Combination therapy with macrocyclic indazole compounds

Abstract

This disclosure relates to methods and compositions for treating cancer by combining a macrocyclic indazole compound with at least one other cancer therapeutic agent, such as a Bcl-2 inhibitor, FLT3 inhibitor, KRAS inhibitor, ALK inhibitor, PARP inhibitor, chemotherapy, or EGFR inhibitor.

Description

Reference to related applications

[0001] This application claims the interests of U.S. Provisional Application No. 63 / 510,056 filed June 23, 2023, U.S. Provisional Application No. 63 / 588,518 filed October 6, 2023, U.S. Provisional Application No. 63 / 575,674 filed April 6, 2024, and U.S. Provisional Application No. 63 / 659,580 filed June 13, 2024, all of which are incorporated herein by reference. [Technical Field]

[0002] This disclosure relates to methods and compositions for treating cancer by combining a macrocyclic indazole compound with at least one other cancer therapeutic agent, such as a Bcl-2 inhibitor, FLT3 inhibitor, KRAS inhibitor, ALK inhibitor, PARP inhibitor, chemotherapy, and EGFR inhibitor. [Background technology]

[0003] Protein kinases are tightly controlled signaling proteins that regulate the activation of signaling cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli. The human genome encodes approximately 518 protein kinases (Manning G, et al. The protein kinase complement of the human genome. Science. 2002, 298:1912-34). Dysregulation of kinase activity is associated with a variety of diseases, including cancer, cardiovascular disease, degenerative diseases, immune diseases, infectious diseases, inflammatory diseases, and metabolic diseases (Levitzki, A. Protein kinase inhibitors as a therapeutic modality. Acc. Chem. Res. 2003, 36:462-469). Molecular mechanisms that lead to various diseases include gain-of-function and loss-of-function mutations in kinases, gene amplification and deletion, splicing changes and translocations (Wilson LJ, et al New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome. Cancer Res. 2018, 78:15-29). Due to the important role of kinases in cancer and other diseases, kinases are attractive targets for pharmaceutical inventions, and 62 small molecule kinase inhibitors have been approved, 55 of which are cancer-targeted therapies (Roskoski R Jr, Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2021 Update. Pharmacol Res 2021, 165:105463). While kinase inhibitors have achieved dramatic success in cancer-targeted therapy, the development of treatment resistance remains a challenge for small molecule kinase inhibitors.When secondary mutations are acquired within the kinase domain during treatment, therapeutic resistance to kinase inhibitors often develops (Pottier C, et al. Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy. Cancers (Basel), 2020, 12:731). Resistance can also arise from subpopulations of resistant / persistent cells that survive even in the presence of therapeutic agents. The emergence of resistant / persistent cells involves various processes, including pathway rebound due to the disengagement of negative feedback loops, transcriptional rearrangement through chromatin remodeling, and autocrine / paracrine communication between tumor cells and within the tumor microenvironment (Swayden M, et al. Tolerant / Persister Cancer Cells and the Path to Resistance to Targeted Therapy. Cells 2020, 9, 2601). Therefore, there is a need to invent kinase inhibitors that can target not only kinase carcinogenesis drivers that overcome the most frequent resistance mutations, but also resistant / persistent cancer cells that overcome resistance and achieve better efficacy and longer-term disease control. One of the aforementioned mechanisms can occur through alternative splicing. Cdc-like kinases (CLKs) are evolutionarily conserved bispecific kinases capable of phosphorylating serine, threonine, and tyrosine residues. CLKs catalyze the phosphorylation of SR proteins, i.e., serine / arginine-rich splicing factors 1-12 (SRSF1-12), and regulate the spliceosome molecular mechanism (Martin Moyano P, et al Cdc-Like Kinases (CLKs): Biology, Chemical Probes, and Therapeutic Potential. Int J Mol Sci 2020, 21(20):7549). Abnormalities in alternative splicing are characteristic of cancer.

[0004] Acute myeloid leukemia (AML) is an example of a cancer with a complex treatment and resistance profile. AML is a complex malignancy characterized by numerous cytogenetic or chromosomal abnormalities. The most frequently identified mutation in AML is FMS-like tyrosine kinase 3 (FLT3), with approximately 25% of adult patients having FLT3 internal tandem duplication (FLT3-ITD) and 7-10% having point mutations or deletions (Daver N, et al Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia 2019, 33:299-312). Switching of survival-promoting splice isoforms is characteristic of secondary AML leukemia stem cells (LSCs), and spliceosome modulators inhibit the maintenance of AML LSCs in humanized preclinical models (Crews LA et al; RNA splicing modulation selectively impairs leukemia stem cell maintenance in secondary human AML. Cell Stem Cell 2016, 19: 599-612). Two FLT3 inhibitors have been approved by the U.S. Food and Drug Administration (FDA) for AML: midostaurin in combination with standard induction and intensification chemotherapy for newly diagnosed FLT3-mutated AML, and gilteritinib monotherapy for relapsed or refractory FLT3-mutated AML. In addition to FLT3 inhibitors, other targets are needed for the treatment of AML. For example, venetoclax is approved by the FDA as a Bcl-2 inhibitor for use in AML, as well as chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). While significant progress has been made in the treatment of AML, leukemia relapse remains a major cause of treatment failure.

[0005] High-frequency mutations in SF3B1 or SRSF2 have been reported in patients with myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia, and acute myeloid leukemia (AML) (Papaemmanuil et al, Genomic classification and prognosis in acute myeloid leukemia). Mutations in splicing factor genes occur in more than 50% of MDS patients, with SF3B1, SRSF2, U2AF1, and ZRSR2 being the most frequently mutated splicing factor genes in MDS (Mian SA, et al Spliceosome mutations exhibit specific associations with epigenetic modifiers and proto-oncogenes mutated in myelodysplastic syndrome. Haematologica 2013, 98: 1058-1066). Thirteen percent of AML patients have splicing mutations that prevent them from receiving targeted therapies (Kantarjian H, et al, Acute myeloid leukemia: current progress and future directions. Blood Cancer J. 2921, 11:41). Furthermore, mutations in splicing-related genes are also present in various solid cancers (e.g., lung cancer, breast cancer, and pancreatic cancer) (Dvinge H, et al RNA splicing factors as oncoproteins and tumor suppressors. Nat Rev Cancer 2016, 16:413-430).

[0006] Upregulation of the survival-promoting proteins MCL-1 and BCL-XL due to TP53 mutations and FLT3-ITD proliferation leads to resistance to venetoclax treatment (Xu Y, et al Progress in understanding the mechanisms of resistance to BCL-2 inhibitors. Experimental Hematology & Oncology 2022, 11:31). Regulation of mRNA precursor splicing by inhibiting CLK kinase is an attractive antitumor strategy, particularly for cancers exhibiting abnormal mRNA precursor splicing.

[0007] In this technology field, there is a great medical need for satisfactory treatments for cancers with complex resistance mechanisms. One approach to overcome the nonresponsiveness exhibited by resistant cancers is the use of combination therapy. [Overview of the project]

[0008] (Summary of the invention) One approach to overcoming resistance mechanisms in cancer treatment caused by alternative splicing is to combine cancer drugs with compounds that can inhibit regulators of mRNA precursor splicing (e.g., CLK inhibitors).

[0009] It has been found that combining a CLK inhibitor with at least one anticancer drug elicits a potent response in cancers that exhibit alternative splicing as a resistance mechanism.

[0010] In one embodiment, the present disclosure provides a method for treating cancer in a host animal, the method comprising administering to the host animal a therapeutically effective dose of a CLK inhibitor in combination with a therapeutically effective dose of at least one additional anticancer agent. In some embodiments, the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor, or a pharmaceutically acceptable salt thereof.

[0011] In another aspect, the present disclosure provides a CLK inhibitor or a pharmaceutically acceptable salt thereof for use in treating cancer in a patient, in combination with a therapeutically effective amount of at least one additional anti-cancer agent. In some embodiments, the additional anti-cancer agent is a Bcl-2 inhibitor, an FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor or an EGFR inhibitor, or a pharmaceutically acceptable salt thereof.

[0012] In another aspect, the present disclosure provides the use of a CLK inhibitor or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product comprising a therapeutically effective amount of a CLK inhibitor for treating cancer in a patient, in combination with a therapeutically effective amount of at least one additional anti-cancer agent. In some embodiments, the additional anti-cancer agent is a Bcl-2 inhibitor, an FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor or an EGFR inhibitor, or a pharmaceutically acceptable salt thereof.

[0013] In another aspect, the present disclosure provides a composition comprising a therapeutically effective amount of a CLK inhibitor or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of at least one additional anti-cancer agent, for use in treating cancer in a patient. In some embodiments, the additional anti-cancer agent is a Bcl-2 inhibitor, an FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor or an EGFR inhibitor, or a pharmaceutically acceptable salt thereof.

[0014] In another aspect, the present disclosure provides a pharmaceutical product comprising a CLK inhibitor or a pharmaceutically acceptable salt thereof, in combination with a Bcl-2 inhibitor, an FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor or an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, in a fixed dose or a free combination.

[0015] In another embodiment, the disclosure provides a composition exhibiting a synergistic effect of a CLK inhibitor and a Bcl-2 inhibitor, FLT3 inhibitor, KRAS inhibitor, ALK inhibitor, PARP inhibitor, or EGFR inhibitor, wherein the two components are in contact with each other at a gene locus.

[0016] In another embodiment, the disclosure provides a composition exhibiting a synergistic effect of a CLK inhibitor and a Bcl-2 inhibitor, FLT3 inhibitor, KRAS inhibitor, ALK inhibitor, PARP inhibitor, or EGFR inhibitor, wherein the two components come into contact with each other only within the human body.

[0017] In some embodiments of the above aspects, the CLK inhibitor is (17E)-16-ethyl-8,12,14-trimethyl-2,11,12,14-tetrahydro-8H-3,5-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxyazacyclopentadecin-13(10H)-one (compound I): [ka] or a pharmaceutically acceptable salt thereof. Compound I is described in International Patent Application No. PCT / US2023 / 068071 (WO2023240140, published December 14, 2023), the entire contents of which are incorporated herein by reference.

[0018] Additional embodiments, features, and advantages of this disclosure will become apparent through the following detailed description and implementation of this disclosure. The compounds of this disclosure may be described as embodiments in any of the following enumerated clauses. It will be understood that any of the embodiments described herein can be used in conjunction with other embodiments described herein, to the extent that the embodiments are not inconsistent with each other.

[0019] Clause 1. A method for treating cancer in a host animal, comprising the step of administering to the host animal a therapeutically effective dose of a CLK inhibitor in combination with a therapeutically effective dose of at least one additional anticancer agent. Clause 2. CLK inhibitors are defined by formula I: [ka] The method according to Clause 1, or a pharmaceutically acceptable salt thereof. Clause 3. The method according to Clause 1 or 2, wherein the cancer is a humoral tumor or a solid tumor. Clause 4. Cancer is defined as acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER + Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), The method according to any one of the following clauses 1 to 3, selected from the group consisting of pediatric glioma, prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous or clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer. Clause 5. The method described in any one of the preceding clauses, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer. Clause 6. The method described in any one of Clauses 1 to 5, wherein the cancer is acute myeloid leukemia (AML). Clause 7. The method described in any one of Clauses 1 to 5, wherein the cancer is chronic lymphocytic leukemia (CLL). Clause 8. The method described in any one of Clauses 1 to 5, wherein the cancer is non-small cell lung cancer (NSCLC). Clause 9. The method described in any one of Clauses 1 to 5, wherein the cancer is ovarian cancer. Clause 10. The method according to any one of Clauses 1 to 9, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor. Clause 11. The method according to Clause 10, wherein the additional anticancer agent is a Bcl-2 inhibitor. Clause 12. The method according to Clause 10, wherein the additional anticancer agent is an FLT3 inhibitor. Clause 13. The method according to Clause 10, wherein the additional anticancer agent is a KRAS inhibitor. Clause 14. KRAS inhibitors are compounds II shown in the following formula: [ka] The method according to Clause 13, or a pharmaceutically acceptable salt thereof. Clause 15. The method according to Clause 10, wherein the additional anticancer agent is an ALK inhibitor. Clause 16. The method according to Clause 10, wherein the additional anticancer agent is an EGFR inhibitor. Clause 17. EGFR inhibitors are compounds III shown in the following formula: [ka] The method according to Clause 16, or a pharmaceutically acceptable salt thereof. Clause 18. The method according to Clause 16, wherein the EGFR inhibitor is osimertinib. Clause 19. The method according to any one of Clauses 1-13, 15, or 16, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine, carboplatin, cytarabine or decitabine, or a pharmaceutically acceptable salt thereof. Clause 20. The method according to any one of Clauses 1 to 11 or 19, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof. Clause 21. The method according to any one of Clauses 1-10, 12, or 19, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof. Clause 22. The method according to any one of Clauses 1-10, 13, or 19, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof. Clause 23. The method according to any one of Clauses 1-10, 13, or 19, wherein the additional anticancer agent is adaglacib or sotracib, or a pharmaceutically acceptable salt thereof. Clause 24. The method according to any one of Clauses 1 to 23, wherein the combination of a CLK inhibitor and at least one additional anticancer agent in a therapeutically effective dose yields an HSA synergy score of at least approximately 11 in cancer cell lines. Clause 25. The method according to any one of Clauses 1 to 24, wherein a combination of a CLK inhibitor and at least one additional anticancer agent yields an HSA synergy score of at least about 15 in cancer cell lines. Clause 26. CLK inhibitors or pharmaceutically acceptable salts thereof for use in the treatment of cancer in a patient, in combination with at least one additional anticancer agent in a therapeutically effective dose. Clause 27. CLK inhibitors are defined by formula I: [ka] or a pharmaceutically acceptable salt thereof, the compound described in Clause 26. Clause 28. The compound described in Clause 26 or 27, wherein the cancer is a humoral tumor or a solid tumor. Clause 29. Cancer is defined as acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER + Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), small Compounds described in any one of clauses 26 to 28, selected from the group consisting of pediatric glioma, prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, cutaneous malignant melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous or clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer. Clause 30. A compound according to any one of Clauses 26-29, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer. Clause 31. A compound described in any one of Clauses 26-30, wherein the cancer is acute myeloid leukemia (AML). Clause 32. The cancer is chronic lymphocytic leukemia (CLL), and the compound is one of the compounds described in any one of Clauses 26-30. Clause 33. A compound described in any one of Clauses 26-30, wherein the cancer is non-small cell lung cancer (NSCLC). Clause 34. The cancer is ovarian cancer, and the compound is one of the compounds described in any one of Clauses 26-30. Clause 35. A compound according to any one of Clauses 26-34, wherein the additional anticancer agent is a Bcl-2 inhibitor, FLT3 inhibitor, KRAS inhibitor, ALK inhibitor, PARP inhibitor, or EGFR inhibitor. Clause 36. The compound described in Clause 35, wherein the additional anticancer agent is a Bcl-2 inhibitor. Clause 37. The compound described in Clause 35, wherein the additional anticancer agent is an FLT3 inhibitor. Clause 38. The additional anticancer agent is a compound described in Clause 35, which is a KRAS inhibitor. Clause 39. KRAS inhibitors are compounds II shown in the following formula: [ka] The compounds described in Clause 38, or pharmaceutically acceptable salts thereof. Clause 40. The additional anticancer agent is an ALK inhibitor, as described in Clause 35. Clause 41. The additional anticancer agent is an EGFR inhibitor, as described in Clause 35. Clause 42. EGFR inhibitors are compounds III shown in the following formula: [ka] The compounds described in Clause 41, or pharmaceutically acceptable salts thereof. Clause 43. The compound described in Clause 41, wherein the EGFR inhibitor is osimertinib. Clause 44. The additional anticancer agent is any of the compounds described in any one of Clauses 26-38, 40 or 41, which is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine, carboplatin, cytarabine or decitabine, or a pharmaceutically acceptable salt thereof. Clause 45. A compound described in any one of Clauses 26-36 or 44, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof. Clause 46. A compound described in any one of Clauses 26-35, 37, or 44, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof. Clause 47. The additional anticancer agent is MRTX1133, adaglacib, or sotracib, or any pharmaceutically acceptable salt thereof, as described in any one of Clauses 26-35, 38, or 44. Clause 48. A compound described in any one of Clauses 26-35, 38, or 44, wherein the additional anticancer agent is adaglacib or sotracib, or a pharmaceutically acceptable salt thereof. Clause 49. A compound according to any one of Clauses 26 to 48, which, when combined with a CLK inhibitor and at least one additional anticancer agent in a therapeutically effective dose, yields an HSA synergy score of at least approximately 11 in cancer cell lines. Clause 50. A compound according to any one of Clauses 26 to 49, which, when combined with a CLK inhibitor and at least one additional anticancer agent, yields an HSA synergy score of at least about 15 in cancer cell lines. Clause 51. Use of a CLK inhibitor or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product comprising a therapeutically effective amount of the compound for the treatment of cancer in a patient, in combination with at least one additional anticancer agent in a therapeutically effective amount. Clause 52. CLK inhibitors are defined by formula I: [ka] The use described in Clause 51, or a pharmaceutically acceptable salt thereof. Clause 53. Use as described in Clause 51 or 52, if the cancer is a humoral tumor or a solid tumor. Clause 54. Cancer is defined as acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER +Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), small Use as described in any one of Clauses 51 to 53, selected from the group consisting of pediatric glioma, prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous or clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer. Clause 55. Use as described in any one of Clauses 51-54, where the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer. Clause 56. Use as described in any one of Clauses 51-55, where the cancer is acute myeloid leukemia (AML). Clause 57. Use as described in any one of Clauses 51-55, where the cancer is chronic lymphocytic leukemia (CLL). Clause 58. Use as described in any one of Clauses 51-55, wherein the cancer is non-small cell lung cancer (NSCLC). Article 59. Use as described in any one of Articles 51-55, where the cancer is ovarian cancer. Clause 60. Use as described in any one of Clauses 51-59, wherein the additional anticancer agent is a Bcl-2 inhibitor, FLT3 inhibitor, KRAS inhibitor, ALK inhibitor, PARP inhibitor, or EGFR inhibitor. Clause 61. Use as described in Clause 60, wherein the additional anticancer agent is a Bcl-2 inhibitor. Clause 62. Use as described in Clause 60, wherein the additional anticancer agent is an FLT3 inhibitor. Clause 63. Use as described in Clause 60, wherein the additional anticancer agent is a KRAS inhibitor. Clause 64. KRAS inhibitors are compounds II shown in the following formula: [ka] or a pharmaceutically acceptable salt thereof, as used in the manner described in Clause 63. Clause 65. Use as described in Clause 60, wherein the additional anticancer agent is an ALK inhibitor. Clause 66. Use as described in Clause 60, wherein the additional anticancer agent is an EGFR inhibitor. Clause 67. EGFR inhibitors are compounds III shown in the following formula: [ka] The use described in Clause 66, or a pharmaceutically acceptable salt thereof. Clause 68. Use as described in Clause 66, where the EGFR inhibitor is osimertinib. Clause 69. Uses described in any one of Clauses 51-63, 65 or 66, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine, carboplatin, cytarabine or decitabine, or a pharmaceutically acceptable salt thereof. Clause 70. Use as described in any one of Clauses 51-61 or 69, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof. Clause 71. Use as described in any one of Clauses 51-60, 62, or 69, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof. Clause 72. Use as described in any one of Clauses 51-60, 63, or 69, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof. Clause 73. Use as described in any one of Clauses 51-60, 63, or 69, wherein the additional anticancer agent is adaglacib or sotracib, or a pharmaceutically acceptable salt thereof. The use described in any one of the clauses 51 to 73, wherein the combination of a CLK inhibitor and at least one additional anticancer agent in a therapeutically effective dose yields an HSA synergy score of at least approximately 11 in cancer cell lines. Clause 75. Use as described in any one of Clauses 51 to 74, wherein the combination of a CLK inhibitor and at least one additional anticancer agent yields an HSA synergy score of at least approximately 15 in cancer cell lines. Clause 76. A composition comprising a therapeutically effective amount of a CLK inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of cancer in a patient, in combination with at least one additional anticancer agent in a therapeutically effective amount. Clause 77. CLK inhibitors are, Formula I: [ka] The composition according to Clause 76, or a pharmaceutically acceptable salt thereof. Clause 78. The composition according to Clause 76 or 77, wherein the cancer is a humoral tumor or a solid tumor. Article 79. Cancer is defined as acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER +Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), small A composition according to any one of the clauses 76 to 78, selected from the group consisting of pediatric glioma, prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, cutaneous malignant melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous or clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer. Clause 80. The composition according to any one of Clauses 76 to 79, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer. Clause 81. The composition according to any one of Clauses 76 to 80, wherein the cancer is acute myeloid leukemia (AML). Clause 82. The composition according to any one of Clauses 76 to 80, wherein the cancer is chronic lymphocytic leukemia (CLL). Clause 83. A composition according to any one of Clauses 76 to 80, wherein the cancer is non-small cell lung cancer (NSCLC). Clause 84. A composition according to any one of Clauses 76 to 80, wherein the cancer is ovarian cancer. Clause 85. The composition according to any one of Clauses 76 to 84, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor. Clause 86. The composition according to Clause 85, wherein the additional anticancer agent is a Bcl-2 inhibitor. Clause 87. The composition according to Clause 85, wherein the additional anticancer agent is an FLT3 inhibitor. Clause 88. The composition according to Clause 85, wherein the additional anticancer agent is a KRAS inhibitor. Clause 89. KRAS inhibitors are compounds II shown in the following formula: [ka] The composition described in Clause 88, or a pharmaceutically acceptable salt thereof. Clause 90. The composition according to Clause 85, wherein the additional anticancer agent is an ALK inhibitor. Clause 91. The composition according to Clause 85, wherein the additional anticancer agent is an EGFR inhibitor. Clause 92. EGFR inhibitors are compounds III shown in the following formula: [ka] The composition according to Clause 91, or a pharmaceutically acceptable salt thereof. Clause 93. The composition according to Clause 91, wherein the EGFR inhibitor is osimertinib. Clause 94. A composition according to any one of Clauses 76-88, 90 or 91, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine, carboplatin, cytarabine or decitabine, or a pharmaceutically acceptable salt thereof. Clause 95. The composition according to any one of Clauses 76-86 or 94, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof. Clause 96. The composition according to any one of Clauses 76-85, 87, or 94, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof. Clause 97. A composition according to any one of Clauses 76-85, 88, or 94, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof. Clause 98. A composition according to any one of Clauses 76-85, 88, or 94, wherein the additional anticancer agent is adaglacib or sotracib, or a pharmaceutically acceptable salt thereof. Clause 99. The composition according to any one of Clauses 76 to 98, wherein the combination of a CLK inhibitor and at least one additional anticancer agent in a therapeutically effective amount yields an HSA synergistic score of at least about 11 in a cancer cell line. Clause 100. The composition according to any one of Clauses 76 to 99, wherein the combination of a CLK inhibitor and at least one additional anticancer agent yields an HSA synergy score of at least about 15 in cancer cell lines. Clause 101. A pharmaceutical product comprising a CLK inhibitor or a pharmaceutically acceptable salt thereof in combination with at least one additional anticancer agent, either in a fixed dose or in a free combination. Clause 102. CLK inhibitors are, Formula I: [ka] or a pharmaceutically acceptable salt thereof, as described in Clause 101. Clause 103. The Medicinal Products described in Clause 101 or 102, wherein cancer is a humoral tumor or a solid tumor. Clause 104. Cancer is defined as acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER +Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), pediatric A pharmaceutical product as described in any one of clauses 101 to 103, selected from the group consisting of glioma, prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous or clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer. Clause 105. A medicine described in any one of Clauses 101-104, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer. Article 106. A medicine described in any one of Articles 101 to 105, wherein the cancer is acute myeloid leukemia (AML). Article 107. A medicine described in any one of Articles 101-105, wherein the cancer is chronic lymphocytic leukemia (CLL). Article 108. A medicine described in any one of Articles 101 to 105, wherein the cancer is non-small cell lung cancer (NSCLC). Article 109. A medicine described in any one of Articles 101 to 105, wherein the cancer is ovarian cancer. Clause 110. A pharmacopoeia as described in any one of Clauses 101 to 109, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor. Clause 111. The pharmacopoeia described in Clause 110, wherein the additional anticancer agent is a Bcl-2 inhibitor. Clause 112. The pharmacopoeia described in Clause 110, wherein the additional anticancer agent is an FLT3 inhibitor. Clause 113. The pharmacopoeia described in Clause 110, wherein the additional anticancer agent is a KRAS inhibitor. Clause 114. KRAS inhibitors are compounds II shown in the following formula: [ka] or a pharmaceutically acceptable salt thereof, as described in Article 113. Clause 115. The pharmacopoeia described in Clause 110, wherein the additional anticancer agent is an ALK inhibitor. Clause 116. The pharmacopoeia described in Clause 110, wherein the additional anticancer agent is an EGFR inhibitor. Clause 117. EGFR inhibitors are compounds III shown in the following formula: [ka] or a pharmaceutically acceptable salt thereof, as described in Article 116. Clause 118. The pharmacopoeia described in Clause 116, wherein the EGFR inhibitor is osimertinib. Article 119. A medicament described in any one of Articles 101-113, 115 or 116, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine, carboplatin, cytarabine or decitabine, or a pharmaceutically acceptable salt thereof. Clause 120. A medicament described in any one of Clauses 101-111 or 119, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof. Clause 121. A medicament described in any one of Clauses 101-110, 112, or 119, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof. Clause 122. A pharmacopoeia as described in any one of Clauses 101-110, 113, or 119, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof. Clause 123. A pharmacopoeia as described in any one of Clauses 101-110, 113, or 119, wherein the additional anticancer agent is adaglacib or sotracib, or a pharmaceutically acceptable salt thereof. Clause 124. A pharmacopoeia according to any one of Clauses 101 to 123, wherein the combination of a CLK inhibitor and at least one additional anticancer agent in a therapeutically effective dose yields an HSA synergy score of at least approximately 11 in cancer cell lines. Clause 125. A pharmacopoeia according to any one of Clauses 101 to 124, wherein the combination of a CLK inhibitor and at least one additional anticancer agent yields an HSA synergy score of at least approximately 15 in cancer cell lines. Clause 126. A composition exhibiting a synergistic effect of a CLK inhibitor and at least one anticancer agent, wherein two components are in contact with each other at a gene locus. Clause 127. CLK inhibitors are, Formula I: [ka] A composition exhibiting the synergistic effect described in Clause 126, which is a pharmaceutically acceptable salt thereof. Clause 128. A composition exhibiting the synergistic effect described in Clause 126 or 127, wherein the cancer is a humoral tumor or a solid tumor. Clause 129. Cancer is defined as acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER +Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), pediatric glioma A composition exhibiting the synergistic effect described in any one of Clauses 126 to 128, selected from the group consisting of prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous or clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer. Clause 130. A composition exhibiting the synergistic effects described in any one of Clauses 126 to 129, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer. Clause 131. A composition exhibiting the synergistic effect described in any one of Clauses 126 to 130, wherein the cancer is acute myeloid leukemia (AML). Clause 132. A composition exhibiting the synergistic effect described in any one of Clauses 126 to 130, wherein the cancer is chronic lymphocytic leukemia (CLL). Clause 133. A composition exhibiting the synergistic effect described in any one of Clauses 126 to 130, wherein the cancer is non-small cell lung cancer (NSCLC). Clause 134. A composition exhibiting the synergistic effect described in any one of Clauses 126 to 130, wherein the cancer is ovarian cancer. Clause 135. A composition exhibiting the synergistic effect described in any one of Clauses 126 to 134, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor. Clause 136. A composition exhibiting the synergistic effect described in Clause 135, wherein the additional anticancer agent is a Bcl-2 inhibitor. Clause 137. A composition exhibiting the synergistic effect described in Clause 135, wherein the additional anticancer agent is an FLT3 inhibitor. Clause 138. A composition exhibiting the synergistic effect described in Clause 135, wherein the additional anticancer agent is a KRAS inhibitor. Clause 139. KRAS inhibitors are compounds II shown in the following formula: [ka] A composition exhibiting the synergistic effect described in Clause 138, which is a pharmaceutically acceptable salt thereof. Clause 140. The synergistic composition according to Clause 135, wherein the additional anticancer agent is an ALK inhibitor. Clause 141. The synergistic composition according to Clause 135, wherein the additional anticancer agent is an EGFR inhibitor. Clause 142. EGFR inhibitors are compounds III shown in the following formula: [ka] A composition exhibiting the synergistic effect described in Clause 141, which is a pharmaceutically acceptable salt thereof. Clause 143. A composition exhibiting the synergistic effect described in Clause 141, wherein the EGFR inhibitor is osimertinib. Clause 144. A composition exhibiting the synergistic effects described in any one of Clauses 126-138, 140, or 141, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine, carboplatin, cytarabine or decitabine, or a pharmaceutically acceptable salt thereof. Clause 145. A composition exhibiting the synergistic effect described in any one of Clauses 126-136 or 144, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof. Clause 146. A composition exhibiting the synergistic effect described in any one of Clauses 126-135, 137, or 144, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof. Clause 147. A composition exhibiting the synergistic effects described in any one of Clauses 126-135, 138, or 144, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof. Clause 148. A composition exhibiting the synergistic effects described in any one of Clauses 126-135, 138, or 144, wherein the additional anticancer agent is adaglacib or sotracib, or a pharmaceutically acceptable salt thereof. Clause 149. A composition exhibiting the synergistic effect described in any one of Clauses 126 to 148, wherein a combination of a CLK inhibitor and at least one additional anticancer agent in a therapeutically effective amount results in an HSA synergistic score of at least about 11 in a cancer cell line. Clause 150. A composition exhibiting the synergistic effect described in any one of Clauses 126 to 149, wherein a CLK inhibitor and at least one additional anticancer agent, in combination, yield an HSA synergistic score of at least about 15 in a cancer cell line. Clause 151. A composition exhibiting a synergistic effect of a CLK inhibitor and at least one anticancer agent, wherein the two components come into contact with each other only within the human body. Clause 152. CLK inhibitors are, Formula I: [ka] A composition exhibiting the synergistic effect described in Clause 151, which is a pharmaceutically acceptable salt thereof. Clause 153. A composition exhibiting the synergistic effect described in Clause 151 or 152, wherein the cancer is a humoral tumor or a solid tumor. Clause 154. Cancer is defined as acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER +Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), pediatric glioma A composition exhibiting the synergistic effect described in any one of Clauses 151 to 153, selected from the group consisting of prostate cancer, squamous cell carcinoma of the lung, serous cystadenocarcinoma of the ovary, malignant melanoma of the skin, castration-resistant prostate cancer, Hodgkin lymphoma, serous or clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer. Clause 155. A composition exhibiting the synergistic effects described in any one of Clauses 151 to 154, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer. Clause 156. A composition exhibiting the synergistic effect described in any one of Clauses 151 to 155, wherein the cancer is acute myeloid leukemia (AML). Clause 157. A composition exhibiting the synergistic effect described in any one of Clauses 151 to 155, wherein the cancer is chronic lymphocytic leukemia (CLL). Clause 158. A composition exhibiting the synergistic effect described in any one of Clauses 151 to 155, wherein the cancer is non-small cell lung cancer (NSCLC). Clause 159. A composition exhibiting the synergistic effect described in any one of Clauses 151 to 155, wherein the cancer is ovarian cancer. Clause 160. A composition exhibiting the synergistic effect described in any one of Clauses 151 to 159, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor. Clause 161. A composition exhibiting the synergistic effect described in Clause 160, wherein the additional anticancer agent is a Bcl-2 inhibitor. Clause 162. A composition exhibiting the synergistic effect described in Clause 160, wherein the additional anticancer agent is an FLT3 inhibitor. Clause 163. A composition exhibiting the synergistic effect described in Clause 160, wherein the additional anticancer agent is a KRAS inhibitor. Clause 164. KRAS inhibitors are compounds shown in the following formula: [ka] A composition exhibiting the synergistic effect described in Clause 163, which is a pharmaceutically acceptable salt thereof. Clause 165. A composition exhibiting the synergistic effect described in Clause 160, wherein the additional anticancer agent is an ALK inhibitor. Clause 166. A composition exhibiting the synergistic effect described in Clause 160, wherein the additional anticancer agent is an EGFR inhibitor. Article 167. EGFR inhibitors are compounds III shown in the following formula: [ka] A composition exhibiting the synergistic effect described in Clause 166, which is a pharmaceutically acceptable salt thereof. Clause 168. A composition exhibiting the synergistic effect described in Clause 166, wherein the EGFR inhibitor is osimertinib. Clause 169. A composition exhibiting the synergistic effects described in any one of Clauses 151-163, 165, or 166, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine, carboplatin, cytarabine or decitabine, or a pharmaceutically acceptable salt thereof. Clause 170. A composition exhibiting the synergistic effect described in any one of Clauses 151-161 or 169, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof. Clause 171. A composition exhibiting the synergistic effect described in any one of Clauses 151-160, 162, or 169, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof. Clause 172. A composition exhibiting the synergistic effect described in any one of Clauses 151-160, 163, or 169, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof. Clause 173. A composition exhibiting the synergistic effects described in any one of Clauses 151-160, 163, or 169, wherein the additional anticancer agent is adaglacib or sotracib, or a pharmaceutically acceptable salt thereof. Clause 174. A composition exhibiting the synergistic effect described in any one of Clauses 151 to 173, wherein a combination of a CLK inhibitor and at least one additional anticancer agent in a therapeutically effective amount yields an HSA synergistic effect score of at least about 11 in a cancer cell line. Clause 175. A composition exhibiting the synergistic effect described in any one of Clauses 151 to 174, wherein a combination of a CLK inhibitor and at least one additional anticancer agent yields an HSA synergistic effect score of at least about 15 in cancer cell lines. [Brief explanation of the drawing]

[0020] Matrix-based synergistic assay [Figure 1] Figure 1 is a graph showing the HSA synergy map for the combination of compound I and venetoclax in an in vitro proliferation assay matrix combination study using the AML cell line MOLM13. Table 1 shows representative synergy area scores (dark areas) at various concentrations of compound I and venetoclax. [Figure 2] Figure 2 is a graph showing the HSA synergy effect map for the combination of compound I and AMG-510 in an in vitro proliferation assay matrix combination test using NSCLC cell line H358. Table 2 shows representative synergy area scores (dark areas) at various concentrations of compound I and AMG-510. [Figure 3] Figures 3a and 3b are graphs showing the in vivo effects of the combination of compound I and gilteritinib in the MOLM-13 CDX tumor model. (●) Vehicle; (▲) Gilteritinib administered at 25 mg / kg QD; (○) Compound I administered at 25 mg / kg MWF; (▼) Compound I administered at 25 mg / kg MWF + gilteritinib administered at 25 mg / kg QD; (□) Compound I administered at 25 mg / kg QD; (■) Compound I administered at 25 mg / kg QD + gilteritinib administered at 25 mg / kg QD. (Figure 3a) Antitumor activity; (Figure 3b) Body weight. [Figure 4] Figures 4a and 4b are graphs showing the in vivo effects of the combination of compound I and venetoclax in the MOLM-13 CDX tumor model. (●) Vehicle, (▲) Venetoclax administered at 100 mg / kg QD; (▼) Compound I administered at 25 mg / kg MWF; (■) Compound I administered at 25 mg / kg MWF + venetoclax administered at 100 mg / kg QD; (◆) Compound I administered at 25 mg / kg QW + venetoclax administered at 100 mg / kg QD. (Figure 4a) Antitumor activity; (Figure 4b) Body weight. [Figure 5] Figure 5 is a graph showing the results of a 3D spheroid proliferation assay measured by the total bright-field target area of ​​SW480 cell lines treated with DMSO, compound I, compound II, or a combination of compound I and compound II. (●) DMSO; (■) compound I administered at 62 nM; (▲) compound II administered at 37 nM; (▼) compound I administered at 62 nM + compound II administered at 37 nM. [Figure 6] Figure 6 shows an HSA synergy map highlighting the dose ranges that demonstrate the synergistic effect of compound I and compound II in a matrix combination study using the CRC cell line SW480. Table 3 shows representative synergy area scores (dark areas) at various concentrations of compound I and compound II. [Figure 7]Figure 7 is a graph showing the growth of H1975 cell lines treated with DMSO, compound I, compound III, or a combination of compound I and compound III, as measured by phase-symmetric confluence. (●) DMSO; (■) compound III administered at 11 nM; (▲) compound I administered at 50 nM; (▼) compound I administered at 50 nM + compound III administered at 11 nM. [Figure 8] Figure 8 is a graph showing the growth of H1975 cell lines treated with DMSO, compound I, osimertinib, or a combination of compound I and osimertinib, as measured by phase-controlled confluence. (●) DMSO; (■) osimertinib administered at 11 nM; (▲) compound I administered at 50 nM; (▼) compound I administered at 50 nM + osimertinib administered at 11 nM. [Figure 9] Figure 9 shows an HSA synergy map highlighting the dose ranges that demonstrate the synergistic effect of compound I and MRTX1133 in a matrix combination study using the PDAC cell line Suit-2. Table 4 shows representative synergy area scores (dark areas) at various concentrations of compound I and MRTX1133. [Figure 10] Figure 10 shows an HSA synergy map highlighting the dose ranges that demonstrate the synergistic effect of compound I and MRTX1133 in a matrix combination study using the CRC cell line GP2D. Table 5 shows representative synergy area scores (dark areas) at various concentrations of compound I and MRTX1133. [Figure 11] Figure 11 shows an HSA synergy map highlighting the dose ranges that demonstrate the synergistic effect of compound I and adagrasib in a matrix combination study using the CRC cell line SW1463. Table 6 shows representative synergy area scores (dark areas) at various concentrations of compound I and adagrasib. [Figure 12]Figures 12a and 12b are graphs showing the in vivo effects of combinations of compound I and venetoclax in the MOLM-13 CDX tumor model after 16 days of venetoclax pretreatment. (■) Venetoclax administered at 100 mg / kg QD + compound I administered at 25 mg / kg MWF; (○) Venetoclax administered at 100 mg / kg QD + compound I administered at 25 mg / kg QW; (▲) Venetoclax administered at 100 mg / kg QD + gilteritinib administered at 25 mg / kg QD. (Figure 12a) Antitumor activity; (Figure 12b) Body weight. [Figure 13] Figures 13a and 13b are graphs showing the in vivo effects of the combination of compound I and azacitidine in the MOLM-13 CDX tumor model. (●) Vehicle; (▲) Compound I administered at 25 mg / kg QD; (▼) Azacitidine administered at 5 mg / kg IP QD x 7; (■) Compound I administered at 25 mg / kg QD + azacitidine administered at 5 mg / kg IP QD x 7 simultaneously; (◆) Azacitidine administered at 5 mg / kg IP QD x 7, followed by compound I administered at 25 mg / kg QD. (Figure 13a) Antitumor activity; (Figure 13b) Body weight. [Figure 14] Figures 14a and 14b are graphs showing the in vivo effects of the combination of compound I and carboplatin in the OVCAR3 CDX tumor model. (●) Vehicle; (▼) Compound I 25 mg / kg QD; (▲) Carboplatin 50 mg / kg IP QW; (■) Compound I 25 mg / kg QD + Carboplatin 50 mg / kg IP QW. (Figure 14a) Antitumor activity; (Figure 14b) Body weight. [Figure 15] Figures 15a and 15b are graphs showing the in vivo effects of the combination of compound I and osimertinib in the H1975 CDX tumor model. (●) Vehicle; (□) Compound I 25 mg / kg QD; (▲) Osimertinib 1 mg / kg QD; (■) Compound I 25 mg / kg QD + Osimertinib 1 mg / kg QD. (Figure 15a) Antitumor activity; (Figure 15b) Body weight. [Figure 16a]Figure 16a is a graph showing the in vivo effects of the combination of compound I and adaglacib in the SW1463 CDX tumor model. (●) Vehicle; (□) Compound I 25 mg / kg QD; (▲) Adaglacib 30 mg / kg QD; (■) Compound I 25 mg / kg QD + Adaglacib 30 mg / kg QD. (Figure 16a) Antitumor activity. [Figure 16b] Figure 16b is a graph showing the in vivo effects of the combination of compound I and adaglacib in the SW1463 CDX tumor model. (●) Vehicle; (□) Compound I 25 mg / kg QD; (▲) Adaglacib 30 mg / kg QD; (■) Compound I 25 mg / kg QD + Adaglacib 30 mg / kg QD. (Figure 16b) Survival analysis. [Figure 16c] Figure 16c is a graph showing the in vivo effects of the combination of compound I and adaglacib in the SW1463 CDX tumor model. (●) Vehicle; (□) Compound I 25 mg / kg QD; (▲) Adaglacib 30 mg / kg QD; (■) Compound I 25 mg / kg QD + Adaglacib 30 mg / kg QD. (Figure 16c) Body weight. [Figure 17] Figures 17a and 17b are graphs showing the in vivo effects of the combination of compound I and cytarabine in the MOLM-13 CDX tumor model. (●) Vehicle; (▲) Compound I 25 mg / kg QD; (▼) Cytarabine 50 mg / kg QD × 7; (■) Compound I 25 mg / kg QD + Cytarabine 50 mg / kg QD × 7. (Figure 17a) Antitumor activity; (Figure 17b) Body weight. Detailed description of the invention

[0021] Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described. Furthermore, the terms used herein are solely for illustrative purposes and not intended to limit the scope of the present invention, as the scope of the invention is limited only to the appended claims.

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in which the present invention pertains. All patents, applications, published applications, and other publications referenced herein are incorporated in their entirety by reference. If any definition set forth herein contradicts or is inconsistent with any definition set forth herein in any patent, application, or other publication incorporated herein by reference, the definition set forth herein shall prevail.

[0023] Where used herein and in the appended claims, the singular forms "a," "an," and "the" include plural reference terms unless the context clearly indicates otherwise. Furthermore, it should be noted that claims may be written to exclude any element. In such cases, this statement is intended to serve as a precedent when using exclusive terms such as "alone," "only," or the "excluded" limitation in relation to the description of the components of the claims.

[0024] As used herein, the terms “inclusive,” “contains,” and “includes” are used in an open-ended and non-restrictive sense.

[0025] For the sake of providing a more concise explanation, some of the quantitative expressions expressed herein are not modified with the term “approximately.” Whether or not the term “approximately” is explicitly used, all quantities expressed herein are meant to refer to the actual values ​​obtained, and also to approximations of such obtained values ​​that can be reasonably inferred in the ordinary art of a person skilled in the art, including equivalents and approximations under experimental and / or measurement conditions relating to such obtained values. Where a yield is expressed as a percentage, the yield represents the mass of the substance for which the yield is expressed relative to the maximum amount of the same substance obtainable under specific stoichiometric conditions. Unless otherwise specified, concentrations expressed as percentages mean mass ratios.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in which the present invention pertains. Similar or equivalent methods and materials to those described herein may also be used in carrying out or testing the present invention, but preferred methods and materials will be described hereafter. All publications referenced herein are incorporated herein by reference for disclosures and descriptions relating to the methods and / or materials in which those publications are cited.

[0027] Unless otherwise stated, the methods and techniques of this embodiment are generally carried out in accordance with the prior art known in the art, as described in the various general and more specific literature referenced and discussed herein. See, for example, Loudon, *Organic Chemistry*, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; and Smith and March, *March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure*, Fifth Edition, Wiley-Interscience, 2001.

[0028] The names of the compounds described herein can be derived from chemical nomenclature using commercially available software such as ACD / Name2014 (ACD / Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).

[0029] For clarity, it is understood that certain features of the invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the invention described in the context of a single embodiment may also be provided separately or in any appropriate subcombination.

[0030] In this specification, the term “therapeutic dose” refers to the amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a patient, including relief of the symptoms of the disease or disorder being treated. In some embodiments, a therapeutic dose is the amount that can treat or alleviate the disease or symptoms. A specific therapeutically effective dose level for a particular patient varies depending on a variety of factors, including the disorder being treated and its severity, the activity of the particular compound used, the particular composition used, the patient’s age, weight, general health, sex and diet, administration time, route of administration and elimination rate, duration of treatment, any drugs used concomitantly or concurrently with the particular compound used, and similar factors. Exemplary doses range from about 0.1 mg to 1.5 g per day, about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 mg to 250 mg per day, or about 250 mg to 1 g per day. The total dose may be administered in single dose units or divided dose units (e.g., QD, QW, BID, TID, QID).

[0031] The terms “patient,” “subject,” “host animal,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, domestic animals (e.g., cattle, pigs), companion animals (e.g., dogs, cats), and rodents (e.g., mice and rats).

[0032] "Administering" or "dosing" a substance, compound, or drug to a target can be carried out using any of the various methods known to those skilled in the art. For example, compounds or drugs can be administered intravenously, intra-arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, intraocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intrathecally, intracerebrally, and transdermally (e.g., by absorption via skin sweat ducts). Compounds or drugs can also be appropriately administered by refillable polymer devices or biodegradable polymer devices or other devices (e.g., patches and pumps), or by formulations that provide sustained release, sustained release, or controlled release of the compound or drug. Administration can also be, for example, a single dose, multiple doses, and / or one or more doses over a long period of time.

[0033] The appropriate method for administering a substance, compound, or drug to a subject may also be modified, for example, by the subject's age and / or physical condition, and by the chemical and biological properties of the compound or drug (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, the compound or drug is administered orally, for example, by ingestion. In some embodiments, the orally administered compound or drug is in the form of a sustained-release formulation or a sustained-release formulation, or is administered using a device for such a sustained-release or sustained-release formulation.

[0034] As used herein, the term “cancer” includes both solid tumors and humoral tumors, where humoral tumors may be cancers of the blood cells, bone marrow, or lymphoid system. The term cancer includes acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastoma, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, and ER. +Breast cancer, triple-negative breast cancer, colorectal adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in epithelioid, intrahepatic cholangiocarcinoma, thyroid cancer, Spitz-like tumor, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related carcinoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML) This includes, but is not limited to, pediatric glioma, prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer. The term "cancer" will be understood to include both primary cancer or primary tumor and metastatic cancer or metastatic tumor. For example, metastatic NSCLC, metastatic CRC, metastatic pancreatic cancer, metastatic HER2-overexpressing breast cancer, metastatic EGFR-expressing colorectal cancer, and metastatic HNSCC. It should be understood that the term "cancer" includes cancers that involve the upregulation of specific genes or gene mutations in specific genes that lead to disease progression (for example, upregulation of the epidermal growth factor receptor).

[0035] As used herein, “independently” means that the event or situation described thereafter can be read in itself in relation to other similar events or situations. For example, in a situation where several equivalent hydrogen groups may optionally be substituted by another group described in that situation, the use of “independently as desired” means that each hydrogen atom on a group may be substituted by another group, where the group substituting each hydrogen atom may be the same or different. Or, for example, if there are multiple groups and all of them can be selected from a group of possible groups, the use of “independently” means that each group can be selected from a group of possible groups different from the other groups, where the groups selected in that situation may be the same or different.

[0036] As used herein, the term “pharmaceutically acceptable salt” refers to those salts with counterions that can be used in pharmaceuticals. See, for general reference, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. A preferred pharmaceutically acceptable salt is one that is pharmaceutically effective and suitable for contact with the target tissue without excessive toxicity, irritation, or allergic reaction. The compounds described herein may have sufficient acidic groups, sufficient basic groups, both functional groups, or one or more functional groups of each type, and accordingly can react with many inorganic or organic bases and inorganic or organic acids to form pharmaceutically acceptable salts. Such salts include: (1) Acid addition salts: Salts obtained by the reaction of the free base of the parent compound with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid) or an organic acid (e.g., acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid, and malonic acid); or (2) Salts formed when any of the acidic protons present in the parent compound are substituted with a metal ion (e.g., alkali metal ions, alkaline earth ions, or aluminum ions) or coordinate with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, trimamine, N-methylglucamine).

[0037] Medicinally acceptable salts are well known to those skilled in the art, and such medicatile salts may be considered in connection with the embodiments described herein. Examples of medicatile salts include sulfates, disulfates, bisulfates, sulfites, bisulfite salts, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propions, decanoates, capries, acrylates, formates, isobutyrates, capronates, heptanoates, propions, oxalates, malons, succinates, suberates, sebacinates, fumarates, maleates, butin-1,4-diates, hexinates Examples include 1,6-diotes, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besilates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, and mandelates. A list of other suitable pharmaceutically acceptable salts is provided in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0038] Embodiment In some embodiments, the methods described herein relate to the treatment of cancer, characterized by administering a therapeutically effective dose of a CLK inhibitor in combination with an additional anticancer agent to a patient in need of treatment. In some embodiments, the additional anticancer agent may include a Bcl-2 inhibitor, an additional anticancer agent, a KRAS inhibitor, and a FLT3 inhibitor. In some embodiments, the additional anticancer agent may include a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor. An inhibitor will be understood to mean any substance that reduces or inhibits the activity of another substance, such as a cell surface receptor (i.e., receptor tyrosine kinase) or a kinase (i.e., non-receptor tyrosine kinase). The definition of “inhibitor” is well known to those skilled in the art, and the use of the general term “inhibitor” herein will be understood to mean its usual idiomatic meaning. A “CLK inhibitor” will be understood to mean a compound that may have affinity for one or more of the biological targets CLK1, CLK2, CLK3, or CLK4.

[0039] The compounds described herein are CLK inhibitors and have been found to be usable in combination with additional anticancer agents to treat cancer in patients requiring treatment. In some embodiments, the combination of a CLK inhibitor and an additional anticancer agent (e.g., Bcl-2 inhibitors, EGFR inhibitors, KRAS inhibitors, and FLT3 inhibitors) can provide a synergistic response in patients requiring cancer treatment. In some embodiments, the combination of a CLK inhibitor and an additional anticancer agent [e.g., Bcl-2 inhibitors, FLT3 inhibitors, KRAS inhibitors, ALK inhibitors, PARP inhibitors, chemotherapy (e.g., platinum therapy), EGFR inhibitors, etc.] can provide a synergistic response in patients requiring cancer treatment. In some embodiments, there is a method for treating cancer characterized by administering a combination of a therapeutically effective dose of a CLK inhibitor and a therapeutically effective dose of an additional anticancer agent. In some embodiments, the CLK inhibitor and the additional anticancer agent can be a combination drug. In some embodiments, the CLK inhibitor and the additional anticancer agent are administered simultaneously. In some embodiments, the CLK inhibitor and the additional anticancer agent are formulated individually and administered simultaneously. In some embodiments, the CLK inhibitor and the additional anticancer agent are formulated separately and administered sequentially. In some embodiments, sequential administration of the CLK inhibitor and the additional anticancer agent can be achieved by administering the CLK inhibitor first and the additional anticancer agent second. In some embodiments, sequential administration of the CLK inhibitor and the additional anticancer agent can be achieved by administering the additional anticancer agent first and the CLK inhibitor second.

[0040] In some embodiments, the CLK inhibitor is expressed by formula I: [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0041] Compound I is described in International Patent Application No. PCT / US2023 / 068071 (WO2023240140, published on December 14, 2023), the entire content of which is incorporated herein by reference.

[0042] The cancer can be a liquid tumor cancer or a solid tumor cancer [e.g., acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER + breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epitheloid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid cancer, spinous cell neoplasm, sarcoma, astrocytoma, low-grade glioma of the brain, secretory breast cancer, breast-like cancer, congenital mesoblastic nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, squamous cell carcinoma of the head and neck, chronic myelomonocytic leukemia (CML), pediatric glioma, prostate cancer, squamous cell carcinoma of the lung, serous cystadenocarcinoma of the ovary, cutaneous malignant melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine body cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer and lung cancer]. It will be appreciated that in certain embodiments, the cancer can be a liquid tumor, such as a liquid tumor such as a blood cancer, a bone marrow cancer or a lymphatic cancer. In some embodiments, the cancer can be a solid tumor such as NSCLC, breast cancer or colon cancer.

[0043] In some embodiments, the present disclosure provides a method for treating a disease in a patient who has been pre-treated with one or more therapeutic agents. In one embodiment, the patient has previously been treated with one or more anticancer agents. In yet another embodiment, the patient has previously been treated with one or more anticancer agents and has acquired resistance to that treatment. In yet another embodiment, the patient has previously been treated with one or more anticancer agents and has acquired resistance to that treatment. In yet another embodiment, the patient has previously been treated with one or more anticancer agents and has acquired resistance to treatment controlled by Bcl-2, FLT3, KRAS, EGFR, etc. In yet another embodiment, the patient has previously been treated with one or more anticancer agents and has acquired resistance to treatment controlled by Bcl-2, FLT3, KRAS, ALK, PARP, EGFR, etc.

[0044] Other anticancer agents that a patient may be treated with prior to treatment with one or more compounds described herein include, but are not limited to, kinase inhibitors, adrenocorticotropic hormone and corticosteroids, alkylating agents, peptide and peptide-mimicking signaling inhibitors, antiandrogens, antiestrogens, androgens, acramycin and acramycin derivatives, estrogens, antimetabolites, platinum compounds, amanitin, plant alkaloids, mitomycin, discodermoride, microtubule inhibitors, epothilone, inflammatory and pro-inflammatory agents, purine analogs, pyrimidine analogs, camptothecin and drastatin.

[0045] It will be understood that additional anticancer agents for use in connection with the combination therapies described herein may be any additional anticancer agent as defined herein. Preferred examples of additional anticancer agents include Bcl-2 inhibitors, FLT3 inhibitors, KRAS inhibitors, ALK inhibitors, PARP inhibitors, or EGFR inhibitors. In some embodiments, additional anticancer agents include compounds such as venetoclax, gilteritinib, MRTX1133, adaglasib, sotrasib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine, carboplatin, cytarabine, or decitabine, or pharmaceutically acceptable salts thereof. In some embodiments, additional anticancer agents used with a CLK inhibitor (e.g., compound I) are venetoclax, gilteritinib, compound II, compound III, MRTX1133, adaglacib, osimertinib, azacitidine, carboplatin or cytarabine, or pharmaceutically acceptable salts thereof.

[0046] In some embodiments, the additional anticancer agent is chemotherapy. Chemotherapy includes chemicals such as doxorubicin, 5-fluorouracil, cytosine arabinoside, cyclophosphamide, thiotepa, busulfan, cytotoxin, taxol, methotrexate, cisplatin, melphalan, vinblastine, cytarabine, and carboplatin. The manufacturing and administration schedules for such chemotherapeutic agents can be determined according to the manufacturer's instructions.

[0047] In some embodiments, the additional anticancer agent is a KRAS inhibitor. An example of a KRAS inhibitor for use in combination with the CLK inhibitor described herein is compound II: [ka] or a pharmaceutically acceptable salt thereof.

[0048] Compound II is described in International Patent Application No. PCT / US2023 / 027125 (WO2024015262, published January 18, 2024), the entire contents of which are incorporated herein by reference.

[0049] In some embodiments, the additional anticancer agent is an EGFR inhibitor. An example of an EGFR inhibitor for use in combination with the CLK inhibitor described herein is compound III: [ka] Examples include pharmaceutically acceptable salts thereof. Compound III is described in International Patent Application No. PCT / US2024 / 027195, the entirety of which is incorporated herein by reference.

[0050] In some embodiments, a combination of a CLK inhibitor and at least one additional anticancer agent in a therapeutically effective dose exhibits a synergistic effect. In certain embodiments, the synergistic effect of this combination is determined using a cell proliferation assay in cancer-like cell lines (e.g., cancer cell lines such as MOLM13 cells, H358 cells, SW480 cells, Suit-2 cells, GP2D cells, or SW1463 cells). The synergistic score, referred to as the HSA score, exhibits a value of at least about 10, at least about 11, at least about 15, at least about 20, or at least about 25. In some embodiments, the synergistic score, referred to as the HSA score, is in the range of about 10 to about 50, about 10 to about 40, about 10 to about 35, or about 15 to about 35. The synergistic score (e.g., the HSA score) may be determined as described in Examples 1, 2, 4, 6, 7, or 8, or by other methods known in the art.

[0051] In some embodiments, a specific concentration of CLK inhibitor exhibits a synergistic effect in combination with at least one additional anticancer agent in a therapeutically effective dose. The specific concentration of the CLK inhibitor may be in the range of approximately 0.05 nM to approximately 50 nM, approximately 0.1 nM to approximately 50 nM, approximately 0.05 nM to approximately 30 nM, approximately 0.1 nM to approximately 30 nM, approximately 1 nM to approximately 1000 nM, approximately 1 nM to approximately 800 nM, approximately 1 nM to approximately 300 nM, approximately 1 nM to approximately 250 nM, approximately 2 nM to approximately 1000 nM, approximately 2 nM to approximately 800 nM, approximately 2 nM to approximately 300 nM, or approximately 2 nM to approximately 250 nM, providing a synergistic effect in combination with at least one additional anticancer agent in a therapeutically effective dose.

[0052] In some embodiments, the combinations described herein include specific ratios (e.g., molar ratios) that exhibit a synergistic effect with respect to the concentrations of the CLK inhibitor and at least one additional anticancer agent.

[0053] In certain embodiments, the molar ratio of compound I to venetoclax yields a synergistic effect in the range of about 50:1 to about 1:10,000, about 10:1 to about 1:100, about 5:1 to about 1:100, about 1:1 to about 1:50, or about 1:2 to about 1:20. For example, the molar ratio of compound I to venetoclax can be about 1:4 or about 1:10.

[0054] In certain embodiments, the molar ratio of compound I to AMG510 yields a synergistic effect in the range of about 1000:1 to about 1:20, about 100:1 to about 1:10, about 50:1 to about 1:1, or about 20:1 to about 2:1. For example, the molar ratio of compound I to AMG510 can be about 5:1 or about 10:1.

[0055] In certain embodiments, the molar ratio of compound I to compound II yields a synergistic effect in the range of about 1000:1 to about 1:1000, about 100:1 to about 1:100, about 50:1 to about 1:50, about 20:1 to about 1:10, or about 10:1 to about 1:5. For example, the molar ratio of compound I to compound II can be about 1:2 or about 6:1.

[0056] In certain embodiments, the molar ratio of compound I to MRTX-1133 yields a synergistic effect in the range of about 1000:1 to about 1:20, about 100:1 to about 1:10, about 50:1 to about 1:1, or about 20:1 to about 2:1. For example, the molar ratio of compound I to MRTX-1133 can be about 5:1, about 10:1, or about 15:1.

[0057] In certain embodiments, the molar ratio of compound I to adagrasib yields a synergistic effect in the range of about 1000:1 to about 1:20, about 100:1 to about 1:10, about 50:1 to about 1:1, or about 20:1 to about 2:1. For example, the molar ratio of compound I to adagrasib can be about 10:1 or about 15:1.

[0058] In some embodiments, a combination of a specific concentration of a CLK inhibitor and a specific concentration of at least one additional anticancer agent is administered to a host animal. For example, the host animal may be a human. In certain embodiments, the total daily dose of compound I can be achieved by any of the administration schedules provided herein. In certain embodiments, the total daily dose of compound I present in combination with at least one additional anticancer agent is in the range of about 10 mg to about 500 mg per day, about 25 mg to about 250 mg per day, about 50 mg to about 200 mg per day, or about 100 mg to about 150 mg per day in humans. Administration of compound I can be carried out according to any of the administration schedules described herein.

[0059] In certain embodiments, combinations of Compound I and gilteritinib in a concentration range of about 0.1 mg / kg to about 10 mg / kg, combinations of Compound I in a concentration range of 1 mg / kg to about 5 mg / kg and gilteritinib in a concentration range of about 1 mg / kg to about 5 mg / kg, or combinations of Compound I in a concentration range of about 1 mg / kg to about 3 mg / kg and gilteritinib in a concentration range of about 1 mg / kg to about 3 mg / kg can be administered to humans, for example, to treat AML. The dosage and administration schedule of gilteritinib can be followed according to the manufacturer's instructions or implemented as described herein. In certain embodiments, the total daily dose of Compound I and gilteritinib can be achieved by any of the administration schedules provided herein.

[0060] In certain embodiments, compound I is administered in combination with a total daily dose of gilteritinib in humans, for example, to treat AML, ranging from about 10 mg to about 500 mg per day, about 25 mg to about 250 mg per day, about 50 mg to about 200 mg per day, or about 100 mg to about 150 mg per day. The dosage and administration schedule of gilteritinib can be carried out according to the manufacturer's instructions or as described herein. In certain embodiments, the total daily dose of compound I and gilteritinib can be achieved by any of the administration schedules provided herein.

[0061] In certain embodiments, combinations of Compound I in a concentration range of about 0.1 mg / kg to about 10 mg / kg and venetoclax in a concentration range of about 0.1 mg / kg to about 10 mg / kg, combinations of Compound I in a concentration range of about 1 mg / kg to about 5 mg / kg and venetoclax in a concentration range of about 5 mg / kg to about 10 mg / kg, or combinations of Compound I in a concentration range of about 1 mg / kg to about 3 mg / kg and venetoclax in a concentration range of about 7 mg / kg to about 9 mg / kg can be administered to humans, for example, to treat CLL or SLL. The dosage and administration schedule of venetoclax can be followed according to the manufacturer's instructions or implemented as described herein. In certain embodiments, the total daily dose of Compound I and venetoclax can be achieved by any of the administration schedules provided herein.

[0062] In certain embodiments, compound I is administered in combination with a total daily dose of venetoclax in humans ranging from about 10 mg to about 750 mg per day, about 20 mg to about 600 mg per day, about 100 mg to about 500 mg per day, about 200 mg to about 500 mg per day, or about 300 mg to about 500 mg per day, for example, to treat CLL or SLL. The dosage and administration schedule of venetoclax can be carried out according to the manufacturer's instructions or as described herein. In certain embodiments, the total daily dose of compound I and venetoclax can be achieved by any of the administration schedules provided herein.

[0063] In certain embodiments, combinations of compound I in a concentration range of about 0.1 mg / kg to about 10 mg / kg with azacitidine in a concentration range of about 0.1 mg / kg to about 10 mg / kg, combinations of compound I in a concentration range of about 1 mg / kg to about 5 mg / kg with azacitidine in a concentration range of about 0.1 mg / kg to about 5 mg / kg, or combinations of compound I in a concentration range of about 1 mg / kg to about 3 mg / kg with azacitidine in a concentration range of about 0.2 mg / kg to about 2 mg / kg can be administered to humans, for example, to treat AML. The dosage and administration schedule of azacitidine can be carried out according to the manufacturer's instructions or as described herein. In certain embodiments, the total daily dose of compound I and azacitidine can be achieved by any of the administration schedules provided herein.

[0064] In certain embodiments, compound I is administered in combination with a total daily dose of azacitidine in humans ranging from about 1 mg to about 400 mg per day, about 1 mg to about 300 mg per day, about 1 mg to about 200 mg per day, about 10 mg to about 200 mg per day, about 1 mg to about 100 mg per day, about 5 mg to about 100 mg per day, about 10 mg to about 100 mg per day, or about 10 mg to about 50 mg per day, for example, to treat AML. The dosage and administration schedule of azacitidine can be carried out according to the manufacturer's instructions or as described herein. In certain embodiments, the total daily dose of compound I and azacitidine can be achieved by any of the administration schedules provided herein.

[0065] In certain embodiments, combinations of compound I in a concentration range of about 0.1 mg / kg to about 10 mg / kg and carboplatin in a concentration range of about 0.1 mg / kg to about 15 mg / kg, combinations of compound I in a concentration range of about 1 mg / kg to about 5 mg / kg and carboplatin in a concentration range of about 1 mg / kg to about 10 mg / kg, or combinations of compound I in a concentration range of about 1 mg / kg to about 3 mg / kg and carboplatin in a concentration range of about 3 mg / kg to about 7 mg / kg can be administered to humans, for example, to treat ovarian cancer. The dosage and administration schedule of carboplatin can be carried out according to the manufacturer's instructions or as described herein. In certain embodiments, the total daily dose of compound I and carboplatin can be achieved by any of the administration schedules provided herein.

[0066] In certain embodiments, compound I is administered in humans, for example, to treat ovarian cancer, in combination with a total dose of carboplatin ranging from about 10 mg to about 800 mg per dose, about 25 mg to about 700 mg per dose, about 50 mg to about 600 mg per dose, about 100 mg to about 600 mg per dose, about 200 mg to about 600 mg per dose, about 100 mg to about 500 mg per dose, about 200 mg to about 500 mg per dose, or about 200 mg to about 400 mg per dose. The dosage and administration schedule of carboplatin can be carried out according to the manufacturer's instructions or as described herein. In certain embodiments, the total daily dose of compound I and carboplatin can be achieved by any of the administration schedules provided herein.

[0067] In certain embodiments, combinations of Compound I at a concentration range of about 0.1 mg / kg to about 10 mg / kg with osimertinib at a concentration range of about 0.01 mg / kg to about 5 mg / kg, combinations of Compound I at a concentration range of about 1 mg / kg to about 5 mg / kg with osimertinib at a concentration range of about 0.01 mg / kg to about 2 mg / kg, or combinations of Compound I at a concentration range of about 1 mg / kg to about 3 mg / kg with osimertinib at a concentration range of about 0.05 mg / kg to about 0.5 mg / kg can be administered to humans, for example, to treat non-small cell lung cancer (NSCLC). The dosage and administration schedule of osimertinib can be carried out according to the manufacturer's instructions or as described herein. In certain embodiments, the total daily dose of Compound I and osimertinib can be achieved by any of the administration schedules provided herein.

[0068] In certain embodiments, compound I is administered in combination with a total daily dose of osimertinib in humans at concentrations ranging from approximately 0.1 mg to approximately 200 mg per day, approximately 0.1 mg to approximately 150 mg per day, approximately 1 mg to approximately 100 mg per day, approximately 5 mg to approximately 100 mg per day, approximately 10 mg to approximately 100 mg per day, approximately 1 mg to approximately 50 mg per day, or approximately 1 mg to approximately 25 mg per day, for example, to treat non-small cell lung cancer (NSCLC). The dosage and administration schedule of osimertinib can be carried out according to the manufacturer's instructions or as described herein. In certain embodiments, the total daily dose of compound I and osimertinib can be achieved by any of the administration schedules provided herein.

[0069] In certain embodiments, combinations of Compound I in a concentration range of about 0.1 mg / kg to about 10 mg / kg and adagrasib in a concentration range of about 1 mg / kg to about 25 mg / kg, combinations of Compound I in a concentration range of about 1 mg / kg to about 5 mg / kg and adagrasib in a concentration range of about 1 mg / kg to about 10 mg / kg, or combinations of Compound I in a concentration range of about 1 mg / kg to about 3 mg / kg and adagrasib in a concentration range of about 1 mg / kg to about 5 mg / kg can be administered to humans, for example, to treat non-small cell lung cancer (NSCLC). The dosage and administration schedule of adagrasib can be carried out according to the manufacturer's instructions or as described herein. In certain embodiments, the total daily dose of Compound I and adagrasib can be achieved by any of the administration schedules provided herein.

[0070] In certain embodiments, compound I is administered in combination with a total daily dose of adaglasib ranging from about 10 mg to about 1.5 g / day, about 100 mg to about 1.5 g / day, about 10 mg to about 1 g / day, about 100 mg to about 1 g / day, about 25 mg to about 800 mg / day, about 100 mg to about 600 mg / day, about 100 mg to about 500 mg / day, or about 100 mg to about 300 mg / day in humans to treat non-small cell lung cancer (NSCLC), for example. The dosage and administration schedule of adaglasib can be carried out according to the manufacturer's instructions or as described herein. In certain embodiments, the total daily dose of compound I and adaglasib can be achieved by any of the administration schedules provided herein.

[0071] In certain embodiments, combinations of Compound I in a concentration range of about 0.1 mg / kg to about 10 mg / kg with cytarabine in a concentration range of about 0.1 mg / kg to about 10 mg / kg, combinations of Compound I in a concentration range of about 1 mg / kg to about 5 mg / kg with cytarabine in a concentration range of about 1 mg / kg to about 8 mg / kg, or combinations of Compound I in a concentration range of about 1 mg / kg to about 3 mg / kg with cytarabine in a concentration range of about 2 mg / kg to about 5 mg / kg can be administered to humans, for example, to treat leukemia and lymphoma. The dosage and administration schedule of cytarabine can be carried out according to the manufacturer's instructions or as described herein. In certain embodiments, the total daily dose of Compound I and cytarabine can be achieved by any of the administration schedules provided herein.

[0072] In certain embodiments, compound I is administered in humans, for example, to treat leukemia and lymphoma, in combination with a total dose of cytarabine ranging from about 1 mg to about 500 mg per dose, about 50 mg to about 500 mg per dose, about 100 mg to about 500 mg per dose, about 10 mg to about 400 mg per dose, about 50 mg to about 400 mg per dose, about 100 mg to about 400 mg per dose, about 50 mg to about 300 mg per dose, about 100 mg to about 300 mg per dose, or about 150 mg to about 300 mg per dose. The dose and administration schedule of cytarabine can be carried out according to the manufacturer's instructions or as described herein. In certain embodiments, the total daily dose of compound I and cytarabine can be achieved by any of the administration schedules provided herein.

[0073] Pharmaceutical composition For therapeutic purposes, a pharmaceutical composition comprising the compounds described herein may further comprise one or more pharmaceutically acceptable excipients. A pharmaceutically acceptable excipient is a substance that is non-toxic and biocompatible for administration to a subject. Such excipients facilitate the administration of the compounds described herein and are compatible with the active ingredients. Examples of pharmaceutically acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, colorants, fillers, emulsifiers, or flavoring agents. In preferred embodiments, the pharmaceutical composition according to the present invention is a sterile composition. The pharmaceutical composition can be manufactured using known formulation techniques or formulation techniques available to those skilled in the art.

[0074] Sterile compositions are also intended in this invention, and include compositions that comply with the regulations of the national or regional regulatory authorities that govern such compositions.

[0075] The pharmaceutical compositions and compounds described herein can be formulated as solutions, emulsions, suspensions or dispersions in a suitable pharmaceutical solvent or carrier, or together with a solid carrier to produce various dosage forms such as pills, tablets, lozenges, suppositories, sachets, dragées, granules, powders, re-dissolving powders or capsules, according to conventional methods known in the art. The pharmaceutical compositions of the present invention can be administered by a suitable delivery route, e.g., orally, parenterally, rectally, nasally, topically, or ophthalmally, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.

[0076] For oral administration, the compounds of the present invention can be provided as solid formulations such as tablets or capsules, or as solutions, emulsions, or suspensions. To produce oral compositions, the compounds of the present invention can be formulated to dosages of, for example, about 0.1 mg to 1 g per day, about 1 mg to 50 mg per day, about 50 mg to 250 mg per day, or about 250 mg to 1 g per day. Oral tablets may contain the active ingredient mixed with pharmaceutically acceptable excipients such as diluents, disintegrants, binders, lubricants, sweeteners, flavorings, colorants, and preservatives. Suitable inactive extenders include sodium carbonate, calcium carbonate, sodium phosphate, calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, and sorbitol. Exemplary liquid oral excipients include ethanol, glycerol, and water. Examples of disintegrants include starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, and microcrystalline cellulose, and alginic acid is an exemplary disintegrant. Binders may include starch and gelatin. Lubricants, if present, may be magnesium stearate, stearic acid, or talc. If necessary, tablets may be coated with materials such as glyceryl monostearate or glyceryl distearate to slow absorption in the gastrointestinal tract, or may be enterically coated.

[0077] Capsules for oral administration include hard gelatin capsules and soft gelatin capsules. To manufacture hard gelatin capsules, the active ingredient can be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules can be manufactured by mixing the active ingredient with water, oil (e.g., peanut oil or olive oil), liquid paraffin, a mixture of monoglycerides and diglycerides of short-chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0078] The liquid for oral administration may be in the form of a suspension, solution, emulsion or syrup, or it may be lyophilized or exist as a dried product for dissolution in water or other suitable vehicle before use. The liquid composition may optionally contain pharmaceutically acceptable excipients, e.g., suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel); non-aqueous vehicles, e.g., oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (e.g., p-hydroxybenzoate methyl or propyl, or sorbic acid); humectants, e.g., lecithin; and, if necessary, flavoring agents or colorants.

[0079] For use via parenteral routes, such as intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the present invention may be supplied in a sterile aqueous solution or suspension buffered to an appropriate pH and isotonic pressure, or in an oil that is acceptable for parenteral administration. Suitable aqueous vehicles include Ringer's solution or isotonic sodium chloride. Such forms may exist in unit-dose forms such as ampoules or disposable syringes, multi-dose forms such as vials from which appropriate doses can be drawn, or in solid or pre-concentrated forms that can be used for the preparation of injectable formulations. Exemplary infusion doses range from about 1 to 1000 μg / kg / min of the agent mixed with the pharmaceutical carrier over a period of several minutes to several days.

[0080] For nasal, inhalation, or oral administration, the pharmaceutical compositions of the present invention can be administered, for example, using a spray formulation containing a suitable carrier. The compositions of the present invention can also be formulated as suppositories for rectal administration.

[0081] For topical application, the compounds of the present invention are preferably formulated as a cream or ointment, or a similar vehicle suitable for topical administration. For topical administration, the compounds of the present invention can be mixed with a pharmaceutical carrier at a drug concentration of about 0.1% to about 10% relative to the vehicle. Another method of administering the drugs of the present invention is transdermal administration using a patch formulation.

[0082] Another aspect 1. A method for treating cancer in a host animal, comprising the step of administering to the host animal a therapeutically effective dose of a CLK inhibitor in combination with a therapeutically effective dose of at least one additional anticancer agent. 2. CLK inhibitors, Formula I: [ka] The method according to embodiment 1, wherein the compound or a pharmaceutically acceptable salt thereof. 3. The method according to embodiment 1 or 2, wherein the cancer is a humoral tumor or a solid tumor. 4. Cancers include acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, and ER. +Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), The method according to any one of embodiments 1 to 3, selected from the group consisting of pediatric glioma, prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, cutaneous malignant melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous / clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer. 5. The method according to any one of the above embodiments, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer. 6. The method according to any one of embodiments 1 to 5, wherein the cancer is acute myeloid leukemia (AML). 7. The method according to any one of embodiments 1 to 5, wherein the cancer is chronic lymphocytic leukemia (CLL). 8. The method according to any one of embodiments 1 to 5, wherein the cancer is non-small cell lung cancer (NSCLC). 9. The method according to any one of embodiments 1 to 5, wherein the cancer is ovarian cancer. 10. The method according to any one of embodiments 1 to 9, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor. 11. The method according to embodiment 10, wherein the additional anticancer agent is a Bcl-2 inhibitor. 12. The method according to embodiment 10, wherein the additional anticancer agent is an FLT3 inhibitor. 13. The method according to embodiment 10, wherein the additional anticancer agent is a KRAS inhibitor. 14. The method according to embodiment 10, wherein the additional anticancer agent is an ALK inhibitor. 15. The method according to any one of embodiments 1 to 14, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine or decitabine, or a pharmaceutically acceptable salt thereof. 16. The method according to any one of claims 1 to 11 or 15, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof. 17. The method according to any one of Embodiments 1-10, 12, or 15, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof. 18. The method according to any one of embodiments 1 to 10, 13, or 15, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof. 19. A CLK inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of a patient's cancer in combination with at least one additional anticancer agent in a therapeutically effective dose. 20. CLK inhibitors, Formula I: [ka] The compound according to embodiment 19, which is a compound or a pharmaceutically acceptable salt thereof. 21. The compound according to embodiment 19 or 20, wherein the cancer is a humoral tumor or a solid tumor. 22. Cancers include acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, and ER. +Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), small A compound according to any one of embodiments 19 to 21, selected from the group consisting of pediatric glioma, prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, cutaneous malignant melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous / clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer. 23. The compound according to any one of embodiments 19 to 22, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer. 24. The compound according to any one of embodiments 19 to 23, wherein the cancer is acute myeloid leukemia (AML). 25. The compound according to any one of embodiments 19 to 23, wherein the cancer is chronic lymphocytic leukemia (CLL). 26. The compound according to any one of embodiments 19 to 23, wherein the cancer is non-small cell lung cancer (NSCLC). 27. The compound according to any one of embodiments 19 to 23, wherein the cancer is ovarian cancer. 28. The compound according to any one of embodiments 19 to 27, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor. 29. The compound according to embodiment 28, wherein the additional anticancer agent is a Bcl-2 inhibitor. 30. The compound according to embodiment 28, wherein the additional anticancer agent is an FLT3 inhibitor. 31. The compound according to embodiment 28, wherein the additional anticancer agent is a KRAS inhibitor. 32. The compound according to embodiment 28, wherein the additional anticancer agent is an ALK inhibitor. 33. The compound according to any one of embodiments 19 to 32, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine or decitabine, or a pharmaceutically acceptable salt thereof. 34. The compound according to any one of embodiments 19-29 or 33, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof. 35. The compound according to any one of embodiments 19-28, 30, or 33, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof. 36. The compound according to any one of embodiments 19-28, 31, or 33, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof. 37. Use of a CLK inhibitor or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product comprising a therapeutically effective amount of the compound for the treatment of cancer in a patient, in combination with at least one anticancer agent in a therapeutically effective amount. 38. CLK inhibitors, Formula I: [ka] The use according to embodiment 37, wherein the compound or a pharmaceutically acceptable salt thereof. 39. Use of aspect 37 or 38, wherein the cancer is a humoral tumor or a solid tumor. 40. Cancers include acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, and ER. +Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), small Use according to any one of embodiments 37 to 39, selected from the group consisting of pediatric glioma, prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, cutaneous malignant melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous / clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer. 41. Use according to any one of embodiments 37 to 40, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer. 42. Use according to any one of embodiments 37 to 41, wherein the cancer is acute myeloid leukemia (AML). 43. Use according to any one of embodiments 37 to 41, wherein the cancer is chronic lymphocytic leukemia (CLL). 44. Use according to any one of embodiments 37 to 41, wherein the cancer is non-small cell lung cancer (NSCLC). 45. Use according to any one of embodiments 37 to 41, wherein the cancer is ovarian cancer. 46. ​​The use according to any one of embodiments 37 to 45, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor. 47. The use according to embodiment 46, wherein the additional anticancer agent is a Bcl-2 inhibitor. 48. The use according to embodiment 46, wherein the additional anticancer agent is an FLT3 inhibitor. 49. The use according to embodiment 46, wherein the additional anticancer agent is a KRAS inhibitor. 50. The use according to embodiment 46, wherein the additional anticancer agent is an ALK inhibitor. 51. The use according to any one of embodiments 37 to 50, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine or decitabine, or a pharmaceutically acceptable salt thereof. 52. The use according to any one of embodiments 37-46 or 51, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof. 53. The use according to any one of embodiments 37-46, 48, or 51, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof. 54. The use according to any one of embodiments 37-46, 49, or 51, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof. 55. A composition comprising a therapeutically effective amount of a CLK inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of cancer in a patient, in combination with at least one additional anticancer agent in a therapeutically effective amount. 56. CLK inhibitors, Formula I: [ka] The composition according to embodiment 55 is a compound or a pharmaceutically acceptable salt thereof. 57. The composition according to embodiment 55 or 56, wherein the cancer is a humoral tumor or a solid tumor. 58. Cancers include acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, and ER. +Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), small A composition according to any one of embodiments 55 to 57, selected from the group consisting of pediatric glioma, prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, cutaneous malignant melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous / clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer. 59. The composition according to any one of embodiments 55 to 58, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer. 60. The composition according to any one of embodiments 55 to 59, wherein the cancer is acute myeloid leukemia (AML). 61. The composition according to any one of embodiments 55 to 59, wherein the cancer is chronic lymphocytic leukemia (CLL). 62. The composition according to any one of embodiments 55 to 59, wherein the cancer is non-small cell lung cancer (NSCLC). 63. The composition according to any one of embodiments 55 to 59, wherein the cancer is ovarian cancer. 64. The composition according to any one of embodiments 55 to 63, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor. 65. The composition according to embodiment 64, wherein the additional anticancer agent is a Bcl-2 inhibitor. 66. The composition according to embodiment 64, wherein the additional anticancer agent is an FLT3 inhibitor. 67. The composition according to embodiment 64, wherein the additional anticancer agent is a KRAS inhibitor. 68. The composition according to embodiment 64, wherein the additional anticancer agent is an ALK inhibitor. 69. The composition according to any one of embodiments 55 to 68, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine or decitabine, or a pharmaceutically acceptable salt thereof. 70. The composition according to any one of embodiments 55 to 65 or 69, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof. 71. The composition according to any one of embodiments 55-64, 66, or 69, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof. 72. The composition according to any one of embodiments 55-64, 67, or 69, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof. 73. A pharmaceutical product comprising a CLK inhibitor or a pharmaceutically acceptable salt thereof in combination with at least one additional anticancer agent, either in a fixed dose or in a free combination. 74. CLK inhibitors, Formula I: [ka] A pharmaceutical product according to embodiment 73, which is a compound or a pharmaceutically acceptable salt thereof. 75. The pharmaceutical product according to embodiment 73 or 74, wherein the cancer is a humoral tumor or a solid tumor. 76. Cancers include acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, and ER. +Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), small A pharmaceutical product according to any one of embodiments 73 to 75, selected from the group consisting of pediatric glioma, prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, cutaneous malignant melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous / clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer. 77. A pharmaceutical product according to any one of embodiments 73 to 76, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer. 78. A pharmaceutical product according to any one of the embodiments 73 to 77, wherein the cancer is acute myeloid leukemia (AML). 79. A pharmaceutical product according to any one of the embodiments 73 to 77, wherein the cancer is chronic lymphocytic leukemia (CLL). 80. A pharmaceutical product according to any one of embodiments 73 to 77, wherein the cancer is non-small cell lung cancer (NSCLC). 81. A pharmaceutical product according to any one of the embodiments 73 to 77, wherein the cancer is ovarian cancer. 82. The pharmaceutical product according to any one of embodiments 73 to 81, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor. 83. The pharmaceutical product according to embodiment 82, wherein the additional anticancer agent is a Bcl-2 inhibitor. 84. The pharmaceutical product according to embodiment 82, wherein the additional anticancer agent is an FLT3 inhibitor. 85. The pharmaceutical product according to embodiment 82, wherein the additional anticancer agent is a KRAS inhibitor. 86. The pharmaceutical product according to embodiment 82, wherein the additional anticancer agent is an ALK inhibitor. 87. The pharmaceutically acceptable pharmacopoeia according to any one of embodiments 73 to 86, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine or decitabine, or a pharmaceutically acceptable salt thereof. 88. The pharmacopoeia according to any one of embodiments 73 to 83 or 87, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof. 89. The pharmacopoeia according to any one of embodiments 73-82, 84, or 87, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof. 90. The pharmacopoeia according to any one of embodiments 73-82, 85, or 87, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof. 91. A composition exhibiting a synergistic effect of a CLK inhibitor and at least one anticancer agent, wherein two components are in contact with each other at a gene locus. 92. CLK inhibitors, Formula I: [ka] A composition exhibiting the synergistic effect described in embodiment 90, wherein the compound or a pharmaceutically acceptable salt thereof. 93. A composition exhibiting a synergistic effect according to embodiment 91 or 92, wherein the cancer is a humoral tumor or a solid tumor. 94. Cancers include acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, and ER. +Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in epithelioid, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, squamous cell carcinoma of the head and neck, chronic myelomonocytic leukemia (CML), pediatric glioma A composition exhibiting a synergistic effect according to any one of embodiments 91 to 93, selected from the group consisting of tumors, prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, cutaneous malignant melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous / clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer. 95. A composition exhibiting a synergistic effect according to any one of embodiments 91 to 94, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer. 96. A composition exhibiting a synergistic effect according to any one of embodiments 91 to 95, wherein the cancer is acute myeloid leukemia (AML). 97. A composition exhibiting a synergistic effect according to any one of embodiments 91 to 95, wherein the cancer is chronic lymphocytic leukemia (CLL). 98. A composition exhibiting the synergistic effect according to any one of embodiments 91 to 95, wherein the cancer is non-small cell lung cancer (NSCLC). 99. A composition exhibiting the synergistic effect described in any one of embodiments 91 to 95, wherein the cancer is ovarian cancer. 100. A composition exhibiting a synergistic effect according to any one of embodiments 91 to 99, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor. 101. The composition exhibiting the synergistic effect according to embodiment 100, wherein the additional anticancer agent is a Bcl-2 inhibitor. 102. The composition exhibiting a synergistic effect according to embodiment 100, wherein the additional anticancer agent is an FLT3 inhibitor. 103. The composition exhibiting the synergistic effect according to embodiment 100, wherein the additional anticancer agent is a KRAS inhibitor. 104. The composition exhibiting the synergistic effect according to embodiment 100, wherein the additional anticancer agent is an ALK inhibitor. 105. A composition exhibiting a synergistic effect according to any one of embodiments 91 to 104, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine or decitabine, or a pharmaceutically acceptable salt thereof. 106. A composition exhibiting the synergistic effect according to any one of embodiments 91 to 101 or 105, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof. 107. A composition exhibiting a synergistic effect according to any one of embodiments 91-100, 102, or 105, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof. 108. A composition exhibiting a synergistic effect according to any one of embodiments 91-100, 103, or 105, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof. 109. A composition exhibiting a synergistic effect of a CLK inhibitor and at least one anticancer agent, wherein two components come into contact with each other only within the human body. 110. CLK inhibitors, Formula I: [ka] A composition exhibiting the synergistic effect described in Embodiment 109, wherein the compound or a pharmaceutically acceptable salt thereof. 111. A composition exhibiting a synergistic effect according to embodiment 109 or 110, wherein the cancer is a humoral tumor or a solid tumor. 112. Cancers include acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, and ER. + Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), pediatric glioma A composition exhibiting a synergistic effect according to any one of embodiments 109 to 111, selected from the group consisting of prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous / clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer. 113. A composition exhibiting a synergistic effect according to any one of embodiments 109 to 112, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer. 114. A composition exhibiting a synergistic effect according to any one of embodiments 109 to 113, wherein the cancer is acute myeloid leukemia (AML). 115. A composition exhibiting a synergistic effect according to any one of embodiments 109 to 113, wherein the cancer is chronic lymphocytic leukemia (CLL). 116. A composition exhibiting a synergistic effect according to any one of embodiments 109 to 113, wherein the cancer is non-small cell lung cancer (NSCLC). 117. A composition exhibiting a synergistic effect according to any one of embodiments 109 to 113, wherein the cancer is ovarian cancer. 118. A composition exhibiting a synergistic effect according to any one of embodiments 109 to 117, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor. 119. The composition exhibiting the synergistic effect according to embodiment 118, wherein the additional anticancer agent is a Bcl-2 inhibitor. 120. The composition exhibiting the synergistic effect according to embodiment 118, wherein the additional anticancer agent is an FLT3 inhibitor. 121. The composition exhibiting the synergistic effect according to embodiment 118, wherein the additional anticancer agent is a KRAS inhibitor. 122. The composition exhibiting the synergistic effect according to embodiment 118, wherein the additional anticancer agent is an ALK inhibitor. 123. A composition exhibiting a synergistic effect according to any one of embodiments 109 to 118, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine or decitabine, or a pharmaceutically acceptable salt thereof. 124. A composition exhibiting a synergistic effect according to any one of embodiments 109-119 or 123, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof. 125. A composition exhibiting a synergistic effect according to any one of embodiments 109-118, 120, or 123, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof. 126. A composition exhibiting a synergistic effect according to any one of embodiments 109-118, 121, or 123, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof. [Examples]

[0083] Chemicals and reagents Compound I was prepared according to the method described in International Patent Application No. PCT / US2023 / 068071 (WO2023240140, published December 14, 2023). Specifically, for the preparation of Example 6 described in the aforementioned application, please refer to the content described as General Method B. International Patent Application No. PCT / US2023 / 068071 (WO2023240140, published December 14, 2023) is incorporated herein by reference for the preparation of Example 6.

[0084] Preparation of 2-(5-bromo-1-tetrahydropyran-2-ylindazole-3-yl)ethinyl-triisopropylsilane (I-2) [ka] Step 1. A solution of commercially available 5-bromo-1H-indazole (21.0 g, 107 mmol, 1 eq) in THF (250 mL) was cooled on an ice bath, and KOtBu (35.9 g, 320 mmol, 3 eq) was added in small amounts. The resulting slurry was stirred at 0°C, and a solution of I2 (54.1 g, 213 mmol, 42.9 mL, 2 eq) in THF (250 mL) was added dropwise. The mixture was stirred at 25°C for 12 hours. Upon completion of the reaction, the reaction mixture was filtered, the filtrate was diluted with H2O (20 mL), and extracted with siRNA (20 mL x 3). The combined organic layers were washed with saline solution (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to obtain 5-bromo-3-iodo-1H-indazole (120 g, 350 mmol, yield 82%, purity 94%) as a white solid. LCMS: 324.7 (M+1).

[0085] Step 2. To a mixture of 5-bromo-3-iodo-1H-indazole (25.0 g, 77.4 mmol, 1 eq) and 3,4-dihydro-2H-pyran (13.0 g, 155 mmol, 2 eq) in toluene (250 mL), 4-methylbenzenesulfonic acid (2.67 g, 15.5 mmol, 0.2 eq) was added. The mixture was stirred at 90°C for 12 hours. Upon completion of the reaction, the reaction mixture was diluted with H2O and extracted with siRNA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to obtain 5-bromo-3-iodo-1-tetrahydropyran-2-yl-indazole (24.0 g, 58.9 mmol, yield 76%) as a white solid. 1 H NMR (400MHz, CDCl3)δ= 7.64 (d, J = 1.6Hz, 1H), 7.54 - 7.44 (m, 2H), 5.68 (dd, J = 3.2, 9.1Hz, 1H), 4.04 - 3.95 (m, 1H), 3.79 - 3.66 (m, 1H), 2.58 - 2.46 (m, 1H), 2.20 - 2.03 (m, 2H), 1.87 - 1.54 (m, 3H).

[0086] Step 3. To a mixture of 5-bromo-3-iodo-1-tetrahydropyran-2-yl-indazole (23.0 g, 56.5 mmol, 1 eq) and ethinyl(triisopropyl)silane (11.3 g, 62.2 mmol, 1.1 eq) in DMF (250 mL), Cs2CO3 (55.2 g, 170 mmol, 3 eq), Pd(dppf)Cl2 (2.48 g, 3.39 mmol, 0.06 eq), and CuI (646 mg, 3.39 mmol, 0.06 eq) were added under N2. The mixture was stirred at 25°C for 3 hours. After the reaction was complete, the reaction mixture was diluted with H2O and extracted with siRNA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to obtain compound 2-(5-bromo-1-tetrahydropyran-2-ylindazole-3-yl)ethinyl-triisopropylsilane (I-2, 38.0 g, 79.9 mmol, 70% yield) as a white solid. 1 H NMR (400MHz, CDCl3.)δ= 7.87 (s, 1H), 7.57 - 7.43 (m, 2H), 5.70 (dd, J = 2.4, 9.2Hz, 1H), 4.02 (bd, J = 11.2Hz, 1H), 3.80 - 3.65 (m, 1H), 2.59 - 2.41 (m, 1H), 2.14 (d, J = 3.2Hz, 1H), 2.08 (s, 1H), 1.79 - 1.70 (m, 2H), 1.67 (s, 1H), 1.22 - 1.18 (m, 18H), 1.18 - 1.14 (m, 3H).

[0087] Manufacturing of tert-butyl N-methyl-N-[3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-3-yl]oxyethyl]carbamate (I-4) [ka] Step 1: A mixture of commercially available 2-methylpyrazole-3-ol (5 g, 50.9 mmol, 1 eq.) and tert-butyl N-(2-bromoethyl)carbamate (13.7 g, 61.1 mmol, 1.2 eq.) in DMF (50 mL) was mixed with K2CO3 (21.1 g, 152 mmol, 3 eq.). The mixture was stirred at 80°C for 2 hours. After the reaction was complete, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain tert-butyl N-[2-(2-methylpyrazole-3-yl)oxyethyl]carbamate (11 g, 45.5 mmol, 89.45% yield) as a black oil. LCMS: (M+1:242.2)

[0088] Step 2: To a solution of tert-butyl N-[2-(2-methylpyrazole-3-yl)oxyethyl]carbamate (2 g, 8.29 mmol, 1 eq.) in THF (20 mL), NaH (497 mg, 12.4 mmol, 60% purity, 1.5 eq.) was added at 0°C, and the mixture was stirred at 25°C for 0.5 hours. Then CH3I (1.41 g, 9.95 mmol, 619 μL, 1.2 eq.) was added at 25°C. The mixture was stirred at 25°C for 3 hours. After the reaction was complete, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain tert-butyl N-methyl-N-[2-(2-methylpyrazole-3-yl)oxyethyl]carbamate (2 g, 7.83 mmol, 94.5% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6.)δ= 7.20 (d, J = 2.0Hz, 1H), 5.65 (d, J = 2.0Hz, 1H), 4.17 - 4.10 (m, 2H), 3.58 - 3.48 (m, 5H), 2.85 (d, J = 6.4Hz, 3H), 1.37 (d, J = 19.2Hz, 9H).

[0089] Step 3: To a solution of tert-butyl N-methyl-N-[2-(2-methylpyrazole-3-yl)oxyethyl]carbamate (2 g, 7.83 mmol, 1 eq.) in ACN (20 mL), NBS (1.44 g, 8.07 mmol, 1.03 eq.) was added. The mixture was stirred at 25°C for 2 hours. Upon completion of the reaction, the mixture was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0~1:1) to obtain tert-butyl N-[2-(4-bromo-2-methylpyrazole-3-yl)oxyethyl]-N-methyl-carbamate (1.73 g, 5.18 mmol, 66.08% yield) as a red oil. 1 H NMR(400MHz, DMSO-d6)δ= 7.32(s, 1H), 4.24(t, J = 5.6Hz, 2H), 3.54 (s, 3H), 3.48 (t, J = 5.6Hz, 2H), 2.81 (s, 3H), 1.31 (d, J = 4.0Hz, 9H).

[0090] Step 4. To a solution of tert-butyl N-[2-(4-bromo-2-methylpyrazole-3-yl)oxyethyl]-N-methyl-carbamate (I-3, 20.0 g, 59.8 mmol, 1 eq) prepared according to the method described in WO2022 / 133037 (the entirety of which is incorporated herein by reference) (specifically, to prepare N-[2-(4-bromo-2-methylpyrazole-3-yl)oxyethyl]-N-methyl-carbamate) in THF (200 mL), n-BuLi (2.5 M, 23.9 mL, 1 eq) was added at -78°C, and the mixture was stirred at this temperature for 30 minutes. Then, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (22.2 g, 119 mmol, 2 eq) was added dropwise at -78°C. The mixture was stirred at -78°C for 2 hours. Upon completion of the reaction, the mixture was quenched with water (200 mL) and extracted with ethyl acetate (250 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography to obtain I-4 (21.2 g, 55.6 mmol, 92% yield) as a yellow oil. LCMS: m / z 381.9 (M+1).

[0091] (17E)-16-ethyl-8,12,14-trimethyl-2,11,12,14-tetrahydro-8H-3,5-ethenotripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-13(10H)-one (compound I) [ka] Step 1. Dioxane (50 mL) contains 2-(5-bromo-1-tetrahydropyran-2-yl-indazole-3-yl)ethinyl-triisopropylsilane (I-2, 5.00 g, 10.83 mmol, 1 eq), tert-butyl N-methyl-N-[2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-3-yl]oxyethyl]carbamate (I-4, 4.96 g, 13.00 mmol, 1.2 eq), Pd(dppf)Cl2 (1.59 g, 2.17 mmol, 0.2 eq), and Cs2CO3 (2M, 16.25 mL, 3 The mixture of eq) was degassed, purged three times with N2, and then stirred at 80°C for 5 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure and the solvent was removed. The residue was diluted with H2O (50 mL) and extracted with toluene (60 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried on anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain the residue, which was purified by column chromatography to obtain I-5 (5.00 g, 7.86 mmol, 72.6% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3.)δ= 7.82 (s, 1H), 7.65 - 7.55 (m, 3H), 5.72 (dd, J = 2.8, 9.2Hz, 1H), 4.00 (s, 2H), 3.76 (s, 3H), 3.56 - 3.47 (m, 2H), 2.99 - 2.93 (m, 3H), 2.62 - 2.48 (m, 1H), 2.16 (dd, J = 3.6, 8.4Hz, 1H), 1.83 - 1.59 (m, 5H), 1.47 (s, 3H), 1.41 - 1.31 (m, 6H), 1.21 - 1.18 (m, 21H).

[0092] Step 2. ZnBr2 (1.77 g, 7.86 mmol, 5 eq) was added to a solution of I-5 (1 g, 1.57 mmol, 1 eq) / CH2Cl2 (10 mL). The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the solvent was removed. The residue was purified by column chromatography to obtain I-6 (800 mg, 1.49 mmol, 95.0% yield) as a yellow solid. LCMS: m / z 536.1 (M+1).

[0093] Step 3. To a solution of I-6 (1.5 g, 2.80 mmol, 1 eq) and 5-ethyl-4-iodo-2-methylpyrazole-3-carboxylic acid (commercial product, 705 mg, 2.52 mmol, 0.9 eq) in CH2Cl2 (30 mL), DIPEA (2.89 g, 22.4 mmol, 8 eq) and T3P (3.56 g, 5.60 mmol, 50% purity, 2 eq) were added. The reaction mixture was stirred at 40°C for 12 hours. The reaction mixture was then partitioned between H2O (50 mL) and CH2Cl2 (30 mL). The organic phase was separated, washed with saline solution (30 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by column chromatography to obtain I-7 (1.15 g, 1.37 mmol, 49.0% yield, 95.1% purity) as a yellow, rubbery substance. LCMS: (M+1: 798.4).

[0094] Step 4. To a solution of I-7 (1.15 g, 1.44 mmol, 1 eq) in DMSO (12 mL), CsF (438 mg, 2.88 mmol, 2 eq) was added. The mixture was stirred at 40°C for 12 hours. The reaction mixture was partitioned between H2O (10 mL) and HCl (10 mL). The organic phase was separated, washed with saline solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash silica gel chromatography to obtain I-8 (650 mg, 1.01 mmol, 70.3% yield) as a yellow oil. 1H NMR (400MHz, DMSO-d6)δ= 7.87 - 7.43 (m, 4H), 5.93 - 5.85 (m, 1H), 4.55 (d, J = 7.6Hz, 1H), 4.22 - 4.09 (m, 1H), 3.94 - 3.61 (m, 8H), 3.58 - 3.46 (m, 2H), 3.16 - 3.00 (m, 3H), 2.56 - 2.52 (m, 3H), 2.40 - 2.28 (m, 1H), 2.09 - 1.95 (m, 2H), 1.81 - 1.68 (m, 1H), 1.65 - 1.55 (m, 2H), 1.20 - 1.13 (m, 3H).

[0095] Step 5. A mixture of I-8 (650 mg, 1.01 mmol, 1 eq), Pin2B2 (257 mg, 1.01 mmol, 1 eq), PPh3 (266 mg, 1.01 mmol, 1 eq), and Cu2O (72.5 mg, 0.507 mmol, 0.5 eq) in dioxane (12 mL) was degassed three times with N2, purged, and stirred at 100°C for 12 hours under an N2 atmosphere. The reaction mixture was partitioned between H2O (30 mL) and siRNA (30 mL). The organic phase was separated, washed with saline solution (20 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by flash silica gel chromatography to obtain I-9 (750 mg, 0.974 mmol, 96.2% yield) as a yellow solid. LCMS: m / z 770.4 (M+1).

[0096] Step 6. A mixture of I-9 (700 mg, 0.91 mmol, 1 eq), Cs2CO3 (889 mg, 2.73 mmol, 3 eq) and Pd(dppf)Cl2 (66.6 mg, 0.91 mmol, 0.1 eq) in dioxane (12 mL) and H2O (1.2 mL) was degassed and purged three times with N2. Then the mixture was stirred at 90 °C for 12 h under a N2 atmosphere. The reaction mixture was partitioned between H2O (10 mL) and EtOAc (10 mL). The organic phase was separated, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography to give I-10 (140 mg, 0.271 mmol, 29.7% yield) as a yellow oil. LCMS: m / z 516.3 (M+1).

[0097] Step 7. TFA (1 mL) was added to a solution of I-10 (140 mg, 0.271 mmol, 1 eq) in CH2Cl2 (2 mL). The mixture was stirred at 15 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with NaHCO3 (10 mL) and extracted with CH2Cl2 (5 mL×2). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography to give Compound I (56.9 mg, 0.130 mmol, 48.0% yield) as an off-white solid.

[0098] Compound II was prepared according to the method described in International Patent Application No. PCT / US2023 / 027125 (WO2024015262, published on January 18, 2024). Specifically, see the preparation of Example 1 described in the said application specification. International Patent Application No. PCT / US2023 / 027125 (WO2024015262, published on January 18, 2024) is incorporated herein by reference to the preparation of Example 1 described in such specification.

[0099] 5-Ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-ol (Compound II)

Chem.

[0100] Step 1. Commercially available 4-amino-2,6-dichloro-5-fluoropyridine-3-carboxylic acid (II-1, 2.9 g, 12.89 mmol, 1 eq) was added to SOCl2 (82.00 g, 689.25 mmol, 53.48 eq), and the mixture was stirred at 50 °C for 1 hour. At the completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove SOCl2, and 4-amino-2,6-dichloro-5-fluoropyridine-3-carbonyl chloride (II-2, 2.2 g, 9.04 mmol, crude product) was obtained as a brown oil.

[0101] Step 2. NH4SCN (1.97 g, 25.88 mmol, 3 eq) was added to a solution of 4-amino-2,6-dichloro-5-fluoropyridine-3-carbonyl chloride (II-2, 2.1 g, 8.63 mmol, 1 eq) in acetone (60 mL). The mixture was stirred at 25 °C for 1 hour. At the completion of the reaction, the reaction mixture was concentrated to remove the solvent, and 5,7-dichloro-8-fluoro-2-sulfanylpyrido[4,3-d]pyrimidin-4(3H)-one (II-3, 1.2 g, 4.51 mmol, crude product) was obtained as a brown solid. LCMS: m / z 263.1 (M+1).

[0102] Step 3.5,7-Dichloro-8-fluoro-2-sulfanylpyrido[4,3-d]pyrimidine-4(3H)-one (II-3, 1.1 g, 4.13 mmol, 1 eq) was dissolved in MeOH (7.5 mL), to which NaOH (0.1 M, 82.68 mL, 2 eq) and MeI (1.17 g, 8.27 mmol, 2 eq) were added. The mixture was stirred at 25°C for 1 hour. Upon completion of the reaction, the mixture was diluted with water (50 mL), 6 M hydrochloric acid was added to adjust the pH to 6, filtered, and the filtrate was concentrated under reduced pressure to remove MeOH, yielding 5,7-Dichloro-8-fluoro-2-(methylsulfanyl)pyrido[4,3-d]pyrimidine-4(3H)-one (II-4, 1.1 g, 3.93 mmol, crude product) as a gray solid. LCMS: m / z 279.9 (M+1).

[0103] Step 4. To a 10 mL solution of commercially available tert-butyl(2S)-2-(hydroxymethyl)piperidine-1-carboxylate (II-5, 845.46 mg, 3.93 mmol, 1 eq) in THF (0°C), NaH (314.14 mg, 7.85 mmol, 60% purity, 2 eq.) was added and stirred for 0.5 hours. Then, 5,7-dichloro-8-fluoro-2-(methylsulfanyl)pyrido[4,3-d]pyrimidine-4(3H)-one (II-4, 1.1 g, 3.93 mmol, 1 eq) was added at 0°C. The mixture was stirred at 25°C for 1.5 hours. Upon completion of the reaction, the reaction mixture was quenched by adding a saturated aqueous solution of NH4Cl / water (10 mL) at 0°C. The residue was diluted with 50 mL of H2O and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, CH2Cl2 / MeOH = 1 / 0~0 / 1) to obtain tert-butyl(2S)-2-({[7-chloro-8-fluoro-4-hydroxy-2-(methylsulfanyl)pyrido[4,3-d]pyrimidine-5-yl]oxy}methyl)piperidine-1-carboxylate (II-6, 650 mg, 1.42 mmol, 36% yield) as a yellow solid. LCMS: m / z 358.9 (M-100+1).

[0104] Step 5. A solution of tert-butyl(2S)-2-({[7-chloro-8-fluoro-4-hydroxy-2-(methylsulfanyl)pyrido[4,3-d]pyrimidine-5-yl]oxy}methyl)piperidine-1-carboxylate (II-6, 500 mg, 1.09 mmol, 1 eq) in POCl3 (16.50 g, 107.61 mmol, 98.77 eq) was stirred at 80°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the POCl3. Next, CH2Cl2 (10 mL) was added, followed by DIEA (422.42 mg, 3.27 mmol, 3 eq) at 0°C, and the mixture was stirred for 1 hour. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~0 / 1) to obtain (8aS)-5-chloro-4-fluoro-2-(methylsulfanyl)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (II-7, 180 mg, 0.528 mmol, 49% yield) as a white solid. LCMS: m / z 340.9 (M+1).

[0105] Step 6. (8aS)-5-chloro-4-fluoro-2-(methylsulfanyl)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (II-7, 90 mg, 0.264 mmol, 1 eq) is dissolved in THF (1 mL) and H2O (0.2 mL) with K3PO4 (168.17 mg, 0.792 mmol, 3 eq), and commercially available {[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl]ethinyl}tri(propan-2-yl)silane (II-8, 203.03 mg, 0.396 mmol, 1.5 eq) and [2-(2-aminophenyl)phenyl]palladium(1+); bis(1-adamantyl)-butyl-phosphine; methanesulfonate (19.23 mg, 0.0264 mmol, 0.1 eq) were added under N2 conditions. The mixture was stirred under microwave at 80°C for 2 hours. Upon completion of the reaction, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4:1 to 1:1) to obtain (8aS)-4-fluoro-5-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalene-1-yl]-2-(methylsulfanyl)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (II-9, 94 mg, 0.136 mmol, 52% yield) as a brown solid. 1H NMR (400MHz, CHLOROFORM-d)δ= 7.69 - 7.56 (m, 1H), 7.41 - 7.32 (m, 1H), 7.30 - 7.24 (m, 1H), 7.20 - 7.11 (m, 2H), 5.22 - 5.13 (m, 2H), 4.40 - 4.24 (m, 2H), 3.47 - 3.33 (m, 3H), 2.04 - 1.90 (m, 2H), 1.88 - 1.80 (m, 2H), 1.79 - 1.70 (m, 2H), 1.67 - 1.56 (m, 2H), 1.55 - 1.49 (m, 3H), 1.04 - 0.65 (m, 21H).LCMS:m / z 691.4 (M+1).

[0106] Step 7. (8aS)-4-fluoro-5-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalene-1-yl]-2-(methylsulfanyl)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (II-9, 84 mg, 0.122 mmol, 1 eq) was dissolved in CH2Cl2 (1 mL) and m-CPBA (61.71 mg, 0.304 mmol, 85% purity, 2.5 eq) was added at 0°C. The mixture was stirred at 25°C for 1 hour. Upon completion of the reaction, the reaction mixture was quenched at 0°C by adding a saturated solution of Na2SO3 / water (30 mL) and extracted with CH2Cl2 (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 1 / 0~0 / 1) to obtain (8aS)-4-fluoro-5-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalene-1-yl]-2-(methanesulfonyl)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (II-10, 65 mg, 0.0899 mmol, 74% yield) as a brown oil. LCMS: m / z 723.4 (M+1).

[0107] Step 8. A 0.5 mL solution of (8aS)-4-fluoro-5-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalene-1-yl]-2-(methanesulfonyl)-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (II-10, 65 mg, 0.0899 mmol, 1 eq) and t-BuOK (30.27 mg, 0.270 mmol, 3 eq) is degassed / purged three times with N2 at 0°C, and then commercially available [(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl]methanol (II-11, 42.94 mg (0.270 mmol, 3 eq) was added at 0°C, and the mixture was stirred at 25°C for 1 hour under an N2 atmosphere. Upon completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4:1 to 0:1) to obtain (8aS)-4-fluoro-5-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalene-1-yl]-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl]methoxy}8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (II-12, 75 mg, 0.0888 mmol, 99% yield) as a white solid. LCMS: m / z 802.4 (M+1).

[0108] Step 9. (8aS)-4-fluoro-5-[7-fluoro-3-(methoxymethoxy)-8-{[tri(propan-2-yl)silyl]ethynyl}naphthalene-1-yl]-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl]methoxy}8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene (II-12, 68 mg, 0.0848 mmol, 1 eq) was dissolved in CH2Cl2 (1 mL) and HCl / dioxane (4 M, 0.2 mL, 9.44 eq) was added. The mixture was stirred at 25°C for 0.5 hours. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain 6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (II-13, 55 mg, crude product). LCMS: m / z 758.3 (M+1).

[0109] Step 10.6-Fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl]methoxy}8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]-5-{[tri(propan-2-yl)silyl]ethynyl}naphthalen-2-ol (II-13, 55 mg, 0.0726 mmol, 1 eq) was dissolved in DMSO (0.5 mL) and CsF (66.14 mg, 0.435 mmol, 6 eq) was added. The mixture was stirred at 25°C for 1 hour. Upon completion of the reaction, the mixture was filtered. The filtrate was purified by prep-HPLC [column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 22%~42%, 58 min] to obtain 5-ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl]methoxy}8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol (compound II, 16.59 mg, 0.0256 mmol, 35.30% yield as formate) as a brown, rubbery substance. 1H NMR (400MHz, DMSO-d6)δ= 10.29 - 9.99 (m, 1H), 7.99 - 7.93 (m, 1H), 7.46 (t, J = 8.8Hz, 1H), 7.37 (d, J = 2.4Hz, 1H),7.18 - 7.12 (m, 1H), 5.38 - 5.19 (m, 1H), 4.52 - 4.38 (m, 2H), 4.06 (s, 2H), 4.01 - 3.91 (m, 2H), 3.13 - 3.07 (m, 2H), 3.03 (br s, 2H), 2.87 - 2.79 (m, 1H), 2.15 - 2.05 (m, 2H), 2.03 - 1.98 (m, 1H), 1.95 - 1.66 (m, 10H). LCMS: m / z 602.2 (M+1).

[0110] (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f]:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]propan-1-ol (compound (III)); also described in International Patent Application No. PCT / US2024 / 027195, the entire contents of which are incorporated herein by reference.

[0111] Part I: Preparation of (2S)-2-[2,5-dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-methylpropane-1-amine (III-1) [ka]

[0112] Step 1. To a mixture of 2,4-dimethylpyridine-3-amine (25.0 g, 204.64 mmol, 1 eq) / CH2Cl2 (500 mL), a solution of Br2 (163 g, 1.02 mol, 52.75 mL, 5 eq.) in CH2Cl2 (300 mL) was added dropwise at 0°C, and the mixture was stirred at 25°C for 12 hours. To this mixture, an aqueous solution of Na2SO3 (300 mL) was added, and the mixture was stirred at 25°C for 1 hour, after which NaHCO3 (300 mL) was slowly added to adjust the pH to 7. The mixture was extracted with CH2Cl2 (300 mL × 3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:1) to obtain 6-bromo-2,4-dimethylpyridine-3-amine (62.0 g, 308 mmol, 75.3% yield, 100% purity) as a yellow oily substance. 1 H NMR (400MHz, CDCl3.) δ= 7.02 (s, 1H), 3.45 (d, J = 16.4Hz, 2H), 2.37 (s, 3H), 2.13 (s, 3H).

[0113] Step 2. To a mixture of 6-bromo-2,4-dimethylpyridine-3-amine (25.0 g, 204.64 mmol, 1 eq) / AcOH (300 mL), NaNO2 (11.3 g, 164 mmol, 1.1 eq) was added at 0°C, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with H2O (50 mL) and extracted with CH2Cl2 (50 mL × 3). The combined organic layers were washed with saline solution (30 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reverse-phase HPLC (0.1% FA conditions) to obtain the compound 5-bromo-7-methyl-1H-pyrazolo[3,4-c]pyridine (20.0 g, 94.3 mmol, yield 63.2%) as a yellow solid. 1H NMR (400MHz, CDCl3) δ = 11.63 - 11.02 (m, 1H), 8.09 (s, 1H), 7.71 (s, 1H), 2.84 (s, 3H).

[0114] Step 3. To a solution of 5-bromo-7-methyl-1H-pyrazolo[3,4-c]pyridine (34.0 g, 160 mmol, 1 eq) in THF (450 mL), t-BuOK (54.0 g, 481 mmol, 3 eq) was added, followed by I2 (40.7 g, 160 mmol, 32.3 mL, 1 eq). The mixture was stirred at 25°C for 3 hours. Upon completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by CombiFlash (12 g silica gel column, PE with 0-100% THF) to obtain 5-bromo-3-iodo-7-methyl-1H-pyrazolo[3,4-c]pyridine (3.10 g, 9.17 mmol, 1 eq) as a yellow solid. LCMS: (M+1: 337.9).

[0115] Step 4. To a solution of 5-bromo-3-iodo-7-methyl-1H-pyrazolo[3,4-c]pyridine (3.10 g, 9.17 mmol, 1 eq) in toluene (31 mL), TsOH (316 mg, 1.83 mmol, 0.2 eq.) and 3,4-dihydro-2H-pyran (1.93 g, 22.9 mmol, 2.10 mL, 2.5 eq) were added. The mixture was stirred at 90°C for 16 hours, filtered, and the filtrate was concentrated under vacuum. The residue was purified by CombiFlash (12 g silica gel column, ELISA 0-100% / PE). 5-bromo-3-iodo-7-methyl-1-tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridine (2.57 g, 6.09 mmol, 66.38% yield) was obtained as a pale yellow solid. 1H NMR (400MHz, DMSO-d6.)δ= 7.53 (s, 1H), 6.12 (dd, J = 9.2, 2.2Hz, 1H), 3.88 (d, J = 11.6Hz, 1H), 3.73 (d, J = 2.4Hz, 1H), 2.90 (s, 3H), 2.45 - 2.37 (m, 1H), 2.12 - 2.03 (m, 2H), 1.81 - 1.66 (m, 2H), 1.47 - 1.43 (m, 1H). LCMS:(M+1:421.9).

[0116] Step 5. Potassium hydride; trifluoro(vinyl)boron (816 mg, 6.09 mmol, 1 eq.), and 5-bromo-3-iodo-7-methyl-1-tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridine (2.57 g, 6.09 mmol, 1 eq.) were dissolved in a mixed solvent of dioxane (25 mL) and H2O (5 mL). Pd(dppf)Cl2 (445 mg, 609 mmol, 0.1 eq.) and Na2CO3 (1.94 g, 18.3 mmol, 3 eq.) were added to this solution. The mixture was stirred under N2 at 80°C for 16 hours. It was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by CombiFlash (20 silica gel column, CH2Cl2 100%) to obtain 5-bromo-7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine (1.00 g, 3.10 mmol, 50.9% yield) as a dark brown solid. LCMS: (M+1:322.0).

[0117] In a mixture of 5-bromo-7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine (1.10 g, 3.41 mmol, 1 eq), commercially available 2,5-dimethylpyrazol-3-ol (498 mg, 4.44 mmol, 1.3 eq.), and K2CO3 (1.42 g, 10.24 mmol, 3 eq.) in dioxane (11 mL), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-tert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (117 mg, 136 μmol, 0.04 eq.) was added, and after purging three times with N2, the mixture was stirred at 110 °C for 1.5 h under a N2 atmosphere. At the completion of the reaction, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by combiflash (20 g silica gel column, THF 0 - 100% / PE) to give 2,5-dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol (970 mg, 2.74 mmol, 1 eq) as a yellow oil. LCMS: (M+1: 354.1).

[0118] Step 7.2,5-dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinylpyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-ol (970 mg, 2.74 mmol, 1 eq.) in a 10 mL THF solution was mixed with commercially available tert-butyl N-[(2R)-2-hydroxypropyl]carbamate (962 mg, 5.49 mmol, 2 eq.), PPh3 (1.44 g, 5.49 mmol, 2 eq.), and DBAD (948 mg, 4.12 mmol, 1.5 eq.). The mixture was stirred at 25°C for 2 hours. Upon completion of the reaction, the mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified using CombiFlash (20 g silica gel column, THF 0-100% / PE) to obtain tert-butyl N-[(2S)-2-[2,5-dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxypropyl]carbamate (1.75 g, crude product) as a yellow oily substance. 1 H NMR (400MHz, DMSO-d6.)δ= 6.79 (s, 1H), 6.59 (d, J = 8.0Hz, 1H), 6.16 (br d, J = 8.0Hz, 1H), 5.59 (d, J = 3.6Hz, 1H),5.37 (s, 2H), 4.06 (s, 6H), 1.58 (q, J = 7.6Hz, 3H), 0.49 - 0.25 (m, 17H). LCMS:(M+1:511.6).

[0119] Step 8. To a solution of tert-butyl N-[(2S)-2-[2,5-dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinylpyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxypropyl]carbamate (1.70 g, 3.33 mmol, 1 eq) in DMF (17 mL), NaH (399 mg, 9.99 mmol, purity 60%, 3 eq.) and CH3I (709 mg, 4.99 mmol, 311 μL, 1.5 eq.) were added. The mixture was stirred at 20°C for 1 hour. Upon completion of the reaction, the reaction mixture was quenched with H2O (70 mL) at 25°C and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with H2O (40 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by CombiFlash (20 g silica gel column, THF 0-100% / PE) to obtain tert-butyl N-[(2S)-2-[2,5-dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxypropyl]-N-methyl-carbamate (1.76 g, 1.68 mmol, 50% yield, 50% purity) as a yellow solid. LCMS: (M+1:525.3).

[0120] Step 9. To a solution of tert-butyl N-[(2S)-2-[2,5-dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxypropyl]-N-methyl-carbamate (1.70 g, 3.24 mmol, 1 eq) in CH2Cl2 (17 mL), ZnBr2 (3.65 g, 16.2 mmol, 811 μL, 5 eq) was added. The mixture was stirred at 25°C for 2 hours. After completion, the reaction mixture was quenched with H2O (25 mL) at 25°C, extracted with CH2Cl2 (15 mL x 4), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by CombiFlash (20 g silica gel column, THF 0-100% / PE) to obtain (2S)-2-[2,5-dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-methylpropan-1-amine (III-1, 550 mg, 1.30 mmol, 40% yield) as a white solid. 1 H NMR (400MHz, MeOD-d4.) δ = 7.82 (d, J = 3.2Hz, 1H), 7.05 (dd, J = 11.6, 18.0Hz, 1H), 6.16 (d, J = 18.0Hz, 1H),6.07 - 6.01 (m, 1H), 5.59 (d, J = 11.6Hz, 1H), 4.42 - 4.32 (m, 1H), 4.04 - 3.95 (m, 1H), 3.90 - 3.80 (m, 1H), 3.71 (s, 3H), 3.17 -3.10 (m, 1H), 3.03 - 2.98 (m, 4H), 2.70 - 2.61 (m, 1H), 2.58 (d, J = 2.4Hz, 3H), 2.25(d, J = 1.2Hz, 3H), 2.22 - 2.15 (m, 2H), 1.92 - 1.78 (m, 1H), 1.75 - 1.61 (m, 2H), 1.14 (dd, J = 2.8, 6.4Hz, 3H).LCMS:(M+1:425.2).

[0121] Part II: Preparation of 2-[[5-(bromomethyl)-1-[(1S)-2-[tert-butyl(dimethyl)silyl]-oxy-1-methyl-ethyl]-4-iodopyrazole-3-yl]oxymethoxy]ethyl-trimethylsilane (III-2) [ka] Step 1. Commercially available ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (10.0 g, 64 mmol, 1 eq), SEM-Cl (42.7 g, 256 mmol, 4 eq), and TEA (38.9 g, 384 mmol, 6 eq) were mixed in CH2Cl2 (100 mL) at 0°C, and the mixture was stirred at 25°C for 1 hour. Upon completion of the reaction, the mixture was diluted with water (500 mL) and extracted with CH2Cl2 (100 mL x 3). The combined organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by silica gel column chromatography (120 g silica gel, ethyl acetate from 0% to 100% in petroleum ether) to obtain 3-(2-trimethylsilylethoxymethoxy)-1H-pyrazole-5-carboxylate (10.6 g, 35.8 mmol, 56% yield) as a colorless oil. LCMS: (M+1-28: 259.0).

[0122] Step 2. To a mixture of ethyl 3-(2-trimethylsilylethoxymethoxy)-1H-pyrazole-5-carboxylate (10.0 g, 34.9 mmol, 1 eq), (2R)-1-[tert-butyl(dimethyl)silyl]oxypropan-2-ol (13.3 g, 69.8 mmol, 2 eq), and PPh3 (20.1 g, 76.8 mmol, 2.2 eq) in THF (230 mL), DIAD (17.7 g, 87.3 mmol, 2.5 eq) was added at 0°C. The resulting mixture was stirred under N2 at 25°C for a further 2 hours. Upon completion of the reaction, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (80 g silica gel, ethyl acetate from 0% to 100% in petroleum ether) to obtain ethyl 2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-(2-trimethylsilylethoxymethoxy)pyrazole-3-carboxylate (16.1 g, 31.6 mmol, 90% yield) as a yellow oily substance. 1 H NMR (400MHz, DMSO-d6) δ = 6.33 - 6.28 (m, 1H), 5.38 - 5.28 (m, 1H), 5.21 - 5.16 (m, 2H), 4.29 - 4.21 (m, 2H), 3.72 - 3.65 (m, 4H), 0.92 - 0.83 (m, 6H), 0.73 (s, 9H), 0.05 - 0.02 (m, 2H), -0.01 - 0.04 (m, 9H), -0.09 (s, 3H), -0.17 (s, 3H).

[0123] Step 3. To a solution of ethyl 2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-(2-trimethylsilylethoxymethoxy)pyrazole-3-carboxylate in THF (155 mL), LiAlH4 (2.50 M, 13.5 mL, 1 eq) was added at 0°C. The mixture was stirred at 25°C for 0.5 hours. Upon completion of the reaction, the mixture was quenched at 0°C by slowly adding water (1.5 ml), 15% aqueous sodium hydroxide solution (1.5 ml), and water (5 ml). The reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography using silica gel (40 g silica gel, ethyl acetate 0% to 100% / petroleum ether) to obtain [2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-(2-trimethylsilylethoxymethoxy)pyrazole-3-yl]methanol (7.25 g, 17.3 mmol, 51% yield) as a colorless oil. LCMS: (M+1:417.1).

[0124] Step 4. To a solution of [2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-5-(2-trimethylsilylethoxymethoxy)pyrazole-3-yl]methanol (6.70 g, 16.1 mmol, 1 eq) in ACN (70 mL), NIS (3.98 g, 17.7 mmol, 1.1 eq) was added at 0°C for 0.5 hours. The mixture was then stirred at 25°C for 1.5 hours. Upon completion of the reaction, the reaction mixture was quenched with saturated sodium sulfite aqueous solution (70 mL) at 0°C, diluted with H2O (260 mL), and extracted with ethyl acetate (100 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g silica gel, ethyl acetate 0% to 100% / petroleum ether) to obtain [2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-4-iodo-5-(2-trimethylsilylethoxymethoxy)pyrazole-3-yl]methanol (7.60 g, 13.6 mmol, 85% yield) as a colorless oil. LCMS: (M+1:543.1).

[0125] Step 5.2-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-4-iodo-5-(2-trimethylsilylethoxymethoxy)pyrazole-3-yl]methanol (7.00 g, 12.9 mmol, 1 eq) and CBr4 (5.13 g, 15.5 mmol, 1.2 eq) in CH2Cl2 (70 mL) were mixed with PPh3 (4.06 g, 15.5 mmol, 1.2 eq) at 0°C. The mixture was stirred at 25°C for 1.5 hours. After the reaction was complete, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography using silica gel (40 g silica gel, ethyl acetate 0% to 100% / petroleum ether) to obtain 2-[[5-(bromomethyl)-1-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-4-iodopyrazole-3-yl]oxymethoxy]ethyl-trimethylsilane (III-2, 3.50 g crude product, purity approximately 62%) as a colorless oil. LCMS: (M+1: 607.0). This crude product was used directly in the following alkylation reaction.

[0126] Part III: Preparation of (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecine-14-yl]propan-1-ol (Compound III) [ka]

[0127] Step 1. K2CO3 (186 mg, 1.34 mmol, 3 eq.) was added to a 2 mL solution of (2S)-2-[2,5-dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl)-oxy-N-methylpropan-1-amine (III-1, 190 mg, 447 μmol, 1 eq.) and 2-[[5-(bromomethyl)-1-[(1S)-2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethyl]-4-iodopyrazole-3-yl]oxymethoxy]ethyl-trimethylsilane (III-2, 325 mg, 537 μmol, 1.2 eq.) in DMF (2 mL). The reaction mixture was stirred at 80°C for 1 hour. Upon completion of the reaction, the reaction mixture was quenched with H2O (8 mL) at 25°C and extracted with ethyl acetate (8 mL x 3). The combined organic layers were washed with H2O (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by CombiFlash (4 g silica gel column, THF 0-100% / PE) to obtain (2S)-N-[[2-[(1S)-2-[tert-butyl(dimethyl)silyl]-oxy-1-methyl-ethyl]-4-iodo-5-(2-trimethylsilylethoxymethoxy)pyrazole-3-yl]methyl]-2-[2,5-dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-methyl-propan-1-amine (III-3, 340 mg, 358 μmol, 80% yield) as a brown oily substance. LCMS: (M+1:949.7).

[0128] Step 2. (2S)-N-[[2-[(1S)-2-[tert-butyl(dimethyl)silyl]-oxy-1-methyl-ethyl]-4-iodo-5-(2-trimethylsilylethoxymethoxy)pyrazole-3-yl]methyl]-2-[2,5-dimethyl-4-(7-methyl-1-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridine-5-yl)pyrazole-3-yl]oxy-N-methyl-propan-1-amine (III-3, 330 mg, 348 μmol, 1 eq.), TBAC (96.6 mg, 348 μmol, 97.2 μL, 1 eq), NaHCO3 (73.0 mg, 869 μmol, 33.8 μL, 2.5 eq), and Pd(OAc)2 (15.6 mg, A 69.5 μmol (0.2 eq) solution in 16.5 mL of DMF was degassed / purged three times with N2, and the mixture was stirred at 130°C for 1.5 hours under an N2 atmosphere. Upon completion of the reaction, the reaction mixture was quenched with 30 mL of H2O at 25°C and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with 20 mL of H2O, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by CombiFlash (12 g silica gel column, THF 0-100% / PE) to obtain (10S,17E)-14-[(2S)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl]-6,8,10,12,20-pentamethyl-2-(oxan-2-yl)-16-{[2-(trimethylsilyl)ethoxy]methoxy}-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin (III-4, 275 mg, 335 μmol, 96% yield) as a brown oily substance. LCMS: (M+1:821.8).

[0129] Step 3. To a solution of (10S,17E)-14-[(2S)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-yl]-6,8,10,12,20-pentamethyl-2-(oxan-2-yl)-16-{[2-(trimethylsilyl)ethoxy]methoxy}-2,10,11,12,13,14-hexahydro-8H-5,3-(acenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadesine (III-4, 260 mg, 317 μmol, 1 eq.) in THF (2.6 mL), TBAF (1 M, 1.90 mL, 6 eq.) was added. The mixture was stirred at 70°C for 3 hours. Upon completion of the reaction, the reaction mixture was quenched with H2O (10 mL) at 25°C and extracted with ethyl acetate (8 mL x 3). The combined organic layers were washed with H2O (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain (10S,17E)-14-[(2S)-1-hydroxypropan-2-yl]-6,8,10,12,20-pentamethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-ol (III-5, 200 mg, 243 μmol, yield 77%, purity 70%) as a brown oil. LCMS:(M+1:577.2).

[0130] Step 4. (10S,17E)-14-[(2S)-1-hydroxypropan-2-yl]-6,8,10,12,20-pentamethyl-2-(oxan-2-yl)-2,10,11,12,13,14-hexahydro-8H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-16-ol (III-5, 90.0 mg, 156 μmol, 1 eq.) was dissolved in DMF (2 mL) and K2CO3 (43.1 mg, 312 μmol, 2 eq) and iodoethane (29.2 mg, 187 μmol, 15.0 μL, 1.2 eq) were added. The mixture was stirred at 80°C for 1 hour. Upon completion of the reaction, 8 mL of H2O was added to the reaction mixture at 25°C to quench it, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with H2O (6 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2-(oxan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (III-6, 90.0 mg, 149 μmol, 95% yield) as a brown oil. LCMS: (M+1:605.3).

[0131] Step 5. (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2-(oxan-2-yl)-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (III-6, 80.0 mg, 132 μmol, 1 eq.) was dissolved in CH2Cl2 (2 mL) and HCl / siRNA (4 M, 1 mL, 30.2 eq.) was added. The mixture was stirred at 25°C for 0.25 hours. Upon completion of the reaction, the mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (column): Phenomenex luna C18 150×25mm×10um; mobile phase: [water (FA)-ACN]; gradient: 16% to 46% over 10 minutes (B), (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometeno)tripyrazolo[3,4f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol (compound III, 4.63 mg, 7.96 μmol, yield 6.02%, purity 97.42%, FA) as a yellow solid. 1 H NMR (400MHz, MeOD-d4.)δ= 8.28 - 8.19 (m, 2H), 7.24 (d, J = 16.8Hz, 1H), 4.93 - 4.89 (m, 1H), 4.52 - 4.42 (m, 1H), 4.41 - 4.31 (m, 2H), 4.01 - 3.93 (m, 1H), 3.86 - 3.78 (m, 2H), 3.71 - 3.67 (m, 4H), 2.97 - 2.82 (m, 2H), 2.79 (s, 3H), 2.56 (s, 3H), 2.43 (s, 3H), 1.48 (t, J = 7.0Hz, 3H), 1.40 (d, J = 6.8Hz, 3H), 1.10 (d, J = 6.4Hz, 3H). LCMS:(M+1:521.2).

[0132] Venetoclax was purchased from MedChemExpress. Gilteritinib was purchased from Selleckchem. AMG-510 (sotorasib) was purchased from Selleckchem. Osimertinib was purchased from MedChemExpress. MRTX1133 was purchased from MedChemExpress. Adagrasib was purchased from Selleckchem.

[0133] The doses used in the mouse study described below can be converted between animals and humans according to "Nair AB, Jacob S.; A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016 Mar;7(2):27-31". For example, the human equivalent dose (HED) can be calculated by multiplying the dose administered to mice by 0.081. For instance, a mouse dose of 25 mg / kg is equivalent to a human dose of 2.0 mg / kg.

[0134] cell line [Table 1]

[0135] in vitro assay Example 1: Analysis of the synergistic effect of combining venetoclax and compound I using an in vitro growth assay. A matrix-combined synergistic effect assay (compound I and venetoclax) was performed using the AML cell line MOLM13. 2,000 cells / 100 μL / well were seeded in a 96-well black plate with a clear bottom (Corning #3904). The compounds were added in matrix form using a Tecan D300e Digital Dispenser. Venetoclax was added transversely at concentrations of 1000 nM, 333 nM, 111 nM, 37 nM, 12.35 nM, 4.12 nM, 1.37 nM, 0.46 nM, and 0.15 nM. Compound I was added longitudinally at concentrations of 50 nM, 12.5 nM, 3.13 nM, 0.78 nM, and 0.2 nM. The plates were cultured at 37°C and 5% CO2 for 5 days. Cell proliferation was measured at 50 μL / well using a CellTiter-Glo 2.0 luciferase-based ATP detection assay (Promega, Madison, WI) according to the manufacturer's protocol. The plates were then read using a TECAN Sparks multimode microplate reader. Survival rate (%) was calculated using DMSO as a control. Data were analyzed using SynergyFinder 2.0 (Ianevski, A., Giri, KA, Aittokallio, T., 2020. SynergyFinder 2.0: visual analytics of multi-drug combination synergies. Nucleic Acids Research. gkaa216, https: / / doi.org / 10.1093 / nar / gkaa216). Synergistic effect scores were calculated using the HSA model (which indicates whether the expected combination effect is the maximum drug response of the single agent at the corresponding concentration). The HSA synergy map is shown in Figure 1, and the HSA synergy scores for the concentration range showing the maximum synergy are shown in Table 1. [Table 2]

[0136] Interpretation of synergy scores: -10 or less: The interaction between the two drugs is likely to be antagonistic. -10 to 10: Interactions between two drugs are likely to be additive. A score greater than 10: The interaction between the two drugs is likely to be synergistic.

[0137] Example 2: Analysis of the synergistic effect of combining AMG-510 (sotracib) and compound I using an in vitro growth assay. A matrix-combined synergistic effect assay (compound I and AMG-510) was performed using the NSCLC cell line H358. 1,000 cells / 100 μL / well were seeded into a 96-well black plate with a clear bottom (Corning #3904). The compounds were added in matrix form using a Tecan D300e Digital Dispenser. AMG-510 was added transversely at concentrations of 333 nM, 111 nM, 37 nM, 12.35 nM, 4.12 nM, 1.37 nM, 0.46 nM, 0.15 nM, and 0.05 nM. Compound I was added longitudinally at concentrations of 1000 nM, 250 nM, 62.5 nM, 15.6 nM, and 3.9 nM. The plates were incubated at 37°C and 5% CO2 for 5 days. Cell proliferation was measured at 50 μL / well using a CellTiter-Glo 2.0 luciferase-based ATP detection assay (Promega, Madison, WI) according to the manufacturer's protocol. The plates were then read using a TECAN Sparks multimode microplate reader. Survival rate (%) was calculated using DMSO as a control. Data were analyzed using SynergyFinder 2.0 (Ianevski, A., Giri, KA, Aittokallio, T., 2020. SynergyFinder 2.0: visual analytics of multi-drug combination synergies. Nucleic Acids Research. gkaa216, https: / / doi.org / 10.1093 / nar / gkaa216). Synergistic effect scores were calculated using the HSA model (which indicates whether the expected combination effect is the maximum drug response of the single agent at the corresponding concentration). The HSA synergy map is shown in Figure 2, and the HSA synergy scores for the concentration range showing the maximum synergy are shown in Table 2. [Table 3]

[0138] Interpretation of synergy scores: -10 or less: The interaction between the two drugs is likely to be antagonistic. -10 to 10: Interactions between two drugs are likely to be additive. A score greater than 10: The interaction between the two drugs is likely to be synergistic.

[0139] Example 3: IncuCyte using CRC cell line SW480 (登録商標) S3 3D Spheroid Growth Assay IncuCyte (登録商標) The S3 3D spheroid proliferation assay (compound I and compound II) was performed using the CRC cell line SW480. 2,000 cells / 200 μl / well were seeded into a 96-well ultra-low adhesion plate (Corning #7007). The compounds were added in matrix form using a Tecan D300e Digital Dispenser. Compound II was added transversely at concentrations of 1000 nM, 333 nM, 111 nM, 37 nM, 12.35 nM, 4.12 nM, 1.37 nM, 0.46 nM, and 0.15 nM. Compound I was added longitudinally at concentrations of 1000 nM, 250 nM, 62.5 nM, 15.6 nM, and 3.9 nM. The plates were cultured at 37°C and 5% CO2 for a maximum of 9 days, with the medium changed weekly. 3D Spheroid, IncuCyte (登録商標) Measurements were performed using the S3 Live-Cell Analysis System (Sartorius, Ann Arbor, MI). Scans were performed every 12 hours at 4x magnification using phase and bright-field channels. To measure cell proliferation in 3D spheroid morphology, the total bright-field area was used, and image analysis was performed according to the manufacturer's recommended method. Figure 5 shows the total bright-field area (μm²) for DMSO, monotherapy, and combination therapy at specified concentrations. 2 The graph shown (image) is displayed.

[0140] Example 4: Analysis of the synergistic effect of combining Compound I and Compound II using an in vitro growth assay. A matrix-combined synergistic effect assay (compound I and compound II) was performed using the CRC cell line SW480. 2,000 cells / 200 μl / well were seeded into a 96-well black plate with a clear bottom (Corning #3904). The compounds were added in matrix form using a Tecan D300e Digital Dispenser. Compound II was added transversely at concentrations of 1000 nM, 333 nM, 111 nM, 37 nM, 12.35 nM, 4.12 nM, 1.37 nM, 0.46 nM, and 0.15 nM. Compound I was added longitudinally at concentrations of 1000 nM, 250 nM, 62.5 nM, 15.6 nM, and 3.9 nM. The plates were incubated at 37°C and 5% CO2 for 5 days. Cell proliferation was measured at 50 μl / well using a CellTiter-Glo 2.0 luciferase-based ATP detection assay (Promega, Madison, WI) according to the manufacturer's protocol. The plates were then read using a TECAN Sparks multimode microplate reader. Survival rate (%) was calculated using DMSO as a control. Data were analyzed using SynergyFinder 2.0 (Ianevski, A., Giri, KA, Aittokallio, T., 2020. SynergyFinder 2.0: visual analytics of multi-drug combination synergies. Nucleic Acids Research. gkaa216, https: / / doi.org / 10.1093 / nar / gkaa216). Synergistic effect scores were calculated using the HSA model (which indicates whether the expected combination effect is the maximum drug response of the single agent at the corresponding concentration). The HSA synergy map is shown in Figure 6 (the average HSA synergy score for all test concentrations is 1.161), and the HSA synergy scores for the concentration range showing the maximum synergy are shown in Table 3.

[0141] [Table 4]

[0142] Example 5: IncuCyte using NSCLC cell line H1975 (登録商標) S3 3D Spheroid Growth Assay IncuCyte (登録商標) S3 cell proliferation and confluence assays (compound I and compound III or osimertinib) were performed using NSCLC cell line H1975. 500 cells / 200 μl / well were seeded in 96-well clear plates (Corning #3585). The compounds were added in matrix form using a Tecan D300e Digital Dispenser. Compound III or osimertinib was added transversely at concentrations of 300 nM, 100 nM, 33 nM, 11 nM, 4.12 nM, 3.7 nM, and 1.2 nM. Compound I was added longitudinally at concentrations of 50 nM, 100 nM, and 200 nM. The plates were cultured at 37°C and 5% CO2 for up to 21 days, with the medium changed weekly. After the first week, the medium was changed and the compounds were removed from the plates. After two weeks, the medium was changed and the compounds were added back to the plates. Cell proliferation and confluence are detected by IncuCyte (登録商標) Measurements were performed using the S3 Live-Cell Analysis System (Sartorius, Ann Arbor, MI). Scans were performed every 12 hours, and four images were taken per well at 10x magnification, using a scan type specific to each adherent cell. Confluence was used to measure cell proliferation, and image analysis was performed according to the manufacturer's recommended method. Figures 7 and 8 show graphs of phase-contrast object confluence (%) for DMSO, monotherapy, and combination therapy, respectively.

[0143] Example 6: Analysis of the synergistic effect of combining MRTX1133 and compound I using an in vitro growth assay. A matrix-combined synergistic effect assay (compound I and MRTX1133) was performed using the PDAC cell line Suit-2. 2,000 cells / 100 μL / well were seeded in a 96-well black plate with a clear bottom (Corning #3904). The compounds were added in matrix form using a Tecan D300e Digital Dispenser. MRTX1133 was added transversely at concentrations of 1000 nM, 333 nM, 111 nM, 37 nM, 12.35 nM, 4.12 nM, 1.37 nM, 0.46 nM, and 0.15 nM. Compound I was added longitudinally at concentrations of 1000 nM, 250 nM, 62.5 nM, 15.6 nM, and 3.9 nM. The plates were cultured at 37°C and 5% CO2 for 5 days. Cell proliferation was measured at 50 μL / well using a CellTiter-Glo 2.0 luciferase-based ATP detection assay (Promega, Madison, WI) according to the manufacturer's protocol. The plates were then read using a TECAN Sparks multimode microplate reader. Survival rates were calculated using DMSO as a control. Data were analyzed using SynergyFinder 2.0 (Ianevski, A., Giri, KA, Aittokallio, T., 2020. SynergyFinder 2.0: visual analytics of multi-drug combination synergies. Nucleic Acids Research. gkaa216, https: / / doi.org / 10.1093 / nar / gkaa216). Synergistic effect scores were calculated using the HSA model (which indicates whether the expected combination effect is the maximum drug response of the single agent at the corresponding concentration). The HSA synergy map is shown in Figure 9 (the average HSA synergy score for all test concentrations is 4.145), and the HSA synergy scores for the concentration range showing the maximum synergy are shown in Table 4.

[0144] [Table 5]

[0145] Interpretation of synergy scores: -10 or less: The interaction between the two drugs is likely to be antagonistic. -10 to 10: Interactions between two drugs are likely to be additive. A score greater than 10: The interaction between the two drugs is likely to be synergistic.

[0146] Example 7: Analysis of the synergistic effect of combining MRTX1133 and compound I using an in vitro growth assay. A matrix-combined synergistic effect assay (compound I and MRTX1133) was performed using the CRC cell line GP2D. 1,000 cells / 100 μL / well were seeded into a 96-well black plate with a clear bottom (Corning #3904). The compounds were added in matrix form using a Tecan D300e Digital Dispenser. MRTX1133 was added transversely at concentrations of 1000 nM, 333 nM, 111 nM, 37 nM, 12.35 nM, 4.12 nM, 1.37 nM, 0.46 nM, and 0.15 nM. Compound I was added longitudinally at concentrations of 1000 nM, 250 nM, 62.5 nM, 15.6 nM, and 3.9 nM. The plates were cultured at 37°C and 5% CO2 for 5 days. Cell proliferation was measured at 50 μL / well using a CellTiter-Glo 2.0 luciferase-based ATP detection assay (Promega, Madison, WI) according to the manufacturer's protocol. The plates were then read using a TECAN Sparks multimode microplate reader. Survival rate (%) was calculated using DMSO as a control. Data were analyzed using SynergyFinder 2.0 (Ianevski, A., Giri, KA, Aittokallio, T., 2020. SynergyFinder 2.0: visual analytics of multi-drug combination synergies. Nucleic Acids Research. gkaa216, https: / / doi.org / 10.1093 / nar / gkaa216). Synergistic effect scores were calculated using the HSA model (which indicates whether the expected combination effect is the maximum drug response of the single agent at the corresponding concentration). The HSA synergy map is shown in Figure 10 (the average HSA synergy score for all test concentrations is 5.304), and the HSA synergy scores for the concentration range showing the maximum synergy are shown in Table 5. [Table 6]

[0147] Interpretation of synergy scores: -10 or less: The interaction between the two drugs is likely to be antagonistic. -10 to 10: Interactions between two drugs are likely to be additive. A score greater than 10: The interaction between the two drugs is likely to be synergistic.

[0148] Example 8: Analysis of the synergistic effect of combining adagrasib and compound I using an in vitro growth assay. A matrix-combined synergistic effect assay (compound I and adaglasib) was performed using the CRC cell line SW1463. 2,000 cells / 100 μL / well were seeded in a 96-well black plate with a clear bottom (Corning #3904). The compounds were added in matrix form using a Tecan D300e Digital Dispenser. Adaglacib was added transversely at concentrations of 1000 nM, 333 nM, 111 nM, 37 nM, 12.35 nM, 4.12 nM, 1.37 nM, 0.46 nM, and 0.15 nM. Compound I was added longitudinally at concentrations of 1000 nM, 250 nM, 62.5 nM, 15.6 nM, and 3.9 nM. The plates were cultured at 37°C and 5% CO2 for 5 days. Cell proliferation was measured at 50 μL / well using a CellTiter-Glo 2.0 luciferase-based ATP detection assay (Promega, Madison, WI) according to the manufacturer's protocol. The plates were then read using a TECAN Sparks multimode microplate reader. Survival rate (%) was calculated using DMSO as a control. Data were analyzed using SynergyFinder 2.0 (Ianevski, A., Giri, KA, Aittokallio, T., 2020. SynergyFinder 2.0: visual analytics of multi-drug combination synergies. Nucleic Acids Research. gkaa216, https: / / doi.org / 10.1093 / nar / gkaa216). Synergistic effect scores were calculated using the HSA model (which indicates whether the expected combination effect is the maximum drug response of the single agent at the corresponding concentration). The HSA synergy map is shown in Figure 11 (the average HSA synergy score for all test concentrations is 7.443), and the HSA synergy scores for the concentration range showing the maximum synergy are shown in Table 6. [Table 7]

[0149] Interpretation of synergy scores: -10 or less: The interaction between the two drugs is likely to be antagonistic. -10 to 10: Interactions between two drugs are likely to be additive. A score greater than 10: The interaction between the two drugs is likely to be synergistic.

[0150] Example 9: In vivo testing Tumor cells were cultured using the standard method described above, harvested, and pelletized by centrifugation at 1000 rpm for 5 minutes. The pelleted cells were washed once with serum-free medium and then resuspended in serum-free medium supplemented with 50% Matrigel (Corning, Inc.). Five million tumor cells were subcutaneously transplanted into the right flank of immunodeficient mice, and tumor volume and body weight were measured once or twice a week using electronic calipers (Fowler) and a balance. Generally, when the average tumor size reached a predetermined volume, the mice were grouped and treated with the vehicle, compound I, the FDA-approved drug, or a combination of compound I and the FDA-approved drug, and antitumor activity was evaluated. In specific studies, the treatment plan and sequence may be modified, and additional dose levels may be added. Compound I was administered orally, and the FDA-approved drug was administered via the PO or IP route. Mice were monitored daily by cage-side observation during the treatment period. Tumor volume (TV) and body weight were measured two to three times a week during the treatment period. Four to five weeks after administration, or when the tumor volume of the mouse reaches 1000 to 2000 mm² 3 The trial was terminated when the threshold was reached. The tumor growth inhibition rate (TGI) is calculated as follows: TV 治療最終日 >TV 治療初日 In this case, 100% × {1 - [(TV 治療最終日 -TV 治療初日 ) / (TV 治療最終日の対照 -TV 治療初日の対照 )]}. TV 治療最終日 <TV 治療初日 In this case, TGI is 100% × (2-TV 治療最終日 / TV 治療初日 It was calculated as follows:

[0151] Example 10: Antitumor effect of compound I and gilteritinib combined in a MOLM-13 cell-derived xenograft (CDX) tumor model. MOLM-13 is an AML cell line with an FLT3-ITD mutation. Gilteritinib is an FLT3 inhibitor that targets the FLT3 mutation in AML. In this study, six groups of mice with MOLM-13 tumors were treated with vehicle QD (once daily), gilteritinib 25 mg / kg QD, compound I 25 mg / kg QD, compound I 25 mg / kg QD and gilteritinib 25 mg / kg QD, compound I 25 mg / kg MWF (once daily on Mondays, Wednesdays, and Fridays), and compound I 25 mg / kg MWF and gilteritinib 25 mg / kg QD, respectively. On day 14, gilteritinib treatment, compound I QD treatment, and compound I MWF treatment resulted in TGI rates of 94%, 94%, and 37%, respectively; however, combination therapy with compound I QD and gilteritinib, and combination therapy with compound I MWF and gilteritinib induced tumor regression, with TGI rates of 138% and 114%, respectively (Figure 3a). This treatment approach was continued for the gilteritinib treatment group, compound I QD treatment group, combination therapy with compound I QD and gilteritinib group, and combination therapy with compound I MWF and gilteritinib group. On day 24 of treatment, tumor volume increased to approximately 585% of baseline in the gilteritinib treatment group and approximately 555% of baseline in the compound I QD group (Figure 3a). In contrast, the combination of compound I and gilteritinib led to deep tumor regression. Combination therapy with compound I QD and gilteritinib, and combination therapy with compound I MWF and gilteritinib resulted in TGIs of 192% and 154%, respectively (Figure 3a). Mice were monitored for toxicity by body weight during the treatment period, but no significant toxicity based on weight loss was observed during the treatment period (Figure 3b).

[0152] Example 11: Antitumor effect of compound I and venetoclax combined in the MOLM-13 CDX tumor model Venetoclax is a BCL2 inhibitor used in combination with other drugs in patients with AML. In this study, five groups of mice with MOLM-13 tumors were treated with vehicle QD, venetoclax 100 mg / kg QD, compound I 25 mg / kg MWF, compound I 25 mg / kg MWF and venetoclax 100 mg / kg QD, and compound I 25 mg / kg QW (once weekly) and venetoclax 100 mg / kg QD, respectively. On day 14, treatment with venetoclax 100 mg / kg QD and treatment with compound I 25 mg / kg MWF resulted in TGI rates of 38% and 34%, respectively (Figure 4a). In contrast, the combination of compound I MWF and venetoclax resulted in a 195% TGI (in other words, 95% tumor regression) on day 14, and a 200% TGI (i.e., complete tumor regression) on day 18, when treatment was continued. Combination therapy was extended to day 28, and no tumor regrowth was observed. Furthermore, the combination therapy of compound I QW and venetoclax resulted in a 95% TGI on day 14 (Figure 4a). No significant weight loss was observed during the treatment period (Figure 4b).

[0153] Example 12: Antitumor effect of compound I and venetoclax combined in a MOLM-13 CDX tumor model pretreated with venetoclax. The combined effect of compound I and venetoclax was evaluated after 16 days of pretreatment with venetoclax at 100 mg / kg QD. Mice were then randomly assigned to one of three groups for 9 days each: compound I 25 mg / kg MWF and venetoclax 100 mg / kg QD, compound I 25 mg / kg QW and venetoclax, or gilteritinib 25 mg / kg QD and venetoclax. Using the mean tumor volume at day 9 as baseline, the compound I MWF and venetoclax combination group showed a 42% reduction in mean tumor volume (in other words, a TGI of 142%), while the compound I QW and venetoclax combination group showed an increase to 122% of baseline, and the gilteritinib and venetoclax combination group showed an increase to 346% of baseline (Figure 12a). No apparent toxicity based on weight loss was observed during the treatment period (Figure 12b).

[0154] Example 13: Antitumor effect of compound I and azacitidine combined in the MOLM-13 CDX tumor model Azacitidine is a standard treatment drug used in the treatment of AML patients. In this study, five groups of mice with MOLM-13 tumors were treated with vehicle QD, azacitidine 5 mg / kg QD for 7 days (QDx7), compound I 25 mg / kg QD, compound I 25 mg / kg QD and azacitidine in combination (concurrent combination), and compound I 25 mg / kg QD and azacitidine in combination (sequential combination) starting the day after the end of azacitidine treatment. On day 11, the TGI was 75% and 67% with compound I and azacitidine treatment, respectively (Figure 13a). In contrast, the TGI was 98% and 96% with compound I and azacitidine in combination, respectively (Figure 13a). No significant decrease in body weight was observed during the treatment period (Figure 13b).

[0155] Example 14: Antitumor effect of compound I and carboplatin combined in an OVCAR3 CDX tumor model OVCAR3 is a cell line established from malignant ascites in patients with advanced ovarian adenocarcinoma. Carboplatin is the standard treatment for ovarian cancer. In this study, four groups of mice with OVCAR3 tumors were treated with vehicle QD, carboplatin 50 mg / kg QW, compound I 25 mg / kg QD, or compound I 25 mg / kg QD and carboplatin 50 mg / kg QW. On day 28, treatment with compound I and carboplatin resulted in TGI rates of 77% and 56%, respectively (Figure 14a). In contrast, the combination of compound I and carboplatin resulted in a TGI rate of 97% (Figure 14a). No significant weight loss was observed during the treatment period (Figure 14b).

[0156] Example 15: Antitumor effect of compound I and osimertinib combined in the H1975 CDX tumor model. H1975 is a non-small cell lung cancer (NSCLC) cell line possessing the EGFR L858R / T790M mutation in addition to the RBM10 mutation. Osimertinib is a drug used to treat NSCLC patients with EGFR gene mutations. In this study, four groups of mice with H1975 tumors were treated with vehicle QD, osimertinib 1 mg / kg QD, compound I 25 mg / kg QD, or compound I 25 mg / kg QD and osimertinib 1 mg / kg QD. On day 22, the combination of compound I and osimertinib resulted in TGI of 65% and 26%, respectively (Figure 15a). In contrast, the combination of compound I and osimertinib resulted in a 108% TGI (Figure 15a), and tumor regression was observed in 6 out of 10 mice. No significant weight loss was observed in the mice during the treatment period (Figure 15b).

[0157] Example 16: Antitumor effect of compound I and adaglav combined in the SW1463 CDX tumor model SW1463 is a colorectal cancer (CRC) cell line carrying the KRAS G12C mutation. Adaglasiv is a drug that targets the KRAS G12C mutation in NSCLC and is being investigated in clinical trials targeting CRC patients with the KRAS G12C mutation. In this trial, four groups of mice with SW1643 tumors were treated with vehicle QD, adaglasiv 30 mg / kg QD, compound I 25 mg / kg QD, or compound I 25 mg / kg QD and adaglasiv 30 mg / kg QD in combination. On day 15, adaglasiv treatment showed no inhibition of tumor growth (Figure 16a). The TGI was 24% with compound I treatment, but 56% with the combination of compound I and adaglasiv (Figure 16a). 2,000 mm 3 When tumor size was used as the criterion for death, combination therapy with compound I and adaglacib resulted in the longest median survival time of 21 days, significantly longer than the 15 days in the vehicle-based treatment group (Figure 16b). No significant weight loss was observed in the mice during the treatment period (Figure 16c).

[0158] Example 17: Antitumor effect of compound I and cytarabine combined in the MOLM-13 CDX tumor model Cytarabine is a standard treatment drug used in the treatment of AML patients. In this study, four groups of mice with MOLM-13 tumors were treated with vehicle QD and cytarabine 50 mg / kg QD for 7 days (QDx7, IP), compound I 25 mg / kg QD, and compound I 25 mg / kg QD and cytarabine 50 mg / kg QD simultaneously for 7 days (QDx7, IP). On day 11, treatment with compound I and cytarabine resulted in TGI rates of 75% and 33%, respectively (Figure 17a). In contrast, the combination of compound I and cytarabine resulted in a TGI rate of 95% (Figure 17b). No significant weight loss was observed during the treatment period (Figure 17b).

Claims

1. A method for treating cancer in a host animal, comprising the step of administering a therapeutically effective dose of a CLK inhibitor to the host animal in combination with a therapeutically effective dose of at least one additional anticancer agent.

2. CLK inhibitors, Formula I: 【Chemistry 1】 The method according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 or 2, wherein the cancer is a humoral tumor or a solid tumor.

4. Cancers include acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, and ER. ＋ Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), The method according to any one of claims 1 to 3, selected from the group consisting of pediatric glioma, prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, cutaneous malignant melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous or clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer.

5. The method according to any one of claims 1 to 4, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer.

6. The method according to any one of claims 1 to 5, wherein the cancer is acute myeloid leukemia (AML).

7. The method according to any one of claims 1 to 5, wherein the cancer is chronic lymphocytic leukemia (CLL).

8. The method according to any one of claims 1 to 5, wherein the cancer is non-small cell lung cancer (NSCLC).

9. The method according to any one of claims 1 to 5, wherein the cancer is ovarian cancer.

10. The method according to any one of claims 1 to 9, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor.

11. The method according to claim 10, wherein the additional anticancer agent is a Bcl-2 inhibitor.

12. The method according to claim 10, wherein the additional anticancer agent is an FLT3 inhibitor.

13. The method according to claim 10, wherein the additional anticancer agent is a KRAS inhibitor.

14. KRAS inhibitors include compound II shown in the following formula: 【Chemistry 2】 The method according to claim 13, or a pharmaceutically acceptable salt thereof.

15. The method according to claim 10, wherein the additional anticancer agent is an ALK inhibitor.

16. The method according to claim 10, wherein the additional anticancer agent is an EGFR inhibitor.

17. EGFR inhibitors are compounds III shown in the following formula: 【Transformation 3】 The method according to claim 16, or a pharmaceutically acceptable salt thereof.

18. The method according to claim 16, wherein the EGFR inhibitor is osimertinib.

19. The method according to any one of claims 1 to 13, 15 or 16, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine, carboplatin, cytarabine or decitabine, or a pharmaceutically acceptable salt thereof.

20. The method according to any one of claims 1 to 11 or 19, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof.

21. The method according to any one of claims 1 to 10, 12, or 19, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof.

22. The method according to any one of claims 1 to 10, 13, or 19, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof.

23. The method according to any one of claims 1 to 10, 13, or 19, wherein the additional anticancer agent is adaglasib or sotrasib, or a pharmaceutically acceptable salt thereof.

24. The method according to any one of claims 1 to 23, wherein a combination of a CLK inhibitor and at least one additional anticancer agent in a therapeutically effective dose yields an HSA synergy score of at least about 11 in cancer cell lines.

25. The method according to any one of the claims, wherein a combination of a CLK inhibitor and at least one additional anticancer agent yields an HSA synergy score of at least about 15 in a cancer cell line.

26. A CLK inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of cancer in a patient, in combination with at least one additional anticancer agent in a therapeutically effective dose.

27. CLK inhibitors, Formula I: 【Chemistry 4】 The compound according to claim 26, which is a compound of or a pharmaceutically acceptable salt thereof.

28. The compound according to claim 26 or 27, wherein the cancer is a humoral tumor or a solid tumor.

29. Cancers include acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, and ER. ＋ Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), pediatric A compound according to any one of claims 26 to 28, selected from the group consisting of glioma, prostate cancer, squamous cell carcinoma of the lung, serous cystadenocarcinoma of the ovary, malignant melanoma of the skin, castration-resistant prostate cancer, Hodgkin lymphoma, serous or clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer.

30. The compound according to any one of claims 26 to 29, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer.

31. The compound according to any one of claims 26 to 30, wherein the cancer is acute myeloid leukemia (AML).

32. The compound according to any one of claims 26 to 30, wherein the cancer is chronic lymphocytic leukemia (CLL).

33. The compound according to any one of claims 26 to 30, wherein the cancer is non-small cell lung cancer (NSCLC).

34. The compound according to any one of claims 26 to 30, wherein the cancer is ovarian cancer.

35. The compound according to any one of claims 26 to 34, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor.

36. The compound according to claim 35, wherein the additional anticancer agent is a Bcl-2 inhibitor.

37. The compound according to claim 35, wherein the additional anticancer agent is an FLT3 inhibitor.

38. The compound according to claim 35, wherein the additional anticancer agent is a KRAS inhibitor.

39. KRAS inhibitors include compound II shown in the following formula: 【Transformation 5】 The compound according to claim 38, or a pharmaceutically acceptable salt thereof.

40. The compound according to claim 35, wherein the additional anticancer agent is an ALK inhibitor.

41. The compound according to claim 35, wherein the additional anticancer agent is an EGFR inhibitor.

42. EGFR inhibitors are compounds III shown in the following formula: 【Transformation 6】 The compound according to claim 41, or a pharmaceutically acceptable salt thereof.

43. The compound according to claim 41, wherein the EGFR inhibitor is osimertinib.

44. The compound according to any one of claims 26-38, 40, or 41, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine, carboplatin, cytarabine or decitabine, or a pharmaceutically acceptable salt thereof.

45. The compound according to any one of claims 26 to 36 or 44, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof.

46. The compound according to any one of claims 26-35, 37, or 44, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof.

47. The compound according to any one of claims 26-35, 38, or 44, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof.

48. The compound according to any one of claims 26-35, 38, or 44, wherein the additional anticancer agent is adaglacib or sotracib, or a pharmaceutically acceptable salt thereof.

49. The compound according to any one of claims 26 to 48, wherein a combination of a CLK inhibitor and at least one additional anticancer agent in a therapeutically effective dose yields an HSA synergy score of at least about 11 in cancer cell lines.

50. The compound according to any one of claims 26 to 49, which, when combined with a CLK inhibitor and at least one additional anticancer agent, yields an HSA synergy score of at least about 15 in cancer cell lines.

51. Use of a CLK inhibitor or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product containing a therapeutically effective amount of the compound for treating cancer in a patient, in combination with at least one additional anticancer agent in a therapeutically effective amount.

52. CLK inhibitors, Formula I: 【Transformation 7】 The use according to claim 51, which is a compound or a pharmaceutically acceptable salt thereof.

53. The use according to claim 51 or 52, wherein the cancer is a humoral tumor or a solid tumor.

54. Cancers include acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, and ER. ＋ Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), small Use according to any one of claims 51 to 53, selected from the group consisting of pediatric glioma, prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, cutaneous malignant melanoma, castration-resistant prostate cancer, Hodgkin lymphoma, serous or clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer.

55. The use according to any one of claims 51 to 54, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer.

56. The use according to any one of claims 51 to 55, wherein the cancer is acute myeloid leukemia (AML).

57. The use according to any one of claims 51 to 55, wherein the cancer is chronic lymphocytic leukemia (CLL).

58. The use according to any one of claims 51 to 55, wherein the cancer is non-small cell lung cancer (NSCLC).

59. The use according to any one of claims 51 to 55, wherein the cancer is ovarian cancer.

60. The use according to any one of claims 51 to 59, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor.

61. The use according to claim 60, wherein the additional anticancer agent is a Bcl-2 inhibitor.

62. The use according to claim 60, wherein the additional anticancer agent is an FLT3 inhibitor.

63. The use according to claim 60, wherein the additional anticancer agent is a KRAS inhibitor.

64. KRAS inhibitors include compound II shown in the following formula: 【Transformation 8】 The use according to claim 63, or a pharmaceutically acceptable salt thereof.

65. The use according to claim 60, wherein the additional anticancer agent is an ALK inhibitor.

66. The use according to claim 60, wherein the additional anticancer agent is an EGFR inhibitor.

67. EGFR inhibitors are compounds III shown in the following formula: 【Chemistry 9】 The use according to claim 66, or a pharmaceutically acceptable salt thereof.

68. The use according to claim 66, wherein the EGFR inhibitor is osimertinib.

69. The use according to any one of claims 51-63, 65, or 66, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine, carboplatin, cytarabine or decitabine, or a pharmaceutically acceptable salt thereof.

70. The use according to any one of claims 51 to 61 or 69, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof.

71. The use according to any one of claims 51-60, 62, or 69, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof.

72. The use according to any one of claims 51-60, 63, or 69, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof.

73. The use according to any one of claims 51-60, 63, or 69, wherein the additional anticancer agent is adaglacib or sotracib, or a pharmaceutically acceptable salt thereof.

74. The use according to any one of claims 51 to 73, wherein the combination of a CLK inhibitor and at least one additional anticancer agent in a therapeutically effective dose yields an HSA synergy score of at least about 11 in cancer cell lines.

75. The use according to any one of claims 51 to 74, wherein the combination of a CLK inhibitor and at least one additional anticancer agent yields an HSA synergy score of at least about 15 in cancer cell lines.

76. A composition comprising a therapeutically effective amount of a CLK inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of cancer in a patient, in combination with at least one additional anticancer agent in a therapeutically effective amount.

77. CLK inhibitors, Formula I: 【Chemistry 10】 The composition according to claim 76, which is a compound of or a pharmaceutically acceptable salt thereof.

78. The composition according to claim 76 or 77, wherein the cancer is a humoral tumor or a solid tumor.

79. Cancers include acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, and ER. ＋ Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), pediatric A composition according to any one of claims 76 to 78, selected from the group consisting of glioma, prostate cancer, squamous cell carcinoma of the lung, serous cystadenocarcinoma of the ovary, malignant melanoma of the skin, castration-resistant prostate cancer, Hodgkin lymphoma, serous or clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer.

80. The composition according to any one of claims 76 to 79, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer.

81. The composition according to any one of claims 76 to 80, wherein the cancer is acute myeloid leukemia (AML).

82. The composition according to any one of claims 76 to 80, wherein the cancer is chronic lymphocytic leukemia (CLL).

83. The composition according to any one of claims 76 to 80, wherein the cancer is non-small cell lung cancer (NSCLC).

84. The composition according to any one of claims 76 to 80, wherein the cancer is ovarian cancer.

85. The composition according to any one of claims 76 to 84, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor.

86. The composition according to claim 85, wherein the additional anticancer agent is a Bcl-2 inhibitor.

87. The composition according to claim 85, wherein the additional anticancer agent is an FLT3 inhibitor.

88. The composition according to claim 85, wherein the additional anticancer agent is a KRAS inhibitor.

89. KRAS inhibitors include compound II shown in the following formula: 【Chemistry 11】 The composition according to claim 88, or a pharmaceutically acceptable salt thereof.

90. The composition according to claim 85, wherein the additional anticancer agent is an ALK inhibitor.

91. The composition according to claim 85, wherein the additional anticancer agent is an EGFR inhibitor.

92. EGFR inhibitors are compounds III shown in the following formula: 【Chemistry 12】 The composition according to claim 91, or a pharmaceutically acceptable salt thereof.

93. The composition according to claim 91, wherein the EGFR inhibitor is osimertinib.

94. The composition according to any one of claims 76-88, 90, or 91, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine, carboplatin, cytarabine or decitabine, or a pharmaceutically acceptable salt thereof.

95. The composition according to any one of claims 76 to 86 or 94, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof.

96. The composition according to any one of claims 76-85, 87, or 94, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof.

97. The composition according to any one of claims 76-85, 88, or 94, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof.

98. The composition according to any one of claims 76-85, 88, or 94, wherein the additional anticancer agent is adaglacib or sotracib, or a pharmaceutically acceptable salt thereof.

99. The composition according to any one of claims 76 to 98, wherein a combination of a CLK inhibitor and at least one additional anticancer agent in a therapeutically effective amount yields an HSA synergistic score of at least about 11 in cancer cell lines.

100. The composition according to any one of claims 76 to 99, wherein a CLK inhibitor and at least one additional anticancer agent, in combination, yields an HSA synergy score of at least about 15 in cancer cell lines.

101. A pharmaceutical product comprising a CLK inhibitor or a pharmaceutically acceptable salt thereof in combination with at least one additional anticancer agent, either in a fixed dose or in a free combination.

102. CLK inhibitors, Formula I: 【Chemistry 13】 The pharmaceutical product according to claim 101, which is a compound of or a pharmaceutically acceptable salt thereof.

103. The pharmacopoeia according to claim 101 or 102, wherein the cancer is a humoral tumor or a solid tumor.

104. Cancers include acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, and ER. ＋ Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), pediatric A pharmaceutical product according to any one of claims 101 to 103, selected from the group consisting of glioma, prostate cancer, squamous cell carcinoma of the lung, serous cystadenocarcinoma of the ovary, malignant melanoma of the skin, castration-resistant prostate cancer, Hodgkin lymphoma, serous or clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer.

105. The pharmaceutical product according to any one of claims 101 to 104, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer.

106. The pharmaceutical product according to any one of claims 101 to 105, wherein the cancer is acute myeloid leukemia (AML).

107. The pharmaceutical product according to any one of claims 101 to 105, wherein the cancer is chronic lymphocytic leukemia (CLL).

108. The pharmaceutical product according to any one of claims 101 to 105, wherein the cancer is non-small cell lung cancer (NSCLC).

109. The pharmaceutical product according to any one of claims 101 to 105, wherein the cancer is ovarian cancer.

110. The pharmaceutical product according to any one of claims 101 to 109, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor.

111. The pharmaceutical product according to claim 110, wherein the additional anticancer agent is a Bcl-2 inhibitor.

112. The pharmaceutical product according to claim 110, wherein the additional anticancer agent is an FLT3 inhibitor.

113. The pharmaceutical product according to claim 110, wherein the additional anticancer agent is a KRAS inhibitor.

114. KRAS inhibitors include compound II shown in the following formula: 【Chemistry 14】 The pharmaceutical product according to claim 113, or a pharmaceutically acceptable salt thereof.

115. The pharmaceutical product according to claim 110, wherein the additional anticancer agent is an ALK inhibitor.

116. The pharmaceutical product according to claim 110, wherein the additional anticancer agent is an EGFR inhibitor.

117. EGFR inhibitors are compounds III shown in the following formula: 【Chemistry 15】 The pharmaceutical product according to claim 116, or a pharmaceutically acceptable salt thereof.

118. The pharmaceutical product according to claim 116, wherein the EGFR inhibitor is osimertinib.

119. The pharmacopoeci according to any one of claims 101-113, 115, or 116, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine, carboplatin, cytarabine or decitabine, or a pharmaceutically acceptable salt thereof.

120. The pharmacopoeia according to any one of claims 101 to 111 or 119, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof.

121. The pharmacopoeia according to any one of claims 101-110, 112, or 119, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof.

122. The pharmacopoeia according to any one of claims 101-110, 113, or 119, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof.

123. The pharmacopoeia according to any one of claims 101-110, 113, or 119, wherein the additional anticancer agent is adaglacib or sotracib, or a pharmaceutically acceptable salt thereof.

124. The pharmacopoeia according to any one of claims 101 to 123, wherein a combination of a CLK inhibitor and at least one additional anticancer agent in a therapeutically effective dose yields an HSA synergy score of at least about 11 in cancer cell lines.

125. The pharmaceutical product according to any one of claims 101 to 124, wherein a combination of a CLK inhibitor and at least one additional anticancer agent yields an HSA synergy score of at least about 15 in cancer cell lines.

126. A composition exhibiting a synergistic effect of a CLK inhibitor and at least one anticancer agent, wherein two components are in contact with each other at a gene locus.

127. CLK inhibitors, Formula I: 【Chemistry 16】 A composition exhibiting the synergistic effect according to claim 126, wherein the compound or a pharmaceutically acceptable salt thereof.

128. A composition exhibiting the synergistic effect according to claim 126 or 127, wherein the cancer is a humoral tumor or a solid tumor.

129. Cancers include acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, and ER. ＋ Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), pediatric glioma A composition exhibiting the synergistic effect described in any one of claims 126 to 128, selected from the group consisting of prostate cancer, squamous cell carcinoma of the lung, serous cystadenocarcinoma of the ovary, malignant melanoma of the skin, castration-resistant prostate cancer, Hodgkin lymphoma, serous or clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer.

130. A composition exhibiting the synergistic effect according to any one of claims 126 to 129, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer.

131. A composition exhibiting the synergistic effect according to any one of claims 126 to 130, wherein the cancer is acute myeloid leukemia (AML).

132. A composition exhibiting the synergistic effect according to any one of claims 126 to 130, wherein the cancer is chronic lymphocytic leukemia (CLL).

133. A composition exhibiting the synergistic effect according to any one of claims 126 to 130, wherein the cancer is non-small cell lung cancer (NSCLC).

134. A composition exhibiting the synergistic effect according to any one of claims 126 to 130, wherein the cancer is ovarian cancer.

135. A composition exhibiting the synergistic effect according to any one of claims 126 to 134, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor.

136. The composition exhibiting the synergistic effect according to claim 135, wherein the additional anticancer agent is a Bcl-2 inhibitor.

137. The composition exhibiting the synergistic effect according to claim 135, wherein the additional anticancer agent is an FLT3 inhibitor.

138. The composition exhibiting the synergistic effect according to claim 135, wherein the additional anticancer agent is a KRAS inhibitor.

139. KRAS inhibitors include compound II shown in the following formula: 【Chemistry 17】 A composition exhibiting the synergistic effect described in claim 138, which is a pharmaceutically acceptable salt thereof.

140. The composition exhibiting the synergistic effect according to claim 135, wherein the additional anticancer agent is an ALK inhibitor.

141. The composition exhibiting the synergistic effect according to claim 135, wherein the additional anticancer agent is an EGFR inhibitor.

142. EGFR inhibitors are compounds III shown in the following formula: [Chemistry 18] A composition exhibiting the synergistic effect described in claim 141, which is a pharmaceutically acceptable salt thereof.

143. The composition exhibiting the synergistic effect according to claim 141, wherein the EGFR inhibitor is osimertinib.

144. A composition exhibiting the synergistic effect according to any one of claims 126-138, 140, or 141, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine, carboplatin, cytarabine or decitabine, or a pharmaceutically acceptable salt thereof.

145. A composition exhibiting the synergistic effect according to any one of claims 126-136 or 144, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof.

146. A composition exhibiting the synergistic effect according to any one of claims 126-135, 137, or 144, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof.

147. A composition exhibiting the synergistic effect according to any one of claims 126-135, 138, or 144, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof.

148. A composition exhibiting the synergistic effect according to any one of claims 126-135, 138, or 144, wherein the additional anticancer agent is adaglacib or sotracib, or a pharmaceutically acceptable salt thereof.

149. A composition exhibiting the synergistic effect according to any one of claims 126 to 148, wherein a combination of a CLK inhibitor and at least one additional anticancer agent in a therapeutically effective amount yields an HSA synergistic score of at least about 11 in a cancer cell line.

150. A composition exhibiting the synergistic effect according to any one of claims 126 to 149, wherein a CLK inhibitor and at least one additional anticancer agent, in combination, yields an HSA synergistic score of at least about 15 in cancer cell lines.

151. A composition exhibiting a synergistic effect of a CLK inhibitor and at least one anticancer agent, wherein the two components come into contact with each other only within the human body.

152. CLK inhibitors, Formula I: 【Chemistry 19】 A composition exhibiting the synergistic effect according to claim 151, wherein the compound or a pharmaceutically acceptable salt thereof.

153. A composition exhibiting the synergistic effect according to claim 151 or 152, wherein the cancer is a humoral tumor or a solid tumor.

154. Cancers include acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, and ER. ＋ Breast cancer, triple-negative breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in situ, intrahepatic cholangiocarcinoma, thyroid cancer, acanthocyte neoplasm, sarcoma, astrocytoma, low-grade brain glioma, secretory breast cancer, mammary gland-related cancer, congenital mesenchymal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), pediatric glioma A composition exhibiting the synergistic effect described in any one of claims 151 to 153, selected from the group consisting of prostate cancer, squamous cell carcinoma of the lung, serous cystadenocarcinoma of the ovary, malignant melanoma of the skin, castration-resistant prostate cancer, Hodgkin lymphoma, serous or clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer, and lung cancer.

155. A composition exhibiting the synergistic effect according to any one of claims 151 to 154, wherein the cancer is acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), small lymphocytic lymphoma (SLL), bladder cancer, ovarian cancer, prostate cancer, colon cancer, neuroblastoma, non-small cell lung cancer (NSCLC), and triple-negative breast cancer.

156. A composition exhibiting the synergistic effect according to any one of claims 151 to 155, wherein the cancer is acute myeloid leukemia (AML).

157. A composition exhibiting the synergistic effect according to any one of claims 151 to 155, wherein the cancer is chronic lymphocytic leukemia (CLL).

158. A composition exhibiting the synergistic effect according to any one of claims 151 to 155, wherein the cancer is non-small cell lung cancer (NSCLC).

159. A composition exhibiting the synergistic effect according to any one of claims 151 to 155, wherein the cancer is ovarian cancer.

160. A composition exhibiting the synergistic effect according to any one of claims 151 to 159, wherein the additional anticancer agent is a Bcl-2 inhibitor, a FLT3 inhibitor, a KRAS inhibitor, an ALK inhibitor, a PARP inhibitor, or an EGFR inhibitor.

161. The composition exhibiting the synergistic effect according to claim 160, wherein the additional anticancer agent is a Bcl-2 inhibitor.

162. The composition exhibiting the synergistic effect according to claim 160, wherein the additional anticancer agent is an FLT3 inhibitor.

163. The composition exhibiting the synergistic effect according to claim 160, wherein the additional anticancer agent is a KRAS inhibitor.

164. KRAS inhibitors include compound II shown in the following formula: 【Chemistry 20】 A composition exhibiting the synergistic effect according to claim 163, which is a pharmaceutically acceptable salt thereof.

165. The composition exhibiting the synergistic effect according to claim 160, wherein the additional anticancer agent is an ALK inhibitor.

166. The composition exhibiting the synergistic effect according to claim 160, wherein the additional anticancer agent is an EGFR inhibitor.

167. EGFR inhibitors are compounds III shown in the following formula: 【Chemistry 21】 A composition exhibiting the synergistic effect according to claim 166, or a pharmaceutically acceptable salt thereof.

168. The composition exhibiting the synergistic effect according to claim 166, wherein the EGFR inhibitor is osimertinib.

169. A composition exhibiting the synergistic effect according to any one of claims 151-163, 165, or 166, wherein the additional anticancer agent is venetoclax, gilteritinib, MRTX1133, adaglacib, sotracib, crizotinib, lorlatinib, afatinib, gefitinib, osimertinib, azacitidine, carboplatin, cytarabine or decitabine, or a pharmaceutically acceptable salt thereof.

170. A composition exhibiting the synergistic effect according to any one of claims 151 to 161 or 169, wherein the additional anticancer agent is venetoclax or a pharmaceutically acceptable salt thereof.

171. A composition exhibiting the synergistic effect according to any one of claims 151-160, 162, or 169, wherein the additional anticancer agent is gilteritinib or a pharmaceutically acceptable salt thereof.

172. A composition exhibiting the synergistic effect according to any one of claims 151-160, 163, or 169, wherein the additional anticancer agent is MRTX1133, adaglasib, or sotrasib, or a pharmaceutically acceptable salt thereof.

173. A composition exhibiting the synergistic effect according to any one of claims 151-160, 163, or 169, wherein the additional anticancer agent is adaglacib or sotracib, or a pharmaceutically acceptable salt thereof.

174. A composition exhibiting the synergistic effect according to any one of claims 151 to 173, wherein a combination of a CLK inhibitor and at least one additional anticancer agent in a therapeutically effective amount yields an HSA synergistic effect score of at least about 11 in cancer cell lines.

175. A composition exhibiting the synergistic effect according to any one of claims 151 to 174, wherein a CLK inhibitor and at least one additional anticancer agent, when combined, yield an HSA synergistic effect score of at least about 15 in a cancer cell line.

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