Inhibitors of AKT Activity

Abstract

Invented are novel heterocyclic carboxamide compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis.

1 . The compound:
 N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A compound of  claim 2  which is:
 N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide. 
 
     
     
         3 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         4 . A pharmaceutical composition comprising a compound according to  claim 2  and a pharmaceutically acceptable carrier. 
     
     
         5 . A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound of  claim 1  or a pharmaceutically acceptable salt thereof, which process comprises bringing the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, into association with a pharmaceutically acceptable carrier. 
     
     
         6 . A method of treating a disease or condition selected from: cancer and arthritis, in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The method of  claim 6  wherein the mammal is a human. 
     
     
         8 . The method according to  claim 7  wherein said cancer is selected from: brain cancer (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma and thyroid cancer. 
     
     
         9 . The method of inhibiting Akt activity in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The method of  claim 9  wherein the mammal is a human. 
     
     
         11 . A method of treating cancer in a human in need thereof, which comprises:
 administering to such human a therapeutically effective amount of:
 a) a compound of  claim 1 , or a pharmaceutically acceptable salt thereof; and 
 b) at least one anti-neoplastic agent. 
   
     
     
         12 . The method  claim 11 , wherein the at least one anti-neoplastic agent is selected from the group consisting of: anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, and cell cycle signaling inhibitors. 
     
     
         13 . The method of  claim 11 , wherein the at least one anti-neoplastic agent is an anti-microtubule agent selected from diterpenoids and vinca alkaloids. 
     
     
         14 . The method of  claim 11 , wherein the at least one anti-neoplastic agent is a diterpenoid. 
     
     
         15 . The method of  claim 11 , wherein the at least one anti-neoplastic agent is a vinca alkaloid. 
     
     
         16 . The method of  claim 11 , wherein the at least one anti-neoplastic agent is a platinum coordination complex. 
     
     
         17 . The method of  claim 11 , wherein the at least one anti-neoplastic agent is paclitaxel, carboplatin, or vinorelbine. 
     
     
         18 . The method of  claim 11 , wherein the at least one anti-neoplastic agent is paclitaxel. 
     
     
         19 . The method of  claim 11 , wherein the at least one anti-neoplastic agent is carboplatin. 
     
     
         20 . The method of  claim 11 , wherein the at least one anti-neoplastic agent is vinorelbine. 
     
     
         21 . The method of  claim 11 , wherein the at least one anti-neoplastic agent is a signal transduction pathway inhibitor. 
     
     
         22 . The method of  claim 21 , wherein the signal transduction pathway inhibitor is an inhibitor of a growth factor receptor kinase selected from the group consisting of VEGFR2, TIE2, PDGFR, BTK, IGFR-1, TrkA, TrkB, TrkC, and c-fms. 
     
     
         23 . The method of  claim 21 , wherein the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase selected from the group consisting of rafk, akt, and PKC-zeta. 
     
     
         24 . The method of  claim 21 , wherein the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase selected from the src family of kinases. 
     
     
         25 . The method of  claim 24 , wherein the signal transduction pathway inhibitor is an inhibitor of c-src. 
     
     
         26 . The method of  claim 21 , wherein the signal transduction pathway inhibitor is an inhibitor of Ras oncogene selected from inhibitors of farnesyl transferase and geranylgeranyl transferase. 
     
     
         27 . The method of  claim 21 , wherein the signal transduction pathway inhibitor is an inhibitor of a serine/threonine kinase selected from the group consisting of PI3K. 
     
     
         28 . The method of  claim 11 , wherein the at least one anti-neoplastic agent is a cell cycle signaling inhibitor. 
     
     
         29 . The method of  claim 28 , wherein the cell cycle signaling inhibitor is selected from inhibitors of the group CDK2, CDK4, and CDK6. 
     
     
         30 . The method according to  claim 7  wherein said cancer is selected from:
 brain cancer (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, 
 Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia, 
 malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, 
 neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer. 
 
     
     
         31 . A method of treating or lessening the severity of cancer, wherein said cancer is selected from:
 brain cancer (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer,   Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia,   malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,   neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer,   
       in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of  claim 2 . 
     
     
         32 . A pharmaceutical composition according to  claim 3 , wherein the composition is in tablet form. 
     
     
         33 . A pharmaceutical composition according to  claim 4 , wherein the composition is in tablet form.