Structure of N-(3,4-Dimethoxyphenyl)pyrido [3,2:4,5]-thieno[3,2-d]pyrimidin-4-amine, a New Inhibitor of CLK1 and DYRK1A Kinases

The complete crystal structure of N-(3,4-dimethoxyphenyl)pyrido[3,2:4,5]thieno[3,2-d]pyrimidin-4-amine, synthesized via a Dimroth rearrangement and designed as new inhibitor of CLK1 and DYRK1A kinases, was established by a single-crystal X-ray diffraction. The crystal is orthorhombic, space group Pca2 1 ; a = 13.1593 (9), b = 13.9823 (10), c = 8.5403 (7) Å, α = β = γ = 90, V = 1571.4 (2) Å, and Z = 4, C 17 H 14 N 4 O 2 S. Solid-state data could be used to enlighten the biological mechanism of action.


Introduction
Kinases are one of the largest families of the genome.More than 500 kinases play an important role in the regulation of various cellular processes.These enzymes are involved in all major diseases, including cancer, neurodegenerative disorders, and cardiovascular diseases.
The present crystal structure determination will not only help us to understand the detailed three-dimensional arrangement of the compound, which could be useful for designing new derivatives, but also contribute to the structural database in which there are very few structures containing the benzo[b]thieno [3,2-d]pyrimidine skeleton [6,7].Moreover, solid-state data could be used to clarify the mechanism of action implicating this new CLK1 and DYRK1A kinases inhibitor.

Refinement
A single crystal of the title compound with dimensions 0.10 × 0.10 × 0.01 mm was chosen for X-ray diffraction study.The data were collected on a Rigaku R-axis rapid diffractometer equipped with microfocus rotating anode using the monochromatic Cu-K radiation ( = 1.5418Å) and a curved image plate detector at 293 (2) K.In the range of 6.73 ∘ <  < 72.00 ∘ , a total of 21,370 reflections were collected, of which 2936 were independent ( int = 0.0789) and 2837 were observed with I > 2(I).The structure was solved by direct methods with SHELXS97 [8,9].Nonhydrogen atoms were refined by full-matrix least-squares techniques on F 2 with anisotropic thermal parameters, using SHELXL97 [8,9].H atoms were treated according to the riding model during refinement with fixed bond length, of 0.93 Å, 0.96 Å, and 0.86 Å for C arom -H, C methyl -H, and N-H bonds, respectively.The isotropic displacement parameters have been fixed at 1.2 times the  eq of the sp 2 atom or 1.5 times the  eq of the sp 3 atom from which the H atoms are linked to.All the drawings were performed using the graphical interface found within the OLEX2 package [10].The crystal data and refinement details are listed in Table 1.Table 2 lists the bond geometries and Table 3 lists the hydrogen bonds.

Results and Discussion
The molecular structure of N- (3,  The key bond lengths and bond angles of the title compound are very similar to those given in the literature for substituted phenylbenzo [3,2-d]pyrimidinones [6,7]. The pyrido[3  ,2  :4,5]thieno[3,2-d]pyrimidine system of this new CLK1 and DYRK1A kinases inhibitor is nearly planar with a mean out-of-plane deviation of 0.025 Å with the largest deviation of 0.0424 (18) Å for atom N12.
The amidine bond angle N12-C13-N14, at the junction of the pyrimidine and aniline rings observed at 120.45 (17) ∘ , the relatively short N12-C13 and C13-N14 bond lengths measured at 1.338 (2) and 1.349 (2) Å, respectively, and the planar  Table 3: Hydrogen-bonding geometry ( Å, ∘ ).indicate that the electronic delocalization stops on N14 and is not conjugated with the phenyl group.This feature may be due to the significant tilt angle between the least-squares planes defined by the pyridothienopyrimidine moiety and the aniline system that was approximately measured at 36.4 (1) ∘ .

D-H⋅
The six C-C bonds in the phenyl ring lie in the range 1.373 (3)-1.411(3) Å as expected for a fully  delocalized benzyl system.Furthermore, the two methoxy groups were also found in plane of the phenyl system.Hence, the torsion angles C arom -C arom -O-C methyl bearing the methoxy group deviate from planarity by a maximum of 8.1 (2) ∘ (Table 2).Such planarity denotes a partial delocalization of the  electronic system onto the methoxy groups.The relatively high values of the two C arom -O-CH 3 angles (C19-O23-C24 = 117.4(2) ∘ and C18-O21-C22 = 116.7 (2) ∘ ) confirm this behaviour, as the oxygen atom geometry is consistent with the sp 2 hybridization.This type of geometry is observed for 60% of phenylmethoxy systems within the CSD database [13].
The crystal structure cohesion is essentially ensured by a three-dimensional network of hydrogen bonding interactions as shown by Figure 3.Note that from all the represented hydrogen interactions in Figure 3, only two of them are symmetrically independent and correspond to those listed in Table 3.

Table 1 :
Crystallographic data and structure refinement details.