Benzimidazoles for use in the treatment of cancer and inflammatory diseases

Abstract

Provided herein are methods for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease mediated by a lipid kinase or a protein kinase with benzimidazoles, for example, of Formula I or II, and pharmaceutical compositions thereof. Also provided herein are benzimidazoles, and pharmaceutical compositions thereof; and methods of their use for treating, preventing, or ameliorating one or more symptoms of a proliferative disease.

1 . A method for treating, preventing, or ameliorating a condition, disorder, or disease mediated by a BMX, BTK, PIK3C, PIK3D, ITK, TEC, or TXK kinase in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula II: 
       
         
           
           
               
               
           
         
       
       or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein:
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
 R 2  is C 3-10  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; 
 R 2A  is hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; 
 L 1  is a bond, —O—, —S—, -N(R 1A )-, or -C(R 1A R 1B )-, wherein each R 1A  and R 1B  is independently hydrogen, halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; 
 L 2  is C 3-10  cycloalkylene, C 6-14  arylene, C 7-15  aralkylene, heteroarylene, or heterocyclylene; 
 T is a bond, —O—, —S—, -N=, -N(R 4 )-, or -C(R 4 )=; 
 U is a bond, —O—, —S—, -N=, -N(R 5 )-, or -C(R 5 )=; 
 V is a bond, —O—, —S—, —N═, -N(R 6 )-, or -C(R 6 )=; 
 W is a bond, —O—, —S—, —N═, -N(R 7 )-, or -C(R 7 )=; 
 X and Y are each independently C or N; 
 each R 4 , R 5 , R 6 , and R 7  is independently (a) hydrogen, cyano, halo, or nitro; (b) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; or (c) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(NR 1a )NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(=NR 1a )NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(=NR 1d )NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O) 2 R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O) 2 NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c ; or R 4  and R 5 , R 5  and R 6 , or R 6  and R 7  are linked together to form C 3-7  cycloalkyl, C 6-14  aryl, heteroaryl, or heterocyclyl; 
 each R 1a , R 1b , R 1c , and R 1d  is independently hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-   6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; or R 1a  and R 1c  together with the C and N atoms to which they are attached form heterocyclyl; or R 1b  and R 1c  together with the N atom to which they are attached form heterocyclyl; and 
 each R 1e , R 1f , and R 1g  is independently hydrogen, halo, C 1-6  alkyl, C 2-6  alkenyl, C 2-   6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; 
 with the proviso that no more than one of T, U, V, and W is a bond; 
 wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, where each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) -C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(NR a )NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(=NR a )NR b R c , -OP(O)(OR a ) 2 , -OS(O)R a , -OS(O) 2 R a , -OS(O)NR b R c , -OS(O)2NRbRc, -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(=NR d )NR b R c , -NR a S(O)R d , -NR a S(O) 2 R d , -NR a S(O)NR b R c , -NR a S(O) 2 NR b R c , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR b R c , and -S(O) 2 NRbRc, wherein each R a , R b , R c , and R d  is independently (i) hydrogen; (ii) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; or (iii) R b  and R c  together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; 
 wherein each Q a  is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R f , -C(O)OR f , -C(O)NR g R h , -C(NR f )NR g R h , -OR f , -OC(O)R f , -OC(O)OR f , -OC(O)NR g R h , -OC(=NR f )NR g R h , -OP(O)(OR f ) 2 , -OS(O)R f , -OS(O) 2 R f , -OS(O)NR g R h , -OS(O) 2 NR g R h , -NR g R h , -NR f C(O)R k , -NR f C(O)OR k , -NR f C(O)NR g R h , -NR f C(=NR k )NR g R h , -NR f S(O)R k , -NR f S(O) 2 R k , -NR f S(O)NR g R h , -NR f S(O) 2 NR g R h , -SR f , -S(O)R f , -S(O) 2 R f , -S(O)NR g R h , and -S(O) 2 NR g R h ; wherein each R f , R g , R h , and R k  is independently (i) hydrogen; (ii) C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; or (iii) R g  and R h  together with the N atom to which they are attached form heterocyclyl. 
 
     
     
         2 - 219 . (canceled)