Methods to treat lymphoplasmacytic lymphoma

Abstract

The present invention provides compounds of any one of Formulae (A), (I-11), (II), and (V) (e.g., compounds of Formula (A-1)-(A-18)), and methods for treating Waldenström's macroglobulinemia (WM) and other B cell neoplasm in a subject using the compounds. The methods comprise administering to a subject in need thereof an effective amount of the compounds. Also provided are methods to treat B cell neoplasms using the compounds in combination with inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase.

What is claimed is: 
     
       1. A compound of Formula (A): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof; 
       wherein:
 each instance of R A  is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, —OR A1 , —N(R A1 ) 2 , —CN, —C(═O)R A1 , —(═O)OR A1 , —C(═O)N(R A1 ) 2 , —NO 2 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 S(═O) 2 R A1 , —S(═O) 2 R A1 , or —S(═O) 2 N(R A1 ) 2 ; 
 each instance of R B  is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A1 , —N(R A1 ) 2 , —CN, —C(═O)R A1 , —(═O)OR A1 , —C(═O)N(R A1 ) 2 , —NO 2 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 S(═O) 2 R A1 , —S(═O) 2 R A1 , or —S(═O) 2 N(R A1 ) 2 , provided that at least one instance of R B  is optionally substituted heterocyclyl, optionally substituted —(CH 2 )(heterocyclyl), optionally substituted —(CH 2 ) 2 (heterocyclyl), or optionally substituted —(CH 2 ) 3 (heterocyclyl); 
 each instance of R A1  is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R A1  groups are joined to form an optionally substituted heterocyclic ring; 
 Ring B is of the formula: 
 
       
         
           
           
               
               
           
         
         R Y  is hydrogen, halogen, or substituted or unsubstituted C 1-6  alkyl; 
         R X  is R D , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or —N(R A1 )(R Xa ) —NH 2 , —NH(optionally substituted acyl), —N(R A1 )N(R A1 ) 2 , 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         each instance of Rx Xa  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R A1 , —C(═O)OR A1 , —C(═O)N(R A1 ) 2 , —S(═O)R A1 , —S(═O)N(R A1 ) 2 , —S(═O) 2 R A1 , —S(═O) 2 OR A1 , —S(═O) 2 N(R A1 ) 2 , —N(R A1 ) 2 , or a nitrogen protecting group; 
         each instance of R Xc  is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A1 , —N(R A1 ) 2 , —SR A1 , —CN, —C(═O)R A1 , —C(═O)OR A1 , —C(═O)N(R A1 ) 2 , —NO 2 , —N 3 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 C(═O)N(R A1 ) 2 , —NR A1 S(═O) 2 R A1 , —NR A1 S(═O)R A1 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)N(R A1 ) 2 , —S(═O)R A1 , —S(═O)N(R A1 ) 2 , —S(═O) 2 R A1 , or —S(═O) 2 N(R A1 ) 2 ;  
         k is 0, 1, 2, 3, or 4; 
         l is 1, 2, 3, 4, or 5; and  
         —U—Q— is —NR A (C═O)— or —(C═O)NR A —; and 
         R D  is an electrophilic moiety of any one of Formulae (i-1) to (i-18): 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R D1  is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO 2 , —OR D1a , —N(R D1a ) 2 , —SR D1a , —CH 2 OR D1a , —CH 2 N(R D1a ) 2 , —CH 2 SR D1a , —C(═O)R D1a , —C(═O)OR D1a , —C(═O)SR D1a , —C(═O)N(R D1a ) 2 , —C(═S)R D1a , —C(═S)OR D1a , —C(═S)SR D1a , —C(═S)N(R D1a ) 2 , —C(═NR D1a )R D1a , —C(═NR D1a )OR D1a , —C(═NR D1a )SR D1a , or —C(═NR D1a )N(R D1a ) 2 , wherein each occurrence of R D1a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R D1a  groups are joined to form an optionally substituted heterocyclic ring; 
         R D2  is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO 2 , —OR D2a , —N(R D2a ) 2 , —SR D2a , —CH 2 OR D2a , —CH 2 N(R D2a ) 2 , —CH 2 SR D2a , —C(═O)R D2a , —C(═O)OR D2a , —C(═O)SR D2a , —C(═O)N(R D2a ) 2 , —C(═S)R D2a , —C(═S)OR D2a , —C(═S)SR D2a , —C(═S)N(R D2a ) 2 , —C(═NR D2a )R D2a , —C(═NR D2a )OR D2a , —C(═NR D2a )SR D2a , or —C(═NR D2a )N(R D2a ) 2 , wherein each occurrene of R D2a  is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R D2a  groups are joined to form an optionally substituted heterocyclic ring; 
         R D3  is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO 2 , —OR D3a , —N(R D3a ) 2 , —SR D3a , —CH 2 OR D3a , —CH 2 N(R D3a ) 2 , —CH 2 SR D3a , —C(═O)R D3a , —C(═O)OR D3a , —C(═O)SR D3a , —C(═O)N(R D3a ) 2 , —C(═S)R D3a , —C(═S)OR D3a , —C(═S)SR D3a , —C(═S)N(R D3a ) 2 , —C(═NR D3a )R D3a , —C(═NR D3a )OR D3a , —C(═NR D3a )SR D3a , or —C(═NR D3a )N(R D3a ) 2 , wherein each occurrence of R D3a  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R D3a  groups are joined to form an optionally substituted heterocyclic ring; 
         optionally R D1  and R D3 , or R D2  and R D3 , or R D1  and R D2  are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; 
         R D4  is a leaving group; 
         R D5  is hydrogen, C 1-6  alkyl, or a nitrogen protecting group; 
         Y Z  is —O—, —S—, or —NR D6 —, wherein R D6  is hydrogen, C 1-6  alkyl, or a nitrogen protecting group; 
         a is 1 or 2; and 
         z is 0, 1, 2, 3, 4, 5, or 6; 
         wherein, unless otherwise provided:
 each instance of the alkyl is independently C 1-6  alkyl; 
 each instance of the alkenyl is independently C 2-6  alkenyl; 
 each instance of the alkynyl is independently C 2-6  alkynyl; 
 each instance of the carbocyclyl and carbocyclic ring is independently 3- to 10-membered, monocyclic or bicyclic carbocyclyl; 
 each instance of the heterocyclyl and heterocyclic ring is independently 5- to 10-membered, monocyclic or bicyclic heterocyclyl; 
 each instance of the aryl is independently 6- or 10-membered, monocyclic or bicyclic aryl; and 
 each instance of the heteroaryl is independently 5- to 10-membered, monocyclic or bicyclic heteroaryl. 
 
       
     
     
       2. The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein -U-Q- is 
       
         
           
           
               
               
           
         
       
     
     
       3. The compound of  claim 1 , wherein the compound is of Formula (A1): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof. 
     
     
       4. The compound of  claim 3 , wherein the compound is of Formula (A1-a), (A1-b), (A1-c), or (A1-d): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, 
       wherein:
 each instance of R Xc  is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A1 , —N(R A1 ) 2 , —SR A1 , —CN, —C(═O)R A1 , —C(═O)OR A1 , —C(═O)N(R A1 ) 2 , —NO 2 , —N 3 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 C(═O)(R A1 ) 2 , —NR A1 S(═O) 2 R A1 , —NR A1 S(═O)R A1 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)N(R A1 ) 2 , —S(═O)R A1 , —S(═O)N(R A1 ) 2 , —S(═O) 2 R A1 , or —S(═O) 2 N(R A1 ) 2 . 
 
     
     
       5. The compound of  claim 1 , wherein the compound is of Formula (A3): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotropically labeled derivative thereof. 
       
     
     
       6. The compound of  claim 5 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotropically labeled derivative thereof, wherein R D  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       7. The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein at least one instance of R A  is substituted or unsubstituted, C 1-6  alkyl. 
     
     
       8. The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein l is 1 or 2. 
     
     
       9. The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein at least one instance of R B  is substituted or unsubstituted, C 1-6  alkyl. 
     
     
       10. The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein at least one instance of R B  is substituted or unsubstituted —CH 2 -(piperazinyl). 
     
     
       11. The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein at least one instance of R B  is C 1-6  haloalkyl. 
     
     
       12. The compound of  claim 1 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof. 
     
     
       13. A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and optionally a pharmaceutically acceptable excipient. 
     
     
       14. The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein -U-Q- is 
       
         
           
           
               
               
           
         
       
     
     
       15. The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R X  is —N(R A1 )(R Xa ) —NH(optionally substituted acyl). 
     
     
       16. The compound of  claim 15 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R A1  is hydrogen. 
     
     
       17. The compound of  claim 16 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R Xa  is optionally substituted alkyl or optionally substituted acyl. 
     
     
       18. The compound of  claim 16 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R Xa  is optionally substituted hetercyclyl or optionally substituted heteroaryl. 
     
     
       19. The compound of  claim 16 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R Xa  is —NR(R A1 ) 2 . 
     
     
       20. The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein 
       
         
           
           
               
               
           
         
       
       is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
       21. The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, provided that at least one instance of R B  is optionally substituted —(CH 2 )(heterocyclyl). 
     
     
       22. The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein 
       
         
           
           
               
               
           
         
       
       is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
       23. The A compound of  claim 1 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof. 
     
     
       24. The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R A  is methyl and k is 1.  
     
     
       25. The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R X  is —NH 2 .  
     
     
       26. The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R X  is —NHC(═O)(C 1-6 alkyl) where the alkyl is substituted or unsubstituted, or is —NHC(═O)(3-6 membered cycloalkyl) where the cycloalkyl is substituted or unsubstituted.  
     
     
       27. The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R X  is —N(R A1 )N(R A1 ) 2 .  
     
     
       28. The compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein R X  is 
       
         
           
           
               
               
           
         
        
       
     
     
       29. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof.  
     
     
       30. The compound of  claim 12 , or a pharmaceutically acceptable salt thereof.  
     
     
       31. The compound of  claim 23 , or a pharmaceutically acceptable salt thereof.  
     
     
       32. A pharmaceutical composition comprising a compound of  claim 12 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and optionally a pharmaceutically acceptable excipient.  
     
     
       33. A pharmaceutical composition comprising a compound of  claim 23 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and optionally a pharmaceutically acceptable excipient.