MAP4K1 inhibitors
One embodiment of the disclosure is a compound represented by Formula I or a pharmaceutically acceptable salt thereof. The variables in Formula I are defined herein. Compounds of Formula I are MAP4K1 inhibitors, which can be used to treat a diseases or disorders in a subject that benefits from control of MAP4K1 activity.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
T is selected from
and 4-5 membered heterocycle containing
wherein said heterocycle of T is optionally substituted with 1-2 R 6 ;
Z is absent, O or NH;
Ring A is C 4-6 cycloalkyl or 4-6 membered heterocycle containing nitrogen, wherein said cycloalkyl or heterocycle of Ring A is optionally substituted with 1-2 R 6 ;
L 1 is selected from bond and C 1 -C 3 alkylene, wherein said alkylene of L 1 is optionally substituted with 1-2 R 11 ;
L 2 is selected from bond and C 1 -C 3 alkylene;
B is O or NH;
Q is N or CH;
x is 0, 1, or 2;
n is 0, 1, 2, 3, or 4;
R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, and 4 to 6-membered heterocycle, wherein said alkyl of R 1 and R 2 is optionally substituted with 1-2 R 3 ;
each R 3 is independently selected from halogen, hydroxyl and OR 4 ;
each R 4 is independently selected from C 1-3 alkyl, CF 3 , CH 2 F, and CHF 2 ;
each R 5 is independently selected from C 1-2 alkyl, CF 3 , CH 2 F, and CHF 2 , or
two R 5 attached to the same carbon atom taken together with the carbon atom to which they attach form C 3-5 cycloalkyl; or two R 5 attached to two adjacent carbon atoms taken together with the two adjacent carbon atoms to which they attach form C 4-6 cycloalkyl;
each R 6 is independently selected from CH 3 , methoxy, CF 3 , CH 2 F, and CHF 2 ;
R 7 is selected from C 1-3 alkyl, C 3-6 cycloalkyl, OC 1-4 alkyl, NR 9 R 10 , and 3-5 membered heterocycle containing nitrogen or oxygen, wherein said alkyl, cycloalkyl, or heterocycle of R 7 is optionally substituted with 1-3 R 8 ;
each R 8 is independently selected from halogen, C 1-3 alkyl, hydroxyl and OC 1-3 alkyl, wherein said alkyl of R 8 is optionally substituted with 1-3 R 12 ;
R 9 is selected from C 1-2 alkyl;
R 10 is selected from C 1-2 alkyl;
each R 11 is independently selected from halogen, methoxy, C 1-2 alkyl, CH 2 F, CHF 2 and CF 3 , or two R 11 taken together with the two adjacent carbon atoms to which they attach form cyclopropyl; and
each R 12 is halogen.
2. The compound of claim 1 , wherein the compound is represented by Formula IV:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein the compound is represented by Formula VII:
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
L 1 is bond;
T is
and
L 2 is a bond or methylene.
5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from azetidinylene, cyclobutylene, cyclopentylene and pyrrolidinylene, wherein said azetidinylene, cyclobutylene, cyclopentylene and pyrrolidinylene is optionally substituted with 1-2 R 6 .
6. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
L 1 is C 1 -C 3 alkylene optionally substituted with 1-2 R 11 ; and
T is Z
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from Formula L-1, L-2, L-3, L-4, L-5, L-6 and L-7:
wherein:
represents a bond to B; and
—* represents a bond to T.
8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein Z is O.
9. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
T is 4-5 membered heterocycle containing sulfone, wherein said heterocycle is optionally substituted with 1-2 R 6 ; and
L 1 is selected from bond, methylene and ethylene.
10. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl, wherein said alkyl is optionally substituted with R 3 ;
each R 3 is independently selected from halogen, hydroxyl and OR 4 ; and
each R 4 is C 1-3 alkyl.
11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently selected from hydrogen, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 —OCH 3 and cyclopropyl.
12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein:
R 5 is CH 3 , or two R 5 attached to the same carbon atom taken together with the carbon atom to which they attach form cyclopropyl;
n is 1, 2, 3 or 4;
R 7 is selected from C 1-3 alkyl, CH 2 F, CHF 2 , CF 3 , C 3-6 cycloalkyl and NR 9 R 10 ;
R 9 is selected from C 1-2 alkyl; and
R 10 is selected from C 1-2 alkyl.
13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from CH 3 , CF 3 , CH 2 CH 3 , CH(CH 3 ) 2 , cyclopropyl and N(CH 3 ) 2 ; and
each R 11 is independently CH 3 , CF 3 or CH 2 CH 3 .
14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein each R 11 is CH 3 .
15. A compound, or pharmaceutically acceptable salt thereof, selected from:
Com-
pound
No.
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
and
16. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
17. A method of inhibiting MAP4K1 in a subject in need thereof, comprising contacting MAP4K1 with an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
18. A method for T-cell activation in a subject in need thereof, comprising administering to said subject an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the T-cell activation is characterized by enhanced levels of IL-2 and enhanced levels of T-cell proliferation.
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from
and
21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from
and
22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from
and
25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
27. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is
28. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from
29. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from
30. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from