USP7 inhibitors for treating multiple myeloma
The present disclosure relates to inhibitors of USP7 useful in the treatment of cancers, and other USP7 mediated diseases, having the Formula: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and n are described herein.
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 , R 3 , and R 4 are each H;
R 2 is halogen;
R 5 is —OH;
R 6 is —C(═O)R 10 or —C(O)NR 7 R 8 ;
each R 7 and R 8 is independently H, alkenyl, or alkyl, wherein the alkyl is substituted with one or more R 12 ;
R 10 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, amino, heteroalkyl, alkylamino, aminoalkyl or heteroaryl, wherein the alkyl is substituted with one or more R 13 and the alkenyl and alkynyl are each independently optionally substituted with one or more R 13 ; and wherein the cycloalkyl, heterocycloalkyl, and heteroaryl are each independently substituted with one or more R 12 , and the aryl is optionally substituted with one or more R 12 ;
each R 12 is independently at each occurrence aryl or heteroaryl, wherein the aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, and —OH;
each R 13 is independently at each occurrence —OH, heteroalkyl, aryloxy, —NH 2 , heterocycloalkyl, —O-aryl, —O-heteroaryl, —NR 7 aryl, —NR 7 heteroaryl, or —NR 7 C(═O)R 14 , wherein the heterocycloalkyl is substituted with one or more substituents selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, —NO 2 , and —OH, and the heteroalkyl are each independently optionally substituted with one or more substituents selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, —NO 2 , and —OH;
R 14 is alkyl, haloalkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein the aryl and heteroaryl are each independently optionally substituted with one or more R 15 ; and wherein the alkyl, alkenyl, and alkynyl are each independently optionally substituted with one or more substituents selected from halogen and —OH;
each R 15 is independently at each occurrence halogen, alkyl, CN, —C(═O)alkyl, or —C(═O)alkenyl, wherein the alkyl and alkenyl is each independently substituted with one or more substituents selected from halogen and —OH; and
n is 0 or 1.
2 . The compound of claim 1 , wherein n is 0.
3 . The compound of claim 1 , wherein n is 1.
4 . The compound of claim 1 , wherein R 2 is chloro.
5 . The compound of claim 1 , wherein R 6 is —C(═O)R 10 .
6 . The compound of claim 1 , wherein R 6 is —C(O)NR 7 R 8 .
7 . The compound of claim 1 , wherein R 7 is H.
8 . The compound of claim 5 , wherein R 10 is alkyl, alkenyl, amino, alkylamino, alkynyl, cycloalkyl, heteroaryl, or aminoalkyl.
9 . The compound of claim 5 , wherein R 10 is heteroalkyl.
10 . The compound of claim 1 , wherein the aryl or heteroaryl of R 12 is further substituted with alkyl, halo, or alkyloxy.
11 . The compound of claim 1 , wherein the aryl or heteroaryl of R 12 is further substituted with halo or alkyloxy.
12 . The compound of claim 1 , wherein R 10 is alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl is substituted with one or more R 13 ; the alkenyl and alkynyl are each independently optionally substituted with one or more R 13 ; and the cycloalkyl and heterocycloalkyl are each independently substituted with one or more R 12 .
13 . The compound of claim 12 , wherein each R 13 is independently, at each occurrence, —OH, aryloxy, —NH 2 , or —NR 7 C(═O)R 14 .
14 . The compound of claim 13 , wherein each R 14 is independently at each occurrence alkyl, haloalkyl, arylalkyl, alkenyl, heterocyclyl, or heteroaryl.
15 . The compound of claim 1 , wherein the compound is:
Compound
19
30
31
36
38
39
40
41
42
43
44
45
46
65
74
75
79
80
84
96
97
98
118
121
123
124
127
16 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
17 . A method of treating a disease or disorder modulated by USP7 comprising, administering to a subject in need thereof a compound of claim 1 .
18 . A method of treating cancer, comprising administering to a subject in need thereof a compound of claim 1 .
19 . A compound selected from compounds of the following structures:
Compound
1
4
5
7
8
9
18
20
21
22
23
24
25
26
27
28
32
33
34
35
37
51
52
53
54
55
59
60
61
62
66
67
70
71
81
82
85
87
88
89
91
92
93
94
95
99
100
107
119
120
122
125
126