Substituted 3-amino-4-methylbenzenesulfonamides as small molecule inhibitors of ubiquitin-specific protease 28
The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof and pharmaceutical composition comprising the compound of formula (I). The present composition also relates to methods treating a disease or disorder associated with ubiquitin-specific protease 28 (USP28), methods of treating cancer, and methods of inhibiting USP28.
1 . A compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence,
X 1 is —S(O) 2 R 1 or —C(═O)NR 8 (C 1-3 alkyl), wherein C 1-3 alkyl is optionally substituted with one or more C 6-10 aryl;
R 1 is C 1-2 alkyl or —NR 4 R 5 ;
R 4 is H or C 1-3 alkyl;
R 5 is C 1-3 alkyl or C 6-10 aryl, or
R 4 and R 5 , together with the nitrogen atom to which they are attached, optionally form a C 5-8 heterocyclyl;
R 2 is C 1-3 alkyl, —OR 6 , or halogen;
R 6 is H, C 1-3 alkyl, or —C(halogen) 3 ;
Z 1 is —C(═O)— or —NR 8 —;
each R 8 is independently H or C 1-3 alkyl;
Z 2 is —C(═O)— or —NR 8 —, or
R 2 , Z 2 , and Z 1 , taken together with the atoms to which they are attached, form a C 5-6 heteroaryl,
Z 3 is absent or C 1-3 alkylene; and
R 3 is C 6-10 aryl, C 5-6 heteroaryl, or C 5-8 heterocyclyl, wherein R 3 is substituted with one or more groups independently selected from C 1-3 alkyl, C 5-8 heterocyclyl, —OH, halogen, —NHC(═O)(C 1-3 alkyl), and —NH(C 1-3 alkyl); and wherein
each C 1-3 alkyl, C 6-10 aryl, C 5-6 heteroaryl, and C 5-8 heterocyclyl is independently optionally substituted with one or more groups independently selected from C 1-3 alkyl, C 6-10 aryl, C 5-8 heterocyclyl, halogen, —C(halogen) 3 , —OH, —NO 2 , —NHC(═O) (C 1-3 alkyl), and —NH(C 1-3 alkyl);
provided the compound is not
2 . The compound of claim 1 , wherein the compound is a compound of formula (II)
3 . The compound of claim 1 , wherein R 4 is H.
4 . The compound of claim 1 , wherein R 4 is C 1-3 alkyl.
5 . The compound of claim 1 , wherein R 5 is C 1-3 alkyl.
6 . The compound of claim 1 , wherein R 4 and R 5 , together with the nitrogen atom to which they are attached, form a C 5-8 heterocyclyl.
7 . The compound of claim 1 , wherein R 5 is C 1-3 alkyl substituted with one or more C 6-10 aryl.
8 . The compound of claim 1 , wherein R 5 is C 6-10 aryl optionally substituted with one or more groups independently selected from C 1-3 alkyl, C 6-10 aryl, C 5-8 heterocyclyl, halogen, —C(halogen) 3 , —OH, —NO 2 , —NHC(═O)(C 1-3 alkyl), and —NH(C 1-3 alkyl).
9 . The compound of claim 1 , wherein R 2 is C 1-3 alkyl.
10 . The compound of claim 1 , wherein R 2 is halogen.
11 . The compound of claim 1 , wherein Z 3 is C 1-2 alkylene.
12 . The compound of claim 1 , wherein R 3 is C 6-10 aryl, substituted with one or more groups independently selected from C 1-3 alkyl, C 5-8 heterocyclyl, —OH, halogen, —NHC(═O)(C 1-3 alkyl), and —NH(C 1-3 alkyl).
13 . The compound of claim 12 , wherein R 3 is substituted with one or more halogen.
14 . The compound of claim 1 , wherein R 3 is
15 . The compound of claim 1 , wherein the compound is selected from
or a pharmaceutically acceptable salt thereof.
16 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
17 . A method of treating a disease or disorder associated with ubiquitin-specific protease 28 (USP28), comprising administering to a subject in need thereof a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
18 . The method of claim 17 , wherein the disease or disorder associated with USP28 is cancer.
19 . A compound, or a pharmaceutically acceptable salt thereof, selected from:
20 . A method of treating a disease or disorder associated with ubiquitin-specific protease 15 (USP28), comprising administering to a subject in need thereof a compound, or a pharmaceutically acceptable salt thereof, selected from:
21 . The method of claim 20 , wherein the disease or disorder associated with USP28 is cancer.