Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design

Journal of Medicinal Chemistry

Volumn 60, Issue 13, 2017, Pages 5521-5542

  Lee, Katherine L ^a   Ambler, Catherine M ^c   Anderson, David R ^c,e   Boscoe, Brian P ^d   Bree, Andrea G ^b   Brodfuehrer, Joanne I ^c   Chang, Jeanne S ^d   Choi, Chulho ^d   Chung, Seungwon ^d,f   Curran, Kevin J ^a,g   Day, Jacqueline E ^c,h   Dehnhardt, Christoph M ^a,i   Dower, Ken ^b   Drozda, Susan E ^d   Frisbie, Richard K ^c   Gavrin, Lori K ^a,j   Goldberg, Joel A ^a,k   Han, Seungil ^d   Hegen, Martin ^b   Hepworth, David ^a   Hope, Heidi R ^c,l   Kamtekar, Satwik ^c   Kilty, Iain C ^b   Lee, Arthur ^a   Lin, Lih Ling ^b   Lovering, Frank E ^a   Lowe, Michael D ^a,m   Mathias, John P ^a   Morgan, Heidi M ^c,n   Murphy, Elizabeth A ^b   Papaioannou, Nikolaos ^a,o   Patny, Akshay ^a,p   Pierce, Betsy S ^c,q   Rao, Vikram R ^b   Saiah, Eddine ^a,r   Samardjiev, Ivan J ^d   Samas, Brian M ^d   Shen, Marina W H ^b   Shin, Julia H ^b   Soutter, Holly H ^d,s   Strohbach, Joseph W ^a   Symanowicz, Peter T ^b   Thomason, Jennifer R ^a,v   Trzupek, John D ^a,t   Vargas, Richard ^a,u   Vincent, Fabien ^d   Yan, Jiangli ^e   Zapf, Christoph W ^a,w   Wright, Stephen W ^d   more..

^a Medicine Design   (United States)

^b Inflammation and Immunology Research Unit   (United States)

^c PFIZER INC   (United States)

^d Medicine Design   (United States)

^e Luc Therapeutics Inc   (United States)

^f ABBVIE INC   (United States)

^g Chromocell Corporation   (United States)

^h MilliporeSigma Corporation   (United States)

ⁱ Xenon Pharmaceuticals   (Canada)

^j GLAXOSMITHKLINE   (United States)

^k UNIVERSITY HOSPITALS OF CLEVELAND   (United States)

^l Department of Biochemistry   (United States)

^m BOEHRINGER INGELHEIM PHARMACEUTICALS INC   (United States)

ⁿ ForteBio Inc   (United States)

^o SHIRE   (United States)

^p EMD Serono Research Institute   (United States)

^q Kalexsyn Inc   (United States)

^r Navitor Pharmaceuticals   (United States)

^s X Chem Incorporated   (United States)

^t KSQ THERAPEUTICS   (United States)

^u Forma Therapeutics   (United States)

^v AMGEN INC   (United States)

^w Nurix Inc   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

3 ISOPROPOXY 2 NAPHTHAMIDE; 3 METHOXY 5 [(5 OXOPYRROLIDIN 2 YL)METHOXY] 2 NAPHTHAMIDE; 3,3,6,7 TETRAMETHYLTETRAHYDRO 3H,5H PYRROLO[1,2 C]OXAZOL 5 ONE; 4 ETHYL 5 (HYDROXYMETHYL)PYRROLIDIN 2 ONE; 5 (4 CYANOPHENYL) 3 ISOPROPOXY 2 NAPHTHAMIDE; 5 (HYDROXYMETHYL) 4 (METHOXYMETHYL)PYRROLIDIN 2 ONE; 5 (HYDROXYMETHYL) 4 METHYLPYRROLIDIN 2 ONE; 5 (HYDROXYMETHYL) 4 PROPYLPYRROLIDIN 2 ONE; 6 FLUORO 3,3,7 TRIMETHYLTETRAHYDRO 3H,5H PYRROLO [1,2 C]OXAZOL 5 ONE; 6 ISOPROPOXY 4 (PIPERIDIN 3 YLOXY)QUINOLINE 7 CARBOXAMIDE; 6 METHOXY 4 [(5 OXOPYRROLIDIN 2 YL)METHOXY]QUINOLINE 7 CARBOXAMIDE; 7 (METHOXYMETHYL) 3,3 DIMETHYLTETRAHYDRO 3H,5H PYRROLO[1,2 C]OXAZOL 5 ONE; 7 ETHOXY 1 [(5 OXOPYRROLIDIN 2 YL)METHOXY]ISOQUINOLINE 6 CARBOXAMIDE; 7 ETHYL 6 FLUORO 3,3 DIMETHYLTETRAHYDRO 3H,5H PYRROLO [1,2 C]OXAZOL 5 ONE; 7 ISOPROPOXY 1 (PIPERIDIN 3 YLOXY)ISOQUINOLINE 6 CARBOXAMIDE; 7 ISOPROPOXY 1 [(5 OXOPYRROLIDIN 2 YL)METHOXY]ISOQUINOLINE 6 CARBOXAMIDE; 7 METHOXY 1 [( 3 ETHYL 5 OXOPYRROLIDIN 2 YL)METHOXY]ISOQUINOLINE 6 CARBOXAMIDE; 7 METHOXY 1 [( 3 METHYL 5 OXOPYRROLIDIN 2 YL)METHOXY]ISOQUINOLINE 6 CARBOXAMIDE; 7 METHOXY 1 [( 5 OXO 3 PROPYLPYRROLIDIN 2 YL)METHOXY]ISOQUINOLINE 6 CARBOXAMIDE; 7 METHOXY 1 [(5 OXOPYRROLIDIN 2 YL)METHOXY]ISOQUINOLINE 6 CARBOXAMIDE; 7 METHOXY 1 [[ 3 (METHOXYMETHYL) 5 OXOPYRROLIDIN 2 YL]METHOXY]ISOQUINOLINE 6 CARBOXAMIDE; ANTIRHEUMATIC AGENT; INTERLEUKIN 1 RECEPTOR ASSOCIATED KINASE 4; INTERLEUKIN 1 RECEPTOR BLOCKING AGENT; PROTEIN SERINE THREONINE KINASE INHIBITOR; UNCLASSIFIED DRUG; UNINDEXED DRUG; [(3 ETHYL 4 FLUORO 5 OXOPYRROLIDIN 2 YL)METHOXYL] 7 METHOXYISOQUINOLINE 6 CARBOXAMIDE; 1-(((2S,3S,4S)-3-ETHYL-4-FLUORO-5-OXOPYRROLIDIN-2-YL)METHOXY)-7-METHOXYISOQUINOLINE-6-CARBOXAMIDE; INTERLEUKIN 1 RECEPTOR ASSOCIATED KINASE; IRAK4 PROTEIN, HUMAN; ISOQUINOLINE DERIVATIVE; PROTEIN KINASE INHIBITOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTHRITIS; ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; CRYSTALLIZATION; DRUG DESIGN; DRUG POTENCY; DRUG SCREENING; DRUG SELECTIVITY; DRUG SYNTHESIS; FEMALE; HUMAN; HUMAN CELL; IN VITRO STUDY; LIPOPHILICITY; MALE; MITSUNOBU REACTION; MOLECULAR MODEL; NONHUMAN; NORMAL HUMAN; NUCLEAR MAGNETIC RESONANCE; PHARMACOKINETIC PARAMETERS; RAT; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; DOSE RESPONSE; DRUG DEVELOPMENT; METABOLISM; ORAL DRUG ADMINISTRATION; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; HUMANS; INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASES; ISOQUINOLINES; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTEIN KINASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 85020722283     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.7b00231     Document Type: Article

References (64)

1. Maglione, P. J.; Simchoni, N.; Black, S.; Radigan, L.; Overbey, J. R.; Bagiella, E.; Bussel, J. B.; Bossuyt, X.; Casanova, J.-L.; Meyts, I.; Cerutti, A.; Picard, C.; Cunningham-Rundles, C. IRAK-4 and MyD88 deficiencies impair IgM responses against T-independent bacterial antigens Blood 2014, 124, 3561-3571 10.1182/blood-2014-07-587824
2. Suzuki, N.; Suzuki, S.; Millar, D. G.; Unno, M.; Hara, H.; Calzascia, T.; Yamasaki, S.; Yokosuka, T.; Chen, N.-J.; Elford, A. R.; Suzuki, J.-I.; Takeuchi, A.; Mirtsos, C.; Bouchard, D.; Ohashi, P. S.; Yeh, W.-C.; Saito, T. A critical role for the innate immune signaling molecule IRAK-4 in T cell activation Science 2006, 311, 1927-1932 10.1126/science.1124256
3. Suzuki, N.; Chen, N. J.; Millar, D. G.; Suzuki, S.; Horacek, T.; Hara, H.; Bouchard, D.; Nakanishi, K.; Penninger, J. M.; Ohashi, P. S.; Yeh, W. C. IL-1 receptor-associated kinase 4 is essential for IL-18-mediated NK and Th1 cell responses J. Immunol. 2003, 170, 4031-4035 10.4049/jimmunol.170.8.4031
4. McDonald, D. R.; Goldman, F.; Gomez-Duarte, O. D.; Issekutz, A. C.; Kumararatne, D. S.; Doffinger, R.; Geha, R. S. Impaired T-cell receptor activation in IL-1 receptor-associated kinase-4-deficient patients J. Allergy Clin. Immunol. 2010, 126, 332-337 10.1016/j.jaci.2010.05.013
5. Suzuki, N.; Saito, T. IRAK-4 - a shared NF-kappaB activator in innate and acquired immunity Trends Immunol. 2006, 27, 566-572 10.1016/j.it.2006.10.003
6. Cushing, L.; Stochaj, W.; Siegel, M.; Czerwinski, R.; Dower, K.; Wright, Q.; Hirschfield, M.; Casanova, J. L.; Picard, C.; Puel, A.; Lin, L. L.; Rao, V. R. Interleukin 1/Toll-like receptor-induced autophosphorylation activates interleukin 1 receptor-associated kinase 4 and controls cytokine induction in a cell type-specific manner J. Biol. Chem. 2014, 289, 10865-10875 10.1074/jbc.M113.544809
7. Fraczek, J.; Kim, T. W.; Xiao, H.; Yao, J.; Wen, Q.; Li, Y.; Casanova, J. L.; Pryjma, J.; Li, X. The kinase activity of IL-1 receptor-associated kinase 4 is required for interleukin-1 receptor/toll-like receptor-induced TAK1-dependent NFkappaB activation J. Biol. Chem. 2008, 283, 31697-31705 10.1074/jbc.M804779200
8. Ku, C. L.; von Bernuth, H.; Picard, C.; Zhang, S. Y.; Chang, H. H.; Yang, K.; Chrabieh, M.; Issekutz, A. C.; Cunningham, C. K.; Gallin, J.; Holland, S. M.; Roifman, C.; Ehl, S.; Smart, J.; Tang, M.; Barrat, F. J.; Levy, O.; McDonald, D.; Day-Good, N. K.; Miller, R.; Takada, H.; Hara, T.; Al-Hajjar, S.; Al-Ghonaium, A.; Speert, D.; Sanlaville, D.; Li, X.; Geissmann, F.; Vivier, E.; Marodi, L.; Garty, B. Z.; Chapel, H.; Rodriguez-Gallego, C.; Bossuyt, X.; Abel, L.; Puel, A.; Casanova, J. L. Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity J. Exp. Med. 2007, 204, 2407-2422 10.1084/jem.20070628
9. Yang, K.; Puel, A.; Zhang, S.; Eidenschenk, C.; Ku, C. L.; Casrouge, A.; Picard, C.; von Bernuth, H.; Senechal, B.; Plancoulaine, S.; Al-Hajjar, S.; Al-Ghonaium, A.; Marodi, L.; Davidson, D.; Speert, D.; Roifman, C.; Garty, B. Z.; Ozinsky, A.; Barrat, F. J.; Coffman, R. L.; Miller, R. L.; Li, X.; Lebon, P.; Rodriguez-Gallego, C.; Chapel, H.; Geissmann, F.; Jouanguy, E.; Casanova, J. L. Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda is IRAK-4 dependent and redundant for protective immunity to viruses Immunity 2005, 23, 465-478 10.1016/j.immuni.2005.09.016
10. Sokolove, J.; Zhao, X.; Chandra, P. E.; Robinson, W. H. Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcgamma receptor Arthritis Rheum. 2011, 63, 53-62 10.1002/art.30081
11. Kono, D. H.; Haraldsson, M. K.; Lawson, B. R.; Pollard, K. M.; Koh, Y. T.; Du, X.; Arnold, C. N.; Baccala, R.; Silverman, G. J.; Beutler, B. A.; Theofilopoulos, A. N. Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 12061-12066 10.1073/pnas.0905441106
12. Green, N. M.; Marshak-Rothstein, A. Toll-like receptor driven B cell activation in the induction of systemic autoimmunity Semin. Immunol. 2011, 23, 106-112 10.1016/j.smim.2011.01.016
13. Kim, T. W.; Staschke, K.; Bulek, K.; Yao, J.; Peters, K.; Oh, K. H.; Vandenburg, Y.; Xiao, H.; Qian, W.; Hamilton, T.; Min, B.; Sen, G.; Gilmour, R.; Li, X. A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity J. Exp. Med. 2007, 204, 1025-1036 10.1084/jem.20061825
14. Koziczak-Holbro, M.; Littlewood-Evans, A.; Pollinger, B.; Kovarik, J.; Dawson, J.; Zenke, G.; Burkhart, C.; Muller, M.; Gram, H. The critical role of kinase activity of interleukin-1 receptor-associated kinase 4 in animal models of joint inflammation Arthritis Rheum. 2009, 60, 1661-1671 10.1002/art.24552
15. Rekhter, M.; Staschke, K.; Estridge, T.; Rutherford, P.; Jackson, N.; Gifford-Moore, D.; Foxworthy, P.; Reidy, C.; Huang, X.-d.; Kalbfleisch, M.; Hui, K.; Kuo, M.-S.; Gilmour, R.; Vlahos, C. J. Genetic ablation of IRAK4 kinase activity inhibits vascular lesion formation Biochem. Biophys. Res. Commun. 2008, 367, 642-648 10.1016/j.bbrc.2007.12.186
16. Staschke, K. A.; Dong, S.; Saha, J.; Zhao, J.; Brooks, N. A.; Hepburn, D. L.; Xia, J.; Gulen, M. F.; Kang, Z.; Altuntas, C. Z.; Tuohy, V. K.; Gilmour, R.; Li, X.; Na, S. IRAK4 kinase activity is required for Th17 differentiation and Th17-mediated disease J. Immunol. 2009, 183, 568-577 10.4049/jimmunol.0802361
17. Cameron, B.; Tse, W.; Lamb, R.; Li, X.; Lamb, B. T.; Landreth, G. E. Loss of interleukin receptor-associated kinase 4 signaling suppresses amyloid pathology and alters microglial phenotype in a mouse model of Alzheimer's disease J. Neurosci. 2012, 32, 15112-15123 10.1523/JNEUROSCI.1729-12.2012
18. Tumey, L. N.; Boschelli, D. H.; Bhagirath, N.; Shim, J.; Murphy, E. A.; Goodwin, D.; Bennett, E. M.; Wang, M.; Lin, L.-L.; Press, B.; Shen, M.; Frisbie, R. K.; Morgan, P.; Mohan, S.; Shin, J.; Rao, V. R. Identification and optimization of indolo[2,3-c]quinoline inhibitors of IRAK4 Bioorg. Med. Chem. Lett. 2014, 24, 2066-2072 10.1016/j.bmcl.2014.03.056
19. Kelly, P. N.; Romero, D. L.; Yang, Y.; Shaffer, A. L., III; Chaudhary, D.; Robinson, S.; Miao, W.; Rui, L.; Westlin, W. F.; Kapeller, R.; Staudt, L. M. Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy J. Exp. Med. 2015, 212, 2189-2201 10.1084/jem.20151074
20. Kondo, M.; Tahara, A.; Hayashi, K.; Abe, M.; Inami, H.; Ishikawa, T.; Ito, H.; Tomura, Y. Renoprotective effects of novel interleukin-1 receptor-associated kinase 4 inhibitor AS2444697 through anti-inflammatory action in 5/6 nephrectomized rats Naunyn-Schmiedeberg's Arch. Pharmacol. 2014, 387, 909-919 10.1007/s00210-014-1023-z
21. Dudhgaonkar, S.; Ranade, S.; Nagar, J.; Subramani, S.; Prasad, D. S.; Karunanithi, P.; Srivastava, R.; Venkatesh, K.; Selvam, S.; Krishnamurthy, P.; Mariappan, T. T.; Saxena, A.; Fan, L.; Stetsko, D. K.; Holloway, D. A.; Li, X.; Zhu, J.; Yang, W.-P.; Ruepp, S.; Nair, S.; Santella, J.; Duncia, J.; Hynes, J.; McIntyre, K. W.; Carman, J. A. Selective IRAK4 inhibition attenuates disease in murine lupus models and demonstrates steroid sparing activity J. Immunol. 2017, 198, 1308-1319 10.4049/jimmunol.1600583
22. Wang, Z.; Liu, J.; Sudom, A.; Ayres, M.; Li, S.; Wesche, H.; Powers, J. P.; Walker, N. P. C. Crystal structures of IRAK-4 kinase in complex with inhibitors: A serine/threonine kinase with tyrosine as a gatekeeper Structure (Oxford, U. K.) 2006, 14, 1835-1844 10.1016/j.str.2006.11.001
23. Powers, J. P.; Li, S.; Jaen, J. C.; Liu, J.; Walker, N. P. C.; Wang, Z.; Wesche, H. Discovery and initial SAR of inhibitors of interleukin-1 receptor-associated kinase-4 Bioorg. Med. Chem. Lett. 2006, 16, 2842-2845 10.1016/j.bmcl.2006.03.020
24. Wang, Z.; Sun, D.; Johnstone, S.; Cao, Z.; Gao, X.; Jaen, J. C.; Liu, J.; Lively, S.; Miao, S.; Sudom, A.; Tomooka, C.; Walker, N. P. C.; Wright, M.; Yan, X.; Ye, Q.; Powers, J. P. Discovery of potent, selective, and orally bioavailable inhibitors of interleukin-1 receptor-associate kinase-4 Bioorg. Med. Chem. Lett. 2015, 25, 5546-5550 10.1016/j.bmcl.2015.10.060
25. Buckley, G. M.; Ceska, T. A.; Fraser, J. L.; Gowers, L.; Groom, C. R.; Higueruelo, A. P.; Jenkins, K.; Mack, S. R.; Morgan, T.; Parry, D. M.; Pitt, W. R.; Rausch, O.; Richard, M. D.; Sabin, V. IRAK-4 inhibitors. Part II: a structure-based assessment of imidazo[1,2-a]pyridine binding Bioorg. Med. Chem. Lett. 2008, 18, 3291-3295 10.1016/j.bmcl.2008.04.039
26. Buckley, G. M.; Fosbeary, R.; Fraser, J. L.; Gowers, L.; Higueruelo, A. P.; James, L. A.; Jenkins, K.; Mack, S. R.; Morgan, T.; Parry, D. M.; Pitt, W. R.; Rausch, O.; Richard, M. D.; Sabin, V. IRAK-4 inhibitors. Part III: A series of imidazo[1,2-a]pyridines Bioorg. Med. Chem. Lett. 2008, 18, 3656-3660 10.1016/j.bmcl.2008.04.042
27. McElroy, W. T.; Michael Seganish, W.; Jason Herr, R.; Harding, J.; Yang, J.; Yet, L.; Komanduri, V.; Prakash, K. C.; Lavey, B.; Tulshian, D.; Greenlee, W. J.; Sondey, C.; Fischmann, T. O.; Niu, X. Discovery and hit-to-lead optimization of 2,6-diaminopyrimidine inhibitors of interleukin-1 receptor-associated kinase 4 Bioorg. Med. Chem. Lett. 2015, 25, 1836-1841 10.1016/j.bmcl.2015.03.043
28. McElroy, W. T.; Tan, Z.; Ho, G.; Paliwal, S.; Li, G.; Seganish, W. M.; Tulshian, D.; Tata, J.; Fischmann, T. O.; Sondey, C.; Bian, H.; Bober, L.; Jackson, J.; Garlisi, C. G.; Devito, K.; Fossetta, J.; Lundell, D.; Niu, X. Potent and selective amidopyrazole inhibitors of IRAK4 that are efficacious in a rodent model of inflammation ACS Med. Chem. Lett. 2015, 6, 677-682 10.1021/acsmedchemlett.5b00106
29. Lim, J.; Altman, M. D.; Baker, J.; Brubaker, J. D.; Chen, H.; Chen, Y.; Fischmann, T.; Gibeau, C.; Kleinschek, M. A.; Leccese, E.; Lesburg, C.; MacLean, J. K. F.; Moy, L. Y.; Mulrooney, E. F.; Presland, J.; Rakhilina, L.; Smith, G. F.; Steinhuebel, D.; Yang, R. Discovery of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide inhibitors of IRAK4 ACS Med. Chem. Lett. 2015, 6, 683-688 10.1021/acsmedchemlett.5b00107
30. Chaudhary, D.; Robinson, S.; Romero, D. L. Recent advances in the discovery of small molecule inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4) as a therapeutic target for inflammation and oncology disorders J. Med. Chem. 2015, 58, 96-110 10.1021/jm5016044
31. Hynes, J., Jr.; Nair, S. K. Advances in the discovery of small-molecule IRAK4 inhibitors Annu. Rep. Med. Chem. 2014, 49, 117-133 10.1016/B978-0-12-800167-7.00009-2
32. Seganish, W. M. Inhibitors of interleukin-1 receptor-associated kinase 4 (IRAK4): a patent review (2012-2015) Expert Opin. Ther. Pat. 2016, 26, 917-932 10.1080/13543776.2016.1202926
33. Wang, Z.; Wesche, H.; Stevens, T.; Walker, N.; Yeh, W.-C. IRAK-4 inhibitors for inflammation Curr. Top. Med. Chem. 2009, 9, 724-737 10.2174/156802609789044407
34. Congreve, M.; Chessari, G.; Tisi, D.; Woodhead, A. J. Recent developments in fragment-based drug discovery J. Med. Chem. 2008, 51, 3661-3680 10.1021/jm8000373
35. Erlanson, D. A.; Fesik, S. W.; Hubbard, R. E.; Jahnke, W.; Jhoti, H. Twenty years on: the impact of fragments on drug discovery Nat. Rev. Drug Discovery 2016, 15, 605-619 10.1038/nrd.2016.109
36. Ramsey, V. G.; Cretcher, L. H. Studies in the quinoline series; some 6-beta-hydroxyethoxy-4-aminoquinolines J. Am. Chem. Soc. 1947, 69, 1659-62 10.1021/ja01199a027
37. Robinson, R. A. 1-Dialkylaminoalkylaminoisoquinolines J. Am. Chem. Soc. 1947, 69, 1939-1942 10.1021/ja01200a028
38. Morgentin, R.; Pasquet, G.; Boutron, P.; Jung, F.; Lamorlette, M.; Maudet, M.; Ple, P. Strategic studies in the syntheses of novel 6,7-substituted quinolones and 7- or 6-substituted 1,6- and 1,7-naphthyridones Tetrahedron 2008, 64 (12) 2772-2782 10.1016/j.tet.2008.01.055
39. Kucznierz, R.; Dickhaut, J.; Leinert, H.; Von Der Saal, W. Improved procedures for large scale preparation of 6- and 7-oxy-substituted isoquinolines and a convenient work-up protocol for titanium supported reactions Synth. Commun. 1999, 29, 1617-1625 10.1080/00397919908086144
40. Middleton, D. S.; Maw, G. N.; Challenger, C.; Jessiman, A.; Johnson, P. S.; Million, W. A.; Nichols, C. L.; Price, J. A.; Trevethick, M. Highly potent and selective zwitterionic agonists of the δ-opioid receptor. Part 1 Bioorg. Med. Chem. Lett. 2006, 16, 905-910 10.1016/j.bmcl.2005.10.102
41. Anderson, D. R.; Bunnage, M. E.; Curran, K. J.; Dehnhardt, C. M.; Gavrin, L. K.; Goldberg, J. A.; Han, S.; Hepworth, D.; Huang, H.-C.; Lee, A.; Lee, K. L.; Lovering, F. E.; Lowe, M. D.; Mathias, J. P.; Papaioannou, N.; Patny, A.; Pierce, B. S.; Saiah, E.; Strohbach, J. W.; Trzupek, J. D.; Vargas, R.; Wang, X.; Wright, S. W.; Zapf, C. W. Bicyclic-fused heteroaryl or aryl compounds as IRAK4 inhibitors and their preparation. WO2015150995A1, 2015.
42. Wright, S. W.; Choi, C.; Chung, S.; Boscoe, B. P.; Drozda, S. E.; Mousseau, J. J.; Trzupek, J. D. Reversal of diastereoselection in the conjugate addition of cuprates to unsaturated lactams Org. Lett. 2015, 17, 5204-5207 10.1021/acs.orglett.5b02533
43. Konas, D. W.; Coward, J. K. Electrophilic fluorination of pyroglutamic acid derivatives: Application of substrate-dependent reactivity and diastereoselectivity to the synthesis of optically active 4-fluoroglutamic acids J. Org. Chem. 2001, 66, 8831-8842 10.1021/jo0106804
44. Konas, D. W.; Coward, J. K. Synthesis of L-4,4-difluoroglutamic acid via electrophilic difluorination of a lactam Org. Lett. 1999, 1, 2105-2107 10.1021/ol991150l
45. Davies, S. G.; Dixon, D. J.; Doisneau, G. J. M.; Prodger, J. C.; Sanganee, H. J. Synthesis and utility of the 3,3-dimethyl-5-substituted-2-pyrrolidinone 'Quat' chiral auxiliary Tetrahedron: Asymmetry 2002, 13, 647-658 10.1016/S0957-4166(02)00166-0
46. Nagasaka, T.; Imai, T. Synthesis of chiral pyrrolidine derivatives from (S)-pyroglutamic acid. II. 4-(Hydroxymethyl)-3-azabicyclo[3.1.0]hexan-2-ones and 5,5-disubstituted 2-pyrrolidinones Chem. Pharm. Bull. 1997, 45, 36-42 10.1248/cpb.45.36
47. Zhang, R.; Mamai, A.; Madalengoitia, J. S. Cyclopropanation reactions of pyroglutamic acid-derived synthons with alkylidene transfer reagents J. Org. Chem. 1999, 64, 547-555 10.1021/jo9816109
48. Nagasaka, T.; Imai, T. Synthesis of chiral pyrrolidine derivatives from (S)-pyroglutamic acid. I: 7-substituted (2R,5S)-2-aryl-1-aza-3-oxabicyclo[3.3.0]octan-8-ones, 7-substituted (2R,5S)-2-aryl-1-aza-3-oxabicyclo[3.3.0]oct-6-en-8-ones and 3-substituted (S)-5-(hydroxymethyl)-2-pyrrolidinones Chem. Pharm. Bull. 1995, 43, 1081-8 10.1248/cpb.43.1081
49. Lau, W. F.; Withka, J. M.; Hepworth, D.; Magee, T. V.; Du, Y. J.; Bakken, G. A.; Miller, M. D.; Hendsch, Z. S.; Thanabal, V.; Kolodziej, S. A.; Xing, L.; Hu, Q.; Narasimhan, L. S.; Love, R.; Charlton, M. E.; Hughes, S.; van Hoorn, W. P.; Mills, J. E. Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics J. Comput.-Aided Mol. Des. 2011, 25, 621-636 10.1007/s10822-011-9434-0
50. Leeson, P. D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry Nat. Rev. Drug Discovery 2007, 6, 881-90 10.1038/nrd2445
51. Ryckmans, T.; Edwards, M. P.; Horne, V. A.; Correia, A. M.; Owen, D. R.; Thompson, L. R.; Tran, I.; Tutt, M. F.; Young, T. Rapid assessment of a novel series of selective CB(2) agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis Bioorg. Med. Chem. Lett. 2009, 19, 4406-4409 10.1016/j.bmcl.2009.05.062
52. Lovering, F.; Bikker, J.; Humblet, C. Escape from flatland: Increasing saturation as an approach to improving clinical success J. Med. Chem. 2009, 52, 6752-6756 10.1021/jm901241e
53. Di, L.; Whitney-Pickett, C.; Umland, J. P.; Zhang, H.; Zhang, X.; Gebhard, D. F.; Lai, Y.; Federico, J. J.; Davidson, R. E.; Smith, R.; Reyner, E. L.; Lee, C.; Feng, B.; Rotter, C.; Varma, M. V.; Kempshall, S.; Fenner, K.; El-kattan, A. F.; Liston, T. E.; Troutman, M. D. Development of a new permeability assay using low-efflux MDCKII cells J. Pharm. Sci. 2011, 100, 4974-4985 10.1002/jps.22674
54. Zientek, M.; Miller, H.; Smith, D.; Dunklee, M. B.; Heinle, L.; Thurston, A.; Lee, C.; Hyland, R.; Fahmi, O.; Burdette, D. Development of an in vitro drug-drug interaction assay to simultaneously monitor five cytochrome P450 isoforms and performance assessment using drug library compounds J. Pharmacol. Toxicol. Methods 2008, 58, 206-214 10.1016/j.vascn.2008.05.131
55. Young, T.; Abel, R.; Kim, B.; Berne, B. J.; Friesner, R. A. Motifs for molecular recognition exploiting hydrophobic enclosure in protein-ligand binding Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 808-813 10.1073/pnas.0610202104
56. Wang, L.; Berne, B. J.; Friesner, R. A. Ligand binding to protein-binding pockets with wet and dry regions Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 1326-1330 10.1073/pnas.1016793108
57. Fernandez, A. Keeping dry and crossing membranes Nat. Biotechnol. 2004, 22, 1081-1084 10.1038/nbt0904-1081
58. Fraser, C. M.; Fernandez, A.; Scott, L. R. Dehydron analysis: quantifying the effect of hydrophobic groups on the strength and stability of hydrogen bonds Adv. Exp. Med. Biol. 2010, 680, 473-479 10.1007/978-1-4419-5913-3-53
59. Compound 40 is commercially available via Sigma Aldrich (catalogue no. PZ0327).
60. Bavin, E. M.; Macrae, F. J.; Seymour, D. E.; Waterhouse, P. D. The analgesic and antipyretic properties of some derivatives of salicylamide J. Pharm. Pharmacol. 1952, 4, 872-8 10.1111/j.2042-7158.1952.tb13220.x
61. Woodcock, D.; Davies, B. L. Synthesis of plant-growth regulators. V. (3-Substituted-2-naphthyloxy)-n-alkanecarboxylic acids J. Chem. Soc. 1958, 4723-4728 10.1039/jr9580004723
62. Hegen, M.; Keith, J. C., Jr.; Collins, M.; Nickerson-Nutter, C. L. Utility of animal models for identification of potential therapeutics for rheumatoid arthritis Ann. Rheum. Dis. 2008, 67, 1505-1515 10.1136/ard.2007.076430
63. Patricelli, M. P.; Nomanbhoy, T. K.; Wu, J.; Brown, H.; Zhou, D.; Zhang, J.; Jagannathan, S.; Aban, A.; Okerberg, E.; Herring, C.; Nordin, B.; Weissig, H.; Yang, Q.; Lee, J.-D.; Gray, N. S.; Kozarich, J. W. In situ kinase profiling reveals functionally relevant properties of native kinases Chem. Biol. (Oxford, U. K.) 2011, 18, 699-710 10.1016/j.chembiol.2011.04.011
64. Mayer, M.; Meyer, B. Characterization of ligand binding by saturation transfer difference NMR spectroscopy Angew. Chem., Int. Ed. 1999, 38, 1784-1788 10.1002/(SICI)1521-3773(19990614)38:12<1784::AID-ANIE1784>3.0.CO;2-Q