Mct4 inhibitors for treating disease

Abstract

and/or a salt thereof. The treatment of the monocarboxylate transporter MCT4-mediated disorder may inhibit activity of MCT4, or a mutant thereof, sometimes with at least a 100-fold selectivity for MCT4 over MCT1.

What is claimed is: 
     
         1 . A method for treating a monocarboxylate transporter MCT4-mediated disorder in a subject in need thereof, comprising the step of administering to the subject a compound of structural Formula I 
       
         
           
           
               
               
           
         
         and/or a salt thereof, wherein: 
         A 1 , A 2 , and A 3  are independently chosen from N and C, wherein at least one of A 1 , A 2 , and A 3  is N; 
         L is chosen from a bond and methylene; 
       
       
         
           
           
               
               
           
         
         R 4  and R 5  are independently chosen from C 1 -C 6 alkyl, wherein R 4  and R 5  together comprise no more than 6 carbons; 
         X is H; 
         Y is chosen from alkenyl, alkenylamino, alkyl, aminoalkenyl, aminoalkyl, aryl, cycloalkyl, and heteroaryl, any of which may be optionally substituted with one to three R 2  groups each independently chosen from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, alkylamino, amino, amido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, aryl, and heteroaryl; and 
         Z is chosen from aryl and heteroaryl, either of which may be optionally substituted with one to three R 3  groups each independently chosen from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, amino, amido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, aryl, and heteroaryl. 
       
     
     
         2 . The method as recited in  claim 1 , wherein
 A 1  and A 2  are C; and   A 3  is N.   
     
     
         3 . The method as recited in  claim 2 , wherein
 W is chosen from   
       
         
           
           
               
               
           
         
       
       and
 R 4  and R 5  are independently chosen from alkyl, with R 4  and R 5  together having no more than 6 carbons. 
 
     
     
         4 . The method as recited in  claim 3 , wherein Z is chosen from phenyl and pyridinyl, either of which may be optionally substituted with one to three R 3  groups each independently chosen from alkenyl, alkoxy, alkyl, alkylamino, aryl, halo, heteroaryl, and haloalkyl. 
     
     
         5 . The method as recited in  claim 4 , wherein Y is chosen from aryl and heteroaryl, any of which may be optionally substituted with one to three R 2  groups each independently chosen from alkenyl, alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halo, heteroaryl, and haloalkyl. 
     
     
         6 . The method as recited in  claim 1 , wherein the compound has structural Formula II: 
       
         
           
           
               
               
           
         
         and/or a salt thereof, wherein: 
         L is chosen from a bond and methylene; 
         W is chosen from 
       
       
         
           
           
               
               
           
         
         R 4  and R 5  are independently chosen from C 1 -C 6 alkyl, wherein R 4  and R 5  together comprise no more than 6 carbons; 
         Y is chosen from aryl and heteroaryl, either of which may be optionally substituted with one to three R 2  groups each independently chosen from alkenyl, alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halo, heteroaryl, and haloalkyl; 
         Z is chosen from aryl and heteroaryl, either of which may be optionally substituted with one to three R 3  groups each independently chosen from alkenyl, alkoxy, alkyl, alkylamino, aryl, halo, heteroaryl, and haloalkyl. 
       
     
     
         7 . The method as recited in  claim 6 , wherein Z is chosen from phenyl and pyridinyl, either of which may be optionally substituted with one to three R 3  groups each independently chosen from alkenyl, alkoxy, alkyl, alkylamino, aryl, halo, heteroaryl, and haloalkyl. 
     
     
         8 . The method as recited in  claim 7 , wherein Y is chosen from phenyl, thienyl, and thiazolyl, any of which may be optionally substituted with one to three R 2  groups each independently chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halo, and haloalkyl. 
     
     
         9 . The method as recited in  claim 8 , wherein R 4  and R 5  are chosen from the following combinations:
 R 4  and R 5  are each methyl;   R 4  and R 5  are each ethyl; and   R 4  is methyl and R 5  is ethyl.   
     
     
         10 . The method as recited in  claim 1 , wherein the compound has structural Formula III: 
       
         
           
           
               
               
           
         
         and/or a salt thereof, wherein: 
         L is chosen from a bond and methylene; 
         R 4  and R 5  are independently chosen from C 1 -C 6 alkyl, wherein R 4  and R 5  together comprise no more than 6 carbons; 
         R 6  is chosen from H and methyl; 
         Y is chosen from aryl and heteroaryl, either of which may be optionally substituted with one to three R 2  groups each independently chosen from alkenyl, alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halo, heteroaryl, and haloalkyl; and 
         Z is chosen from phenyl and pyridinyl, either of which may be optionally substituted with one to three R 3  groups each independently chosen from alkenyl, alkoxy, alkyl, alkylamino, aryl, halo, heteroaryl, and haloalkyl. 
       
     
     
         11 . The method as recited in  claim 10 , wherein:
 Y is chosen from aryl and heteroaryl, either of which may be optionally substituted with one to three R 2  groups each independently chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halo, and haloalkyl; and   Z is chosen from phenyl and pyridinyl, either of which may be optionally substituted with one to three R 3  groups each independently chosen from alkoxy, alkyl, alkylamino, halo, and haloalkyl.   
     
     
         12 . The method as recited in  claim 11 , wherein Y is chosen from phenyl, thienyl, and thiazolyl, any of which may be optionally substituted with one to three R 2  groups each independently chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halo, and haloalkyl. 
     
     
         13 . The compound as recited in  claim 12 , wherein R 4  and R 5  are chosen from the following combinations:
 R 4  and R 5  are each methyl;   R 4  and R 5  are each ethyl; and   R 4  is methyl and R 5  is ethyl.   
     
     
         14 . The method as recited in  claim 3 , wherein:
 Y is phenyl, substituted with an R 2  group chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halo, and haloalkyl; and   Z is phenyl, substituted with one or two R 3  groups chosen from alkoxy, alkyl, alkylamino, halo, and haloalkyl.   
     
     
         15 . The method as recited in  claim 1 , wherein the compound has structural Formula III: 
       
         
           
           
               
               
           
         
         and/or a salt thereof, wherein: 
         L is chosen from a bond and methylene; 
         R 4  and R 5  are chosen from the following combinations: 
         R 4  and R 5  are each methyl; 
         R 4  and R 5  are each ethyl; and 
         R 4  is methyl and R 5  is ethyl; 
         R 6  is chosen from H and methyl; 
         Y is phenyl meta-substituted with an R 2  group chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, and haloalkoxy; 
         Z is phenyl, substituted with one or two R 3  groups chosen from alkoxy, alkyl, alkylamino, halo, and haloalkyl. 
       
     
     
         16 . The method as recited in  claim 15 , wherein Y is meta-substituted with an R 2  group chosen from methoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, isopropoxy, isobutoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclopropylmethoxy, cyclobutylmethoxy, and cyclopentylmethoxy. 
     
     
         17 . The method as recited in  claim 14 , wherein Z is ortho-substituted with an R 3  group chosen from alkoxy, alkyl, alkylamino, halo, and haloalkyl. 
     
     
         18 . The method as recited in  claim 17 , wherein Z is ortho-substituted with halo. 
     
     
         19 . The method as recited in  claim 18 , wherein Z is ortho-substituted with chloro. 
     
     
         20 . The method as recited in  claim 14 , wherein R 6  is H. 
     
     
         21 . The method as recited in  claim 13 , wherein:
 Y is thienyl, substituted with an R 2  group chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halo, and haloalkyl; and   Z is phenyl, substituted with one or two R 3  groups chosen from alkoxy, alkyl, alkylamino, halo, and haloalkyl.   
     
     
         22 . The method as recited in  claim 21 , wherein Y is substituted with an R 2  group chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, and haloalkoxy. 
     
     
         23 . The method as recited in  claim 22 , wherein Y is meta-substituted with an R 2  group chosen from methoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, isopropoxy, isobutoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclopropylmethoxy, cyclobutylmethoxy, and cyclopentylmethoxy. 
     
     
         24 . The method as recited in  claim 21 , wherein Z is ortho-substituted with an R 3  group chosen from alkoxy, alkyl, alkylamino, halo, and haloalkyl. 
     
     
         25 . The method as recited in  claim 24 , wherein Z is ortho-substituted with halo. 
     
     
         26 . The method as recited in  claim 25 , wherein Z is ortho-substituted with chloro. 
     
     
         27 . The method as recited in  claim 21 , wherein R 6  is H. 
     
     
         28 . The method as recited in  claim 13 , wherein:
 Y is thiazolyl, substituted with one R 2  group chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halo, and haloalkyl; and   Z is phenyl, substituted with one or two R 3  groups chosen from alkoxy, alkyl, alkylamino, halo, and haloalkyl.   
     
     
         29 . The method as recited in  claim 28 , wherein Y is substituted with one R 2  group chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, and haloalkoxy. 
     
     
         30 . The method as recited in  claim 29 , wherein Y is meta-substituted with an R 2  group chosen from methoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, isopropoxy, isobutoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclopropylmethoxy, cyclobutylmethoxy, and cyclopentylmethoxy. 
     
     
         31 . The method as recited in  claim 28 , wherein Z is ortho-substituted with one R 3  group chosen from alkoxy, alkyl, alkylamino, halo, and haloalkyl. 
     
     
         32 . The method as recited in  claim 31 , wherein Z is ortho-substituted with one halo. 
     
     
         33 . The method as recited in  claim 32 , wherein Z is ortho-substituted with one chloro. 
     
     
         34 . The method as recited in  claim 28 , wherein R 6  is H. 
     
     
         35 . The method as recited in  claim 1 , wherein the compound is chosen from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         36 . The method as recited in  claim 1 , wherein the treatment of the monocarboxylate transporter MCT4-mediated disorder inhibits activity of the monocarboxylate transporter MCT4, or a mutant thereof. 
     
     
         37 . The method as recited in  claim 36 , wherein the activity of the monocarboxylate transporter MCT4, or a mutant thereof, is selectively inhibited over the monocarboxylate transporter MCT1, or a mutant thereof. 
     
     
         38 . The method as recited in  claim 37 , wherein the inhibition is at least 100-fold selective for MCT4 over MCT1. 
     
     
         39 . The method as recited in  claim 1 , wherein the subject is a human. 
     
     
         40 . The method as recited in  claim 1 , wherein the monocarboxylate transporter MCT4-mediated disorder is chosen from an inflammatory disorder and a proliferative disorder. 
     
     
         41 . The method as recited in  claim 40 , wherein the monocarboxylate transporter MCT4-mediated disorder is a proliferative disorder. 
     
     
         42 . The method as recited in  claim 41 , wherein the proliferative disorder is cancer. 
     
     
         43 . The method as recited in  claim 42 , wherein the cancer is chosen from adenocarcinoma, adult T-cell leukemia/lymphoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, carcinoma, myeloid sarcoma, cervical cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladder cancer, gastric cancer, head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, intestinal cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, multiple myeloma, ocular cancer, optic nerve tumor, oral cancer, ovarian cancer, pituitary tumor, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer, sarcoma, skin cancer, spinal tumor, small intestine cancer, stomach cancer, T-cell lymphoma, testicular cancer, thyroid cancer, throat cancer, urogenital cancer, urothelial carcinoma, uterine cancer, vaginal cancer, and Wilms' tumor. 
     
     
         44 . The method as recited in  claim 40 , wherein the monocarboxylate transporter MCT4-mediated disorder is an inflammatory disorder. 
     
     
         45 . The method as recited in  claim 44 , wherein the inflammatory disorder is chosen from Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, muscular dystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma). 
     
     
         46 . The method as recited in  claim 1 , further the sequential or co-administration of another therapeutic agent. 
     
     
         47 . The method as recited in  claim 46 , wherein the therapeutic agent is a protein kinase inhibitor. 
     
     
         48 . The method as recited in  claim 47 , wherein the protein kinase inhibitor is chosen from Aurora B, EGFR, PLK-1, CDKs inhibitors. 
     
     
         49 . The method as recited in  claim 46 , wherein the therapeutic agent is chosen from an antimetabolite, bcr-abl inhibitor, DNA damaging agent, EGFR inhibitor, microtubule stabilizing inhibitor, mitotic arrest inhibitor, S-phase inhibitor, and a taxane. 
     
     
         50 . The method as recited in  claim 49 , wherein the therapeutic agent is a DNA damaging agent chosen from an alkylating agent, anthracycline, antimetabolite agent, crosslinking agent, DNA replication inhibitor, intercalator, microtubule disruptor, PARP inhibitor, radiomimetic agent, radiosensitizer, strand break agent, and topoisomerase II inhibitor. 
     
     
         51 . The method as recited in  claim 46 , wherein the therapeutic agent is chosen from aminoglutethimide, amsacrine, anastrozole, asparaginase, barasertib, bcg, bicalutamide, bleomycin, buserelin, busulfan, campothecin, capecitabine, carboplatin, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ironotecan, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, olaparib, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, perifosine, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, sorafenib, streptozocin, sunitinib, suramin, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, and vinorelbine. 
     
     
         52 . The method as recited in  claim 1 , further comprising administering non-chemical methods of cancer treatment. 
     
     
         53 . The method as recited in  claim 1 , further comprising administering radiation therapy. 
     
     
         54 . The method as recited in  claim 1 , wherein further comprising administering surgery, thermoablation, focused ultrasound therapy, cryotherapy, or any combination thereof.