{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T13:54:14Z","timestamp":1791381254399,"version":"4.3.3"},"reference-count":10,"publisher":"American Chemical Society (ACS)","issue":"5","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>JNJ-6665 is a dihydroorotate dehydrogenase (DHODH) inhibitor progressed for first-in-human studies. We developed a convergent, chromatography-free manufacturing route leveraging a regioselective SNAr coupling of triazolone 5 and isoquinolone 10. Triazolone 5 was prepared through a safe three-step telescoped process using catalytic TBD to deliver very high purity material in 83% overall yield. Isoquinolone 10 was accessed via an elegant Pd-catalyzed \u03b1-arylation, followed by a telescoped hydrolysis\/amination. Coupling of 5 and 10 was performed using a phase-transfer catalyst, affording JNJ-6665 in 91\u201392% isolated yield and 99.2\u201399.6 area% purity after final debenzylation, enabling robust GMP campaigns to support GLP toxicology and FIH clinical studies.<\/jats:p>","DOI":"10.1021\/acsorginorgau.6c00081","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T13:09:23Z","timestamp":1788440963000},"page":"715-721","source":"Crossref","is-referenced-by-count":0,"title":["Process Development\ntoward DHODH Inhibitor JNJ-6665"],"prefix":"10.1021","volume":"6","author":[{"given":"Kangying","family":"Li","sequence":"first","affiliation":[{"name":"Johnson & Johnson (China) Investment Ltd. Beijing Branch 14F , Tower 3, China Central Place, No.77, Jianguo Road, Chaoyang District , ,","place":["Beijing, P. R. China, 100025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Cleator","sequence":"additional","affiliation":[{"name":"Janssen Pharmaceutica NV, a Johnson & Johnson Company , Turnhoutseweg 30 , ,","place":["Beerse, Belgium, 2340"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1979-5838","authenticated-orcid":true,"given":"Simon","family":"Wagschal","sequence":"additional","affiliation":[{"name":"Chemical Process Research and Development, Janssen Pharmaceutica , Hochstrasse 201 , ,","place":["Schaffhausen, Switzerland, 8200"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5825-8085","authenticated-orcid":true,"given":"Shane","family":"Plunkett","sequence":"additional","affiliation":[{"name":"Chemical Process Research and Development, Janssen R&D , , ,","place":["Raritan, New Jersey, United States, 08869"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfeng","family":"Jin","sequence":"additional","affiliation":[{"name":"Pharmaron Beijing Co., Ltd. (China) , 6 Taihe Road, BDA , ,","place":["Beijing, P. R. China, 100176"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Liu","sequence":"additional","affiliation":[{"name":"Janssen (China) R&D Center , 16 F, Building A, Xinyan Mansion, No. 65, Guiqing Road , ,","place":["Shanghai, P. R. China, 200030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoqing","family":"Gong","sequence":"additional","affiliation":[{"name":"Johnson & Johnson (China) Investment Ltd. Beijing Branch 14F , Tower 3, China Central Place, No.77, Jianguo Road, Chaoyang District , ,","place":["Beijing, P. R. China, 100025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff","family":"Grimm","sequence":"additional","affiliation":[{"name":"Chemical Process Research and Development, Janssen R&D , , ,","place":["Raritan, New Jersey, United States, 08869"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Maton","sequence":"additional","affiliation":[{"name":"Janssen Pharmaceutica NV, a Johnson & Johnson Company , Turnhoutseweg 30 , ,","place":["Beerse, Belgium, 2340"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4478-2502","authenticated-orcid":true,"given":"Matthieu","family":"Jouffroy","sequence":"additional","affiliation":[{"name":"Janssen Pharmaceutica NV, a Johnson & Johnson Company , Turnhoutseweg 30 , ,","place":["Beerse, Belgium, 2340"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"2026100709063819700_cit1","doi-asserted-by":"publisher","first-page":"178","DOI":"10.6004\/jadpro.2018.9.2.4","article-title":"Acute Promyelocytic\nLeukemia: a summary","volume":"9","author":"Ryan","year":"2018","journal-title":"J. Adv. Pract. Oncol."},{"key":"2026100709063819700_cit2","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1016\/S0140-6736(12)61727-9","article-title":"Acute myeloid leukaemia\nin adults","volume":"381","author":"Ferrara","year":"2013","journal-title":"Lancet"},{"key":"2026100709063819700_cit3","doi-asserted-by":"publisher","DOI":"10.1186\/s40170-021-00250-z","article-title":"DHODH and cancer: promising\nprospects to be explored","volume":"9","author":"Zhou","year":"2021","journal-title":"Cancer Metab."},{"key":"2026100709063819700_cit4a","doi-asserted-by":"publisher","first-page":"11254","DOI":"10.1021\/acs.jmedchem.4c00809","article-title":"Discovery of JNJ-74856665:\nA Novel Isoquinolinone DHODH Inhibitor for the Treatment of AML","volume":"67","author":"DeRatt","year":"2024","journal-title":"J. Med. Chem."},{"key":"2026100709063819700_cit4b","doi-asserted-by":"publisher","first-page":"129965","DOI":"10.1016\/j.bmcl.2024.129965","article-title":"Identification of\nisoquinolinone DHODH inhibitor isosteres","volume":"113","author":"DeRatt","year":"2024","journal-title":"Bioorg.\nMed. Chem. Lett."},{"key":"2026100709063819700_cit4c","unstructured":"(c)\n          \n            \n              Kuduk, S.; Zhang, Z.; Deratt, L.; Wang, A.\n          Preparation of Substituted Isoquinolinones,\nPhthalazinones and Naphthyridinones as Dihydroorotate Dehydrogenase\nInhibitors. WO Patent WO2020212897A1, 2020."},{"key":"2026100709063819700_cit5","doi-asserted-by":"publisher","first-page":"7662","DOI":"10.1021\/acs.orglett.0c02851","article-title":"Synthesis of 4-Alkylated\nIsocoumarins via Pd-Catalyzed \u03b1-Arylation Reaction","volume":"22","author":"Plunkett","year":"2020","journal-title":"Org. Lett."},{"key":"2026100709063819700_cit6","doi-asserted-by":"publisher","first-page":"3863","DOI":"10.1016\/j.tetlet.2007.03.146","article-title":"A Convenient\nAminolysis of Esters Catalyzed by 1,5,7-Triazabicyclo[4.4.0]dec-5-ene\n(TBD) under Solvent-free Conditions","volume":"48","author":"Sabot","year":"2007","journal-title":"Tetrahedron\nLett."},{"key":"2026100709063819700_cit7a","doi-asserted-by":"publisher","first-page":"1328","DOI":"10.1021\/op2001854","article-title":"Synthesis of a Bicyclic Piperazine\nfrom l-Aspartic Acid and Application of a Fluoride-Promoted SNAr Coupling","volume":"15","author":"Sieser","year":"2011","journal-title":"Org. Process Res. Dev."},{"key":"2026100709063819700_cit7b","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1002\/anie.201409065","article-title":"Phase-Transfer-Catalyzed Asymmetric\nSNAr Reaction of a-Amino Acid Derivatives with Arene Chromium\nComplexes","volume":"54","author":"Shirakawa","year":"2015","journal-title":"Angew. Chem., Int. Ed."}],"container-title":["ACS Organic &amp; Inorganic\nAu"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsorginorgau.6c00081","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aoiab5\/article-pdf\/6\/5\/715\/68148310\/acsorginorgau.6c00081.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aoiab5\/article-pdf\/6\/5\/715\/68148310\/acsorginorgau.6c00081.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T13:12:46Z","timestamp":1791378766000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aoiab5\/article\/6\/5\/715\/5400329\/Process-Development-toward-DHODH-Inhibitor-JNJ"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":10,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,9,1]]},"published-print":{"date-parts":[[2026,10,7]]}},"URL":"https:\/\/doi.org\/10.1021\/acsorginorgau.6c00081","relation":{},"ISSN":["2694-247X"],"issn-type":[{"value":"2694-247X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]}}}