HCK as a therapeutic target in MYD88 mutated diseases
The present disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. The provided compounds may be kinase (e.g., HCK, BTK, LYN, BLK, FRK) inhibitors. Also provided are pharmaceutical compositions and kits including the provided compounds. Further provided are methods of using the provided compounds, pharmaceutical compositions, and kits (e.g., for treating diseases (e.g., proliferative diseases) in a subject in need thereof).
1 . A compound of Formula (II-1):
or a pharmaceutically acceptable salt thereof, wherein:
R is optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —O-optionally substituted carbocyclyl, —CH 2 —O-optionally substituted carbocyclyl, —O-optionally substituted aryl, —CH 2 —O-optionally substituted heteroaryl;
R 1 is 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, or a nitrogen protecting group;
each occurrence of R 2 is independently 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, —OR a , —N(R a ) 2 , or —SR a , wherein R a is independently selected from 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, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom;
each occurrence of R 3 is independently 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, —OR b , —N(R b ) 2 , or —SR b , wherein R b is independently selected from 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, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom;
J is a bond or alkynylene;
m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits;
n is 1, 2, 3, 4, 5, 6, 7, or 8, as valency permits;
R 4 is independently selected from hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, —CN, —SCN, —NO2, —C(═O)R b , —C(═O)N(R b ) 2 , —OR b , —N(R b ) 2 , —C(═NR b )R b , —C(═NR b )OR b , —C(═NR b )N(R b ) 2 , —C(═O)OR b , —NR b C(═O)R b , —NRDC(═O)OR b , —NR b C(═O)N(R b ) 2 , —OC(═O)R b , —OC(═O)OR b , —OC(═O)N(R b ) 2 , or —SR b ,
wherein R b is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom; and
R 5 is independently selected from hydrogen, halogen, optionally substituted acyl, —CN, —SCN, —NO2, —C(═O)R b , —C(═O)N(R b ) 2 , —OR b , —N(R b ) 2 , —C(═NR b )R b , —C(═NR b )OR b , —C(═NR b )N(R b ) 2 , —C(═O)OR b , —NRDC(═O)R b , —NRDC(═O)OR b , —NR b C(═O)N(R b ) 2 , —OC(═O)R b , —OC(═O)OR b , —OC(═O)N(R b ) 2 , or —SR b ,
wherein R b is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom.
2 . A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable excipient.
3 . The pharmaceutical composition of claim 2 , further comprising an additional pharmaceutical agent.
4 . The pharmaceutical composition of claim 3 , wherein the additional pharmaceutical agent is venetoclax.
5 . A method of treating a disease associated with an MYD88 mutation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
6 . The method of claim 5 , wherein the disease is a proliferative disease.
7 . The method of claim 6 , wherein the proliferative disease is cancer.
8 . The method of claim 7 , wherein the cancer is Waldenstrom's macroglobulinemia.
9 . The method of claim 7 , wherein, the cancer is activated B-cell-like (ABC)-DLBCL.
10 . The method of claim 7 , wherein the cancer is associated with aberrant activity of one or more of HCK, BTK, and LYN in a subject.
11 . The method of claim 10 , wherein the aberrant activity is overexpression.