WHOWANT A LA USUNITATE 20180127432A1 UN MAN AT ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2018 /0127432 A1 Trzupek et al. ( 43 ) Pub . Date: May 10 , 2018 ( 54 ) BICYCLIC -FUSED HETEROARYL OR ARYL C07C 69 /94 (2006 .01 ) COMPOUNDS C07D 217 / 24 ( 2006 .01 ) C07D 217 / 22 ( 2006 .01 ) ( 71 ) Applicant: Pfizer Inc. , New York , NY (US ) C07D 217 / 02 ( 2006 .01 ) CO7D 405 / 14 ( 2006 . 01 ) ( 72 ) Inventors : John David Trzupek , Arlington , MA C07D 401/ 14 ( 2006 . 01) (US ) ; Katherine Lin Lee , West C07D 487 / 04 ( 2006 .01 ) Newton , MA (US ); Mark Edward A61K 31 /47 ( 2006 .01 ) Bunnage , Concord , MA (US ) ; Seungil A61K 31/ 4709 ( 2006 .01 ) Han , Mystic , CT (US ) ; David A61K 31/ 4725 ( 2006 .01 ) Hepworth , Concord , MA (US ) ; Frank A61K 31/ 517 (2006 . 01 ) Eldridge Lovering , Acton , MA (US ) ; A61K 31 / 5377 ( 2006 .01 ) John Paul Mathias, Concord , MA A61K 31/ 541 ( 2006 .01 ) (US ) ; Nikolaos Papaioannou , Newton , A61K 45 / 06 (2006 .01 ) MA (US ) ; Betsy Susan Pierce, East CO7D 407 / 14 ( 2006 .01 ) Lyme, CT (US ) ; Joseph Walter C070 215 / 48 ( 2006 . 01 ) Strohbach , Wentzville , MO (US ) ; C070 207/ 26 ( 2006 .01 ) Stephen Wayne Wright, Old Lyme, CT CO7D 401 / 12 ( 2006 .01 ) (US ) ; Christoph Wolfgang Zapf, COZD 403 / 12 ( 2006 . 01 ) Marlborough , MA (US ) ; Lori Krim C07D 405 / 12 ( 2006 .01 ) Gavrin , Villanova , PA (US ) ; Arthur C07D 413 / 12 ( 2006 . 01 ) Lee , Littleton , MA (US ) ; David C070 417/ 12 ( 2006 . 01) Randolph Anderson , Salem , CT (US ) ; A61K 31/ 4015 ( 2006 .01 ) Kevin Joseph Curran , Somerset, NJ (52 ) U .S . CI. (US ) ; Christoph Martin Dehnhardt, CPC . .. .. C07D 491 /056 (2013 .01 ) ; C07D 239 / 88 Burnaby (CA ) ; Eddine Saiah , ( 2013 . 01 ) ; A61K 31/ 4015 ( 2013 . 01 ) ; C07D Brookline, MA (US ) ; Joel Adam 263 / 24 (2013 .01 ) ; C070 207 / 267 ( 2013 .01 ) ; Goldberg , New Orleans , LA (US ) ; A61K 31/ 40 ( 2013 .01 ) ; C070 207 /08 Xiaolun Wang, San Diego , CA (US ); ( 2013 .01 ) ; CO7F 7 / 1856 ( 2013 . 01 ) ; C07D Horng - Chih Huang , Chesterfield , MO 209 / 52 ( 2013 .01 ) ; C07D 498 /04 ( 2013 .01 ) ; (US ) ; Richard Vargas , Bedford , MA C070 207 /273 ( 2013 .01 ) ; C07C 69 /94 (US ) ; Michael Dennis Lowe, White (2013 . 01) ; C07D 217 /24 (2013 . 01 ) ; C07D Plains, NY (US ) ; Akshay Patny , 217 / 22 ( 2013 .01 ) ; C07D 217 /02 ( 2013 . 01 ) ; Waltham , MA (US ) C07D 405 / 14 ( 2013 .01 ) ; C07D 401/ 14 (2013 .01 ) ; C07D 487/ 04 ( 2013 .01 ) ; A61K ( 73 ) Assignee : Pfizer Inc ., New York , NY (US ) 31/ 47 (2013 .01 ) ; A61K 31/ 4709 ( 2013 . 01 ) ; A61K 31/ 4725 ( 2013 .01 ) ; A61K 31/ 517 ( 21 ) Appl . No . : 15 / 862 , 691 ( 2013 . 01 ) ; A61K 31 /5377 ( 2013 .01 ) ; A61K 31/ 541 (2013 .01 ) ; A61K 45 /06 ( 2013 .01 ) ; ( 22 ) Filed : Jan . 5 , 2018 CO7D 407 / 14 ( 2013 . 01 ) ; C07D 215 / 48 (2013 . 01 ) ; C070 207 /26 ( 2013 .01 ) ; C07D Related U . S . Application Data 401 / 12 ( 2013 .01 ) ; C07D 403 / 12 ( 2013 .01 ) ; (63 ) Continuation of application No. 15 / 232, 892 , filed on C07D 405 / 12 ( 2013 . 01 ) ; C07D 413 / 12 Aug. 10 , 2016 , now Pat. No. 9 ,879 ,022 , which is a ( 2013 .01 ) ; CO7D 417 / 12 ( 2013 . 01 ) ; C07D continuation of application No . 14 /678 , 114 , filed on 239 / 86 ( 2013 .01 ) Apr . 3 , 2015 , now Pat. No . 9 ,458 , 168 . ( 57 ) ABSTRACT (60 ) Provisional application No . 61/ 975 ,473 , filed on Apr. Compounds , tautomers and pharmaceutically acceptable 4 , 2014 salts of the compounds are disclosed , wherein the com Publication Classification pounds have the structure of Formula la , (51 ) Int. Ci. R2 CO7D 491/ 056 ( 2006 . 01 ) PopR 8 0 C07D 239 / 88 ( 2006 .01 ) C07D 239/ 86 ( 2006 .01 ) CO7D 263 / 24 ( 2006 . 01 ) CO7D 207 / 267 ( 2006 .01 ) t= ts A61K 31/ 40 ( 2006 .01 ) R6VPo C070 207 /08 ( 2006 .01 ) CO7F 7 / 18 ( 2006 .01 ) R8 CO7D 209 /52 ( 2006 .01 ) as defined in the specification . Corresponding pharmaceu CO7D 498 /04 ( 2006 .01 ) tical compositions, methods of treatment , methods of syn C07D 207 /273 ( 2006 .01 ) thesis , and intermediates are also disclosed . Patent Application Publication May 10 , 2018 Sheet 1 of 2 US 2018 /0127432 A1 FIG . 1 KYYYYYYYYYYYYYYYYYYYYYYYY * * * * * - 0 . 0004 p < 0 . 001 50 . 29 % MeanEarswelling(aumfrombaseline) *** * * * *** * * * * * * * * * * * ** *** ** *** * * ** *** * * ** * * * * * * * ** 45 . Ava Av ** ** * FA ** t Au FA Vehicle 100Examplempk PO296 BID Anti P40400 ugantibody IP D1 ,4 Final Day of Study Patent Application Publication May 10 , 2018 Sheet 2 of 2 US 2018 /0127432 A1 FIG . 2 Change in paw volume vs . time Vehicle 5 ml/kg PO , BID mm Example 26 10 mg/ kg PO , BID . Example 26 10 mg/kg PO , BID Example 26 10 mg /kg PO , BID BIRB796 30 mg/ kg PO , QD 44444444444444444444444444444444444444444444444444444444 Naive * AC0 .05 vs , vehicle b * ekeretmed * e bythingthat to think * tore *from WY meeting Deltapawvolume(sem) AN ADAX VAA pewnym thatthereisthe mostint*smalformationandthingthat t w wit * ** * toset* * ?? $ * * ??? w - + - toutes - - - - - - toinen omwwwwwww um mp 0184986889 1 2 3 4 5 6 7 8 Day Post Treatment US 2018 /0127432 A1 May 10 , 2018 BICYCLIC -FUSED HETEROARYL OR ARYL driven autoimmune diseases while having minimal immu COMPOUNDS nosuppressive side effects . Additional recent studies suggest that targeting IRAK4 may be useful in other inflammatory FIELD OF THE INVENTION pathologies such as atherosclerosis and diffuse large B - cell lymphoma (Rekhter et al 2008 ; Ngo et al 2011 ) . Therefore , [ 0001] This invention pertains to compounds useful for the inhibitors of IRAK4 kinase activity are potential therapeu treatment of autoimmune and inflammatory diseases asso tics for a wide variety of diseases including but not limited ciated with Interleukin - 1 Receptor Associated Kinase to autoimmunity , inflammation , cardiovascular diseases , ( IRAK ) and more particularly compounds that modulate the cancer , and metabolic diseases. See the following references function of IRAK4 . for additional information : N . Suzuki and T . Saito , Trends in Immunology , 2006 , 27 , 566 . T . Kawagoe , S . Sato , A . Jung , BACKGROUND OF THE INVENTION M . Yamamoto , K . Matsui, H . Kato , S . Uematsu , O . Takeuchi 0002 ] Protein kinases are families of enzymes that cata and S . Akira , Journal of ExperimentalMedicine , 2007 , 204 , lyze the phosphorylation of specific residues in proteins , 1013 . J . Fraczek , T . W . Kim , H . Xiao , J . Yao , Q . Wen , Y . Li, broadly classified in tyrosine and serine /threonine kinases. J . - L . Casanova , J . Pryjma and X . Li, Journal of Biological Inappropriate activity arising from dysregulation of certain Chemistry , 2008 , 283 , 31697 . T . W . Kim , K . Staschke , K . kinases by a variety of mechanisms is believed to underlie Bulek , J . Yao , K . Peters , K . - H . Oh , Y . Vandenburg , H . Xiao , the causes of many diseases, including but not limited to , W . Qian , T . Hamilton , B . Min , G . Sen , R . Gilmour and X . cancer, cardiovascular diseases, allergies , asthma, respira Li, Journal of ExperimentalMedicine , 2007 , 204 , 1025 . M . tory diseases , autoimmune diseases , inflammatory diseases , Koziczak -Holbro , A . Littlewood - Evans, B . Pollinger, J . bone diseases , metabolic disorders , and neurological and Kovarik , J . Dawson , G . Zenke, C . Burkhart, M . Muller and neurodegenerative diseases. As such , potent and selective H . Gram , Arthritis & Rheumatism , 2009 , 60 , 1661. M . inhibitors of kinases are sought as potential treatments for a Hernandez and J . F . Bastian , Current Allergy and Asthma variety of human diseases . Reports , 2006 , 6 , 468 . E . Lavine , R . Somech , J. Y . Zhang , A . [ 0003 ] There is considerable interest in targeting the Puel , X . Bossuyt, C . Picard , J . L . Casanova and C . M . innate immune system in the treatment of autoimmune Roifman , Journal of Allergy and Clinical Immunology, diseases and sterile inflammation . Receptors of the innate 2007 , 120 , 948 . M . Rekhter, K . Staschke , T . Estridge, P . immune system provide the first line of defense against Rutherford , N . Jackson , D . Gifford -Moore , P . Foxworthy , C . bacterial and viral insults . These receptors recognize bacte Reidy, X . - d . Huang, M . Kalbfleisch , K . Hui, M . - S . Kuo , R . rial and viral products as well as pro - inflammatory cytokines Gilmour and C . J. Vlahos, Biochemical and Biophysical and thereby initiate a signaling cascade that ultimately Research Communications, 2008 , 367 , 642 . O ' Neill , L . A . results in the up - regulation of inflammatory cytokines such (2003 ) . “ Therapeutic targeting of Toll - like receptors for as TNFO , IL6 , and interferons. Recently it has become inflammatory and infectious diseases. ” Curr Opin Pharma apparent that self- generated ligands such as nucleic acids col 3 ( 4 ) : 396 . Kanzler, H et al. (2007 ) “ Therapeutic targeting and products of inflammation such as high -mobility group of innate immunity with toll - like receptor agonists and protein B1 (HMGB1 ) and Advanced Glycated End - products antagonists .” Nature Medicine 13 :552 . Wagner , H . ( 2006 ) ( AGE) are ligands for Toll - like receptors ( TLRs) which are “ Endogenous TLR ligands and autoimmunity ” Advances in key receptors of the innate immune system ( O 'Neill 2003 , Immunol 91 : 159 . Ngo , V . N . et al . ( 2011 ) " Oncogenically Kanzler et al 2007 , Wagner 2006 ) . This demonstrates the active MyD88 mutations in human lymphoma ” Nature 470 : role of TLRs in the initiation and perpetuation of inflam 115 . mation due to autoimmunity. [0004 ]