Substituted biaryl sulfonamides and the use thereof

Abstract

Provided herein are substituted biaryl sulfonamide compounds, pharmaceutical compositions comprising the compounds, methods of their preparation, and methods of their use. The compounds provided herein are useful for the treatment, prevention, and/or amelioration of various disorders, including cancer and proliferative disorders. In one embodiment, the compounds provided herein modulate initiation of protein translation. In one embodiment, the compounds provided herein are used in combination with surgery, radiation therapy, immuno therapy and/or one or more additional anticancer drugs for the treatment, prevention, and/or amelioration of cancer and proliferative disorders.

What is claimed: 
     
         1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; 
         or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
 X is NH, and Y is S(O) 2 ; or X is S(O) 2 , and Y is NH; 
 R′ is hydrogen, halogen, cyano, OH, OC(O)R a , C(O)R a , C(O)OR a , C(O)NR a R b , NR a C(O)R b , NR a R b , OS(O)R a , SR a , S(O)R a , S(O) 2 R a , S(O) 2 NR a R b , NR a S(O) 2 R b , (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, (C 2 -C 8 )alkenyloxy, (C 2 -C 8 )alkynyloxy, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyloxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyl, and cycloalkyloxy are each optionally substituted with one or more halogen; 
 n is 2, 3, or 4; 
 each occurrence of R is independently hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, or (C 3 -C 8 )cycloalkyl, each of which is optionally substituted with one or more halogen; and 
 R a  and R b  are each independently hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl, (C 7 -C 12 )aralkyl, phenyl, (5 to 6 membered)heteroaryl, or (3 to 7 membered)heterocyclyl; or R a  and R b  together form a 3 to 10 membered ring. 
 
       
     
     
         2 . The compound of  claim 1 , having formula (II): 
       
         
           
           
               
               
           
         
         or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; 
         or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein:
 R 1  is independently (C 1 -C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, or (C 3 -C 8 )cycloalkyl, each of which is optionally substituted with one or more halogen; 
 
         R 2  is independently hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, or (C 3 -C 8 )cycloalkyl, each of which is optionally substituted with one or more halogen; and
 R 3  is independently (C 1 -C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, or (C 3 -C 8 )cycloalkyl, each of which is optionally substituted with one or more halogen. 
 
       
     
     
         3 . The compound of  claim 2 , having formula (II-A): 
       
         
           
           
               
               
           
         
         or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; 
         or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. 
       
     
     
         4 . The compound of  claim 3 , having formula (II-A-1): 
       
         
           
           
               
               
           
         
         or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; 
         or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. 
       
     
     
         5 . The compound of any one of  claims 1 - 4 , wherein X is NH, and Y is S(O) 2 . 
     
     
         6 . The compound of any one of  claims 1 - 4 , wherein X is S(O) 2 , and Y is NH. 
     
     
         7 . The compound of  claim 4 , having formula (III-A-1): 
       
         
           
           
               
               
           
         
         or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof; 
         or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. 
       
     
     
         8 . The compound of any one of  claims 1 - 7 , wherein R′ is hydrogen, halogen, (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkoxy, wherein the alkyl and alkoxyl are each optionally substituted with one or more halogen. 
     
     
         9 . The compound of  claim 8 , wherein R′ is hydrogen, halogen, or (C 1 -C 4 )alkyl optionally substituted with one or more halogen. 
     
     
         10 . The compound of any one of  claims 1 - 8 , wherein R′ is hydrogen, F, Cl, Br, (C 1 -C 4 )alkyl, CF 3 ,or OCF 3 . 
     
     
         11 . The compound of any one of  claims 1 - 10 , wherein R′ is hydrogen, Cl, Br, or (C 1 -C 4 )alkyl. 
     
     
         12 . The compound of any one of  claims 1 - 11 , wherein R′ is hydrogen, chloro, bromo, or methyl. 
     
     
         13 . The compound of any one of  claims 1 - 12 , wherein R′ is hydrogen. 
     
     
         14 . The compound of any one of  claims 1 - 12 , wherein R′ is methyl. 
     
     
         15 . The compound of any one of  claims 1 - 12 , wherein R′ is chloro. 
     
     
         16 . The compound of any one of  claims 1 - 12 , wherein R′ is bromo. 
     
     
         17 . The compound of any one of  claims 2 - 16 , wherein R 1 , R 2 , and R 3  are independently (C 1 -C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, or (C 3 -C 8 )cycloalkyl. 
     
     
         18 . The compound of any one of  claims 2 - 17 , wherein R 1  is (C 1 -C 4 )alkyl. 
     
     
         19 . The compound of any one of  claims 2 - 18 , wherein R 1  is methyl, ethyl, or isopropyl. 
     
     
         20 . The compound of any one of  claims 2 - 19 , wherein R 2  is hydrogen, or (C 1 -C 4 )alkyl. 
     
     
         21 . The compound of any one of  claims 2 - 20 , wherein R 2  is methyl, isopropyl, or tert-butyl. 
     
     
         22 . The compound of any one of  claims 2 - 21 , wherein R 3  is (C 1 -C 4 )alkyl. 
     
     
         23 . The compound of any one of  claims 2 - 22 , wherein R 3  is methyl, ethyl, or isopropyl. 
     
     
         24 . The compound of  claim 6 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         25 . The compound of  claim 4 , wherein X is S(O) 2 , Y is NH, R′ is hydrogen, and R 2 , and R 3  are isopropyl. 
     
     
         26 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 25 , or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and at least one pharmaceutically acceptable excipient or carrier. 
     
     
         27 . The pharmaceutical composition of  claim 25 , further comprising one or more additional active agents. 
     
     
         28 . The pharmaceutical composition of  claim 27 , further comprising paclitaxel or docetaxel . 
     
     
         29 . The pharmaceutical composition of  claims 26 , wherein the composition is formulated for single dose administration. 
     
     
         30 . The pharmaceutical composition of  claim 26 , wherein the composition is formulated as oral, parenteral, or intravenous dosage form. 
     
     
         31 . The pharmaceutical composition of  claim 29 , wherein the oral dosage form is a tablet or capsule. 
     
     
         32 . A method of treating, preventing, or ameliorating one or more symptoms of a disorder mediated by protein translation initiation, comprising administering a compound of any one of  claims 1 - 25 , or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition of  claim 26  or  27 . 
     
     
         33 . A method of treating, preventing, or ameliorating one or more symptoms of a disorder mediated by eIF4E, comprising administering a compound of any one of  claims 1 - 25 , or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition of  claim 26  or  27 . 
     
     
         34 . The method of any one of  claims 32 - 33 , wherein the disorder is cancer, metastatic cancer, a proliferative disorder, breast cancer, triple negative breast cancer, ER+ breast cancer, ER− breast cancer, basal cell nevus syndrome (Gorlin syndrome), basal cell carcinoma, skin cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, brain cancer, medulloblastoma, glioblastoma, colorectal cancer, ovarian cancer, liver cancer, pancreatic cancer, pancreatic carcinoma, pancreatic angiosarcoma, pancreatic adenosarcoma, gastric cancer, gastroesophageal junction cancer, prostate cancer, cervical cancer, bladder cancer, head and neck cancer, lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, multiple myeloma, solid tumors that cannot be removed by surgery, locally advanced solid tumors, metastatic solid tumors, leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or recurrent or refractory tumors. 
     
     
         35 . A method of treating, preventing, or ameliorating one or more symptoms of a disorder, comprising administering a compound of any one of  claims 1 - 25 , or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition of  claim 26  or  27 , wherein the disorder is cancer, metastatic breast cancer, a proliferative disorder, breast cancer, triple negative breast cancer, ER+ breast cancer, ER− breast cancer, basal cell nevus syndrome (Gorlin syndrome), basal cell carcinoma, skin cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, brain cancer, medulloblastoma, glioblastoma, colorectal cancer, ovarian cancer, liver cancer, pancreatic cancer, pancreatic carcinoma, pancreatic angiosarcoma, pancreatic adenosarcoma, gastric cancer, gastroesophageal junction cancer, prostate cancer, cervical cancer, bladder cancer, head and neck cancer, lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, multiple myeloma, solid tumors that cannot be removed by surgery, locally advanced solid tumors, metastatic solid tumors, leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or recurrent or refractory tumors. 
     
     
         36 . The method of any one of  claim 34  or  35 , wherein the cancer is resistant to conventional therapy. 
     
     
         37 . The method of any one of  claim 34  or  35 , wherein the cancer is vincristine-resistant. 
     
     
         38 . The method of any one of  claim 34  or  35 , wherein the cancer is taxol-resistant. 
     
     
         39 . The method of any one of  claim 34  or  35 , wherein the cancer is cytarabine-resistant. 
     
     
         40 . The method of any one of  claim 34  or  35 , wherein the cancer is doxorubicin-resistant. 
     
     
         41 . A method of treating, preventing, or ameliorating one or more symptoms of a disorder mediated by protein translation initiation, comprising administering a compound of any one of  claims 1 - 25 , or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition of  claim 26  or  27 , together with one or more additional active agents. 
     
     
         42 . The method of  claim 41 , wherein the additional active agents comprises paclitaxel or docetaxel. 
     
     
         43 . A method of preventing metastasis comprising administering a compound of any one of  claims 1 - 25 , or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition of  claim 26  or  27 . 
     
     
         44 . A method of treating, preventing, or ameliorating fibrosis, comprising contacting a human fibroblast with a compound of any one of  claims 1 - 25 , or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition of  claim 26  or  27 .