THE MOMENT DE T
`
`US009840491B2
`
`OUR
`
`( 12 ) United States Patent
`Ioannidis et al .
`
`( 10 ) Patent No . :
`( 45 ) Date of Patent :
`
`US 9 , 840 , 491 B2
`Dec . 12 , 2017
`
`( 72 )
`
`( * ) Notice :
`
`( 54 ) QUINAZOLINONES AND
`AZAQUINAZOLINONES AS
`UBIQUITIN - SPECIFIC PROTEASE 7
`INHIBITORS
`( 71 ) Applicant : Forma Therapeutics , Inc . , Watertown ,
`MA ( US )
`Inventors : Stephanos Ioannidis , Natick , MA ( US ) ;
`Adam Charles Talbot , Guilford , CT
`( US ) ; Bruce Follows , Littleton , MA
`( US ) ; Alexandre Joseph Buckmelter ,
`Acton , MA ( US ) ; Minghua Wang ,
`Acton , MA ( US ) ; Ann - Marie
`Campbell , Monroe , CT ( US ) ; David R .
`Lancia , Jr . , Boston , MA ( US )
`( 73 ) Assignee : FORMA Therapeutics , Inc . ,
`Watertown , MA ( US )
`Subject to any disclaimer , the term of this
`patent is extended or adjusted under 35
`U . S . C . 154 ( b ) by 0 days .
`( 21 ) Appl . No . : 15 / 015 , 571
`( 22 ) Filed :
`Feb . 4 , 2016
`Prior Publication Data
`( 65 )
`US 2016 / 0229833 A1 Aug . 11 , 2016
`Related U . S . Application Data
`( 60 ) Provisional application No . 62 / 112 , 487 , filed on Feb .
`5 , 2015 .
`( 51 ) Int . Ci .
`( 2006 . 01 )
`C07D 401 / 06
`CO7D 239 / 88
`( 2006 . 01 )
`C07D 487 / 04
`( 2006 . 01 )
`C070 471 / 04
`( 2006 . 01 )
`U . S . CI .
`CPC . . . . . . . . . COZD 401 / 06 ( 2013 . 01 ) ; C07D 239 / 88
`( 2013 . 01 ) ; C070 471 / 04 ( 2013 . 01 ) ; C07D
`487 / 04 ( 2013 . 01 )
`( 58 ) Field of Classification Search
`. . . . . . . . . . . C07D 400 / 17
`CPC . . . . . . . . . . .
`See application file for complete search history .
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`FOREIGN PATENT DOCUMENTS
`103833646
`*
`6 / 2014
`. . . . . . . . . . . C07D 401 / 06
`103833646 A
`6 / 2014
`( Continued )
`OTHER PUBLICATIONS
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`Ohio , US ; Jul . 4 , 2012 ( Jul . 4 , 2012 ) , XP002755499 , Database
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`Database Registry [ Online ] Chemical Abstracts Service , Columbus ,
`Ohio , US ; Jul . 4 , 2012 ( Jul . 4 , 2012 ) , XP002755500 , Database
`accession No . 1381443 - 96 - 4 .
`Database Registry [ Online ] Chemical Abstracts Service , Columbus ,
`Ohio , US ; Jul . 4 , 2012 ( Jul . 4 , 2012 ) , XP002755501 , Database
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`( Continued )
`Primary Examiner — Paul V Ward
`( 74 ) Attorney , Agent , or Firm — Choate , Hall & Stewart
`LLP ; John P . Rearick ; Michael A . Shinall
`ABSTRACT
`( 57 )
`The present disclosure relates to inhibitors of USP7 inhibi
`tors useful in the treatment of cancers , neurodegenerative
`diseases , immunological disorders , inflammatory disorders ,
`cardiovascular diseases , ischemic diseases , viral infections
`and diseases , and bacterial infections and diseases , having
`the Formula :
`
`RA &
`
`( R3 )
`
`33VA
`
`R2
`
`O = x
`
`where R1 , R2 , R3 , R4 , R4 , X1 , Y1 , Y2 , Y3 , Y4 , n , and m are
`described herein .
`17 Claims , No Drawings
`
`Post-Grant Review Petition for US 9,840,491
`EXHIBIT 1008
`Page 1
`
`

`

`( 56 )
`
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`US 9 , 840 , 491 B2
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`CO7D 401 / 06
`
`CO7D 239 / 90
`514 / 217 . 06
`
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`Database Registry [ Online ] Chemical Abstracts Service , Columbus ,
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`physical interaction with USP7 , " Nat . Cell Biol . 13 ( 1 ) : 102 - 108
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`gates by the proteasome ” Annu . Rev . Biochem . 78 : 477 - 513 , ( 2009 ) .
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`mediated deubiquitination of the histone acetyltransferase TIP60 , "
`Nat . Commun . 4 : 2656 ( 2013 ) .
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`antigen - 1 reveals an interaction with the herpesvirus - associated
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`pathway for p53 stabilization , ” Nature 416 ( 6881 ) : 648 - 653 ( 2002 ) .
`Li , M . , et al . “ A dynamic role of HAUSP in the p53 - Mdm2
`pathway , ” Mol . Cell . 13 ( 6 ) : 879 - 886 ( 2004 ) .
`
`Post-Grant Review Petition for US 9,840,491
`EXHIBIT 1008
`Page 2
`
`

`

`US 9 , 840 , 491 B2
`Page 3
`
`( 56 )
`
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`Saridakis , V . , et al . " Structure of the p53 binding domain of
`HAUSP / USP7 bound to Epstein - Barr nuclear antigen 1 implica
`tions for EBV - mediated immortalization , ” Mol . Cell . 18 ( 1 ) : 25 - 36
`( 2005 ) .
`Sarkari , F . , et al . “ EBNA1 - mediated recruitment of a histone H2B
`deubiquitylating complex to the Epstein - Barr virus latent origin of
`DNA replication , ” PloS pathogens 5 ( 10 ) : e1000624 ( 2009 ) .
`Sheng , Y . , et al . “ Molecular recognition of p53 and MDM2 by
`USP7 / HAUSP , ” Nat . Struct . Mol . Biol . 13 ( 3 ) : 285 - 291 ( 2006 ) .
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`817 ( 2008 ) .
`Trotman , L . C . , et al . “ Ubiquitination regulates PTEN nuclear import
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`* cited by examiner
`
`Post-Grant Review Petition for US 9,840,491
`EXHIBIT 1008
`Page 3
`
`

`

`US 9 , 840 , 491 B2
`
`5
`
`QUINAZOLINONES AND
`lar diseases , ischemic diseases , viral infections and diseases ,
`AZAQUINAZOLINONES AS
`and bacterial infections and diseases .
`For example , USP7 has been shown to stabilize DNMT1 ,
`UBIQUITIN - SPECIFIC PROTEASE 7
`a DNA methyltransferase that maintain epigenetic silencing ,
`INHIBITORS
`to maintain higher steady state - levels of Claspin , a protein
`involved in ataxia telangiectasia and Rad3 - related ( ATR )
`RELATED APPLICATIONS
`phosphorylation of Chkl , and to regulate Tip60 protein
`levels ,
`a histone acetyltransferase and transcriptional
`This application claims the benefit of and priority to U . S .
`coregulator involved in adipogenesis . ( Zhanwen du , Song J . ,
`provisional application No . 62 / 112 , 487 , filed Feb . 5 , 2015 ,
`the entire contents of which are incorporated herein by 10 Wang Y . , et al . “ DNMT1 stability is regulated by proteins
`coordinating deubiquitination and acetylation - driven ubiq
`reference in its entirety .
`uitination , ” Science Signaling 3 ( 146 ) ( 2010 ) ; Faustrup H . ,
`Bekker - Jensen S . , Bartek J . , Lukas J . , Mail N . , Mailand N .
`FIELD OF DISCLOSURE
`“ USP7 counteracts SCFbetaTrCP - but not APCCdh1 - medi
`15 ated proteolysis of Claspin , ” The Journal of cell biology
`The present disclosure is directed to inhibitors of ubiq
`184 ( 1 ) : 13 - 9 ( 2009 ) ; Gao Y . , Koppen A . , Rakhsh M . , et al .
`uitin - specific protease 7 ( USP7 ) useful in the treatment of
`“ Early adipogenesis is regulated through USP7 - mediated
`diseases or disorders associated with USP7 enzymes . Spe
`deubiquitination of the histone acetyltransferase TIP60 , "
`Nature Communications 4 : 2656 ( 2013 )
`cifically , the disclosure is concerned with compounds and
`In addition to regulating the protein stability of poly
`compositions inhibiting USP7 , methods of treating diseases 20
`or disorders associated with USP7 , and methods of synthesis
`ubiquitinated targets , USP7 also acts to control the subcel
`of these compounds .
`lular localization of proteins . Mono - ubiquitination of PTEN
`has been shown to effect its cytoplasmic / nuclear partition
`BACKGROUND OF THE DISCLOSURE
`ing , where nuclear localization of PTEN is important for its
`25 tumor suppression activity . ( Trotman L . C . , Wang X . , Ali
`Ubiquitination is a post translational modification initially
`monti A . , et al . “ Ubiquitination regulates PTEN nuclear
`import and tumor suppression , ” Cell 128 ( 1 ) : 141 - 56 ( 2007 ) ;
`identified as a crucial component of proteasomal degrada -
`tion in the ubiquitin proteasome system ( UPS ) . Chains of
`Song M . S . , Salmena L . , Carracedo A . , et al . “ The deubiq
`Ubiquitin ( Ub ( s ) ) , an 8 . 5 kDa highly conserved protein , are
`uitinylation and localization of PTEN are regulated by a
`covalently attached to substrates to be degraded in the 30 HAUSP - PML network , ” Nature 455 ( 7214 ) : 813 - 7 ( 2008 )
`proteasome . ( Finley D . “ Recognition and processing of
`USP7 has also been shown to bind and deubiquitinate
`ubiquitin - protein conjugates by the proteasome . ” Annual
`FOX04 , a member of the FOXO subfamily of transcription
`review of biochemistry 78 : 477 - 513 , ( 2009 ) ) The molecular
`factors involved in a variety of cell processes including
`mechanisms by which the UPS acts are also varied , with
`metabolism , cell cycle regulation apoptosis , and response to
`different chain linkages of ubiquitination controlling protein 35 oxidative stress , decreasing its nuclear localization and
`turnover , enzymatic activity , subcellular localization , and
`transcriptional activity . ( van der Horst A . , van der Horst O . ,
`protein - protein interactions of substrate proteins . ( Ko -
`de Vries - Smits A . M . M . , et al . " FOX04 transcriptional
`mander D . , et . al . “ The emerging complexity of protein
`activity is regulated by monoubiquitination and USP7 /
`ubiquitination , " Biochem . Soc . Trans . 37 ( Pt 5 ) : 937 - 53
`HAUSP , " Nat . Cell Biol . 8 ( 10 ) : 1064 - 73 ( 2006 )
`Cellular targets of USP7 also include the tumor suppres
`40
`( 2009 ) )
`Ubiquitin - specific protease 7 ( USP7 ) is a Ubiquitin Spe -
`sor p53 and its major E3 ligase , MDM2 , stabilizing p53 via
`the degradation of MDM2 . ( Li M . , Chen D . , Shiloh A . , et al .
`cific Protease ( USP ) family deubiquitinase ( DUB ) that was
`originally identified as an enzyme that interacted with
`“ Deubiquitination of p53 by HAUSP is an important path
`virally - encoded proteins of the Herpes simplex virus and
`way for p53 stabilization , ” Nature 416 ( 6881 ) : 648 - 53
`later the Epstein - Barr virus . ( Everett R . D . , Meredith M . , Orr 45 ( 2002 ) ; Li M . , Brooks C . L . , Kon N . , Gu W . “ A dynamic role
`A . , Cross A , Kathoria M . , Parkinson J . “ A novel ubiquitin -
`of HAUSP in the p53 - Mdm2 pathway , ” Mol . Cell . 13 ( 6 ) :
`specific protease is dynamically associated with the PML
`879 - 86 ( 2004 ) ) Structural studies have also shown that the
`nuclear domain and binds to a herpes virus regulatory
`EBNA1 protein encoded by the Epstein - Barr virus interacts
`protein , ” EMBO J . 16 ( 7 ) : 1519 - 30 ( 1997 ) ; Holowaty M . N . ,
`at the same binding surface as USP7 on p53 , preventing
`Zeghouf M . , Wu H . , et al . “ Protein profiling with Epstein - 50 USP7 endogenous cellular activity while recruiting USP7 to
`Barr nuclear antigen - 1 reveals an interaction with the her -
`viral promoters in order to activate latent viral gene expres
`pesvirus - associated ubiquitin - specific protease HAUSP /
`sion . ( Saridakis V . , et al . “ Structure of the p53 binding
`USP7 , ” J . Biol . Chem . 278 ( 32 ) : 29987 - 94 ( 2003 ) ) Ubiquitin
`domain of HAUSP / USP7 bound to Epstein - Barr nuclear
`Specific Proteases ( USPs ) specifically cleave the isopeptide
`antigen 1 implications for EBV - mediated immortalization , ”
`bond at the carboxy terminus of ubiquitin . In contrast to 55 Mol . Cell . 18 ( 1 ) : 25 - 36 ( 2005 ) ; Sarkari F . , Sanchez - Alcaraz
`other DUB classes , which are thought to generally regulate
`T . , Wang S . , Holowaty M . N . , Sheng Y . , Frappier L .
`ubiquitin homeostasis or to be involved in pre - processing of
`“ EBNA1 - mediated recruitment of a histone H2B deubiqui
`linear ubiquitin chains , USPs remove ubiquitin from specific
`tylating complex to the Epstein - Barr virus latent origin of
`targets . Given this substrate specificity combined with the
`DNA replication , " PLoS pathogens 5 ( 10 ) ( 2009 ) ; Sheng Y . ,
`numerous roles ubiquitination has in the cell , USPs are 60 et al . “ Molecular recognition of p53 and MDM2 by USP7 /
`important regulators of a multitude of pathways , ranging
`HAUSP , ” Nat . Struct . Mol . Biol . 13 ( 3 ) : 285 - 91 ( 2006 ) ) Simi
`from preventing the proteolysis of ubquitinated substrates ,
`larly , the gene product of TSPYL5 , a gene frequently
`amplified in breast cancer and associated with poor clinical
`to controlling their nuclear localization .
`USP7 deubiquitinates a variety of cellular targets
`outcome , alters the ubiquitination status of p53 via its
`involved in different processes related to cancer and metas - 65 interaction with USP7 . ( Epping M . T . , et al . “ TSPYL5
`tasis , neurodegenerative diseases , immunological disorders ,
`suppresses p53 levels and function by physical interaction
`osteoporosis , arthritis inflammatory disorders , cardiovascu -
`with USP7 , ” Nat . Cell Biol . 13 ( 1 ) : 102 - 8 ( 2011 ) )
`
`Post-Grant Review Petition for US 9,840,491
`EXHIBIT 1008
`Page 4
`
`

`

`R4
`
`| RA
`Ri
`
`( R3 ) m
`
`R23
`
`US 9 , 840 , 491 B2
`
`5
`
`12
`13 = TA
`
`eroaryl , or - NH - heteroaryl , wherein the alkyl , aryl , het
`Inhibition of USP7 with small molecule inhibitors there -
`eroaryl , cycloalkyl , and heterocycloalkyl are optionally sub
`fore has the potential to be a treatment for cancers and other
`stituted with one or more R14 ;
`disorders . For this reason , there remains a considerable need
`wherein R5 , Ro , and R , are not all simultaneously H ;
`for novel and potent small molecule inhibitors of USP7 .
`each R , is independently D , ( C , - C ) alkyl , ( C , - Co )
`SUMMARY OF THE DISCLOSURE
`alkoxy , ( C , - C . ) haloalkyl , ( C . - C . ) haloalkoxy , halogen , CN ,
`( C , - C3 ) - alkylene - O
`( C . - C . ) alkyl ,
`( Co - C4 ) - alkylene
`aryl ,
`( Co - C4 ) - alkylene - heteroaryl , ( Cz - C10 ) cycloalkyl ,
`A first aspect of the disclosure relates to compounds of
`heterocycloalkyl ,
`( Co - C4 ) - alkylene - O - aryl ,
`( Co - C4 )
`Formula ( I ) :
`10 alkylene - O - heteroaryl ,
`0
`( C3 - C3 ) cycloalkyl ,
`S - het
`eroaryl ,
`C ( O ) R21 ,
`CO ( O ) R21
`C ( O ) NR21 R22 ,
`- S ( O ) , R21 , - S ( O ) , NR21 R22 , NR 21S ( O ) , R22 ,
`( Co
`C3 ) - alkylene - NR21 R22 , — NR21C ( O ) R22 , - NR2C ( O ) C ( O )
`15 R22 , NR2 , C ( O ) NR2 , R22 , P ( O ) ( CZ - C ) alkyl ) 2 , PO )
`( aryl ) 2 ,
`SiMez ,
`SFs , or OR21 , wherein the alkyl ,
`alkylene , aryl , heteroaryl , cycloalkyl , and heterocycloalkyl
`are optionally substituted with one or more Rg ; or
`two Rg together when on adjacent atoms form a ( C3 - C , )
`20 cycloalkyl optionally substituted with one or more Rg ; or
`two R , together when on adjacent atoms form a heterocy
`and pharmaceutically acceptable salts , hydrates , solvates ,
`cloalkyl ring optionally substituted with one or more Rg ; or
`prodrugs , stereoisomers , and tautomers thereof ,
`two Rg together when on adjacent atoms form an aryl ring
`wherein :
`optionally substituted with one or more Rg ; or two Rg
`X , is C , S , or S ( O ) ;
`25 together when on adjacent atoms form an heteroaryl ring
`Y , is N or CH ;
`optionally substituted with one or more Rg ;
`Y , is N or CRs ;
`each R , is independently ( CZ - C6 ) alkyl , ( C , - C . ) alkoxy ,
`Y , is N or CR ;
`( C . - C . ) haloalkyl , ( C , - C . ) haloalkoxy , halogen , ( C3 - C )
`YA is N or CR7 ;
`cycloalkyl , heterocycloalkyl ,
`( Co - C3 ) - alkylene - ( C6 - C14 )
`R
`is H , OH , — SH , NH , , or F ;
`30 aryl ,
`( Co - C3 ) - alkylene - heteroaryl , NH , OH ,
`C ( O )
`R2 is ( C1 - C6 ) alkyl , ( C6 - C14 ) aryl , heteroaryl , ( C3 - C3 )
`R23 ,
`- C ( O ) NR 23R 247
`- NR23C ( O ) R24 )
`- NR23R 249
`cycloalkyl , heterocycloalkyl ,
`— NR1R11 ,
`or
`— OR 10 ,
`S ( O ) , R23 ,
`- S ( O ) , NR23R24 - NR23S ( O ) , R24 , oxo ,
`wherein the alkyl , aryl , heteroaryl , cycloalkyl , and hetero
`— P ( O ) ( ( C / - Co ) alkyl ) 2 , — P ( O ) ( aryl ) 2 ,
`SiMez ,
`SF 5 ,
`cycloalkyl are optionally substituted with one or more Rg ;
`O - aryl , CN , or
`O - heteroaryl , wherein alkyl , aryl , het
`each Rz is independently at each occurrence selected from 35 35
`eroaryl , cycloalkyl , and heterocycloalkyl are optionally sub
`D , ( C1 - C6 ) alkyl , ( C6 - C14 ) aryl , heteroaryl , ( C2 - C3 )
`stituted with one or more R19 ;
`cycloalkyl , or heterocycloalkyl , wherein the alkyl , aryl .
`Rio and R11 are independently H , ( C . - C . ) alkyl , ( C6 - C14 )
`heteroaryl , cycloalkyl , and heterocycloalkyl are optionally
`aryl , heteroaryl , ( C5 - C3 ) cycloalkyl , or heterocycloalkyl ,
`substituted with one or more R20 ; or
`two R , together when on adjacent carbons form a ( Cz - C ) 40 wherein the alkyl , aryl , heteroaryl , cycloalkyl , and hetero
`cycloalkyl optionally substituted with one or more Ryo ; or
`cycloalkyl are optionally substituted with one or more Riz ;
`two R , together when attached to the same carbon atom form
`or
`a ( C3 - Cg ) spirocycloalkyl optionally substituted with one or
`Rio and R11 together with the nitrogen to which they are
`more R20 ; or two Rz together when attached to the same
`attached form a heterocycloalkyl ring optionally substituted
`carbon atom form a spiroheterocycloalkyl optionally sub - 45 with one or more R17 ;
`stituted with one or more R20 ; or two Rz together when on
`each R 2 is independently ( C , Co ) alkyl , ( C , - C . ) alkoxy ,
`adjacent carbons form an aryl ring optionally substituted
`( C . - C . ) haloalkyl , ( C , - Co ) haloalkoxy , halogen , CN ,
`with one or more R20 ; or two Rz together when on adjacent
`C ( O ) ( C , - C6 ) alkyl ,
`S ( O ) , ( C , - C . ) alkyl , - NH2 , ( C1
`carbons form an heteroaryl ring optionally substituted with
`Co ) alkylamino , or di ( C , - C ) alkylamino ;
`50
`each R13 is independently D , ( C , - C . ) alkyl , ( C , - C )
`one or more R20 ;
`R4 and R4 , are independently H , D , ( C , - C . ) alkyl , ( C2 - C6 )
`alkoxy , ( C , - C . ) haloalkyl , ( C . - C . ) haloalkoxy , halogen , CN ,
`alkenyl , ( C2 - C . ) alkynyl , ( C , - C . ) alkoxy , ( C , - C . ) haloalkyl ,
`OH , - NH2 ,
`C ( O ) ( CZ - C ) alkyl , - S ( O ) , ( C , - C . ) alkyl ,
`( C2 - C6 ) haloalkoxy , halogen , or CN ;
`( C7 - C ) alkylamino , di ( C2 - Co ) alkylamino , ( Co - C14 ) aryl ,
`R , is H , ( C2 - C6 ) alkyl , ( C2 - C . ) alkenyl , ( C2 - C . ) alkynyl ,
`heteroaryl , ( C3 - C ) cycloalkyl , heterocycloalkyl ,
`O - aryl ,
`( C - C . ) haloalkyl , halogen , NO2 , or CN , wherein the alkyl , 55
`O - heteroaryl ,
`O - heterocycloalkyl ,
`- 0
`( C3 - C ) cy
`alkenyl , and alkynyl are optionally substituted with one or
`cloalkyl ,
`- C ( O ) O ( C , - C6 )
`alkyl ,
`- C ( O ) NR26R27 ,
`- S ( O ) , NR26R27
`NR26R27
`NR 26C ( O ) NR26R27 ,
`more R12 ;
`Ro is H , D , ( C , - C . ) alkyl , ( C2 - C . ) alkenyl , ( C2 - C6 )
`- NR26C ( O ) OR279
`NR26S ( O ) , R27 ,
`NR26C ( O ) R279
`alkynyl , ( C Co ) alkoxy ,
`halogen , — P ( O ) ( ( C - C6 ) alkyl ) 2 , — P ( O ) ( aryl ) 2 ,
`SiMe3 ,
`( C , - C6 ) haloalkyl , ( C , - C )
`haloalkoxy , halogen , CN , NO2 , - NH2 , — NHC ( O ) ( C , - C . ) 60 or — SF5 , wherein in the alkyl , aryl , heteroaryl , cycloalkyl ,
`alkyl , ( C6 - C14 ) aryl , heteroaryl , ( Cz - C3 ) cycloalkyl , or het -
`and heterocycloalkyl are optionally substituted with one or
`erocycloalkyl , wherein the alkyl , aryl , heteroaryl ,
`more Ris ;
`cycloalkyl , and heterocycloalkyl are optionally substituted
`each R14 is independently D , ( C , - C . ) alkyl , ( C , - C6 )
`alkoxy , ( C , - C . ) haloalkyl , ( C , - C . ) haloalkoxy , halogen , CN ,
`with one or more R13 ;
`R , is H , ( C , - C . ) alkyl , ( C . - C14 ) aryl , heteroaryl , ( C3 - C3 ) 65 OH , - NH2 ,
`C ( O ) ( C . - C . ) alkyl , - S ( O ) , ( C , - C6 ) alkyl ,
`cycloalkyl , heterocycloalkyl ,
`( C . - C . ) alkylamino , di ( C1 - C6 ) alkylamino , ( Co - C14 ) aryl ,
`O - aryl ,
`O - heteroaryl ,
`- N ( ( C / - C . ) alkyl ) - aryl , NH - aryl , - N ( ( C - C . ) alkyl ) - het -
`heteroaryl , ( Cz - Cg ) cycloalkyl , heterocycloalkyl ,
`O - aryl ,
`
`Post-Grant Review Petition for US 9,840,491
`EXHIBIT 1008
`Page 5
`
`

`

`US 9 , 840 , 491 B2
`5
`C ( O ) ( C , - C ) alkyl , - S ( O ) , ( C , - C . )
`O - ( Cz - C3 ) cy -
`haloalkoxy , halogen ,
`- O - heteroaryl ,
`O - heterocycloalkyl ,
`- C ( O ) NR26R27
`cloalkyl ,
`- C ( O ) O ( CZ - C )
`alkyl ,
`alkyl , - NH2 , ( C , - Co ) alkylamino , di ( C1 - Co ) alkylamino ,
`- S ( O ) , NR25R27 ,
`NR26R27 ,
`NR26C ( O ) NR25R27 ,
`OH , or CN ;
`- NR26C ( O ) OR27 ,
`- NR26S ( O ) , R27
`- NR26C ( O ) R27 ,
`mis 0 , 1 , 2 , 3 , or 4 ;
`halogen , — P ( O ) ( ( C . - C . ) alkyl ) 2 , — P ( O ) ( aryl ) ,
`SiMez , 5
`n is 0 , 1 , 2 , or 3 ;
`or SF5 , wherein in the alkyl , aryl , heteroaryl , cycloalkyl ,
`q is independently at each occurrence 0 , 1 , or 2 ; and
`provided that when R , is optionally substituted alkyl , R ,
`and heterocycloalkyl are optionally substituted with one or
`is H , and R , is H , R , is not chloro .
`more R 16 ,
`Another aspect of the present disclosure relates to a
`each Ris is independently ( C - C6 ) alkyl , ( C1 - C6 ) alkoxy , 10 method of treating a disease or disorder associated with
`( C , - C6 ) haloalkyl , ( C , - C . ) haloalkoxy , halogen , - C ( O )
`modulation of USP7 . The method comprises administering
`( C , - C ) alkyl , - S ( O ) , ( C , - C6 ) alkyl , - NH2 , ( C - C . ) alky
`to a patient in need of a treatment for diseases or disorders
`lamino , di ( C . - C . ) alkylamino , OH , or CN ;
`associated with modulation of USP7 an effective amount of
`each R16 is independently ( C1 - C6 ) alkyl , ( C1 - C7 ) alkoxy ,
`a compound of Formula ( I ) , or a pharmaceutically accept
`( C - C ) haloalkyl , ( C . - C . ) haloalkoxy , halogen ,
`C ( O )
`b
`) 15 able salt , hydrate , solvate , prodrug , stereoisomer , or tau
`( C , - C6 ) alkyl , - S ( O ) , ( C , - C . ) alkyl , - NH2 , ( C , - C . ) alky
`to
`lamino , di ( C - C . ) alkylamino , ( Co - C14 ) aryl , heteroaryl ,
`Another aspect of the present disclosure is directed to a
`( Cz - C3 ) cycloalkyl , heterocycloalkyl ,
`O - aryl ,
`O - het
`method of inhibiting USP7 . The method involves adminis
`eroaryl ,
`O - heterocycloalkyl ,
`0
`( C3 - Cg ) cycloalkyl ,
`tering to a patient in need thereof an effective amount of a
`- OH , or CN , wherein in the alkyl , aryl , heteroaryl , 20 compound of Formula ( I ) , or a pharmaceutically acceptable
`cycloalkyl , and heterocycloalkyl are optionally substituted
`salt , hydrate , solvate , prodrug , stereoisomer , or tautomer
`with one or more R28 ;
`thereof .
`each R17 is independently ( CZ - C ) alkyl , ( C , - C6 ) alkoxy ,
`Another aspect of the present disclosure relates to a
`( C . - C . ) haloalkyl , ( C , - C . ) haloalkoxy , halogen , ( C , Co )
`method of treating cancer . The method comprises adminis
`hydroxyalkyl , — OH , CN ,
`C ( O ) ( C , - C . ) alkyl , - S ( O ) , 25 tering to a patient in need thereof an effective amount of a
`( C - C6 ) alkyl , - NH2 , ( C - C ) alkylamino , di ( C1 - C6 ) alky
`compound of Formula ( 1 ) , or a pharmaceutically acceptable
`lamino , ( Co - C14 ) aryl , heteroaryl , ( C3 - C3 ) cycloalkyl , or
`salt , hydrate , solvate , prodrug , stereoisomer , or tautomer
`heterocycloalkyl , wherein in the alkyl , aryl , heteroaryl ,
`thereof .
`cycloalkyl , and heterocycloalkyl are optionally substituted
`Another aspect of the present disclosure relates to a
`30 method of treating a neurodegenerative disease . The method
`with one or more Ris ;
`each R18 is independently ( C , - C ) alkyl , ( C1 - C6 ) alkoxy ,
`comprises administering to a patient in need thereof an
`( C . - C . ) haloalkyl , ( C1 - C6 ) haloalkoxy , halogen ,
`effective amount of a compound of Formula ( I ) , or a
`C ( O )
`( C - C ) alkyl , - S ( O ) , ( C , - C . ) alkyl , - NH2 , ( C , - C . ) alky -
`pharmaceutically acceptable salt , hydrate , solvate