GSK3β inhibitor, AZD8926

Scheme I:

Scheme 1

Anilines of formula (III) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

Process b). Compounds of formula (IV) and amines of formula (V) may be reacted together under standard Buchwald conditions as described in Process a.

A synthesis of pyrimidines of formula (IV) is described in Scheme 2(R^X may be the same or different and is Q.βalkytyT should not be there

Scheme 2

Compounds of formula (V) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

Compounds of formula (VI) in which R⁶ has the general structure R^a-CH-R^b (wherein R^a and R^b are as defined in formula I and R^x may be the same or different and is C_1-6alkyl) and R⁹ is F may be prepared according to Scheme 3

(VI) (VIf)

Scheme 3

Example 104

[4- [5-Fluoro-4- [3-tetr ahydropy r an-4-yl-2-(trifluor omethyl)imidazol-4-yl] -pyrimidin- 20 2-yl] aminophenyl]-(4-methylpiperazin-l-yl)-methanone hydrochloride

The title compound was prepared in accordance with the general method E and work-up procedure B. The product was purified by flash chromatography (CH₂Cl₂MeOH 30:1, 20:1 then 15:1). Using 5-fluoro-4-[l-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)-lH- 25 imidazol-5-yl]pyrimidin-2-amme (obtained from Example 34(d)) (33 mg, 0.1 mmol), l-(4- bromobenzoyl)-4-methylpiperazine (0.027 g, 0.095 mmol), Cs₂CO₃ (65 mg, 0.2 mmol), Pd₂(dba)₃ (6.8 mg, 0.0075 mmol) and X-Phos (7 mg, 0.015 mmol), the base of the title compound (35 mg, 70%) was obtained as a solid. The hydrochloride was prepared in accordance with the method described in general method D. ¹H NMR (DMSO-<fc, 300 MHz) δ 10.60 (br s, 1 H), 10.11 (s, 1 H), 8.82 (s, 1 H), 7.74 (d, J = 8.4 Hz, 2 H), 7.56 (s, 1 H), 7.42 (d, J= 8.4 Hz, 2 H), 4.80 (t, 1 H), 3.80 (d, J= 8.4 Hz, 2 H), 3.22 (t, J= 11.5 Hz, 2 H), 3.2-3.0 (m, 2 H), 2.78 (s, 3 H), 2.2-2.1 (m, 2 H), 2.0-1.8 (m, 2 H); 6 Hydrogens were not assigned in the region 3.6 -2.2 ppm due to the presence of the water and DMSO peaks in this region; MS (ESI) m/z 534.5 (M+ 1); MS (ESI) m/z 532.5 (M-I).

Example 34 (d) 5-Fluoro-4-[l-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)-lH- imidazol-5-yl]pyrimidin-2-amine

The title compound was prepared in accordance with the general method B with the exception that guanidine carbonate was used. Using (2Z)-3-dimethylamino-2-fluoro-l-[l- (tetrahydro-2H-pyran-4-yl)-2-trifluoromethyl- lH-imidazol-5 -y l]prop-2-en- 1 -one (0.330 g, 1.0 mmol, obtained from Example 34(c)) and guanidine carbonate (0.45 g, 2.50 mmol). After purification by flash chromatography (heptane/EtOAc 1 :2), the title compound was obtained (0.170 g, 51 %) as a white solid.

¹HNMR (CDCl₃₅ 300 MHz) δ 8.29 (s, 1 H)₅ 7.63 (d, J= 2.7 Hz, 1 H)₅ 5.10 (br.s., 2 H)₅ 4.88-4.76 (m, 1 H), 4.16-4.07 (m, 2 H)₅3.53-3.42 (m₅ 2 H)₅ 2.80-2.65 (m, 2 H), 1.89-1.81 (m, 2 H); MS (ES) m/z 332 (M+l).

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