Inhibitors of tyrosine kinases and uses thereof

Abstract

Disclosed herein are compounds that inhibit the activity of particular tyrosine kinases. Methods for the preparation of such compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the compounds disclosed, alone or in combination with other therapeutic agents, for the treatment of tyrosine kinase-mediated diseases or conditions or tyrosine kinase-dependent diseases or conditions are provided.

1 .- 23 . (canceled) 
     
     
         24 . A method for treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula III: 
       
         
           
           
               
               
           
         
       
       wherein:
 R a  and R b  are each independently selected from among H, halogen, CN, NO 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy; 
 T is 1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene, or 1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,6-ylene; 
 L is —X 250a —Y 250 — or —Y 250 —X 250a —, wherein,
 X 250a  is a substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 5 -C 8 cycloalkenyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 haloalkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, or substituted or unsubstituted C 2 -C 6 haloalkynyl; 
 Y 250  is a bond, —O—, —S(O)—, —S(═O) 2 —, —C(═O)—, —NR 45 —, —NH—, —NHC(═O)—, —NR 45 C(═O)—, —NR 45 C(═O)NR 45 —, —C(═O)NH—, —C(═O)NR 45 —, —OC(═O)—, —C(═O)O—, —NHSO 2 —, —NR 45 SO 2 —, —SO 2 NH—, —SO 2 NR 45 —, —C(R 45 )═NO—, —CH═NO—, —ON═CH—, heteroaryl, aryl, —NHC(═O)O—, —OC(═O)NH—, —NR 45 C(═O)O—, or —OC(═O)NR 45 —; 
 where each R 45  is independently selected from among hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 7 -C 6 alkenyl, substituted or unsubstituted C 1 -C 6 alkynyl; 
 
 M is N or CH; 
 W is 
 
       
         
           
           
               
               
           
         
         
           E is oxygen or sulfur; 
           R 200  is halogen, —OH, or an optionally substituted group selected from among C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, C 1 -C 4 alkyl(phenyl), C 3 -C 8 cycloalkyl, C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), C 1 -C 8 heterocycloalkyl, C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl), heteroaryl, C 1 -C 4 alkyl(heteroaryl), C 1 -C 6 alkoxy, C 1 -C 6 alkenyloxy, C 1 -C 6 alkynyloxy, or —NR 102a R 102b ; 
           R 102a  and R 102b  are independently hydrogen, or an optionally substituted group selected from among C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, C 3 -C 8 cycloalkyl, C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), C 2 -C 8 heterocycloalkyl, and C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); 
           R 200  is an optionally substituted group selected from among C 7 -C 10 acyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkyl(C 3 -C 6 cycloalkyl), aryl, heteroaryl, heteroaralkyl, C 1 -C 6 alkylsulfonyl, C 2 -C 6 alkenylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C 1 -C 10 alkoxycarbonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, di(C 1 -C 6 alkyl)aminosulfonyl, and C 1 -C 6 alkylsulfonylamino; 
         
         R 350a  is hydrogen, a substituted or unsubstituted C 1 -C 6 alkyl, a substituted or unsubstituted C 2 -C 6 alkenyl, a substituted or unsubstituted C 2 -C 6 alkynyl, a substituted or unsubstituted C 1 -C 6 haloalkyl, a substituted or unsubstituted C 2 -C 6 haloalkenyl, or a substituted or unsubstituted C 2 -C 6 haloalkynyl; 
         n is 0, 1, or 2; or a 
       
       pharmaceutically active metabolite, a pharmaceutically acceptable solvate, a pharmaceutically acceptable salt, or a pharmaceutically acceptable prodrug thereof. 
     
     
         25 . The method of  claim 24 , wherein the cancer is a B-cell proliferative disorder. 
     
     
         26 . The method of  claim 25 , wherein the B-cell proliferative disorder is chronic lymphocytic lymphoma, diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, or lymphomatoid granulomatosis. 
     
     
         27 . The method of  claim 24 , wherein T is 1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene substituted at the 2 position with 
       
         
           
           
               
               
           
         
       
       and substituted at the 7 position with 
       
         
           
           
               
               
           
         
       
     
     
         28 . The method of  claim 27 , wherein Y 250  is a bond, —O—, —S(═O)—, —C(═O)—, —NH—, —NHC(═O)—, —NHC(═O)NH—, —C(═O)NH—, —OC(═O)—, —C(═O)O—, —NHSO 2 —, —SO 2 NH—, —NHC(═O)O—, or —OC(═O)NH—;
 E is O; and 
 R 350a  is hydrogen, a substituted or unsubstituted C 1 -C 6 alkyl, or a substituted or unsubstituted C 1 -C 6 haloalkyl. 
 
     
     
         29 . The method of  claim 28 , wherein:
 X 250a  is a substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 haloalkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, or substituted or unsubstituted C 2 -C 6 haloalkynyl; and   n is 1.   
     
     
         30 . The method of  claim 29 , wherein the compound has a structure selected from among: 
       
         
           
           
               
               
           
         
       
     
     
         31 . The method of  claim 30 , wherein:
 R 200  is halogen, or an optionally substituted group selected from among C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, C 1 -C 4 alkyl(phenyl), C 3 -C 8 cycloalkyl, C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), C 2 -C 8 heterocycloalkyl, C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl), heteroaryl, and C 1 -C 4 alkyl(heteroaryl); and   R 200  is an optionally substituted group selected from among C 2 -C 10 acyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkyl(C 3 -C 6 cycloalkyl), aryl, heteroaryl, heteroaralkyl, C 1 -C 6 alkylsulfonyl, C 2 -C 6 alkenylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C 1 -C 10 alkoxycarbonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, and di(C 1 -C 6 alkyl)aminosulfonyl.   
     
     
         32 . The method of  claim 31 , wherein:
 R 350a  is hydrogen; and   Y 250  is a bond, —C(═O)—, —NHC(═O)—, —C(═O)NH—.   
     
     
         33 . The method of  claim 32 , wherein L is selected from among C 1 -C 4 alkyl, 
       
         
           
           
               
               
           
         
       
     
     
         34 . The method of  claim 33 , wherein the compound has a structure of Formula (IIIc). 
     
     
         35 . The method of  claim 34 , wherein:
 L is C 1 -C 4 alkyl or   
       
         
           
           
               
               
           
         
       
       and
 R 200  is an optionally substituted group selected from among C 2 -C 10 acyl, aryl, heteroaryl, heteroaralkyl, C 1 -C 6 alkylsulfonyl, C 2 -C 6 alkenylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C 1 -C 10 alkoxycarbonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, and di(C 1 -C 6 alkyl)aminosulfonyl. 
 
     
     
         36 . The method of  claim 24 , wherein:
 T is 1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,6-ylene substituted at the 2 position with   
       
         
           
           
               
               
           
         
       
       and substituted at the 6 position with 
       
         
           
           
               
               
           
         
       
     
     
         37 . The method of  claim 36 , wherein
 Y 250  is a bond, —O—, —S(═O)—, —S(═O) 2 —, —C(═O)—, —NH—, —NHC(═O)—, —NHC(═O)NH—, —C(═O)NH—, —OC(═O)—, —C(═O)O—, —NHSO 2 —, —SO 2 NH—, —NHC(═O)O—, or —OC(═O)NH—;   E is O; and   R 350a  is hydrogen, or a substituted or unsubstituted C 1 -C 6 alkyl.   
     
     
         38 . The method of  claim 37 , wherein
 X 250a  is a substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 haloalkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, or substituted or unsubstituted C 2 -C 6 haloalkynyl; and   n is 1.   
     
     
         39 . The method of  claim 38 , wherein compound has a structure selected from among: 
       
         
           
           
               
               
           
         
       
     
     
         40 . The method of  claim 39 , wherein:
 R 100  is halogen, or an optionally substituted group selected from among C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, C 1 -C 4 alkyl(phenyl), C 3 -C 8 cycloalkyl, C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), C 2 -C 8 heterocycloalkyl, C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl), heteroaryl, and C 1 -C 4 alkyl(heteroaryl); and   R 200  is an optionally substituted group selected from among C 2 -C 10 acyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkyl(C 3 -C 6 cycloalkyl), aryl, heteroaryl, heteroaralkyl, C 1 -C 6 alkylsulfonyl, C 2 -C 6 alkenylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C 1 -C 10 alkoxycarbonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, and di(C 1 -C 6 alkyl)aminosulfonyl.   
     
     
         41 . The method of  claim 40 , wherein:
 R 350a  is hydrogen;   Y 250  is —C(═O)—; and   X 250a  is a substituted or unsubstituted C 1 -C 6 alkyl.   
     
     
         42 . The method of  claim 41 , wherein L is 
       
         
           
           
               
               
           
         
       
     
     
         43 . The method of  claim 42 , wherein the compound has a structure of Formula (IIIb). 
     
     
         44 . A method for treating a cancer comprising administering to a subject in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of Formula III: 
       
         
           
           
               
               
           
         
       
       wherein:
 R a  and R b  are each independently selected from among H, halogen, CN, NO 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy; 
 T is 1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene, or 1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,6-ylene; 
 L is —X 250a —Y 250 — or —Y 250 —X 250a —, wherein,
 X 250a  is a substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 5 -C 8 cycloalkenyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 haloalkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, or substituted or unsubstituted C 2 -C 6 haloalkynyl; 
 Y 250  is a bond, —O—, —S(═O)—, —C(═O)—, —NR 45 —, —NH—, —NHC(═O)—, —NR 45 C(═O)—, —NR 45 C(═O)NR 45 —, —C(═O)NH—, —C(═O)NR 45 —, —OC(═O)—, —C(═O)O—, —NHSO 2 —, —NR 45 SO 2 —, —SO 2 NH—, —SO 2 NR 45 —, —C(R 45 )═NO—, —CH═NO—, —ON═CH—, heteroaryl, aryl, —NHC(═O)O—, —OC(═O)NH—, —NR 45 C(═O)O—, or —OC(═O)NR 45 —; 
 where each R 45  is independently selected from among hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl; 
 
 M is N or CH; 
 W is 
 
       
         
           
           
               
               
           
         
         
           E is oxygen or sulfur; 
           R 100  is halogen, —OH, or an optionally substituted group selected from among C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, C 1 -C 4 alkyl(phenyl), C 3 -C 8 cycloalkyl, C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), C 2 -C 8 heterocycloalkyl, C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl), heteroaryl, C 1 -C 4 alkyl(heteroaryl), C 1 -C 6 alkoxy, C 1 -C 6 alkenyloxy, C 1 -C 6 alkynyloxy, or —NR 102a R 102b ; 
           R 102a  and R 102b  are independently hydrogen, or an optionally substituted group selected from among C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, C 3 -C 8 cycloalkyl, C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), C 2 -C 8 heterocycloalkyl, and C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); 
           R 200  is an optionally substituted group selected from among C 2 -C 10 acyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkyl(C 3 -C 6 cycloalkyl), aryl, heteroaryl, heteroaralkyl, C 1 -C 6 alkylsulfonyl, C 2 -C 6 alkenylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C 1 -C 10 alkoxycarbonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, di(C 1 -C 6 alkyl)aminosulfonyl, and C 1 -C 6 alkylsulfonylamino; 
         
         R 350a  is hydrogen, a substituted or unsubstituted C 1 -C 6 alkyl, a substituted or unsubstituted C 2 -C 6 alkenyl, a substituted or unsubstituted C 2 -C 6 alkynyl, a substituted or unsubstituted C 1 -C 6 haloalkyl, a substituted or unsubstituted C 2 -C 6 haloalkenyl, or a substituted or unsubstituted C 2 -C 6 haloalkynyl; 
         n is 0, 1, or 2; or a 
       
       pharmaceutically active metabolite, a pharmaceutically acceptable solvate, a pharmaceutically acceptable salt, or a pharmaceutically acceptable prodrug thereof. 
     
     
         45 . The method of  claim 44 , wherein the composition is formulated for oral administration.