Chemical Compounds - 759

Abstract

The present invention relates to compounds of Formula (I): and to their pharmaceutical compositions, and to their methods of use. These compounds provide a treatment for myeloproliferative disorders and cancer.

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         Q is selected from N and C(R 3 ); 
         D is selected from N and CH; 
         R 1  is selected from H, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 5-membered carbocyclyl, 5-membered heterocyclyl, —OR 1a , —SR 1a , —N(R 1a ) 2 , —N(R 1a )C(O)R 1b , —N(R 1a )N(R 1a ) 2 , —NO 2 , —C(O)H, —C(O)R 1b , —C(O) 2 R 1a , —C(O)N(R 1a ) 2 , —OC(O)N(R 1a ) 2 , —N(R 1a )C(O) 2 R 1a , —N(R 1a )C(O)N(R 1a ) 2 , —OC(O)R 1b , —S(O)R 1b , —S(O) 2 R 1b , —S(O) 2 N(R 1a ) 2 , —N(R 1a )S(O) 2 R 1b , —C(R 1a )═N(R 1a ), and —C(R 1a )═N(OR 1a ), wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl are optionally substituted with one or more R 10 ; 
         R 1a  in each occurrence is independently selected from H and C 1-6 alkyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl, wherein said C 1-6 alkyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl in each occurrence are optionally and independently substituted with one or more R 10 ; 
         R 1b  in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl in each occurrence are optionally and independently substituted with one or more R 10 ; 
         R 2  is selected from H, halo, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, —OR 2a , —SR 2a , —N(R 2a ) 2 , —N(R 2a )C(O)R 2b , —N(R 2a )N(R 2a ) 2 , —NO 2 , —C(O)H, —C(O)R 2b , —C(O) 2 R 2a , —C(O)N(R 2a ) 2 , —OC(O)N(R 2a ) 2 , —N(R 2a )C(O) 2 R 2a , —N(R 2a )C(O)N(R 2a ) 2 , —OC(O)R 2b , —S(O)R 2b , —S(O) 2 R 2b , —S(O) 2 N(R 2a ) 2 , —N(R 2a )S(O) 2 R 2b , —C(R 2a )═N(R 2a ), and —C(R 2a )═N(OR 2a ), wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 20 ; 
         R 2a  in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 20 ; 
         R 2b  in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 20 ; 
         R 3  is selected from H, halo, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, OR 3a , —SR 3a , —N(R 3a ) 2 , —N(R 3a )C(O)R 3b , —N(R 3a )N(R 3a ) 2 , —NO 2 , —C(O)H, —C(O)R 3b , —C(O) 2 R 3a , —C(O)N(R 3a ) 2 , —OC(O)N(R 3a ) 2 , —N(R 3a )C(O) 2 R 3a , —N(R 3a )C(O)N(R 3a ) 2 , —OC(O)R 3b , —S(O)R 3b , —S(O) 2 R 3b , —S(O) 2 N(R 3a ) 2 , —N(R 3a )S(O) 2 R 3b , —C(R 3a )═N(R 3a ), and —C(R 3a )═N(OR 3a ), wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 30 ; 
         R 3a  in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 30 ; 
         R 3b  in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 30 ; 
         R 4  is selected from H, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, —N(R 4a )C(O)R 4b , —N(R 4a )N(R 4a ) 2 , —NO 2 , —C(O)H, —C(O)R 4b , —C(O) 2 R 4a , —C(O)N(R 4a ) 2 , —OC(O)N(R 4a ) 2 , —N(R 4a )C(O) 2 R 4a , —N(R 4a )C(O)N(R 4a ) 2 , —OC(O)R 4b , —S(O)R 4b , —S(O) 2 R 4b , —S(O) 2 N(R 4a ) 2 , —N(R 4a )S(O) 2 R 4b , —C(R 4a )═N(R 4a ), and —C(R 4a )═N(OR 4a ), wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 40 ; 
         R 4a  in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 40 ; 
         R 4b  in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R 40 ; 
         R 5  is independently selected from halo, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, —OR 5a , —SR 5a , —N(R 5a ) 2 , —N(R 5a )C(O)R 5b , —N(R 5a )N(R 5a ) 2 , —NO 2 , —C(O)H, —C(O)R 5b , —C(O) 2 R 5a , —C(O)N(R 5a ) 2 , —OC(O)N(R 5a ) 2 , —N(R 5a )C(O) 2 R 5a , —N(R 6a )C(O)N(R 5a ) 2 , —OC(O)R 5b , —S(O)R 5b , —S(O) 2 R 5b , —S(O) 2 N(R 5a ) 2 , —N(R 5a )S(O) 2 R 5b , —C(R 5a )═N(R 5a ), and —C(R 5a )═N(OR 5a ); 
         R 5a  in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl; 
         R 5b  in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl; 
         R 10  in each occurrence is independently selected from halo, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, —OR 10a , —SR 10a , —N(R 10a ) 2 , —N(R 10a )C(O)R 10b , —N(R 10a )N(R 10a ) 2 , —NO 2 , —C(O)H, —C(O)R 10b , —C(O) 2 R 10a , —C(O)N(R 10a ) 2 , —OC(O)N(R 10a ) 2 , —N(R 10a )C(O) 2 R 10a , —N(R 10a )C(O)N(R 10a ) 2 , —OC(O)R 10b , —S(O)R 10b , —S(O) 2 R 10b , —S(O) 2 N(R 10a ) 2 , —N(R 10a )S(O) 2 R 10b , —C(R 10a )═N(R 10a ), and —C(R 10a )═N(OR 10a ); 
         R 10a  in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl; 
         R 10b  in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl; 
         R 20  in each occurrence is independently selected from halo, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, —OR 20a , —SR 20a , —N(R 20a ) 2 , —N(R 20a )C(O)R 20b , —N(R 20a )N(R 20a ) 2 , —NO 2 , —C(O)H, —C(O)R 20b , —C(O) 2 R 20a , —C(O)N(R 20a ) 2 , —OC(O)N(R 20a ) 2 , —N(R 20a )C(O) 2 R 20a , —N(R 20a )C(O)N(R 20a ) 2 , —OC(O)R 20b , —S(O) R   20b , —S(O) 2 R 20b , —S(O) 2 N(R 20a ) 2 , —N(R 20a )S(O) 2 R 20b , —C(R 20a )═N(R 20a ), and —C(R 20a )═N(OR 20a ); 
         R 20a  in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl; 
         R 20b  in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl; 
         R 30  in each occurrence is independently selected from halo, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, —OR 30a , —SR 30a , —N(R 30a ) 2 , —N(R 30a )C(O)R 30b , —N(R 30a )N(R 30a ) 2 , —NO 2 , —C(O)H, —C(O)R 30b , —C(O) 2 R 30a , —C(O)N(R 30a ) 2 , —OC(O)N(R 30a ) 2 , —N(R 30a )C(O) 2 R 30a , —N(R 30a )C(O)N(R 30a ) 2 , —OC(O)R 30b , —S(O)R 30b , —S(O) 2 R 30b , —S(O) 2 N(R 30a ) 2 , —N(R 30a )S(O) 2 R 30b , —C(R 30a )═N(R 30a ), and —C(R 30a )═N(OR 30a ); 
         R 30a  in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl; 
         R 30b  in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl; 
         R 40  in each occurrence is independently selected from halo, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, —OR 40a , —SR 40a , —N(R 40a ) 2 , —N(R 40a )C(O)R 40b , —N(R 40a )N(R 40a ) 2 , —NO 2 , —C(O)H, —C(O)R 40b , —C(O) 2 R 40a , —C(O)N(R 40a ) 2 , —OC(O)N(R 40a ) 2 , —N(R 40a )C(O) 2 R 40a , —N(R 40a )C(O)N(R 40a ) 2 , —OC(O)R 40b , —S(O)R 40b , —S(O) 2 R 40b , —S(O) 2 N(R 40a ) 2 , —N(R 40a )S(O) 2 R 40b , —C(R 40a )═N(R 40a ), and —C(R 40a )═N(OR 40a ); 
         R 40a  in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl; and 
         R 40b  in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl. 
       
     
     
         2 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein
 Q is selected from N and C(R 3 ); and   R 3  is selected from H and halo.   
     
     
         3 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein
 R 1  is selected from H, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 5-membered carbocyclyl, 5-membered heterocyclyl, —OR 1a , —SR 1a , —N(R 1a ) 2 , —N(R 1a )C(O)R 1b , —N(R 1a )N(R 1a ) 2 , —NO 2 , —C(O)H, —C(O)R 1b , —C(O) 2 R 1a , —C(O)N(R 1a ) 2 , —OC(O)N(R 1a ) 2 , —N(R 1a )C(O) 2 R 1a , —N(R 1a )C(O)N(R 1a ) 2 , —OC(O)R 1b , —S(O)R 1b , —S(O) 2 R 1b , —S(O) 2 N(R 1a ) 2 , —N(R 1a )S(O) 2 R 1b , —C(R 1a )═N(R 1a ), and —C(R 1a )═N(OR 1a );   R 1a  in each occurrence is independently selected from H, C 1-6 alkyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl;   R 1b  in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 5-membered carbocyclyl, and 5-membered heterocyclyl.   
     
     
         4 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein
 R 2  is selected from H, halo, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, —OR 2a , —SR 2a , —N(R 2a ) 2 , —N(R 2a )C(O)R 2b , —N(R 2a )N(R 2a ) 2 , —NO 2 , —C(O)H, —C(O)R 2b , —C(O) 2 R 2a , —C(O)N(R 2a ) 2 , —OC(O)N(R 2a ) 2 , —N(R 2a )C(O) 2 R 2a , —N(R 2a )C(O)N(R 2a ) 2 , —OC(O)R 2b , —S(O)R 2b , —S(O) 2 R 2b , —S(O) 2 N(R 2a ) 2 , —N(R 2a )S(O) 2 R 2b , —C(R 2a )═N(R 2a ), and —C(R 2a )═N(OR 2a );   R 2a  in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl; and   R 2b  in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl.   
     
     
         5 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein
 R 4  is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl may be optionally substituted with one or more R 40 ;   R 40  in each occurrence is independently selected from halo, —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, —OR 40a , —SR 40a , —N(R 40a ) 2 , —N(R 40a )C(O)R 40b , —N(R 40a )N(R 40a ) 2 , —NO 2 , —C(O)H, —C(O)R 40b , —C(O) 2 R 40a , —C(O)N(R 40a ) 2 , —OC(O)N(R 40a ) 2 , —N(R 40a )C(O) 2 R 40a , —N(R 40a )C(O)N(R 40a ) 2 , —OC(O)R 40b , —S(O)R 40b , —S(O) 2 R 40b , —S(O) 2 N(R 40a ) 2 , —N(R 40a )S(O) 2 R 40b , —C(R 40a )═N(R 40a ), and —C(R 40a )═N(OR 40a );   R 40a  in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl; and   R 40b  in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl.   
     
     
         6 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein
 R 5  is halo.   
     
     
         7 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         Q is selected from N and C(R 3 ); 
         D is selected from N and CH; 
         R 1  is selected from methyl, cyclopropyl, isopropoxy, and ethoxy; 
         R 2  is selected from H, methoxy, morpholin-4-yl, 2-morpholin-4-yl-2-oxoethyl, and tetrahydro-2H-pyran-4-ylamino; 
         R 3  is selected from H, fluoro, and chloro; 
         R 4  is selected from methyl, ethyl, and hydroxymethyl; and 
         R 5  is fluoro. 
       
     
     
         8 . A method for treating cancer in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 . 
     
     
         9 . A pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , and at least one pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         10 . A process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein said process is selected from:
 1) Process A—reacting a compound of Formula (A):   
       
         
           
           
               
               
           
         
         with a compound of Formula (B): 
       
       
         
           
           
               
               
           
         
       
       and
 2) Process B—reacting a compound of Formula (C): 
 
       
         
           
           
               
               
           
         
         with a compound of Formula (D): 
       
       
         
           
           
               
               
           
         
         and thereafter if appropriate:
 i. converting a compound of Formula (I) into another compound of Formula (I); 
 ii. removing any protecting groups; and/or 
 iii. forming a pharmaceutically acceptable salt, 
 
         wherein 
         L in each occurrence is the same or different, and is a leaving group.