Smac peptidometics useful as iap inhibitors

Abstract

The present invention is directed to a compound of the formula: or pharmaceutically acceptable salts thereof and use of such compounds for treating proliferative diseases such as cancer, in mammals.

1 - 20 . (canceled) 
     
     
         21 . A method for treating a mammal suffering from a proliferative disease which comprises administering to said mammal in need of treatment a therapeutically effective amount of (S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide, or a pharmaceutically acceptable salt. 
     
     
         22 . A method of modulating cell proliferation comprising administering an effective amount of (S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide, or a pharmaceutically acceptable salt to modulate cell proliferation to a cell or mammal in need thereof. 
     
     
         23 . A method of inhibiting cell proliferation comprising administering an effective amount of (S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide, or a pharmaceutically acceptable salt to inhibit cell proliferation to a cell or mammal in need thereof. 
     
     
         24 . The method according to  claim 23 , wherein the cell proliferation that is inhibited is cancer cell proliferation. 
     
     
         25 . A method of treating a mammal afflicted with cancer comprising administering to said mammal a therapeutically effective amount of a compound according to (S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide, or a pharmaceutically acceptable salt. 
     
     
         26 . The method of  claim 21  where said proliferative disease is cancer, hyperplasias, fibrosis, angiogenesis, psoriasis, atherosclerosis or smooth muscle proliferation in the blood vessels. 
     
     
         27 . The method of  claim 26  wherein said cancer is selected from leukemia, breast cancer, lung cancer, gastrointestinal cancer, a genitourinary cancer, epidermoid cancer, melanoma, ovarian cancer, pancreas cancer, neuroblastoma, head cancer, neck cancer, bladder cancer, renal cancer, brain cancer, gastric cancer, lymphoma, myeloma, metastatic carcinoma, sarcoma, adenoma and nervous system cancer. 
     
     
         28 . The method of  claim 27  wherein said cancer is selected from a breast tumor, an epidermoid tumor, an epidermoid head and/or neck tumor, a mouth tumor, a small cell or non-small cell lung tumor, a colorectal tumor, and a prostate tumor. 
     
     
         29 . The method of  claim 27  wherein said cancer is selected from acute lymphoblastic leukemia (ALL), acute myelocytic leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL) and juvenile myelo-monocytic leukemia (JMML), Bcells Burkitts lymphobia, Hodgkin's lymphomas, non-Hodgkin's lymphomas, T-cell lymphomas, histiocytic lymphomas and multiple myelomas. 
     
     
         30 . The method of  claim 27  wherein said cancer is ovarian cancer. 
     
     
         31 . The method of  claim 27  wherein said cancer is breast cancer. 
     
     
         32 . A combination of (S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide, or a pharmaceutically acceptable salt and one or more antiproliferative agents. 
     
     
         33 . The combination of  claim 32  wherein said antiproliferative agent or agents are each independently selected from aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active agents; alkylating agents; histone deacetylase inhibitors; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity, anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; bisphosphonates; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; agents used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors; temozolomide (TEMODAL®); and leucovorin.