Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor and/or a JAK-2 Inhibitor

Abstract

Therapeutic combinations of a Janus kinase-2 (JAK-2) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, and/or a phosphoinositide 3-kinase (PI3K) inhibitor, including PI3K inhibitors selective for the γ- and δ-isoforms and selective for both γ- and δ-isoforms, are described. In some embodiments, the invention provides pharmaceutical compositions comprising combinations of (1) a PI3K-δinhibitor and a BTK inhibitor, (2) a JAK-2 inhibitor and a BTK inhibitor, or (3) a JAK-2 inhibitor, PI3K-δ inhibitor, and BTK inhibitor, and methods of using the pharmaceutical compositions for treating a disease, in particular a cancer.

We claim: 
     
         1 . A method of treating a hyperproliferative disease, comprising co-administering, to a mammal in need thereof, therapeutically effective amounts of (1) a Janus kinase-2 (JAK-2) inhibitor or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and (2) a Bruton's tyrosine kinase (BTK) inhibitor or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. 
     
     
         2 . The method of  claim 1 , wherein the JAK-2 inhibitor is administered to the mammal before administration of the BTK inhibitor. 
     
     
         3 . The method of  claim 1 , wherein the JAK-2 inhibitor is administered to the mammal simultaneously with the administration of the BTK inhibitor. 
     
     
         4 . The method of  claim 1 , wherein the JAK-2 inhibitor is administered to the mammal after administration of the BTK inhibitor. 
     
     
         5 . The method of any one of  claims 1 - 4 , wherein the BTK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates, and prodrugs thereof. 
       
     
     
         6 . The method of any one of  claims 1 - 4 , wherein the BTK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates, and prodrugs thereof. 
       
     
     
         7 . The method of any one of  claims 1 - 6 , wherein the JAK-2 inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates, or prodrugs thereof. 
       
     
     
         8 . The method of any one of  claims 1 - 7 , further comprising the step of administering a therapeutically effective amount of an anti-CD20 antibody selected from the group consisting of rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, and fragments, derivatives, conjugates, variants, radioisotope-labeled complexes, biosimilars thereof, and combinations thereof. 
     
     
         9 . The method of any one of  claims 1 - 8 , further comprising the step of administering a phosphoinositide 3-kinase (PI3K) inhibitor or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. 
     
     
         10 . The method of  claim 9 , wherein the PI3K inhibitor is a PI3K-δ inhibitor. 
     
     
         11 . The method of any one of  claims 9 - 10 , wherein the PI3K inhibitor is administered to the mammal before administration of the BTK inhibitor. 
     
     
         12 . The method of any one of  claims 9 - 10 , wherein the PI3K inhibitor is administered to the mammal concurrently with the administration of the BTK inhibitor. 
     
     
         13 . The method of any one of  claims 9 - 10 , wherein the PI3K inhibitor is administered to the mammal after administration of the BTK inhibitor. 
     
     
         14 . The method of any one of  claims 9 - 13 , wherein the PI3K inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, solvates, hydrates, cocrystals, and prodrugs thereof. 
       
     
     
         15 . The method of any one of  claims 1 - 14 , wherein the hyperproliferative disease is a cancer, and the cancer is a B cell hematological malignancy, and wherein the B cell hematological malignancy is selected from the group consisting of chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), non-Hodgkin's lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin's lymphoma, B cell acute lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma, and myelofibrosis. 
     
     
         16 . The method of any one of  claims 1 - 14 , wherein the hyperproliferative disease is a cancer, and wherein the cancer is a solid tumor cancer, and wherein the solid tumor cancer is selected from the group consisting of bladder cancer, non-small cell lung cancer, cervical cancer, anal cancer, pancreatic cancer, squamous cell carcinoma including head and neck cancer, renal cell carcinoma, melanoma, ovarian cancer, small cell lung cancer, glioblastoma, gastrointestinal stromal tumor, breast cancer, lung cancer, colorectal cancer, thyroid cancer, bone sarcoma, stomach cancer, oral cavity cancer, oropharyngeal cancer, gastric cancer, kidney cancer, liver cancer, prostate cancer, esophageal cancer, testicular cancer, gynecological cancer, colon cancer, and brain cancer. 
     
     
         17 . The method of  claim 16 , further comprising the step of administering a therapeutically effective amount of gemcitabine. 
     
     
         18 . The method of  claim 16 , further comprising the step of administering a therapeutically effective amount of albumin-bound paclitaxel. 
     
     
         19 . A method of treating a cancer in a human comprising the step of co-administering (1) a therapeutically effective amount of a Janus kinase-2 (JAK-2) inhibitor or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and (2) a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein the therapeutically effective amount is effective to inhibit signaling between a tumor cell of the cancer and at least one tumor microenvironment selected from the group consisting of macrophages, monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory T cells, natural killer cells, myeloid-derived suppressor cells, regulatory B cells, neutrophils, dendritic cells, and fibroblasts. 
     
     
         20 . The method of  claim 19 , wherein the cancer is a solid tumor cancer selected from the group consisting of bladder cancer, non-small cell lung cancer, cervical cancer, anal cancer, pancreatic cancer, squamous cell carcinoma including head and neck cancer, renal cell carcinoma, melanoma, ovarian cancer, small cell lung cancer, glioblastoma, gastrointestinal stromal tumor, breast cancer, lung cancer, colorectal cancer, thyroid cancer, bone sarcoma, stomach cancer, oral cavity cancer, oropharyngeal cancer, gastric cancer, kidney cancer, liver cancer, prostate cancer, esophageal cancer, testicular cancer, gynecological cancer, colon cancer, and brain cancer. 
     
     
         21 . The method of  claim 19  or  20 , wherein the therapeutically effective amount is further effective to increase immune system recognition and rejection of the solid tumor by the human. 
     
     
         22 . The method of any one of  claims 19 - 21 , wherein the BTK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates, or prodrugs thereof. 
       
     
     
         23 . The method of any one of  claims 19 - 22 , wherein the JAK-2 inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates, and prodrugs thereof. 
       
     
     
         24 . The method of any one of  claims 19 - 23 , further comprising the step of administering a therapeutically effective amount of a phosphoinositide 3-kinase (PI3K) inhibitor or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. 
     
     
         25 . The method of  claim 24 , wherein the PI3K inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts, solvates, hydrates, cocrystals, and prodrugs thereof. 
       
     
     
         26 . A method of treating a cancer in a human intolerant to a bleeding event comprising the step of administering (1) a therapeutically effective amount of a Janus kinase-2 (JAK-2) inhibitor or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and (2) a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein the BTK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates, or prodrugs thereof. 
       
     
     
         27 . The method of  claim 26 , wherein the bleeding event is selected from the group consisting of subdural hematoma, gastrointestinal bleeding, hematuria, post-procedural hemorrhage, bruising, petechiae, and combinations thereof. 
     
     
         28 . The method of  claim 26  or  27 , wherein the JAK-2 inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates, and prodrugs thereof. 
       
     
     
         29 . The method of any one of any of  claims 26 - 28 , further comprising the step of administering a therapeutically effective amount of an anticoagulant or antiplatelet active pharmaceutical ingredient. 
     
     
         30 . The method of  claim 29 , wherein the anticoagulant or antiplatelet active pharmaceutical ingredient is selected from the group consisting of acenocoumarol, anagrelide, anagrelide hydrochloride, abciximab, aloxiprin, antithrombin, apixaban, argatroban, aspirin, aspirin with extended-release dipyridamole, beraprost, betrixaban, bivalirudin, carbasalate calcium, cilostazol, clopidogrel, clopidogrel bisulfate, cloricromen, dabigatran etexilate, darexaban, dalteparin, dalteparin sodium, defibrotide, dicumarol, diphenadione, dipyridamole, ditazole, desirudin, edoxaban, enoxaparin, enoxaparin sodium, eptifibatide, fondaparinux, fondaparinux sodium, heparin, heparin sodium, heparin calcium, idraparinux, idraparinux sodium, iloprost, indobufen, lepirudin, low molecular weight heparin, melagatran, nadroparin, otamixaban, parnaparin, phenindione, phenprocoumon, prasugrel, picotamide, prostacyclin, ramatroban, reviparin, rivaroxaban, sulodexide, terutroban, terutroban sodium, ticagrelor, ticlopidine, ticlopidine hydrochloride, tinzaparin, tinzaparin sodium, tirofiban, tirofiban hydrochloride, treprostinil, treprostinil sodium, triflusal, vorapaxar, warfarin, warfarin sodium, ximelagatran, salts thereof, solvates thereof, hydrates thereof, and combinations thereof. 
     
     
         31 . The method of any one of  claims 26 - 30 , wherein the cancer is selected from the group consisting of bladder cancer, squamous cell carcinoma including pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung carcinoma, thyoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia, thymus cancer, brain cancer, squamous cell cancer, skin cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral cavity and oropharyngeal cancers, gastric cancer, stomach cancer, cervical cancer, head and neck cancer, renal cancer, kidney cancer, liver cancer, ovarian cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, acquired immune deficiency syndrome (AIDS)-related cancers (e.g., lymphoma and Kaposi's sarcoma), viral-induced cancer, glioblastoma, esophageal tumors, hematological neoplasms, non-small-cell lung cancer, chronic myelocytic leukemia, diffuse large B-cell lymphoma, esophagus tumor, follicle center lymphoma, head and neck tumor, hepatitis C virus infection, hepatocellular carcinoma, Hodgkin's disease, metastatic colon cancer, multiple myeloma, non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma, ovary tumor, pancreas tumor, renal cell carcinoma, small-cell lung cancer, stage IV melanoma, chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), mature B-cell ALL, follicular lymphoma, mantle cell lymphoma, Burkitt's lymphoma, and myelofibrosis. 
     
     
         32 . A composition comprising therapeutically effective amounts of (1) a Janus kinase-2 (JAK-2) inhibitor or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof; and (2) a Bruton's tyrosine kinase (BTK) inhibitor or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, for use in the treatment of cancer. 
     
     
         33 . The composition of  claim 32 , for use as a medicament. 
     
     
         34 . The composition of  claim 32  or  33 , for use in the treatment of cancer. 
     
     
         35 . The composition of any one of  claims 32 - 34 , wherein the BTK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates, and prodrugs thereof. 
       
     
     
         36 . The composition of any one of  claims 32 - 35 , wherein the BTK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates, and prodrugs thereof. 
       
     
     
         37 . The composition of any one of  claims 32 - 36 , wherein the JAK-2 inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates, and prodrugs thereof. 
       
     
     
         38 . The composition of any one of  claims 32 - 37 , further comprising a therapeutically effective amount of an anti-CD20 antibody selected from the group consisting of rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, and fragments, derivatives, conjugates, variants, radioisotope-labeled complexes, and biosimilars thereof. 
     
     
         39 . The composition of any one of  claims 32 - 38 , further comprising a phosphoinositide 3-kinase (PI3K) inhibitor or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. 
     
     
         40 . The composition of  claim 39 , wherein the PI3K inhibitor is a PI3K-δ inhibitor. 
     
     
         41 . The composition of  claim 40 , wherein the PI3K-δ inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, solvates, hydrates, cocrystals, and prodrugs thereof. 
       
     
     
         42 . The composition of any one of  claims 32 - 39 , for use in the treatment of cancer, wherein the cancer is a B cell hematological malignancy, and wherein the B cell hematological malignancy is selected from the group consisting of chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), non-Hodgkin's lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin's lymphoma, B cell acute lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenstrom's macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma, or myelofibrosis. 
     
     
         43 . The composition of any one of  claims 32 - 39 , for use in the treatment of cancer, wherein the cancer is a solid tumor cancer, and wherein the solid tumor cancer is selected from the group consisting of bladder cancer, non-small cell lung cancer, cervical cancer, anal cancer, pancreatic cancer, squamous cell carcinoma including head and neck cancer, renal cell carcinoma, melanoma, ovarian cancer, small cell lung cancer, glioblastoma, gastrointestinal stromal tumor, breast cancer, lung cancer, colorectal cancer, thyroid cancer, bone sarcoma, stomach cancer, oral cavity cancer, oropharyngeal cancer, gastric cancer, kidney cancer, liver cancer, prostate cancer, esophageal cancer, testicular cancer, gynecological cancer, colon cancer, and brain cancer. 
     
     
         44 . The composition of any one of  claims 41 - 43 , further comprising a therapeutically effective amount of gemcitabine. 
     
     
         45 . The composition of any one of  claims 41 - 44 , further comprising a therapeutically effective amount of albumin-bound paclitaxel. 
     
     
         46 . A composition comprising (1) a therapeutically effective amount of a Janus kinase-2 (JAK-2) inhibitor or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof; and (2) a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, for use in treating a solid tumor cancer, wherein the therapeutically effective amount is effective to inhibit signaling between the cells of the solid tumor cancer and at least one tumor microenvironment selected from the group consisting of macrophages, monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory T cells, natural killer cells, myeloid-derived suppressor cells, regulatory B cells, neutrophils, dendritic cells, and fibroblasts. 
     
     
         47 . The composition of  claim 46 , wherein the solid tumor cancer is selected from the group consisting of bladder cancer, non-small cell lung cancer, cervical cancer, anal cancer, pancreatic cancer, squamous cell carcinoma including head and neck cancer, renal cell carcinoma, melanoma, ovarian cancer, small cell lung cancer, glioblastoma, gastrointestinal stromal tumor, breast cancer, lung cancer, colorectal cancer, thyroid cancer, bone sarcoma, stomach cancer, oral cavity cancer, oropharyngeal cancer, gastric cancer, kidney cancer, liver cancer, prostate cancer, esophageal cancer, testicular cancer, gynecological cancer, colon cancer, and brain cancer. 
     
     
         48 . The composition of any one of  claims 46 - 47 , wherein the dose is further effective to increase immune system recognition and rejection of the solid tumor by the human. 
     
     
         49 . The composition of any one of  claims 46 - 48 , wherein the BTK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates, and prodrugs thereof. 
       
     
     
         50 . The composition of any one of  claims 46 - 49 , wherein the JAK-2 inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates, and prodrugs thereof. 
       
     
     
         51 . The composition of any one of  claims 46 - 50 , further comprising a therapeutically effective amount of a phosphoinositide 3-kinase (PI3K) inhibitor or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. 
     
     
         52 . The composition of  claim 51 , wherein the PI3K inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof. 
       
     
     
         53 . A composition comprising (1) a therapeutically effective amount of a Janus kinase-2 (JAK-2) inhibitor or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and (2) a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, wherein the BTK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates, and prodrugs thereof, for use in the treatment of a cancer in a human intolerant to a bleeding event. 
       
     
     
         54 . The composition of  claim 53 , wherein the bleeding event is selected from the group consisting of subdural hematoma, gastrointestinal bleeding, hematuria, post-procedural hemorrhage, bruising, petechiae, and combinations thereof. 
     
     
         55 . The composition of any one of  claims 53 - 54 , wherein the JAK-2 inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts, cocrystals, hydrates, solvates, and prodrugs thereof. 
       
     
     
         56 . The composition of any one of  claims 51 - 53 , further comprising a therapeutically effective dose of an anticoagulant or antiplatelet active pharmaceutical ingredient. 
     
     
         57 . The composition of  claim 56 , wherein the anticoagulant or antiplatelet active pharmaceutical ingredient is selected from the group consisting of acenocoumarol, anagrelide, anagrelide hydrochloride, abciximab, aloxiprin, antithrombin, apixaban, argatroban, aspirin, aspirin with extended-release dipyridamole, beraprost, betrixaban, bivalirudin, carbasalate calcium, cilostazol, clopidogrel, clopidogrel bisulfate, cloricromen, dabigatran etexilate, darexaban, dalteparin, dalteparin sodium, defibrotide, dicumarol, diphenadione, dipyridamole, ditazole, desirudin, edoxaban, enoxaparin, enoxaparin sodium, eptifibatide, fondaparinux, fondaparinux sodium, heparin, heparin sodium, heparin calcium, idraparinux, idraparinux sodium, iloprost, indobufen, lepirudin, low molecular weight heparin, melagatran, nadroparin, otamixaban, parnaparin, phenindione, phenprocoumon, prasugrel, picotamide, prostacyclin, ramatroban, reviparin, rivaroxaban, sulodexide, terutroban, terutroban sodium, ticagrelor, ticlopidine, ticlopidine hydrochloride, tinzaparin, tinzaparin sodium, tirofiban, tirofiban hydrochloride, treprostinil, treprostinil sodium, triflusal, vorapaxar, warfarin, warfarin sodium, ximelagatran, salts thereof, solvates thereof, hydrates thereof, and combinations thereof. 
     
     
         58 . The composition of any one of  claims 53 - 57 , wherein the cancer is selected from the group consisting of bladder cancer, squamous cell carcinoma including pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung carcinoma, thyoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia, thymus cancer, brain cancer, squamous cell cancer, skin cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral cavity and oropharyngeal cancers, gastric cancer, stomach cancer, cervical cancer, head and neck cancer, renal cancer, kidney cancer, liver cancer, ovarian cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, acquired immune deficiency syndrome (AIDS)-related cancers (e.g., lymphoma and Kaposi's sarcoma), viral-induced cancer, glioblastoma, esophageal tumors, hematological neoplasms, non-small-cell lung cancer, chronic myelocytic leukemia, diffuse large B-cell lymphoma, esophagus tumor, follicle center lymphoma, head and neck tumor, hepatitis C virus infection, hepatocellular carcinoma, Hodgkin's disease, metastatic colon cancer, multiple myeloma, non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma, ovary tumor, pancreas tumor, renal cell carcinoma, small-cell lung cancer, stage IV melanoma, chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), mature B-cell ALL, follicular lymphoma, mantle cell lymphoma, and Burkitt's lymphoma. 
     
     
         59 . A JAK-2 inhibitor in combination with a BTK inhibitor and/or in combination with a PI3K inhibitor, for use in treating a hyperproliferative disorder. 
     
     
         60 . A pharmaceutical composition comprising a JAK-2 inhibitor in combination with a BTK inhibitor and/or in combination with a PI3K inhibitor, and at least one pharmaceutically acceptable excipient. 
     
     
         61 . The pharmaceutical composition of  claim 60 , for use in treating a hyperproliferative disorder. 
     
     
         62 . A kit comprising a pharmaceutical composition comprising a JAK-2 inhibitor, a pharmaceutical composition comprising a PI3K inhibitor and a pharmaceutical composition comprising a BTK inhibitor, for co-administration of the JAK-2 inhibitor and the BTK inhibitor and/or the PI3K inhibitor, either simultaneously or separately. 
     
     
         63 . The kit of  claim 62 , for use in treating a hyperproliferative disorder. 
     
     
         64 . A JAK-2 inhibitor in combination with a BTK inhibitor for use in treating a hyperproliferative disorder. 
     
     
         65 . A pharmaceutical composition comprising a JAK-2 inhibitor in combination with a BTK inhibitor and at least one pharmaceutically acceptable excipient. 
     
     
         66 . The pharmaceutical composition of  claim 65 , for use in treating a hyperproliferative disorder. 
     
     
         67 . A kit comprising a pharmaceutical composition comprising a JAK-2 inhibitor and a pharmaceutical composition comprising a BTK inhibitor, for co-administration of the JAK-2 inhibitor and the BTK inhibitor, either simultaneously or separately. 
     
     
         68 . The kit of  claim 67 , for use in treating a hyperproliferative disorder.