Compounds and methods for kinase modulation, and indications therefor

Abstract

Compounds and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described. In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, and forms thereof are active on each of BRaf and c-Raf-1 protein kinase, and may also be active on either or both of A-Raf and B-Raf V600E protein kinase. Also described are methods of use thereof to treat diseases and conditions, including melanoma, colorectal cancer, thyroid cancer, ovarian cancer, and biliary tract cancer.

1 . A compound having the chemical structure of Formula I, 
       
         
           
           
               
               
           
         
       
       or a salt, a prodrug, or a tautomer thereof,
 wherein: 
 R 1  is selected from the group consisting of 
 
       
         
           
           
               
               
           
         
          wherein 
       
       
         
           
           
               
               
           
         
          indicates the point of attachment of R 1  to the S(O) 2  shown in Formula 1;
 R 2  is hydrogen or fluoro; 
 R 3  is hydrogen, chloro, methoxy or cyano; 
 R 4  is selected from the group consisting of hydrogen, chloro, methyl, methoxy, cyano, 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
            wherein 
         
       
       
         
           
           
               
               
           
         
         
            indicates the point of attachment of R 4  to the 5-position of the pyrrolo[2,3-b]pyridine ring shown in Formula I; 
         
         when R 1  is 
       
       
         
           
           
               
               
           
         
          R 3  is hydrogen and R 4  is cyano, R 2  is hydrogen or fluoro; 
         when R 1  is 
       
       
         
           
           
               
               
           
         
          R 2  is fluoro, and R 3  is hydrogen, R 4  is methyl, methoxy, cyano, or 
       
       
         
           
           
               
               
           
         
         when R 2  is fluoro, R 4  is hydrogen, and R 3  is chloro, methoxy, or cyano, R 1  is 
       
       
         
           
           
               
               
           
         
         when R 2  is hydrogen, R 3  is hydrogen, and R 4  is cyano, R 1  is 
       
       
         
           
           
               
               
           
         
         when R 1  is 
       
       
         
           
           
               
               
           
         
          R 2  is fluoro, and R 3  is hydrogen, R 4  is methyl or 
       
       
         
           
           
               
               
           
         
         when R 1  is 
       
       
         
           
           
               
               
           
         
          R 2  is fluoro, and R 3  is hydrogen, R 4  is chloro, methyl, cyano, or 
       
       
         
           
           
               
               
           
         
         when R 1  is 
       
       
         
           
           
               
               
           
         
          R 2  is fluoro, and R 3  is hydrogen, R 4  is chloro, methyl, methoxy, or 
       
       
         
           
           
               
               
           
         
          and 
         when R 1  is 
       
       
         
           
           
               
               
           
         
          R 2  is fluoro, and R 3  is hydrogen, R 4  is chloro, methyl, or cyano. 
       
     
     
         2 . A composition comprising a pharmaceutically acceptable carrier; and a compound according to  claim 1 . 
     
     
         3 . A kit comprising a compound according to  claim 1 . 
     
     
         4 . A kit comprising a composition according to  claim 2 . 
     
     
         5 . A method for treating a subject suffering from or at risk of a disease or condition, comprising administering to the subject in need thereof an effective amount of a compound according to  claim 1 , wherein the disease or condition is selected from the group consisting of melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, prostate cancer, liver cancer, gallbladder cancer, gastrointestinal stromal tumors, and biliary tract cancer. 
     
     
         6 . A method for treating a subject suffering from or at risk of a disease or condition, comprising administering to the subject in need thereof an effective amount of a compound according to  claim 1 , wherein the disease or condition is selected from the group consisting of melanoma, liver cancer, biliary tract cancer, colorectal cancer, lung cancer, bladder cancer, breast cancer, pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer, cervical cancer, endometrial cancer, and acute myeloid leukemia. 
     
     
         7 . A method for treating a subject suffering from or at risk of a disease or condition, comprising administering to the subject in need thereof an effective amount of a compound according to  claim 1 , wherein the disease or condition is selected from the group consisting of melanoma, colorectal cancer, thyroid cancer, ovarian cancer and biliary tract cancer. 
     
     
         8 . A method for treating a subject suffering from or at risk of a disease or condition, comprising administering to the subject in need thereof an effective amount of a composition according to  claim 2 , wherein the disease or condition is selected from the group consisting of melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, prostate cancer, liver cancer, gallbladder cancer, gastrointestinal stromal tumors, and biliary tract cancer. 
     
     
         9 . A method for treating a subject suffering from or at risk of a disease or condition, comprising administering to the subject in need thereof an effective amount of a composition according to  claim 2 , wherein the disease or condition is selected from the group consisting of melanoma, liver cancer, biliary tract cancer, colorectal cancer, lung cancer, bladder cancer, breast cancer, pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer, cervical cancer, endometrial cancer, and acute myeloid leukemia. 
     
     
         10 . A method for treating a subject suffering from or at risk of a disease or condition, comprising administering to the subject in need thereof an effective amount of a composition according to  claim 2 , wherein the disease or condition is selected from the group consisting of melanoma, colorectal cancer, thyroid cancer, ovarian cancer and biliary tract cancer. 
     
     
         11 . The compound according to  claim 1 , wherein the compound is selected from the group consisting of:
 N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2002),   N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2003),   N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-fluoro-benzenesulfonamide (P-2009),   N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-2010),   N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2011),   N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-fluoro-benzenesulfonamide (P-2014),   N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-2015),   N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide (P-2016),   N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2017),   N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2018),   N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide (P-2019),   N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2020),   N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-fluoro-benzenesulfonamide (P-2021),   N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-2022),   N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide (P-2023),   N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,6-difluoro-benzenesulfonamide (P-2024),   N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2029),   N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2033),   N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2036),   N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2037),   N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide (P-2039),   N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2-fluoro-benzenesulfonamide (P-2041),   N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-2042),   N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,6-difluoro-benzenesulfonamide (P-2043),   N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide (P-2045),   N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide (P-2046),   N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2051),   N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2052),   N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3-fluoro-benzenesulfonamide (P-2053),   N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2054),   N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-benzenesulfonamide (P-2056),   Pyridine-3-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2069),   Pyridine-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2071),   Pyridine-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2072),   Pyridine-3-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2073),   Pyridine-3-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2074),   Pyridine-3-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2077),   Pyridine-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2086), and any salt, prodrug, or tautomer thereof.