Substituted thiatriazaacenaphthylene-6-carbonitrile kinase inhibitors

Abstract

The present invention is directed to substituted thiatriazaacenaphthylene-6-carbonitrile compounds of formula (I): and forms thereof, their synthesis and use for treating, preventing or ameliorating a chronic or acute protein kinase mediated disease, disorder or condition.

1 .- 19 . (canceled) 
   
   
       20 . A process for preparing a pharmaceutical composition comprising the step of admixing a pharmaceutically acceptable carrier and a compound of Formula 1: 
     
       
         
         
             
             
         
       
       and a form thereof, wherein 
       R 1  is selected from the group consisting of —N(Ra,Rb), —O(Ra) and —N(Ra)-(CH 2 ) p —Ar 1 ; 
       Ra is selected from the group consisting of hydrogen and C 1-8 alkyl; 
       Rb is selected from the group consisting of hydrogen, C 1-8 alkyl and hydroxy-(C 1-8 )alkyl; 
       alternatively, when R 1  is —N(Ra,Rb), then Ra and Rb may be taken together with the nitrogen of attachment to form a heterocyclyl ring having at least one said nitrogen atom, wherein said ring is optionally substituted with one, two or three substituents each selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 -alkoxy, halogen, hydroxy, hydroxy-(C 1-8 )alkyl, hydroxy-(C 1-8 )alkoxy, amino and C 1-8 alkyl-amino; 
       p is 0, 1, 2, 3 or 4; 
       Ar 1  is selected from the group consisting of aryl, heteroaryl, benzofused heteroaryl, heterocyclyl and benzofused heterocyclyl each optionally substituted with one, two or three substituents each selected from the group consisting of R 4 —(C 1-8 )alkyl, R 4 —(C 2-8 )alkenyl, R 4 —(C 2-8 )alkynyl, R 4 —(C 1-8 )alkoxy, cyano, halogen, nitro, halo-(C 1-8 )alkyl, halo-(C 1-8 )alkoxy, hydroxy, hydroxy-(C 1-8 )alkyl, hydroxy-(C 1-8 )alkoxy, C 1-8 alkoxy-carbonyl, C 1-8 alkoxy-carbonyl-amino, amino-(C 1-8 )alkyl, C 1-8 alkyl-amino-(C 1-8 )alkyl, amino, C 1-8 alkyl-amino, C 3-8 cycloalkyl-amino, heterocyclyl-amino (optionally substituted on heterocyclyl with one or two C 1-8 alkyl substituents) and heterocyclyl-(C 1-8 )alkyl-amino (optionally substituted on heterocyclyl with one or two C 1-8 alkyl substituents); 
       R 4  is hydrogen or is one, two or three substituents each selected from the group consisting of C 3-8 cycloalkyl, aryl, heteroaryl and heterocyclyl each optionally substituted with one, two or three substituents each selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkoxy-(C 1-8 )alkyl, cyano, halogen, hydroxy, halo-(C 1-8 )alkyl, halo-(C 1-8 )alkoxy, hydroxy-(C 1-8 )alkyl, hydroxy-(C 1-8 )alkoxy, C 1-8 alkoxy-carbonyl, amino-(C 1-8 )alkyl, C 1-8 alkyl-amino-(C 1-8 )alkyl, amino, C 1-8 alkyl-amino, C 1-8 alkoxy-carbonyl-amino; 
       R 2  is selected from the group consisting of aryl, heteroaryl, benzofused heteroaryl, heterocyclyl and benzofused heterocyclyl each optionally substituted with one, two or three substituents each selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, cyano, halogen, halo-(C 1-8 )alkyl, halo-(C 1-8 )alkoxy, hydroxy, heteroaryl-oxy, aryl-oxy (optionally substituted on heteroaryl and aryl with one, two or three substituents each selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy and halogen); and 
       R 3  is hydrogen or is selected from the group consisting of R 4 —(C 1-8 )alkyl, R 4 —(C 2-8 )alkenyl, R 4 —(C 2-8 )alkynyl, halogen, hydroxy, C 3 -cycloalkyl, heteroaryl, aryl and heterocyclyl, optionally substituted on heteroaryl and aryl with one, two or three substituents each selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy and halogen. 
     
   
   
       21 .- 29 . (canceled) 
   
   
       30 . A process for preparing a compound of Formula 1 comprising the steps of:
 a. reacting a compound of Formula A1 with a compound of Formula A2 in the presence of a base to provide a compound of Formula A3:   
     
       
         
         
             
             
         
       
       b. reacting the compound of Formula A3 with a compound of Formula A4 (wherein Ra is as defined herein) in the presence of a weak organic base to provide a compound of Formula A5: 
     
     
       
         
         
             
             
         
       
       c. reacting the compound of Formula A5 with a compound of Formula A6 in the presence of a non-nucleophilic base to provide a compound of Formula A7: 
     
     
       
         
         
             
             
         
       
       d. reacting the compound of Formula A7 with a carbonyl source in the presence of a non-nucleophilic base to provide a compound of Formula A8, representative of a compound of any of claim  1  to  27 , wherein R 1  is —O(Ra): 
     
     
       
         
         
             
             
         
       
       e. reacting the compound of Formula A8 with a halogenating reagent to provide a compound of Formula A9 (wherein X is a halogen atom), representative of a compound of any of claim  1  to  27 , wherein R 1  is —O(Ra): 
     
     
       
         
         
             
             
         
       
       f. reacting the compound of Formula A9 under catalytic conditions with a compound of Formula A10 (wherein Y and R 3  are both hydrogen) in the optional presence of a base, to provide a compound of Formula A11, representative of a compound of any of claim  1  to  27 , wherein R 1  is —O(Ra): 
     
     
       
         
         
             
             
         
       
       
         wherein said compound of Formula 1 is 
       
     
     
       
         
         
             
             
         
       
       and a form thereof, wherein 
       R 1  is selected from the group consisting of —N(Ra,Rb), —O(Ra) and —N(Ra)-(CH 2 ) p —Ar 1 ; 
       Ra is selected from the group consisting of hydrogen and C 1-8 alkyl; 
       Rb is selected from the group consisting of hydrogen, C 1-8 alkyl and hydroxy-(C 1-8 )alkyl; 
       alternatively, when R 1  is —N(Ra,Rb), then Ra and Rb may be taken together with the nitrogen of attachment to form a heterocyclyl ring having at least one said nitrogen atom, wherein said ring is optionally substituted with one, two or three substituents each selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, halogen, hydroxy, hydroxy-(C 1-8 allyl, hydroxy-(C 1-8 )alkoxy, amino and C 1-8 alkyl-amino; 
       p is 0, 1, 2, 3 or 4; 
       Ar 1  is selected from the group consisting of aryl, heteroaryl, benzofused heteroaryl, heterocyclyl and benzofused heterocyclyl each optionally substituted with one, two or three substituents each selected from the group consisting of R 4 —(C 1-8 )alkyl, R 4 —(C 2-8 )alkenyl, R 4 —(C 2-8 )alkynyl, R 4 —(C 1-8 )alkoxy, cyano, halogen, nitro, halo-(C 1-8 )alkyl, halo-(C 1-8 )alkoxy, hydroxy, hydroxy-(C 1-8 )alkyl, hydroxy-(C 1-8 )alkoxy, C 1-8 alkoxy-carbonyl, C 1-8 alkoxy-carbonyl-amino, amino-(C 1-8 )alkyl, C 1-8 alkyl-amino-(C 1-8 )alkyl, amino, C 1-8 alkyl-amino, C 3-8 cycloalkyl-amino, heterocyclyl-amino (optionally substituted on heterocyclyl with one or two C 1-8 alkyl substituents) and heterocycyl-(C 1-8 )alkyl-amino (optionally substituted on heterocyclyl with one or two C 1-8 alkyl substituents); 
       R 4  is hydrogen or is one, two or three substituents each selected from the group consisting of C 3-8 cycloalkyl, aryl, heteroaryl and heterocyclyl each optionally substituted with one, two or three substituents each selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkoxy-(C 1-8 )alkyl, cyano, halogen, hydroxy, halo-(C 1-8 )alkyl, halo-(C 1-8 )alkoxy, hydroxy-(C 1-8 )alkyl, hydroxy-(C 1-8 )alkoxy, C 1-8 alkoxy-carbonyl, amino-(C 1-8 )alkyl, C 1-8 alkyl-amino-(C 1-8 )alkyl, amino, C 1-8 alkyl-amino, C 1-8 alkoxy-carbonyl-amino; 
       R 2  is selected from the group consisting of aryl, heteroaryl, benzofused heteroaryl, heterocyclyl and benzofused heterocyclyl each optionally substituted with one, two or three substituents each selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, cyano, halogen, halo-(C 1-8 )alkyl, halo-(C 1-8 )alkoxy, hydroxy, heteroaryl-oxy, aryl-oxy (optionally substituted on heteroaryl and aryl with one, two or three substituents each selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy and halogen); and 
       R 3  is hydrogen or is selected from the group consisting of R 4 —(C 1-8 )alkyl, R 4 —(C 2-8 )alkenyl, R 4 —(C 2-8 )alkynyl, halogen, hydroxy, C 3 -cycloalkyl, heteroaryl, aryl and heterocyclyl, optionally substituted on heteroaryl and aryl with one, two or three substituents each selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy and halogen. 
     
   
   
       31 . A process for preparing a compound of Formula 1 comprising the steps of:
 a. reacting a compound of Formula B1 (representative of a compound of any of claim  1  to  27 , wherein R 1  is —O(Ra) and Ra is alkyl) with a basic solution to provide a compound of Formula B2, representative of a compound of any of claim  1  to  27 , wherein R 1  is —O(Ra) and Ra is hydrogen:   
     
       
         
         
             
             
         
       
       b. reacting the compound of Formula B2 with a compound of Formula B3 (wherein Rx represents NH(Ra,Rb), NH(Ra,Rb) wherein Ra and Rb are taken together with the nitrogen of attachment to form a heterocyclyl ring and NH(Ra)-(CH 2 ) p —Ar 1 ) to provide a compound of Formula B4, representative of a compound of any of claim  1  to  27 , wherein R 1  is selected from —N(Ra,Rb), —N(Ra,Rb) wherein Ra and Rb are taken together with the nitrogen of attachment to form a heterocyclyl ring and —N(Ra)-(CH 2 ) p —Ar 1 : 
     
     
       
         
         
             
             
         
       
       
         wherein said compound of Formula 1 is 
       
     
     
       
         
         
             
             
         
       
       and a form thereof, wherein 
       R 1  is selected from the group consisting of —N(Ra,Rb), —O(Ra) and —N(Ra)-(CH 2 ) p —Ar 1 ; 
       Ra is selected from the group consisting of hydrogen and C 1-8 alkyl; 
       Rb is selected from the group consisting of hydrogen, C 1-8 alkyl and hydroxy-(C 1-8 )alkyl; 
       alternatively, when R 1  is —N(Ra,Rb), then Ra and Rb may be taken together with the nitrogen of attachment to form a heterocyclyl ring having at least one said nitrogen atom, wherein said ring is optionally substituted with one, two or three substituents each selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, halogen, hydroxy, hydroxy-(C 1-8 )alkyl, hydroxy-(C 1-8 )alkoxy, amino and C 1-8 alkyl-amino; 
       p is 0, 1, 2, 3 or 4; 
       Ar 1  is selected from the group consisting of aryl, heteroaryl, benzofused heteroaryl, heterocyclyl and benzofused heterocyclyl each optionally substituted with one, two or three substituents each selected from the group consisting of R 4 —(C 1-8 )alkyl, R 4 —(C 2-8 )alkenyl, R 4 —(C 2-8 )alkynyl, R 4 —(C 1-8 )alkoxy, cyano, halogen, nitro, halo-(C 1-8 )alkyl, halo-(C 1-8 )alkoxy, hydroxy, hydroxy-(C 1-8 )alkyl, hydroxy-(C 1-8 )alkoxy, C 1-8 alkoxy-carbonyl, C 1-8 alkoxy-carbonyl-amino, amino-(C 1-8 )alkyl, C 1-8 alkyl-amino-(C 1-8 )alkyl, amino, C 1-8 alkyl-amino. C 3-8 cycloalkyl-amino, heterocyclyl-amino (optionally substituted on heterocyclyl with one or two C 1-8 alkyl substituents) and heterocyclyl-(C 1-8 )alkyl-amino (optionally substituted on heterocyclyl with one or two C 1-8 alkyl substituents); 
       R 4  is hydrogen or is one, two or three substituents each selected from the group consisting of C 3-8 cycloalkyl, aryl, heteroaryl and heterocyclyl each optionally substituted with one, two or three substituents each selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkoxy-(C 1-8 )alkyl, cyano, halogen, hydroxy, halo-(C 1-8 )alkyl, halo-(C 1-8 )alkoxy, hydroxy-(C 1-8 )alkyl, hydroxy-(C 1-8 )alkoxy, C 1-8 alkoxy-carbonyl, amino-(C 1-8 )alkyl, C 1-8 -alkyl-amino-(C 1-8 )alkyl, amino, C 1-8 alkyl-amino, C 1-8 alkoxy-carbonyl-amino; 
       R 2  is selected from the group consisting of aryl, heteroaryl, benzofused heteroaryl, heterocyclyl and benzofused heterocyclyl each optionally substituted with one, two or three substituents each selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, cyano, halogen, halo-(C 1-8 )alkyl, halo-(C 1-8 )alkoxy, hydroxy, heteroaryl-oxy, aryl-oxy (optionally substituted on heteroaryl and aryl with one, two or three substituents each selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy and halogen); and 
       R 3  is hydrogen or is selected from the group consisting of R 4 —(C 1-8 )alkyl, R 4 —(C 2-8 )alkenyl, R 4 —(C 2-8 )alkynyl, halogen, hydroxy, C 3 -cycloalkyl, heteroaryl, aryl and heterocyclyl, optionally substituted on heteroaryl and aryl with one, two or three substituents each selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy and halogen.