Substituted pyridines as DNMT1 inhibitors
The invention relates to substituted pyridine derivatives that are inhibitors of the activity of DNA methyltransferase 1 (DNMT1). The invention also relates to pharmaceutical compositions comprising such compounds and methods of using such compounds in the treatment of cancer, pre-cancerous syndromes, beta haemoglobinopathy disorders, and other diseases associated with inappropriate DNMT1 activity.
1. An anhydrous crystalline glycine salt having a formula of
which provides an XRPD pattern substantially as set out in Table I:
TABLE I
XRPD Summay of Diffraction Angles and d-Spacing
Peak #
Diff. Angle [°2θ]
d-spacing [Å]
1
5.42
16.3027
2
5.78
15.2672
3
7.44
11.8749
4
9.59
9.2110
5
10.56
8.3679
6
10.81
8.1745
7
11.55
7.6557
8
13.04
6.7854
9
14.46
6.1218
10
14.84
5.9641
11
15.56
5.6903
12
16.25
5.4518
13
17.01
5.2072
14
18.32
4.8394
15
18.82
4.7116
16
19.00
4.6665
17
19.20
4.6182
18
19.60
4.5246
19
20.49
4.3310
20
20.99
4.2287
21
21.18
4.1924
22
21.54
4.1216
23
21.69
4.0934
24
22.34
3.9755
25
22.65
3.9233
26
23.20
3.8313
27
23.95
3.7127
28
24.42
3.6426
29
24.99
3.5610
30
25.17
3.5354
31
26.22
3.3958
32
26.54
3.3559.
2. An anhydrous crystalline glycine salt having a formula of
which provides an XRPD pattern substantially in accordance with FIG. 1 .
3. An anhydrous crystalline glycine salt having a formula of
which provides an XRPD pattern that has representative diffraction peaks at 10.56, 14.46, 16.25, 20.99, 21.18, 21.54, 21.69, and 26.22° 2θ.
4. A crystalline monohydrate glycine salt having a formula of
which provides an XRPD pattern substantially as set out in Table II:
TABLE II
Example 1 Mono-Hydrate Glycinate Salt Summay
of XRPD Diffraction Angles and d-Spacing
Peak #
Diff. Angle [°2θ]
d-spacing [Å]
1
5.13
17.2011
2
5.75
15.3532
3
7.27
12.1458
4
9.28
9.5245
5
10.26
8.6117
6
10.61
8.3277
7
11.52
7.6772
8
12.87
6.8726
9
13.86
6.3858
10
14.56
6.0794
11
15.43
5.7389
12
16.31
5.4293
13
17.32
5.1171
14
18.52
4.7872
15
19.15
4.6299
16
19.89
4.4604
17
20.84
4.2586
18
21.23
4.1824
19
22.11
4.0168
20
22.55
3.9404
21
23.13
3.8421
22
23.83
3.7305
23
24.13
3.6847
24
25.47
3.4942
25
26.06
3.4171
26
27.91
3.1941
27
28.65
3.1137
28
29.05
3.0716
29
29.90
2.9860
30
30.42
2.9363
31
30.82
2.8990
32
31.34
2.8522
33
32.91
2.7196
34
33.38
2.6825
35
36.72
2.4456.
5. A crystalline monohydrate glycine salt having a formula of
which provides an XRPD pattern substantially in accordance with FIG. 4 .
6. A crystalline monohydrate glycine salt having a formula of
which provides an XRPD pattern that has representative diffraction peaks at 7.27, 10.26, 11.52, 13.86, 15.43, 20.84, 21.23, 22.11, and 26.06° 2θ.