Methods to treat lymphoplasmacytic lymphoma
The present invention provides compounds of any one of Formulae (I) to (V) (e.g., compounds of any one of Formulae (I-1) to (I-9)), and methods for treating Waldenström's macroglobulinemia (WM) and other B cell neoplams 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.
1. A compound of Formula (I-a):
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof;
wherein:
R A is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, —OR A1 , —N(R A1 ) 2 , —CN, —C(═O)R A1 , —C(═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 , —C(═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 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;
R X is optionally substituted heteroaryl;
and
l is 1, 2, 3, 4, or 5.
2. The compound of claim 1 , wherein the compound is of Formula (I-a1), (I-a2), or (I-a3):
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof,
wherein:
R 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)N(R A1) 2 , —S(═O)R A1 , —S(═O)N(R A1 ) 2 , —S(═O) 2 R A1 , —S(═O) 2 N(R A1 ) 2 , or a nitrogen protecting group; and
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 .
3. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein R A is substituted or unsubstituted, C 1-6 alkyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein l is 1 or 2.
5. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein at least one instance of R B is substituted or unsubstituted, C 1-6 alkyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein one instance of R B is substituted or unsubstituted —CH 2 -(piperazinyl).
7. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein one instance of R B is haloalkyl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein at least one instance of R B is substituted or unsubstituted imidazolyl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein at least one instance of R B is substituted or unsubstituted piperazinyl.
10. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein at least one instance of R B is substituted or unsubstituted morpholinyl.
11. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof.
12. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.
13. A method of treating a non-Hodgkin's lymphoma in a subject comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, to the subject.
14. A kit comprising a container, a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, and instructions for use in a subject.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein R X is optionally substituted, 5- or 6-membered, monocyclic heteroaryl.
17. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein R X is optionally substituted, 5-membered, monocyclic heteroaryl.
18. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein R A is halogen.
19. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
20. The method of claim 13 , wherein the non-Hodgkin's lymphoma is Waldenström's macroglobulinemia.
21. The pharmaceutical composition of claim 12 comprising a compound of Formula (I-1):
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.
22. The pharmaceutical composition of claim 12 comprising a compound of Formula (I-1):
or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
23. The method of claim 13 comprising administering to the subject an effective amount of a compound of Formula (I-1):
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof.
24. The compound of claim 2 , wherein the compound is of Formula (I-a1):
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof.
25. The compound of claim 2 , wherein the compound is of any one of Formulae (I-a4) to (I-a12):
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein each instance of R B is independently 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 , —C(═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 .
26. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein
wherein each instance of R B is independently 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 , —C(═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 .