Preparation of substituted 1,2-diaminoheterocyclic compound derivatives and their use as pharmaceutical agents
This invention relates to compounds which are microtubule associated serine/threonine-like kinase (MASTL) inhibitors and the use of the compounds in the treatment of diseases and medical conditions mediated by MASTL, for example in the treatment of cancer and other target related diseases.
1 . A compound of the formula (I), or a pharmaceutically acceptable salt thereof:
wherein;
wherein the H ring in formula (I) is bonded to the carbon atom * 1 or * 2 ;
R 1 is selected from: H, C 1-6 alkyl and C 1-6 haloalkyl;
R 2 is selected from: H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and Q 3 -L 3 -,
wherein said C 1-6 alkyl is optionally substituted by one or more R 6 substituents;
R 3 is each independently selected from: halo, C 1-6 alkyl and amino;
X 1 is N and X 2 is CR 4 , or
X 1 is C and X 2 is NR 5 ;
X 3 is N;
R 4 is selected from: H, halo, CN, C 1-6 alkyl and C 1-6 haloalkyl;
R 5 is selected from: H, C 1-6 alkyl, Q 4 -L 4 -
wherein said C 1-6 alkyl is optionally substituted by one or more R 9 ,
L 4 is a bond or C 1-4 alkylene;
Q 4 is selected from: C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6-12 aryl, and 5 or 6 membered heteroaryl,
wherein said C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl is optionally substituted by one or more R 10 , and said C 6-12 aryl, and 5- or 6-membered heteroaryl is optionally substituted by one or more R 11 ;
L 1 is NR 12 or O;
R 12 is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-4 alkyl and C 1-4 alkyl-OR A5 ,
wherein said C 3-6 cycloalkyl and C 3-6 cycloalkyl-C 1-4 alkyl is optionally substituted by one or more substituents selected from: ═O, halo, C 1-4 alkyl and C 1-4 haloalkyl,
L 2 is a bond or —[CR 13 R 14 ] p —,
p is an integer selected from 1 or 2;
R 13 and R 14 are each independently selected from: H, C 1-4 alkyl, C 1-4 haloalkyl, OH, COOH, C(O)NR X1 R X2 , and C 3-6 cycloalkyl, or an R 13 and an R 14 attached to the same carbon atom in L 2 together form a C 3-6 cycloalkyl or 3-6-membered heterocyclyl,
wherein said C 1-4 alkyl is optionally substituted by OH, O—C 1-4 alkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, or C 6-10 aryl optionally substituted by halogen or C 1-6 haloalkyl;
wherein R X1 and R X2 are independently selected from: H, C 1-4 alkyl optionally substituted by OH or 3- to 6-membered heterocyclyl, and 5- to 10-membered heteroaryl, or an R X1 and an R X2 attached to the same nitrogen atom together to form a 3- to 6-membered heterocyclyl;
wherein said C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted by one or more substituents selected from: ═O, halo, C 1-4 alkyl and C 1-4 haloalkyl;
Q 1 is selected from: C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3- to 7-membered heterocyclyl, C 6-10 aryl, 5- to 9-membered heteroaryl, COOH, C(O)NR Z1 R Z2 , and C(O)O—C 1-6 alkyl;
wherein each R Z1 and R Z2 is each independently selected from; H, C 1-6 alkyl optionally substituted by OH, C 3-6 cycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl; or an R Z1 and an R Z2 attached to the same nitrogen atom together to form a 3-6-membered heterocyclyl;
wherein said C 3-12 cycloalkyl, C 3-12 cycloalkenyl and 3- to 7-membered heterocyclyl is optionally substituted by one or more R 15 ,
wherein said C 6-10 aryl and 5- to 9-membered heteroaryl is optionally substituted by one or more R 16 ;
each R 15 is independently selected from: halo, ═O, —CN, —NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, —OR 17 , —S(O) x1 R 17 , —NR 17 R B1 , —C(O)R 17 , —OC(O)R 17 , —C(O)OR 17 , —NR B1 C(O)R 17 , —NR B1 C(O)OR 17 , —C(O)NR 17 R B1 , —OC(O)NR 17 R B1 , —NR B1 SO 2 R 17 , —SO 2 NR 17 R B1 and —NR A1 C(O)NR 17 R B1 ,
wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl is optionally substituted by 1 or more R 18 , and
R 17 is selected from: H, C 1-6 alkyl and C 1-6 haloalkyl, wherein said C 1-6 alkyl is optionally substituted by one or more R 19 ;
each R 16 is independently selected from: halo, —CN, —NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, —OR 20 , —S(O) x2 R 20 , —NR 20 R B2 , —C(O)R 20 , —OC(O)R 20 , —C(O)OR 20 , —NR B2 C(O)R 20 , —NR B2 C(O)OR 20 , —C(O)NR 20 R B2 , —OC(O)NR 20 R B2 , —NR B2 SO 2 R 20 , —SO 2 NR 20 R B2 and —NR A2 C(O)NR 20 R B2 ,
wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl is optionally substituted by 1 or more R 21 , and
wherein R 20 is selected from: H, C 1-6 alkyl and C 1-6 haloalkyl, wherein said C 1-6 alkyl is optionally substituted by one or more R 22 ;
R 6 , R 9 , R 10 , R 18 , R 19 , R 21 and R 22 are each independently selected from: halo, ═O, —CN, —NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, —OR A3 , —S(O) x3 R A4 , —NR A3 R B3 , —C(O)R A3 , —OC(O)R A3 , —C(O)OR A3 , —NR B3 C(O)R A3 , —NR B3 C(O)OR A3 , —C(O)NR A3 R B3 , —NR B4 SO 2 R A3 and —SO 2 NR A3 R B3 ;
R 11 are each independently selected from: halo, ═O, —CN, —NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, —OR A4 , —S(O) x4 R A4 , —NR A4 R B4 , —C(O)R A4 , —OC(O)R A4 , —C(O)OR A4 , —NR B4 C(O)R A4 , —NR B4 C(O)OR A4 , —C(O)NR A4 R B4 , —NR B4 SO 2 R A4 and —SO 2 NR A4 R B4 ;
R 1A , R 1B , R A2 , R B2 , R A3 , R B3 , R A4 , R B4 and R A5 are each independently selected from: H, C 1-4 alkyl and C 1-4 haloalkyl,
or any —NR A3 R B3 , —NR A4 R B4 , —NR 17 R B1 or —NR 20 R B2 , within a substituent may form a 4- to 6-membered heterocyclyl, wherein said 4- to 6-membered heterocyclyl is optionally substituted by one or more substituents selected from: halo, ═O, C 1-4 alkyl and C 1-4 haloalkyl;
n is an integer from 0 to 4; and
x1, x2, x3 and x4 are each independently selected from: 0, 1 or 2.
2 . The compound of claim 1 , wherein the compound is selected from a compound of the formula (IV) or (IX):
3 . The compound of claim 1 , wherein each R 3 is halo, optionally wherein each R 3 is independently selected from fluoro and chloro.
4 . The compound of claim 1 , wherein R 4 or R 5 is H or C 1-6 alkyl, optionally methyl.
5 . The compound of claim 1 , wherein L 1 is NR 12 and R 12 is selected from C 3-6 cycloalkyl, C 1-4 alkyl and —C 1-4 alkyl-OR A5 .
6 . The compound of claim 1 , wherein L 1 is NH.
7 . The compound of claim 1 , wherein L 2 is —[CR 13 R 14 ] p , wherein p is an integer from 1 to 2, and R 13 and R 14 are each independently selected from: H and C 1-4 alkyl, or an R 13 and an R 14 attached to the same carbon atom in L 2 together form a C 3-6 cycloalkyl.
8 . The compound of claim 1 , wherein L 2 is a bond.
9 . The compound of claim 1 , wherein Q 1 is a 5- or 6-membered heteroaryl group comprising one or two heteroatoms independently selected from O, N and S, optionally wherein the heteroaryl group is substituted by one or more R 16 .
10 . The compound of claim 1 , wherein Q 1 is
wherein ring A is a 5- or 6-membered heteroaryl comprising a ring nitrogen in the ortho-position relative to the bond to -L 1 -L 2 - and optionally 1 or 2 further heteroatoms independently selected from O, S and N, optionally wherein the heteroaryl is substituted by one or more R 16 .
11 . The compound of claim 1 , wherein Q 1 is a C 6-10 aryl, optionally substituted by one or more R 16 .
12 . The compound of claim 1 , wherein Q 1 is a 8-, 9- or 10-membered bicyclic heteroaryl group comprising 1, 2 or 3 heteroatoms independently selected from O, N and S, optionally wherein the bicyclic heteroaryl group is substituted by one or more R 16 .
13 . The compound of claim 1 , wherein Q 1 has a structure selected from:
wherein x is 0, 1, 2 or 3.
14 . The compound of claim 1 , wherein Q 1 is substituted by one, two or three R 15 or R 16 , wherein R 15 or R 16 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl.
15 . A compound or a pharmaceutically acceptable salt thereof, wherein the compound is any one selected from the group consisting of Compound Nos. 1 to 107, 109 to 148, 150 to 152, 159 to 198, 206 to 208, 212 to 223, and 225 to 229 below:
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
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
150
151
152
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
193
194
195
196
197
198
206
207
208
212
213
214
215
216
217
218
219
220
221
222
223
225
226
227
228
16 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
17 . A pharmaceutical composition comprising a compound of claim 15 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.