Combination therapy including a METTL3 inhibitor and an additional anticancer drug

Abstract

The present invention relates to a novel combination therapy for treating proliferative disorders, such as cancer. The combination therapy comprises the administration of (i) a cancer immunotherapy or therapy; (ii) a BCL2 inhibitor or a pharmaceutically acceptable salt thereof; (iii) an anthracycline topoisomerase 2 inhibitor or a pharmaceutically acceptable salt thereof; (iv) a cytarabine or a pharmaceutically acceptable salt thereof; (v) a hypomethylating agent or a pharmaceutically acceptable salt thereof; or (vi) a METTL3 inhibitor in combination with a FLT3 inhibitor or a pharmaceutically acceptable salt thereof.

Description

[Technical field]

[0001] The present invention relates to novel combination therapies for treating cancer. [Background technology]

[0002] Cancer is caused by uncontrolled and unregulated cell proliferation. What exactly causes cells to become malignant and proliferate in an uncontrolled and unregulated manner has been the focus of intensive research over the last decades. This research has led to the identification of several molecular targets and key metabolic pathways that are known to be associated with malignant tumors.

[0003] Despite many advances in the treatment of cancer, there remains a need for new therapies that offer improved outcomes.

[0004] One particular target that has attracted interest is METTL3. 6 -Methyladenosine (m 6 A) is an abundant internal RNA modification that is primarily catalyzed by the METTL3-METTL14 methyltransferase complex. 6 The A methyltransferase METTL3 has been implicated in the initiation and maintenance of acute myeloid leukemia (AML). Yankova et al. (Nature: volume 593, pages 597-601 (2021)) describe the identification and characterization of STM2457, a highly potent and selective first-in-class catalytic inhibitor of METTL3. Treatment with STM2457 led to a decrease in AML proliferation, as well as an increase in differentiation and apoptosis. These cellular effects were due to the upregulation of methyltransferases on known leukemic mRNAs. 6A levels, and their expression, consistent with translational abnormalities. Pharmacological inhibition of METTL3 in vivo resulted in impaired engraftment and extended survival in various mouse models of AML, specifically targeting a key stem cell subpopulation in AML. Thus, METTL3 is a potential therapeutic strategy for AML, and targeting RNA-modifying enzymes more generally represents a promising avenue for anticancer therapy.

[0005] WO 2020 / 050898 describes further small molecule METTL3 inhibitors suitable for the treatment of cancer.

[0006] METTL3 inhibitors clearly show promise for the treatment of AML and other cancers. However, there is a constant need to identify new therapeutic strategies that can be used to further improve treatment outcomes.

[0007] It is with the above in mind that the present invention has been devised. Summary of the Invention

[0008] <1. Combination of METTL3 inhibitors and immuno-oncology agents (e.g., immune checkpoint inhibitors)> The data presented in the Examples section of this specification show that administering METTL3 inhibitor compound STM3480 in combination with immune checkpoint inhibitors (anti-PD1 and anti-PD-L1) significantly increases the observed anti-tumor immune response (when compared to vehicle control and treatment with either METTL3 inhibitor or immune checkpoint inhibitor alone). Data is presented for tumor killing co-culture cell assay (see Example 1) and in vivo testing using A20 B cell lymphoma model, EMT6 breast cancer model and CT26 colorectal cancer model (see Example 2). Taken together, these data suggest that administering METTL3 inhibitor in conjunction with immune checkpoint inhibitor significantly enhances anti-tumor immune response. Thus, METTL3 inhibition may play a role in sensitizing cancer cells to immune checkpoint inhibitor therapy.

[0009] Thus, in one aspect, the present invention relates to a METTL3 inhibitor, or a pharma- ceutically acceptable salt thereof, as defined herein, for use as an immunosensitizer.

[0010] The present invention also relates to the use of a METTL3 inhibitor, or a pharma- ceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for use as an immunosensitizer.

[0011] The present invention also relates to a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer administered in combination with an immuno-cancer agent or therapy (e.g., an immune checkpoint inhibitor (e.g., a PD1, PD-L1 inhibitor, a LAG3, CTLA-4, TIGIT, TIM3 or VISTA inhibitor), a STING agonist, a TLR agonist, an anti-CD137 antibody, a CD28 antibody, an OX40 stimulant, a CD40 antibody, an ICOS agonist, a GITR agonist, an A2AR antagonist, a bispecific T cell engager (BiTE), an oncolytic virus, a cancer vaccine, and / or a CAR-T cell therapy).

[0012] The present invention also relates to the use of a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer, wherein the METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, is administered in combination with an immuno-cancer drug or therapy (e.g., an immune checkpoint inhibitor (e.g., a PD1, PD-L1 inhibitor, a LAG3, CTLA-4, TIGIT, TIM3 or VISTA inhibitor), a STING agonist, a TLR agonist, an anti-CD137 antibody, a CD28 antibody, an OX40 stimulant, a CD40 antibody, an ICOS agonist, a GITR agonist, an A2AR antagonist, a bispecific T cell engager (BiTE), an oncolytic virus, a cancer vaccine, and / or a CAR-T cell therapy).

[0013] The present invention also relates to a method of treating cancer comprising administering to a patient a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, in combination with a cancer immuno-agent or therapy (e.g., an immune checkpoint inhibitor (e.g., a PD1, PD-L1 inhibitor, a LAG3, CTLA-4, TIGIT, TIM3 or VISTA inhibitor), a STING agonist, a TLR agonist, an anti-CD137 antibody, a CD28 antibody, an OX40 stimulator, a CD40 antibody, an ICOS agonist, a GITR agonist, an A2AR antagonist, a bispecific T-cell engager (BiTE), an oncolytic virus, a cancer vaccine, and / or a CAR-T cell therapy).

[0014] Suitably, a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, is administered simultaneously, sequentially or separately with an immuno-cancer drug or therapy (e.g., an immune checkpoint inhibitor (e.g., a PD1, PD-L1 inhibitor, a LAG3, CTLA-4, TIGIT, TIM3 or VISTA inhibitor), a STING agonist, a TLR agonist, an anti-CD137 antibody, a CD28 antibody, an OX40 stimulant, a CD40 antibody, an ICOS agonist, a GITR agonist, an A2AR antagonist, a bispecific T cell engager (BiTE), an oncolytic virus, a cancer vaccine, and / or a CAR-T cell therapy).

[0015] In one aspect, the invention relates to a combination comprising a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, or a pharma- ceutically acceptable salt thereof.

[0016] In another aspect, the invention relates to a pharmaceutical product comprising a combination as defined herein.

[0017] In another aspect, the present invention relates to a pharmaceutical composition comprising a combination as defined herein and one or more pharma- ceutically acceptable excipients.

[0018] In another aspect, the invention relates to a combination as defined herein, or a medicament as defined herein, or a pharmaceutical composition as defined herein, for use in therapy.

[0019] In another aspect, the invention relates to a combination as defined herein, or a medicament as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of cancer.

[0020] In another aspect, the invention relates to the use of a combination as defined herein in the manufacture of a medicament for treating cancer.

[0021] In another aspect, the present invention relates to a method of treating cancer in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of a combination as defined herein.

[0022] In another aspect, the invention relates to a method of enhancing an immune response against a tumor, comprising the step of administering a therapeutically effective amount of a combination as defined herein to a patient in need of such treatment.

[0023] In another aspect, the invention relates to a METTL3 inhibitor, or a pharma- ceutical acceptable salt thereof, as defined herein, for use in the treatment of cancer, for simultaneous, separate or sequential administration with an immune checkpoint inhibitor, or a pharma- ceutical acceptable salt thereof.

[0024] In another aspect, the present invention relates to an immune checkpoint inhibitor, or a pharma- ceutical acceptable salt thereof, for simultaneous, separate or sequential administration with a METTL3 inhibitor, or a pharma- ceutical acceptable salt thereof, as defined herein, for use in the treatment of cancer.

[0025] In another aspect, the invention relates to the use of a METTL3 inhibitor, or a pharma- ceutical acceptable salt thereof, as defined herein, in the manufacture of a medicament for treating cancer, wherein the medicament is for simultaneous, separate or sequential administration with an immune checkpoint inhibitor, or a pharma- ceutical acceptable salt thereof.

[0026] In another aspect, the invention relates to the use of an immune checkpoint inhibitor, or a pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for treating cancer, wherein the medicament is for simultaneous, separate or sequential administration with a METTL3 inhibitor, or a pharma- ceutical acceptable salt thereof, as defined herein.

[0027] In another aspect, the present invention relates to a method of treating cancer, comprising the step of administering to a subject in need thereof therapeutically effective amounts of a METTL3 inhibitor, or a pharma- ceutically acceptable salt thereof, as defined herein and an immune checkpoint inhibitor, or a pharma- ceutically acceptable salt thereof, wherein the METTL3 inhibitor, or a pharma- ceutically acceptable salt thereof, as defined herein and the immune checkpoint inhibitor, or a pharma- ceutically acceptable salt thereof, are administered sequentially, separately or simultaneously with each other.

[0028] In another aspect, the present invention relates to a method of treating cancer or enhancing the effect of a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, comprising the step of administering a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, to a patient in need of such treatment, separately, sequentially or simultaneously with an immune checkpoint inhibitor, or a pharma- ceutically acceptable salt thereof.

[0029] In another aspect, the present invention relates to a method of enhancing an immune response against a tumor, comprising the step of administering to a patient in need of such treatment therapeutically effective amounts of a METTL3 inhibitor, or a pharma- ceutically acceptable salt thereof, as defined herein and an immune checkpoint inhibitor, or a pharma- ceutically acceptable salt thereof, wherein the METTL3 inhibitor, or a pharma- ceutically acceptable salt thereof, as defined herein and the immune checkpoint inhibitor, or a pharma- ceutically acceptable salt thereof, are administered sequentially, separately or simultaneously with each other.

[0030] Suitably the cancer is a solid tumour.

[0031] <2. Combination of METTL3 inhibitor and BCL2 inhibitor (e.g., venetoclax)> The data presented in the Examples section show that METTL3 inhibitor compounds STM3480, STM3006 and STM3675, when administered in combination with a BCL2 inhibitor (venetoclax), resulted in a synergistic increase in the observed anti-cancer effect. Data is presented for Kasumi1 and MOLM13 AML cell lines (see Example 3). Taken together, these data suggest that METTL3 inhibition synergistically enhances the anti-tumor effect of BCL2 inhibitor (e.g., venetoclax) therapy. Thus, the combination of METTL3 inhibitors and BCL2 inhibitors (e.g., venetoclax) provides a promising treatment for diseases or conditions where BCL2 inhibitor therapy is beneficial (e.g., treatment of cancers such as acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and myelodysplastic syndrome (MDS)).

[0032] Thus, the present invention also relates to a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof, for use in the treatment of a disease or condition in which BCL2 inhibitor therapy is beneficial (e.g., the treatment of cancer), administered in combination with a BCL2 inhibitor (e.g., venetoclax).

[0033] The present invention also relates to the use of a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disease or condition in which BCL2 inhibitor therapy is beneficial (e.g., the treatment of cancer), wherein the METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof, is administered in combination with a BCL2 inhibitor (e.g., venetoclax).

[0034] The present invention also relates to a method of treating a disease or condition in which BCL2 inhibitor therapy is beneficial (e.g., treating cancer), comprising administering to a patient a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof, in combination with a BCL2 inhibitor (e.g., venetoclax).

[0035] Suitably, the METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, is administered simultaneously, sequentially or separately from the BCL2 inhibitor (eg, venetoclax) therapy.

[0036] In one aspect, the invention relates to a combination comprising a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, and a BCL2 inhibitor (e.g., venetoclax), or a pharma- ceutically acceptable salt thereof.

[0037] In another aspect, the invention relates to a pharmaceutical product comprising a combination as defined above.

[0038] In another aspect, the invention relates to a pharmaceutical composition comprising a combination as defined above and one or more pharma- ceutically acceptable excipients.

[0039] In another aspect, the invention relates to a combination as defined above, or a medicament as defined above, or a pharmaceutical composition as defined above, for use in therapy.

[0040] In another aspect, the invention relates to a combination as defined herein, or a medicament as defined above, or a pharmaceutical composition as defined above, for use in the treatment of a disease or condition in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancer).

[0041] In another aspect, the invention relates to the use of a combination as defined above in the manufacture of a medicament for the treatment of a disease or condition in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancer).

[0042] In another aspect, the present invention relates to a method for treating a disease or condition in a subject in need thereof that would benefit from BCL2 inhibitor therapy (e.g., treating cancer), comprising administering to said subject a therapeutically effective amount of a combination as defined above.

[0043] In another aspect, the invention relates to a METTL3 inhibitor, or a pharma- ceutical acceptable salt thereof, as defined herein, for use in the treatment of cancer, for simultaneous, separate or sequential administration with a BCL2 inhibitor (e.g., venetoclax), or a pharma- ceutical acceptable salt thereof.

[0044] In another aspect, the present invention relates to a BCL2 inhibitor (e.g., venetoclax), or a pharma- ceutical acceptable salt thereof, for use in the treatment of cancer, for simultaneous, separate or sequential administration with a METTL3 inhibitor, or a pharma- ceutical acceptable salt thereof, as defined herein.

[0045] In another aspect, the invention relates to the use of a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for treating cancer, wherein the medicament is for simultaneous, separate or sequential administration with a BCL2 inhibitor (e.g., venetoclax), or a pharma- ceutical acceptable salt thereof.

[0046] In another aspect, the invention relates to the use of a BCL2 inhibitor (e.g., venetoclax) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer, wherein the medicament is for simultaneous, separate or sequential administration with a METTL3 inhibitor or a pharmaceutically acceptable salt thereof as defined herein.

[0047] In another aspect, the present invention relates to a method of treating cancer, comprising the step of administering to a subject in need thereof therapeutically effective amounts of a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, and a BCL2 inhibitor (e.g., venetoclax) or a pharma- ceutically acceptable salt thereof, wherein the METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, and the BCL2 inhibitor (e.g., venetoclax) or a pharma- ceutically acceptable salt thereof, are administered sequentially, separately or simultaneously with each other.

[0048] In another aspect, the present invention relates to a method of treating cancer or enhancing the effect of a BCL2 inhibitor (e.g., venetoclax) or a pharma- ceutically acceptable salt thereof, comprising administering a therapeutically effective amount of a BCL2 inhibitor (e.g., venetoclax) or a pharma- ceutically acceptable salt thereof to a patient in need of such treatment, separately, sequentially or simultaneously with a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof.

[0049] In another aspect, the present invention relates to a method of treating cancer or enhancing the effect of a METTL3 inhibitor as defined herein or a pharma- ceutically acceptable salt thereof, comprising the step of administering a therapeutically effective amount of a METTL3 inhibitor as defined herein or a pharma- ceutically acceptable salt thereof to a patient in need of such treatment, separately, sequentially or simultaneously with a BCL2 inhibitor (e.g., venetoclax) or a pharma- ceutically acceptable salt thereof.

[0050] Suitably, the cancer is selected from acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and myelodysplastic syndrome (MDS).

[0051] <3. Combination of METTL3 inhibitor with anthracycline topoisomerase 2 inhibitor (e.g., daunorubicin), cytarabine, hypomethylating agent (e.g., 5-azacytidine or decitabine), or FLT3 inhibitor (e.g., quizartinib)> The data presented in the Examples section herein show that METTL3 inhibitor compounds STM3480 and STM3006, when administered in combination with various standard therapies for treating AML, such as daunorubicin, cytarabine, 5-azacytidine and quizartinib, provided enhanced therapeutic effects in Kasumi1 or MOLM-14 AML cell lines (see Example 4). Collectively, these data suggest that administration of METTL3 inhibitors enhances the antitumor effects of AML standard therapies, including anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin), cytarabine, hypomethylating agents (e.g., 5-azacytidine or decitabine), and / or FLT3 inhibitors (e.g., quizartinib).

[0052] Thus, the combination of a METTL3 inhibitor with either an anthracycline topoisomerase 2 inhibitor (e.g., daunorubicin), cytarabine, a hypomethylating agent (e.g., 5-azacytidine or decitabine), and / or an FLT3 inhibitor (e.g., quizartinib) provides a promising therapeutic strategy for treating cancer (e.g., acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and myelodysplastic syndromes (MDS)).

[0053] Thus, the present invention also provides a method for producing a method for the treatment of atopic dermatitis. (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer, administered in combination with one or more additional agents selected from:

[0054] The present invention also relates to the use of a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer, the METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof comprising: (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutical acceptable salt thereof.

[0055] The present invention also provides a method of treating cancer, comprising administering a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof, to a patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof, (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutically acceptable salt thereof.

[0056] Suitably, the METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutically acceptable salt thereof They may be administered simultaneously, sequentially or separately.

[0057] In one aspect, the present invention relates to a METTL3 inhibitor as defined herein or a pharma- ceutical acceptable salt thereof. (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutically acceptable salt thereof.

[0058] In another aspect, the invention relates to a pharmaceutical product comprising a combination as defined above.

[0059] In another aspect, the invention relates to a pharmaceutical composition comprising a combination as defined above and one or more pharma- ceutically acceptable excipients.

[0060] In another aspect, the invention relates to a combination as defined above, or a medicament as defined above, or a pharmaceutical composition as defined above, for use in therapy.

[0061] In another aspect, the invention relates to a combination as defined above, or a medicament as defined above, or a pharmaceutical composition as defined above, for use in the treatment of cancer.

[0062] In another aspect, the present invention relates to the use of a combination as defined above in the manufacture of a medicament for treating cancer.

[0063] In another aspect, the present invention relates to a method of treating cancer in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of the combination as defined above.

[0064] In another aspect, the present invention provides a method for producing a composition comprising: (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutical acceptable salt thereof, for use in the treatment of cancer, wherein the pharma-ceutical agent is a METTL3 inhibitor or a pharma-ceutical acceptable salt thereof, wherein the pharma-ceutical agent is a METTL3 inhibitor or a pharma-ceutical acceptable salt thereof,

[0065] In another aspect, the present invention relates to a compound according to the present invention for use in the treatment of cancer, which compound is for simultaneous, separate or sequential administration with a METTL3 inhibitor as defined herein or a pharma- ceutical acceptable salt thereof. (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutically acceptable salt thereof.

[0066] In another aspect, the invention relates to the use of a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for treating cancer, the medicament comprising: (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharmaceutically acceptable salt thereof, wherein the compound is for simultaneous, separate or sequential administration with one or more additional agents selected from the group consisting of

[0067] In another aspect, the present invention relates to a method for the manufacture of a medicament for treating cancer, comprising: (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutical acceptable salt thereof, wherein the medicament is for simultaneous, separate or sequential administration with a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof.

[0068] In another aspect, the present invention provides a method of treating cancer comprising administering to a patient a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof. (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutically acceptable salt thereof to a subject in need thereof; The present invention relates to a method, wherein the METTL3 inhibitor or a pharma- ceutically acceptable salt thereof and the agent or a pharma- ceutically acceptable salt thereof as defined herein are administered sequentially, separately or simultaneously with each other.

[0069] In another aspect, the present invention provides a method for treating cancer, or (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutical acceptable salt thereof, comprising the step of administering a therapeutically effective amount of the agent or a pharma- ceutical acceptable salt thereof to a patient in need of such treatment separately, sequentially or simultaneously with a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof.

[0070] In another aspect, the present invention provides a method of treating cancer or enhancing the effect of a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, comprising administering to a patient in need of such treatment a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof: (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutically acceptable salt thereof.

[0071] Suitably, the cancer is selected from acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and myelodysplastic syndrome (MDS), in particular AML.

[0072] The preferred, suitable, and optional features of any one particular embodiment of the invention described herein are also preferred, suitable, and optional features of any other embodiment.

[0073] Embodiments of the present invention will now be described, by way of example only, with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0074] [Figure 1]FIG. 1 shows that the combination of STM3480 and pembrolizumab results in the most potent reduction in SKOV3 tumor survival (NLR strength) and enhanced efficacy compared to either agent alone. [Diagram 2] FIG. 1 shows that the combination of STM3480 and avelumab results in the most potent reduction in SKOV3 tumor survival (NLR strength) and enhanced efficacy compared to either agent alone. [Diagram 3] Figure 1 shows the mean tumor volumes of A20 lymphomas shown after the indicated treatments + standard error of the mean (SEM) shown. Vehicle treatment (solid black line, open circles) shows rapid progressive tumor growth. STM3480 treatment (dotted grey line, open squares) shows a reduction in tumor growth compared to vehicle controls. Anti-PD1 treatment (dashed grey line, open circles) shows a modest reduction in tumor growth. The combination of STM3480 and anti-PD1 (dashed black line, filled triangles) shows complete tumor regression in 6 / 10 animals. Abbreviations: TV - tumor volume; BID - administered twice daily; BIW - administered twice weekly. [Figure 4] Figure 2 shows A20 lymphoma tumor growth shown for individual tumors after the indicated treatments. Vehicle treatment (black solid line, top left panel) shows progressive tumor growth in 9 / 10 animals. STM3480 treatment (grey dashed line, top right panel) shows progressive tumor growth in 8 / 10 animals. Anti-PD1 treatment (black dotted line, bottom left panel) shows progressive tumor growth in 8 / 10 animals. The combination of STM3480 and anti-PD1 (black dotted and dashed line, bottom right panel) shows progressive tumor growth in 2 / 10 animals, tumor regression in 8 / 10 animals, and complete tumor regression in 6 / 10 animals. Abbreviations: TV - tumor volume; BID - administered twice daily; BIW - administered twice weekly. [Diagram 5] 1 shows that no adverse effects of treatment on body weight were observed in either group. Note that the decrease in body weight in the vehicle-treated group from day 25 onwards was the result of disease progression and large tumor burden, and not due to the treatment itself. [Figure 6]FIG. 1 shows that STM3480 exhibits synergistic interaction with venetoclax in the Kasmi1 AML cell line, with increasing concentrations of STM3480 resulting in decreasing IC50 of venetoclax as shown in the table below. [Figure 7] FIG. 1 shows that STM3480 exhibits synergistic interactions with venetoclax in MOLM13 AML cell lines, with increasing concentrations of STM3480 resulting in decreasing IC50 of venetoclax as shown in the table below. [Figure 8] FIG. 1 shows that STM3006 exhibits synergistic interaction with venetoclax in the Kasumi1 AML cell line, with increasing concentrations of STM3006 resulting in a decreasing IC50 of venetoclax as shown in the table below. [Figure 9] FIG. 1 shows that STM3006 demonstrates synergistic interaction with venetoclax in MOLM13 AML cell lines, with increasing concentrations of STM3006 resulting in a decreasing IC50 of venetoclax as shown in the table below. [Figure 10] FIG. 1 shows that STM3675 exhibits synergistic interaction with venetoclax in the Kasumi1 AML cell line, with increasing concentrations of STM3675 resulting in a decreasing IC50 of venetoclax as shown in the table below. [Figure 11] FIG. 1 shows that STM3675 exhibits synergistic interaction with venetoclax in MOLM13 AML cell lines, with increasing concentrations of STM3675 resulting in decreasing IC50 of venetoclax as shown in the table below. [Figure 12] FIG. 1 shows that STM3480 exhibits an additive interaction with daunorubicin in the Kasumi1 AML cell line, with increasing concentrations of STM3480 resulting in decreased viability. No change in the IC50 of daunorubicin was observed, indicating an additive interaction. [Figure 13]1 shows that STM3006 exhibits an additive interaction with daunorubicin in the Kasumi1 AML cell line, with increasing concentrations of STM3006 resulting in decreased viability. No change in the IC50 of daunorubicin was observed, indicating an additive interaction. [Figure 14] 1 shows that STM3480 exhibits an additive interaction with cytarabine in the Kasumi1 AML cell line, with increasing concentrations of STM3480 resulting in decreased viability. No change in the IC50 of cytarabine was observed, indicating an additive interaction. [Figure 15] 1 shows that STM3006 exhibits an additive interaction with cytarabine in the Kasumi1 AML cell line, with increasing concentrations of STM3006 resulting in decreased viability. No change in the IC50 of cytarabine was observed, indicating an additive interaction. [Figure 16] FIG. 1 shows that STM3480 exhibits an additive interaction with 5'-azacytidine in the Kasumi1 AML cell line, with increasing concentrations of STM3480 resulting in decreased viability. No change in the IC50 of 5'-azacytidine was observed, indicating an additive interaction. [Figure 17] FIG. 1 shows that STM3006 exhibits an additive interaction with 5'-azacytidine in the Kasumi1 AML cell line, with increasing concentrations of STM3006 resulting in decreased viability. No change in the IC50 of 5'-azacytidine was observed, indicating an additive interaction. [Figure 18] 1 shows that STM3480 exhibits an additive interaction with Quizartinib in FLT3 mutated MOLM-14 AML cell lines, with increasing concentrations of STM3480 resulting in decreased viability. No change in the IC50 of Quizartinib was observed, indicating an additive interaction. [Figure 19] 1 shows that STM3006 exhibits an additive interaction with Quizartinib in FLT3 mutated MOLM-14 AML cell lines, with increasing concentrations of STM3006 resulting in decreased viability. No change in the IC50 of Quizartinib was observed, indicating an additive interaction. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0075] [Definition] Unless otherwise stated, the following terms used in the specification and claims have the following meanings indicated below.

[0076] It should be recognized that references to "treating" or "treatment" include prevention of a condition as well as the alleviation of established symptoms of a condition. Thus, "treating" or "treatment" of a condition, disorder or condition includes (1) preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition that develops in a person who may be affected or susceptible to the condition, disorder or condition, but who has not experienced or exhibited clinical or subclinical symptoms of the condition, disorder or condition, (2) inhibiting the condition, disorder or condition, i.e., arresting, alleviating or delaying the onset of the disease or its recurrence (in the case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) alleviating or attenuating the disease, i.e., causing regression of the condition, disorder or condition, or at least one of its clinical or subclinical symptoms.

[0077] "Therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" varies depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0078] "Inhibitor" can be a polypeptide, a nucleic acid, a carbohydrate, a lipid, a low molecular weight compound, an oligonucleotide, an oligopeptide, an siRNA, an antisense, a recombinant protein, an antibody, a peptibody, or a conjugate or fusion protein thereof. For a general overview of siRNA, see Milhavet O, Gary DS, Mattson MP. (Pharmacol Rev. 2003 Dec; 55 (4): 629-48). For a general overview of antisense, see Opalinska JB, Gewirtz AM. Sci STKE. 2003 Oct 28; 2003 (206): p47. Low molecular weight compound refers to a compound with a molecular weight of less than 2000 Daltons, less than 1000 Daltons, less than 700 Daltons, or less than 500 Daltons.

[0079] Reference to "pharmaceutical acceptable salt" of the inhibitor as defined herein refers to any salt form suitable for pharmaceutical use. Examples of pharmaceutical acceptable salts include acid addition salts of the inhibitor of the present invention that are sufficiently basic, such as inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid or maleic acid. In addition, suitable pharmaceutical acceptable salts of the inhibitor of the present invention that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that provide pharmaceutical acceptable cations, such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0080] Reference herein to the METTL3 inhibitors or pharma- ceutically acceptable salts thereof, and immune checkpoint inhibitors or pharma- ceutically acceptable salts thereof, as defined herein, includes, where appropriate, all isomeric, tautomeric, polymorphic, amorphous and solvated (e.g., hydrated) forms of the inhibitors. The inhibitors may also be administered in the form of prodrugs that are broken down in the human or animal body to release the active inhibitor. Examples of prodrugs include in vivo cleavable ester derivatives of the inhibitors that may be formed at carboxy or hydroxy groups in the inhibitor compounds, and in vivo cleavable amide derivatives that may be formed at carboxy or amino groups in the inhibitor compounds. Various forms of prodrugs are available, for example: a)Methods in Enzymology,Vol.42,p.309-396,edited by K.Widder,et al.(Academic Press,1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c)A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard,Chapter 5 “Design and Application of Pro-drugs”, by H.Bundgaard p.113-191(1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N.Kakeya,et al.,Chem.Pharm.Bull.,32,692(1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987 This is described in the literature.

[0081] Unless otherwise specified, references herein to a METTL3 inhibitor, or a pharma- ceutically acceptable salt thereof, as defined herein, administered "in combination with" another agent, or a pharma- ceutically acceptable salt thereof, or vice versa, include inhibitors administered sequentially, separately or simultaneously with each other.

[0082] As used herein, "co-administration" refers to a therapy in which both agents (e.g., a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor) are administered at the same time, suitably as a monotherapy.

[0083] As used herein, "sequential administration" means that one agent is administered after the other, but the period between administration of each agent is such that both agents can act therapeutically at the same time. Thus, "sequential" administration can allow one agent to be administered within seconds, minutes, or hours after the other, provided that the circulating half-life of the first administered agent is such that both are present at the same time in therapeutically effective amounts. The time delay between administration of the agents can vary depending on the exact nature of the agents, the interaction between them, and their respective half-lives.

[0084] As used herein, "separate administration" means that one agent is administered after the other, but the period between administrations is such that when the second agent is administered, the first administered agent is no longer present in therapeutically effective amount.Therefore, the two agents exert their therapeutic effect separately.Nevertheless, the overall therapeutic effect observed when the two agents act therapeutically separately can be greater than either agent used alone.

[0085] As used herein, "subject" and / or "patient" preferably refers to a mammal, such as a human and non-human mammals such as livestock (e.g., cows, sheep, goats) or companion animals (e.g., cats, dogs, horses, rabbits). Preferably, the subject and / or patient is human.

[0086] As used herein, "pharmaceutical product" refers to a product containing a medicine. For example, examples of pharmaceutical products include medical devices, pharmaceutical compositions, and, preferably, kits of parts containing one or more devices, containers and / or medicines.

[0087] [Combination Therapy of the Invention] <METTL3 inhibitor> The present invention relates to the recognition that METTL3 inhibitors are (i) cancer immunotherapeutic agents (e.g., immune checkpoint inhibitors); (ii) BCL2 inhibitors (e.g., venetoclax); (iii) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (iv) cytarabine; (v) hypomethylating agents (e.g., 5-azacytidine or decitabine); and / or (vi) FLT3 inhibitors (e.g., quizartinib) and are viable agents for use in combination therewith.

[0088] Any suitable METTL3 inhibitor can be used in the combination therapy defined herein.

[0089] Examples of suitable METTL3 inhibitors include (i) compounds defined in International Publication No. WO 2020 / 050898 having the general formula I shown below; (ii) specific compounds of formula I shown in List 1 below; (iii) compounds of formula (II), (VI) or (VII) defined below; (iv) specific compounds of formula II shown in List 2 below; or (v) specific compounds STM3006, STM3480 and STM3675, as further defined below Examples include:

[0090] (i) a compound as defined in WO 2020 / 050898 The entire contents of WO 2020 / 050898 are hereby incorporated by reference.

[0091] The compounds defined therein have the following formula (I): XYZ (I) (In the formula, X is [ka] Selected from; R 1a , R 1b , R 1c , R 1d , R 1e and R 1f is hydrogen, cyano, halo or the formula: -L 1a -L 1b -Q1 (In the formula, L 1a is non-existent, or C 1~3 Alkylene and C 3~5 cycloalkylene, C 1~3 Alkylene and C 3~5 Cycloalkylene is optionally selected from aryl, aryl-(1-2C)alkyl, heteroaryl, aryl-(1-2C)alkyl, C 1~3 Alkyl, Cyano, C 1~3 Alkoxy, halo, hydroxy, C 1~3 Haloalkoxy, -OC 3~4 cycloalkyl, NH2 or oxo; 3~6 Cycloalkyl, aryl, aryl-(1-2C)alkyl, heteroaryl, aryl-(1-2C)alkyl or C 1~3The alkyl may also optionally be substituted with cyano, hydroxy, 1~3 Alkoxy, Halo, C 1~3 Haloalkoxy, -OC 3~4 is further substituted by one or more substituents selected from cycloalkyl or NH; 3~6 Cycloalkyl is optionally further substituted with halo, cyano or hydroxy; or C 1~3 Alkylene is optionally selected from the group consisting of aryl, aryl, and alkyl. 1~2 Alkyl, C 1~2 Haloalkyl, cyano, hydroxy, C 1~2 Alkoxy, halo or C 1~2 spiro-fused to a 3-5 membered cycloalkyl or heterocyclic ring, or spirocyclic ring system, substituted by one or more substituents selected from haloalkoxy; L 1b is absent or O, S, SO, SO2, N(R r ), C(O), C(O)O, OC(O), C(O)N(R r ), N(R r )C(O),N(R r )C(O)N(R s ), S(O)2N(R r ) or N(R r )SO2, R r and R s is hydrogen or C 1~3 each independently selected from alkyl, C 1~3 Alkyl is optionally cyano, hydroxy, C 1~2 Alkoxy, Halo, C 1~2 Haloalkoxy, NH2, C 3~6 Further substituted by cycloalkyl or 3- to 6-membered heterocyclyl, C 3~6 Cycloalkyl or 3- to 6-membered heterocyclyl may also optionally be substituted with halo, hydroxy, C 1~2 Alkoxy or C 1~2 further substituted with haloalkoxy; Q1 is hydrogen, cyano, C 1~6 Alkyl, C 3~8Cycloalkyl (spirocyclic, carbocyclic and bridged C 3~8 (including cycloalkyl), C 2~3 Alkenyl, C 2~3 alkynyl, aryl, heterocyclyl (including monocyclic or bicyclic, spirocyclic, or bridged heterocyclic ring systems) or heteroaryl; Q is optionally C 1~4 Alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, oxo, cyano, hydroxy, carboxy, carbamoyl, sulfamoyl, NR t R u , OR t , C(O)R t , C(O)OR t , O.C.(O)R t , C(O)N(R t )R u , N(R t )C(O)R u , -S(O) 0~2 R t R u , S(O) y R t (wherein y is 0, 1 or 2), SO2N(R t )R u , N(R t )SO2R u or (CH2) z NR t R u where z is 1, 2 or 3; and C 1~4 Similarly, alkyl may optionally be substituted with cyano, hydroxy, C 1~2 Alkoxy, Halo, C 1~2 substituted by one or more substituents selected from haloalkoxy, -O-C3 cycloalkyl, where -O-C3 cycloalkyl is optionally substituted with halo, cyano, or hydroxy; R t and R u is hydrogen or C 1~4 alkyl; or Q1 optionally has the formula: -L 1c -L 1d-Z1 (In the formula, L 1c is non-existent or possibly C 1~2 C substituted by alkyl or oxo 1~3 is alkylene; L 1d is non-existent or C(O), O, C(O)O, OC(O), C(O)N(R v ), N(R v )C(O),N(R v )C(O)N(R w ), S(O)2N(R v ) or N(R v )SO2, R v and R w is hydrogen or C 1~2 each independently selected from alkyl; Z1 is C 3~8 Cycloalkyl (spirocyclic, carbocyclic and bridged C 3~8 cycloalkyl), heterocyclyl (including monocyclic or bicyclic, spirocyclic, or bridged heterocyclic ring systems), aryl, or heteroaryl; Z is optionally C 1~4 Alkyl, C 3~6 Cycloalkyl, heterocyclyl, halo, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 1~4 Alkoxy, cyano, hydroxyl, NR t1 R u1 , OR t1 , C(O)R t1 , C(O)OR t1 , O.C.(O)R t1 , C(O)N(R t1 )R u1 , N(R t1 )C(O)R u1 , -S(O) 0~2 R t1 R u1 , S(O) y R t1 (wherein y is 0, 1 or 2), SO2N(R t1 )R u1 , N(R t1 )SO2Ru1 or (CH2) z NR t1 R u1 where z is 1, 2 or 3; and R t1 and R u1 is hydrogen or C 1~4 alkyl; Z1 is C 3~8 When Z is cycloalkyl or heterocyclyl, Z is optionally 3~6 spiro-fused to a cycloalkyl or heterocyclyl ring and is substituted with one or more groups are independently selected from the group R 1a’ is selected from hydrogen, halo, and methyl; R 2a , R 2b and R 2c is hydrogen, halo or of the formula: -L 2a -L 2b -Q2 (In the formula, L 2a is non-existent or possibly C 1~2 C substituted by alkyl or oxo 1~3 is alkylene; L 2b is absent or O, S, SO, SO2, N(R n ), C(O), C(O)O, OC(O), C(O)N(R n ), N(R n )C(O),N(R n )C(O)N(R o ), S(O)2N(R n ) or N(R n )SO2, R n and R o is hydrogen or C 1~2 each independently selected from alkyl; Q2 is hydrogen, cyano, C 1~6 Alkyl, C 3~6cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, NR p R q , OR p , C(O)R p , C(O)OR p , O.C.(O)R p , C(O)N(R p )R q , N(R r )C(O)R p , S(O) y R p (wherein y is 0, 1 or 2), SO2N(R p )R q , N(R r )SO2R p or (CH2) z NR p R q where z is 1, 2 or 3; and R p and R q is hydrogen or C 1~4 alkyl) is selected from the group consisting of: Y is [ka] Selected from JPEG2024520713000003.jpg68170; R 3a1 , R 3b1 , R 3c1 , R 3d1 , R 3e1 , R 3f1 , R 3g1 , R 3h1 , R 3i1 , R 3j1 , R 3k1 , R 3l1 , R 3m1 , R 3n1 , R 3o1 , R 3p1 , R 3q1, R 3r1 and R 3s1 is hydrogen (including deuterium), C 1~6 Alkyl, C 3~4 C is independently selected from cycloalkyl, hydroxy, and halo; 1~6 Alkyl or C 3~4 Cycloalkyl is optionally substituted with one or more substituents selected from halo, amino, cyano and hydroxy; R 3a2 , R 3b2 , R 3c2 , R 3d2 , R 3e2 , R 3f2 , R 3g2 , R 3h2 , R 3i2 , R 3j2 , R 3k2 , R 3l2 , R 3m2 , R 3n2 , R 3o2 , R 3p2 , R 3q2 , R 3r2 and R 3s2 is hydrogen or halo; However, when n=1 or n=2, R 3a1 , R 3b1 , R 3i1 , R 3l1 , R 3o1 , R 3r1 , R 3a2 , R 3b2 , R 3i2 , R 3l2 , R 3o2 and R 3s1 cannot be halo and the carbon atom to which they are attached is linked to an oxygen or nitrogen atom; Or, R 3a1 and R 3a2 , R 3b1 and R 3b2 , R 3c1 and R 3c2 , R 3d1 and R 3d2 , R 3e1 and R 3e2 , R 3f1 and R 3f2 , R 3g1 and R 3g2, R 3h1 and R 3h2 , R 3i1 and R 3i2 , R 3j1 and R 3j2 , R 3k1 and R 3k2 , R 3l1 and R 3l2 , R 3m1 and R 3m2 , R 3n1 and R 3n2 , R 3o1 and R 3o2 , R 3p1 and R 3p2 , R 3q1 and R 3q2 , or R 3r1 and R 3r2 Or R 3s1 and R 3s2 together with the carbon atom to which they are attached, are spiro-fused C which are optionally substituted with one or more substituents selected from halo, methyl, amino, cyano and hydroxy. 3~4 may be linked to form a cycloalkyl; Z is [ka] Selected from; R4, R7, R 4a and R 7a is independently selected from hydrogen, halo, cyano, and methyl; R5, R 5a , R 5b and R 5c is independently selected from hydrogen, halo, cyano, and methyl; R6, R8, R 6a and R 8a is independently selected from hydrogen, halo, cyano, and methyl; R9, R 9a , R 10 and R 11 are hydrogen, NH2, halo, cyano and C 1~6 independently selected from alkyl; or R9 and R 10may be joined together to form a fused 5- or 6-membered saturated or unsaturated ring system, or R 10 and R 11 may be linked together to form a fused 5- or 6-membered saturated or unsaturated ring system; either of the fused 5- or 6-membered saturated or unsaturated ring systems may optionally be linked together with C 1~2 Alkyl, Cyano, C 1~2 Haloalkyl, Hydroxy, C 1~2 Alkoxy, Halo, C 1~2 Haloalkoxy, NR 1ia R 1ja or -S(O) 0~2 R 1ia R 1ja and R 1ia and R 1ja is H or C 1~2 is alkyl; R Z1 and R Z1a is hydrogen, C 1~4 Alkyl, Cyano, Halo, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 1~4 Alkoxy, C 3~6 Cycloalkyl and -OC 3~6 cycloalkyl, C 3~6 Cycloalkyl and -OC 3~6 The cycloalkyl is optionally substituted by one or more of halo, methyl, or methoxy; R Z2 and R Z2a is hydrogen, C 1~4 Alkyl, cyano, halo, NH2 and C 1~4 alkoxy; R Z3a is hydrogen, C 1~4 Alkyl, cyano, halo, NH2 and C 1~4 alkoxy; A1 is CR 12 and N; A2 is CR 13 and N; A3 is CR14 and N; A4 is CR 15 and N; A5 is CR 16 and N; A6 is CR 17 and N; A7 is CR 18 and N; A8 is CR 19 R 20 and N.R. 21 Selected from; A9 is CR 22 R 23 and N.R. 24 Selected from; A 10 is CR 25 R 26 and N.R. 27 Selected from; A 11 is CR 28 R 29 and N.R. 30 Selected from; R 12 and R 14 is hydrogen, halo, cyano and C 1~4 independently selected from alkyl; R 13 is selected from hydrogen, halo, cyano, methoxy and methyl; R 15 is selected from hydrogen, halo, cyano, methoxy and methyl; R 16 is hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 3~4 Cycloalkyl, 3-4 membered heterocyclyl and C 3~4 cycloalkoxy; R 17 is hydrogen, hydroxy, halo, cyano, C 1~5 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4Haloalkoxy, C 2~4 Alkenyl, C 2~4 Alkynyl, phenyl, 5- or 6-membered heteroaryl, C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, heterocyclyl, -O-heterocyclyl (carbon bond), -(OCH2CH2) m -NR p R r , -(OCH2CH2) m -OCH3 (wherein m is an integer of 1 to 6), NR q R r , -C(O)-NR q R r , -C(O)OR q Selected from; R q and R r are each independently hydrogen, C 1~5 Alkyl, C 3~6 Cycloalkyl, 3-6 membered carbon-bonded heterocyclyl, C 1~5 Alkyl, C 3~6 Cycloalkyl, 3-6 membered carbon-bonded heterocyclyl are optionally 1~2 Alkyl, Cyano, C 1~2 Haloalkyl, Hydroxy, C 1~2 Alkoxy, Halo, C 1~2 Haloalkoxy, NR 1ea R 1fa or -S(O) 0~2 R 1ea R 1fa and R 1ea and R 1fa is H or C 1~2 is alkyl; Or, R q and R r together with the nitrogen atom to which they are attached, may be C 1~2 Alkyl, Cyano, C 1~2 Haloalkyl, Hydroxy, C 1~2 Alkoxy, Halo, C 1~2are linked together to form a 3- to 6-membered heterocyclic ring optionally substituted by one or more substituents selected from haloalkoxy; Either C 1~5 Alkyl, C 1~4 Alkoxy, C 2~4 Alkenyl, C 2~4 Alkynyl, phenyl, 5- or 6-membered heteroaryl, C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, heterocyclyl or -O-heterocyclyl(carbon bond) are also optionally represented by C 1~2 Alkyl, Cyano, C 1~2 Haloalkyl, Hydroxy, C 1~2 Alkoxy, Halo, C 1~2 Haloalkoxy, NR 1ea R 1fa or -S(O) 0~2 R 1ea R 1fa and R 1ea and R 1fa is H or C 1~2 is alkyl; R 18 is hydrogen, halo, cyano, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, 5- or 6-membered heteroaryl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 3~4 Cycloalkyl, 3-4 membered heterocyclyl and C 3~4 cycloalkoxy; R 19 , R 20 , R 25 and R 26 is hydrogen, halo, cyano and C 1~4 alkyl; R 22 and R 23 is selected from hydrogen, halo, cyano and methyl; R 28 and R 29is selected from hydrogen, methoxy and methyl; R 21 , R 24 , R 27 and R 30 is hydrogen; n is 0, 1 or 2) having However, the compound is 2-((1H-benzo[d]imidazol-2-yl)methyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; 2-((6-chloro-1-phenyl-1H-benzo[d]imidazol-2-yl)methyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole; Not N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-5-carboxamide.

[0092] (ii) Specific Compounds of Formula I—List 1 Particular compounds of formula I disclosed in WO 2020 / 050898 include any of the following in List 1 below, or a pharma- ceutically acceptable salt thereof: Listing 1 N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide; N-({7-bromoimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide; N-({6-bromoimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide; N-({6-chloroimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide; N-({7-fluoroimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide; N-({6-fluoroimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide; N-({7-methoxyimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide; N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-6-(1H-pyrazol-5-yl)-1H-indazole-4-carboxamide; N-({7-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide; 6-Bromo-N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide; 6-Bromo-N-({7-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide; N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-chromene-2-carboxamide; N-({imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-chromene-2-carboxamide; 6-ethynyl-N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide; N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({7-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-chromene-2-carboxamide; N-({7-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-cyanoimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 8-Methoxy-N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-5-carboxamide; 7-Chloro-N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-fluoroimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-bromoimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-methoxyimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({7-methoxyimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({8-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-pyrazolo[4,3-c]pyridine-4-carboxamide; N-({7-bromoimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-(2-hydroxy-1-{6-methylimidazo[1,2-a]pyridin-2-yl}ethyl)-1H-indazole-4-carboxamide; 4-(3-{imidazo[1,2-a]pyridin-2-yl}-2,5-dihydro-1H-pyrrole-1-carbonyl)-1H-indazole; N-[(6-{[(pyridin-3-yl)methyl]amino}imidazo[1,2-a]pyridin-2-yl)methyl]-1H-indazole-4-carboxamide; N-[(6-{[(1-methyl-1H-imidazol-4-yl)methyl]amino}imidazo[1,2a]pyridin-2-yl)methyl]-1H-indazole-4-carboxamide; N-{[6-(3-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl]methyl}-1H-indazole-4-carboxamide; N-{[6-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-2-yl]methyl}-1H-indazole-4-carboxamide; N-[[6-(3-chlorophenyl)imidazo[1,2-a]pyridin-2-yl]methyl]-1H-indazole-4-carboxamide; N-({6-[(pyridin-3-yl)amino]imidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide; N-({6-[(piperazin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide; N-{[6-(aminomethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-1H-indazole-4-carboxamide; N-{[6-(acetamidomethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-1H-indazole-4-carboxamide; {6-methylimidazo[1,2-a]pyridin-2-yl}methyl 1H-indazole-4-carboxylate; {6-methylimidazo[1,2-a]pyridin-2-yl}methyl 1H-indazole-4-carboxylate hydrochloride; N-{[6-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-1H-indazole-4-carboxamide; N-({6-hydroxyimidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide; N-({6-[(methylamino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide; N-({6-[(methylamino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide dihydrochloride; N-[(6-{[(2-hydroxyethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-1H-indazole-4-carboxamide; N-[(6-{[(2,2,2-trifluoroethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-1H-indazole-4-carboxamide; N-{[6-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-1H-indazole-4-carboxamide; N-({6-[hydroxy(phenyl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide; N-({6-formylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-(aminomethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(6-{[(2,2,2-trifluoroethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(2-hydroxyethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(6-{[(2-phenylethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(benzylamino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(6-{[(3-phenylpropyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[hydroxy(phenyl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-ethenylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-cyclopropylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({7-ethenylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 2-(1H-indazol-4-yl)-5-[(6-methylimidazo[1,2-a]pyridin-2-yl)methyl]-1,3,4-oxadiazole; N-{[6-(2-aminoethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H,6H,7H,8H,9H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-{[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; tert-Butyl N-(2-{2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)methyl]imidazo[1,2-a]pyridin-6-yl}ethyl)carbamate; N-benzyl-2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)methyl]imidazo[1,2-a]pyridine-6-carboxamide; N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-chromene-2-carboxamide; 7-Chloro-N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-chromene-2-carboxamide; 6-Chloro-N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-chromene-2-carboxamide; N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H,6H,7H,8H,9H-pyrido[1,2-a]pyrimidine-2-carboxamide; 6-Amino-N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]pyridine-3-carboxamide; N-({6-[(benzyloxy)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(benzylamino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide; N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-7-fluoro-4-oxo-4H-chromene-2-carboxamide; N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-7-methyl-4-oxo-4H-chromene-2-carboxamide; N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-1H-indazole-4-carboxamide; 8-Chloro-N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-chromene-2-carboxamide; 6-Bromo-N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-1H-indazole-4-carboxamide; N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]quinoline-3-carboxamide; N-[(6-{1-[(cyclohexylmethyl)amino]ethyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 6-Chloro-N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-1H-indazole-4-carboxamide; 4-[5-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1,3,4-thiadiazol-2-yl]-1H-indazole; 4-[1-({6-methylimidazo[1,2-a]pyridin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; N-[(6-{[(3-chlorophenyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(1-cyclohexyl-2-hydroxyethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-{[6-({[(pyridin-3-yl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(4-methoxyphenyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(4-chlorophenyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[benzyl(methyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-oxo-N-{[6-({[(1R)-1-phenylethyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-oxo-N-{[6-({[(1S)-1-phenylethyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(2-fluorophenyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(6-{[(2-phenylpropan-2-yl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(3-fluorophenyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(4-fluorophenyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(6-{[(4,4,4-trifluorobutyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(oxan-4-yl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(3,3-difluorocyclobutyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(cyclopropylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(6-{[(3,3,3-trifluoropropyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(cyclohexylamino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-({6-[({[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]methyl}amino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(oxan-2-yl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(6-{[(3-phenyloxetan-3-yl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(oxan-3-yl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(1-fluorocyclohexyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(3-cyclopropylphenyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(3,3-dimethylbutyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-{[6-({[2-(trifluoromethoxy)ethyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-{[6-({[(oxolan-2-yl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(2-methanesulfonylethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-({6-[(3-phenylpyrrolidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(1-cyclohexylcyclopropyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-{[6-({[(1,3-thiazol-5-yl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; tert-Butyl 3-{[({2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)amino]methyl}piperidine-1-carboxylate; N-{[6-({[(4,4-difluorocyclohexyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; tert-Butyl 2-{[({2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)amino]methyl}piperidine-1-carboxylate; N-[(6-{[(2-cyclopropylethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-({6-[(piperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-oxo-N-({6-[({[1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]methyl}amino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(1-methylcyclohexyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-{[6-({[2-(pyridin-3-yl)ethyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(1,4-dioxan-2-yl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(cyclopropylamino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(3,3-difluorocyclobutyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(oxetan-3-yl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-oxo-N-{[6-({[(1R,2R)-2-(trifluoromethyl)cyclopropyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(2,2-dimethylpropyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(cyclohexylmethyl)(methyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(4,4-difluorocyclohexyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[({bicyclo[1.1.1]pentan-1-yl}amino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-({6-[({[(2S)-oxolan-2-yl]methyl}amino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-({6-[({[(2R)-oxolan-2-yl]methyl}amino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(2,2-difluoroethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-{[6-({[(oxolan-3-yl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(1-methylcyclopropyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(6-{[(oxolan-3-yl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; Methyl 3-methyl-2-[({2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)amino]butanoate; N-[(6-{[(oxan-3-yl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-oxo-N-{[6-({[(2S)-3,3,3-trifluoro-2-hydroxypropyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(cyclobutylamino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(tert-butylamino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(2-fluoroethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(4,4-difluoropiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-({6-[(4-phenylpiperazin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-({6-[(1,2,3,4-tetrahydroisoquinolin-2-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(diethylamino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-({6-[(pyrrolidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(6-{[3-(pyridin-2-yl)azetidin-1-yl]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(dicyclopropylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(cyclopropylmethyl)(methyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(4-methylpiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(6-{[4-(trifluoromethyl)piperidin-1-yl]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(3-methylpiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(6-{[({spiro[2.2]pentan-1-yl}methyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(3,3-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(6-{[3-(trifluoromethyl)piperidin-1-yl]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(5,5-dimethyloxolan-2-yl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(4-fluoropiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(3-methoxypropyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(1-methylcyclohexyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(4,4-dimethyloxolan-2-yl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(1-methylcyclopentyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-({6-[(propylamino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(3,3-dimethyloxolan-2-yl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(2-methylpropyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[2-(tert-butoxy)ethyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(4-chlorophenyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[2-(oxan-2-yl)ethyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(4-benzylpiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-({6-[(4-phenoxypiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(2,2-difluorocyclopropyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(2,2-dimethylcyclopropyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(2-methyloxolan-2-yl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(4-tert-butylpiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(4-tert-butylcyclohexyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(2-cyclopentylethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[4-(2,2-dimethylpropanoyl)piperazin-1-yl]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(4-acetylpiperazin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({7-azabicyclo[2.2.1]heptan-7-yl}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(4,4-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(2,2-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(6-{[(2,3,3-trimethylbutan-2-yl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(5-fluoropyridin-2-yl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[({[1,1'-bi(cyclopropane)]-1-yl}amino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(1-fluorocyclopentyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(2,6-dimethylmorpholin-4-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; Methyl 1-({2-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)piperidine-3-carboxylate; N-[(6-{[(2-fluoro-2-methylpropyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(1-cyclohexylethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(2-cyclopropylethyl)(methyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(2,2-dimethylpropyl)(methyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(1-fluorocyclobutyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(4-fluoro-4-methylpiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(3,3-difluoropiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(1-hydroxycyclohexyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(cyclopentylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(3,3-difluorocyclopentyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(cyclobutylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[2-(3,3-difluorocyclobutyl)ethyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(2-fluorocyclobutyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({[(2S)-3,3-dimethylbutan-2-yl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-({6-azaspiro[2.5]octan-6-yl}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-({6-[({[(1r,3r)-3-fluorocyclobutyl]methyl}amino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-({6-[(2-phenylethyl)amino]imidazo[1,2-a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[2-(benzylamino)ethyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[2-(cyclohexylamino)ethyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-({6-[(phenylformamido)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(cyclohexylformamido)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-{[6-({[(piperidin-3-yl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-{[6-({[(piperidin-2-yl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[(azetidin-3-yl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(cyclohexylamino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-chromene-2-carboxamide; N-[(6-{[(2-cyclopropylethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-chromene-2-carboxamide; 4-Oxo-N-({6-[(piperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4H-chromene-2-carboxamide; N-{[6-({[(4-chlorophenyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-chromene-2-carboxamide; N-({6-[(benzylamino)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-chromene-2-carboxamide; N-{[6-({[(1-methylcyclohexyl)methyl]amino}methyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-chromene-2-carboxamide; N-[(6-{[(2,2-dimethylpropyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-chromene-2-carboxamide; 4-Oxo-N-[(7-{[(2-phenylethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(7-{[(cyclohexylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(7-{[(cyclopropylmethyl)amino]methyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{1-[(cyclohexylmethyl)amino]cyclopropyl}imidazo[1,2-a]pyridin-2-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[6-(2-amino-3-phenylpropyl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; (Cyclohexylmethyl)[(2-{[4-(1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]methyl}imidazo[1,2-a]pyridin-6-yl)methyl]amine; N-(cyclohexylmethyl)-2-{[4-(1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]methyl}imidazo[1,2-a]pyridine-6-carboxamide; (2,2-dimethylpropyl)[(2-{[4-(1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]methyl}imidazo[1,2-a]pyridin-6-yl)methyl]amine; 4-[1-({6-[(4,4-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; [(2-{[4-(6-bromo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]methyl}imidazo[1,2-a]pyridin-6-yl)methyl][(3,3-difluorocyclobutyl)methyl]amine; [(2-{[4-(6-bromo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]methyl}imidazo[1,2-a]pyridin-6-yl)methyl](2,2-dimethylpropyl)amine; [(2-{[4-(6-bromo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]methyl}imidazo[1,2-a]pyridin-6-yl)methyl](cyclohexylmethyl)amine; 6-Bromo-4-[1-({6-[(4,4-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]-1H-indazole; (2-{[4-(6-bromo-1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]methyl}imidazo[1,2-a]pyridin-6-yl)methanol; (2,2-dimethylpropyl)[(2-{[4-(1H-indazol-5-yl)-1H-1,2,3-triazol-1-yl]methyl}imidazo[1,2-a]pyridin-6-yl)methyl]amine; ((cyclohexylmethyl)[1-(2-{[4-(1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]methyl}imidazo[1,2-a]pyridin-6-yl)ethyl]amine; (2,2-dimethylpropyl)({2-[(4-{1H-pyrazolo[3,4-c]pyridin-4-yl}-1H-1,2,3-triazol-1-yl)methyl]imidazo[1,2-a]pyridin-6-yl}methyl)amine; {2-[(4-{1H-pyrazolo[3,4-c]pyridin-4-yl}-1H-1,2,3-triazol-1-yl)methyl]imidazo[1,2-a]pyridin-6-yl}methanol; N-({6-[(3R,5S)-5-tert-butylmorpholin-3-yl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(3S,5R)-5-tert-butylmorpholin-3-yl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(3S,5R)-5-cyclohexylmorpholin-3-yl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(3S,5R)-5-cyclohexylmorpholin-3-yl]imidazo[1,2-a]pyridin-2-yl}methyl)-1H-indazole-4-carboxamide; N-({6-[(3S,5R)-5-cyclohexylmorpholin-3-yl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-chromene-2-carboxamide; N-({6-[4-(2,2-dimethylpropyl)morpholin-3-yl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({6-[(3S,5R)-5-methylmorpholin-3-yl]imidazo[1,2-a]pyridin-2-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; and N-{[6-(9-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepin-3-yl)imidazo[1,2-a]pyridin-2-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]triazol-4-yl]-1H-indazol-6-ol; 4-[1-[[6-[[(1-hydroxycyclobutyl)methylamino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]triazol-4-yl]-1H-indazol-6-ol; 1-[[[2-[[4-(5-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methylamino]methyl]cyclobutanol; 1-[[[2-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methylamino]methyl]cyclobutanol; N-(cyclobutylmethyl)-1-[2-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamine; N-(cyclobutylmethyl)-1-[2-[[4-(5-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamine; 4-[1-[(6-methylimidazo[1,2-a]pyridin-2-yl)methyl]triazol-4-yl]-1H-indazol-3-amine N-[[6-[[(1-methoxycyclobutyl)methylamino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-(1,4-oxazepan-3-yl)imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[[(2-cyano-2-methyl-propyl)amino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methylamino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[[6-[(spiro[3.3]heptan-2-ylmethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[[6-[(spiro[2.3]hexan-5-ylmethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[(1-bicyclo[1.1.1]pentanylmethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[[6-[(spiro[2.3]hexan-2-ylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[[(2-methoxy-2-methyl-propyl)amino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[[(1-methylcyclobutyl)methylamino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-(butylaminomethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[[(1-hydroxycyclopentyl)methylamino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[(2-methylbutylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[(2-cyclobutylethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[[(2-hydroxy-2-methyl-propyl)amino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[[(1-hydroxycyclobutyl)methylamino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[(2-hydroxybutylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[[(3-methylcyclobutyl)methylamino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[[(3,3-dimethylcyclobutyl)methylamino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[(2,2-dimethylbutylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[[[(2S)-2-methylbutyl]amino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; 1-[[[2-[[4-(6-bromo-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methylamino]methyl]cyclohexanol; 1-[[[2-[[4-(6-bromo-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methylamino]methyl]cyclobutanol; 1-[2-[[4-(6-bromo-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]-N-(cyclobutylmethyl)methanamine; 4-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]triazol-4-yl]-1H-indazole-6-carboxylic acid; 4-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]triazol-4-yl]-1H-indazole-6-carboxamide; 4-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]triazol-4-yl]-N,N-dimethyl-1H-indazole-6-carboxamide; [4-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]triazol-4-yl]-1H-indazol-6-yl]-morpholino-methanone; 4-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]triazol-4-yl]-N-(2-hydroxyethyl)-1H-indazole-6-carboxamide; 1-[2-[[4-(6-chloro-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]-N-(cyclobutylmethyl)methanamine; 1-[[[2-[[4-(6-chloro-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methylamino]methyl]cyclobutanol; N-[[2-[[4-(6-chloro-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methyl]-2,2-dimethyl-propan-1-amine; N-(cyclobutylmethyl)-1-[2-[[4-(7-fluoro-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamine; 1-[[[2-[[4-(7-fluoro-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methylamino]methyl]cyclohexanol; N-(cyclohexylmethyl)-1-[2-[[4-(7-fluoro-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamine; 1-[[[2-[[4-(7-fluoro-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methylamino]methyl]cyclobutanol; 1-[[[2-[[4-(7-fluoro-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methylamino]methyl]cyclopentanamine; N-[[6-[(4,4-dimethyl-1-piperidyl)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-5-fluoro-4-oxo-chromene-2-carboxamide; N-(cyclobutylmethyl)-1-[2-[[4-(6-morpholino-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamine; 6-[2-(2-aminoethoxy)ethoxy]-N-[[6-[(4,4-dimethyl-1-piperidyl)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-1H-indazole-4-carboxamide; N-[[6-[1-(cyclobutylmethylamino)-2-phenyl-ethyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[1-[bis(cyclobutylmethyl)amino]-2-phenyl-ethyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; 1-[2-[[4-(7-chloro-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]-N-(cyclobutylmethyl)methanamine; 1-[[[2-[[4-(7-chloro-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methylamino]methyl]cyclobutanol; [2-[[4-(6-fluoro-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanol N-(cyclobutylmethyl)-1-[2-[[4-(6-fluoro-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamine; 1-[[[2-[[4-(6-fluoro-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methylamino]methyl]cyclobutanol; N-(cyclohexylmethyl)-1-[2-[[4-(6-fluoro-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamine; N-[[2-[[4-(6-cyclopropyl-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methyl]-2,2-dimethyl-propan-1-amine; N-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-1H-indazole-4-carboxamide; N-(cyclobutylmethyl)-1-[2-[[4-(1H-pyrazolo[4,3-c]pyridin-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamine; N-(cyclohexylmethyl)-1-[2-[[4-(1H-pyrazolo[4,3-c]pyridin-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamine; 1-[[[2-[[4-(1H-pyrazolo[4,3-c]pyridin-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methylamino]methyl]cyclobutanol; N-(cyclobutylmethyl)-1-[2-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamine; 1-[[[2-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methylamino]methyl]cyclohexanol; 2-[[4-(1H-indazol-4-yl)imidazol-1-yl]methyl]-6-methyl-imidazo[1,2-a]pyridine; N-[[6-[2-cyano-1-(cyclobutylmethylamino)ethyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-(6-methylmorpholin-3-yl)imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-(7-bromo-9-methoxy-2,3,4,5-tetrahydro-1,4-benzoxazepin-3-yl)imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(6-piperazin-2-ylimidazo[1,2-a]pyridin-2-yl)methyl]pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-(6-cyclohexyl-4-oxo-2-piperidyl)imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; 1-[2-(1H-indazol-4-yl)thiazol-5-yl]-1-(6-methylimidazo[1,2-a]pyridin-2-yl)ethanol; 2-[[1-(1H-indazol-4-yl)triazol-4-yl]methyl]imidazo[1,2-a]pyridine; N-[(3,3-difluorocyclobutyl)methyl]-1-[2-[[1-(1H-indazol-4-yl)triazol-4-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamine; 4-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]triazol-4-yl]-1H-indazole-6-carbonitrile; N-(cyclobutylmethyl)-1-[2-[[4-(1H-indazol-4-yl)imidazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamine; N-[[6-[[acetyl(cyclobutylmethyl)amino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-(cyclobutylmethyl)-1-[2-[[3-(1H-indazol-4-yl)-1,2,4-triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamine; 2-[1-[[6-[(cyclobutylmethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]triazol-4-yl]pyrido[1,2-a]pyrimidin-4-one; N-[[6-[(2-bicyclo[2.2.1]hept-5-enylmethylamino)methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[[[(1R,2R,4S)-norbornan-2-yl]methylamino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[[[(1R,2S,4S)-norbornan-2-yl]methylamino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-(2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-(2-azabicyclo[2.2.1]heptan-2-ylmethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-(2-azabicyclo[2.2.2]octan-2-ylmethyl)imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[6-[[(2,2-difluorospiro[3.3]heptan-6-yl)amino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[[6-[[[rac-(1S,2S,4S)-7-oxabicyclo[2.2.1]hept-5-en-2-yl]methylamino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide; 4-oxo-N-[[6-[[[rac-(1S,2R,4S)-7-oxabicyclo[2.2.1]hept-5-en-2-yl]methylamino]methyl]imidazo[1,2-a]pyridin-2-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide; and N-[(1-methoxycyclobutyl)methyl]-1-[2-[[4-(6-methoxy-1H-indazol-4-yl)triazol-1-yl]methyl]imidazo[1,2-a]pyridin-6-yl]methanamine.

[0093] (iii) a compound of formula (II), (VI) or (VII) A further group of METTL3 inhibitors is represented by Formula II, shown below: XYZ (II) (In the formula, X is [ka] Selected from; Q1 is NH, NC 1~4 alkyl, O or S; Q 2a is N or CR 2a Selected from; Q 2b is N or CR 2b Selected from; Q 2c is N or CR 2c Selected from; Q 2d is N or CR 2d Selected from; Q3 is N or CR 1b Selected from; Q4 is N or CR 1x Selected from; However, Q1, Q 2a , Q 2b , Q 2c , Q 2d , no more than three of Q3 and Q4 are nitrogen; R 1a teeth, (i) each of which is optionally halo, cyano, hydroxy, C 3~6 Cycloalkyl, C 1~4 Alkoxy, C 1~4 C substituted with haloalkoxy, aryl or heteroaryl 1~4 Alkyl or C 1~4 Alkoxy; or (ii) Formula: -(CR 1c R 1d ) p -NR 1e R 1f (In the formula, p is an integer selected from 0, 1, 2, or 3; R 1c and R 1d teeth, (i) Hydrogen (including deuterium); (ii) optionally cyano, oxo, hydroxy, C 1~4 Alkoxy, Halo, C 1~4 Haloalkoxy, C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, NR 1ca R 1da or -S(O) 0~2 R 1ca R 1da (In the formula, R 1ca and R 1da is H or C 1~2 Alkyl; C 3~6 Cycloalkyl and -OC 3~6 Cycloalkyl is optionally further substituted with halo, cyano or hydroxy. 1~6 Alkyl; (iii) each of which may be C 1~4 Alkyl, C 1~4 Haloalkyl, cyano, hydroxy, C 1~2 Alkoxy, Halo, C 1~2 Haloalkoxy, NR 1ca R 1da or -S(O) 0~2 R 1ca R 1da (In the formula, R1ca and R 1da is H or C 1~2 C substituted with alkyl 3~4 Cycloalkyl or 3-5 membered heterocyclyl are independently selected from; (iv) or R 1c and R 1d together with the carbon atom to which they are attached, each of which may optionally be C 1~2 Alkyl, C 1~2 Haloalkyl, cyano, hydroxy, C 1~2 Alkoxy, Halo, C 1~2 Haloalkoxy, NR 1ca R 1da or -S(O) 0~2 R 1ca R 1da (In the formula, R 1ca and R 1da is H or C 1~2 are linked together to form a 3-6 membered cycloalkyl or heterocyclic ring, or a spirocyclic ring system, substituted by one or more substituents selected from: R 1e and R 1f teeth, (i) Hydrogen (including deuterium); (ii) optionally cyano, oxo, hydroxy, C 1~2 Alkoxy, Halo, C 1~2 Haloalkoxy, NR 1ea R 1fa or -S(O) 0~2 R 1ea R 1fa (In the formula, R 1ea and R 1fa is H or C 1~2 C is substituted by one or more substituents selected from 1~6 Alkyl; Formula (iii): -(CR 1g R 1h ) q -T1 (In the formula, q is 0, 1, 2, 3, 4, 5 or 6; R 1g and R 1h teeth, a) hydrogen; b) optionally cyano, hydroxy, C 1~4 Alkoxy, Halo, C 1~4 Haloalkoxy, -OC 3~6 Cycloalkyl, NR 1ga R 1ha or -S(O) 0~2 R 1ga R 1ha (In the formula, R 1ga and R 1ha is H or C 1~2 Alkyl; -OC 3~6 Cycloalkyl is optionally substituted by one or more substituents selected from halo, cyano, or hydroxy. 1~6 Alkyl; c) each of which may be C 1~2 Alkyl, Cyano, C 1~2 Haloalkyl, Hydroxy, C 1~2 Alkoxy, Halo, C 1~2 Haloalkoxy, NR 1ga R 1ha or -S(O) 0~2 R 1ga R 1ha (In the formula, R 1ga and R 1ha is H or C 1~2 aryl-C 1~6 Alkyl, Heteroaryl C 1~6 Alkyl, C 3~6 Cycloalkyl or C 3~6 Cycloalkyl C 1~6 Alkyl group are independently selected from; d) or R 1g and R 1h optionally together with the carbon atom to which they are attached, 1~2 Alkyl, Cyano, C 1~2 Haloalkyl, Hydroxy, C 1~2 Alkoxy, Halo, C1~2 Haloalkoxy, NR 1ga R 1ha or -S(O) 0~2 R 1ga R 1ha (In the formula, R 1ga and R 1ha is H or C 1~2 are linked together to form a 3-6 membered cycloalkyl or heterocyclic ring substituted by one or more substituents selected from: T1, each of which may be C 1~2 Alkyl, C 1~2 Haloalkyl, cyano, hydroxy, C 1~2 Alkoxy, Halo, C 1~2 Haloalkoxy, NR 3t R 4t or -S(O) 0~2 R 3t R 4t (In the formula, R 3t and R 4t is H or C 1~2 and alkyl, substituted by one or more substituents selected from hydrogen, cyano, hydroxy, NR 1t R 2t Or -S(O) 0~2 R 1t R 2t (In the formula, R 1t and R 2t is H or C 1~4 alkyl), C 3~8 Cycloalkyl, C 2~3 Alkenyl, C 2~3 Alkynyl, aryl, heterocyclyl, heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C 3~8 Cycloalkyl, Bridged Bicyclic C 5~12 cycloalkyl, or a bridged heterocyclic ring system A group having are each independently selected from (iv) or R 1e and R 1f together with the nitrogen atom to which they are attached, may be C 1~4 Alkyl, C1~4 Haloalkyl, cyano, hydroxy, C 1~4 Alkoxy, Halo, C 1~4 Haloalkoxy, NR 1i R 1j Or -S(O) 0~2 R 1i R 1j (In the formula, R 1i and R 1j is H or C 1~4 and / or R 1e and R 1f The monocyclic or bicyclic heterocyclic ring formed by 1~4 Alkyl, C 1~4 Haloalkyl, cyano, hydroxy, C 1~4 Alkoxy, Halo, C 1~4 Haloalkoxy, NR 1i R 1j Or -S(O) 0~2 R 1i R 1j (In the formula, R 1i and R 1j is H or C 1~4 C substituted by one or more substituents selected from 3~6 spiro-fused to a cycloalkyl or heterocyclic ring Based on Selected from; R 1b is hydrogen, cyano, halo or C 1~3 alkyl; R 1x is hydrogen, cyano, halo or C 1~3 alkyl; R 2a , R 2b , R 2c and R 2d is hydrogen, cyano, halo or the formula: -L 2a -L 2b -Q2 (In the formula, L2a is non-existent or possibly C 1~2 C substituted by alkyl or oxo 1~3 is alkylene; L 2b is absent or O, S, SO, SO2, N(R n ), C(O), C(O)O, OC(O), C(O)N(R n ), N(R n )C(O),N(R n )C(O)N(R o ), S(O)2N(R n ) or N(R n )SO2 (where R n and R o is hydrogen or C 1~2 alkyl); Q2, each of which is optionally selected from halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, C 1~4 Alkyl, NR p R q , OR p , C(O)R p , C(O)OR p , O.C.(O)R p , C(O)N(R p )R q , N(R r )C(O)R p , S(O) y R p (wherein y is 0, 1 or 2), SO2N(R p )R q , N(R r )SO2R p or (CH2) z NR p R q where z is 1, 2 or 3. p and R q is hydrogen or C 1~4 substituted by one or more substituents selected from hydrogen, cyano, C 1~6 Alkyl, C 3~6cycloalkyl, aryl, heterocyclyl or heteroaryl) are independently selected from the group Y is [ka] Selected from JPEG2024520713000007.jpg111170; R 3a1 , R 3b1 , R 3c1 , R 3d1 , R 3e1 , R 3f1 , R 3g1 , R 3h1 , R 3i1 , R 3j1 , R 3k1 , R 3l1 , R 3m1 , R 3n1 , R 3o1 , R 3p1 , R 3q1 , R 3r1 and R 3s1 is hydrogen (including deuterium), C 1~6 Alkyl, C 3~4 C is independently selected from cycloalkyl, hydroxy, and halo; 1~6 Alkyl or C 3~4 Cycloalkyl is optionally substituted with one or more substituents selected from halo, amino, cyano and hydroxy; R 3a2 , R 3b2 , R 3c2 , R 3d2 , R 3e2 , R 3f2 , R 3g2 , R 3h2 , R 3i2 , R 3j2 , R 3k2 , R 3l2 , R 3m2 , R 3n2 , R 3o2 , R 3p2 , R 3q2 , R 3r2 and R 3s2 is hydrogen or halo; However, when n=1 or n=2, R3a1 , R 3b1 , R 3i1 , R 3l1 , R 3o1 , R 3r1 , R 3a2 , R 3b2 , R 3i2 , R 3l2 , R 3o2 and R 3s1 cannot be halo and the carbon atom to which they are attached is linked to an oxygen or nitrogen atom; Or, R 3a1 and R 3a2 , R 3b1 and R 3b2 , R 3c1 and R 3c2 , R 3d1 and R 3d2 , R 3e1 and R 3e2 , R 3f1 and R 3f2 , R 3g1 and R 3g2 , R 3h1 and R 3h2 , R 3i1 and R 3i2 , R 3j1 and R 3j2 , R 3k1 and R 3k2 , R 3l1 and R 3l2 , R 3m1 and R 3m2 , R 3n1 and R 3n2 , R 3o1 and R 3o2 , R 3p1 and R 3p2 , R 3q1 and R 3q2 , or R 3r1 and R 3r2 or R 3s1 and R 3s2 together with the carbon atom to which they are attached, are spiro-fused C which are optionally substituted with one or more substituents selected from halo, methyl, amino, cyano and hydroxy. 3~4 may be linked to form a cycloalkyl; n is 0, 1 or 2; Z has the following structure: (i) [ka] (In the formula, B1 is A5, and A5 is CR 16 and N; R 16 is hydrogen, halo, cyano, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, 5- or 6-membered heteroaryl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 3~4 Cycloalkyl, 3-4 membered heterocyclyl and C 3~4 cycloalkoxy; B2 is A6, and A6 is N or CR 17 Selected from R 17 , R H2 , R H4 and R H5 is hydrogen, hydroxy, halo, cyano, C 1~5 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 2~4 Alkenyl, C 2~4 Alkynyl, phenyl, 5- or 6-membered heteroaryl, C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, heterocyclyl, -O-heterocyclyl (carbon bond), -(OCH2CH2) m -NR q R r , -(OCH2CH2) m -OCH3 (wherein m is an integer of 1 to 6), NR q R r , -C(O)-NR q R r , -C(O)OR q is selected from R q and R r are each independently hydrogen, C 1~5 Alkyl, C 3~6cycloalkyl, 3- to 6-membered carbon-bonded heterocyclyl, or R q and R r are linked together to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered heterocyclic ring; Either C 1~5 Alkyl, C 1~4 Alkoxy, C 2~4 Alkenyl, C 2~4 Alkynyl, phenyl, 5- or 6-membered heteroaryl, C 3~6 Cycloalkyl, -OC 3~6 Cycloalkyl, heterocyclyl or -O-heterocyclyl(carbon bond) are also optionally represented by C 1~2 Alkyl, Cyano, C 1~2 Haloalkyl, Hydroxy, C 1~2 Alkoxy, Halo, C 1~2 Haloalkoxy, NR 1ea R 1fa or -S(O) 0~2 R 1ea R 1fa (In the formula, R 1ea and R 1fa is H or C 1~2 alkyl); B3 is N or CR Z1 and R Z1 is hydrogen, C 1~4 Alkyl, Cyano, Halo, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 1~4 Alkoxy, C 3~6 Cycloalkyl and -OC 3~6 cycloalkyl, C 3~6 Cycloalkyl and -OC 3~6 The cycloalkyl is optionally substituted by one or more of halo, methyl, or methoxy; B4 is selected from C or N; B5 is CR zi1b or NR B5N is selected from R Zi1b is hydrogen, C 1~4Alkyl, cyano, halo, NH2 and C 1~4 alkoxy; R B5N is hydrogen or C 1~4 alkyl; B7 is N, NR Z2N or CR Z2 and R Z2 is hydrogen, C 1~4 Alkyl, cyano, halo, NH2 and C 1~4 alkoxy; R Z2N is hydrogen or C 1~4 alkyl; B8 is selected from C or N; However, four or less of B1 to B6 are N. (ii) [ka] (In the formula, Y2 is A7, and A7 is CR 18 and N; R 18 is hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 3~4 Cycloalkyl, 3-4 membered heterocyclyl and C 3~4 cycloalkoxy; Y3 is N or CR z1a and R Z1a is hydrogen, hydroxyl, C 1~4 Alkyl, Cyano, Halo, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 1~4 Alkoxy, C 3~6 Cycloalkyl and -OC 3~6 cycloalkyl, C 3~6 Cycloalkyl and -OC 3~6 The cycloalkyl is optionally substituted by one or more of halo, methyl, or methoxy; Y4 is C or N; Y5 is CRY5 or NR Y5N and R Y5 is hydrogen, C 1~4 Alkyl, cyano, halo, NH2 and C 1~4 alkoxy; R Y5N is hydrogen or C 1~4 alkyl; Y6 is CR Zi2e or N and R Zi2e is hydrogen, C 1~4 Alkyl, cyano, halo, NH2 and C 1~4 alkoxy; Y7 is O, S, CR Z2a or N and R Z2a is hydrogen, C 1~4 Alkyl, cyano, halo, NH2 and C 1~4 alkoxy; Y8 is C or N; Y9 is CR Z3a or N, R Z3a is hydrogen, C 1~4 Alkyl, cyano, halo, NH2 and C 1~4 alkoxy; However, four or less of Y1 to Y8 are N. (iii) [ka] (In the formula, X1 is N or CR Z9 and R Z9 is hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 haloalkoxy; X2 is selected from N or CR4; R4 is selected from hydrogen, halo, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy (e.g., hydrogen, halo, cyano, and methyl); X3 is N; X4 is N or C; X5 is N, CR5 and CR X5a R X5b is selected from R5 is hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 haloalkoxy (e.g., hydrogen, halo, cyano, and methyl); R X5a and R X5b is hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 independently selected from haloalkoxy (e.g., hydrogen, halo, cyano, and methyl); X6 is A1 and X7 is A2; or X6 is A8, X7 is A9 or A 11 and A1 is CR 12 and N, R 12 is hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy and C 1~4 Haloalkoxy (e.g., hydrogen, halo, cyano and C 1~4 alkyl); A2 is CR 13 and N, R 13 is hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 haloalkoxy (e.g., hydrogen, halo, cyano, methoxy, and methyl); A8 is CR 19 R 20 and N.R. 21 is selected from R 19 and R 20 is hydrogen, halo, cyano, C1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy (e.g., hydrogen, halo, cyano and C 1~4 alkyl), R 21 is hydrogen or C 1~4 is alkyl; A9 is CR 22 R 23 and N.R. 24 is selected from R 22 and R 23 is hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 independently selected from haloalkoxy (e.g., hydrogen, halo, cyano, and methyl); R 24 is hydrogen or C 1~4 alkyl; A 11 is CR 28 R 29 and N.R. 30 is selected from R 28 and R 29 is selected from hydrogen, halo, methoxy and methyl; R 30 is hydrogen or C 1~4 alkyl; X8 is CR6, N or CR X6a R X6b is selected from R6 is hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy and C 1~4 haloalkoxy; R X6a and R X6b is hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy and C 1~4each independently selected from haloalkoxy; X9 is N or C; However, four or less of X2 to X9 are N. (iv) [ka] (In the formula, Z 10 is N or CR Z10 and R Z10 is hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 haloalkoxy; Z 11 is N or CR Z11 and R Z11 is hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 haloalkoxy; Z 12 is N or CR Z12 and R Z12 is hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 haloalkoxy; Z 13 is N or CR Z13 and R Z13 is hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 haloalkoxy; Z 14 is N or CR Z14 and R Z14 is hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4haloalkoxy; Z 15 is N or CR Z15 and R Z15 is hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 haloalkoxy; Z 16 is N or CR Z16 and R Z16 is hydrogen, halo, cyano, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 haloalkoxy; However, Z 10 ~Z 16 (3 or less of which are N) (v) [ka] (In the formula, Q7 is CR7 or N; Q8 is CR8 or N; Q9 is CR9 or N; Q 10 is CR 10 or N; Q 11 is CR 11 or N; Q 11a is NR 11N or CR 11a R 11b and; R7, R8, R9, R 10 , R 11 , R 11a and R 11b is hydrogen, NH2, halo, cyano, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~6 Alkyl, -CH2OCH3, -CH2SO2CH3, -SO2CH3, -NHC(O)CH3 and -C(O)NR v1 R v2 (In the formula, Rv1 and R v2 are each independently selected from hydrogen and methyl; R 11N are hydrogen, NH2, halo, cyano and C 1~6 selected from alkyl; or R9 and R 10 may be linked together to form, together with the atom to which they are attached, a fused 5- or 6-membered saturated or unsaturated ring system, or R 10 and R 11 may be linked together to form, together with the atom to which they are attached, a fused 5- or 6-membered saturated or unsaturated ring system, either of which may optionally be selected from the group consisting of C 1~2 Alkyl, Cyano, C 1~2 Haloalkyl, Hydroxy, C 1~2 Alkoxy, Halo, C 1~2 Haloalkoxy, NR 1ia R 1ja or -S(O) 0~2 R 1ia R 1ja (In the formula, R 1ia and R 1ja is H or C 1~2 alkyl); However, Q7~Q 11 (3 or fewer of these are N) (chosen from one of the following) is defined as follows:

[0094] In a particular group of compounds of formula II above, the compound has the formula: [ka] (In the formula, R 1a , Y, Z, n, R 3a1 and R 3a2 each having one of the meanings defined above) or a pharma- ceutically acceptable salt thereof.

[0095] Suitably, n is 1 and R 3a1 and R 3a2 is hydrogen.

[0096] Appropriately, R 1a is the expression: -(CR 1c R 1d ) p -NR 1e R 1f (In the formula, p is 1; R 1c and R 1d is hydrogen (including deuterium) or C 1~2 independently selected from alkyl; R 1e is hydrogen (including deuterium) or C 1~2 alkyl; R 1f is the expression: -(CR 1g R 1h ) q -T1 (In the formula, q is 1; R 1g and R 1h is hydrogen (including deuterium) or C 1~2 independently selected from alkyl; T1 may each be C 1~2 Alkyl, C 1~2 Haloalkyl, cyano, hydroxy, C 1~2 Alkoxy, Halo, C 1~2 Haloalkoxy or C 3~6 cycloalkyl; C 3~4 Cycloalkyl, heterocyclyl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C 3~8 Cycloalkyl, Bridged Bicyclic C 5~12 cycloalkyl, or a bridged heterocyclic ring system; Any alkyl or alkoxy is optionally further substituted with one or more substituents selected from cyano, hydroxy, or halo. is a group having the formula is the basis.

[0097] Most appropriately, R 1a teeth, [ka] is selected from.

[0098] Suitably, Y is [ka] (wherein n is 1 and R 3a1 and R 3a2 is hydrogen) It is.

[0099] Suitably, Z is [ka] It is.

[0100] (iv) Specific Compounds of Formula II - List 2 Particular compounds of formula II above include any of the following, or a pharma- ceutically acceptable salt thereof: Listing 2 N-({2-[(4,4-dimethylpiperidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[[(3,3-difluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[[(1-hydroxycyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[[(1-fluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[[(1-methylcyclopropyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-(2-azabicyclo[2.1.1]hexan-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-(3-azabicyclo[3.1.1]heptanean-3-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[[2-(hydroxymethyl)pyrrolidin-1-yl]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-(morpholinomethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(1-adamantylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide 4-Oxo-N-[[2-(1-piperidylmethyl)-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(4-fluoro-1-piperidyl)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide 4-Oxo-N-[[2-[[[rac-(1S,2S,4S)-7-oxabicyclo[2.2.1]heptan-5-en-2-yl]methylamino]methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[[(1-hydroxycyclopentyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide 4-Oxo-N-[[2-[[[rac-(1S,2R,4S)-7-oxabicyclo[2.2.1]heptan-5-en-2-yl]methylamino]methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(1-bicyclo[1.1.1]pentanylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(cyclobutylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-({2-[({bicyclo[2.2.1]heptanean-2-yl}amino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(cyclopropylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-(2-azabicyclo[2.2.2]octan-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[[(2,2-difluorocyclopropyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(cyclohexylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[[(1-hydroxycyclohexyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(cyclopentylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(cyclopentylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[[(1-methoxycyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(isobutylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(cyclohexylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(cyclopropylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide 4-Oxo-N-[[2-[(prop-2-ynylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(oxetan-2-ylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(2,2-dimethylpropylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(1-bicyclo[1.1.1]pentanylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-{[2-({[(1S,2S)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-{[2-({[(1R,2R)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-{[2-({[(1S,2R)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-{[2-({[(1R,2S)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(cyclopropylmethylamino)methyl]-5-fluoro-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(cyclobutylmethylamino)methyl]-5-fluoro-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide 4-Oxo-N-[[2-[(2,2,2-trifluoroethylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[N-(cyclobutylmethyl)acetamido]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide 4-Oxo-N-{[2-(piperidin-2-yl)-1H-indol-6-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[(cyclobutylmethyl)amino]methyl}-3-fluoro-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[(cyclobutylmethyl)amino]methyl}-1-methyl-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(cyclobutylmethylamino)-dideuterio-methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-1H-indazole-4-carboxamide N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[3,2-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-(1H-indol-6-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-(1H-indol-2-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-(indolizin-2-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(6-{[4-(1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]methyl}-1H-indol-2-yl)methyl]cyclopropanamine (1R,2S)-2-[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamino]cyclopentanol N-[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methyl]cyclopentanamine N-(cyclopropylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine 1-[[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamino]methyl]cyclobutanol N-(Cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine N-(Cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-b]pyridin-2-yl]methanamine N-(Cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine N-(Cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine 2-[1-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]triazol-4-yl]pyrido[1,2-a]pyrimidin-4-one N-(Cyclobutylmethyl)-1-[6-[[4-(6-methoxyimidazo[1,5-a]pyridin-8-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine N-(Cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)imidazol-1-yl]methyl]-1H-indol-2-yl]methanamine N-(Cyclobutylmethyl)-1-[6-[[3-(1H-indazol-4-yl)-1,2,4-oxadiazol-5-yl]methyl]-1H-indol-2-yl]methanamine N-[[2-(2-azaspiro[3.3]heptanean-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(benzylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-(3-azabicyclo[3.1.0]hexan-3-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[[cyclobutylmethyl(methyl)amino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-1,3-benzodiazol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[(but-2-yn-1-yl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[(3-cyclopropylprop-2-yn-1-yl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-({2-[({bicyclo[3.1.0]hexan-6-yl}amino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[({bicyclo[2.1.1]hexan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[({3-methylbicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-({2-[(3-methylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-({2-[(3-fluoroazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-({2-[(azetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-{[2-({2-azaspiro[3.4]octan-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-({2-[(3-hydroxyazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-({2-[(3,3-dimethylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide 4-Oxo-N-[(2-{[3-(2,2,2-trifluoroethoxy)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[3-(difluoromethyl)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-({2-[(3-methoxyazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[3-(tert-butoxy)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide 4-Oxo-N-[(2-{[3-(trifluoromethyl)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-({2-[(3-ethoxyazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-{[2-({2-azaspiro[3.5]nonan-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-({2-[(2-methylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-({2-[(3,3-dimethylpyrrolidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-{[2-({6-fluoro-2-azaspiro[3.3]heptane-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-{[2-({6,6-difluoro-2-azaspiro[3.3]heptane-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-({2-[(3-cyclobutylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-({2-[(3-cyclopropylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-({2-[(3-tert-butylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[(1-tert-butylcyclopropyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-{[2-({[(3-methylcyclobutyl)methyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide 4-Oxo-N-[(2-{[(2,3,3-trimethylbutan-2-yl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[({imidazo[1,2-a]pyridin-2-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-({2-[(3,3-diethylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide 4-Oxo-N-[(2-{[(pent-3-yn-1-yl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-{[2-({6-azaspiro[3.4]octan-6-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-({2-[(2,2-dimethylpyrrolidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-{[2-({octahydrocyclopenta[c]pyrrol-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-{[2-({5-azaspiro[2.4]heptane-5-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[({3-methoxybicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide 4-Oxo-N-[(2-{[({spiro[2.2]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide 4-Oxo-N-({2-[({spiro[2.3]hexan-1-yl}amino)methyl]-1H-indol-6-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[({3-cyanobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-{[2-({1-oxa-6-azaspiro[3.4]octan-6-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-{[2-({2-azaspiro[4.4]nonan-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[(1-methylcyclopentyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-{[2-(hydroxymethyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[(1-cyclobutylcyclopropyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-{[2-({[(1-methylcyclobutyl)methyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide 4-Oxo-N-[(2-{[({spiro[2.3]hexan-5-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-({2-[({[3-(fluoromethyl)bicyclo[1.1.1]pentan-1-yl]methyl}amino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[(1-{3-fluorobicyclo[1.1.1]pentan-1-yl}ethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-({2-[(tert-butylamino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide 4-(1-{[2-({2-azaspiro[3.3]heptane-2-yl}methyl)-1H-indol-6-yl]methyl}-1H-1,2,3-triazol-4-yl)-1H-indazole N-{[2-(2-{2-azaspiro[3.3]heptane-2-yl}ethyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide ({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)({6-[(4-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-7-carboxamide N-[(2-{[({bicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[({3-methylbicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[({bicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H,6H,7H,8H,9H-pyrido[1,2-a]pyrimidine-2-carboxamide (Cyclobutylmethyl)({6-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-imidazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine (Cyclobutylmethyl)({6-[(4-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine N-[(2-{[(2,2-dimethylpropyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (Cyclobutylmethyl)({6-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine N-[[2-(2-azabicyclo[2.2.1]heptanean-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide N-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methyl]-1-[6-[(4-imidazo[1,5-a]pyridin-8-yltriazol-1-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine (Cyclobutylmethyl)[(6-{[1-(1H-indazol-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine [(3,3-difluorocyclobutyl)methyl][(6-{[1-(1H-indazol-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine (Cyclobutylmethyl)[(6-{[1-(isoquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine (Cyclobutylmethyl)({6-[(1-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-4-yl)methyl]-1H-indol-2-yl}methyl)amine 3-[1-({2-[({(bicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile; 3-[1-({2-[({(3-fluorobicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile; 5-Methoxy-3-[1-({2-[({(3-methylbicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-2-pyridinecarbonitrile; 3-{1-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarbonitrile; 3-{1-[(2-{(6-aza-6-spiro[3.4]octyl)methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarbonitrile; 3-[1-({2-[(4,4-dimethyl-1-piperidyl)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile; N-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide 3-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-5-fluoropicolinonitrile 1-Cyclobutyl-N-((6-((4-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine; 5-chloro-3-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)picolinonitrile; 2-((6-azaspiro[3.4]octan-6-yl)methyl)-6-((4-(imidazo[1,5-a]pyridin-8-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-pyrrolo[3,2-c]pyridine; 3-[1-({2-[({(bicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile; 3-[1-({2-[({(3-fluorobicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile; 5-Methoxy-3-[1-({2-[({(3-methylbicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-2-pyridinecarbonitrile; 3-{1-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarbonitrile; 3-{1-[(2-{(6-aza-6-spiro[3.4]octyl)methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarbonitrile; and 3-[1-({2-[(4,4-dimethyl-1-piperidyl)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile.

[0101] (v) Specific compounds STM3006, STM3480 and STM3675 One particular compound of formula I as defined above disclosed in WO 2020 / 050898 is 6-bromo-4-[1-({6-[(4,4-dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]-1H-indazole, having the structure shown below: [ka] The STM3006 has the following features:

[0102] Two particular compounds of formula II, VI and VII defined above are STM3480 and STM3675.

[0103] The STM3480 has the following structure: [ka] N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide having the formula:

[0104] STM3675 is N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide, and its structure is: [ka] As shown in.

[0105] The METTL3 inhibitor used in the combination therapy of the present invention can be any METTL3 inhibitor.

[0106] In certain embodiments, the METTL3 inhibitor is a compound of Formula I, II, VI or VII as defined herein, or a pharma- ceutically acceptable salt thereof.

[0107] In another embodiment, the METTL3 inhibitor is any one of the specific compounds listed in List 1 and / or List 2 above, or a pharma- ceutically acceptable salt thereof.

[0108] In another embodiment, the METTL3 inhibitor is any one of the specific compounds STM3006, STM3480 or STM3675 identified above, or a pharma- ceutically acceptable salt thereof.

[0109] In certain embodiments, the METTL3 inhibitor is STM3480, as identified above, or a pharma- ceutically acceptable salt thereof.

[0110] <1. Combination of a METTL3 inhibitor as defined herein with an immuno-oncology drug (e.g., an immune checkpoint inhibitor)> One aspect of the present invention resides in the recognition that the METTL3 inhibitor compound, STM3480, is particularly suitable for use in combination with immune checkpoint inhibitors (see Examples 1 and 2).

[0111] Immune checkpoint inhibitors are a class of anti-cancer drugs that have shown great promise in some cancer patients. Blockade of immune checkpoints (e.g., CTLA4, LAG3, PD1 or PD-L1 inhibitors) enhances the immune response against tumors. However, some cancers do not respond well enough to immune checkpoint inhibitor therapy alone, so improved treatment strategies are needed.

[0112] The present inventors have surprisingly discovered that the METTL3 inhibitor compound STM3480 can significantly enhance the therapeutic effect of immune checkpoint inhibitors. In one embodiment, the METTL3 inhibitor compound STM3480 synergistically enhances the therapeutic effect of immune checkpoint inhibitors (or vice versa), thereby making the tumor more sensitive to the combination therapy (i.e., the observed therapeutic effect is greater than the additive effect of the two drugs individually).

[0113] Thus, the combination treatment of the present invention has the potential to provide better therapeutic outcomes in cancer patients, particularly those who do not respond adequately to treatment with a METTL3 inhibitor or an immune checkpoint inhibitor alone.

[0114] In one aspect, the invention provides a combination comprising a METTL3 inhibitor as defined herein (e.g., STM3480), or a pharma- ceutically acceptable salt thereof, and an immune checkpoint inhibitor, or a pharma-ceutically acceptable salt thereof.

[0115] In another aspect, the present invention provides a pharmaceutical product comprising a combination of a METTL3 inhibitor as defined herein (e.g., STM3480), or a pharma- ceutical acceptable salt thereof, and an immune checkpoint inhibitor, or a pharma- ceutical acceptable salt thereof.

[0116] In one embodiment, the pharmaceutical product may comprise a kit of parts comprising separate formulations of a METTL3 inhibitor (e.g., STM3480) or a pharmaceutically acceptable salt thereof as defined herein and an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof. The separate formulations of a METTL3 inhibitor (e.g., STM3480) or a pharmaceutically acceptable salt thereof as defined herein and an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof may be administered sequentially, separately and / or simultaneously.

[0117] In another embodiment, the pharmaceutical agent comprises: a first container comprising a METTL3 inhibitor as defined herein (e.g., STM3480), or a pharma- ceutically acceptable salt thereof, in combination with a pharma- ceutically acceptable adjuvant, diluent or carrier; a second container comprising an immune checkpoint inhibitor, or a pharma- ceutically acceptable salt thereof, in combination with a pharma- ceutically acceptable adjuvant, diluent, or carrier; container means for containing said first container and said second container; It is a kit of parts including:

[0118] In one embodiment, the pharmaceutical product may contain one or more unit dosage forms (e.g., vials, tablets, or capsules in blister packs). In one embodiment, each unit dosage contains only one agent selected from a METTL3 inhibitor (e.g., STM3480) compound as defined herein and an immune checkpoint inhibitor. In another embodiment, the unit dosage form contains both a METTL3 inhibitor (e.g., STM3480) compound as defined herein and an immune checkpoint inhibitor.

[0119] In one embodiment the pharmaceutical or kit-of-parts further comprises a means for promoting compliance with the administration regimen, for example instructions detailing how to administer the combination.

[0120] In one embodiment the medicament or kit-of-parts further comprises instructions indicating that the combination defined herein can be used in the treatment of cancer.

[0121] In one embodiment, the pharmaceutical agent is a pharmaceutical composition.

[0122] <Immune checkpoint inhibitors> Any immune checkpoint inhibitor may be used in the combination therapy defined herein.

[0123] In one embodiment, the immune checkpoint inhibitor is selected from a PD1, a PD-L1 inhibitor, a LAG3 inhibitor, and a CTLA-4 inhibitor. In a particular embodiment, the immune checkpoint inhibitor is a PD1 or PD-L1 inhibitor.

[0124] PD-1 is a cell surface receptor protein present on T cells. PD-1 plays an important role in downregulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. The PD-1 protein is an immune checkpoint that protects against autoimmunity through a dual mechanism that promotes apoptosis (programmed cell death) of antigen-specific T cells in lymph nodes while simultaneously reducing apoptosis of regulatory T cells (anti-inflammatory suppressive T cells).

[0125] PD-1 therefore inhibits the immune system, which helps prevent autoimmune diseases but can also prevent the immune system from killing cancer cells.

[0126] PD1 binds two ligands, PD-L1 and PD-L2. PD-L1 is of particular interest because it is highly expressed in several cancers, and thus the role of PD1 in cancer immune evasion is well established. Monoclonal antibodies targeting PD-1, which boost the immune system, have been developed to treat cancer. Many tumor cells express PD-L1, an immunosuppressive PD-1 ligand; inhibiting the interaction between PD-1 and PD-L1 can enhance T cell responses in vitro and mediate preclinical antitumor activity. This is known as immune checkpoint blockade.

[0127] Examples of drugs that target PD-1 include pembrolizumab (Keytruda) and nivolumab (Opdivo). These drugs have been shown to be effective in treating several types of cancer, including cutaneous melanoma, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancer, and Hodgkin's lymphoma. They are also being investigated for use against many other types of cancer. Examples of drugs in development include BMS-936559 (Bristol Myers Squibb), MGA012 (MacroGenics), and MEDI-0680 (MedImmune).

[0128] Examples of drugs that block PD-L1 include atezolizumab (Tecentriq), avelumab (Bavencio) and durvalumab (Imfinzi). These drugs have also been shown to be beneficial in treating various types of cancer, including bladder cancer, non-small cell lung cancer and Merkel cell skin cancer (Merkel cell carcinoma). They are also being studied for use in other types of cancer.

[0129] Examples of LAG3 inhibitors include BMS-986016 / leratolimab, TSR-033, REGN3767, MGD013 (a bispecific DART that binds PD-1 and LAG-3), GSK2831781 and LAG525.

[0130] Examples of CTLA-4 inhibitors include MDX-010 / ipilimumab, AGEN1884 and CP-675,206 / tremelimumab.

[0131] In one embodiment, the immune checkpoint inhibitor is selected from BMS-986016 / leratolimab, TSR-033, REGN3767, MGD013 (a bispecific DART that binds PD-1 and LAG-3), GSK2831781, LAG525, MDX-010 / ipilimumab, AGEN1884 and CP-675,206 / tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, or a pharmaceutically acceptable salt thereof.

[0132] In another embodiment, the immune checkpoint inhibitor is selected from BMS-986016 / leratolimab, MDX-010 / ipilimumab, CP-675,206 / tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, and durvalumab, or a pharmaceutically acceptable salt thereof.

[0133] In another embodiment, the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, atezolizumab, avelumab, and durvalumab, or a pharmaceutically acceptable salt thereof.

[0134] In another embodiment, the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, atezolizumab, avelumab, and durvalumab, or a pharmaceutically acceptable salt thereof.

[0135] In another embodiment, the immune checkpoint inhibitor is selected from pembrolizumab and avelumab, or a pharmaceutically acceptable salt thereof.

[0136] <Treatment use> Thus, in one aspect, the present invention relates to a METTL3 inhibitor, or a pharma- ceutically acceptable salt thereof, as defined herein, for use as an immunosensitizer.

[0137] The present invention also relates to the use of a METTL3 inhibitor, or a pharma- ceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for use as an immunosensitizer.

[0138] The present invention also relates to a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer administered in combination with an immuno-cancer agent or therapy (e.g., an immune checkpoint inhibitor (e.g., a PD1, PD-L1 inhibitor, a LAG3, CTLA-4, TIGIT, TIM3 or VISTA inhibitor), a STING agonist, a TLR agonist, an anti-CD137 antibody, a CD28 antibody, an OX40 stimulant, a CD40 antibody, an ICOS agonist, a GITR agonist, an A2AR antagonist, a bispecific T cell engager (BiTE), an oncolytic virus, a cancer vaccine, and / or a CAR-T cell therapy).

[0139] The present invention also relates to the use of a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer, wherein the METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, is administered in combination with an immuno-cancer drug or therapy (e.g., an immune checkpoint inhibitor (e.g., a PD1, PD-L1 inhibitor, a LAG3, CTLA-4, TIGIT, TIM3 or VISTA inhibitor), a STING agonist, a TLR agonist, an anti-CD137 antibody, a CD28 antibody, an OX40 stimulant, a CD40 antibody, an ICOS agonist, a GITR agonist, an A2AR antagonist, a bispecific T cell engager (BiTE), an oncolytic virus, a cancer vaccine, and / or a CAR-T cell therapy).

[0140] The present invention also relates to a method of treating cancer comprising administering to a patient a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, in combination with a cancer immuno-agent or therapy (e.g., an immune checkpoint inhibitor (e.g., a PD1, PD-L1 inhibitor, a LAG3, CTLA-4, TIGIT, TIM3 or VISTA inhibitor), a STING agonist, a TLR agonist, an anti-CD137 antibody, a CD28 antibody, an OX40 stimulator, a CD40 antibody, an ICOS agonist, a GITR agonist, an A2AR antagonist, a bispecific T-cell engager (BiTE), an oncolytic virus, a cancer vaccine, and / or a CAR-T cell therapy).

[0141] Suitably, a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, is administered simultaneously, sequentially or separately with an immuno-cancer drug or therapy (e.g., an immune checkpoint inhibitor (e.g., a PD1, PD-L1 inhibitor, a LAG3, CTLA-4, TIGIT, TIM3 or VISTA inhibitor), a STING agonist, a TLR agonist, an anti-CD137 antibody, a CD28 antibody, an OX40 stimulant, a CD40 antibody, an ICOS agonist, a GITR agonist, an A2AR antagonist, a bispecific T cell engager (BiTE), an oncolytic virus, a cancer vaccine, and / or a CAR-T cell therapy).

[0142] Suitably, the immuno-cancer agent is an immune checkpoint inhibitor (e.g. a PD1, PD-L1 inhibitor, LAG3 or CTLA-4 inhibitor).

[0143] In another aspect, the invention relates to a combination as defined herein, or a medicament as defined herein, or a pharmaceutical composition as defined herein, for use in therapy.

[0144] In another aspect, the invention relates to a combination as defined herein, or a medicament as defined herein, or a pharmaceutical composition as defined herein, for use in the treatment of cancer.

[0145] In another aspect, the invention relates to the use of a combination as defined herein in the manufacture of a medicament for treating cancer.

[0146] In another aspect, the present invention relates to a method of treating cancer in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of a combination as defined herein.

[0147] In another aspect, the invention relates to a method of enhancing an immune response against a tumor, comprising the step of administering a therapeutically effective amount of a combination as defined herein to a patient in need of such treatment.

[0148] In another aspect, the invention relates to a METTL3 inhibitor, or a pharma- ceutical acceptable salt thereof, as defined herein, for use in the treatment of cancer, for simultaneous, separate or sequential administration with an immune checkpoint inhibitor, or a pharma- ceutical acceptable salt thereof.

[0149] In another aspect, the present invention relates to an immune checkpoint inhibitor, or a pharma- ceutical acceptable salt thereof, for simultaneous, separate or sequential administration with a METTL3 inhibitor, or a pharma- ceutical acceptable salt thereof, as defined herein, for use in the treatment of cancer.

[0150] In another aspect, the invention relates to the use of a METTL3 inhibitor, or a pharma- ceutical acceptable salt thereof, as defined herein, in the manufacture of a medicament for treating cancer, wherein the medicament is for simultaneous, separate or sequential administration with an immune checkpoint inhibitor, or a pharma- ceutical acceptable salt thereof.

[0151] In another aspect, the invention relates to the use of an immune checkpoint inhibitor, or a pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for treating cancer, wherein the medicament is for simultaneous, separate or sequential administration with a METTL3 inhibitor, or a pharma- ceutical acceptable salt thereof, as defined herein.

[0152] In another aspect, the present invention relates to a method of treating cancer, comprising the step of administering to a subject in need thereof therapeutically effective amounts of a METTL3 inhibitor, or a pharma- ceutically acceptable salt thereof, as defined herein and an immune checkpoint inhibitor, or a pharma- ceutically acceptable salt thereof, wherein the METTL3 inhibitor, or a pharma- ceutically acceptable salt thereof, as defined herein and the immune checkpoint inhibitor, or a pharma- ceutically acceptable salt thereof, are administered sequentially, separately or simultaneously with each other.

[0153] In another aspect, the present invention relates to a method of treating cancer or enhancing the effect of an immune checkpoint inhibitor, or a pharma- ceutically acceptable salt thereof, comprising the step of administering a therapeutically effective amount of an immune checkpoint inhibitor, or a pharma- ceutically acceptable salt thereof, to a patient in need of such treatment, separately, sequentially or simultaneously with a METTL3 inhibitor, or a pharma- ceutically acceptable salt thereof, as defined herein.

[0154] In another aspect, the present invention relates to a method of treating cancer or enhancing the effect of a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, comprising the step of administering a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, to a patient in need of such treatment, separately, sequentially or simultaneously with an immune checkpoint inhibitor, or a pharma- ceutically acceptable salt thereof.

[0155] In another aspect, the present invention relates to a method of enhancing an immune response against a tumor, comprising the step of administering to a patient in need of such treatment therapeutically effective amounts of a METTL3 inhibitor, or a pharma- ceutically acceptable salt thereof, as defined herein and an immune checkpoint inhibitor, or a pharma- ceutically acceptable salt thereof, wherein the METTL3 inhibitor, or a pharma- ceutically acceptable salt thereof, as defined herein and the immune checkpoint inhibitor, or a pharma- ceutically acceptable salt thereof, are administered sequentially, separately or simultaneously with each other.

[0156] The term "cancer" is used herein to refer to unwanted, uncontrolled, and abnormal malignant cell growth, whether in vitro or in vivo. This term includes benign, pre-malignant, and malignant cell growth. Any type of cell can be treated, including, but not limited to, lung, colon, breast, ovary, prostate, liver, pancreas, brain, bladder, kidney, bone, nerve, and skin.

[0157] The anti-proliferative effect of the combination therapy of the present invention has particular application in the treatment of human cancer.In particular, the combination therapy of the present invention is useful for the treatment of any human cancer in which METTL3 and / or immune checkpoint activity is involved.This includes any cancer that has been unresponsive to treatment with either METTL3 inhibitor or immune checkpoint inhibitor alone.

[0158] In certain embodiments of the present invention, the anti-tumor effects of the combination therapy of the present invention have particular application in the treatment and / or prevention of a wide range of cancers, including, but not limited to, non-solid tumors such as leukemia, e.g., acute myeloid leukemia, multiple myeloma, hematological malignancies or lymphomas, as well as solid tumors and their metastases, such as melanoma, non-small cell lung cancer, glioma, hepatocellular (liver) cancer, glioblastoma, thyroid cancer, cholangiocarcinoma, bone cancer, gastric cancer, brain / CNS cancer, head and neck cancer, liver cancer, stomach cancer, prostate cancer, breast cancer, renal cancer, testicular cancer, ovarian cancer, skin cancer, cervical cancer, lung cancer, muscle cancer, neural cancer, esophageal cancer, bladder cancer, lung cancer, uterine cancer, vulvar cancer, endometrial cancer, kidney cancer, colorectal cancer, pancreatic cancer, pleural / peritoneal cancer, salivary gland cancer, and epidermoid tumors and hematological malignancies.

[0159] Suitably the cancer is a solid tumour.

[0160] In one embodiment, the cancer is selected from lung cancer, colon cancer, rectal cancer, breast cancer, ovarian cancer, bladder cancer, kidney cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, bone cancer, blood cancer and skin cancer.

[0161] In one embodiment, the cancer is human cancer.Suitably, the human cancer is selected from lung cancer, colon cancer, breast cancer, ovarian cancer, bladder cancer, kidney cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, bone cancer, blood cancer and skin cancer.In one embodiment, the human cancer is selected from glioblastoma, lung cancer, breast cancer, renal cell carcinoma and Hodgkin's lymphoma.

[0162] Anti-cancer effects may occur through one or more mechanisms including, but not limited to, promoting anti-tumor immune responses, modulating cell proliferation, inhibiting angiogenesis (the formation of new blood vessels), inhibiting metastasis (the spread of a tumor from its origin), inhibiting invasion (the spread of tumor cells into adjacent normal structures or within organs), or promoting apoptosis (programmed cell death).

[0163] As set forth above, the immune checkpoint inhibitor can be any immune checkpoint inhibitor defined in any of the embodiments herein, and the METTL3 inhibitor can be any known METTL3 inhibitor.

[0164] In one embodiment, the immune checkpoint inhibitor is selected from BMS-986016 / leratolimab, TSR-033, REGN3767, MGD013 (a bispecific DART that binds PD-1 and LAG-3), GSK2831781, LAG525, MDX-010 / ipilimumab, AGEN1884, and CP-675,206 / tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, and durvalumab, or a pharmaceutically acceptable salt thereof; and the METTL3 inhibitor is as defined herein.

[0165] In another embodiment, the immune checkpoint inhibitor is selected from BMS-986016 / relatolimab, MDX-010 / ipilimumab, CP-675,206 / tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, and durvalumab, or a pharmaceutically acceptable salt thereof; and the METTL3 inhibitor is selected from STM3006, STM3480 or STM3675, as defined herein, or a pharmaceutically acceptable salt thereof.

[0166] In another embodiment, the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, or a pharmaceutically acceptable salt thereof; and the METTL3 inhibitor is selected from STM3006, STM3480 or STM3675, as defined herein, or a pharmaceutically acceptable salt thereof.

[0167] Suitably the METTL3 inhibitor is STM3480.

[0168] <2. Combination of METTL3 inhibitor and BCL2 inhibitor (e.g., venetoclax)> One aspect of the present invention resides in the recognition that the METTL3 inhibitor compounds, STM3480, STM3006 and STM3675, when administered in combination with a BCL2 inhibitor (venetoclax), provided a synergistic increase in efficacy (see Example 3).

[0169] Thus, administration of a METTL3 inhibitor synergistically enhances the antitumor effect of BCL2 inhibitor (e.g., venetoclax) therapy, and vice versa. Thus, the combination of a METTL3 inhibitor with a BCL2 inhibitor (e.g., venetoclax) provides a promising treatment for diseases or conditions in which BCL2 inhibitor therapy is beneficial (e.g., treatment of cancers including acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and myelodysplastic syndromes (MDS)).

[0170] The combination treatments of the present invention have the potential to provide better therapeutic outcomes in cancer patients, particularly those who do not respond adequately to treatment with a METTL3 inhibitor or a BCL2 inhibitor (e.g., venetoclax) alone.

[0171] In one aspect, the invention provides a combination comprising a METTL3 inhibitor as defined herein (e.g., STM3480, STM3006 and STM3675), or a pharma- ceutically acceptable salt thereof, and a BCL2 inhibitor (e.g., venetoclax), or a pharma- ceutically acceptable salt thereof.

[0172] In another aspect, the present invention provides a pharmaceutical product comprising a combination of a METTL3 inhibitor as defined herein (e.g., STM3480, STM3006 and STM3675), or a pharma- ceutical acceptable salt thereof, and a BCL2 inhibitor (e.g., venetoclax), or a pharma- ceutical acceptable salt thereof.

[0173] In one embodiment, the pharmaceutical product may comprise a kit of parts comprising separate formulations of a METTL3 inhibitor (e.g., STM3480, STM3006 and STM3675) or a pharma- ceutically acceptable salt thereof as defined herein and a BCL2 inhibitor (e.g., venetoclax) or a pharma- ceutically acceptable salt thereof. The separate formulations of a METTL3 inhibitor (e.g., STM3480, STM3006 and STM3675) or a pharma- ceutically acceptable salt thereof as defined herein and a BCL2 inhibitor (e.g., venetoclax) or a pharma- ceutically acceptable salt thereof may be administered sequentially, separately and / or simultaneously.

[0174] In another embodiment, the pharmaceutical agent is a first container comprising a METTL3 inhibitor as defined herein (e.g., STM3480, STM3006 and STM3675) or a pharma- ceutically acceptable salt thereof, in combination with a pharma- ceutically acceptable adjuvant, diluent or carrier; a second container comprising a BCL2 inhibitor (e.g., venetoclax), or a pharma- ceutically acceptable salt thereof, in combination with a pharma- ceutically acceptable adjuvant, diluent, or carrier; container means for containing said first container and said second container; It is a kit of parts including:

[0175] In one embodiment, the pharmaceutical product may comprise one or more unit dosage forms (e.g., capsules within vials, tablets or blister packs). In one embodiment, each unit dose comprises only one agent selected from the METTL3 inhibitors (e.g., STM3480, STM3006 and STM3675) compounds and BCL2 inhibitors (e.g., venetoclax) as defined herein. In another embodiment, the unit dosage form comprises both a METTL3 inhibitor (e.g., STM3480, STM3006 and STM3675) compound and a BCL2 inhibitor (e.g., venetoclax) as defined herein.

[0176] In one embodiment, the pharmaceutical product or kit of parts further comprises means for facilitating compliance with the dosing regimen, such as instructions detailing the manner of administration of the combination.

[0177] In one embodiment, the pharmaceutical product or kit of parts further comprises instructions indicating that the combination as defined herein can be used for the treatment of cancer.

[0178] In one embodiment, the pharmaceutical product is a pharmaceutical composition.

[0179] <BCL2 inhibitor> Any suitable BCL2 inhibitor approved for therapeutic use can be used in this combination therapy of the present invention.

[0180] Suitably, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. The chemical name of venetoclax is 4-{4-[(4'-chloro-5,5-dimethyl[3,4,5,6-tetrahydro[1,1'-biphenyl]]-2-yl)methyl]piperazin-1-yl}-N-(3-nitro-4-{[(oxan-4-yl)methyl]amino}benzene-1-sulfonyl)-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide, and its chemical structure is as follows:

Chemical formula

[0181] <Treatment use> The present invention also relates to a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof, for use in the treatment of a disease or condition in which BCL2 inhibitor therapy is beneficial (e.g., the treatment of cancer), administered in combination with a BCL2 inhibitor (e.g., venetoclax).

[0182] The present invention also relates to the use of a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a disease or condition in which BCL2 inhibitor therapy is beneficial (e.g., the treatment of cancer), wherein the METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof, is administered in combination with a BCL2 inhibitor (e.g., venetoclax).

[0183] The present invention also relates to a method of treating a disease or condition in which BCL2 inhibitor therapy is beneficial (e.g., treating cancer), comprising administering to a patient a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof, in combination with a BCL2 inhibitor (e.g., venetoclax).

[0184] Suitably, the METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, is administered simultaneously, sequentially or separately from the BCL2 inhibitor (eg, venetoclax) therapy.

[0185] In one aspect, the invention relates to a combination comprising a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, and a BCL2 inhibitor (e.g., venetoclax), or a pharma- ceutically acceptable salt thereof.

[0186] In another aspect, the invention relates to a pharmaceutical product comprising a combination as defined above.

[0187] In another aspect, the invention relates to a pharmaceutical composition comprising a combination as defined above and one or more pharma- ceutically acceptable excipients.

[0188] In another aspect, the invention relates to a combination as defined above, or a medicament as defined above, or a pharmaceutical composition as defined above, for use in therapy.

[0189] In another aspect, the invention relates to a combination as defined herein, or a medicament as defined above, or a pharmaceutical composition as defined above, for use in the treatment of a disease or condition in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancer).

[0190] In another aspect, the invention relates to the use of a combination as defined above in the manufacture of a medicament for the treatment of a disease or condition in which BCL2 inhibitor therapy is beneficial (e.g. the treatment of cancer).

[0191] In another aspect, the present invention relates to a method for treating a disease or condition in a subject in need thereof that would benefit from BCL2 inhibitor therapy (e.g., treating cancer), comprising administering to said subject a therapeutically effective amount of a combination as defined above.

[0192] In another aspect, the invention relates to a METTL3 inhibitor, or a pharma- ceutical acceptable salt thereof, as defined herein, for use in the treatment of cancer, for simultaneous, separate or sequential administration with a BCL2 inhibitor (e.g., venetoclax), or a pharma- ceutical acceptable salt thereof.

[0193] In another aspect, the present invention relates to a BCL2 inhibitor (e.g., venetoclax), or a pharma- ceutical acceptable salt thereof, for use in the treatment of cancer, for simultaneous, separate or sequential administration with a METTL3 inhibitor, or a pharma- ceutical acceptable salt thereof, as defined herein.

[0194] In another aspect, the invention relates to the use of a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for treating cancer, wherein the medicament is for simultaneous, separate or sequential administration with a BCL2 inhibitor (e.g., venetoclax), or a pharma- ceutical acceptable salt thereof.

[0195] In another aspect, the invention relates to the use of a BCL2 inhibitor (e.g., venetoclax) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer, wherein the medicament is for simultaneous, separate or sequential administration with a METTL3 inhibitor or a pharmaceutically acceptable salt thereof as defined herein.

[0196] In another aspect, the present invention relates to a method of treating cancer, comprising the step of administering to a subject in need thereof therapeutically effective amounts of a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, and a BCL2 inhibitor (e.g., venetoclax) or a pharma- ceutically acceptable salt thereof, wherein the METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, and the BCL2 inhibitor (e.g., venetoclax) or a pharma- ceutically acceptable salt thereof, are administered sequentially, separately or simultaneously with each other.

[0197] In another aspect, the present invention relates to a method of treating cancer or enhancing the effect of a BCL2 inhibitor (e.g., venetoclax) or a pharma- ceutically acceptable salt thereof, comprising administering a therapeutically effective amount of a BCL2 inhibitor (e.g., venetoclax) or a pharma- ceutically acceptable salt thereof to a patient in need of such treatment, separately, sequentially or simultaneously with a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof.

[0198] In another aspect, the present invention relates to a method of treating cancer or enhancing the effect of a METTL3 inhibitor as defined herein or a pharma- ceutically acceptable salt thereof, comprising the step of administering a therapeutically effective amount of a METTL3 inhibitor as defined herein or a pharma- ceutically acceptable salt thereof to a patient in need of such treatment, separately, sequentially or simultaneously with a BCL2 inhibitor (e.g., venetoclax) or a pharma- ceutically acceptable salt thereof.

[0199] The anti-proliferative effect of the combination therapy of the present invention has particular application in the treatment of human cancer.In particular, the combination therapy of the present invention is useful for treating any human cancer that is associated with METTL3 and / or BCL2 activity.This includes any cancer that has been unresponsive to treatment that includes either METTL3 inhibitor or BCL2 inhibitor alone.

[0200] Suitably, the cancer is selected from acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and myelodysplastic syndrome (MDS).

[0201] In certain embodiments, the combination therapy of the present invention is suitable for the treatment of acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL).

[0202] Anti-cancer effects may occur through one or more mechanisms including, but not limited to, promoting anti-tumor immune responses, modulating cell proliferation, inhibiting angiogenesis (the formation of new blood vessels), inhibiting metastasis (the spread of a tumor from its origin), inhibiting invasion (the spread of tumor cells into adjacent normal structures or within organs), or promoting apoptosis (programmed cell death).

[0203] As noted above, the BCL2 inhibitor can be any BCL2 inhibitor, and the METTL3 inhibitor can be any known METTL3 inhibitor.

[0204] In one embodiment, the BCL2 inhibitor is venetoclax or a pharma- ceutically acceptable salt thereof; and the METTL3 inhibitor is as defined herein.

[0205] In one embodiment, the BCL2 inhibitor is venetoclax or a pharma- ceutically acceptable salt thereof; and the METTL3 inhibitor is selected from any compound of formula I, II, VI or VII as defined above, or a pharma- ceutically acceptable salt thereof.

[0206] In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof; and the METTL3 inhibitor is selected from STM3006, STM3480, or STM3675, or a pharmaceutically acceptable salt thereof.

[0207] In one embodiment, the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof; and the METTL3 inhibitor is STM3480 or a pharmaceutically acceptable salt thereof.

[0208] <3. Combination of METTL3 inhibitor with anthracycline topoisomerase 2 inhibitor (e.g., daunorubicin), cytarabine, hypomethylating agent (e.g., 5-azacytidine), FLT3 inhibitor (e.g., quizartinib), and decitabine> One aspect of the present invention resides in the recognition that METTL3 inhibitor compounds, STM3480 and STM3006, when administered in combination with daunorubicin, cytarabine, 5-azacytidine and quizartinib, provided enhanced therapeutic effects in Kasumi1 or MOLM-14 AML cell lines (see Example 4).

[0209] Taken together, these data suggest that administration of a METTL3 inhibitor enhances the antitumor effects of these AML standard treatments. Thus, the combination of a METTL3 inhibitor with either an anthracycline topoisomerase 2 inhibitor (e.g., daunorubicin), cytarabine, hypomethylating agents (e.g., 5-azacytidine or decitabine) and / or an FLT3 inhibitor (e.g., quizartinib) offers promising therapies for the treatment of cancer, particularly acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and / or myelodysplastic syndrome (MDS).

[0210] Thus, this combination treatment of the present invention has the potential to provide better therapeutic outcomes in cancer patients, particularly those who do not respond adequately to treatment with METTL3 inhibitors or anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin), cytarabine, hypomethylating agents (e.g., 5-azacytidine or decitabine) and / or FLT3 inhibitors (e.g., quizartinib).

[0211] In one aspect, the present invention provides a combination comprising a METTL3 inhibitor as defined herein (e.g., STM3480, STM3006 and STM3675), or a pharmaceutically acceptable salt thereof, and an anthracycline topoisomerase 2 inhibitor (e.g., daunorubicin), cytarabine, a hypomethylating agent (e.g., 5-azacytidine or decitabine), and / or a FLT3 inhibitor (e.g., quizartinib), or a pharmaceutically acceptable salt thereof.

[0212] In another aspect, the present invention provides a pharmaceutical product comprising a combination of a METTL3 inhibitor as defined herein (e.g., STM3480, STM3006 and STM3675), or a pharma- ceutical acceptable salt thereof, and an anthracycline topoisomerase 2 inhibitor (e.g., daunorubicin), cytarabine, a hypomethylating agent (e.g., 5-azacytidine or decitabine), and / or a FLT3 inhibitor (e.g., quizartinib), or a pharma- ceutical acceptable salt thereof.

[0213] In one embodiment, the pharmaceutical product may comprise a kit of parts comprising separate formulations of a METTL3 inhibitor as defined herein (e.g., STM3480, STM3006 and STM3675) or a pharmaceutically acceptable salt thereof and an anthracycline topoisomerase 2 inhibitor (e.g., daunorubicin), cytarabine, hypomethylating agent (e.g., 5-azacytidine or decitabine) and / or an FLT3 inhibitor (e.g., quizartinib) or a pharmaceutically acceptable salt thereof. The separate formulations of a METTL3 inhibitor as defined herein and an anthracycline topoisomerase 2 inhibitor (e.g., daunorubicin), cytarabine, hypomethylating agent (e.g., 5-azacytidine or decitabine) and / or an FLT3 inhibitor (e.g., quizartinib) or a pharmaceutically acceptable salt thereof may be administered sequentially, separately and / or simultaneously.

[0214] In another embodiment, the pharmaceutical agent comprises: a first container comprising a METTL3 inhibitor as defined herein (e.g., STM3480, STM3006 and STM3675) or a pharma- ceutically acceptable salt thereof, in combination with a pharma- ceutically acceptable adjuvant, diluent or carrier; a second container comprising an anthracycline topoisomerase 2 inhibitor (e.g., daunorubicin), cytarabine, a hypomethylating agent (e.g., 5-azacytidine or decitabine) and / or an FLT3 inhibitor (e.g., quizartinib), or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable adjuvant, diluent or carrier; container means for containing said first container and said second container; It is a kit of parts including:

[0215] In one embodiment, the pharmaceutical product may contain one or more unit dosage forms (e.g., vials, tablets, or capsules in blister packs). In one embodiment, each unit dosage contains only one agent selected from a METTL3 inhibitor (e.g., STM3480, STM3006, and STM3675) as defined herein and an anthracycline topoisomerase 2 inhibitor (e.g., daunorubicin), cytarabine, hypomethylating agent (e.g., 5-azacytidine or decitabine), and / or an FLT3 inhibitor (e.g., quizartinib). In another embodiment, the unit dosage form contains both a METTL3 inhibitor (e.g., STM3480, STM3006, and STM3675) as defined herein and an anthracycline topoisomerase 2 inhibitor (e.g., daunorubicin), cytarabine, hypomethylating agent (e.g., 5-azacytidine or decitabine), and / or an FLT3 inhibitor (e.g., quizartinib).

[0216] In one embodiment the pharmaceutical or kit-of-parts further comprises a means for promoting compliance with the administration regimen, for example instructions detailing how to administer the combination.

[0217] In one embodiment the medicament or kit-of-parts further comprises instructions indicating that the combination defined herein can be used in the treatment of cancer.

[0218] In one embodiment, the pharmaceutical agent is a pharmaceutical composition.

[0219] <Anthracycline topoisomerase 2 inhibitors, hypomethylating agents and FLT3 inhibitors> Any suitable anthracycline topoisomerase 2 inhibitor, hypomethylating agent and FLT3 inhibitor may be used in this combination therapy of the present invention.

[0220] Suitably, the anthracycline topoisomerase 2 inhibitor is selected from daunorubicin, doxorubicin, epirubicin or idarubicin.Most suitably, the anthracycline topoisomerase 2 inhibitor is selected from daunorubicin and doxorubicin.In one embodiment, the anthracycline topoisomerase 2 inhibitor is daunorubicin.

[0221] Suitably, the hypomethylating agent is selected from 5-azacytidine or decitabine. In one embodiment, the hypomethylating agent is 5-azacytidine. In another embodiment, the hypomethylating agent is decitabine.

[0222] Suitably, the FLT3 inhibitor is selected from sorafenib, lestaurtinib, midostaurin, quizartinib, crenolanib or gilteritinib. More suitably, the FLT3 inhibitor is selected from midostaurin, quizartinib or gilteritinib. In one embodiment, the FLT3 inhibitor is midostaurin. In another embodiment, the FLT3 inhibitor is quizartinib. In another embodiment, the FLT3 inhibitor is gilteritinib.

[0223] <Treatment use> The present invention also provides (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer, administered in combination with one or more additional agents selected from:

[0224] The present invention also relates to the use of a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer, the METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof comprising: (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutical acceptable salt thereof.

[0225] The present invention also provides a method of treating cancer, comprising administering a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof, to a patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof, (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutically acceptable salt thereof.

[0226] Suitably, the METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutically acceptable salt thereof They may be administered simultaneously, sequentially or separately.

[0227] In another aspect, the invention relates to a pharmaceutical product comprising a combination as defined above.

[0228] In another aspect, the invention relates to a pharmaceutical composition comprising a combination as defined above and one or more pharma- ceutically acceptable excipients.

[0229] In another aspect, the invention relates to a combination as defined above, or a medicament as defined above, or a pharmaceutical composition as defined above, for use in therapy.

[0230] In another aspect, the invention relates to a combination as defined above, or a medicament as defined above, or a pharmaceutical composition as defined above, for use in the treatment of cancer.

[0231] In another aspect, the present invention relates to the use of a combination as defined above in the manufacture of a medicament for treating cancer.

[0232] In another aspect, the present invention relates to a method of treating cancer in a subject in need thereof, comprising the step of administering to said subject a therapeutically effective amount of the combination as defined above.

[0233] In another aspect, the present invention provides a method for producing a composition comprising: (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutical acceptable salt thereof, for use in the treatment of cancer, wherein the pharma-ceutical agent is a METTL3 inhibitor or a pharma-ceutical acceptable salt thereof, wherein the pharma-ceutical agent is a METTL3 inhibitor or a pharma-ceutical acceptable salt thereof,

[0234] In another aspect, the present invention relates to a compound according to the present invention for use in the treatment of cancer, which compound is for simultaneous, separate or sequential administration with a METTL3 inhibitor as defined herein or a pharma- ceutical acceptable salt thereof, (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutically acceptable salt thereof.

[0235] In another aspect, the invention relates to the use of a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for treating cancer, the medicament comprising: (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharmaceutically acceptable salt thereof, wherein the compound is for simultaneous, separate or sequential administration with one or more additional agents selected from the group consisting of

[0236] In another aspect, the present invention relates to a method for the manufacture of a medicament for treating cancer, comprising: (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutical acceptable salt thereof, wherein the medicament is for simultaneous, separate or sequential administration with a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof.

[0237] In another aspect, the present invention provides a method of treating cancer comprising administering to a patient a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof. (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutically acceptable salt thereof to a subject in need thereof; The present invention relates to a method, wherein the METTL3 inhibitor or a pharma- ceutically acceptable salt thereof and the agent or a pharma- ceutically acceptable salt thereof as defined herein are administered sequentially, separately or simultaneously with each other.

[0238] In another aspect, the present invention provides a method for treating cancer, or (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutical acceptable salt thereof, comprising the step of administering a therapeutically effective amount of the agent or a pharma- ceutical acceptable salt thereof to a patient in need of such treatment separately, sequentially or simultaneously with a METTL3 inhibitor as defined herein, or a pharma- ceutical acceptable salt thereof.

[0239] In another aspect, the present invention provides a method of treating cancer or enhancing the effect of a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, comprising administering to a patient in need of such treatment a therapeutically effective amount of a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof: (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutically acceptable salt thereof.

[0240] The anti-proliferative effects of the combination therapies of the present invention have particular use in the treatment of human cancers.

[0241] Suitably, the cancer is selected from acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and myelodysplastic syndrome (MDS).

[0242] In certain embodiments, the combination therapy of the present invention is suitable for the treatment of acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL).

[0243] Anti-cancer effects may occur through one or more mechanisms including, but not limited to, promoting anti-tumor immune responses, modulating cell proliferation, inhibiting angiogenesis (the formation of new blood vessels), inhibiting metastasis (the spread of a tumor from its origin), inhibiting invasion (the spread of tumor cells into adjacent normal structures or within organs), or promoting apoptosis (programmed cell death).

[0244] As noted above, any suitable anthracycline topoisomerase 2 inhibitor, hypomethylating agent and FLT3 inhibitor may be used in the combination therapy of the present invention.

[0245] In certain embodiments, the METTL3 inhibitor is as defined herein and the second agent is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, 5-azacytidine, decitabine, sorafenib, lestaurtinib, midostaurin, quizartinib, crenolanib, gilteritinib, or cytarabine.

[0246] In certain embodiments, the METTL3 inhibitor is selected from any of the compounds of formula I, II, VI or VII as defined above, or a pharma- ceutically acceptable salt thereof, and the second agent is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, 5-azacytidine, decitabine, sorafenib, lestaurtinib, midostaurin, quizartinib, crenolanib, gilteritinib, or cytarabine.

[0247] In certain embodiments, the METTL3 inhibitor is selected from any compound of formula I, II, VI or VII as defined above, or a pharma- ceutically acceptable salt thereof, and the second agent is selected from daunorubicin, doxorubicin, 5-azacytidine, decitabine, midostaurin, quizartinib, gilteritinib, or cytarabine.

[0248] In certain embodiments, the METTL3 inhibitor is selected from any of the compounds of formula I, II, VI or VII as defined above, or a pharma- ceutically acceptable salt thereof, and the second agent is selected from daunorubicin, 5-azacytidine, decitabine, quizartinib, or cytarabine.

[0249] In certain embodiments, the METTL3 inhibitor is selected from STM3006, STM3480, or STM3675, or a pharma- ceutically acceptable salt thereof, and the second agent is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, 5-azacytidine, decitabine, sorafenib, lestaurtinib, midostaurin, quizartinib, crenolanib, gilteritinib, or cytarabine.

[0250] In certain embodiments, the METTL3 inhibitor is selected from STM3006, STM3480, or STM3675, or a pharma- ceutically acceptable salt thereof, and the second agent is selected from daunorubicin, doxorubicin, 5-azacytidine, decitabine, midostaurin, quizartinib, gilteritinib, or cytarabine.

[0251] In certain embodiments, the METTL3 inhibitor is selected from STM3006, STM3480, or STM3675, or a pharma- ceutically acceptable salt thereof, and the second agent is selected from daunorubicin, 5-azacytidine, decitabine, quizartinib, or cytarabine.

[0252] In certain embodiments, the METTL3 inhibitor is STM3480 or a pharma- ceutically acceptable salt thereof, and the second agent is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, 5-azacytidine, decitabine, sorafenib, lestaurtinib, midostaurin, quizartinib, crenolanib, gilteritinib, or cytarabine.

[0253] In certain embodiments, the METTL3 inhibitor is STM3480 or a pharma- ceutically acceptable salt thereof, and the second agent is selected from daunorubicin, doxorubicin, 5-azacytidine, decitabine, midostaurin, quizartinib, gilteritinib, or cytarabine.

[0254] In certain embodiments, the METTL3 inhibitor is STM3480 or a pharma- ceutically acceptable salt thereof, and the second agent is selected from daunorubicin, 5-azacytidine, decitabine, quizartinib, or cytarabine.

[0255] <Pharmaceutical Composition> In one aspect, the present invention relates to a pharmaceutical composition comprising a combination of a METTL3 inhibitor as defined herein, or a pharma- ceutically acceptable salt thereof, with another agent present in the combination as defined above, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

[0256] Pharmaceutical compositions of the invention may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder) or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0257] The pharmaceutical compositions of the invention will typically be for parenteral administration, particularly when the inhibitor is an antibody.

[0258] The pharmaceutical compositions can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use can contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0259] There will be an effective amount of each component of the combination therapy, such amount being an amount sufficient to treat or prevent, slow the progression of, and / or reduce the symptoms associated with the cancer conditions referred to herein.

[0260] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain from 0.5 mg to 0.5 g of active agent (more suitably 0.5 to 100 mg, e.g., 1 to 30 mg), compounded with an appropriate and conventional amount of excipient, which may vary, for example, from about 5 to about 98 percent by weight of the total composition.

[0261] The size of a dose of the combination of the present invention for therapeutic or prophylactic purposes will naturally vary according to the nature and severity of the pathology, the age and sex of the animal or patient, and the route of administration, in accordance with well-known medical principles.

[0262] When using the combination of the present invention for therapeutic or prophylactic purposes, it will generally be administered within the therapeutically effective dose of the particular drug involved. These dosages are known in the art and will vary depending on the drug. The dosage may be, for example, in the range of 0.1 mg / kg to 30 mg / kg body weight. The administration schedule will also vary depending on the immune checkpoint inhibitor. Suitable administration schedules are known in the art.

[0263] <Administration route> The combination of the present invention or a pharmaceutical composition comprising said combination may be administered to a subject by any suitable or conventional route of administration, whether systemic / peripheral or local (ie, to the desired site of action).

[0264] Depending on the nature of the agent, routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patch, cast, etc.); transmucosal (including, e.g., by patch, cast, etc.); intranasal (e.g., by nose drops); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, e.g., through the mouth or nose, via aerosol); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); by injection, including, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; parenteral, e.g., subcutaneous or intramuscular, by implantation of a depot or reservoir.

[0265] <Combination with additional therapeutic agents> The combination treatment defined herein may be applied as a sole therapy for treating the specified condition or may involve, in addition to the combination therapy of the present invention, one or more additional therapies (including treatment with another therapeutic agent, surgery or other therapeutic interventions such as radiation therapy in cancer treatment).

[0266] Typically, the other therapeutic agent used in combination with the combination therapy of the invention will be one or more therapeutic agents used as a standard of care to treat the disease or condition involved. The other therapeutic agent may include, for example, another drug used to treat the condition involved, or an agent that modulates the biological response to the combination therapy of the invention, such as, for example, an immunomodulatory agent.

[0267] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage ranges described above and the other pharmacologic active agent(s) within their approved dosage ranges.

[0268] For example, the combination therapy defined above may be applied as a monotherapy or may involve, in addition to the compound of the present invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include antitumor agents from the following categories: Other antiproliferative / antineoplastic drugs and combinations thereof used in medical oncology, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosoureas); antimetabolites (e.g., gemcitabine and folate antagonists, such as fluoropyrimidines, e.g., 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumor antibiotics (e.g., anthracyclines, anti-mitotic agents (e.g., vinca alkaloids, e.g., vincristine, vinblastine, vindesine, and vinorelbine, and taxoids, e.g., taxol and taxotere, and polo kinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins, e.g., etoposide and teniposide, amsacrine, topotecan, and camptothecin); Cytostatics, such as antiestrogens (e.g. tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (e.g. bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or agonists (e.g. goserelin, leuprorelin and buserelin), progestogens (e.g. megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase, such as finasteride; Invasion inhibitors [e.g., c-Src kinase family inhibitors, such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; WO 01 / 94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazine- 1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606), as well as metalloproteinase inhibitors, such as marimastat, an inhibitor of urokinase-type plasminogen activator receptor function or antibodies against heparanase]; Inhibitors of growth factor function: For example, such inhibitors include growth factor and growth factor receptor antibodies (e.g., the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225], and any of the growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, pp 11-29); such inhibitors also include tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (Geffi)). tinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI1033), erbB2 tyrosine kinase inhibitors, e.g. lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; blood Inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., Ras / Raf signaling inhibitors, such as farnesyltransferase inhibitors, e.g., sorafenib (BAY43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell signaling through MEK and / or AKT kinases, c-kinases, t inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; Aurora kinase inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK4 inhibitors; Antiangiogenic drugs, such as those that inhibit the effects of vascular endothelial growth factor [e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin™) and, for example, VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-2-propanediol ( ... -6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 in WO 00 / 47212), compounds disclosed in WO 97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354 as well as compounds acting by other mechanisms (e.g. linomide, an inhibitor of integrin αvβ3 function and angiostatin); Vascular damaging agents, such as combretastatin A4 and compounds disclosed in WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213; endothelin receptor antagonists, such as zibotentan (ZD4054) or atrasentan; Antisense therapies, such as those directed to the targets listed above, e.g. ISIS2503, anti-ras antisense; gene therapy approaches, including approaches to replace abnormal genes, such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) approaches, such as those using cytosine deaminase, thymidine kinase or bacterial nitroreductase enzymes, and approaches to improve a patient's tolerance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; and Immunotherapeutic approaches including, for example, ex vivo and in vivo approaches to enhance the immunogenicity of patient tumor cells, e.g., transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony-stimulating factor, approaches to reduce T cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, and approaches using anti-idiotypic antibodies. may further include one or more of:

[0269] In certain embodiments, the combination therapy defined above may involve, in addition to the combination therapy of the present invention, conventional surgery or radiation therapy or chemotherapy.

[0270] Such conjoint treatment may be achieved by way of simultaneous, sequential or separate administration of the individual components of the treatment. Such combination products employ the combination therapy of this invention within the dosage ranges set forth above and the other pharmacologic active agent(s) within their approved dosage ranges.

[0271] According to this aspect of the invention there is provided a combination as defined previously for use in the treatment of cancer as defined herein, comprising a combination therapy of the invention as defined previously and another anti-tumour agent.

[0272] According to this aspect of the invention there is provided a combination for use in the treatment of cancer as defined herein comprising the combination therapy of the invention as previously defined and any one of the anti-tumour agents listed herein above.

[0273] In a further aspect of the invention there is provided a combination product of the invention for use in the treatment of cancer, optionally in combination with another anti-tumour drug, selected from those listed herein above.

[0274] In a particular embodiment, the present invention provides a combination of a METTL3 inhibitor and a BCL2 inhibitor as defined above for use in the treatment of acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) or myelodysplastic syndrome (MDS), wherein the METTL3 inhibitor and the BCL2 inhibitor are administered in combination with an additional anti-tumor drug.

[0275] In a further aspect, the present invention provides a combination of STM3480 and venetoclax for use in the treatment of acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) or myelodysplastic syndromes (MDS), wherein STM3480 and venetoclax are administered in combination with another anti-tumor agent.

[0276] Suitably, the additional anti-tumour agent is selected from agents that are standard of care for treating AML, CLL, SLL or MDS. In particular, the additional anti-tumour agent is (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutically acceptable salt thereof may be selected from:

[0277] More particularly, the additional antitumor agent may be selected from daunorubicin, doxorubicin, epirubicin, idarubicin, 5-azacytidine, decitabine, sorafenib, lestaurtinib, midostaurin, quizartinib, crenolanib, gilteritinib or cytarabine. Suitably, the combination is for treating AML, CLL or SLL, particularly AML.

[0278] In one particular embodiment, the present invention provides a combination of STM3480 and venetoclax for use in the treatment of acute myeloid leukemia (AML), wherein STM3480 and venetoclax are administered in combination with another anti-tumor agent. Suitably, the additional anti-tumor agent is selected from agents that are standard of care for treating AML. In particular, the additional anti-tumor agent is (i) anthracycline topoisomerase 2 inhibitors (e.g., daunorubicin); (ii) cytarabine; (iii) a hypomethylating agent (e.g., 5-azacytidine or decitabine); or (iv) FLT3 inhibitors (e.g., quizartinib) or a pharma- ceutically acceptable salt thereof More particularly, the additional antitumor agent may be selected from daunorubicin, doxorubicin, epirubicin, idarubicin, 5-azacytidine, decitabine, sorafenib, lestaurtinib, midostaurin, quizartinib, crenolanib, gilteritinib or cytarabine. Suitably, the combination is for treating AML, CLL or SLL, particularly AML. EXAMPLES

[0279] <Preparation of Compounds STM3480, STM3675, and STM3006> The following abbreviations are used: AIBN - Azobisisobutyronitrile DBU-1,8-diazabicyclo[5.4.0]undec-7-ene DCE - Dichloroethane DCM - Dichloromethane DIBAL - Diisobutylaluminum hydride DIPEA-N-ethyl-N-isopropyl-propan-2-amine DMAP-4-Dimethylaminopyridine DMF - Dimethylformamide DMSO - Dimethyl sulfoxide DPPA-Diphenylphosphoryl azide HATU-[Dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium;Hexafluorophosphate HPLC - High Performance Liquid Chromatography IPA - Isopropanol LCMS - Liquid Chromatography Mass Spectrometry NBS-N-Bromosuccinimide NMP-N-Methyl-2-pyrrolidone Phase Separation Cartridges - Telos Phase Separator 6mL RBF - Round bottom flask RM-Reaction Mixture RT-retention time STAB-Sodium triacetoxyborohydride T3P-Propylphosphonic anhydride TBAF-Tetra-n-butylammonium fluoride TEA - Triethylamine TFA - Trifluoroacetic acid TFAA-Trifluoroacetic anhydride THF - Tetrahydrofuran

[0280] The following methodology was used in the examples. LCMS method A refers to a low pH analysis using a mobile phase consisting of 0.1% formic acid in a gradient of 5-100% MeCN in water over 1.2 min at a flow rate of 1.2 mL / min. The stationary phase consisted of Kinetex Core-Shell C18, 2.1 mm x 50 mm, 5 μm. Experiments were performed at 40 °C.

[0281] LCMS method B refers to a high pH analysis using a mobile phase consisting of 2 mM ammonium bicarbonate buffered to pH 10 in a gradient of 5 to 100% MeCN in water over 2.1 min at a flow rate of 1.0 mL / min. The stationary phase consisted of Phenomenex Gemini-NX C18, 2.0 × 50 mm, 3 μm. Experiments were performed at 40 °C.

[0282] LCMS method C refers to high pH analysis using a mobile phase consisting of 2 mM ammonium bicarbonate buffered to pH 10 in a gradient of 5 - 100% MeCN in water over 5.8 minutes at a flow rate of 0.6 mL / min. The stationary phase consisted of Waters UPLC® BEH C18, 2.1×100 mm, 1.7 μm. The experiment was carried out at 40 °C.

[0283] Intermediate 1: 4 - Oxopyrido[1,2 - a]pyrimidine - 2 - carboxylic acid

[0284]

Chem.

[0285] <Preparation of STM3480 - N - [(2 - {[(cyclobutylmethyl)amino]methyl}-1H - indol - 6 - yl)methyl]-4 - oxo - 4H - pyrido[1,2 - a]pyrimidine - 2 - carboxamide>

[0286]

Chem.

[0287]

Chem.

[0288] Step 2: 2-(diethoxymethyl)-1H-indole-6-carbonitrile

[0289] [ka] To a stirred solution of 3-amino-4-(3,3-diethoxyprop-1-ynyl)benzonitrile (8.00 g, 31.1 mmol) in NMP (99 mL) at 0° C. was added potassium tert-butoxide (6.98 g, 62.2 mmol) (the color of the solution changed from orange to dark red). After warming to RT, the solution was stirred at ambient temperature for 16 h. Saturated aqueous ammonium chloride (25 mL) was added and the resulting mixture was partitioned between EtOAc (250 mL) and water (250 mL). The layers were separated and the organic layer was washed two more times with water (2×200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown oil. The first aqueous layer was re-extracted with EtOAc (200 mL) and the layers were separated. The organic layer was washed two times with water (2×200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give an orange oil. The crude material was purified by chromatography on SiO2 [BIOTAGE KP-Sil 100 g, eluting with 0-50% EtOAc in heptane]. The product-containing fractions were combined and concentrated in vacuo. The residue (yellow solid) was recrystallized from EtOAc / heptane to give the title compound (5.86 g, 24.0 mmol, 77%) as a colorless crystalline solid. Method B: LC-MS (electrospray): m / z=262.3 (M+H) + , RT=1.69 minutes.

[0290] Step 3: [2-(diethoxymethyl)-1H-indol-6-yl]methanamine

[0291] [ka] To a degassed solution of 2-(diethoxymethyl)-1H-indole-6-carbonitrile (5.8 g, 24 mmol) in ethanol (70 mL) was added ammonia in MeOH (7 M, 20 mL, 0.14 mmol) and the reaction was degassed and backfilled with nitrogen three times. Raney Nickel (assumed 50%, ca. 5.4 g, 0.1 mmol) was added and the reaction was evacuated and backfilled with nitrogen three times. The flask was evacuated one last time, placed under a hydrogen atmosphere and stirred at ambient temperature for 3 h. Further Raney Nickel (ca. 2.7 g) was added and the reaction was evacuated, placed under a hydrogen atmosphere and stirred at ambient temperature for 16 h. The catalyst was removed by filtration (through diatomaceous earth) and washed with methanol (50 mL). The filtrate was concentrated under reduced pressure to give the title compound (5.96 g, 100%) as a colorless oil that crystallized on standing. Method C: LC-MS (electrospray): m / z = 247.3 (MH) - , RT = 2.74 minutes.

[0292] Step 4: N-[(2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[0293] [ka] To a stirred solution of 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (455 mg, 2.39 mmol) (Intermediate 1) and DIPEA (1.0 mL, 5.98 mmol) in DMF (10 mL) was added HATU (910 mg, 2.39 mmol). A color change from colorless to green was observed and a suspension formed. After stirring at ambient temperature for an additional 30 min, a solution of [2-(diethoxymethyl)-1H-indol-6-yl]methanamine (500 mg, 1.99 mmol) in DMF (5 mL) was added dropwise to the reaction. A color change from green to red was observed and the reaction became homogenous and was stirred at ambient temperature overnight.

[0294] The mixture was partitioned between EtOAc (100 mL) and saturated NaHCO3 solution (50 mL). The organic layer was separated, washed with water (80 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give a viscous red oil.

[0295] The crude product was dissolved in THF (10 mL), water (1 mL) and acetic acid (0.5 mL) were added and the mixture was stirred at ambient temperature for 2 h.

[0296] The THF was removed in vacuo and water (10 mL) was added to the resulting mixture to precipitate more solid. The brown solid was collected by washing with water (2×5 mL) then ether (3×5 mL) and dried under vacuum to give the title compound (520 mg, 75%) as a brown solid. Method C: LC-MS (electrospray): m / z = 347.2 (M+H) + , RT = 2.37 minutes.

[0297] Step 5: N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[0298] [ka] A pressure vial was charged with N-[(2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide (185 mg, 0.53 mmol), DCE (5 mL) and 1-cyclobutylmethanamine (0.13 mL, 1.0 mmol) at ambient temperature. The vial was sealed and the mixture was stirred at 65° C. for 2 h. After cooling to RT, sodium triacetoxyborohydride (340 mg, 1.85 mmol) was added and the mixture was heated to 65° C. for 2 h.

[0299] The mixture was partitioned between EtOAc (40 mL) and saturated sodium bicarbonate solution (30 mL). The organic layer was separated, washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue (pale yellow oil) was purified by reverse-phase chromatography (basic method, SNAP ULTRA 30 g cartridge, MeCN + 0.1% NH3 / H2O + 0.1% NH3, eluting with 10 - 90%). Freeze-drying the fractions containing the desired product overnight gave the title compound (85 mg, 38%) as an off-white solid. Method C: LC-MS (electrospray): m / z = 416.4 (M+H) + , RT = 3.14 min.

[0300] <Preparation of STM3675 - N-[(2-{[({3-Fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide>

[0301]

Chemical Structure

[0302] <Preparation of STM3006 - (6-Bromo-4-[1-({6-[(4,4-Dimethylpiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl}methyl)-1H-1,2,3-triazol-4-yl]-1H-indazole)>

[0303]

Chemical Structure

[0304] [Example 1: Combination of METTL3 inhibitor (STM3480) and immune checkpoint inhibitor] <Tumor Killing Assay (TKA)> This experiment evaluates the efficacy of human donor peripheral blood mononuclear cells (PBMCs) to attack and kill fluorescently labeled tumor cells in a co-culture assay. Briefly, test agents are incubated at various concentrations with SKOV3 human ovarian cancer cells in the presence or absence of human donor PBMCs, and tumor growth is continuously monitored by real-time imaging of NucLight Red-labeled SKOV3 cells over several days.

[0305] <Tumor killing assay> Upon transfer of NucLight Red (Incucyte, Essen Biosciences) transfected SK-OV-3 (SK-OV-3-NLR) cells into ultra-low attachment surface 96-well plates, spontaneous spheroid formation occurred over a 48-hour period. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy single-donor buffy coats by density separation. Prior to co-culture of SK-OV-3-NLR spheroids with PBMCs, SK-OV-3-NLR spheroids were treated with 10ng / ml interferon gamma (IFNγ). All treatments, including STM3480 and pembrolizumab, were added at the time of co-culture in a final total volume of 200μl / well. The assay plate was transferred to an IncuCyte S3 and images were collected every 2 hours over a 7-day period. Following completion of the experiment, analysis definitions were applied to quantify the total NLR integrated intensity present on a per well basis. Changes in spheroid size were quantified by plotting the total NLR integrated intensity against time.

[0306] [Table 1]

[0307] <Result> Figure 1 shows the change in tumor viability (normalized NucLight Red [NLR] fluorescence on the y-axis) over time (hours on the x-axis). Vehicle-treated cells (filled black squares) show a steady but moderate decrease in fluorescence intensity over time. Pembrolizumab (anti-PD1 antibody)-treated cells (filled grey circles) show a greater decrease in viable tumor cells at the end of the study. 0.05 micromolar STM3480 treatment (open triangles) produced a greater antitumor effect compared to vehicle, with the combination of STM3480 and pembrolizumab (open circles) giving the greatest decrease in tumor cell viability, beyond the effects seen with the individual agents.

[0308] Similarly, treatment of SKOV3 / PBMC co-cultures with STM3480 and / or avelumab (anti-PD-L1 antibody; open circles) resulted in maximal anti-tumor activity that was greater than that seen with either single agent alone (grey circles, open triangles), demonstrating the surprising beneficial effect of this combination treatment (see Figure 2).

[0309] Example 2: Combination of METTL3 inhibitor (STM3480) and immune checkpoint inhibitor - in vivo study The in vivo effect of METTL3 inhibition in combination with anti-PD1 immune checkpoint inhibitors was investigated using syngeneic mouse tumor models in immune-competent hosts. Mouse tumor models were grown in appropriate host strains and widely used to investigate the effect of therapeutics on the immune system and cancer growth. A limited range of mouse syngeneic tumor models are available, far fewer than human cell lines, and these are widely used in the art to support the potential clinical utility of immune stimulatory approaches across multiple indications. We illustrate the potential role of STM3480 and its combination with immune checkpoint inhibitors such as anti-PD-1 antibodies in multiple tumor models, including A20 (mouse B-cell lymphoma), EMT-6 (mouse breast cancer) and CT-26 (mouse colorectal cancer).

[0310] 1.A20 Lymphoma Model <Protocol> The objective of this study was to evaluate the antitumor efficacy of STM3480 in combination with anti-PD1 in a subcutaneous A20 murine B-cell lymphoma cancer model in female BALB / c mice.

[0311] A20 (number ATCC TIB-208) mouse B cell lymphoma cells were cultured in (RPMI-1640 + 10% non-HIFBS + 0.05 mM 2-mercaptoethanol) medium. 5 × 10 5 Live cells were injected subcutaneously into the left flank of 7-9 week-old female BALB / cN (BALB / cAnNCrl)Crl mice using a 27-gauge needle after skin disinfection with 70% ethanol.

[0312] Tumors were measured three times per week and the mean tumor size was calculated by measuring the tumor in two dimensions using electronic calipers for the duration of the study, using the formula 0.5(L × W 2 ) was used to estimate tumor volume.

[0313] Mice were randomly assigned to four treatment groups and tumors were grown to a mean volume of approximately 50–100 mm 3 Treatment was initiated when tumor volume reached 100 μg / kg / day. Mice were assigned to treatment groups with uniform mean tumor volumes between groups. Treatment continued for up to 3 weeks or until individual mice were sacrificed for humane reasons per headquarters license regulations (e.g., weight loss >20%; tumor volume >1500 mm3; tumor ulceration; loss of clinical pathology). The final dose was administered on day 32 after implantation.

[0314] <Preparation> Vehicle for STM3480 - Hydroxypropyl-β-cyclodextrin (HPBCD) / Sodium acetate buffer pH 4.6 50 mM (10% / 90%; w / v): Weigh out 1.025 g anhydrous sodium acetate. Add 700 μl glacial acetic acid, then make up to 500.0 ml with ultrapure water. pH 4.6 50 mM.

[0315] For a 1 ml volume of 5 mg / ml STM3480 dosing solution: Weigh out 5.0 mg of STM00003480 compound (Batch: EV-WZM001-421-002). Add 1.0 mL of HPBCD / Acetate buffer pH 4.6 50 mM (10% / 90%; w / v). Magnetically stir at high speed at ambient temperature. If there is any sign of precipitation, overnight stirring may be required. The formulation is a slightly yellow solution with very few particles suspended. Homogenize by vortexing before dosing.

[0316] For PD-1 treatment, mouse specific anti-PD1 antibodies (clone ID RMP1-14) were used, dissolved in PBS, as described in the table below.

[0317] [Table 2]

[0318] Animal welfare for this study complied with the UK Scientific Procedures in Animals Act 1986 (ASPA), in line with Directive 2010 / 63 / EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes.

[0319] <Data> Vehicle treatment (solid black line, top left panel) shows progressive tumor growth in 9 / 10 animals. STM3480 treatment (dashed grey line, top right panel) shows progressive tumor growth in 8 / 10 animals. Anti-PD1 treatment (dotted black line, bottom left panel) shows progressive tumor growth in 8 / 10 animals. The combination of STM3480 and anti-PD1 (dashed black line, bottom right panel) shows progressive tumor growth in 2 / 10 animals, tumor regression in 8 / 10 animals, and complete tumor regression in 6 / 10 animals.

[0320] Animals treated with the combination of STM3480 and anti-PD1 antibody showed complete tumor regression (i.e., no measurable tumor remaining) in the majority of treated animals. 6 / 10 animals remained tumor-free for 29 days after treatment was stopped, indicating that all of these animals were cured.

[0321] <Result> See Table 5 below and Figure 3 [A20 B cell lymphoma in vivo model (mean tumor volume)], Figure 4 [A20 B cell lymphoma in vivo model (individual tumor curves)] and Figure 5 [A20 B cell lymphoma in vivo model (survival)].

[0322] 2.EMT6 Breast Cancer Model <Protocol> The objective of this study was to evaluate the antitumor efficacy of STM3480 in combination with anti-PD1 in the subcutaneous EMT6 murine breast cancer model in female BALB / c mice.

[0323] EMT6 (ATCC CRL-2755) mouse breast cancer cells were cultured in (Waymouse MB752 / 1 medium containing 2 mM L-glutamine, 85%; fetal bovine serum (non-heat inactivated), 15%) at 5 × 10 4 Live cells were injected subcutaneously into the left flank of 8-9 week-old female BALB / cN (BALB / cAnNCrl)Crl mice using a 27-gauge needle after skin disinfection with 70% ethanol.

[0324] Tumors were measured three times per week and the mean tumor size was calculated by measuring the tumor in two dimensions using electronic calipers for the duration of the study, using the formula 0.5(L × W 2 ) was used to estimate tumor volume.

[0325] Mice were randomly assigned to four treatment groups and tumors were grown to a mean volume of approximately 50–100 mm 3 Treatment was initiated when tumor volume reached 100 μg / kg / day. Mice were assigned to treatment groups with uniform mean tumor volumes between groups. Treatment continued for up to 3 weeks or until individual mice were sacrificed for humane reasons per headquarters license regulations (e.g., weight loss >20%; tumor volume >1500 mm3; tumor ulceration; loss of clinical pathology). The final dose was administered on day 32 after implantation.

[0326] [Table 3]

[0327] Animal welfare for this study complied with the UK Scientific Procedures in Animals Act 1986 (ASPA), in line with Directive 2010 / 63 / EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes.

[0328] <Result> Please see Table 5 below.

[0329] 3.CT26 Colorectal Cancer Model <Protocol> The objective of this study was to evaluate the antitumor efficacy of STM3480 in combination with anti-PD1 in the subcutaneous CT26 murine colorectal cancer model in female BALB / c mice.

[0330] CT26.WT (CRL-2638) mouse breast cancer cells were cultured in (RPMI-1640 + 10% FBS + 2 mM L-glutamine) medium. 1 × 10 5 Live cells were injected subcutaneously into the left flank of 8-9 week-old female BALB / cN (BALB / cAnNCrl)Crl mice using a 27-gauge needle after skin disinfection with 70% ethanol.

[0331] Tumors were measured three times per week and the mean tumor size was calculated by measuring the tumor in two dimensions using electronic calipers for the duration of the study, using the formula 0.5(L × W 2 ) was used to estimate tumor volume.

[0332] Mice were randomly assigned to four treatment groups and tumors were grown to a mean volume of approximately 50–100 mm 3 Treatment was initiated when tumor volume reached 100 μg / kg / day. Mice were assigned to treatment groups with uniform mean tumor volumes between groups. Treatment continued for up to 3 weeks or until individual mice were sacrificed for humane reasons per headquarters license regulations (e.g., weight loss >20%; tumor volume >1500 mm3; tumor ulceration; loss of clinical pathology). The final dose was administered on day 32 after implantation.

[0333] [Table 4]

[0334] Animal welfare for this study complied with the UK Scientific Procedures in Animals Act 1986 (ASPA), in line with Directive 2010 / 63 / EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes.

[0335] <Result> Please see Table 5 below.

[0336] [Table 5]

[0337] The combination of STM3480 and an anti-PD-1 antibody was highly effective in multiple in vivo syngeneic cancer models from a variety of cancer indications (Table). In each case, combination treatment caused the greatest number of tumor regressions compared to the single agents, and in two models (A20 and EMT6), these regressions were complete, with no tumors detectable after treatment, indicating a significant anti-tumor response.

[0338] [Example 3: Combination of METTL3 inhibitors (STM3480 / STM3006 / STM3675) and venetoclax] The sensitivity of AML cell lines to the combination of METTL3 inhibitors and standard of care was determined as described. Dose-response curves for venetoclax were determined alone or in the presence of different concentrations of METTL3 inhibitors known to be active in cells.

[0339] A synergistic interaction occurs when the IC50 value is decreased in the presence of a METTL3 inhibitor. An additive interaction occurs when the IC50 value is unchanged in the presence of a METTL3 inhibitor. An antagonistic interaction occurs when the IC50 value is increased in the presence of a METTL3 inhibitor.

[0340] <Result> Please refer to Figures 6 to 11.

[0341] Figure 6 - STM3480 demonstrates synergistic interaction with venetoclax in the Kasmi1 AML cell line, with increasing concentrations of STM3480 resulting in decreasing IC50 of venetoclax as shown in the table below.

[0342] In Figure 6, the IC50 of venetoclax in Kasumi1 cells was 238.5 nM. In the presence of 316.2 nM STM3480, the venetoclax IC50 was reduced to 50.93 nM, and in the presence of 1000 nM STM3480, the venetoclax IC50 was further reduced to 22.23 nM. This increased potency indicates a synergistic interaction.

[0343] The same synergistic interactions and reduced IC50 values ​​were observed in the Kasumi1 cell line with additional METTL3 inhibitors, as well as in other AML cell lines (see Figures 7-11).

[0344] Figure 7 - STM3480 demonstrates synergistic interaction with venetoclax in MOLM13 AML cell lines, with increasing concentrations of STM3480 resulting in decreasing IC50 of venetoclax as shown in the table below.

[0345] Figure 8 - STM3006 demonstrates synergistic interaction with venetoclax in the Kasumi1 AML cell line, with increasing concentrations of STM3006 resulting in a decreasing IC50 of venetoclax as shown in the table below.

[0346] Figure 9 - STM3006 demonstrates synergistic interaction with venetoclax in MOLM13 AML cell lines, with increasing concentrations of STM3006 resulting in decreasing IC50 of venetoclax as shown in the table below.

[0347] Figure 10 - STM3675 demonstrates synergistic interaction with venetoclax in the Kasumi1 AML cell line, with increasing concentrations of STM3675 resulting in a decreasing IC50 of venetoclax as shown in the table below.

[0348] Figure 11 - STM3675 demonstrates synergistic interaction with venetoclax in MOLM13 AML cell lines, with increasing concentrations of STM3675 resulting in decreasing IC50 of venetoclax as shown in the table below.

[0349] [Example 4: Combination with other standard AML treatments] <Material> - RPMI 1640 medium, glutamine free (Gibco number 31870-025) - Fetal bovine serum (Sigma F7524-500ML) - GlutaMAX™ supplement (Gibco number 35050038) - Sodium pyruvate (100 mM) (Gibco number 11360039) - DMSO (Sigma number D2650) - 1x DPBS (Gibco number 14190-094) - IFN gamma (R / D Systems, reference number 285-IF) (200 μg / ml) - Cell culture 384-well plate SBIO Ultra-Low Attachment Surface (SBio, MS-9384WZ) - Grip Tips Viaflo 384, sterile (Integra 6464) - CellTiter-Glo Luminescent Cell Viability Assay (Promega #G7571) - T8+ Dispense Head Cassette HP (Fisher number 15429293) - D4+ Dispense Head Cassette HP (Fisher number 15577409)

[0350] [Table 6]

[0351] [Table 7]

[0352] A. Cell preparation 24 hours prior to cell treatment, cells are homogenized, stained with trypan blue and viable cells are counted using a CellOMeter Auto T4. The next day, cells are diluted to 400,000 cells / ml in culture medium to ensure exponential growth.

[0353] On the day of treatment, homogenize, stain with trypan blue, and count viable cells using a CellOMeter Auto T4. Dilute to appropriate cell seeding density according to Table 6 in cell culture medium.

[0354] B. Cell Treatment - Drugs (see Table 7) and METTL3 inhibitors are dispensed in semi-log dose-response matrix and DMSO in 384-well plates using a D300e nanodispenser (Tecan). - 6x compound solution preparation: add 40 μL of cell media to compound-containing plates and homogenize using a ViaFlo device (Integra). - Using a ViaFlow device (Integra), dispense 30 μl of cell suspension per well into triplicate 384-well white ultra-low attachment surface plates (Sbio). - Transfer 6 μL of 6× compound solution to each 30 μL cell suspension containing plate. - Incubate at 37°C, 5% CO2 for 3-5 days.

[0355] C. Cell Titer Glo Assay - Using a ViaFlo device (Integra), add 35 μL of CellTiter-Glo (Promega) to the wells (vol / vol). - Incubate for 10 min at RT in the dark with stirring for the first minute and read luminescence on an Ensight device (Perkin Elmer).

[0356] D. Data Analysis Raw data was converted to % viability by normalization to DMSO control. IC50 determinations were performed using GraphPad Prism by fitting curves to a standard nonlinear regression 4-parameter equation (Y=min+(max-min) / (1+(IC50 / X)^Hill slope)) least squares method, and synergy was assessed by comparison of IC50 values ​​of standard treatment in the presence or absence of different concentrations of METTL3 inhibitors (see Figures 12-19).

[0357] 1. Daunorubicin (anthracycline topoisomerase 2 inhibitor) Daunorubicin is a major component of the standard of care for treating AML.

[0358] Additive interactions occur when the combination results in increased loss of tumor cell viability with the addition of a METTL3 inhibitor, but the IC50 value remains unchanged.

[0359] <Result> Figure 12 - STM3480 demonstrates an additive interaction with daunorubicin in the Kasumi1 AML cell line, with increasing concentrations of STM3480 resulting in decreased viability. No change in the IC50 of daunorubicin was observed, indicating an additive interaction.

[0360] In Figure 12, the addition of STM3480 results in a dose-dependent decrease in Kasumi1 cell viability. In the presence of 400 nM or 1265 nM STM3480, the daunorubicin IC50 did not change significantly, indicating an additive interaction.

[0361] The same additive interaction was observed in the Kasumi1 cell line with the additional METTL3 inhibitor STM3006 (see FIG. 13).

[0362] Figure 13 - STM3006 demonstrates an additive interaction with daunorubicin in the Kasumi1 AML cell line, with increasing concentrations of STM3006 resulting in decreased viability. No change in the IC50 of daunorubicin was observed, indicating an additive interaction.

[0363] 2. Cytarabine (nucleoside analogue) Cytarabine is a major component of the standard of care for treating AML.

[0364] <Result> Figure 14 - STM3480 demonstrates an additive interaction with cytarabine in the Kasumi1 AML cell line, with increasing concentrations of STM3480 resulting in decreased viability. No change in the IC50 of cytarabine was observed, indicating an additive interaction.

[0365] Figure 15 - STM3006 demonstrates an additive interaction with cytarabine in the Kasumi1 AML cell line, with increasing concentrations of STM3006 resulting in decreased viability. No change in the IC50 of cytarabine was observed, indicating an additive interaction.

[0366] 3. 5'-Azacytidine (hypomethylating agent) <Result> Figure 16 - STM3480 demonstrates an additive interaction with 5'-azacytidine in the Kasumi1 AML cell line, with increasing concentrations of STM3480 resulting in decreased viability. No change in the IC50 of 5'-azacytidine was observed, indicating an additive interaction.

[0367] Figure 17 - STM3006 demonstrates an additive interaction with 5'-azacytidine in the Kasumi1 AML cell line, with increasing concentrations of STM3006 resulting in decreased viability. No change in the IC50 of 5'-azacytidine was observed, indicating an additive interaction.

[0368] 4. Quizartinib (FLT3 inhibitor) MOLM-14 cells harbor a FLT3 mutation and are known to be highly dependent on FLT3 activity for survival, and are highly sensitive to FLT3 inhibitors such as quizartinib.

[0369] <Result> Figure 18 - STM3480 demonstrates an additive interaction with Quizartinib in FLT3-mutated MOLM-14 AML cell lines, with increasing concentrations of STM3480 resulting in decreased viability. No change in the IC50 of Quizartinib was observed, indicating an additive interaction.

[0370] Figure 19 - STM3006 demonstrates an additive interaction with Quizartinib in FLT3-mutated MOLM-14 AML cell lines, with increasing concentrations of STM3006 resulting in decreased viability. No change in the IC50 of Quizartinib was observed, indicating an additive interaction.

[0371] All references cited in this specification, including publications, patent applications, and patents, are incorporated herein by reference in their entirety to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was fully set forth herein (to the maximum extent permitted by law).

[0372] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0373] The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to better illustrate the invention and does not pose limitations on the scope of the invention unless specifically stated. No language in the specification should be construed as indicating any unspecified element as essential to the practice of the invention.

[0374] The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability, and / or enforceability of such patent documents.

[0375] This invention includes all modifications and equivalents of the subject matter specifically recited herein as permitted by applicable law.

Claims

1. A METTL3 inhibitor or a pharma- ceutically acceptable salt thereof, and: (i) an Immuno-Cancer agent or therapy; (ii) a BCL2 inhibitor or a pharma- ceutically acceptable salt thereof; (iii) an anthracycline topoisomerase 2 inhibitor or a pharma- ceutically acceptable salt thereof; (iv) cytarabine or a pharma- ceutically acceptable salt thereof; (v) a hypomethylating agent or a pharma- ceutically acceptable salt thereof; or (vi) an FLT3 inhibitor or a pharma- ceutically acceptable salt thereof; A combination including:

2. 2. The combination of claim 1, wherein the cancer immunotherapy or therapy is selected from the group consisting of immune checkpoint inhibitors (e.g., PD1, PD-L1 inhibitors, LAG3, CTLA-4, TIGIT, TIM3 or VISTA inhibitors), STING agonists, TLR agonists, anti-CD137 antibodies, CD28 antibodies, OX40 stimulants, CD40 antibodies, ICOS agonists, GITR agonists, A2AR antagonists, bispecific T-cell engagers (BiTEs), oncolytic viruses, cancer vaccines, and / or CAR-T cell therapies.

3. 2. The combination of claim 1, wherein said cancer immunotherapy or therapy is treatment with an immune checkpoint inhibitor or a pharma- ceutical acceptable salt thereof.

4. 3. The combination of claim 2, wherein the immune checkpoint inhibitor is selected from a PD1, a PD-L1 inhibitor, a LAG3 inhibitor and a CTLA-4 inhibitor.

5. 3. The combination of claim 2, wherein said immune checkpoint inhibitor is selected from a PD1 or PD-L1 inhibitor.

6. 3. The combination of claim 2, wherein the immune checkpoint inhibitor is selected from BMS-986016 / leratolimab, TSR-033, REGN3767, MGD013 (a bispecific DART that binds PD-1 and LAG-3), GSK2831781, LAG525, MDX-010 / ipilimumab, AGEN1884 and CP-675,206 / tremelimumab, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, or a pharmaceutically acceptable salt thereof.

7. 7. The combination of claim 6, wherein the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, or a pharmaceutically acceptable salt thereof.

8. 2. The combination of claim 1, wherein the BCL2 inhibitor is venetoclax or a pharma- ceutically acceptable salt thereof.

9. the anthracycline topoisomerase 2 inhibitor is selected from daunorubicin, doxorubicin, epirubicin, or idarubicin, or a pharma- ceutically acceptable salt thereof; the hypomethylating agent is selected from 5-azacytidine or decitabine, or a pharma- ceutically acceptable salt thereof; The FLT3 inhibitor is selected from sorafenib, lestaurtinib, midostaurin, quizartinib, crenolanib or gilteritinib, or a pharmaceutically acceptable salt thereof; The combination according to claim 1.

10. 2. The combination of claim 1, wherein the METTL3 inhibitor is a compound of formula I, II, VI or VII as defined herein, or a pharma- ceutically acceptable salt thereof.

11. 2. The combination of claim 1, wherein the METTL3 inhibitor is selected from STM3480, STM3675 or STM3006, or a pharma- ceutically acceptable salt thereof.

12. A pharmaceutical comprising a combination according to any one of claims 1 to 11.

13. A pharmaceutical composition comprising a combination according to any one of claims 1 to 11 and one or more pharma- ceutically acceptable excipients.

14. (i) an immuno-oncology agent or therapy according to claim 1; (ii) the BCL2 inhibitor according to claim 1 or a pharma- ceutically acceptable salt thereof; (iii) the anthracycline topoisomerase 2 inhibitor according to claim 1 or a pharma- ceutically acceptable salt thereof; (iv) cytarabine according to claim 1 or a pharma- ceutically acceptable salt thereof; (v) the hypomethylating agent according to claim 1 or a pharma- ceutically acceptable salt thereof; or (vi) The FLT3 inhibitor according to claim 1 or a pharma- ceutically acceptable salt thereof.

23. A pharmaceutical composition comprising a METTL3 inhibitor or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer, administered in combination with

15. 15. A pharmaceutical composition comprising a METTL3 inhibitor or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer according to claim 14, administered in combination with an immune checkpoint inhibitor.

16. A pharmaceutical composition comprising a METTL3 inhibitor, or a pharma- ceutical acceptable salt thereof, for use in the treatment of a solid tumor, administered in combination with an immune checkpoint inhibitor.

17. 17. A pharmaceutical composition comprising a METTL3 inhibitor or a pharma- ceutical acceptable salt thereof for use in the treatment of cancer according to claim 15 or for use in the treatment of a solid tumor according to claim 16, administered in combination with an immune checkpoint inhibitor or a pharma- ceutical acceptable salt thereof as defined in any one of claims 4 to 7, selected from STM3480, STM3675 or STM3006, or a pharma- ceutical acceptable salt thereof.

18. 15. A pharmaceutical composition comprising a METTL3 inhibitor, or a pharma- ceutical acceptable salt thereof, for use in the treatment of cancer according to claim 14, administered in combination with a BCL2 inhibitor, or a pharma- ceutical acceptable salt thereof, according to claim 1 or claim 8.

19. 19. A pharmaceutical composition comprising a METTL3 inhibitor or a pharma- ceutical acceptable salt thereof selected from STM3480, STM3675 or STM3006, or a pharma- ceutical acceptable salt thereof, administered in combination with venetoclax or a pharma- ceutical acceptable salt thereof, for use in the treatment of cancer according to claim 18.

20. A pharmaceutical composition comprising STM3480, or a pharma- ceutical acceptable salt thereof, administered in combination with venetoclax, or a pharma- ceutical acceptable salt thereof, for use in the treatment of acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or myelodysplastic syndromes (MDS).

21. A pharmaceutical composition comprising STM3480, or a pharma- ceutical acceptable salt thereof, administered in combination with venetoclax, or a pharma- ceutical acceptable salt thereof, for use in the treatment of acute myeloid leukemia (AML).

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