Late-Stage Functionalization for the Optimization of Reversible BTK Inhibitors

Sriram Tyagarajan; Deodial Guiadeen; Eric Streckfuss; Xiaolei Gao; Alexei V. Buevich; George Doss; Jian Liu; Petr Vachal; Shane W. Krska

doi:10.1055/s-0040-1719923

Synlett, Table of Contents

Synlett 2022; 33(13): 1259-1265
DOI: 10.1055/s-0040-1719923

cluster

Late-Stage Functionalization

Late-Stage Functionalization for the Optimization of Reversible BTK Inhibitors

Sriram Tyagarajan

^aDiscovery Chemistry, Merck & Co., Inc, Kenilworth, NJ 07033, USA

,

Deodial Guiadeen

^aDiscovery Chemistry, Merck & Co., Inc, Kenilworth, NJ 07033, USA

,

Eric Streckfuss

^bDiscovery Chemistry, Merck & Co., Inc, West Point, PA 19486, USA

,

Xiaolei Gao

^aDiscovery Chemistry, Merck & Co., Inc, Kenilworth, NJ 07033, USA

,

Alexei V. Buevich

^cAnalytical Research & Development, Merck & Co., Inc, Kenilworth, NJ 07033, USA

,

George Doss

^cAnalytical Research & Development, Merck & Co., Inc, Kenilworth, NJ 07033, USA

,

Jian Liu

^aDiscovery Chemistry, Merck & Co., Inc, Kenilworth, NJ 07033, USA

,

Petr Vachal

^aDiscovery Chemistry, Merck & Co., Inc, Kenilworth, NJ 07033, USA

,

Shane W. Krska ∗

^aDiscovery Chemistry, Merck & Co., Inc, Kenilworth, NJ 07033, USA

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Abstract

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Abstract

Late-stage functionalization (LSF) enables medicinal chemists to quickly explore structure–activity relationships (SAR) of novel analogues derived from a fully elaborated parent structure. Using several known C–H functionalization chemistries, we have systematically applied the LSF strategy to modify different regions of a Bruton’s tyrosine kinase (BTK) reversible inhibitor lead series. This approach allowed for broad SAR exploration across several key subunits of the molecule at positions that were previously difficult to explore with traditional synthesis, providing analogues with high potency and improved pharmacokinetic properties. This case study illustrates both the promise and the challenges associated with applying LSF to complex lead molecules.

Key words

LSF - C–H activation - BTK

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References

References and Notes
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24 Procedure for the Synthesis of 4-{8-Amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[6-isopropyl-4-(trifluoromethyl)pyridin-2-yl]benzamide (2a) Potassium isopropyltrifluoroborate (16.81 mg, 0.112mmol) and benzamide 1 (30 mg, 0.056 mmol) were dissolved in a 1:1 mixture of acetic acid/water (0.8 mL) and TFA (4.32 μL, 0.056 mmol). The resulting mixture was stirred at room temperature until complete dissolution. Then manganese(III) acetate dihydrate (37.5 mg, 0.140 mmol) was added in one portion. The reaction mixture was stirred at 50 °C for 18 h. After cooling to room temperature, the mixture was slowly added to a saturated aq. solution of Na₂CO₃ (5 mL). The aqueous layer then was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (2 × 10 mL), then dried using magnesium sulfate, filtered, and evaporated under vacuum. The residue was purified by preparative reverse-phase HPLC (Waters CSH C18 OBD Prep Column, 19 mm × 150 mm, 5 mm particle size 5 mm, flow = 25 mL/min, gradient: starting with 35% MeCN/water to 80% MeCN/water buffered with 0.16% TFA), to give the the product as a yellowish cream color solid after lyophilization (8 mg, 25% yield). ¹H NMR (499 MHz, CD₃OD): δ = 8.47 (s, 1 H), 8.19–8.15 (m, 2 H), 7.86–7.82 (m, 2 H), 7.68 (d, J = 5.2 Hz, 1 H), 7.32 (s, 1 H), 7.11 (d, J = 5.2 Hz, 1 H), 4.32 (ddd, J = 12.8, 4.4, 1.8 Hz, 1 H), 3.75–3.69 (m, 1 H), 3.35–3.27 (m, 1 H), 3.21–3.13 (m, 2 H), 2.50–2.47 (m, 2 H), 2.42–2.30 (m, 1 H), 2.23 (d, J = 13.9 Hz, 1 H), 2.17–1.96 (m, 2 H), 1.79–1.73 (m, 1 H), 1.55 (qd, J = 13.0, 3.4 Hz, 1 H), 1.40–1.33 (m, 6 H). LCMS (ESI): m/z calcd for [(C₃₀H₃₀F₃N₇O₂) + H]⁺: 578.25; found: 578.43. Procedure for the Synthesis of 4-{8-Amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[6-cyclobutyl-4-(trifluoromethyl)pyridin-2-yl]benzamide (2b) Synthesized as outlined for compound 2a except using potassium cyclobutyltrifluoroborate (15 mg, 0.093 mmol) as the radical source. Product obtained as a white solid (6 mg, 22% yield). ¹H NMR (499 MHz, CD₃OD): δ = 8.46 (s, 1 H), 8.20–8.14 (m, 2 H), 7.86–7.82 (m, 2 H), 7.68 (d, J = 5.2 Hz, 1 H), 7.28 (s, 1 H), 7.11 (d, J = 5.1 Hz, 1 H), 4.32 (ddd, J = 12.9, 4.4, 1.8 Hz, 1 H), 3.84–3.65 (m, 2 H), 3.34–3.27 (m, 1 H), 3.19 (t, J = 12.3 Hz, 1 H), 2.52–2.31 (m, 7 H), 2.25–2.20 (m, 1 H), 2.18–1.90 (m, 4 H), 1.76 (m, 1 H), 1.55 (qd, J = 13.0, 3.4 Hz, 1 H). LCMS (ESI): m/z calcd for [(C₃₁H₃₀F₃N₇O₂) + H]⁺: 590.25; found: 590.4. Procedure for the Synthesis of 4-{8-Amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]benzamide (2c) and 4-{8-Amino-3-[(6R,8aS)-3-oxooctahydroindolizin-6-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[3-methyl-4-(trifluoromethyl)pyridin-2-yl]benzamide (2d) A solution of benzamide 1 (50 mg, 0.093 mmol), tris(4,7-diphenyl-1,10-phenanthroline)ruthenium(II) dichloride complex (1.09 mg, 93 μmol), and tert-butylperacetate (123 mg, 0.46 mmol) in 0.93 mL MeCN/0.09 mL TFA was degassed by bubbling nitrogen through it for 5 min and then irradiated with a 30 W blue LED lamp for 16 h. The reaction mixture was filtered through a 0.25 micron frit, diluted with DMSO, and purified using preparative reverse-phase HPLC (Waters Xbridge C-18, 30 × 250 mm Prep Column, 30 mm × 250 mm, 5 mm particle size, flow = 50 mL/min, gradient: starting with 20% MeCN/water to 100% MeCN/water buffered with 0.16% NH₄OH), to give the two products 2c and 2d. Prior to evaporation, the two products were analyzed (Waters BEH C-18 column, 2.1 mm × 50 mm, 1.7 μm particle size, flow = 1 mL/min, gradient: starting with 0% MeCN/water to 100% MeCN/water buffered with 0.16% NH₄OH in 1.4 min) to provide the retention times as shown below. Lyophilization provided the products 2c and 2d as white solids. Compound 2c: t_R = 0.84 min; major product (8 mg, 26%). ¹H NMR (600 MHz, CDCl₃): δ = 8.71 (s, 1 H), 8.52 (s, 1 H), 8.11–8.04 (m, 2 H), 7.87–7.83 (m, 2 H), 7.33 (d, J = 5.1 Hz, 1 H), 7.18 (s, 1 H), 7.16 (d, J = 5.0 Hz, 1 H), 4.45 (ddd, J = 12.8, 4.2, 1.8 Hz, 1 H), 3.65–3.59 (m, 1 H), 3.16–3.03 (m, 2 H), 2.58 (s, 3 H), 2.50–2.46 (m, 2 H), 2.37–2.29 (m, 1 H), 2.28–2.08 (m, 3 H), 1.77–1.67 (m, 1 H), 1.44 (tdd, J = 13.1, 11.4, 3.8 Hz, 1 H), 4.45 (ddd, J = 12.8, 4.2, 1.8 Hz, 1 H), 3.65–3.59 (m, 1 H), 3.16–3.03 (m, 2 H), 2.58 (s, 3 H), 2.50–2.46 (m, 2 H), 2.37–2.29 (m, 1 H), 2.28–2.08 (m, 3 H), 1.77–1.67 (m, 1 H), 1.44 (tdd, J = 13.1, 11.4, 3.8 Hz, 1 H). LCMS (ESI): m/z calcd for [(C₂₈H₂₆F₃N₇O₂) + H]⁺: 550.22; found: 550.2. Compound 2d: t_R = 0.76 min; minor product (2 mg, 6.5%). ¹H NMR (600 MHz, CDCl₃): δ = 8.46 (d, J = 5.1 Hz, 1 H), 8.41 (s, 1 H), 8.09 (d, J = 7.9 Hz, 2 H), 7.83 (d, J = 8.1 Hz, 2 H), 7.49 (d, J = 5.0 Hz, 1 H), 7.32 (d, J = 5.1 Hz, 1 H), 7.13 (d, J = 5.1 Hz, 1 H), 5.54 (br s, 2 H), 4.44 (ddd, J = 12.8, 4.3, 1.8 Hz, 1 H), 3.65–3.60 (m, 1 H), 3.16–3.01 (m, 2 H), 2.52–2.38 (m, 5 H), 2.36–2.28 (m, 1 H), 2.28–2.06 (m, 3 H), 1.75–1.69 (m, 1 H), 1.49–1.37 (m, 1 H). LCMS (ESI): m/z calcd for [(C₂₈H₂₆F₃N₇O₂) + H]⁺: 550.22; found: 550.2

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