Protein kinase inhibitors
View Patent ↗The present invention relates to a novel family of inhibitors of protein kinases of Formula (1) wherein X is selected from CH2, O, S(0)n, or NR6; and process for their production and pharmaceutical compositions thereof. In particular, the present invention relates to inhibitors of the members of the Tec, Src, Btk and Lck protein kinase families.
1. A compound of Formula 1:
m is 0;
X is CH 2 or O;
n is an integer from 0 to 2;
R 1 is
wherein Y is selected from O or CH 2 ;
wherein X 2 , X 3 , X 5 , X 6 , X 2′ , X 3′ , X 4′ , X 5′ , X 6′ are independently selected from CR and N;
each R is independently selected from hydrogen, halogen, —NO 2 , —CN, alkyl, alkenyl, alkynyl, —OR 3 , —OC(O)R 3 , —OC(O)NR 4 R 5 , —NR 4 R 5 , —S(O) n R 3 , —C(O)R 3 , —C(O)OR 3 , —C(O)NR 4 R 5 , —S(O) 2 NR 4 R 5 , —NR 2 C(O)R 3 , —NR 2 S(O) n R 3 , —NR 2 C(O)NR 4 R 5 , —NR 2 S(O) 2 NR 4 R 5 , aryl, heteroaryl, carbocyclyl, and heterocyclyl;
R 2 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl,
R 2a , R 2b , R 2c , R 2d , R 2e , R 2f are independently selected from hydrogen, alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl;
R 3 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; and
R 4 and R 5 are independently selected from hydrogen, alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; or R 4 and R 5 can be fused to form a 3 to 8 membered heterocyclyl ring system.
2. The compound of claim 1 wherein Formula I is:
3. The compound according to claim 1 , wherein R 1 is selected from the group consisting of:
wherein R 7 is substituted or unsubstituted alkyl, aryl and heteroaryl.
4. The compound of according to claim 1 , wherein R 1 is selected from the group consisting of:
5. The compound according to claim 1 represented by formulas 1a, 1b or 1c:
wherein R 1 is selected from the group consisting of:
6. The compound according to claim 1 represented by formula 1c:
wherein R 1 is selected from the group consisting of:
7. A compound selected from the group consisting of:
Com-
pound
Structure
1
2
3
4
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
64
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
8. The compound according to claim 7 , wherein the compound is selected from the group consisting of compounds 25, 41, 43, 44, 46, 49, 50, 53, 54, 56, 57, 58, 59, 61, 62, 64, 67, 68, 75, 77, 78, 85, 86, 87, 89, 93, 94, 95, 96, 97, 99, 100, 102, 103, 104, 105, 106, 107, 108, 109, 115, 112, 123, 124, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 140, 141, 142, 143, and 144.
9. The compound according to claim 7 , wherein the compound is selected from the group consisting of compounds 47, 66, 69, 70, 76, 80, 81, 82, 84, 111, 112, 114, 118, 119, 120, 121, 125, 126, and 127.
10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
11. A process for preparing a compound of claim 1 of Formula 1-v, comprising the steps of:
a) alkylation of R 1 NH2 with bromoacetonitrile to provide intermediate 1-i
b) condensation of 1-i with 1-ii
in the presence of an acid to provide intermediate 1-iii
c) treatment of intermediate 1-iii with a base to provide intermediate 1-iv
d) treatment of intermediate 1-iv with formamadine acetate in an alcohol to provide a compound of formula 1-v
12. The process according to claim 11 , comprising the following steps:
13. The compound according to claim 7 , wherein the compound is selected from the group consisting of compounds 1, 20, 21, 23, 24, 28, 29, 31, 32, 33, 34, 35, 37, 39, 40, and 45.