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1. (WO2019023786) COMBINATION THERAPIES FOR INHIBITION OF TTK PROTEIN KINASE
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CLAIMS

What is claimed is:

1. A method for treating cancer, comprising:

administering to a subject an effective amount of a compound represented by the formula:


or a pharmaceutically acceptable salt thereof and an effective amount of an immune checkpoint inhibitor.

2. The method according to claim 1 , wherein the immune checkpoint inhibitor is an antibody or an antigen binding fragment thereof.

3. The method according to any one of claims 1 and 2, wherein the immune checkpoint inhibitor is a monoclonal antibody or an antigen binding fragment thereof.

4. The method according to any one of claims 1-3, wherein the immune checkpoint inhibitor is one or more selected from a CD40L inhibitor, a DR3 inhibitor, a TLIA inhibitor, a GITR inhibitor, a GITRL inhibitor, a 4- IBB inhibitor, a 4-lBBL inhibitor, an OX40 inhibitor, an OX40L inhibitor, a CD27 inhibitor, a CD70 inhibitor, a TMIGD2 inhibitor, an HHLA2 inhibitor, an ICOS inhibitor, an ICOSL inhibitor, a B7RP1 inhibitor, a CD28 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a CTLA-4 inhibitor, a CD80 inhibitor, a CD86 inhibitor, a KIR inhibitor, a TCR inhibitor, a LAG3 inhibitor, an MHCI inhibitor, an MHCII inhibitor, a CD80 inhibitor, a TIM-3 inhibitor, a GAL9 inhibitor, a BTLA inhibitor, an HVEM inhibitor, a CD160 inhibitor, a CD137 inhibitor, a CD137L inhibitor, a LIGHT inhibitor, a phosphatidylserine inhibitor, a VISTA inhibitor, a BTNL2 inhibitor, a B7-H3 inhibitor and a B7-H4 inhibitor.

5. The method according to any one of claims 1-4, wherein the checkpoint inhibitor is one or more selected from a PD-1 inhibitor, a PD-L1 inhibitor and a CTLA-4 inhibitor.

6. The method according to any one of claims 1-5, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

7. The method according to any one of claims 1-5, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.

8. The method according to any one of claims 1-6, wherein the immune checkpoint inhibitor restores anti -tumor T-cell activity.

9. The method according to any one of claims 1-5 and 7, wherein the immune checkpoint inhibitor blocks T-cell-inhibitory cell activity.

10. The method according to any one of claims 1-5, wherein the immune checkpoint inhibitor is one or more selected from pembrolizumab, ipilimumab, nivolumab, atezolizumab, avelumab and durvalumab.

11. The method according to any one of claims 1 -4, wherein the immune checkpoint inhibitor is one or more selected from JS001, SHR-1210, BGB-A317, IBI-308, REGN2810, JS003, SHR-1316, KN035, BMS-936559, LAG525, BMS-986016, MBG453, MEDI-570, OREG-103/BY40 and lirilumab.

12. The method according to claims 1-6, 8 and 11, wherein the immune checkpoint inhibitor is one or more selected fromCJSOOl, SHR-1210, BGB-A317, IBI-308 and REGN2810.

13. The method according to claims 1-5, 7, 9 and 11, wherein the immune checkpoint inhibitor is one or more selected from JS003, SHR-1316, KN035 and BMS-936559.

14. The method according to any one of claims 1-13, wherein the cancer is selected from the group consisting of breast cancer, colon cancer, rectal cancer, colorectal cancer, lung cancer , cancer of the peritoneum, gastric or stomach cancer, gastrointestinal cancer, cervical cancer, liver cancer, bladder cancer, hepatoma, ovarian cancer, endometrial or uterine cancer, prostate cancer, testicular cancer, leukemias, lymphomas, hematological malignancies, brain cancer, head and neck cancer, pancreatic cancer, melanoma, hepatocellular cancer, kidney or renal cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, Merkel cell cancer, mycoses fungoids, esophageal cancer, tumors of the biliary tract, salivary gland cancer, sarcomas, retinoblastoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumors, gastrinoma, islet cell cancer, mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, squamous cell cancer and epithelial squamous cell cancer.

15. The method according to any one of claims 1-13, wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, breast cancer, colon cancer, brain cancer, neuroblastoma, prostate cancer, melanoma, glioblastoma multiforme, ovarian cancer, lymphoma, leukemia, melanoma, sarcoma, paraneospasia, osteosarcoma, germinoma, glioma and mesothelioma.

16. The method according to any one of claims 1-13, wherein the cancer is selected from renal cell carcinoma, non-small cell lung cancer, urothelial cancer, head and neck cancer, ovarian cancer, lymphoma, melanoma, pancreatic cancer, myeloma, acute myeloid leukemia, bladder cancer and Hodgkin's lymphoma.

17. A pharmaceutical composition comprising a compound represented by the formula:


or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor.

18. The pharmaceutical composition according to claim 17, wherein the immune checkpoint inhibitor is an antibody or an antigen binding fragment thereof.

19. The pharmaceutical composition according to any one of claims 17 and 18, wherein immune the checkpoint inhibitor is a monoclonal antibody or an antigen binding fragment thereof.

20. The pharmaceutical composition according to any one of claims 17-19, wherein the immune checkpoint inhibitor is one or more selected from a CD40L inhibitor, a DR3 inhibitor, a TL1 A inhibitor, a GITR inhibitor, a GITRL inhibitor, a 4-1BB inhibitor, a 4-1BBL inhibitor, an OX40 inhibitor, an OX40L inhibitor, a CD27 inhibitor, a CD70 inhibitor, a TMIGD2 inhibitor, an HHLA2 inhibitor, an ICOS inhibitor, an ICOSL inhibitor, a B7RP1 inhibitor, a CD28 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a CTLA-4 inhibitor, a CD80 inhibitor, a CD86 inhibitor, a KIR inhibitor, a TCR inhibitor, a LAG3 inhibitor, an MHCI inhibitor, an MHCII inhibitor, a CD80 inhibitor, a TIM-3 inhibitor, a GAL9 inhibitor, a BTLA inhibitor, an HVEM inhibitor, a CD 160 inhibitor, a CD 137 inhibitor, a CD137L inhibitor, a LIGHT inhibitor, a phosphatidylserine inhibitor, a VISTA inhibitor, a BTNL2 inhibitor, a B7-H3 inhibitor and a B7-H4 inhibitor.

21. The pharmaceutical composition according to any one of claims 17-20, wherein the immune checkpoint inhibitor is one or more selected from a PD-1 inhibitor, a PD-Ll inhibitor and a CTLA-4 inhibitor.

22. The pharmaceutical composition according to any one of claims 17-21, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

23. The pharmaceutical composition according to any one of claims 17-21, wherein the immune checkpoint inhibitor is a PD-Ll inhibitor.

24. The pharmaceutical composition according to any one of claims 17-22, wherein the immune checkpoint inhibitor restores anti-tumor T cell activity.

25. The pharmaceutical composition according to any one of claims 17-21 and 23, wherein the immune checkpoint inhibitor blocks T-cell-inhibitory cell activity.

26. The pharmaceutical composition according to any one of claims 17-21, wherein the immune checkpoint inhibitor is one or more selected from pembrolizumab, ipilimumab, nivolumab, atezolizumab, avelumab and durvalumab.

27. The pharmaceutical composition according to any one of claims 17-20, wherein the immune checkpoint inhibitor is one or more selected from JS001, SHR-1210, BGB-A317, IBI-308, REGN2810, JS003, SHR-1316, KN035, BMS-936559, LAG525, BMS-986016, MBG453, MEDI-570, OREG-103/BY40 and lirilumab.

28. The pharmaceutical composition according to claims 17-22, 24 and 27, wherein the immune checkpoint inhibitor is one or more selected from CJSOOl, SHR-1210, BGB-A317, IBI-308 and REGN2810.

29. The pharmaceutical composition according to claims 17-21, 23, 25 and 27, wherein the immune checkpoint inhibitor is one or more selected from JS003, SHR-1316, KN035 and BMS-936559.