A Concise Synthesis of a Key Azabicyclo[2.1.1]hexane Building Block for N-Heteroaryl Indazole LRRK2 Kinase Inhibitors

David A. Candito; Vladimir Simov; Ping Liu; Michael J. Ardolino; Theodore Martinot; Thomas Lyons; Ji Qi; Jingjun Yin; Jinglai Hao; Bin Hu; Meng Chen; Jun Zhang; Yu-hong Lam; Peter H. Fuller; J. Michael Ellis; Matthew Maddess

doi:10.1055/s-0043-1775430

Synlett, Inhaltsverzeichnis

Synlett
DOI: 10.1055/s-0043-1775430

letter

Small Molecules in Medicinal Chemistry

A Concise Synthesis of a Key Azabicyclo[2.1.1]hexane Building Block for N-Heteroaryl Indazole LRRK2 Kinase Inhibitors

David A. Candito ∗

^aDiscovery Chemistry, Merck & Co., Inc., Boston, MA 02115, USA

,

Vladimir Simov

^aDiscovery Chemistry, Merck & Co., Inc., Boston, MA 02115, USA

,

Ping Liu

^aDiscovery Chemistry, Merck & Co., Inc., Boston, MA 02115, USA

,

Michael J. Ardolino

^bProcess Research and Development, Merck & Co., Inc., Boston, MA 02115, USA

,

Theodore Martinot

^bProcess Research and Development, Merck & Co., Inc., Boston, MA 02115, USA

,

Thomas Lyons

^bProcess Research and Development, Merck & Co., Inc., Boston, MA 02115, USA

,

Ji Qi

^cProcess Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA

,

Jingjun Yin

^cProcess Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA

,

Jinglai Hao

^dWuXi AppTec (Shanghai), No. 1 Building, 288 Fute Zhong Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. of China

,

Bin Hu

^dWuXi AppTec (Shanghai), No. 1 Building, 288 Fute Zhong Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. of China

,

Meng Chen

^dWuXi AppTec (Shanghai), No. 1 Building, 288 Fute Zhong Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. of China

,

Jun Zhang

^dWuXi AppTec (Shanghai), No. 1 Building, 288 Fute Zhong Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, P. R. of China

,

Yu-hong Lam

^eComputational and Structural Chemistry, Merck & Co., Inc., Rahway, NJ 07065, USA

,

Peter H. Fuller

^aDiscovery Chemistry, Merck & Co., Inc., Boston, MA 02115, USA

,

J. Michael Ellis

^aDiscovery Chemistry, Merck & Co., Inc., Boston, MA 02115, USA

,

Matthew Maddess

^bProcess Research and Development, Merck & Co., Inc., Boston, MA 02115, USA

› Institutsangaben

Abstract

Alle Artikel dieser Rubrik

Abstract

Increasing the fraction of sp³ character in lead compounds has been shown to increase their drug-likeness by improving their potency, selectivity, and physicochemical properties. Azabicyclo[2.1.1]hexanes have recently garnered much interest in the synthetic community as pyrrolidine analogues for their interesting biological properties and stereoelectronic effects. During the course of our optimization of N-heteroaryl LRRK2 inhibitors, we discovered that this unique bicyclic system leads to improvements in solubility and metabolic clearance. Herein, we outline a match-pair analysis showcasing the broad impact of this unique azabicyclo[2.1.1]hexane system on key drug-like properties, as well as a concise and scalable synthesis of this building block, featuring an intramolecular cyclization to forge a strained amide bond.

Key words

amides - bicyclic compounds - drugs - heterocycles - lactams - medicinal chemistry

Volltext

Referenzen

References and Notes
1 Theodore Martinot is now affiliated to Parabalis Medicines (formerly FogPharma). Thomas Lyons is now affiliated to Takeda Pharmaceutical Company. J. Michael Ellis is now affiliated to Bristol Myers Squibb. Michael J. Ardolino is now affiliated with LifeMine Therapeutics.

2a Candito DA, Simov V, Gulati A, Kattar S, Chau RW, Lapointe BT, Methot JL, DeMong DE, Graham TH, Kurukulasuriya R, Keylor MH, Tong L, Morriello GJ, Acton JJ, Pio B, Liu W, Scott JD, Ardolino MJ, Martinot TA, Maddess ML, Yan X, Gunaydin H, Palte RL, McMinn SE, Nogle L, Yu H, Minnihan EC, Lesburg CA, Liu P, Su J, Hegde LG, Moy LY, Woodhouse JD, Faltus R, Xiong T, Ciaccio P, Piesvaux JA, Otte KM, Kennedy ME, Bennett DJ, DiMauro EF, Fell MJ, Neelamkavil S, Wood HB, Fuller PH, Ellis JM. J. Med. Chem. 2022; 65: 16801
2b Scott JD, DeMong DE, Greshock TJ, Basu K, Dai X, Harris J, Hruza A, Li SW, Lin SI, Liu H, Macala MK, Hu Z, Mei H, Zhang H, Walsh P, Poirier M, Shi ZC, Xiao L, Agnihotri G, Baptista MA, Columbus J, Fell MJ, Hyde LA, Kuvelkar R, Lin Y, Mirescu C, Morrow JA, Yin Z, Zhang X, Zhou X, Chang RK, Embrey MW, Sanders JM, Tiscia HE, Drolet RE, Kern JT, Sur SM, Renger JJ, Bilodeau MT, Kennedy ME, Parker EM, Stamford AW, Nargund R, McCauley JA, Miller MW.. J. Med. Chem. 2017; 60: 2983
2c Gulati A, Yeung CS, Lapointe B, Kattar SD, Gunaydin H, Scott JD, Childers KK, Methot JL, Simov V, Kurukulasuriya R, Pio B, Morriello GJ, Liu P, Tang H, Neelamkavil S, Wood HB, Rada VL, Ardolino MJ, Yan XC, Palte R, Otte K, Faltus R, Woodhouse J, Hegde LG, Ciaccio P, Minnihan EC, DiMauro EF, Fell MJ, Fuller PH, Ellis JM. RSC Med. Chem. 2021; 12: 1164
2d Keylor MH, Gulati A, Kattar SD, Johnson RE, Chau RW, Margrey KA, Ardolino MJ, Zarate C, Poremba KE, Simov V, Morriello GJ, Acton JJ, Pio B, Yan X, Palte RL, McMinn SE, Nogle L, Lesburg CA, Adpressa D, Lin S, Neelamkavil S, Liu P, Su J, Hegde LG, Woodhouse JD, Faltus R, Xiong T, Ciaccio PJ, Piesvaux J, Otte KM, Wood HB, Kennedy ME, Bennett DJ, DiMauro EF, Fell MJ, Fuller PH. J. Med. Chem. 2022; 65: 838
2e Logan KM. Kaplan W, Simov V, Zhou H, Li D, Torres L, Morriello GJ, Acton JJ, Pio B, Chen Y.-H, Keylor MH, Johnson R, Kattar SD, Chau R, Yan X, Ardolino M, Zarate C, Otte KM, Palte RL, Xiong T, McMinn SE, Lin S, Neelamkavil SF, Liu P, Su J, Hegde LG, Woodhouse JD, Moy LY, Ciaccio PJ, Piesvaux J, Zebisch M, Henry C, Barker J, Wood HB, Kennedy ME, DiMauro EF, Fell MJ, Fuller PH. J. Med. Chem. 2024; 67: 16807

3a Zheng Y, Tice CM, Singh S. Bioorg. Med. Chem. Lett. 2014; 24: 3673
3b Carreira EM, Fessard TC. Chem. Rev. 2014; 114: 8257
3c Marson CM. Chem. Soc. Rev. 2011; 40: 5514

4 Lovering F, Bikker J, Humblet C. J. Med. Chem. 2009; 52: 6752

5a Griffen E, Leach AG, Robb GR, Warner DJ. J. Med. Chem. 2011; 54: 7739
5b Kenny PW, Sadowski J. In Chemoinformatics in Drug Discovery . Oprea TI. Wiley; Blackwell: 2004. Chap. 11, 271

For reports on the synthesis of azabicyclo[2.1.1]hexanes, see:

6a Pirrung MC. Tetrahedron Lett. 1980; 21: 4577
6b Hughes P, Martin M, Clardy J. Tetrahedron Lett. 1980; 21: 4579
6c Hughes P, Clardy J. J. Org. Chem. 1988; 53: 4793
6d Tkachenko AN, Radchenko DS, Mykhailiuk PK, Grygorenko OO, Komarov IV. Org. Lett. 2009; 11: 5674
6e Cox B, Zdorichenko V, Cox PB, Booker-Milburn KI, Paumier R, Elliott LD, Robertson-Ralph M, Bloomfield G. ACS Med. Chem. Lett. 2020; 11: 1185
6f Levterov VV, Michurin O, Borysko PO, Zozulya S, Sadkova IV, Tolmachev AA, Mykhailiuk PK. J. Org. Chem. 2018; 83: 14350
6g Mykhailiuk PK, Kubyshkin V, Bach T, Budisa N. J. Org. Chem. 2017; 82: 8831
6h Liao H, Li A, Chen X, Liang K, Shen Y, Liang Q, Xu K, Shore DG. M, Villemure E, Siu M, Huestis MP. Synlett 2016; 27: 2251
6i Krow GR, Edupuganti R, Gandla D, Yu F, Sender M, Sonnet PE, Zdilla MJ, DeBrosse C, Cannon KC, Ross CW. III, Choudhary A, Shoulders MD, Raines RT. J. Org. Chem. 2011; 76: 3626
6j Jenkins CL, Lin G, Duo J, Rapolu D, Guzei IA, Raines RT, Krow GR. J. Org. Chem. 2004; 69: 8565
6k Krow GR, Herzon SB, Lin G, Qiu F, Sonnet PE. Org. Lett. 2002; 4: 3151
6l Krow GR, Lin G, Rapolu D, Fang Y, Lester WS, Herzon SB, Sonnet PE. J. Org. Chem. 2003; 68: 5292
6m Varnes JG, Lehr GS, Moore GL, Hulsizer JM, Albert JS. Tetrahedron Lett. 2010; 51: 3756
6n Rammeloo T, Stevens CV, De Kimpe N. J. Org. Chem. 2002; 67: 6509
6o Piotrowski DW. A. Synlett 1999; 1091
6p Gaoni Y. Org. Prep. Proced. Int. 1995; 27: 185

7 Szostak M, Aubé J. Chem. Rev. 2013; 113: 5701
8 Bruckner R. Organic Mechanisms: Reactions, Stereochemistry and Synthesis. Harmata M. Springer; Berlin: 2010
9 Bürgi HB, Dunitz JD, Lehn JM, Wipff G. Tetrahedron 1974; 30: 1563
10 2-(2-Azabicyclo[2.1.1]hex-4-yl)propan-2-ol (9) A 500 mL three-necked round-bottomed flask was charged with 15 (4.75 g, 0.031 mol, 1 equiv) and THF (150 mL). The solution was cooled to 0 °C (ice–salt bath), and BH₃·Me₂S (16.1 mL, 0.161 mol, 5.3 equiv) was added dropwise over 0.5 h while the temperature was maintained between 0 and 5 °C. When the addition was complete, the mixture was warmed to 25 °C and stirred for 1 h then heated to 50 °C for 15 h. The mixture was cooled to 0 °C, and MeOH (50 mL) was added slowly over 2 h. The resulting mixture was heated to 50 °C for 2 h and then concentrated to give the crude intermediate. A 1 M solution of HCl in MeOH (200 mL) was added dropwise at 20 °C over 0.5 h, and the resulting mixture was stirred at 50 °C for 12 h. The mixture was then concentrated to provide a crude residue. 50 wt% aq K₂CO₃ (200 mL) was added, and the resultant mixture was extracted with 2-methyltetrahydrofuran (4 × 250 mL). The organic layer was dried (Na₂SO₄), filtered, and concentrated to give a colorless oil; yield: 3 g (69%). ¹H NMR (400 MHz, MeOD): δ = 3.73–3.72 (m, 1 H), 3.53 (s, 1 H), 2.94 (s, 2 H), 1.84–1.83 (m, 2 H), 1.38–1.36 (m, 2 H), 1.21 (s, 6 H). ¹³C NMR (101 MHz, CD₃CN): δ = 117.9, 70.09, 69.6, 61.0, 55.8, 47.7, 39.8, 26.0. LCMS: m/z [M + H]+ calcd: 142.1; found; 142.4.

Zusatzmaterial

Supporting Information