TGF-ß INHIBITORS

Abstract

Disclosed are aryl pyrimidine compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structureand pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein A, Z, R and R′ are as described herein. In certain embodiments, a compound disclosed herein inhibits the activity of one or more members of the TGF-β superfamily, and can be used to treat disease by blocking such activity.

What is claimed: 
     
         1 . A method for treating a disease or condition mediated by or involving a member of the TGF-β receptor superfamily in a subject in need thereof, comprising administering an effective TGF-β receptor superfamily inhibiting amount of a compound having the structure of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof, 
         wherein 
         A is phenyl optionally substituted with one to five R 1  groups, wherein each R 1  is independently halogen, cyano, —OR a , —SR a , —N(R a ) 2 , C 1-6  alkyl, C 1-6 haloalkyl or C 3-8 cycloalkyl, 
         wherein each R a  is independently hydrogen, C 1-6  alkyl or C 1-6  haloalkyl; 
         Z is 
         a fused bicyclic ring of the formula, 
       
       
         
           
           
               
               
           
         
       
       wherein
 ring A is phenyl or pyrazole, 
 optionally substituted with one to four R 2  groups, wherein each R 2  is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OR b , —C(O)NR b   2 , —C(O)CH 2 NR b   2 , —CH 2 —OP(O)(OR c ) 2 , or heteroaryl, 
 wherein each R b  is independently hydrogen, C 1-6  alkyl or C 1-6 haloalkyl, and 
 wherein each R c  is independently hydrogen or C 1-6  alkyl; 
 ring B is phenyl or pyridyl, each optionally substituted with one to three R 3  groups, 
 
       wherein each R 3  is independently halogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl or heteroaryl;
 R and R′ are independently hydrogen, halogen, C 1-6 alkyl or C 1-6  haloalkyl; and 
 wherein each alkyl, haloalkyl cycloalkyl or heteroaryl group is optionally substituted with one or two —R Z  groups that are each independently halogen, C 1-6 alkyl or C 1-6 haloalkyl. 
 
     
     
         2 . The method of  claim 1 , wherein the compound has a structure according to formula (II) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof; 
         wherein: 
         R and R′ are independently hydrogen, halogen, C 1-6 alkyl or C 1-6  haloalkyl; 
         R 1  is halogen, cyano, —SR a , —N(R a ) 2 , C 1-6  alkyl, C 1-6 haloalkyl or C 3-8 cycloalkyl, 
       
       wherein each R a  is independently hydrogen, C 1-6  alkyl or C 1-6  haloalkyl;
 m is 0, 1, 2, 3 or 4; 
 X is N or C(H); 
 R 2  is hydrogen, —C(O)CH 2 NR b   2 , —CH 2 —OP(O)(OR c ) 2 , C 1-6  alkyl, C 1-6 haloalkyl, or heteroaryl, wherein each R b  is independently hydrogen or C 1-6  alkyl, and wherein each R c  is independently hydrogen or C 1-6  alkyl; and 
 R 3  is halogen, C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl or heteroaryl. 
 
     
     
         3 . The method of  claim 2 , wherein the compound has a structure according to formula (IIa): 
       
         
           
           
               
               
           
         
         wherein 
         R is hydrogen, halogen, C 1-6  alkyl or C 1-6  haloalkyl; 
         R 1  is halogen, cyano, C 1-6  alkyl, —NH 2 , C 1-6  haloalkyl or C 3-6  cycloalkyl; 
         m is 0, 1, 2, 3 or 4; 
         R 2  is hydrogen, C 1-6  alkyl, —C(O)CH 2 NR b   2 , —CH 2 —OP(O)(OR c ) 2 , C 1-6  haloalkyl, or C 5-6  heteroaryl, 
         wherein each R b  is independently hydrogen or C 1-6  alkyl, and 
         wherein each R c  is independently hydrogen or C 1-6  alkyl; and 
         R 3  is halogen, C 1-6  alkyl or C 1-6  haloalkyl. 
       
     
     
         4 . The method of  claim 3 , wherein:
 R is hydrogen, halogen, C 1-6  alkyl or C 1-6  haloalkyl;   R 1  is halogen, cyano, C 1-6  alkyl or —NH 2 ;   m is 0, 1, 2, 3 or 4;   R 2  is hydrogen, C 1-6  alkyl, —C(O)CH 2 NR b   2 , or —CH 2 —OP(O)(OR c ) 2 ,   wherein each R b  is independently hydrogen or C 1-6  alkyl, and   wherein each R c  is independently hydrogen or C 1-6  alkyl; and   R 3  is halogen or C 1-6  alkyl.   
     
     
         5 . The method of  claim 2 , wherein the compound has the structure 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 1 , wherein the compound has a structure according to formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof, 
         wherein 
         Z is: 
       
       
         
           
           
               
               
           
         
         
           wherein 
           R 2  is —C(O)CH 2 NR b   2 , 
           wherein R b  is C 1-6  alkyl; and 
           R 3  is C 1-6 alkyl; or 
         
       
       
         
           
           
               
               
           
         
         
           wherein 
           R 2  is hydrogen or —OR b , 
           wherein R b  is hydrogen or C 1-6  alkyl; and 
           n is 0, 1 or 2; 
         
         R and R′ are independently hydrogen or C 1-6 alkyl; 
         R 1  is halogen, cyano, or C 1-6  alkyl; and 
         m is 0, 1 or 2. 
       
     
     
         7 . The method of  claim 6 , wherein the compound has a structure 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 1 , wherein the compound is selected from:
 2-(Dimethylamino)-1-(5-((2-(2,5-dimethylphenyl)pyrimidin-4-yl)amino)-1H-indazol-1-yl)ethan-1-one;   N-(2-(3,4-Difluorophenyl)pyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;   N-(2-(4-Fluorophenyl)pyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;   N-(5-Fluoro-2-(4-fluoro-2-methylphenyl)pyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;   N-(2-(3-Fluorophenyl)-5-methylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;   N-(2-(4-Fluorophenyl)-5-methylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;   N-(2-(3,4-Difluorophenyl)-5-methylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;   N-(2-(3-Methylphenyl)-5-methylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;   N-(2-(2-Fluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(3-Fluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-Phenylpyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(2-Methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   6-Fluoro-N-(2-(2-fluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(5-Fluoro-2-(2-fluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(5-fluoro-2-methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(3,5-Difluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(3-Fluoro-4-methoxyphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(3-Cyanophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(2,5-Dimethylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(3-Aminophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(3-Methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(4-Fluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(5-Fluoro-2-(methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(3,4-Difluorophenyl)-5-fluoropyrimidin-4-yl)-1H-indazol-5-amine;   N-(5-Fluoro-2-(3-fluorophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(5-Fluoro-2-phenylpyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(2-Fluorophenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(2-Methylphenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(3,4-Difluorophenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(2,5-Dimethylphenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(4-Fluoro-2-methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(4-Fluoro-3-methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(2-Aminophenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(3-Trifluoromethylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(4-Methoxy-2-methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(4-Fluoro-2-methylphenyl)pyrimidin-4-yl)-6,7-dimethoxyquinolin-4-amine;   N-(2-(2-Fluoro-5-methylphenyl)pyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(4-Fluoro-3-methylphenyl)-5-methylpyrimidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine;   N-(2-(4-Fluoro-3-methylphenyl)-5-methylpyrimidin-4-yl)-6-methyl-1H-indazol-5-amine;   N-(2-(3-Methylphenyl)-5-methylpyrimidin-4-yl)-6-methyl-1H-indazol-5-amine;   N-(2-(4-Fluorophenyl)-5-methylpyrimidin-4-yl)-6-methyl-1H-indazol-5-amine;   N-(2-(3,4-Difluorophenyl)-5-methylpyrimidin-4-yl)-6-methyl-1H-indazol-5-amine;   N-(2-(2,5-Dimethylphenyl)-5-methylpyrimidin-4-yl)-6-methyl-1H-indazol-5-amine;   N-(2-(4-Fluoro-3-methylphenyl)-5-methylpyrimidin-4-yl)-6-methyl-1H-indazol-5-amine;   6-Fluoro-N-(2-(3-fluorophenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;   6-Fluoro-N-(2-(3-methylphenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;   6-Fluoro-N-(2-(2,5-dimethylphenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;   6-Fluoro-N-(2-(3,4-difluorophenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;   6-Fluoro-N-(2-(4-fluoro-3-methylphenyl)-5-methylpyrimidin-4-yl)-1H-indazol-5-amine;   N-(2-(2-Fluorophenyl)-5-methylpyrimidin-4-yl)-6-methoxy-1H-indazol-5-amine;   N-(2-(3,4-Difluorophenyl)-5-methylpyrimidin-4-yl)-6-methoxy-1H-indazol-5-amine;   
       or a pharmaceutically acceptable salt, prodrug, or N-oxide thereof, or a solvate or hydrate thereof. 
     
     
         9 . The method of  claim 1 , wherein the disease or condition is mediated by or involves GDF-8 or TGF-β. 
     
     
         10 . The method of  claim 9 , wherein the disease or condition is pulmonary hypertension, chronic renal disease, acute renal disease, wound healing, arthritis, osteoporosis, kidney disease, congestive heart failure, ulcer, ocular disorder, corneal wound, diabetic nephropathy, impaired neurological function, Alzheimer's disease, atherosclerosis, peritoneal or sub-dermal adhesion, kidney fibrosis, lung fibrosis, idiopathic pulmonary fibrosis, liver fibrosis, hepatitis B, hepatitis C, alcohol-induced hepatitis, cancer, haemochromatosis, primary biliary cirrhosis, restenosis, retroperitoneal fibrosis, mesenteric fibrosis, endometriosis, keloids, cancer, abnormal bone function, inflammatory disorder, scarring or photoaging of the skin. 
     
     
         11 . The method of  claim 9 , wherein the disease or condition is benign or malignant tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina or thyroid, sarcoma, glioblastomas, multiple myeloma or gastrointestinal cancer, colon carcinoma or colorectal adenoma, tumor of the neck and head, epidermal hyperproliferation, melanoma, psoriasis, prostate hyperplasia, neoplasia, neoplasia of epithelial character, leukemias, lymphomas, mammary carcinoma or leukemia. 
     
     
         12 . The method of  claim 9 , wherein the disease or condition is Cowden syndrome, Lhermitte-Dudos disease, Bannayan-Zonana syndrome, or other disease in which the PI3K/PKB pathway is aberrantly activated. 
     
     
         13 . The method of  claim 9 , wherein the disease is cancer, and the compound is administered in combination with the administration of a therapeutically effective amount of one or more chemotherapeutic agents. 
     
     
         14 . The method of  claim 13 , wherein the one or more chemotherapeutic agents is independently selected from the group consisting of antimetabolites, alkylating agents, coordination compounds, platinum complexes, DNA cross-linking compounds, inhibitors of transcription enzymes, tyrosine kinase inhibitors, protein kinase inhibitors, topoisomerase inhibitors, DNA minor-groove binding compounds, vinca alkyloids, taxanes, antitumor antibiotics, hormones, aromatase inhibitors, enzymes, growth factor receptors antibodies, cytokines, cell surface markers antibodies, HDAC inhibitors, HSP 90 inhibitors, BCL-2 inhibitors, B-raf inhibitors, MEK inhibitors, mTOR inhibitors, proteasome inhibitors and monoclonal antibodies. 
     
     
         15 . The method of  claim 13 , wherein the one or more chemotherapeutic agents is independently selected from the group consisting of ABT-199, mechlorothamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines, procarbazine, dacarbazine, temozolomide, busulfan, carmustine, lomustine, methotrexate, fluorouracil, capecitabine, cytarabine, gemcitabine, cytosine arabinoside, mecaptopurine, fludarabine, cladribine, thioguanine, azathioprine, vinblastine, vincristine, paclitaxel, docetaxel, colchicine, actinomycin D, daunorubicin, bleomycin, L-asparaginase, cisplatin, carboplatin, oxaliplatin, prednisone, dexamethasone, amino glutethimide, formestane, anastrozole, hydroxyprogesterone caproate, medroxyprogesterone, tamoxifen, amsacrine, mitoxantrone, topotecan, irinotecan, camptothecin, afatinib, axitinib, bosutinib, bortezomib, carfilzomib, cabozantinib, cediranib, crizotinib, dasatinib, dabrafenib, evorolimus, ibrutinib, LDK378, LGX818, MEK162, regorafenib, ruxolitinib, selumetinib, sorafenib, trametinib, vemurafenib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, palbociclib, pazopanib, pomatinib, semaxanib, sirolimus, sunitinib, temsirolimus, vatalanib, vandetanib, anti Her2 antibodies, interferon-α, interferon-γ, interleukin 2, GM CSF, anti CTLA 4 antibodies, rituximab, anti CD33 antibodies, MGCD0103, vorinostat, 17-AAG, thalidomide, lenalidomide, rapamycin, CCI-779, doxorubicine, gemcitabine, melphalan, NPI052, gemtuzumab, alemtuzumab, cetuximab, ibritumomab tiuxaetan, tositumomab, iodine-131 tositumomab, trastuzumab, ado-trastuzumab emtansine, obinutuzumab, bevacizumab, rituximab, and anti-TRAIL death receptor antibodies.