A. Gennaro, 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.

[0113] As used herein, "solvate" refers to a complex formed by solvation (combination of solvent molecules with molecules or ions of the active agent of the present invention), or an aggregate consisting of solute ions or molecules (active agent of the present invention) and one or more solvent molecules. In the present invention, preferred solvates are hydrates. Examples of hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, hexahydrates, and the like. It will be appreciated by those of ordinary skill in the art that pharmaceutically acceptable salts of the present compounds may also exist in the form of solvates. Solvates are typically formed by hydration (as part of the preparation of the present compounds) or by the natural absorption of water by the anhydrous compounds of the present invention. Solvates, including hydrates, may be composed of, for example, two, three, or four salt molecules in a stoichiometric ratio per solvate or hydrate molecule. Another possibility is, for example, two salt molecules stoichiometrically associated with three, five, or seven solvent or hydrate molecules. Solvents used for crystallization, such as alcohols, especially methanol and ethanol; aldehydes; ketones, especially acetone; esters, such as ethyl acetate; may be embedded in the crystal grating. Pharmaceutically acceptable solvents are preferred.

[0114] The terms "excipient," "carrier," and "vehicle" are used interchangeably throughout this application and refer to a substance with which a compound of the invention is administered.

[0115] "Therapeutically effective amount" means an amount of a compound or therapeutic agent that, when administered to a patient for the treatment of a disease or other undesirable medical condition, is sufficient to have a beneficial effect on the disease or condition. The therapeutically effective amount will vary depending on the type of compound or therapeutic agent selected, the disease or condition and its severity, and the age, weight, etc. of the patient to be treated. Determining a therapeutically effective amount of a given compound or therapeutic agent is within the ordinary skill in the art and requires only routine experimentation.

[0116] The term "combination therapy" refers to a first therapy comprising a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, combined with a second therapy (e.g., treatment, surgery, and / or additional agents) useful for treating, stabilizing, preventing, and / or delaying a disease or symptom. Administration "in combination with" another therapeutically active agent includes administration sequentially, simultaneously, or continuously by the same or different routes, in the same or different compositions and / or combinations. In some embodiments, the combination therapy optionally comprises one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds, and / or inert substances.

[0117] As used herein, the terms "pharmaceutical combination," "therapeutic combination," or "combination" refer to a single dosage form comprising at least two therapeutically active agents, or separate dosage forms comprising at least two therapeutically active agents, either together or separately, for use in combination therapy. For example, one therapeutically active agent can be formulated into one dosage form, and the other therapeutically active agent can be formulated into a single or different dosage form. For example, one therapeutically active agent can be formulated into a solid oral dosage form, while the second therapeutically active agent can be formulated into a solution dosage form for parenteral administration.

[0118] As used herein, the term "additional agent" or "additional therapeutic agent" or "additional therapeutically active agent" with respect to the compounds described herein refers to an agent, other than a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, that is administered to elicit a therapeutic effect. The agent may be directed toward a therapeutic effect associated with the condition (e.g., cancer) that the disclosed compounds are intended to treat or prevent, or the agent may be intended to treat or prevent symptoms of the underlying condition (e.g., tumor growth, bleeding, ulcers, pain, lymphadenopathy, cough, jaundice, swelling, weight loss, cachexia, sweating, anemia, paraneoplasia, thrombosis, etc.) or to further reduce the appearance or severity of side effects of the disclosed compounds.

[0119] The term "immunotherapeutic agent" refers to chemicals and biological agents that modulate a person's immune response to confer a desired therapeutic effect.

[0120] The term "anticancer agent" refers to chemicals and biological agents that can treat, reduce, prevent, or ameliorate the symptoms caused by cancer or tumor growth.

[0121] The term "anti-angiogenic agent" or "angiogenesis inhibitor" refers to chemicals that block the formation of new blood vessels (angiogenesis) by tumor and cancer cells.

[0122] The term "radiation therapy" or "radiotherapy" refers to the treatment of cancer or tumors by using beams of ionizing radiation, as is well known in the art.

[0123] As used herein, the phrase "disorder characterized by cell proliferation" or "condition characterized by cell proliferation" includes, but is not limited to, cancer, benign and malignant tumors. Examples of cancers and tumors include, but are not limited to, colorectal, breast, lung, liver, pancreas, lymph node, colon, prostate, brain, head and neck, skin, kidney, blood, and heart cancers or tumor growths (e.g., leukemias, lymphomas, carcinomas).

[0124] The terms "treat," "treating," or "treatment" with respect to a particular disease or condition include preventing the disease or condition, and / or alleviating, modifying, improving, or eliminating the symptoms and / or pathology of the disease or condition. In general, the terms as used herein refer to improving, alleviating, alleviating, and eliminating the symptoms of a disease or condition. The candidate molecules or compounds described herein may be in a formulation or medicament in a therapeutically effective amount, which is an amount capable of causing a biological effect, such as apoptosis of certain cells (e.g., cancer cells), reduced proliferation of certain cells, or resulting in, for example, improvement, alleviation, or removal of the symptoms of a disease or condition. The terms may also refer to reducing or stopping the rate of cell proliferation (e.g., slowing or stopping tumor growth) or reducing the number of proliferating cancer cells (e.g., removing part or all of a tumor). These terms are also applicable to reducing the titer of microorganisms in a system (i.e., a cell, tissue, or subject) infected by a microorganism, reducing the rate of microbial reproduction, reducing the number of symptoms or symptomatic effects associated with a microbial infection, and / or removing a detectable amount of microorganisms from a system. Examples of microorganisms include, but are not limited to, viruses, bacteria, and fungi.

[0125] As used herein, the term "inhibit" or "reduce" cell proliferation means slowing, reducing, or, for example, stopping the amount of cell proliferation by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%, when compared to proliferating cells that have not been subjected to the methods, compositions, and combinations of the present application, as measured using methods known to those of ordinary skill in the art.

[0126] As used herein, the term "apoptosis" refers to an intrinsic cellular self-destruction or suicide program. In response to a triggering stimulus, cells undergo a series of events, including cell shrinkage, cell membrane blebbing, and chromosome condensation and fragmentation. These events lead to the transformation of cells into clusters of membrane-bound particles (apoptotic bodies), which are subsequently engulfed by macrophages.

[0127] As used herein, the term "patient" or "subject" includes humans and animals, preferably mammals.

[0128] Compound

[0129] The present invention provides quinolone compounds of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenus thereof, or Compound A or salts, solvates, esters and / or prodrugs thereof. The compounds disclosed herein can be used in combination with at least one additional therapeutic agent or therapy (combination therapy).

[0130] In one embodiment, the present invention comprises a compound of formula (IA),

[0131]

[0132] or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof;

[0133] in:

[0134] X 1 is CH or N;

[0135] X 2 、X 3 、X 4 、X 5 、X 6 and X 7 Independently NR 4 , CH2, CHQ or C(Q)2, provided that: (i) X 2 、X 3 、X 4 、X 5 、X 6 and X 7 Zero, one or two of them are NR 4 (ii) When X 1 When N, X 2 and X 7 Neither is NR 4 (iii) When X 1 When N, X 3 and X 6 Not NR 4 ; and (iv) when X 1 is CH and X 2 、X 3 、X 4 、X 5 、X 6 and X 7 Two of them are NR 4 When the two NR 4 Located at adjacent ring positions or separated by two or more other ring positions;

[0136] A and V are independently H, halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 、-R 3 , -W, -LW, -W 0 , or-LN(R)-W 0 ;

[0137] Each Q is independently halogen, azide, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 、-R 3 , -W, -LW, -W 0 , or-LN(R)-W 0 ;

[0138] In each-NR 1 R 2 In, R 1 and R 2 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains one additional heteroatom selected from N, O and S as a ring member;

[0139] R 1 is H, or C1-C6 alkyl optionally substituted by one or more halogens, or ═O;

[0140] R 2 is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0141] R 3 is optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0142] Each R 4 are independently H or C1-C6 alkyl; or R 4 Can be -W, -LW, or -LN(R)-W 0 ;

[0143] Each R is independently H, or C1-C6 alkyl;

[0144] R 7 is H, and R 8is C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens; or in the case of –NR 7 R 8 In, R 7 and R 8 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains additional heteroatoms selected from N, O and S as ring members;

[0145] m is 0, 1, 2, 3 or 4;

[0146] n is 0, 1, 2, 3, 4 or 5;

[0147] L is a C1-C10 alkylene, C1-C10 heteroalkylene, C2-C10 alkenylene, or C2-C10 heteroalkenylene linker, each of which may be optionally substituted with a substituent selected from the group consisting of halogen, oxo (═O), or C1-C6 alkyl;

[0148] W is an optionally substituted 4-7 membered nitrogen heterocycle, which optionally contains additional heteroatoms selected from N, O and S as ring members; and

[0149] W 0 is an optionally substituted 3-4 membered carbocyclic ring, or a C1-C6 alkyl group substituted by 1 to 4 fluorine atoms.

[0150] In some embodiments of these compounds, X 1 is CH and X 2 、X 3 、X 4 、X 5 、X 6 and X 7 Two of them are NR 4 In some embodiments, X 1 is CH and X 2 、X 3 、X 4 、X 5 、X 6 and X 7 One of them is NR 4 In other embodiments, X 1 is CH and X 2 、X 3 、X 4 、X 5 、X 6 and X 7 Neither is NR 4In yet other embodiments, X 1 is N and X 2 、X 3 、X 4 、X 5 、X 6 and X 7 Neither is NR 4 In still other embodiments, X 1 is N and X 4 or X 5 One of them is NR 4 .

[0151] In one embodiment, the present invention provides a compound of formula (IB),

[0152]

[0153] or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof;

[0154] in:

[0155] X 1 is CH or N;

[0156] X 2 、X 3 、X 4 、X 5 、X 6 and X 7 Independently NR 4 , CH2, CHQ or C(Q)2, provided that X 2 、X 3 、X 4 、X 5 、X 6 and X 7 Zero, one or two of them are NR 4 ;

[0157] A and V are independently H, halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 、-R 3 , -W, -LW, -W 0 , or-LN(R)-W 0 ;

[0158] Each Q is independently halogen, azide, -CN, -CF3, -CONR 1 R 2 、-NR1 R 2 、-SR 2 、-OR 2 、-R 3 , -W, -LW, -W 0 , or-LN(R)-W 0 ;

[0159] In each-NR 1 R 2 In, R 1 and R 2 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains one additional heteroatom selected from N, O and S as a ring member;

[0160] R 1 is H, or C1-C6 alkyl optionally substituted by one or more halogens, or ═O;

[0161] R 2 is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0162] R 3 is optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0163] Each R 4 are independently H, or C1-C6 alkyl; or R 4 Can be -W, -LW, or -LN(R)-W 0 ;

[0164] Each R is independently H, or C1-C6 alkyl;

[0165] R 7 is H, and R 8 is C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens; or in the case of –NR7 R 8 In, R 7 and R 8 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains additional heteroatoms selected from N, O and S as ring members;

[0166] m is 0, 1, 2, 3 or 4;

[0167] n is 0, 1, 2, 3, 4 or 5;

[0168] L is a C1-C10 alkylene, C1-C10 heteroalkylene, C2-C10 alkenylene, or C2-C10 heteroalkenylene linker, each of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, oxo (═O), or C1-C6 alkyl;

[0169] W is an optionally substituted 4-7 membered nitrogen heterocycle, which optionally contains additional heteroatoms selected from N, O and S as ring members; and

[0170] W 0 is an optionally substituted 3-4 membered carbocyclic ring, or a C1-C6 alkyl group substituted by 1 to 4 fluorine atoms.

[0171] In one embodiment, the present invention provides a compound of formula (I),

[0172]

[0173] or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof;

[0174] in:

[0175] X 1 is CH or N;

[0176] X 2 、X 3 、X 4 、X 5 、X 6 and X 7 Independently NR 4 , CH2, CHQ or C(Q)2, provided that X 2 、X 3 、X 4 、X 5 、X 6 and X 7 Zero, one or two of them are NR 4 ;

[0177] A and V are independently H, halogen, azido, -CN, -CF3, -CONR 1 R2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ;

[0178] Each Q is independently halogen, azide, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ;

[0179] In each-NR 1 R 2 In, R 1 and R 2 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains one additional heteroatom selected from N, O and S as a ring member;

[0180] R 1 is H, or C1-C6 alkyl optionally substituted by one or more halogens, or ═O;

[0181] R 2 is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0182] R 3 is optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0183] R 4 are independently H, or C1-C6 alkyl;

[0184] R 7 is H, and R 8is C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens; or in the case of –NR 7 R 8 In, R 7 and R 8 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains one additional heteroatom selected from N, O and S as a ring member;

[0185] m is 0, 1, 2, 3 or 4; and

[0186] n is 0, 1, 2, 3, 4 or 5.

[0187] In one embodiment, the present invention provides a compound of formula (IIA),

[0188]

[0189] or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof;

[0190] in:

[0191] A and V are independently H, halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 、-R 3 , -W, -LW, -W 0 , or-LN(R)-W 0 ;

[0192] Each Q is independently halogen, azide, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 、-R 3 , -W, -LW, -W 0 , or-LN(R)-W 0 ;

[0193] In each-NR 1 R 2 In, R 1 and R 2Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains additional heteroatoms selected from N, O and S as ring members;

[0194] R 1 is H, or C1-C6 alkyl optionally substituted by one or more halogens, or ═O;

[0195] R 2 is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0196] R 3 is optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0197] Each R 4 are independently H, or C1-C6 alkyl; or R 4 Can be -W, -LW, or -LN(R)-W 0 ;

[0198] Each R is independently H, or C1-C6 alkyl;

[0199] m is 0, 1, 2, 3 or 4;

[0200] n is 0, 1, 2, 3, 4 or 5;

[0201] p is 0, 1, 2, or 3;

[0202] L is a C1-C10 alkylene, C1-C10 heteroalkylene, C2-C10 alkenylene, or C2-C10 heteroalkenylene linker, each of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, oxo (═O), or C1-C6 alkyl;

[0203] W is an optionally substituted 4-7 membered nitrogen heterocycle, which optionally contains additional heteroatoms selected from N, O and S as ring members; and

[0204] W 0 is an optionally substituted 3-4 membered carbocyclic ring, or a C1-C6 alkyl group substituted by 1 to 4 fluorine atoms.

[0205] In one embodiment, the present invention provides a compound of formula (II),

[0206]

[0207] or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof;

[0208] in:

[0209] A and V are independently H, halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ;

[0210] Each Q is independently halogen, azide, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ;

[0211] In each-NR 1 R 2 In, R 1 and R 2 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains additional heteroatoms selected from N, O and S as ring members;

[0212] R 1 is H, or C1-C6 alkyl optionally substituted by one or more halogens, or ═O;

[0213] R 2 is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0214] R 3is optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0215] Each R 4 are independently H, or C1-C6 alkyl;

[0216] m is 0, 1, 2, 3 or 4;

[0217] n is 0, 1, 2, 3, 4 or 5; and

[0218] p is 0, 1, 2 or 3.

[0219] In another embodiment, the present invention provides a compound of formula (IIIA),

[0220]

[0221] or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof;

[0222] in:

[0223] A and V are independently H, halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 、-R 3 , -W, -LW, -W 0 , or-LN(R)-W 0 ;

[0224] Each Q is independently halogen, azide, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 、-R 3 , -W, -LW, -W 0 , or-LN(R)-W 0 ;

[0225] In each-NR 1 R 2 In, R 1 and R 2Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains additional heteroatoms selected from N, O and S as ring members;

[0226] R 1 is H, or C1-C6 alkyl optionally substituted by one or more halogens, or ═O;

[0227] R 2 is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0228] R 3 is optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0229] Each R 4 are independently H, or C1-C6 alkyl; or R 4 Can be -W, -LW, or -LN(R)-W 0 ;

[0230] Each R is independently H, or C1-C6 alkyl;

[0231] R 7 is H, and R 8 is C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens; or in the case of –NR 7 R 8 In, R 7 and R 8 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains additional heteroatoms selected from N, O and S as ring members;

[0232] m is 0, 1, 2, 3 or 4;

[0233] n is 0, 1, 2, 3, 4 or 5;

[0234] L is a C1-C10 alkylene, C1-C10 heteroalkylene, C2-C10 alkenylene, or C2-C10 heteroalkenylene linker, each of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, oxo (═O), or C1-C6 alkyl;

[0235] W is an optionally substituted 4-7 membered nitrogen heterocycle comprising additional heteroatoms selected from N, O and S as ring members; and

[0236] W 0 is an optionally substituted 3-4 membered carbocyclic ring, or a C1-C6 alkyl group substituted by 1 to 4 fluorine atoms.

[0237] In another embodiment, the present invention provides a compound of formula (III),

[0238]

[0239] or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof;

[0240] in:

[0241] A and V are independently H, halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ;

[0242] Each Q is independently halogen, azide, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ;

[0243] In each-NR 1 R 2 In, R 1 and R 2 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains additional heteroatoms selected from N, O and S as ring members;

[0244] R 1 is H, or C1-C6 alkyl optionally substituted by one or more halogens, or ═O;

[0245] R 2is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0246] R 3 is optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0247] Each R 4 are independently H, or C1-C6 alkyl;

[0248] R 7 is H, and R 8 is C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0249] m is 0, 1, 2, 3 or 4; and

[0250] n is 0, 1, 2, 3, 4 or 5.

[0251] In one embodiment, the present disclosure provides 2-(4-methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-sulfur-1,11b-diazo-benzo[c]fluorene-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide (Compound A) as shown below.

[0252]

[0253] In another embodiment, the present invention provides a salt and / or solvate of Compound A.

[0254] Additional therapeutically active agents

[0255] In one embodiment, the present invention provides a combination therapy comprising a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA), and / or subgenera thereof, or Compound A, and at least one additional therapeutic agent or treatment. The therapeutic agents, therapeutically active agents, and treatments described below may be used in conjunction with the administration of the compounds described above.

[0256] Immunotherapeutic agents

[0257] Immunotherapy refers to a method for treating a subject with a disease, or at risk of an infectious disease, or at risk of encountering a recurrence of a disease, by including induction, enhancement, suppression or otherwise modifying an immune response. In one embodiment, an immunotherapeutic agent destroys, reduces or suppresses signal transduction from an inhibitory immunomodulator. Most immunotherapy methods themselves have limited benefits for most cancers. The reasons include immunomodulation mediated by various cell expressions and secretory molecules by cancer cells and white blood cell colonies. For example, anti-tumor immunity in the tumor microenvironment is suppressed by various tumor-infiltrating white blood cells, including regulatory T cells (Treg), bone marrow-derived suppressor cells (MDSC) and alternatively activated (type 2) macrophages (M2). These cell types include secretion of cytokines such as IL-10 and TGFβ and expression of inhibitory receptors such as CTLA-4 and PD-L1 in order to suppress effective immunity. Tumor cells can actively suppress immunotherapy through many mechanisms, such as secreting cytokines (such as VEGF and TGFβ) that actively inhibit T cell recognition and tumor cell destruction, or producing programmed cell death-1 ligand (PD-L1), which inhibits the function of PD-1 expressed on activated T cells, see (Devaud et al., Oncolmmunology 2:8e25961, 2013).

[0258] The present invention provides a pharmaceutical combination comprising a compound described herein (e.g., Compound A) and at least one immunotherapeutic agent. The combination is suitable for treating or ameliorating cell proliferative disorders, such as cancer. In some embodiments, the combination provides a synergistic therapeutic effect compared to a single compound or a single immunotherapeutic agent.

[0259] Without wishing to be bound by any particular theory, such drug combinations are effective in treating or improving cell proliferation disorders through one or more mechanisms described herein. In some embodiments, the immunotherapeutic agent of the present invention increases one or more cytokines produced locally that have cytotoxic effects on tumor cells. Such cytokines include but are not limited to tumor necrosis factor α (TNFα) and interferon gamma (IFNγ). The chemical compounds described herein (e.g., compound A) can enhance the cytotoxic effects of TNF-α and / or IFN-γ, so the combination can achieve a greater therapeutic effect. In some embodiments, the chemical compounds described herein (e.g., compound A) can induce chemokine production in tumor cells, such as tumor cells with homologous recombination defects (e.g., tumor cells with BRCA1 and / or BRCA2 mutations). The chemokines produced then attract immune cells, dendritic cells (DCs), activated effector T cells (e.g., CD8+ lymphocytes), and / or natural killer (NK) cells to tumor cells and destroy tumor cells. In some embodiments, the induced chemokines are CCL19, CCL20, and / or CCL21 that attract dendritic cells. In some embodiments, the induced chemokine is CX3CL1 that attracts activated effector T cells (e.g., CD8+ lymphocytes). In some embodiments, the induced chemokine is CXCL9 and / or CXCL10 that attracts activated effector T cells (e.g., CD8+ lymphocytes) and NK cells.

[0260] In one embodiment, the immunotherapeutic agent is a monoclonal antibody, immune effector cell, adoptive cell transfer, immunotoxin, vaccine, and / or cytokine.

[0261] In one embodiment, the immunotherapeutic agent is an agent that can regulate the physiological levels of one or more cytokines in the tumor microenvironment of cancer. In one embodiment, the cytokines regulated by the immunotherapeutic agent are selected from one or more of the group consisting of TNF-α, IFN-γ, IL-10, TGFβ and VEGF. In some embodiments, the immunotherapeutic agent induces the production of endogenous cytokines (such as TNF-α or IFN-γ) that have a cytotoxic effect on tumor cells. In some embodiments, the immunotherapeutic agent suppresses the production of endogenous cytokines that interfere with T cell recognition and cancer cell destruction, such as IL-10, TGFβ or VEGF.

[0262] In other embodiments, immunotherapeutic agents are agents that can induce tumor cells to produce one or more chemokines that lure immune cells to tumor cells, such as dendritic cells, effector T cells (e.g., CD8+ lymphocytes), and natural killer (NK) cells. In some embodiments, chemokines include but are not limited to CCL19, CCL20, CCL21, CX3CL1, CXCL9, and CXCL10.

[0263] In other embodiments, the immunotherapeutic agent is an agent that induces immune checkpoint blockade, such as PD-1 blockade and CTLA-4 blockade.

[0264] In some embodiments, the immunotherapeutic agent is an antibody or antigen-binding portion thereof that destroys the interaction between PD-1 and PD-L1. In some embodiments, the immunotherapeutic agent is an anti-PD-1 antibody, a PD-1 antagonist, an anti-PD-L1 antibody, an siRNA targeting PD-1 expression, an siRNA targeting PD-L1 expression, or a peptide, fragment, dominant negative form, or soluble form of PD-1 or PD-L1. In one embodiment, the anti-PD-1 antibody is a monoclonal antibody and / or a humanized antibody. Cytotoxic T lymphocyte antigen 4 (CTLA4, also known as CD152) is a member of the immunoglobulin superfamily expressed only on T cells. CTLA4 acts to inhibit T cell activation and has been reported to inhibit helper T cell activity and enhance regulatory T cell immunosuppressive activity. In some embodiments, the immunotherapeutic agent is an antibody that destroys CTLA4. In other embodiments, the immunotherapeutic agent is a CTLA-4 antagonist, an anti-CTLA-4 antibody, an siRNA targeting CTLA-4 expression, or a peptide, fragment, dominant negative form, or soluble form of CTLA-4. Other immunoglobulin superfamily members include, but are not limited to, CD28, ICOS, and BTLA.

[0265] In some embodiments, the immunotherapeutic agent is selected from the group consisting of anti-PD-1 antibodies, nivolumab (BMS-936558, ONO-4538), lambrolizumab (MK-3475), pidilizumab (CT-011), alemtuzumab, bevacizumab, brentuximab, cetuximab, gemtuzumab tuximab, ipilimumab tiuxetan, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, tremelimumab, lirlumab, trevilizumab, AB134090, 1115 9-H03H, 11159-H08H, PA5-29572, PA5-23967, PA5-26465, MA1-12205, MA1-35914, AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, MIH1, anti-B7-H4, anti-B7-H1, anti-LAG3, BTLA, anti-Tim3, anti-B7-DC, anti-CD160, MR antagonist, anti-4-1BB, anti-OX40, anti-CD27, CD40 agonist, clone UC10-4F10-11, clone RPM1-14, clone 9D9, clone 10F.9G2 and analogs thereof, and mixtures thereof.

[0266] In one embodiment, the immunotherapeutic agent is an anti-PD-1 antibody. In another embodiment, the immunotherapeutic agent is nivolumab or pembrolizumab. In other embodiments, the immunotherapeutic agent is an anti-CTLA-4 antibody. In one embodiment, the immunotherapeutic agent is ipilimumab.

[0267] anticancer agents

[0268] Anticancer agents used in combination with the compounds of the present invention may include agents selected from any class of agents known to those of ordinary skill in the art, including, for example, alkylating agents, antimetabolites, plant alkaloids and terpenoids (e.g., taxanes), topoisomerase inhibitors, antitumor antibiotics, kinase inhibitors, hormone therapy, molecular targeted agents, etc. Generally speaking, such anticancer agents are alkylating agents, antimetabolites, vinca alkaloids, taxanes, topoisomerase inhibitors, antitumor antibiotics, tyrosine kinase inhibitors, immunosuppressive macrolides, Akt inhibitors, HDAC inhibitors, Hsp90 inhibitors, mTOR inhibitors, PI3K / mTOR inhibitors, PI3K inhibitors, CDK (cyclin-dependent kinase) inhibitors, CHK (checkpoint kinase) inhibitors, PARP (poly (DP-ribose) polymerase) inhibitors, and the like.

[0269] Alkylating agents include (a) alkylating platinum-based chemotherapeutic agents, such as cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, and (SP-4-3)-(cis)-ammoniadichloro-[2-methylpyridine]platinum(II); (b) alkyl sulfonates, such as busulfan; (c) ethyleneimine and methylmelamine derivatives, such as altretamine and thiotepa; (d) nitrogen mustards, such as nitrogen mustard phenylbutyrate, cyclophosphamide, estramustine, ifosfamide, dichloromethyldiethylamine, trofosamide, prednimustine, melphalan, and uramustine; (e) nitrosoureas, such as carmustine, lomustine, fotemustine, nimustine, ranimustine, and streptozocin; (f) triazenes and imidazotetrazines, such as dacarbazine, procarbazine, temozolamide, and temozolomide.

[0270] Antimetabolites include (a) purine analogs such as fludarabine, cladribine, chlorodeoxyadenosine, clofarabine, mercaptopurine, pentostatin, and thioguanine; (b) pyrimidine analogs such as fluorouracil, gemcitabine, capecitabine, cytarabine, azacitidine, edatrexate, floxuridine, and troxacitabine; (c) antifolates such as methotrexate, pemetrexed, raltitrexed, and trimetrexate. Antimetabolites also include thymidylate synthase inhibitors such as fluorouracil, raltitrexed, capecitabine, floxuridine, and pemetrexed; and ribonucleotide reductase inhibitors such as cladribine, clofarabine, and fludarabine.

[0271] Plant alkaloid and terpenoid-derived agents include mitotic inhibitors such as the vinca alkaloids vinblastine, vincristine, vindesine, and vinorelbine; and microtubule polymer stabilizers such as taxanes, including but not limited to paclitaxel, docetaxel, larotaxel, ortataxel, and tesetaxel.

[0272] Topoisomerase inhibitors include topoisomerase I inhibitors such as camptothecin, topotecan, irinotecan, rubitecan, and belotecan; and topoisomerase II inhibitors such as etoposide, teniposide, and amsacrine.

[0273] Antitumor antibiotics include (a) anthracyclines, such as daunorubicin (including liposomal daunorubicin), doxorubicin (including liposomal doxorubicin), epirubicin, idarubicin, and valrubicin; (b) Streptomyces-related agents, such as bleomycin, actinomycin, mithramycin, mitomycin, porfibrinocin; and (c) anthracenediones, such as mitoxantrone and pyrantrone. Anthracyclines have three mechanisms of action: insertion between base pairs of DNA / RNA chains; inhibition of topoisomerase II enzymes; and generation of iron-mediated oxygen free radicals that damage DNA and cell membranes. Anthracyclines are generally characterized as topoisomerase II inhibitors.

[0274] Hormonal therapies include (a) androgens such as fluoxymesterone and testolactone; (b) antiandrogens such as bicalutamide, cyproterone acetate, flutamide, and nilutamide; (c) aromatase inhibitors such as aminoglutethimide, anastrozole, exemestane, formestane, and letrozole; (d) corticosteroids such as dexamethasone and prednisone; (e) estrogens such as diethylstilbestrol; (f) antiestrogens such as fulvestrant, raloxifene, tamoxifen, and toremifene; (g) LHRH agonists and antagonists such as buserelin, goserelin, leuprorelin, and triptorelin; (h) progestins such as medroxyprogesterone acetate and megestrol acetate; and (i) thyroid hormones such as levothyroxine and deiothyroxine.

[0275] Molecularly targeted agents include (a) receptor tyrosine kinase (RTK) inhibitors, such as inhibitors of EGFR, including erlotinib, gefitinib, and neratinib; inhibitors of VEGFR, including vandetanib, semaxinib, and cediranib; and inhibitors of PDGFR; also include RTK inhibitors that act on multiple receptor sites, such as lapatinib, which inhibits both EGFR and HER2, and those that act on each of C-kit, PDGFR, and VEGFR, including but not limited to axitinib, sunitinib, sorafenib, and toceranib; also include inhibitors of BCR-ABL, c-kit, and PD GFR inhibitors, such as imatinib; (b) FKBP binders, such as immunosuppressive macrolide antibiotics, including bafilomycin, rapamycin (sirolimus), and everolimus; (c) gene therapy agents, antisense therapy agents, and gene expression regulators, such as retinoids and retinoids, such as adapalene, bexarotene, trans-retinoic acid, 9-cis retinoic acid, and N(4-hydroxyphenyl)retinamide; (d) phenotype-targeted therapeutics, including monoclonal antibodies, such as alemtuzumab, bevacizumab, cetuximab, ibritumomab tiuxetan, rituximab, and trastuzumab; (e) immunotoxins, such as gemtuzumab ozogamicin; (f) radioimmunoconjugates, such as 131I-tositumomab; and (g) cancer vaccines.

[0276] Akt inhibitors include, but are not limited to, 1L6 hydroxymethyl-chiro-inositol-2-(R)-2-O-methyl-3-O-octadecyl-sn-glycerol carbonate, SH-5 (Calbiochem Catalog No. 124008), SH-6 (Calbiochem Catalog No. 124009), Calbiochem Catalog No. 124011, triciribine (NSC 154020, Calbiochem catalog number 124012), 10-(4'-(N-diethylamino)butyl)-2-chlorophenoxazine, Cu(II)Cl2(3-formylchromonethiosemicarbazone), 1,3-dihydro-1-(1-((4-(6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)phenyl)methyl)-4-piperidinyl)-2H-benzimidazol-2-one, GSK690693(4-(2-(4-amino-1,2,5-oxadiazole-3- [(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol), SR13668 ((2,10-diethoxycarbonyl-6-methoxy-5,7-dihydro-indolo[2,3-b]carbazole), GSK2141795, Perifosine, GSK21110183, XL418, XL147, PF-04691502, BEZ-235 [2-methyl-2-[4- (3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile], PX-866 ((acetic acid (1S,4E,10R,11R,13S,14R)-[4-diallylaminomethylene-6-hydroxy-1-methoxymethyl-10,13-dimethyl-3,7,17-trioxo-1,3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxa-cyclopentadienyl] a]phenanthren-11-yl ester]), D106669, CAL-101, GDC0941 (2-(1H-indazol-4-yl)-6-(4-methylsulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine), SF1126, SF1188, SF2523, TG100-115 [3-[2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol. Many of these inhibitors, such as BEZ-235, PX-866, D 106669, CAL 101, GDC0941, SF1126, and SF2523 are also identified in this invention as PI3K / mTOR inhibitors; other examples, such as PI-103 [3-[4-(4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride], are well known to those of ordinary skill in the art.Other well-known PI3K inhibitors include LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] and wortmannin. mTOR inhibitors known to those of ordinary skill in the art include temsirolimus, deforolimus, sirolimus, everolimus, zotarolimus, and biolimus A9. A representative subset of such inhibitors includes temsirolimus, deforolimus, zotarolimus, and biolimus A9.

[0277] HDAC inhibitors include, but are not limited to, (i) hydroxamic acids such as trichostatin A, vorinostat (suberoylanilide hydroxamic acid (SAHA)), panobinostat (LBH589), and belinostat (PXD101), (ii) cyclic peptides such as trapoxin B and depsipeptides such as romidepsin (NSC 630176), (iii) benzamides, such as MS-275 (3-pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate), CI994 (4-acetamido-N-(2-aminophenyl)-benzamide) and MGCD0103 (N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide), (iv) electrophilic ketones, (v) fatty acid compounds, such as phenylbutyrate and valproic acid. In one embodiment, the PI3K inhibitor is idelalisib (CAL-101).

[0278] Hsp90 inhibitors include, but are not limited to, benzoquinone ansamycins such as geldanamycin, 17DMAG (17-dimethylamino-ethylamino-17-demethoxygeldanamycin), tanespimycin (17AAG, 17-allylamino-17-demethoxygeldanamycin), EC5, retaspimycin (IPI-504, 18,21-didehydro-17-demethoxy-18,21-dideoxy-18,21-dihydroxy-17 -(2-propenylamino)-geldanamycin), and herbimycin; pyrazoles, such as CCT018159 (4-[4-(2,3-dihydro-1,4-benzodioxepin-6-yl)-5-methyl-1H-pyrazol-3-yl]-6-ethyl-1,3-benzenediol); macrolides, such as radicicol; and BIIB021 (CNF2024), SNX-5422, STA-9090, and AUY922.

[0279] CDK inhibitors include, but are not limited to, AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC202, R-roscovitine), ZK-304709AT7519M, P276-00, SCH727965, AG-024322, LEE011, LY2835219, P1446A-05, BAY 1000394, SNS-032, and the like.

[0280] CHK inhibitors include, but are not limited to, 5-(3-fluorophenyl)-3-ureidothiophene-N-[(S)-piperidin-3-yl]-2-carboxamide (AZD7762), 7-nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}amide (PV1019), 5-(8-chloro-3-isoquinolinyl)amino]-3-[(1R)-2-(dimethylamino)-1-methylethoxy]-2-pyrazinecarbonitrile (SAR-020106), PF- 00477736, CCT241533, 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(3R)-3-piperidinyl-pyrazolo[1,5-a]pyrimidin-7-amine (SCH900776), 7-hydroxystaurosporine (UCN-01), 4-[((3S)-1-azabicyclo[2.2.2]octan-3-yl)amino]-3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one (CHIR124) , 7-aminodactinomycin (7-AAD), isogranulatimide, debromohymenialdisine, N-[5-bromo-4-methyl-2-[(2S)-2-morpholinylmethoxy]-phenyl]-N'-(5-methyl-2-pyrazinylurea) (LY2603618), sulforaphane (4-methylsulfinylbutyl isothiocyanate), 9,10,11,12-tetrahydro- 9,12-Epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazepine-1,3(2H)-dione (SB-218078), TAT-S216A (synthetic peptide; see US9415118, the entire contents of which are incorporated herein by reference), CBP501 (see US20100112089A1, the entire contents of which are incorporated herein by reference), and analogs thereof.

[0281] PARP inhibitors include, but are not limited to, 4-(3-(1-(cyclopropanecarbonyl)piperazine-4-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (olaparib, AZD2281, Ku-0059436), 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (veliparib, ABT-888), (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (trapanib, BMN 673), 4-iodo-3-nitrobenzamide (eniparib, BSI-201), 8-fluoro-5-(4-((methylamino)methyl)phenyl)-3,4-dihydro-2H-azepin[5,4,3-cd]indol-1(6H)-one phosphate (rucaparib, AG-014699, PF-01367338), 2-[4-[(dimethylamino)methyl]phenyl]-5,6-dihydroimidazo[ 4,5,1-jk][1,4]benzodiazepine-7(4H)-one (AG14361), 3-aminobenzamide (INO-1001), 2-(2-fluoro-4-((S)-pyrrolidin-2-yl]phenyl)-3H-benzo[d]imidazole-4-carboxamide (A-966492), N-(5,6-dihydro-6-oxo-2-phenanthridinyl)-2-acetamide hydrochloride (PJ34, PJ34 HCl), MK-4827, 3,4-dihydro-4-oxo-3,4-dihydro-4-oxo-N-[(1S)-1-phenylethyl]-2-quinazolinepropionamide (ME0328), 5-(2-oxo-2-phenylethoxy)-1(2H)-isoquinolinone (UPF-1069), 4-[[4-fluoro-3-[(4-methoxy-1-piperidinyl)carbonyl]phenyl]methyl]-1(2H)-phthalazinone (AZD 2461), and analogs thereof. In one embodiment, the PARP inhibitor is olaparib.

[0282] Various agents include altretamine, arsenic trioxide, gallium nitrate, hydroxyurea, levamisole, mitotane, octreotide, procarbazine, suramin, thalidomide, photodynamic compounds such as methoxsalen and porfibril sodium, and proteasome inhibitors such as bortezomib.

[0283] Biological therapeutics include interferons such as interferon-α2a and interferon-α2b, and interleukins such as aldesleukin, denileukin, and oprelvekin.

[0284] In addition to anticancer agents intended to act on cancer cells, combination therapies involving the use of protective or adjuvant agents are also contemplated, including: cytoprotectants such as armifostine, dexrazonxane, and mesna, phosphonates such as parmidronate and zoledronic acid, and stimulatory factors such as epoetin, darbeopetin, filgrastim, PEG-filgrastim, and sargramostim.

[0285] Anti-angiogenic agents

[0286] Angiogenesis refers to the formation of new blood vessels. Chemicals released by cancer cells and tumors signal the growth and formation of new blood vessels. Angiogenesis plays an important role in the proliferation of cancer and tumor cells because the formation of new blood vessels allows the delivery of necessary nutrients to the growing cells. Angiogenesis inhibitors are an important group of chemicals because they can prevent cancer growth by blocking the formation of new blood vessels from surrounding tissues to solid tumors.

[0287] Angiogenesis inhibitors include endothelial-specific receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR) inhibitors, thrombin analogs vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors, and analogs thereof.

[0288] Angiogenesis inhibitors may also include, but are not limited to, 2-methoxyestradiol, AG3340, pumastat, batimastat, BAY 12-9566, carboxyamidotriazole, CC-1088, dextromethorphan acetic acid, dimethylxanthenone acetic acid, EMD 121974, endostatin, IM-862, marimastat, matrix metalloproteinases, penicillamine, PTK787 / ZK 222584, RPI.4610, squalamine, squalamine lactate, 3-[2,4-dimethylpyrrol-5-yl-methyl-indenyl]-2-indolinone (SU5416), (±)-thalidomide, S-thalidomide, R-thalidomide, O-(chloroacetylcarbamoyl)fumagillol (TNP-470), cobricosides, paclitaxel, tamoxifen, COL-3, neovastat, BMS-275291, SU6668, 2-ME, interferon-α, anti-VEGF antibody, Medi-522 (Vitaxin II), CAI (calcium influx inhibitor), celecoxib, interleukin-12, IM862, amiloride, Protein, angiostatin K1-3, angiostatin K1-5, captopril, DL-α-difluoromethylornithine, DL-α-difluoromethylornithine HCl, Endostatin TM protein, fumagillin, herbimycin A, 4-hydroxyphenylretinamide, gamma-interferon, juglone, laminin, laminin hexapeptide, laminin pentapeptide, fumonisin A, medroxyprogesterone, medroxyprogesterone acetate, minocycline, minocycline HCl, placental ribonuclease inhibitor, suramin, suramin sodium salt, human thrombospondin, tissue inhibitor of metalloproteinase-1, neutrophil tissue inhibitor of metalloproteinase-1, rheumatoid synovial fibroblast tissue inhibitor of metalloproteinase-2, and analogs thereof.

[0289] Radiation therapy

[0290] Radiation therapy uses high-energy x-rays given as external beam radiation therapy or internal beam radiation therapy to prevent or reduce further proliferation of cancer cells or to induce apoptosis in cancer cells. Although radiation therapy affects cancer cells as well as healthy cells, healthy cells are better able to resist or recover from the effects of radiation.

[0291] In one embodiment, radiation therapy can be useful when administered in combination with administration of a therapeutically effective amount of a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate, and / or prodrug thereof. In some embodiments, radiation therapy can be administered before, during, or after a subject begins or ends a treatment regimen comprising a therapeutically effective amount of a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate, and / or prodrug thereof.

[0292] Combination therapy

[0293] In one embodiment, the present invention provides a method for treating a condition associated with cell proliferation in a patient in need thereof. In one embodiment, the present invention provides a method for treating a cancer or tumor. The method comprises co-administering to a patient in need thereof a therapeutically effective amount of at least one compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and at least one additional therapeutically active agent. In some embodiments, the at least one additional therapeutically active agent is selected from the group consisting of an immunotherapeutic agent, an anticancer agent, and an anti-angiogenic agent.

[0294] In one embodiment, the compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, is administered at a dose of about 5 mg / day to about 500 mg / day. In one embodiment, the at least one additional therapeutically active agent is administered at a dose of about 1 mg / day to about 500 mg / day.

[0295] In another embodiment, the compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenus thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof and / or at least one additional therapeutically active agent is administered at about 1 mg / m 2 About 3g / m 2 , about 5mg / m 2 About 1g / m 2 , or about 10 mg / m 2 to about 500 mg / m 2 Dosage administration.

[0296] The dosage can be mg / m 2 The patient's body surface area (BSA) can be calculated as m using various available formulas, using the patient's height and weight. 2 Alternatively, the administered dose can be expressed in mg / day without regard to the patient's BSA. Conversion from one unit to the other is straightforward given the patient's height and weight.

[0297] The term "co-administration" or "co-administration" refers to the administration of (a) a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenera, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and (b) at least one additional therapeutically active agent together in a synergistic manner. For example, co-administration can be simultaneous administration, sequential administration, overlapping administration, intermittent administration, continuous administration, or a combination thereof. In one embodiment, a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenera, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and at least one additional therapeutically active agent are formulated into a single dosage form. In another embodiment, Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenera, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and at least one additional therapeutically active agent are provided in separate dosage forms.

[0298] In one embodiment, co-administration is carried out for one or more treatment cycles. A "treatment cycle" refers to a predetermined period of time during which Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenus, or Compound A, or its pharmaceutically acceptable salts, esters, solvates and / or prodrugs, and at least one additional therapeutic agent are co-administered. Typically, the patient is examined at the end of each treatment cycle to assess the effect of the combination therapy. In one embodiment, co-administration is carried out for 1 to 48 treatment cycles. In another embodiment, co-administration is carried out for 1 to 36 treatment cycles. In another embodiment, co-administration is carried out for 1 to 24 treatment cycles.

[0299] In one embodiment, each treatment cycle has about 3 or more days. In another embodiment, each treatment cycle has about 3 to about 60 days. In another embodiment, each treatment cycle has about 5 to about 50 days. In another embodiment, each treatment cycle has about 7 to about 28 days. In another embodiment, each treatment cycle has 28 days. In one embodiment, the treatment cycle has about 29 days. In another embodiment, the treatment cycle has about 30 days. In another embodiment, the treatment cycle has a treatment cycle of about one month. In another embodiment, the treatment cycle has about 4 to about 6 weeks.

[0300] Depending on the patient's condition and the expected therapeutic effect, the frequency of administration of each of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenus, or Compound A, or its pharmaceutically acceptable salts, esters, solvates and / or prodrugs, and at least one therapeutically active agent can vary from once a day to six times a day. That is, the frequency of administration can be once a day, twice a day, three times a day, four times a day, five times a day, or six times a day. In some embodiments, the frequency of administration can be one to six times a week or one to four times a month. In one embodiment, the frequency of administration can be once a week, once every two weeks, once every three weeks, once every four weeks, or once a month.

[0301] There may be one or more blank days in a treatment cycle. A "blank day" means a day on which no compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenera, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, or at least one therapeutically active agent is administered. In other words, no compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenera, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and at least one therapeutically active agent is administered on a blank day. Any treatment cycle must have at least one non-blank day. A "non-blank day" means a day on which at least one of a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenera, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and at least one therapeutically active agent is administered.

[0302] "Simultaneous administration" means that the compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or pharmaceutically acceptable salts, esters, solvates and / or prodrugs thereof, and at least one therapeutically active agent are administered on the same day. For simultaneous administration, the compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or pharmaceutically acceptable salts, esters, solvates and / or prodrugs thereof, and at least one therapeutically active agent can be administered simultaneously or one at a time.

[0303] In one embodiment of simultaneous administration, the compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate, and / or prodrug thereof, is administered 1 to 4 times per day, 1 to 4 times per week, once every two weeks, once every three weeks, once every four weeks, or 1 to 4 times per month; and the at least one additional therapeutically active agent is administered 1 to 4 times per day, 1 to 4 times per week, once every two weeks, once every three weeks, once every four weeks, or 1 to 4 times per month. In another embodiment of simultaneous administration, the compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate, and / or prodrug thereof, is administered once per week, once every two weeks, once every three weeks, once every four weeks, or once per month; and the at least one additional therapeutically active agent is administered 1 to 4 times per day, 1 to 4 times per week, once every two weeks, once every three weeks, once every four weeks, or 1 to 4 times per month.

[0304] "Sequential administration" means that only one of the compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenus thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and at least one therapeutically active agent is administered on any given day during a period of two or more consecutive days of co-administration without any blank day.

[0305] In one embodiment of sequential administration, the compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate, and / or prodrug thereof, is administered 1 to 4 times per day, 1 to 4 times per week, once every two weeks, once every three weeks, once every four weeks, or 1 to 4 times per month; and the at least one additional therapeutically active agent is administered 1 to 4 times per day, 1 to 4 times per week, once every two weeks, once every three weeks, once every four weeks, or 1 to 4 times per month. In another embodiment of sequential administration, the compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate, and / or prodrug thereof, is administered once per week, once every two weeks, once every three weeks, once every four weeks, or once per month; and the at least one additional therapeutically active agent is administered 1 to 4 times per day, 1 to 4 times per week, once every two weeks, once every three weeks, once every four weeks, or 1 to 4 times per month.

[0306] "Overlapping administration" means that during a period of two or more consecutive days of co-administration without any blank day, there is at least one day of simultaneous administration and at least one day of administration of only one of the compounds of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenus thereof, or Compound A, or pharmaceutically acceptable salts, esters, solvates and / or prodrugs thereof, and at least one therapeutically active agent.

[0307] "Interval administration" means that the period of co-administration has at least one blank day. "Continuous administration" means that the period of co-administration does not have any blank day. Continuous administration can be simultaneous, sequential or overlapping, as described above.

[0308] In this method, co-administration includes oral administration, parenteral administration or its combination. Examples of parenteral administration include but are not limited to intravenous (IV) administration, intra-arterial administration, intramuscular administration, subcutaneous administration, intraosseous administration, intrathecal administration or its combination. Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) compound and / or its subgenus or compound A or its pharmaceutically acceptable salt, ester, solvate and / or prodrug and at least one therapeutically active agent can be administered orally or parenterally alone. In one embodiment, formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) compound and / or its subgenus or compound A or its pharmaceutically acceptable salt, ester, solvate and / or prodrug and at least one therapeutically active agent are administered parenterally. Parenteral administration can be carried out via injection or infusion.

[0309] In one embodiment of the present method, Compound A is provided for use in combination therapy with at least one additional therapeutic agent. In one embodiment, the combination therapy involves co-administration of Compound A with an immunotherapeutic agent, an anticancer agent, or an anti-angiogenic agent. In another embodiment, the combination therapy of the present disclosure provides Compound A with at least one additional therapeutic agent selected from nivolumab, pembrolizumab, and ipilimumab.

[0310] In one embodiment, Compound A and at least one additional therapeutically active agent are administered orally, subcutaneously, or intravenously.

[0311] pharmaceutical preparations

[0312] In another embodiment, the present invention provides a pharmaceutical composition and / or pharmaceutical combination comprising a therapeutically effective amount of a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenerics thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof as described herein, as an active ingredient in combination with a pharmaceutically acceptable excipient or carrier. Excipients are added to the formulation for various purposes.

[0313] In some embodiments, the compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenera, or Compound A, or its pharmaceutically acceptable salts, esters, solvates and / or prodrugs, and at least one therapeutically active agent can be formulated into a single pharmaceutical composition and / or pharmaceutical combination. In some embodiments, the compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenera, or Compound A, or its pharmaceutically acceptable salts, esters, solvates and / or prodrugs, and at least one therapeutically active agent are formulated into a single pharmaceutical composition and / or pharmaceutical combination containing a pharmaceutically acceptable excipient or carrier.

[0314] In one embodiment, at least one therapeutically active agent in the single pharmaceutical composition and / or combined composition is an immunotherapeutic agent, an anti-cancer agent and / or an anti-angiogenic agent.

[0315] In one embodiment, the immunotherapeutic agent in the composition is a monoclonal antibody, an immune effector cell, an adoptive cell transfer, an immunotoxin, a vaccine and / or a cytokine. In one embodiment, the immunotherapeutic agent is a cytokine. In one embodiment, the cytokine as an immunotherapeutic agent is selected from TNF-α and / or IFN-γ.

[0316] In some embodiments, the immunotherapeutic agent in the composition is an antibody or antigen-binding portion thereof that destroys the interaction between PD-1 and PD-L1, thereby attracting T cells to cancer cells. In some embodiments, the immunotherapeutic agent in the composition is an anti-PD-1 antibody, a PD-1 antagonist, an anti-PD-L1 antibody, an siRNA targeting PD-1 expression, an siRNA targeting PD-L1 expression, or a peptide, fragment, dominant negative form, or soluble form of PD-1 or PD-L1. In one embodiment, the anti-PD-1 antibody is a monoclonal antibody and / or a humanized antibody. Cytotoxic T lymphocyte antigen 4 (CTLA4, also known as CD152) is a member of the immunoglobulin superfamily expressed only on T cells. CTLA4 acts to inhibit T cell activation and has been reported to inhibit helper T cell activity and enhance regulatory T cell immunosuppressive activity. In some embodiments, the immunotherapeutic agent in the composition is an antibody that destroys CTLA4. In other embodiments, the immunotherapeutic agent in the composition is a CTLA-4 antagonist, an anti-CTLA-4 antibody, an siRNA targeting CTLA-4 expression, or a peptide, fragment, dominant negative form, or soluble form of CTLA-4. Other immunoglobulin superfamily members include, but are not limited to, CD28, ICOS, and BTLA.

[0317] In some embodiments, the immunotherapeutic agent in the composition is selected from the group consisting of anti-PD-1 antibodies, nivolumab (BMS-936558, ONO-4538), pembrolizumab (MK-3475), pidilizumab (CT-011), alemtuzumab, bevacizumab, brentuximab, cetuximab, gemtuzumab tuximab, ipilimumab tiuxetan, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, trolimumab, rilumab, trevelimumab, AB134090, 11159-H03H, 11159-H08H, PA5-29572, PA 5-23967, PA5-26465, MA1-12205, MA1-35914, AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, MIH1, anti-B7-H4, anti-B7-H1, anti-LAG3, BTLA, anti-Tim3, anti-B7-DC, anti-CD160, MR antagonist, anti-4-1BB, anti-OX40, anti-CD27, CD40 agonist, clone UC10-4F10-11, clone RPM1-14, clone 9D9, clone 10F.9G2 and analogs thereof, and mixtures thereof.

[0318] In one embodiment, the immunotherapeutic agent in the composition is an anti-PD-1 antibody. In another embodiment, the immunotherapeutic agent in the composition is nivolumab or pembrolizumab. In other embodiments, the immunotherapeutic agent in the composition is an anti-CTLA-4 antibody. In one embodiment, the immunotherapeutic agent in the composition is ipilimumab.

[0319] In some embodiments, the immunotherapeutic agent in the composition is an antibody that destroys CTLA4. In other embodiments, the immunotherapeutic agent in the composition is a CTLA-4 antagonist, an anti-CTLA-4 antibody, an siRNA targeting CTLA-4 expression, or a peptide, fragment, dominant negative form, or soluble form of CTLA-4. Other immunoglobulin superfamily members include, but are not limited to, CD28, ICOS, and BTLA.

[0320] In some embodiments, the immunotherapeutic agent in the composition is selected from the group consisting of: pidilizumab (CT-011), alemtuzumab, bevacizumab, brentuximab, cetuximab, gemtuzumab tuximab, ipilimumab tiuxetan, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, trolimumab, rilutumomab, trevelimumab, AB134090, 11159-H03H, 11159-H08H, PA5-29572, PA5-23967, PA5-26465, MA1-1220 5. MA1-35914, AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, MIH1, anti-B7-H4, anti-B7-H1, anti-LAG3, BTLA, anti-Tim3, anti-B7-DC, anti-CD160, MR antagonist, anti-4-1BB, anti-OX40, anti-CD27, CD40 agonist antibody, clone UC10-4F10-11, clone RPM1-14, clone 9D9, clone 10F.9G2, and analogs thereof, and mixtures thereof.

[0321] In other embodiments, the immunotherapeutic agent in the composition is an anti-CTLA-4 antibody. In one embodiment, the immunotherapeutic agent in the composition is ipilimumab.

[0322] The anticancer agent in the composition of the present application may include any type of agent known to those skilled in the art, including, for example, alkylating agents, antimetabolites, plant alkaloids and terpenoids (e.g., taxanes), topoisomerase inhibitors, antitumor antibiotics, kinase inhibitors, hormone therapy, molecular targeted agents, and analogs thereof. Generally speaking, such anticancer agents are alkylating agents, antimetabolites, vinca alkaloids, taxanes, topoisomerase inhibitors, antitumor antibiotics, tyrosine kinase inhibitors, immunosuppressive macrolides, Akt inhibitors, HDAC inhibitors, Hsp90 inhibitors, mTOR inhibitors, PI3K / mTOR inhibitors, PI3K inhibitors, CDK (cyclin-dependent kinase) inhibitors, CHK (checkpoint kinase) inhibitors, PARP (poly (DP-ribose) polymerase) inhibitors, and analogs thereof.

[0323] The alkylating agent in the composition can include (a) alkylating platinum-based chemotherapeutic agents, such as cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin and (SP-4-3)-(cis)-aminodichloro-[2-methylpyridine]platinum(II); (b) alkyl sulfonates, such as busulfan; (c) ethyleneimine and methylmelamine derivatives, such as hexamethylmelamine and thiotepa; (d) nitrogen mustards, such as nitrogen mustard phenylbutyrate, cyclophosphamide, estramustine, ifosfamide, dichloromethyldiethylamine, trexamide, prednimustine, melphalan and uramustine; (e) nitrosoureas, such as carmustine, lomustine, fotemustine, nimustine, ranimustine and streptozocin; (f) triazenes and imidazotetrazines, such as dacarbazine, procarbazine, temozolomide and dimondol.

[0324] The antimetabolites in the composition include (a) purine analogs such as fludarabine, cladribine, chlorodeoxyadenosine, clofarabine, mercaptopurine, pentostatin and thioguanine; (b) pyrimidine analogs such as fluorouracil, gemcitabine, capecitabine, cytarabine, azacitidine, edatrexate, floxuridine and troxacitabine; (c) antifolates such as methotrexate, pemetrexed, raltitrexed and trimetrexate. Antimetabolites also include thymidylate synthase inhibitors such as fluorouracil, raltitrexed, capecitabine, floxuridine and pemetrexed; and ribonucleotide reductase inhibitors such as cladribine, clofarabine and fludarabine.

[0325] Plant alkaloid and terpenoid derivative agents in the composition may include mitotic inhibitors such as the vinca alkaloids vinblastine, vincristine, vindesine, and vinorelbine; and microtubule polymer stabilizers such as taxanes, including but not limited to paclitaxel, docetaxel, larotaxel, ortataxel, and tesetaxel.

[0326] The topoisomerase inhibitor in the composition may include topoisomerase I inhibitors such as camptothecin, topotecan, irinotecan, rubitecan, and belotecan; and topoisomerase II inhibitors such as etoposide, teniposide, and amsacrine.

[0327] The antitumor antibiotics in the composition may include (a) anthracyclines, such as daunorubicin (including liposomal daunorubicin), doxorubicin (including liposomal doxorubicin), epirubicin, idarubicin, and valrubicin; (b) Streptomyces-related agents, such as bleomycin, actinomycin, mithramycin, mitomycin, porfibrinocin; and (c) anthracenediones, such as mitoxantrone and pyrantrone. Anthracyclines have three mechanisms of action: insertion between base pairs of DNA / RNA chains; inhibition of topoisomerase II enzymes; and generation of iron-mediated free oxygen radicals that damage DNA and cell membranes. Anthracyclines are generally characterized as topoisomerase II inhibitors.

[0328] The hormone therapy in the composition can include (a) androgens such as fluoxymesterone and testolactone; (b) antiandrogens such as bicalutamide, cyproterone acetate, flutamide, and nilutamide; (c) aromatase inhibitors such as aminoglutethimide, anastrozole, exemestane, formestane, and letrozole; (d) corticosteroids such as dexamethasone and prednisone; (e) estrogens such as diethylstilbestrol; (f) antiestrogens such as fulvestrant, raloxifene, tamoxifen, and toremifene; (g) LHRH agonists and antagonists such as buserelin, goserelin, leuprorelin, and triptorelin; (h) progestins such as medroxyprogesterone acetate and megestrol acetate; and (i) thyroid hormones such as levothyroxine and deiothyroxine.

[0329] The molecularly targeted agents in the composition may include (a) receptor tyrosine kinase (RTK) inhibitors, such as inhibitors of EGFR, including erlotinib, gefitinib and neratinib; inhibitors of VEGFR, including vandetanib, semaquine and cediranib; and inhibitors of PDGFR; also included are RTK inhibitors that act on multiple receptor sites, such as lapatinib, which inhibits both EGFR and HER2, and those that act on each of c-kit, PDGFR and VEGFR, including but not limited to axitinib, sunitinib, sorafenib and toceranib; also included are inhibitors of BCR-ABL, c-kit and PDGFR, such as imatinib, sutrin ... (b) FKBP binders, such as immunosuppressive macrolide antibiotics, including bafilomycin, rapamycin (sirolimus), and everolimus; (c) gene therapy agents, antisense therapy agents, and gene expression modulators, such as retinoids and retinoids, such as adapalene, bexarotene, trans-retinoic acid, 9-cis-retinoic acid, and N(4-hydroxyphenyl)retinamide; (d) phenotype-targeted therapeutics, including monoclonal antibodies, such as alemtuzumab, bevacizumab, cetuximab, ibritumomab tiuxetan, rituximab, and trastuzumab; (e) immunotoxins, such as gemtuzumab ozogamicin; (f) radioimmunoconjugates, such as 131I-tositumomab; and (g) cancer vaccines.

[0330] The Akt inhibitor in the composition may include, but is not limited to, 1L6 hydroxymethyl-chiro-inositol-2-(R)-2-O-methyl-3-O-octadecyl-sn-glycerol carbonate, SH-5 (Calbiochem catalog number 124008), SH-6 (Calbiochem catalog number 124009), Calbiochem catalog number 124011, triciribine (NSC 154020, Calbiochem catalog number 124012), 10-(4'-(N-diethylamino)butyl)-2-chlorophenoxazine, Cu(II)Cl2(3-formylchromonethiosemicarbazone), 1,3-dihydro-1-(1-((4-(6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)phenyl)methyl)-4-piperidinyl)-2H-benzimidazol-2-one, GSK690693(4-(2-(4-amino-1,2,5 -oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol), SR13668 ((2,10-diethoxycarbonyl-6-methoxy-5,7-dihydro-indolo[2,3-b]carbazole), GSK2141795, Perifosine, GSK21110183, XL418, XL147, PF-04691502, BEZ- 235[2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile], PX-866((acetic acid (1S,4E,10R,11R,13S,14R)-[4-diallylaminomethylene-6-hydroxy-1-methoxymethyl-10,13-dimethyl-3,7,17-trioxo-1,3,4,7,10,11,12,13,14,15, 1-H-dodecahydro-2-oxocyclopenta[a]phenanthrene-11-yl ester]), D106669, CAL-101, GDC0941 (2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine), SF1126, SF1188, SF2523, TG100-115 [3-[2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol.Many of these inhibitors, such as BEZ-235, PX-866, D 106669, CAL101, GDC0941, SF1126, and SF2523 have also been identified in the art as PI3K / mTOR inhibitors; other examples, such as PI-103 [3-[4-(4-morpholinylpyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride], are well known to those of ordinary skill in the art. Other well-known PI3K inhibitors in the composition may include LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] and wortmannin. mTOR inhibitors known to those of ordinary skill in the art include temsirolimus, deforolimus, sirolimus, everolimus, zotarolimus, and biotin A9. A representative subset of such inhibitors in the composition may include temsirolimus, deforolimus, zotarolimus, and biotin A9.

[0331] The HDAC inhibitor in the composition can include, but is not limited to, (i) hydroxamic acids, such as trichostatin A, vorinostat (suberoylanilide hydroxamic acid (SAHA)), panobinostat (LBH589), and belinostat (PXD101), (ii) cyclic peptides such as pentopicin B and depsipeptides such as romidepsin (NSC 630176), (iii) benzamides, such as MS-275 (3-pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate), CI994 (4-acetamido-N-(2-aminophenyl)-benzamide), and MGCD0103 (N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide), (iv) electrophilic ketones, (v) fatty acid compounds, such as phenylbutyrate and valproic acid. In one embodiment, the PI3K inhibitor in the composition is idelalisib (CAL-101).

[0332] The Hsp90 inhibitor in the composition may include, but is not limited to, benzoquinone ansamycins such as geldanamycin, 17DMAG (17-dimethylamino-ethylamino-17-demethoxygeldanamycin), tanespimycin (17AAG, 17-allylamino-17-demethoxygeldanamycin), EC5, retamycin (IPI-504, 18,21-didehydro-17-demethoxy-18,21-dideoxy-18,21-dihydroxy-17-(2-propenylamino)-geldanamycin), and herbimycin; pyrazoles such as CCT 018159 (4-[4-(2,3-dihydro-1,4-benzodioxol-6-yl)-5-methyl-1H-pyrazol-3-yl]-6-ethyl-1,3-benzenediol); macrolides, such as radicicol; and BIIB021 (CNF2024), SNX-5422, STA-9090, and AUY922.

[0333] The CDK inhibitor in the composition can include, but is not limited to, AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopiridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, celecoxib (CYC202, R-loscovitine), ZK-304709AT7519M, P276-00, SCH 727965, AG-024322, LEE011, LY2835219, P1446A-05, BAY 1000394, SNS-032, and the like.

[0334] The CHK inhibitors in the composition may include, but are not limited to, 5-(3-fluorophenyl)-3-ureidothiophene-N-[(S)-piperidin-3-yl]-2-carboxamide (AZD7762), 7-nitro-1H-indole-2-carboxylic acid {4-[1-(guanidinohydrazone)-ethyl]-phenyl}amide (PV1019), 5-(8-chloro-3-isoquinolinyl)amino]-3-[(1R)-2-(dimethylamino)-1-methylethoxy ]-2-pyrazinecarbonitrile (SAR-020106), PF-00477736, CCT241533, 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(3R)-3-piperidinyl-pyrazolo[1,5-a]pyrimidin-7-amine (SCH900776), 7-hydroxystaurosporine (UCN-01), 4-[((3S)-1-azabicyclo[2.2.2]oct-3-yl)amino] -3-(1H-benzimidazol-2-yl)-6-chloroquinolin-2(1H)-one (CHIR124), 7-aminodactinomycin (7-AAD), isoglutamic acid imide, debromoaconitine, N-[5-bromo-4-methyl-2-[(2S)-2-morpholinylmethoxy]-phenyl]-N'-(5-methyl-2-pyrazinylurea) (LY2603618), sulforaphane (4-methylsulfinylbutyl isothiocyanate), 9,10,11,12-Tetrahydro-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazepine-1,3(2H)-dione (SB-218078), TAT-S216A (synthetic peptide; YGRKKRRQRRRLYRSPAMPENL), CBP501 ((d-Bpa)sws(d-Phe-F5)(d-Cha)rrrqrr), and analogs thereof.

[0335] The PARP inhibitors in the composition may include, but are not limited to, 4-(3-(1-(cyclopropanecarbonyl)piperazine-4-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (olaparib, AZD2281, Ku-0059436), 2-[(2R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (Veliparib, ABT-888), (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (talazoparib, BMN 673), 4-iodo-3-nitrobenzamide (iniparib, BSI-201), 8-fluoro-5-(4-((methylamino)methyl)phenyl)-3,4-dihydro-2H-aza[5,4,3-cd]indol-1(6H)-one phosphate (Rucaparib, AG-014699, PF-01367338), 2-[4-[(dimethylamino)methyl]phenyl]-5,6-dihydro Imidazolo[4,5,1-jk][1,4]benzodiazepine-7(4H)-one (AG14361), 3-aminobenzamide (INO-1001), 2-(2-fluoro-4-((S)-pyrrolidin-2-yl]phenyl)-3H-benzo[d]imidazole-4-carboxamide (A-966492), N-(5,6-dihydro-6-oxo-2-phenanthridinyl)-2-acetamide hydrochloride (PJ34, PJ34 HCl), MK-4827, 3,4-dihydro-4-oxo-3,4-dihydro-4-oxo-N-[(1S)-1-phenylethyl]-2-quinazolinepropionamide (ME0328), 5-(2-oxo-2-phenylethoxy)-1(2H)-isoquinolinone (UPF-1069), 4-[[4-fluoro-3-[(4-methoxy-1-piperidinyl)carbonyl]phenyl]methyl]-1(2H)-phthalazinone (AZD 2461), and analogs thereof. In one embodiment, the PARP inhibitor in the composition is olaparib.

[0336] Other various agents in the composition may include altretamine, arsenic trioxide, gallium nitrate, hydroxyurea, levamisole, mitotane, octreotide, procarbazine, suramin, thalidomide, photodynamic compounds such as methoxsalen and porfibril sodium, and proteasome inhibitors such as bortezomib.

[0337] The biological therapeutic agents in the composition may include interferons, such as interferon-α2a and interferon-α2b, and interleukins, such as aldesleukin, denileukin, and oprelukin.

[0338] In addition to anticancer agents intended to act on cancer cells, combination therapies that include the use of protective or adjuvant agents in the compositions are also contemplated, including: cytoprotectants such as amifostine, diazepam, and mesna, phosphonates such as pamidronate and zoledronic acid, and stimulatory factors such as epoetin, darbepoetin, filgrastim, PEG-filgrastim, and sargramostim.

[0339] The angiogenesis inhibitor in the composition may include an endothelial-specific receptor tyrosine kinase (Tie-2) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an insulin growth factor-2 receptor (IGFR-2) inhibitor, a matrix metalloproteinase-2 (MMP-2) inhibitor, a matrix metalloproteinase-9 (MMP-9) inhibitor, a platelet-derived growth factor receptor (PDGFR) inhibitor, a thrombin analog vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitor, and analogs thereof.

[0340] The angiogenesis inhibitors in the composition may also include, but are not limited to, 2-methoxyestradiol, AG3340, pumastat, batimastat, BAY 12-9566, carboxyamidotriazole, CC-1088, dextromethorphan acetic acid, dimethylxanthenone acetic acid, EMD121974, endostatin, IM-862, marimastat, matrix metalloproteinases, penicillamine, PTK787 / ZK 222584, RPI.4610, squalamine, squalamine lactate, 3-[2,4-dimethylpyrrol-5-yl-methyl-indenyl]-2-indolinone (SU5416), (±)-thalidomide, S-thalidomide, R-thalidomide, O-(chloroacetylcarbamoyl)fumagillol (TNP-470), cobricosides, paclitaxel, tamoxifen, COL-3, neovastat, BMS-275291, SU6668, 2-ME, interferon-α, anti-VEGF antibody, Medi-522 (Vitaxin II), CAI (calcium influx inhibitor), celecoxib, interleukin-12, IM862, amiloride, Protein, angiostatin K1-3, angiostatin K1-5, captopril, DL-α-difluoromethylornithine, DL-α-difluoromethylornithine HCl, Endostatin TMprotein, fumagillin, herbimycin A, 4-hydroxyphenylretinamide, gamma-interferon, juglone, laminin, laminin hexapeptide, laminin pentapeptide, fumonisin A, medroxyprogesterone, medroxyprogesterone acetate, minocycline, minocycline HCl, placental ribonuclease inhibitor, suramin, suramin sodium salt, human thrombospondin, tissue inhibitor of metalloproteinase-1, neutrophil tissue inhibitor of metalloproteinase-1, rheumatoid synovial fibroblast tissue inhibitor of metalloproteinase-2, and analogs thereof.

[0341] In a specific embodiment, Compound A or its pharmaceutically acceptable salt, ester, solvate and / or prodrug, and at least one therapeutically active agent can be formulated as a single pharmaceutical composition and / or a combination composition. In another embodiment, the composition may contain an amount of about 5 mg to about 500 mg of Compound A as disclosed herein or its pharmaceutically acceptable salt, ester, solvate and / or prodrug. In another embodiment, the amount is about 20 mg to about 400 mg. In another embodiment, the amount is about 50 mg to about 300 mg. In another embodiment, the amount is about 100 mg to about 200 mg.

[0342] In another embodiment, the composition may comprise Compound A or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and a PARP inhibitor. In another embodiment, the PARP inhibitor is olaparib.

[0343] In another embodiment, the composition may comprise Compound A or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof and Olaparib, wherein the amount of Olaparib in the composition is from about 10 mg to about 800 mg. In another embodiment, the amount of Olaparib is from about 20 mg to about 600 mg. In another embodiment, the amount of Olaparib is from about 100 mg to about 500 mg. In another embodiment, the amount of Olaparib is from about 300 mg to about 400 mg.

[0344] In another embodiment, the composition may comprise Compound A or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and a PI3K inhibitor. In another embodiment, the PI3K inhibitor is idelalisib.

[0345] In another embodiment, the composition may comprise Compound A, or a pharmaceutically acceptable salt, ester, solvate, and / or prodrug thereof, and idelalisib, wherein the amount of idelalisib in the composition is from about 10 mg to about 500 mg. In another embodiment, the amount of idelalisib is from about 40 mg to about 300 mg. In another embodiment, the amount of idelalisib is from about 75 mg to about 200 mg. In another embodiment, the amount of idelalisib is from about 100 mg to about 175 mg.

[0346] In another embodiment, the composition may comprise Compound A or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and one or more immunotherapeutic agents that induce endogenous production of cytokines. In another embodiment, the cytokines are TNF-α and / or IFN-γ.

[0347] In another embodiment, the composition can include compound A or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof and an immunotherapeutic agent that induces endogenous production of TNF-α, wherein the amount of TNF-α induced in the tumor microenvironment (e.g., physiological levels measured by ELISA) is from about 0.01 ng / ml to about 20 ng / ml. In another embodiment, the amount of TNF-α is from about 0.1 ng / ml to about 10 ng / ml. In another embodiment, the amount of TNF-α is from about 0.2 ng / ml to about 5 ng / ml. In another embodiment, the amount of TNF-α is from about 0.5 ng / ml to about 2 ng / ml. The amount of TNF-α induction can be measured by any appropriate method, such as enzyme-linked immunosorbent assay (ELISA).

[0348] In another embodiment, the composition may include compound A or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof and an immunotherapeutic agent that induces endogenous production of IFN-γ, wherein the amount of IFN-γ induced in the tumor microenvironment (e.g., physiological levels measured by ELISA) is from about 0.01 ng / ml to about 20 ng / ml. In another embodiment, the amount of IFN-γ is from about 0.1 ng / ml to about 10 ng / ml. In another embodiment, the amount of IFN-γ is from about 0.2 ng / ml to about 5 ng / ml. In another embodiment, the amount of IFN-γ is from about 0.5 ng / ml to about 2 ng / ml. The induction amount of IFN-γ can be determined by any appropriate method, such as enzyme-linked immunosorbent assay (ELISA).

[0349] In another embodiment, the composition may comprise Compound A or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and an immunotherapeutic agent that induces endogenous secretion of TNF-α and IFN-γ within the above ranges.

[0350] In another embodiment, the composition may comprise Compound A or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and an immunotherapeutic agent that induces endogenous secretion of TNF-α and / or IFN-γ within the above range, wherein the immunotherapeutic agent is a PD-1 inhibitor. In another embodiment, the composition may comprise Compound A or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and an immunotherapeutic agent that induces endogenous secretion of TNF-α and / or IFN-γ within the above range, wherein the PD-1 inhibitor is nivolumab. In a specific embodiment, the concentration of nivolumab in the composition is about 1 mg / mL to about 50 mg / mL. In another embodiment, the concentration is about 2.5 mg / mL to about 25 mg / mL. In another embodiment, the concentration is about 5 mg / mL to about 15 mg / mL. In another embodiment, the amount of nivolumab in the composition is about 25 mg to about 1,000 mg. In another embodiment, the amount of nivolumab in the composition is about 50 mg to about 500 mg. In another embodiment, the amount of nivolumab in the composition is about 150 mg to about 300 mg.

[0351] Pharmaceutically acceptable excipients can be added to the composition / preparation. For example, a diluent can be added to the preparation of the present invention. The diluent increases the volume of the solid pharmaceutical composition and / or the combination, and can make the pharmaceutical dosage form containing the composition and / or the combination easier for the patient and the caregiver to handle. The diluent used for solid composition and / or the combination includes, for example, microcrystalline cellulose (such as AVICEL), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextran ester (dextrate), dextrin, glucose, calcium hydrogen phosphate dihydrate, tricalcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (such as EUDRAGIT (r)), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

[0352] Solid pharmaceutical compositions and / or combinations compressed into dosage forms (e.g., tablets) may include excipients whose function is to help bind active ingredients together with other excipients after compression. Adhesives for solid pharmaceutical compositions and / or combinations include gum arabic, alginic acid, carbomer (e.g., carbopol), sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, tragacanth, hydrogenated vegetable oils, hydroxyethylcellulose, hydroxypropylcellulose (e.g., KLUCEL), hydroxypropylmethylcellulose (e.g., METHOCEL), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, polyvidone (e.g., KOLLIDON, PLASDONE), pregelatinized starch, sodium alginate, and starch.

[0353] The dissolution rate of a compacted solid pharmaceutical composition and / or combination in a patient's stomach can be increased by adding a disintegrant to the composition and / or combination. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, cross-linked polyvinylpyrrolidone (e.g., KOLLIDON and POLYPLASDONE), guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., EXPLOTAB), potato starch, and starch.

[0354] Glidants may be added to improve the flowability of the non-compacted solid composition and / or combination and to improve the accuracy of administration.Excipients that may act as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tricalcium phosphate.

[0355] When preparing dosage forms such as tablets by compacting powdered compositions and / or combinations, the compositions and / or combinations are subjected to pressure from the punch and die. Some excipients and active ingredients have a tendency to adhere to the surface of the punch and die, which can cause the product to have dents and other surface irregularities. Lubricants can be added to the compositions and / or combinations to reduce adhesion and allow the product to be easily discharged from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, stearyl palmitin, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.

[0356] Flavorings and flavor enhancers make the dosage form more palatable to the patient. Common flavorings and flavor enhancers used in pharmaceutical products that may be included in the compositions and / or combinations of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0357] Solid and liquid compositions and / or combinations may also be dyed using any pharmaceutically acceptable coloring agent to improve their appearance and / or facilitate patient identification of the product and unit dosage level.

[0358] Liquid pharmaceutical compositions and / or combinations can be prepared using the compounds of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenuses thereof, or Compound A, or pharmaceutically acceptable salts, esters, solvates and / or prodrugs thereof, and any other solid excipients, wherein the components are dissolved or suspended in a liquid carrier, such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerol.

[0359] Liquid pharmaceutical compositions and / or combinations may contain an emulsifier to evenly disperse the active ingredient or other excipients that are insoluble in the liquid carrier throughout the composition and / or combination. Emulsifiers that may be suitable for use in the liquid compositions and / or combinations of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, gum arabic, gum tragacanth, carrageenan, pectin, methylcellulose, carbomer, cetearyl alcohol, and cetyl alcohol.

[0360] Liquid pharmaceutical compositions and / or combinations may also contain viscosity-increasing agents to improve the mouthfeel of the product and / or coat the lining of the gastrointestinal tract. Such agents include gum arabic, bentonite alginate, carbomer, calcium or sodium carboxymethylcellulose, cetearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, tragacanth starch, and xanthan gum.

[0361] Sweeteners such as aspartame, lactose, sorbitol, saccharin, saccharin sodium, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.

[0362] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improve storage stability.

[0363] The liquid composition and / or combination may also contain a buffer, such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate. The choice of excipient and the amount used can be readily determined by the formulation scientist based on experience and consideration of standard procedures and reference work in the art.

[0364] Solid compositions and / or combinations of the present invention include powders, granules, aggregates, and compacted compositions and / or combinations. Dosage forms include those suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the best approach of the present invention is oral administration. Dosage forms can be conveniently provided in unit dosage form and prepared by any method known in the pharmaceutical field.

[0365] Dosage forms include solid dosage forms, such as tablets, powders, capsules, suppositories, sachets, lozenges and lozenges, as well as liquid syrups, suspensions, aerosols and elixirs.

[0366] The dosage form of the present invention can be a capsule containing the composition and / or combination (preferably a powdered or granular solid composition and / or combination of the present invention) in a hard or soft shell. The shell can be made of gelatin and optionally contain a plasticizer such as glycerol and sorbitol, and an opacifier or colorant.

[0367] Compositions and / or combinations for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, to agglomerate the powders into granules. The granules are sieved and / or ground, dried, and then sieved and / or ground to the desired particle size. The granules can be tableted, or other excipients, such as glidants and / or lubricants, can be added before tableting.

[0368] Compressed tablet compositions and / or combinations can be prepared conventionally by dry blending. For example, the blended compositions and / or combinations of active substances and excipients can be compacted into blocks or tablets, which are then pulverized into compacted granules. The compacted granules can then be compressed into tablets.

[0369] As an alternative to dry granulation, direct compression can be used to compress the blended composition and / or combination directly into a compacted dosage form. Direct compression produces a more uniform, particle-free tablet. Excipients particularly suitable for direct compression tableting include microcrystalline cellulose, spray-dried lactose, dicalcium phosphate dihydrate, and silica gel. The appropriate use of these and other excipients in direct compression tableting is known to those skilled in the art who have experience and skill in the specific formulation challenges of direct compression tableting.

[0370] The capsule fill of the present invention may comprise any of the aforementioned blends and granules described with reference to tableting; however, the blends and granules are not subjected to a final tableting step.

[0371] The active ingredients and excipients can be formulated into compositions and / or combinations and dosage forms according to methods known in the art.

[0372] In one embodiment, the dosage form can be provided as a kit comprising a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and a pharmaceutically acceptable excipient and carrier as separate components. In one embodiment, the dosage form can be provided as a kit comprising a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, at least one additional therapeutically active agent, and a pharmaceutically acceptable excipient and carrier as separate components. In some embodiments, the dosage form kit allows the physician and patient to prepare oral or injectable solutions by dissolving, suspending, or mixing the compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenera, or its pharmaceutically acceptable salts, esters, solvates and / or prodrugs with pharmaceutically acceptable excipients and carriers prior to use. In one embodiment, a dosage form kit is provided for the compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenera, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug having improved stability compared to preformulated formulations of the compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenera, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug.

[0373] In one embodiment, the compound of formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenera, or Compound A, or pharmaceutically acceptable salts, esters, solvates and / or prodrugs thereof, is used in a formulation. The compound of formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenera, or Compound A, or pharmaceutically acceptable salts, esters, solvates and / or prodrugs thereof of the present invention can be used in pharmaceutical formulations or compositions and / or combinations as a single component or as a mixture with other forms of the compound of formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenera, or Compound A. In one embodiment, the pharmaceutical formulations or compositions and / or combinations of the present invention contain 25-100% or 50-100% by weight of at least one compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenuses thereof, or Compound A, as described herein, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof in the formulation, composition and / or combination.

[0374] Therapeutic uses

[0375] The present invention also provides treatments for conditions associated with cell proliferation. In one embodiment, a method for selectively activating p53 protein is provided, comprising contacting a cell suffering from a condition associated with cell proliferation with the present compound. In one embodiment, the method comprises contacting cancer and / or tumor cells with a compound of formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) as disclosed herein and / or its subgenus, or compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof. In another embodiment, the method comprises contacting cancer and / or tumor cells with a compound of formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) as disclosed herein and / or its subgenus, or compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and at least one therapeutically active agent.

[0376] In another embodiment, the method of contacting cancer and / or tumor cells with a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, as disclosed herein, can induce apoptosis, or mitigate or prevent the progression of the condition. In one embodiment, the method of contacting cancer and / or tumor cells with a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, as disclosed herein, and at least one therapeutically active agent can induce apoptosis, or mitigate or prevent the progression of the condition.

[0377] In another embodiment, methods of contacting cancer and / or tumor cells with a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, as disclosed herein, can reduce the incidence of cancer and / or tumor growth. Additionally, methods for treating cancer, cancer cells, tumors, or tumor cells are disclosed. Non-limiting examples of cancers that can be treated by the methods of the present disclosure include the following: colorectal, breast, ovarian, cervical, lung, liver, pancreatic, lymph node, colon, prostate, brain, head and neck, skin, kidney, bone (e.g., Ewing's sarcoma), and blood and heart (e.g., leukemia, lymphoma, malignant tumors). Non-limiting examples of tumors that can be treated by the methods of the present disclosure include the following tumors and tumor cells: colorectal, breast, ovarian, cervical, lung, liver, pancreatic, lymph node, colon, prostate, brain, head and neck, skin, kidney, bone (e.g., Ewing's sarcoma), and blood and heart (e.g., leukemias, lymphomas, malignancies).

[0378] In one embodiment, the present invention provides a method of reducing or inhibiting cell proliferation, and / or a method of treating cancer, comprising co-administering a therapeutically effective amount of at least one compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and a PI3K inhibitor to a patient in need thereof. In one embodiment of the various methods disclosed herein, the co-administration comprises Compound A and a PI3K inhibitor. In one embodiment, the co-administration for any of the methods disclosed herein comprises Compound A and idelalisib.

[0379] In one embodiment, the present invention provides a method of reducing or inhibiting cell proliferation, and / or a method of treating cancer, comprising co-administering to a patient in need thereof a therapeutically effective amount of at least one compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and a PARP inhibitor. In one embodiment of the various methods disclosed herein, the co-administration comprises Compound A and a PARP inhibitor. In one embodiment, the co-administration for any of the methods disclosed herein comprises Compound A and olaparib.

[0380] In one embodiment, the present invention provides a method of reducing or inhibiting cell proliferation, and / or a method of treating cancer, comprising co-administering a therapeutically effective amount of at least one compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and a cytokine to a patient in need thereof. In one embodiment of the various methods disclosed herein, the co-administration comprises Compound A and a cytokine. In one embodiment, the co-administration for any of the methods disclosed herein comprises Compound A and TNF-α. In another embodiment, the co-administration for any of the methods disclosed herein comprises Compound A and TNF-γ. In another embodiment, the method may include a method of reducing or inhibiting cell proliferation, and / or treating cancer, comprising co-administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and at least one therapeutically active agent to a patient in need thereof, in a single pharmaceutical composition and / or a combination composition. In one embodiment, the method may include a method of reducing or inhibiting cell proliferation, and / or treating cancer, comprising co-administering a therapeutically effective amount of Compound A as disclosed herein, or a pharmaceutically acceptable salt, ester, solvate, and / or prodrug thereof, to a patient in need thereof in an amount of about 5 mg to about 500 mg. In another embodiment, the amount is about 20 mg to about 400 mg. In another embodiment, the amount is about 50 mg to about 300 mg. In another embodiment, the amount is about 100 mg to about 200 mg.

[0381] In another embodiment, the method may include a method of reducing or inhibiting cell proliferation, and / or treating cancer, comprising co-administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and a PARP inhibitor to a patient in need thereof. In another embodiment, the PARP inhibitor is olaparib.

[0382] In another embodiment, the method may include a method of reducing or inhibiting cell proliferation, and / or treating cancer, comprising co-administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and Olaparib to a patient in need thereof, wherein the amount of Olaparib in the composition is from about 10 mg to about 800 mg. In another embodiment, the amount of Olaparib is from about 20 mg to about 600 mg. In another embodiment, the amount of Olaparib is from about 100 mg to about 500 mg. In another embodiment, the amount of Olaparib is from about 300 mg to about 400 mg.

[0383] In another embodiment, the method may include a method of reducing or inhibiting cell proliferation, and / or treating cancer, wherein the method comprises co-administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and a PI3K inhibitor to a patient in need thereof. In another embodiment, the PI3K inhibitor is idelalisib.

[0384] In another embodiment, the method may include a method of reducing or inhibiting cell proliferation, and / or treating cancer, comprising co-administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt, ester, solvate, and / or prodrug thereof, and idelalisib to a patient in need thereof, wherein the amount of idelalisib in the composition is from about 10 mg to about 500 mg. In another embodiment, the amount of idelalisib is from about 40 mg to about 300 mg. In another embodiment, the amount of idelalisib is from about 75 mg to about 200 mg. In another embodiment, the amount of idelalisib is from about 100 mg to about 175 mg.

[0385] In another embodiment, the method may include a method for reducing or inhibiting cell proliferation, and / or treating cancer, comprising co-administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and an immunotherapeutic agent that modulates endogenous secretion of one or more cytokines. In another embodiment, the cytokine is TNF-α and / or IFN-γ.

[0386] In another embodiment, the method may include a method for reducing or inhibiting cell proliferation, and / or treating cancer, comprising co-administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and an immunotherapeutic agent that induces endogenous secretion of TNF-α to a patient in need thereof, wherein the amount of TNF-α induced is from about 0.01 ng / ml to about 20 ng / ml. In another embodiment, the amount of TNF-α induced is from about 0.1 ng / ml to about 10 ng / ml. In another embodiment, the amount of TNF-α induced is from about 0.2 ng / ml to about 5 ng / ml. In another embodiment, the amount of TNF-α induced is from about 0.5 ng / ml to about 2 ng / ml. The amount of endogenous production of induced TNF-α can be quantified by any appropriate method, such as ELISA.

[0387] In another embodiment, the method may include a method for reducing or inhibiting cell proliferation, and / or treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and an immunotherapeutic agent that induces endogenous secretion of IFN-γ, wherein the amount of induced IFN-γ is from about 0.01 ng / ml to about 20 ng / ml. In another embodiment, the amount of induced IFN-γ is from about 0.1 ng / ml to about 10 ng / ml. In another embodiment, the amount of induced IFN-γ is from about 0.2 ng / ml to about 5 ng / ml. In another embodiment, the amount of induced IFN-γ is from about 0.5 ng / ml to about 2 ng / ml. The amount of induced endogenous IFN-γ can be quantified by any appropriate method, such as ELISA.

[0388] In another embodiment, the method may include a method for reducing or inhibiting cell proliferation, and / or treating cancer, comprising co-administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and an immunotherapeutic agent that induces endogenous secretion of TNF-α and / or IFN-γ within the above range.

[0389] In another embodiment, the method may include a method for reducing or inhibiting cell proliferation, and / or treating cancer, comprising co-administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and an immunotherapeutic agent that induces endogenous secretion of TNF-α and / or IFN-γ within the above range to a patient in need thereof, wherein the immunotherapeutic agent is a PD-1 inhibitor. In another embodiment, the method may include a method for reducing or inhibiting cell proliferation, and / or treating cancer, comprising co-administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and an immunotherapeutic agent that induces endogenous secretion of TNF-α and / or IFN-γ within the above range to a patient in need thereof, wherein the PD-1 inhibitor is nivolumab. In a specific embodiment, the concentration of nivolumab in the composition is about 1 mg / mL to about 50 mg / mL. In another embodiment, the concentration is about 2.5 mg / mL to about 25 mg / mL. In another embodiment, the concentration is about 5 mg / mL to about 15 mg / mL. In another embodiment, the amount of nivolumab in the composition is from about 25 mg to about 1,000 mg. In another embodiment, the amount of nivolumab in the composition is from about 50 mg to about 500 mg. In another embodiment, the amount of nivolumab in the composition is from about 150 mg to about 300 mg.

[0390] In one embodiment, co-administration of Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, with olaparib, idelalisib, or an immunotherapeutic agent that induces endogenous secretion of TNF-α and / or IFN-γ to a patient in need thereof can be carried out once a day, twice a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, or ten times a day.

[0391] In some embodiments, the cancer that can be treated by the methods provided by the present disclosure is a homologous recombination-dependent deoxyribonucleic acid double-strand break repair (HR-dependent DNA DSB repair)-deficient cancer, also known as HRD cancer. In some embodiments, the HR-dependent DNA DSB repair-deficient cancer is identified by measuring the HR-dependent DNA DSB repair activity of cancer cells obtained from a subject.

[0392] In one embodiment, the compositions and / or combinations disclosed herein are useful in treating HRD cancer. In one embodiment, co-administration of an effective amount of at least one compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenus, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and at least one therapeutically active agent may be useful in treating HRD cancer. In another embodiment, co-administration of an effective amount of at least one compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenus, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and at least one therapeutically active agent selected from a PI3K inhibitor, a PARP inhibitor and a cytokine may be useful in treating HRD cancer. In another embodiment, co-administration of Compound A and at least one therapeutically active agent selected from a PI3K inhibitor, a PARP inhibitor and a cytokine may be useful in treating HRD cancer.

[0393] The present invention also provides a method for treating, preventing, improving and / or alleviating the disease or condition of progress characterized by cell proliferation in a subject. More specifically, the method of the present invention relates to administering an effective amount of a quinolone compound as described herein to treat a disease or condition characterized by cell proliferation in a subject. Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) compound and / or its subgenus or compound A or its pharmaceutically acceptable salt, ester, solvate and / or prodrug can be administered with the amount of the p53 protein in the effective selective activation cancer and / or tumor cell, which can result in cell death or apoptosis. Throughout this application, the terms "subject" and "patient" are used interchangeably.

[0394] As used herein, administration can be achieved or performed using any of a variety of methods known to those of ordinary skill in the art. A compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate, and / or prodrug thereof, can be administered, for example, subcutaneously, intravenously, parenterally, intraperitoneally, intradermally, intramuscularly, topically, enterally (e.g., orally), rectally, nasally, buccally, sublingually, vaginally, by inhalation spray, by drug pump, or via an implanted reservoir in a dosage form containing a conventional non-toxic, physiologically acceptable carrier or vehicle.

[0395] In addition, the presently disclosed compounds of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or pharmaceutically acceptable salts, esters, solvates and / or prodrugs thereof, can be administered to the local area in need of treatment. This can be achieved, for example, but not limited to, by local infusion during surgery, topical application, transdermal patch, by injection, by catheter, by suppository, or by implant (the implant can optionally be a porous, non-porous, or gel-like material), including a membrane such as a silicone rubber membrane or fiber.

[0396] The form in which a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenera or Compound A or its pharmaceutically acceptable salts, esters, solvates and / or prodrugs is administered (e.g., syrup, elixir, capsule, tablet, foam, emulsion, gel, etc.) will depend in part on the route by which it is administered. For example, for mucosal (e.g., oral mucosa, rectal mucosa, intestinal mucosa, bronchial mucosa) administration, nasal drops, aerosols, inhalants, sprays, eye drops or suppositories can be used. A compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or its subgenera or Compound A or its pharmaceutically acceptable salts, esters, solvates and / or prodrugs can also be used to coat bioimplantable materials to enhance neurite outgrowth, neural survival, or cellular interactions on the implant surface. The compounds of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or pharmaceutically acceptable salts, esters, solvates and / or prodrugs thereof disclosed herein can be administered with other biologically active agents, such as anticancer agents, analgesics, anti-inflammatory agents, anesthetics, and other agents that can control one or more symptoms or causes of a disorder or condition characterized by cell proliferation.

[0397] In one embodiment, a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and an additional therapeutically active agent can be administered with a second therapeutically active agent or more therapeutically active agents. In one embodiment, the second therapeutically active agent is an anticancer agent. In some embodiments, the one or more therapeutically active anticancer agents include but are not limited to paclitaxel, vinblastine, vincristine, etoposide, doxorubicin, hemostatin, lapatinib, gefitinib, erlotinib, tamoxifen, fulvestrant, amantadine, folate, exemestane, fadrozole, cyclophosphamide, clomiphene, melphalan, mechlorethamine, dichloromethyldiethylamine, mechlorethamine, phenylalanine, mustard, cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin, carboplatin, dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitoxantrone, plicamycin, mitomycin, C bleomycin, combinations thereof, and analogs thereof.

[0398] In addition, administration can include administering multiple dosage forms to a subject over an appropriate period of time. Such administration schedules can be determined according to routine methods after reviewing this disclosure.

[0399] The compounds of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or pharmaceutically acceptable salts, esters, solvates and / or prodrugs thereof, of the present invention are typically administered at a dose of about 0.01 mg / kg / dose to about 100 mg / kg / dose. Alternatively, the dose may be from about 0.1 mg / kg / dose to about 10 mg / kg / dose; or from about 1 mg / kg / dose to 10 mg / kg / dose. A time-release formulation may be employed, or the dose may be administered in multiple divided doses when convenient. When other methods (e.g., intravenous administration) are used, the compounds of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or pharmaceutically acceptable salts, esters, solvates and / or prodrugs thereof, are administered to the affected tissue at a rate of about 0.05 to about 10 mg / kg / hour, or about 0.1 to about 1 mg / kg / hour. Such rates are readily maintained when the compounds of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenus thereof, or Compound A, or pharmaceutically acceptable salts, esters, solvates, and / or prodrugs thereof, as discussed herein, are administered intravenously. Generally, the topically administered formulations are administered at a dose ranging from about 0.5 mg / kg / dose to about 10 mg / kg / dose. Alternatively, the topical formulations are administered at a dose ranging from about 1 mg / kg / dose to about 7.5 mg / kg / dose or even from about 1 mg / kg / dose to about 5 mg / kg / dose.

[0400] A range of about 0.1 to about 100 mg / kg is suitable for single doses. Continuous administration is suitable in the range of about 0.05 to about 10 mg / kg.

[0401] Drug doses can also be given in milligrams per square meter of body surface area rather than body weight, as this method correlates well with certain metabolic and excretory functions. In addition, body surface area can be used as a common denominator for drug doses in adults and children, as well as in different animal species (Freireich et al., (1966) Cancer Chemother Rep. 50, 219-244). In short, to express a mg / kg dose for any given species as an equivalent mg / sq m dose, multiply the dose by the appropriate km factor. In an adult, 100 mg / kg is equivalent to 100 mg / kg x 37 kg / sq m = 3700 mg / m 2 .

[0402] The dosage forms of the present invention can contain a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenus thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate, and / or prodrug thereof, as disclosed herein, in an amount from about 5 mg to about 500 mg. That is, the dosage forms of the present invention can contain an amount of about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 225 mg. , 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 275 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 325 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 375 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 425 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 475 mg, 480 mg, 490 mg, or 500 mg of Compound A.

[0403] The dosage form of the present invention can be administered hourly, daily, weekly or monthly. The dosage form of the present invention can be administered twice a day or once a day. The dosage form of the present invention can be administered with or without food.

[0404] Where the compounds of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or pharmaceutically acceptable salts, esters, solvates and / or prodrugs thereof disclosed herein may be in the form of mimetics or fragments thereof, it will be understood that the potency of the effective amount, and therefore the dosage of the effective amount, may vary. However, one skilled in the art can readily assess the potency of the compounds of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or pharmaceutically acceptable salts, esters, solvates and / or prodrugs thereof, presently contemplated by the present application.

[0405] In the case of progressive disorders or conditions characterized by cell proliferation, the compounds of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or pharmaceutically acceptable salts, esters, solvates and / or prodrugs thereof, and at least one additional therapeutically active agent are typically administered on an ongoing basis. In certain instances, administration of the compounds of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or pharmaceutically acceptable salts, esters, solvates and / or prodrugs thereof, and at least one additional therapeutically active agent disclosed herein may be initiated before the development of disease symptoms as part of a strategy to delay or prevent the disease. In other cases, a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenus thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and at least one additional therapeutically active agent disclosed herein is administered after the onset of disease symptoms as part of a strategy to slow or reverse disease progression and / or as part of a strategy to improve cellular function and reduce symptoms.

[0406] It will be understood by those skilled in the art that the dosage range will depend on the specific compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or pharmaceutically acceptable salts, esters, solvates and / or prodrugs thereof, and the at least one additional therapeutically active agent, as well as the potency thereof. It is understood that the dosage range is large enough to produce the desired effect wherein neurodegeneration or other disorders and symptoms associated therewith are ameliorated and / or cell survival is achieved, but not so large as to cause uncontrollable adverse side effects. However, it should be understood that the specific dosage level for any particular patient will depend on various factors, including the activity of the specific compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or pharmaceutically acceptable salts, esters, solvates and / or prodrugs thereof, employed; the age, weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs previously administered; and the severity of the specific disease being treated, as is well known to those skilled in the art. In the event of any complications, the dosage may also be adjusted by the individual physician.No unacceptable toxic effects are expected when Compound A disclosed herein is used in accordance with the present application.

[0407] An effective amount of a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and at least one additional therapeutically active agent disclosed herein includes an amount sufficient to produce a measurable biological response. Actual dosage levels of the active ingredients of the present application can be varied so that an amount of a compound of Formula (I), (IA), (IB), (II), (IIA), (III), (IIIA) and / or subgenera thereof, or Compound A, or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and at least one additional therapeutically active agent is administered to effectively achieve the desired therapeutic response for a particular subject and / or application. Preferably, the minimum dose is administered and the dose is escalated to the minimum effective amount in the absence of dose-limiting toxicities. Determination and adjustment of a therapeutically effective dose, as well as assessment of when and how to make such adjustments, are known to those of ordinary skill in the art.

[0408] The following examples further illustrate the present invention but should not be construed in any way as limiting its scope. Example

[0409] Example 1: Antiproliferative Test

[0410] Three human lymphoma cell lines, Toledo, MC116, and HT, were purchased from Bioresource Collection and Research Center (BCRC, Taiwan). All cells were cultured at 37°C in a humidified atmosphere containing 5% CO2.

[0411] CAL-101 (also known as idelalisib) is a PI3K-δ inhibitor with potential immunomodulatory and anti-malignant tumor activity. The anticancer activity of the combination of Compound A and CAL-101 against three human lymphoma cell lines (Toledo, MC116, HT) was evaluated using an in vitro cell proliferation assay. Cell proliferation of drug-treated human cancer cells was measured using an MTS (Promega) colorimetric assay 96 hours after treatment. The 50% inhibitory concentration (IC) of the test compound was calculated using GraphPad Prism software. 50 ) and 25% IC(IC 25 The antiproliferative effects of Compound A in single and combination treatments on the three cell lines are shown in Tables 1-4.

[0412] Corrected absorbance values ​​were obtained by subtracting the mean 490 nm absorbance of the control wells (medium only, no cells) from all other absorbance values. The percent inhibition of cell growth by compound treatment was calculated using this formula:

[0413]

[0414] Sigmoidal dose-response curves were generated by fitting the percent inhibition values ​​to the logarithmic function of compound concentration using GraphPad Prism software. 50 The IC value is defined as the concentration required for 50% inhibition of cell growth. 25 The value was defined as the concentration required for 25% inhibition of cell growth. All data represent the results of triplicate experiments.

[0415] Single compound treatment

[0416] The results showed that compound A effectively inhibited the cell proliferation of all three human lymphoma cell lines, and the IC 50 The values ​​ranged from 45.9 to 723.1 nM. Compound A exhibited the greatest inhibitory effect on Toledo cells (IC 50 45.9 nM), while the efficacy was lower against MC116 and HT cells (IC 50 CAL-101 exerts an antiproliferative effect only on Toledo cells (IC 50 was 76.0 nM) and was insensitive to the other two cell lines (IC 50 The antiproliferative effect of compound A or CAL-101 was evaluated, and the estimated IC 50 and IC 25 The values ​​are summarized in Table 1.

[0417] Table 1. Estimated IC values ​​of single-drug treatments for three cell lines 50 and IC 25

[0418]

[0419] The estimated IC was calculated based on nonlinear regression of the dose-response curves in which the cell proliferation ratio (%) was a logarithmic function of the drug concentration in a single treatment. 50 and IC 25 value.

[0420] Dual compound combination therapy

[0421] Three human lymphoma cell lines (Toledo, MC116, and HT) were used to evaluate cell proliferation using a dual-drug combination therapy. CAL-101 was combined with Compound A at a concentration close to its estimated IC 50 and IC 25 The antiproliferative effects of compound A on three cell lines in single and combination treatment are shown in Tables 2-4. 25 As shown in the data, the combination treatment with Compound A and CAL-101 synergistically enhanced the anti-proliferative activity in MC116 and HT cells.

[0422] Table 2. Antiproliferative activity of Compound A against Toledo cell lines in single and combination treatments

[0423]

[0424] *Inhibition (%) shows the IC of proliferation inhibition in Toledo cells 50 value.

[0425] Table 3. Antiproliferative activity of compound A against MC116 cell line in single and combination treatment

[0426]

[0427]

[0428] *Inhibition (%) shows the IC of proliferation inhibition in MC116 cells 50 value.

[0429] Table 4. Antiproliferative activity of Compound A against HT cell lines in single and combination treatments

[0430]

[0431] *Inhibition (%) shows the IC of proliferation inhibition in HT cells 50 value.

[0432] Example 2: Analysis of Combination Trials

[0433] Use Horizon's Chalice as outlined in the User Manual TM The Combination Analysis software determines combinatorial interactions across the dose matrix using the Loewe additive model:

[0434] (http: / / chalice.horizondiscovery.com / chalice-portal / documentation / analyzer / home.jsp).

[0435] Synergy was determined by comparing the experimentally observed inhibition levels at each combination point with the additive expected values ​​derived from the single-agent responses along the edges of the matrix. TM , potential synergistic interactions are viewed by plotting the calculated excess inhibition over expectation at each test point in the matrix as a heat map, where brighter / warmer colors indicate higher activity levels.

[0436] The overall combinatorial interaction can be scored using a simple volume fraction that calculates the volume between the measured and predicted reaction surfaces. This volume fraction indicates whether the overall reaction to the combination is synergistic (positive value), antagonistic (negative value), or additive.

[0437] Drug combination studies

[0438] Using Horizon's Chalice TM The Loewe additive model of the combination analysis software was used to evaluate the effect of combining Compound A with Olaparib across a concentration matrix in DLD1 parental and DLD1-BRCA2(- / -) isogenic cell lines. The activity of the compounds was evaluated with short (48 hours) and long (6 days, 144 hours) treatment times.

[0439] Using Chalice TM , potential synergistic interactions were visualized by plotting the calculated excess inhibition over expectation at each test point in the matrix as a heat map, where brighter / warmer colors indicate higher activity levels ( Figures 1A-1B and Figures 2A-2B ).

[0440] The volume score for this combination was positive in both cell lines, further confirming that the interaction is synergistic (positive value) and The volume and synergy scores of the combination in both cell lines are shown in Figures 1C-1D and Figures 2C-2D and Table 5.

[0441] In vivo validation of combination therapy with PARP inhibitors and Compound A

[0442] Combination treatment with olaparib (50 mg / kg) and compound A (50 mg / kg) significantly inhibited tumor growth in a BRCA2-deficient triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) model compared to treatment with the PARP inhibitor olaparib alone. Figures 3A-3B ), confirming that the ability of Compound A to synergize with PARPi in vivo is associated with DNA repair pathways in tumors. In addition, mice implanted with TNBC xenografts ( ) were treated with olaparib (50 mg, qd x 28), followed by 2 subsequent doses of Compound A (50 mg qwk x 2), followed by 7 subsequent doses of olaparib (50 mg, qd x 7). Figures 3B-3C ). Including olaparib pretreatment ( Figure 3B ) or post-treatment ( Figure 3C ) showed significant anti-tumor activity.

[0443] Table 5: Values ​​and synergy scores of the combinations in DLD1 parental and BRCA2(- / -) isogenic cell lines

[0444] Loewe Value:

[0445]

[0446] Example 3: Antiproliferative Test

[0447] BRCA1 negative (UWB1.289-2945) and BRCA1 positive (UWB1.289) human ovarian cancer cell lines were purchased from the American Type Culture Collection (ATCC). The cells were cultured at 37°C in a humidified atmosphere containing 5% CO2.

[0448] The anticancer activity of Compound A against BRCA1-negative and BRCA1-positive human ovarian cancer cell lines was also evaluated using an in vitro cell proliferation assay. The luminescent cell viability assay (Promega) measures cell proliferation in drug-treated human cancer cells. 50 Values ​​were defined as the concentration required for 50% inhibition of cell growth and calculated in GraphPad.The antiproliferative effects of Compound A alone and in combination with cytokines on these two cell lines are shown in Figures 4-6.

[0449] Calculate the percent inhibition of compound-treated cell growth using this formula:

[0450]

[0451] Data were processed using built-in Excel-Macro. Cell viability / proliferation was expressed as the percentage of dead cells relative to the mean signal of the untreated control wells from the corresponding dish. Outliers (triplicates) were excluded during QC. Processed data were plotted using Graphpad software. Statistical analysis was performed using Excel (Microsoft), and paired comparisons of two groups were performed using the Student t-test. All data represent the results of triplicate experiments.

[0452] As shown in Figures 4 and B, BRCA1-negative cell lines ( Figures 5A-5B ) for compound A compared with BRCA1 positive cell lines ( Figures 4A-4B Compound A inhibits the proliferation of BRCA1-negative human ovarian cancer cell lines, IC 50The values ​​ranged from approximately 2.34 ± 1.67 nM to 3.78 ± 2.24 nM. In the BRCA1-positive ovarian cancer cell line UWB1.289, compound A showed a dose-dependent cytotoxicity trend. However, the maximum toxicity observed at the highest concentration (100 nM) did not exceed 40%. Therefore, the IC 50 .

[0453] Early studies on CTLA-4 blockade demonstrated that in vivo treatment induced memory CD8 + Expansion of T cell populations Here, two types of cytokines, TNF-α and IFN-γ (0, 0.008, 0.04, 0.2, 1, 5 ng / mL) were used in response to Compound A.

[0454] The two cytokines, TNF-α and IFN-γ, showed minimal cytotoxicity on their own against ovarian cancer cell lines, but showed increasing cytotoxicity with increasing doses. Combination drug testing was conducted using BRCA1-negative and BRCA1-positive human ovarian cancer cell lines. In the presence of Compound A, the two cytokines, TNF-α and IFN-γ, showed an additive effect on the cytotoxicity of BRCA1-negative human ovarian cancer cells. Figures 6A-6B Shown are dose-response curves of the effects of TNF-α and IFN-γ with different concentrations of Compound A on BRCA1-negative cells.

[0455] Example 4. Pharmaceutical Combinations of Compound A and Immunotherapeutic Agents.

[0456] Example 3 shows that the cytokines TNF-α and IFN-γ have additive cytotoxic effects on BRCA1 negative human ovarian cancer cells in a dose-dependent manner in the presence of Compound A. Therefore, the addition of another agent that increases or induces endogenous cytokine production in cancer cells should also contribute to cancer cell toxicity.

[0457] Therefore, one embodiment of the present invention can be a drug combination comprising a compound of the present invention (e.g., Compound A) and an immunotherapeutic agent, such as an agent that can induce the production of endogenous cytotoxic cytokines (e.g., TNFα and IFN-γ). This drug combination should have a greater effect in treating or improving cell proliferation disorders. Again, without wishing to be bound by any particular theory, it is believed that immunotherapeutic agents can increase one or more cytokines that are locally produced and have a cytotoxic effect on tumor cells, such as tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ). At the same time, the chemical compounds described herein (e.g., Compound A) can enhance the cytotoxic effects of TNF-α and / or IFN-γ, so that the combination can achieve a greater therapeutic effect.

[0458] Indeed, anti-PD-1 antibodies can enhance T cell responses and cytokine production in vitro. For example, Wang et al. (Cancer Immuno Res 2(9):846-856, incorporated by reference in its entirety) demonstrated that blocking PD-1 with nivolumab (BMS-936558) systemically resulted in titratable enhanced IFN-γ release in an allogeneic mixed lymphocyte reaction assay, and enhanced T cell proliferation was observed in some donor T cell / DC pairs. ( Figure 7 , adapted from Wang et al.). Using a CMV restimulation assay, Wang et al. also showed that nivolumab resulted in a concentration-dependent increase in IFN-γ secretion from CMV-responsive donors.

[0459] The results in Example 3 have demonstrated that TNF-α and IFN-γ exhibit additive cytotoxic effects on BRCA1 negative human ovarian cancer cells in the presence of Compound A. Specifically, Figures 6A-6B Compound A was shown to enhance the cytotoxic effects of TNF-α and IFN-γ in a dose-dependent manner. Therefore, a drug combination comprising a compound of the present invention (e.g., Compound A) and an immunotherapeutic agent (e.g., an agent that can induce the production of endogenous cytotoxic cytokines (e.g., TNF-α and IFN-γ)) should produce higher efficiency in killing tumor cells.

[0460] The ability of the compound of the present invention (e.g., Compound A) to increase chemokine production in tumor cells has also been studied. Chemokines are molecules that attract immune cells (e.g., effector T cells) produced by tumor cells. Chemokines and chemokine receptors play a key role in tumor immunogenicity because they are not only included in the main regulatory system that causes leukocyte infiltration in primary tumors, but also intervene in cancer cell proliferation and metastasis guidance. Cancer cells, stromal cells, and infiltrated immune cells can secrete chemokines. Cancer cells themselves can also express chemokine receptors and respond to these chemokines. This forms a complex chemokine network that affects tumor cell growth, survival, migration, angiogenesis, and immune cell infiltration.

[0461] Compound A was applied to HBCx-39 (BRCA2 wild type) and HBCx-17 (BRCA2 mutant) cancer cell lines in vitro. HBCx-17 is a homologous recombination-deficient tumor cell line with BRCA2 mutation. Surprisingly, the results showed that Compound A was able to induce the production of several important chemokines ( Figures 8A to 8C). In addition, in cancer cells with BRCA2 mutants, Compound A treatment increased CCL9, CCL21, and CXCL9 mRNA expression more than in wild-type cancer cells. The results further demonstrate that drug combinations comprising a compound of the present invention (e.g., Compound A) and an immunotherapeutic agent (e.g., an agent that can induce the production of endogenous cytotoxic cytokines (e.g., TNF-α and IFN-γ)) will have greater efficacy in treating cancer because the chemokines induced by Compound A attract immune cells such as dendritic cells (DCs), activated effector T cells (e.g., CD8+ lymphocytes), and / or natural killer (NK) cells to tumor cells, leading to their destruction.

[0462] The dual functionality of the drug combinations of the present invention as described herein means that such drug combinations are unexpectedly effective in treating cancer.

[0463] Example 5. Drug combination of compound A and anti-PD-1 antibody

[0464] In vitro and in vivo experiments were conducted to test drug combinations comprising Compound A and the anti-PD-1 antibody nivolumab for the treatment of cancers such as leukemia, lymphoma, myeloma, multiple myeloma, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, Ewing's sarcoma, head and neck cancer, heme cancer, colorectal cancer, cervical cancer, liver cancer, lymph node cancer, colon cancer, prostate cancer, brain cancer, head and neck cancer, bone cancer, skin cancer, kidney cancer, and heart cancer. In some tests, the cancer is a homologous recombination (HR)-dependent DNA double-strand break (DSB) repair-deficient cancer or a non-homologous end joining (NHEJ) DNA double-strand break (DSB) repair-deficient cancer.

[0465] Compound A and nivolumab were co-administered in vitro or in vivo to applicable cancer cell lines or patients, with Compound A alone and anti-PD-1 antibody alone serving as controls. The results showed that the drug combination exhibited a synergistic effect in treating cancer when compared to Compound A alone and anti-PD-1 antibody alone.

[0466] The patents and publications listed herein describe the general skills in the art and are incorporated herein by reference in their entirety for all purposes, as if each patent and publication were specifically and individually indicated to be incorporated by reference. Nothing herein should be interpreted as an admission that the present invention is not entitled to predate such publications due to prior inventions. In the event of any conflict between the cited references and this specification, the specification shall prevail. In describing the embodiments of the present application, specific terms are used for the sake of clarity. However, the present invention is not intended to be limited to the specific terms selected. Nothing in this specification should be considered to limit the scope of the present invention. After benefiting from the teachings presented in the previous description and the associated drawings, those skilled in the art to which these inventions belong will be able to conceive of many modifications and other embodiments of the inventions described herein. All examples presented are representative and non-limiting. Without departing from the present invention, the above embodiments may be modified or altered, as understood by those skilled in the art in view of the above teachings. Therefore, it should be understood that within the scope of the claims and their equivalents, the present invention may be implemented in a manner different from that specifically described.

[0467] The present invention also relates to embodiments of:

[0468] Item 1. A pharmaceutical combination comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and one or more additional therapeutically active agents selected from the group consisting of an immunotherapeutic agent, an anticancer agent, and an angiogenic agent; wherein:

[0469]

[0470] X 1 is CH or N;

[0471] X 2 、X 3 、X 4 、X 5 、X 6 and X 7 Independently NR 4 , CH2, CHQ or C(Q)2, provided that X 2 、X 3 、X 4 、X 5 、X 6 and X 7 Zero, one or two of them are NR 4 ;

[0472] A and V are independently H, halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R2 、-SR 2 、-OR 2 , or -R 3 ;

[0473] Each Q is independently halogen, azide, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ;

[0474] In each-NR 1 R 2 In, R 1 and R 2 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains one additional heteroatom selected from N, O and S as a ring member;

[0475] R 1 is H, or C1-C6 alkyl optionally substituted by one or more halogens, or ═O;

[0476] R 2 is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0477] R 3 is optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0478] Each R 4 are independently H, or C1-C6 alkyl;

[0479] R 7 is H, and R 8is C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens; or in the case of –NR 7 R 8 In, R 7 and R 8 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains additional heteroatoms selected from N, O and S as ring members;

[0480] m is 0, 1, 2, 3 or 4;

[0481] n is 0, 1, 2, 3, 4 or 5.

[0482] Item 2. The pharmaceutical combination according to Item 1, wherein the compound of formula (I) is represented by formula (II):

[0483]

[0484] in:

[0485] A and V are independently H, halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ;

[0486] Each Q is independently halogen, azide, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ;

[0487] In each-NR 1 R 2 In, R 1 and R 2 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains additional heteroatoms selected from N, O and S as ring members;

[0488] R 1 is H, or C1-C6 alkyl optionally substituted by one or more halogens, or ═O;

[0489] R2 is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0490] R 3 is optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0491] R 4 are independently H, or C1-C6 alkyl;

[0492] m is 0, 1, 2, 3 or 4;

[0493] n is 0, 1, 2, 3, 4 or 5; and

[0494] p is 0, 1, 2 or 3.

[0495] Item 3. The pharmaceutical combination according to Item 1, wherein the compound of formula (I) is represented by formula (III):

[0496]

[0497] in:

[0498] A and V are independently H, halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ;

[0499] Each Q is independently halogen, azide, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ;

[0500] In each-NR 1 R 2In, R 1 and R 2 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains additional heteroatoms selected from N, O and S as ring members;

[0501] R 1 is H, or C1-C6 alkyl optionally substituted by one or more halogens, or ═O;

[0502] R 2 is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0503] R 3 is optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0504] Each R 4 are independently H, or C1-C6 alkyl;

[0505] R 7 is H, and R 8 is C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0506] m is 0, 1, 2, 3 or 4; and

[0507] n is 0, 1, 2, 3, 4 or 5.

[0508] Item 4. The pharmaceutical combination according to Item 3, wherein the compound is Compound A:

[0509]

[0510] Item 5. The pharmaceutical combination of Item 1, wherein the compound of formula (I) and the at least one additional therapeutically active agent are in a single dosage form or separate dosage forms.

[0511] Item 6. The pharmaceutical combination according to Item 5, wherein the separate dosage forms are administered by the same administration route or different administration routes.

[0512] Item 7. The pharmaceutical combination of Item 6, wherein the separate dosage forms are co-administered by simultaneous administration, sequential administration, overlapping administration, intermittent administration, continuous administration, or a combination thereof.

[0513] Item 8. The pharmaceutical combination of Item 1, wherein the at least one additional therapeutically active agent comprises at least one immunotherapeutic agent.

[0514] Item 9. The pharmaceutical combination of Item 8, wherein the at least one immunotherapeutic agent is selected from one or more of the group consisting of: monoclonal antibodies, immune effector cells, adoptive cell transfer, immunotoxins, vaccines, or cytokines.

[0515] Item 10. The drug combination of Item 8, wherein the at least one immunotherapeutic agent is an antibody or an antigen-binding portion thereof that disrupts the interaction between programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1).

[0516] Item 11. A drug combination as described in Item 8, wherein the at least one immunotherapeutic agent is one or more selected from the group consisting of: anti-PD-1 antibodies, PD-1 antagonists, anti-PD-L1 antibodies, siRNA targeting PD-1 expression, siRNA targeting PD-L1 expression, and peptides, fragments, dominant negative forms or soluble forms of PD-1 or PD-L1.

[0517] Item 12. The pharmaceutical combination of Item 11, wherein the anti-PD-1 antibody is a monoclonal antibody.

[0518] Item 13. The pharmaceutical combination of Item 11, wherein the anti-PD-1 antibody is a humanized antibody.

[0519] Item 14. The drug combination of Item 8, wherein the at least one immunotherapeutic agent is selected from one or more of the group consisting of: a CTLA-4 antagonist, an anti-CTLA-4 antibody, an siRNA targeting CTLA-4 expression, and a peptide, fragment, dominant negative or soluble form of CTLA-4.

[0520] Item 15. The drug combination of Item 9, wherein the monoclonal antibody is one or more selected from the group consisting of anti-PD-1 antibody, nivolumab, pembrolizumab, alemtuzumab, bevacizumab, brentuximab, cetuximab, gemtuzumab tuximab, ipilimumab tiuxetan, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, anti-B7-H4, anti-B7-H1, anti-LAG3, BTLA, anti-Tim3, anti-B7-DC, anti-CD160, MR antagonist antibody, anti-4-1BB, anti-OX40, anti-CD27, and CD40 agonist antibody.

[0521] Item 16. The pharmaceutical combination of Item 15, wherein the monoclonal antibody is selected from the group consisting of nivolumab and pembrolizumab.

[0522] Item 17. The pharmaceutical combination of Item 16, wherein the monoclonal antibody is nivolumab.

[0523] Item 18. The pharmaceutical combination of Item 1, wherein the at least one additional therapeutically active agent comprises at least one anticancer agent.

[0524] Item 19. A drug combination as described in Item 18, wherein the at least one anticancer agent is one or more selected from the group consisting of: alkylating agents, antimetabolites, vinca alkaloids, taxanes, topoisomerase inhibitors, antitumor antibiotics, tyrosine kinase inhibitors, immunosuppressive macrolides, Akt inhibitors, HDAC inhibitors, Hsp90 inhibitors, mTOR inhibitors, PI3K / mTOR inhibitors, PI3K inhibitors, CDK (cyclin-dependent kinase) inhibitors, CHK (checkpoint kinase) inhibitors, and PARP (poly (DP-ribose) polymerase) inhibitors.

[0525] Item 20. The pharmaceutical combination of Item 18, wherein the at least one anticancer agent is a PI3K inhibitor.

[0526] Item 21. The pharmaceutical combination of Item 19, wherein the PI3K inhibitor is idelalisib.

[0527] Item 22. The pharmaceutical combination of Item 18, wherein the at least one anticancer agent is a PARP inhibitor.

[0528] Item 23. The pharmaceutical combination of Item 22, wherein the PARP inhibitor is olaparib.

[0529] Item 24. The pharmaceutical combination of Item 1, wherein the at least one additional therapeutically active agent comprises at least one anti-angiogenic agent.

[0530] Item 25. The pharmaceutical combination of Item 25, wherein the at least one anti-angiogenic agent is one or more selected from the group consisting of: 2-methoxyestradiol, AG3340, pumastat, batimastat, BAY 12-9566, carboxyamidotriazole, CC-1088, dextromethorphan acetic acid, dimethylxanthone acetic acid, EMD 121974, endostatin, IM-862, marimastat, matrix metalloproteinases, penicillamine, PTK787 / ZK 222584, RPI.4610, squalamine, squalamine lactate, 3-[2,4-dimethylpyrrol-5-yl-methyl-indenyl]-2-indolinone (SU5416), (±)-thalidomide, S-thalidomide, R-thalidomide, O-(chloroacetylcarbamoyl)fumagillol (TNP-470), cobricosides, paclitaxel, tamoxifen, COL-3, neovastat, BMS-275291, SU6668, 2-ME, interferon-α, anti-VEGF antibody, Medi-522 (Vitaxin II), CAI (calcium influx inhibitor), celecoxib, interleukin-12, IM862, amiloride, Protein, angiostatin K1-3, angiostatin K1-5, captopril, DL-α-difluoromethylornithine, DL-α-difluoromethylornithine HCl, Endostatin TM protein, fumagillin, herbimycin A, 4-hydroxyphenylretinamide, interferon-gamma, juglone, laminin, laminin hexapeptide, laminin pentapeptide, fumonisin A, medroxyprogesterone acetate, minocycline, minocycline HCl, placental ribonuclease inhibitor, suramin, suramin sodium salt, human thrombospondin, tissue inhibitor of metalloproteinases-1, neutrophil tissue inhibitor of metalloproteinases-1, or rheumatoid synovial fibroblast tissue inhibitor of metalloproteinases-2.

[0531] Item 26. The drug combination according to Item 1, which is a pharmaceutical preparation further comprising a pharmaceutically acceptable excipient or a pharmaceutically acceptable carrier.

[0532] Item 27. The pharmaceutical combination of Item 4, wherein Compound A is present in an amount of about 1 mg to about 500 mg.

[0533] Item 28. The pharmaceutical combination of Item 1, wherein the compound is Compound A:

[0534]

[0535] And wherein the at least one additional therapeutically active agent is selected from one or more of the group consisting of a PARP inhibitor and an anti-PD-1 antibody.

[0536] Item 29. The pharmaceutical combination of Item 28, wherein the PARP inhibitor is olaparib.

[0537] Item 30. The drug combination of Item 28, wherein the anti-PD-1 antibody is nivolumab.

[0538] Item 31. A method for treating or ameliorating a cell proliferation disorder in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I);

[0539]

[0540] or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof;

[0541] in:

[0542] X 1 is CH or N;

[0543] X 2 、X 3 、X 4 、X 5 、X 6 and X 7 Independently NR 4 , CH2, CHQ or C(Q)2, provided that X 2 、X 3 、X 4 、X 5 、X 6 and X 7 Zero, one or two of them are NR 4 ;

[0544] A and V are independently H, halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ;

[0545] Each Q is independently halogen, azide, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ;

[0546] In each-NR1 R 2 In, R 1 and R 2 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains one additional heteroatom selected from N, O and S as a ring member;

[0547] R 1 is H, or C1-C6 alkyl optionally substituted by one or more halogens, or ═O;

[0548] R 2 is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0549] R 3 is optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens;

[0550] Each R 4 are independently H, or C1-C6 alkyl;

[0551] R 7 is H, and R 8 is C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, each of which may be optionally substituted with one or more halogens; or in the case of –NR 7 R 8 In, R 7 and R 8 Together with N, may form an optionally substituted nitrogen heterocycle, which optionally contains additional heteroatoms selected from N, O and S as ring members;

[0552] m is 0, 1, 2, 3 or 4;

[0553] n is 0, 1, 2, 3, 4 or 5;

[0554] and administering radiation therapy or at least one additional therapeutically active agent before, during, or after administering the compound of formula (I) to the subject.

[0555] Item 32. The method of Item 31, wherein the cell proliferative disorder is cancer.

[0556] Item 33. The method of Item 32, wherein the cancer is selected from the group consisting of hemoglobin cancer, colorectal cancer, ovarian cancer, breast cancer, cervical cancer, lung cancer, liver cancer, pancreatic cancer, lymph node cancer, colon cancer, prostate cancer, brain cancer, head and neck cancer, bone cancer, Ewing's sarcoma, skin cancer, kidney cancer, and heart cancer.

[0557] Item 34. The method of Item 32, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, Ewing's sarcoma, head and neck cancer, and cervical cancer.

[0558] Item 35. The method of Item 33, wherein the heme cancer is selected from the group consisting of leukemia, lymphoma, myeloma, and multiple myeloma.

[0559] Item 36. A method as described in Item 32, wherein the cancer is a homologous recombination (HR)-dependent DNA double-strand break (DSB) repair-deficient cancer or a non-homologous end joining (NHEJ) DSB repair-deficient cancer.

[0560] Item 37. The method of Item 33, wherein the subject is human.

[0561] Item 38. The method of Item 33, wherein the at least one additional therapeutically active agent is one or more selected from the group consisting of an immunotherapeutic agent, an anticancer agent, and an angiogenic agent.

[0562] Item 39. The method of Item 31, wherein the compound is Compound A:

[0563]

[0564] Item 40. The method of Item 39, wherein the at least one additional therapeutically active agent is selected from one or more of the group consisting of a PARP inhibitor and an anti-PD-1 antibody.

[0565] Item 41. The method of Item 40, wherein the PARP inhibitor is olaparib.

[0566] Item 42. The method of Item 40, wherein the anti-PD-1 antibody is nivolumab.

Claims

1. A pharmaceutical combination comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, ester, solvate and / or prodrug thereof, and one or more additional therapeutically active agents selected from the group consisting of an immunotherapeutic agent, an anticancer agent and an angiogenic agent; wherein: X 1 is CH or N; X 2 , X 3 , X 4 , X 5 , X 6 and X 7 Independently for NR 4 , CH2, CHQ or C(Q)2, provided that X 2 , X 3 , X 4 , X 5 , X 6 and X 7 Zero, one or two of them are NR 4 ; A and V are independently H, halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ; Each Q is independently halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ; In each -NR 1 R 2 In, R 1 and R 2 together with N may form an optionally substituted nitrogen heterocycle which optionally contains one additional heteroatom selected from N, O and S as a ring member; R 1 is H, or C1-C6 alkyl optionally substituted by one or more halogens, or =O; R 2 is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, =O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, wherein each of the C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl may be optionally substituted with one or more halogens; R 3 is optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, =0, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring, wherein the C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, each of which may be optionally substituted by one or more halogens; Each R 4 are independently H, or C1-C6 alkyl; R 7 is H, and R 8 is C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, =O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, wherein each of the C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl may be optionally substituted with one or more halogens; or in -NR 7 R 8 In, R 7 and R 8 together with N may form an optionally substituted nitrogen heterocycle which optionally contains additional heteroatoms selected from N, O and S as ring members; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, 4 or 5.

2. The pharmaceutical combination according to claim 1, wherein the compound of formula (I) is represented by formula (II): in: A and V are independently H, halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ; Each Q is independently halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ; In each -NR 1 R 2 In, R 1 and R 2 together with N may form an optionally substituted nitrogen heterocycle which optionally contains additional heteroatoms selected from N, O and S as ring members; R 1 is H, or C1-C6 alkyl optionally substituted by one or more halogens, or =O; R 2 is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, =O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, wherein each of the C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl may be optionally substituted with one or more halogens; R 3 is optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, =0, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring, wherein the C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, each of which may be optionally substituted by one or more halogens; R 4 are independently H, or C1-C6 alkyl; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3, 4 or 5; and p is 0, 1, 2 or 3.

3. The pharmaceutical combination according to claim 1, wherein the compound of formula (I) is represented by formula (III): in: A and V are independently H, halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ; Each Q is independently halogen, azido, -CN, -CF3, -CONR 1 R 2 、-NR 1 R 2 、-SR 2 、-OR 2 , or -R 3 ; In each -NR 1 R 2 In, R 1 and R 2 together with N may form an optionally substituted nitrogen heterocycle which optionally contains additional heteroatoms selected from N, O and S as ring members; R 1 is H, or C1-C6 alkyl optionally substituted by one or more halogens, or =O; R 2 is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, =O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, wherein each of the C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl may be optionally substituted with one or more halogens; R 3 is optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, =0, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring, wherein the C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl or C6-C12 aralkyl, or a hetero form of one of these, each of which may be optionally substituted by one or more halogens; Each R 4 are independently H, or C1-C6 alkyl; R 7 is H, and R 8 is C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl, =O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring, wherein each of the C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl may be optionally substituted with one or more halogens; m is 0, 1, 2, 3 or 4; and n is 0, 1, 2, 3, 4 or 5.

4. The pharmaceutical combination according to claim 3, wherein the compound is compound A:

5. The pharmaceutical combination of claim 1, wherein the compound of formula (I) and the at least one additional therapeutically active agent are in a single dosage form or in separate dosage forms. The pharmaceutical combination according to claim 5 , wherein the separate dosage forms are administered by the same administration route or different administration routes.

7. The pharmaceutical combination of claim 6, wherein the separate dosage forms are co-administered by simultaneous administration, sequential administration, overlapping administration, intermittent administration, continuous administration, or a combination thereof.

8. The pharmaceutical combination of claim 1, wherein the at least one additional therapeutically active agent comprises at least one immunotherapeutic agent.

9. The pharmaceutical combination of claim 8, wherein the at least one immunotherapeutic agent is selected from one or more of the group consisting of: monoclonal antibodies, immune effector cells, adoptive cell transfer, immunotoxins, vaccines or cytokines.

10. The pharmaceutical combination of claim 8, wherein the at least one immunotherapeutic agent is an antibody or an antigen-binding portion thereof that disrupts the interaction between programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1).

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