Figure 1. Modifications of a high throughput lead (1) resulted in potent Akt inhibitor 2.

Scheme 1. Reagents and conditions: (a) Substituted 2-Boc-aminoethanol, DEAD/PPh₃, THF, rt, 50–90%; (b) ArCHCH₂, P(o-Tol)₃, Pd(OAc)₂, CH₃CN, 80 °C, 8 h, 40–73%; (c) TFA, CH₂Cl₂, rt, 2 h; (d) i—LDA, THF, −78 °C, 30 min, I₂, 30 min, 88%; ii—LDA, THF, −78 °C, 30 min, 81%;⁵ iii—SnBu₃CH₂, Pd₂Cl₂(PPh₃)₂, dioxane, 80 °C, overnight, 38%; (e) P(o-Tol)₃, Pd(Ac)₂, CH₃CN, 80 °C, 8 h, 84%; (f) NaOMe, MeOH, reflux, 8 h, 75%, or PhOH or RSH, KOH, 140 °C, 5–60%, or RNH₂, DMF, 125 °C, 1.5–36 h, 3–60%; (g) i—NaNO₂, AcOH, rt, 18 h, 12%; ii—LiOH, water/THF, 55 °C, overnight, 57%.

Scheme 2. Reagents and conditions: (a) 4-vinylpyridine, Pd₂(dba)₃, P(o-Tol)₃, Et₃N, DMF, 100 °C, 15 h, 36–84%; (b) NaNO₂, 30% H₂SO₄, 0 °C, 5 h, then NaI, 2 h, 70%; (c) Ph₃PCH₃Br, n-BuLi, THF, 0 °C, 30 min, then 13, 2 h, 18%; (d) 14, 9-BBN, 0 °C to rt, overnight, then 12, PdCl₂(dppf), Cs₂CO₃, DMF, 50 °C, 8 h, 40%; (e) TFA, CH₂Cl₂, rt, 2 h, 74–100%; (f) 9, AcOH, MeOH, reflux, 3 h, then NaBH₃CN, 1 h, 35–70%; (g) α-Boc-amino acid, EDC/HOBt/DMAP, THF, overnight, 41–55%.

Scheme 3. Reagents and conditions: (a) RCH₂CN, NaH, DMF, rt, 2 h, 33–99%; (b) BH₃·THF, THF, rt, overnight, 73–84%; (c) (BOC)₂O, CH₃CN, rt, overnight, 78–98%; (d) 4-vinylpyridine, P(o-Tol)₃, Pd(Ac)₂, CH₃CN, 80 °C, 8 h; (e) TFA, CH₂Cl₂, rt, 2 h, 23–27% for two steps.

Figure 2. Stereoview of X-ray structure of compound 2q in complex with PKA in the ATP binding site.

Figure 3. X-ray crystal structure⁷ of 2q in complex with PKA in the active site with key interactions highlighted. The amino acids highlighted in black are from PKA and red are from Akt1.

Activity of Akt inhibitors^a

Activity of Akt inhibitors^a

Activity of Akt inhibitors^a

Selectivity profile and cellular activity of Akt inhibitor2q (IC₅₀^a, nM)

Pharmacokinetic properties of selected Akt inhibitors¹²