Proteolysis Targeting Chimera Compounds and Methods of Preparing and Using Same

Abstract

The present invention includes novel compounds and methods for preventing or treating diseases associated with and/or caused by overexpression and/or uncontrolled activation of a tyrosine kinase in a subject in need thereof. In certain embodiments, the compounds of the present invention comprise a tyrosine kinase inhibitor, a linker and a ubiquitin ligase binder. The methods of the present invention comprise administering to the subject an pharmaceutically effective amount of at least one compound of the invention.

1 - 24 . (canceled) 
     
     
         25 . A method of treating or ameliorating a tyrosine kinase-dependent cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one compound of formula (I):
   TKI-L-(ULM) k   (I),
   
       wherein:
 TKI is a tyrosine kinase inhibitor, 
 L is a linker, 
 each ULM is independently a ubiquitin ligase binder, and 
 k is an integer ranging from 1 to 4, 
 
       wherein TKI is covalently linked to L and wherein each ULM is covalently linked to L; 
       or a salt, enantiomer, stereoisomer, polymorph or N-oxide thereof. 
     
     
         26 . The method of  claim 25 , wherein the cancer is associated with overexpression and/or uncontrolled activation of the tyrosine kinase. 
     
     
         27 . The method of  claim 25 , wherein the tyrosine kinase is oncogenic. 
     
     
         28 . The method of  claim 25 , wherein the subject is a human. 
     
     
         29 . The method of  claim 25 , wherein the cancer comprises chronic myelogenous leukemia (CML). 
     
     
         30 . The method of  claim 25 , wherein the compound is administered to the subject by at least one route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intrathecal and intravenous routes. 
     
     
         31 . The compound of  claim 25 , wherein the TKI is capable of binding to at least one of c-ABL and BCR-ABL. 
     
     
         32 . The method of  claim 25 ,
 wherein the tyrosine kinase-dependent cancer is associated with overexpression or uncontrolled activation of at least one of c-Abl and BCR-ABL,   wherein the TKI is capable of binding to at least one of c-ABL and BCR-ABL.   
     
     
         33 . The method of  claim 32 , wherein the tyrosine kinase-dependent cancer is c-ABL-dependent cancer or BCR-ABL-dependent cancer. 
     
     
         34 . The method of  claim 33 , wherein the cancer comprises chronic myelogenous leukemia (CML). 
     
     
         35 . The method of  claim 32 , wherein the compound is administered to the subject by at least one route selected from the group consisting of nasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intrathecal and intravenous routes. 
     
     
         36 . The method of  claim 25 , wherein the TKI is Imatinib, Dasatinib, or Bosutinib. 
     
     
         37 . The method of  claim 25 , wherein at least one ULM comprises formula (IX): 
       
         
           
           
               
               
           
         
       
     
     
         38 . The method of  claim 25 , wherein at least one ULM comprises formula (X): 
       
         
           
           
               
               
           
         
       
     
     
         39 . The method of  claim 25 , wherein k is 1. 
     
     
         40 . The method of  claim 25 , wherein the compound is selected from the group consisting of: 
       N-(2-chloro-6-methylphenyl)-2-((6-(4-((S)-3-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,2-dimethyl-5-oxo-11,14,17-trioxa-4-azatricosan-23-yl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (DAS-6-2-2-6-VHL): 
       
         
           
           
               
               
           
         
       
       (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(4-((4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino) phenyl)carbamoyl)benzyl)piperazin-1-yl)-4-oxo-10,13,16-trioxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (IMA-6-2-2-6-VHL): 
       
         
           
           
               
               
           
         
       
       N-(2-chloro-6-methylphenyl)-2-((6-(4-(6-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-2-oxoethoxy)ethoxy)hexyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (DAS-6-2-2-VHL): 
       
         
           
           
               
               
           
         
       
       (2S,4R)-1-((S)-3,3-dimethyl-2-(2-(2-((6-(4-(4-((4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)carbamoyl)benzyl)piperazin-1-yl)hexyl)oxy)ethoxy)acetamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (IMA-6-2-2-VHL): 
       
         
           
           
               
               
           
         
       
       N-(2-chloro-6-methylphenyl)-2-((6-(4-((S)-3-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-2,2-dimethyl-5-oxo-7,10,13,16,19,22-hexaoxa-4-azaoctacosan-28-yl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (DAS-6-2-2-2-2-2-2-VHL): 
       
         
           
           
               
               
           
         
       
       (2S,4R)-1-((S)-2-(tert-butyl)-27-(4-(4-((4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)carbamoyl)benzyl)piperazin-1-yl)-4-oxo-6,9,12,15,18,21-hexaoxa-3-azaheptacosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (IMA-6-2-2-2-2-2-2-VHL): 
       
         
           
           
               
               
           
         
       
       N-(2-chloro-6-methylphenyl)-2-((6-(4-(6-((5-((6-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-6-oxohexyl)oxy)pentyl)oxy)hexyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (DAS-6-5-6-VHL): 
       
         
           
           
               
               
           
         
       
       (2S,4R)-1-((S)-3,3-dimethyl-2-(6-((5-((6-(4-(4-((4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)carbamoyl)benzyl)piperazin-1-yl)hexyl)oxy)pentyl)oxy)hexanamido) butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (IMA-6-5-6-VHL): 
       
         
           
           
               
               
           
         
       
       (2S,4R)-1-((S)-2-(tert-butyl)-22-(4-(3-((3-cyano-4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxyquinolin-7-yl)oxy)propyl)piperazin-1-yl)-4-oxo-10,13,16-trioxa-3-azadocosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (BOS-6-2-2-6-VHL): 
       
         
           
           
               
               
           
         
       
       (2S,4R)-1-((S)-2-(2-(2-((6-(4-(3-((3-cyano-4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxyquinolin-7-yl)oxy)propyl)piperazin-1-yl)hexyl)oxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (BOS-6-2-2-VHL): 
       
         
           
           
               
               
           
         
       
       (2S,4R)-1-((S)-2-(tert-butyl)-27-(4-(3-((3-cyano-4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxyquinolin-7-yl)oxy)propyl)piperazin-1-yl)-4-oxo-6,9,12,15,18,21-hexaoxa-3-azaheptacosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (BOS-6-2-2-2-2-2-2-VHL): 
       
         
           
           
               
               
           
         
       
       (2S,4R)-1-((S)-2-(6-((5-((6-(4-(3-((3-cyano-4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxyquinolin-7-yl)oxy)propyl)piperazin-1-yl)hexyl)oxy)pentyl)oxy)hexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (BOS-6-5-6-VHL): 
       
         
           
           
               
               
           
         
       
       N-(2-chloro-6-methylphenyl)-2-((6-(4-(6-(2-(2-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-6-oxohexyl)oxy)ethoxy)ethoxy)hexyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (DAS-6-2-2-6-CRBN): 
       
         
           
           
               
               
           
         
       
       6-(2-(2-((6-(4-(3-((3-cyano-4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxyquinolin-7-yl)oxy)propyl)piperazin-1-yl)hexyl)oxy)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide (BOS-6-2-2-6-CRBN): 
       
         
           
           
               
               
           
         
       
       4-((4-(6-(2-(2-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-6-oxohexyl) oxy)ethoxy)ethoxy)hexyl)piperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide (IMA-6-2-2-6-CRBN): 
       
         
           
           
               
               
           
         
       
       N-(2-chloro-6-methylphenyl)-2-((6-(4-(6-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxoethoxy)ethoxy)hexyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (DAS-6-2-2-CRBN): 
       
         
           
           
               
               
           
         
       
       2-(2-((6-(4-(3-((3-cyano-4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxyquinolin-7-yl)oxy)propyl)piperazin-1-yl)hexyl)oxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide (BOS-6-2-2-CRBN): 
       
         
           
           
               
               
           
         
       
       4-((4-(6-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxoethoxy)ethoxy)hexyl)piperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide (IMA-6-2-2-CRBN): 
       
         
           
           
               
               
           
         
       
       N-(2-chloro-6-methylphenyl)-2-((6-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-1-oxo-3,6,9,12,15,18-hexaoxatetracosan-24-yl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (DAS-6-2-2-2-2-2-2-CRBN): 
       
         
           
           
               
               
           
         
       
       24-(4-(3-((3-cyano-4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxyquinolin-7-yl)oxy) propyl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-3,6,9,12,15,18-hexaoxatetracosanamide (BOS-6-2-2-2-2-2-2-CRBN): 
       
         
           
           
               
               
           
         
       
       N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-24-(4-(4-((4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)carbamoyl)benzyl)piperazin-1-yl)-3,6,9,12,15,18-hexaoxatetracosanamide (IMA-6-2-2-2-2-2-2-CRBN): 
       
         
           
           
               
               
           
         
       
       N-(2-chloro-6-methylphenyl)-2-((6-(4-(6-((5-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-6-oxohexyl)oxy)pentyl)oxy)hexyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide (DAS-6-5-6-CRBN): 
       
         
           
           
               
               
           
         
       
       6-((5-((6-(4-(3-((3-cyano-4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxyquinolin-7-yl)oxy)propyl)piperazin-1-yl)hexyl)oxy)pentyl)oxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide (BOS-6-5-6-CRBN): 
       
         
           
           
               
               
           
         
       
       4-((4-(6-((5-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-6-oxohexyl)oxy)pentyl)oxy)hexyl)piperazin-1-yl)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide (IMA-6-5-6-CRBN): 
       
         
           
           
               
               
           
         
       
     
     
         41 . The method of  claim 25 , wherein the compound is administered to the subject as a pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier. 
     
     
         42 . The method of  claim 25 , wherein the subject is further administered at least one additional therapeutic compound that treats or ameliorates the cancer.