Syk inhibitors

Abstract

The present disclosure relates to compounds that are Syk inhibitors and to their use in the treatment of various disease states, including cancer and inflammatory conditions. In particular embodiments, the structure of the compounds is given by Formula I: wherein R 1 , R 2 , R 3 , and R 4 are as described herein. The present disclosure further provides pharmaceutical compositions that include a compound of Formula I, or pharmaceutically acceptable salts thereof, and methods of using these compounds and compositions to treat conditions mediated by Syk. In certain embodiments, also disclosed are methods for treating a cancer in a subject (e.g., a human) in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a vinca-alkaloid, or a pharmaceutically acceptable salt thereof.

1 .- 28 . (canceled) 
     
     
         29 . A method for treating in a human a disease or condition, wherein the human disease or condition is a cancer, in a subject in need thereof, the method comprising administering to the human in need thereof a therapeutic effective amount of a vinca-alkaloid selected from the group consisting of vindesine, desoxyvincaminol, vincaminol, vinburnine, vincamajine, and vineridine, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound having the structure of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
       
       wherein
    indicates the carbon atom of the indicated phenyl ring of Formula I to which R 1  is attached;   
 R 2  is H or 2-hydroxyethoxyl; 
 R 3  is H or methyl; and
 R 4  is H or methyl. 
 
 
     
     
         30 . The method of  claim 29 , wherein the disease or condition is a cancer selected from the group consisting of a hematologic malignancy and a solid tumor. 
     
     
         31 . The method of  claim 30 , wherein the disease or condition is a hematologic malignancy selected from the group consisting of lymphoma, multiple myeloma, and leukemia. 
     
     
         32 . The method of  claim 30 , wherein the disease or condition is selected from the group consisting of small lymphocytic lymphoma, non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, mantle cell lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, marginal zone lymphoma, immunoblastic large cell lymphoma, lymphoblastic lymphoma, Splenic marginal zone B-cell lymphoma (+/−villous lymphocytes), nodal marginal zone lymphoma (+/−monocytoid B-cells), extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type, cutaneous T-cell lymphoma, extranodal T-cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, mycosis fungoides, B-cell lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, small non-cleaved cell lymphoma, Burkitt's lymphoma, multiple myeloma, plasmacytoma, acute lymphocytic leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, juvenile myelomonocytic leukemia, minimal residual disease, hairy cell leukemia, primary myelofibrosis, secondary myelofibrosis, chronic myeloid leukemia, myelodysplastic syndrome, myeloproliferative disease, and Waldestrom's macroglobulinemia. 
     
     
         33 . The method of  claim 30 , wherein the disease or condition is a solid tumor, wherein the solid tumor is from a cancer selected from the group consisting of pancreatic cancer, urological cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, thyroid cancer, gall bladder cancer, lung cancer (e.g. non-small cell lung cancer, small-cell lung cancer), ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastomas, neuroblastomas, peritoneal effusions, malignant pleural effusions, mesotheliomas, Wilms tumors, trophoblastic neoplasms, hemangiopericytomas, Kaposi's sarcomas, myxoid carcinoma, round cell carcinoma, squamous cell carcinomas, esophageal squamous cell carcinomas, oral carcinomas, cancers of the adrenal cortex, and adrenocorticotropic hormone (ACTH) producing tumors. 
     
     
         34 . The method of  claim 29 , wherein the compound of Formula I is 
       
         
           
           
               
               
           
         
       
     
     
         35 . The method of  claim 34 , wherein the vinca-alkaloid is vindesine. 
     
     
         36 . The method of  claim 34 , wherein the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered before the vinca-alkaloid, or a pharmaceutically acceptable salt thereof. 
     
     
         37 . The method of  claim 34 , wherein the vinca-alkaloid, or a pharmaceutically acceptable salt thereof, is administered before the compound of Formula I or a pharmaceutically acceptable salt thereof. 
     
     
         38 . The method of  claim 34 , wherein the compound of Formula I or a pharmaceutically acceptable salt thereof, and the vinca-alkaloid, or a pharmaceutically acceptable salt thereof, are administered simultaneously. 
     
     
         39 . The method of  claim 34 , wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a dose between 50 mg and 300 mg and the vinca-alkaloid, or a pharmaceutically acceptable salt thereof, is administered at a dose between 0.1 mg-M 2  and 1.5 mg-M 2 . 
     
     
         40 . The method of  claim 34 , wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a dose between 100 mg and 250 mg and the vinca-alkaloid or a pharmaceutically acceptable salt thereof is administered at a dose between 0.25 mg-M 2  and 1.0 mg-M 2 . 
     
     
         41 . The method of  claim 34 , wherein the subject is (i) refractory to at least one chemotherapy treatment, or (ii) is in relapse after treatment with chemotherapy, or a combination thereof. 
     
     
         42 . The method of  claim 34 , wherein the cancer is a hematologic malignancy. 
     
     
         43 . The method of  claim 42 , wherein the cancer is a leukemia. 
     
     
         44 . The method of  claim 43 , wherein the leukemia is chronic lymphocytic leukemia (CLL). 
     
     
         45 . The method of  claim 42 , wherein the cancer is a lymphoma. 
     
     
         46 . The method of  claim 45 , wherein the lymphoma is non-Hodgkin's lymphoma (NHL). 
     
     
         47 . The method of  claim 46 , wherein the NHL is diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), and or marginal zone lymphoma (MZL). 
     
     
         48 . The method of  claim 42 , wherein the cancer is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), Burkitt's lymphoma (BL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, mantle cell lymphoma (MCL), follicular lymphoma (FL), Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL), and marginal zone lymphoma (MZL). 
     
     
         49 . The method of  claim 42 , wherein the cancer is a solid tumor and expresses spleen tyrosine kinase (Syk) activity. 
     
     
         50 . The method of  claim 49 , wherein the solid tumor cancer is selected from the group consisting of pancreatic, lung, colorectal cancer, ovarian, breast, adenocarcinoma, esophageal, and hepatocellular.