Substituted dioxopiperidinyl phthalimide derivatives

Abstract

This invention relates to novel substituted dioxopiperidinyl phthalimide derivatives and pharmaceutically acceptable acid addition salts thereof. The invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions beneficially treated by an immunomodulatory agent.

What is claimed is: 
     
         1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 each W is independently selected from hydrogen or deuterium; 
 each Y is independently selected from hydrogen or deuterium; 
 each Z is independently selected from hydrogen or deuterium; and 
 at least one W, one Y, or one Z is deuterium. 
 
     
     
         2 . The compound of  claim 1 , wherein Z 5  is deuterium. 
     
     
         3 . The compound of  claim 2 , wherein Z 3  and Z 4  are deuterium; W 1 , W 2  and W 3  are simultaneously hydrogen or simultaneously deuterium; Z 1  and Z 2  are simultaneously hydrogen; and Y 1  and Y 2  are simultaneously hydrogen. 
     
     
         4 . The compound of  claim 2 , wherein Z 3  and Z 4  are deuterium; W 1 , W 2  and W 3  are simultaneously hydrogen or simultaneously deuterium; Z 1  and Z 2  are simultaneously hydrogen; and Y 1  and Y 2  are simultaneously deuterium 
     
     
         5 . The compound of  claim 1 , wherein W 1 , W 2  and W 3  are the same. 
     
     
         6 . The compound of  claim 5 , wherein W 1 , W 2  and W 3  are simultaneously hydrogen. 
     
     
         7 . The compound of  claim 6 , wherein Z 1 , Z 2 , Z 3  and Z 4  are the same. 
     
     
         8 . The compound of  claim 7 , wherein Z 1 , Z 2 , Z 3 , Z 4  and Z 5  are simultaneously deuterium. 
     
     
         9 . The compound of  claim 8 , wherein each Y is simultaneously deuterium. 
     
     
         10 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The compound of  claim 1 , which is a compound of Formula Ia or Ib: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The compound of  claim 13 , wherein Z 3  and Z 4  are deuterium; W 1 , W 2  and W 3  are simultaneously hydrogen or simultaneously deuterium; Z 1  and Z 2  are simultaneously hydrogen; and Y 1  and Y 2  are simultaneously hydrogen. 
     
     
         15 . The compound of  claim 13 , wherein Z 3  and Z 4  are deuterium; W 1 , W 2  and W 3  are simultaneously hydrogen or simultaneously deuterium; Z 1  and Z 2  are simultaneously hydrogen; and Y 1  and Y 2  are simultaneously deuterium. 
     
     
         16 - 19 . (canceled) 
     
     
         20 . The compound of  claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance. 
     
     
         21 . A pyrogen-free pharmaceutical composition comprising a compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         22 . The composition of  claim 21 , additionally comprising a second therapeutic agent selected from pemetrexed, topotecan, doxorubicin, bortezomib, gemcitabine, dacarbazine, dexamethasone, biaxin, doxil, vincristine, decadron, azacitidine, rituximab, prednisone, docetaxel, melphalan, and combinations thereof. 
     
     
         23 . A method of treating a disease or condition selected from myelodysplastic syndromes, multiple myeloma, Non-Hodgkins lymphoma; papillary and follicular thyroid carcinoma; prostate cancer; chronic lymphocytic leukemia, amyloidosis, complex regional pain syndrome Type I, malignant melanoma, radiculopathy, myelofibrosis, glioblastoma, gliosarcoma, malignant gliomas, myelogenous leukemia, refractory plasma cell neoplasm, chronic myelomonocytic leukemia, follicular lymphoma, ciliary body and chronic melanoma, iris melanoma, recurrent interocular melanoma, extraocular extension melanoma, solid tumors, T-cell lymphoma, erythroid lymphoma, monoblastic and monocytic leukemia; myeloid leukemia, brain tumor, meningioma, spinal cord tumors, thyroid cancers, mantle cell lymphoma, non-small cell lung cancer, ovarian cancer, prostate cancer, renal cell cancer, myelofibrosis, Burkitt's lymphoma, Hodgkin's lymphoma, large cell lymphoma, or Waldenstrom's macroglobulinemia in a patient in need thereof, the method comprising the step of administering to the patient a composition of  claim 21 . 
     
     
         24 . The method of  claim 23 , wherein the disease is selected from myelodysplastic syndromes or multiple myeloma.