Thienopyranones as Kinase and Epigenetic Inhibitors

Abstract

The invention relates to methods of treating diseases including but not limited to, cancer, non-cancer proliferative disease, sepsis, autoimmune disease, viral infection, atheroscleosis, Type 1 or 2 diabetes, obesity, inflammatory disease, or Myc-depenent disorder including by modulating biological processes by the inhibition of PI3 kinase and/or bromodomain protein binding to substrates comprising the administration of a compound(s) of Formula I-IX (or pharmaceutically acceptable salts thereof) as defined herein.

1 . A method for treating a disease in a human selected from cancer, non-cancer proliferative disease, sepsis, autoimmune disease, viral infaction, atheroscleosis, Type I or 2 diabetes, obesity, inflammatory disease, or Myc-depenent disorder comprising administering a compound of Formula I-IX: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein M is oxygen (O) or sulfur (S); 
         R1 is selected from H, halogen, alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocycle, heteroaryl, formyl, nitro, cyano, amino, carboxylic acid, carboxylic ester, carboxyl amide, reverse carboxyamide, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted carbocycle, substituted aryl, substituted heterocycle, substituted heteroaryl, phosphonic acid, phosphinic acid, phosphoramidate, phosphonic ester, phosphinic ester, ketone, substituted ketone, hydroxamic acid, N-substituted hydroxamic acid, O-substituted hydroxamate, N- and O-substituted hydroxamate, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfonic acid, sulfonic ester, sulfonamide, N-substituted sulfonamide, N,N-disubstituted sulfonamide, boronic acid, boronic ester, azo, substituted azo, azido, nitroso, imino, substituted imino, oxime, substituted oxime, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, thioether, substituted thioether, carbamate, substituted carbamate; 
         R2 is selected from R1 or 
       
       
         
           
           
               
               
           
         
         where X is C, N, P, P(O), SiR b , 
         n is 0, 1, or 2; 
         Y is C—R1, O, S, NR a , —C(O)(NH 2 ), —P(Z) m R a , SiR a R b , BR b ; 
         Z is O or S; 
         m=0 or 1; 
         R a  is hydrogen (H) or independently at each instance any group defined in R1; 
         R b  is hydrogen (H) or independently at each instance any group defined in R1; 
         R3 is selected from R1; 
         R4 is selected from R1; and
 Cyc is an aryl, substituted aryl, heterocyele, substituted heterocycle, carbocycle, and substituted carbocycle. 
 
       
     
     
         2 . A method as in  claim 1  wherein said disease is associated with aberrant PI3K and/or bromodomain protein activity and said compound is selected from Cmpd 0, Cmpd 1, Cmpd 1, Cmpd 2, Cmpd 3, Cmpd 4, Cmpd 5, Cmpd 6, Cmpd 7, Cmpd 8, Cmpd 9, Cmpd 10, Cmpd 11, Cmpd 12, Cmpd 14, Cmpd 15, Cmpd 16, Cmpd 17, Cmpd 18, Cmpd 19, Cmpd 20, Cmpd 21, Cmpd 22, Cmpd 23, Cmpd 24, Cmpd 26, Cmpd 27, Cmpd 28, Cmpd 29, Cmpd 32, Cmpd 35, Cmpd 41, Cmpd 42, Cmpd 45, Cmpd 47, Cmpd 48, Cmpd 49, Cmpd 51, Cmpd 52, Cmpd 56, Cmpd 63, Cmpd 64, Cmpd 66, Cmpd 85, Cmpd 86, Cmpd 88, Cmpd 89, Cmpd 90, Cmpd 91, Cmpd 92, Cmpd 93, Cmpd 94, Cmpd 95, Cmpd 97, Cmpd 98, Cmpd 99, Cmpd 100, Cmpd 101, Cmpd 102, Cmpd 103, Cmpd 105, Cmpd 107, Cmpd 108, Cmpd 110, Cmpd 111, Cmpd 112, Cmpd 113, Cmpd 114, Cmpd 115, Cmpd 116, Cmpd 117, Cmpd 118, Cmpd 120, Cmpd 121, Cmpd 122, Cmpd 123, Cmpd 124, Cmpd 125, Cmpd 126, Cmpd 127, Cmpd 128, Cmpd 129, Cmpd 130, Cmpd 131, Cmpd 132, Cmpd 133, Cmpd 134, Cmpd 135, Cmpd 136, Cmpd 137. 
     
     
         3 . A method of  claim 1  wherein said compound is selected from Cmpd 0, Cmpd 1, Cmpd 1, Cmpd 2, Cmpd 3, Cmpd 4, Cmpd 5, Cmpd 6, Cmpd 7, Cmpd 8, Cmpd 9, Cmpd 10, Cmpd 11, Cmpd 12, Cmpd 14, Cmpd 15, Cmpd 16, Cmpd 17, Cmpd 18, Cmpd 19, Cmpd 20, Cmpd 21, Cmpd 22, Cmpd 23, Cmpd 24, Cmpd 26, Cmpd 27, Cmpd 28, Cmpd 29, Cmpd 32, Cmpd 35, Cmpd 41, Cmpd 42, Cmpd 45, Cmpd 47, Cmpd 48, Cmpd 49, Cmpd 51, Cmpd 52, Cmpd 56, Cmpd 63, Cmpd 64, Cmpd 66, Cmpd 85, Cmpd 86, Cmpd 88, Cmpd 89, Cmpd 90, Cmpd 91, Cmpd 92, Cmpd 93, Cmpd 94, Cmpd 95, Cmpd 97, Cmpd 98, Cmpd 99, Cmpd 100, Cmpd 101, Cmpd 102, Cmpd 103, Cmpd 105, Cmpd 107, Cmpd 108, Cmpd 110, Cmpd 111, Cmpd 112, Cmpd 113, Cmpd 114, Cmpd 115, Cmpd 116, Cmpd 117, Cmpd 118, Cmpd 120, Cmpd 121, Cmpd 122, Cmpd 123, Cmpd 124, Cmpd 125, Cmpd 126, Cmpd 127, Cmpd 128, Cmpd 129, Cmpd 130, Cmpd 131, Cmpd 132, Cmpd 133, Cmpd 134, Cmpd 135, Cmpd 136, Cmpd 137. 
     
     
         4 . A method as in  claim 2  wherein said disease is associated with aberrant bromodomain protein activity. 
     
     
         5 . A method of  claim 4  wherein the bromodomain protein is a BET protein. 
     
     
         6 . A method of  claim 5  wherein the BET protein is BRD4. 
     
     
         7 . A method of  claim 1  wherein said disease is cancer. 
     
     
         8 . A method of  claim 7  wherein said cancer is selected fromadrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AlDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblasfoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangio sarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulioblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma peritonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatmoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor. 
     
     
         9 . A method of  claim 1  wherein said disease is non-cancer proliferative disease. 
     
     
         10 . A method of  claim 9  wherein said non-cancer proliferative disease is selected from meningioma, cerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, multiple endocrine neoplasia, nasal polyps, pituitary tumors, juvenile polyposis syndrome, prolactinoma, pseudotumor benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, vocal cord nodules, polyps, and cysts, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic granuloma, and Castleman disease. 
     
     
         11 . A method of  claim 1  wherein said disease is inflammatory disease. 
     
     
         12 . A method of  claim 11  wherein said inflammatory disease is selected from appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, asthma, allergic rhinitis, chronic obstructive pulmonary disease, autoimmune polyglandular disease/syndrome, autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, hepatitis, gastritis, enteritis, dermatitis, gingivitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, Type I diabetes, septic shock, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Graves' disease, Guillain-Barre syndrome, Behcet's disease, scleracierma, mycosis fungoides, graft versus host disease, irritable bowel syndrome, psoriasis, acute respiratory distress syndrome and ischemia/reperfusion injury. 
     
     
         13 . A method of  claim 1  wherein said disease is Myc-dependent disorder. 
     
     
         14 . A method of  claim 13  wherein said Myc-dependent disorder is selected from CLL, multiple myeloma, neuroblastoma, or medullobiastoma. 
     
     
         15 . A method of  claim 1  wherein the administration of a compound of Formula I-IX is in combination with an additional anticancer agent. 
     
     
         16 . A compound or a pharmaceutically acceptable salt thereof selected from: