US 9 , 840 , 491 B2
`
`67
`EQUIVALENTS
`Those skilled in the art will recognize , or be able to
`ascertain , using no more than routine experimentation ,
`numerous equivalents to the specific embodiments described 5
`specifically herein . Such equivalents are intended to be
`encompassed in the scope of the following claims .
`The invention claimed is :
`1 . A compound of Formula ( I ) :
`
`10 10
`
`68
`Ro is H , D , ( C , - C . ) alkyl , ( C2 - C6 ) alkenyl , ( C2 - C6 )
`alkynyl , ( C , - C . ) alkoxy , ( C , - C ) haloalkyl , ( C , - C )
`haloalkoxy , halogen , CN , NO2 , - NH2 , — NHC ( O )
`( C . - C . ) alkyl , ( Co - C14 ) aryl , 5 - or 6 - membered het
`eroaryl comprising 1 to 3 heteroatoms selected from 0 ,
`N , and S , ( C3 - Cg ) cycloalkyl , or 3 - to 7 - membered
`heterocycloalkyl comprising 1 to
`3 heteroatoms
`selected from
`O , N , and S , wherein the alkyl , aryl ,
`heteroaryl , cycloalkyl , and heterocycloalkyl are option
`ally substituted with one to three R13 ;
`R7 is H , ( C1 - C6 ) alkyl , ( C6 - C14 ) aryl , 5 - or 6 - membered
`heteroaryl comprising 1 to 3 heteroatoms selected from
`O , N , and S , ( C5 - C3 ) cycloalkyl , 3 - to 7 - membered
`heterocycloalkyl comprising 1 to
`3 heteroatoms
`selected from O , N , and S ,
`O
`( C6 - C14 ) aryl ,
`0 - 5
`or 6 - membered heteroaryl comprising 1 to 3 heteroa
`toms selected from O , N , and S , - N ( ( C , - C . ) alkyl )
`( Co - C14 ) aryl ,
`— NH — ( C6 - C14 ) aryl ,
`— N ( ( C / - C )
`alkyl ) - 5 - or 6 - membered heteroaryl comprising 1 to 3
`heteroatoms selected from O , N , and S , or - NH - 5 - or
`6 - membered heteroaryl comprising 1 to 3 heteroatoms
`selected from O , N , and S , wherein the alkyl , aryl ,
`heteroaryl , cycloalkyl , and heterocycloalkyl are option
`ally substituted with one to three R14 ;
`wherein R5 , R . , and R , are not all simultaneously H ;
`each Rg is independently D , ( C , - C . ) alkyl , ( C , - C )
`alkoxy , ( C , - C . ) haloalkyl , ( C , - C . ) haloalkoxy , halo
`gen , CN ,
`( C , - CZ ) - alkylene - 0 - C , - C . )
`alkyl ,
`- ( Co - C4 ) - alkylene - ( C6 - C14 ) aryl ,
`( Co - C4 ) - alky
`lene - 5 - or 6 - membered heteroaryl comprising 1 to 3
`heteroatoms selected from
`O , N , and S , ( C3 - C10 )
`cycloalkyl , 3 - to 7 - membered heterocycloalkyl com
`prising 1 to 3 heteroatoms selected from O , N , and S ,
`( Co - C4 ) - alkylene - 0 — ( C6 - C14 )
`aryl ,
`( Co - C4 )
`alkylene - O - 5 - or 6 - membered heteroaryl comprising 1
`to 3 heteroatoms selected from O , N , and S , - O
`( C3 - C3 ) cycloalkyl ,
`S - 5 - or 6 - membered heteroaryl
`comprising 1 to 3 heteroatoms selected from O , N , and
`S ,
`CO ) R21 ,
`CO ( O ) R21 ,
`2C ( O ) NR2 R22 ,
`S ( O ) , R21 ,
`- S ( O ) , NR21 R22 ,
`- NR21S ( O ) , R22 ,
`- ( Co - C3 ) - alkylene - NR2 R22 ,
`— NR21C ( O ) R22 ,
`- NR2 . C ( O ) C ( O ) R22 , NR2C ( O ) NR2 , R22 , — P ( O )
`( ( C / - C . ) alkyl ) 2 , — P ( O ) ( ( C6 - C14 ) aryl ) 2 ,
`SiMe3 ,
`SF5 , orOR21 , wherein the alkyl , alkylene , aryl ,
`heteroaryl , cycloalkyl , and heterocycloalkyl are option
`ally substituted with one to three Rg ; or
`two R , together when on adjacent atoms form a ( C3 - C2 )
`cycloalkyl optionally substituted with one to three Rg ;
`or two R , together when on adjacent atoms form a 3
`to 7 - membered heterocycloalkyl ring comprising 1 to 3
`heteroatoms selected from O , N , and S , optionally
`substituted with one to three Rg ; or two R , together
`when on adjacent atoms form a
`( Co - C14 ) aryl ring
`optionally substituted with one to three Ro ; or two Re
`together when on adjacent atoms form a 5 - or 6 - mem
`bered heteroaryl ring comprising 1 to 3 heteroatoms
`selected from O , N , and S optionally substituted with
`one to three Rg ;
`each R , is independently ( C . - C . ) alkyl , ( C . - C . ) alkoxy ,
`( C . - C . ) haloalkyl , ( C , - C ) haloalkoxy , halogen , ( C3
`C ) cycloalkyl , 3 - to 7 - membered heterocycloalkyl
`comprising 1 to 3 heteroatoms selected from O , N , and
`S ,
`( Co - C3 ) - alkylene - ( Co - C14 ) aryl ,
`( Co - C3 ) - alky
`lene - 5 - or 6 - membered heteroaryl comprising 1 to 3
`heteroatoms selected from O , N , and S , - NH2 , OH ,
`C ( O ) R23 ,
`- C ( O ) NR 23R 24 ,
`- NR23C ( O ) R 249
`NR23R24 ,
`S ( O ) , R23 ,
`S ( O ) , NR23R24 , NR23S
`
`O . RX R4
`I Ri
`
`( R3 ) m
`
`VA
`
`BER
`
`( 1 )
`
`15 15
`
`20 20
`
`25
`
`30
`
`or a pharmaceutically acceptable salt , stereoisomer , and
`tautomer thereof ,
`wherein :
`X , is C , S , or S ( O ) ;
`Y
`is N or CH ;
`Y , is N or CR5 ;
`Y , is N or CR ;
`YA is N or CR7 ;
`R , is H , OH , — SH , NH , , or F ;
`R2 is ( C1 - C6 ) alkyl , ( Co - C14 ) aryl , 5 - or 6 - membered
`heteroaryl comprising 1 to 3 heteroatoms selected from
`O , N , and S , ( C3 - C ) cycloalkyl , 3 - to 7 - membered
`heterocycloalkyl comprising 1
`to
`3 heteroatoms
`selected from O , N , and S , or — NR1R11 , wherein the 35
`alkyl , aryl , heteroaryl , cycloalkyl , and heterocycloalkyl
`are optionally substituted with one to three Rg ;
`each Rz is independently at each occurrence selected from
`D , ( C - C ) alkyl , ( C6 - C14 ) aryl , 5 . or 6 - membered
`heteroaryl comprising 1 to 3 heteroatoms selected from 40
`O , N , and S , ( C3 - C3 ) cycloalkyl , or 3 - to 7 - membered
`heterocycloalkyl comprising 1 to
`3 heteroatoms
`selected from
`O , N , and S , wherein the alkyl , aryl ,
`heteroaryl , cycloalkyl , and heterocycloalkyl are option
`ally substituted with one to three R20 ; or
`two R , together when on adjacent carbons form a ( Cz - C )
`cycloalkyl optionally substituted with one to three R2o ;
`or two R , together when attached to the same carbon
`atom form a ( Cz - C ) spirocycloalkyl optionally substi
`tuted with one to three Ro ; or two R , together when 50
`attached to the same carbon atom form a 3 - to 7 - mem
`bered spiroheterocycloalkyl comprising 1 to 3 heteroa
`toms selected from O , N , and S , optionally substituted
`with one to three R20 ; or two Rz together when on
`adjacent carbons form a ( Co - C14 ) aryl ring optionally 55
`substituted with one to three Rjo ; or two R , together
`when on adjacent carbons form a 5 - or 6 - membered
`heteroaryl ring comprising 1 to 3 heteroatoms selected
`from O , N , and S optionally substituted with one to
`three R2 ;
`R4 and R4 , are independently H , D , ( C , - C . ) alkyl , ( C2 - C )
`alkenyl , ( C2 - C6 ) alkynyl , ( C - C . ) alkoxy , ( C . - C . )
`haloalkyl , ( C , - CZ ) haloalkoxy , halogen , or CN ;
`R , is H , ( C , - C . ) alkyl , ( C2 - C6 ) alkenyl , ( C2 - C . ) alkynyl ,
`( C . - C . ) haloalkyl , halogen , NO2 , or CN , wherein the 65
`alkyl , alkenyl , and alkynyl are optionally substituted
`with one to three R12 ;
`
`45
`
`Post-Grant Review Petition for US 9,840,491
`EXHIBIT 1028
`Page 1
`
`

`

`US 9 , 840 , 491 B2
`70
`69
`( 0 ) , R24 , oxo ,
`P ( O ) ( C , - Co ) alkyl ) 2 , — P ( O ) ( C6
`each R16 is independently ( C . - C . ) alkyl , ( C , - C . ) alkoxy ,
`C14 ) aryl ) 2 , - SiMez , SF5 , - O - ( Co - C14 ) aryl , CN ,
`( C , - C ) haloalkyl , ( C , - C ) haloalkoxy , halogen ,
`or - 0 - 5 - or 6 - membered heteroaryl comprising 1 to 3
`C ( O ) ( C , - C . ) alkyl , - S ( O ) , ( C , - C . ) alkyl , — NH2 ,
`heteroatoms selected from O , N , and S , wherein alkyl ,
`( C - C . ) alkylamino , di ( C1 - C . ) alkylamino , ( C6 - C14 )
`aryl , heteroaryl , cycloalkyl , and heterocycloalkyl are 5
`aryl , 5 - or 6 - membered heteroaryl comprising 1 to 3
`optionally substituted with one to three R19 ;
`heteroatoms selected from
`O , N , and S , ( C2 - C3 )
`Rio and Ru1 are independently H , ( C , - C ) alkyl , ( Co - C14 )
`cycloalkyl , 3 - to 7 - membered heterocycloalkyl com
`aryl , 5 - or 6 - membered heteroaryl comprising 1 to 3
`prising 1 to 3 heteroatoms selected from O , N , and S ,
`0
`( C6 - C14 ) aryl , - 0 - 5 - or 6 - membered heteroaryl
`heteroatoms selected from
`O , N , and S , ( C . - C . )
`cycloalkyl , or 3 - to 7 - membered heterocycloalkyl com - 10
`comprising 1 to 3 heteroatoms selected from O , N , and
`S ,
`0 - 3 - to 7 - membered heterocycloalkyl comprising
`prising 1 to 3 heteroatoms selected from O , N , and S ,
`wherein the alkyl , aryl , heteroaryl , cycloalkyl , and
`1 to 3 heteroatoms selected from O , N , and S , - 0 %
`heterocycloalkyl are optionally substituted with one to
`( Cz - C3 ) cycloalkyl , OH , or CN , wherein in the alkyl ,
`aryl , heteroaryl , cycloalkyl , and heterocycloalkyl are
`three Riz ; or
`R10 and Ru together with the nitrogen to which they are 15
`optionally substituted with one to three R28 ;
`each R17 is independently ( C2 - C6 ) alkyl , ( C1 - C6 ) alkoxy ,
`attached form
`a 3 - to 7 - membered heterocycloalkyl
`ring comprising 1 to 3 heteroatoms selected from O , N ,
`( C , - C . ) haloalkyl , ( C , - C . ) haloalkoxy , halogen , ( C1
`Co ) hydroxyalkyl , OH , CN , - C ( O ) ( C2 - C6 ) alkyl ,
`and S , optionally substituted with one to three R17 ;
`each R12 is independently ( C , - Co ) alkyl , ( C , - C . ) alkoxy ,
`- S ( O ) , ( C - Co ) alkyl , — NH2 , ( C , - C . ) alkylamino ,
`( C - C ) haloalkyl , ( C , - C . ) haloalkoxy , halogen , CN , 20
`di ( C . - C . ) alkylamino , ( C6 - C14 ) aryl , 5 - or 6 - membered
`- C ( O ) ( C , - C ) alkyl , - S ( O ) , ( C , - Co ) alkyl , — NH2 ,
`heteroaryl comprising 1 to 3 heteroatoms selected from
`( C , - C6 ) alkylamino , or di ( C . - C . ) alkylamino ;
`O , N , and S , ( C5 - C ) cycloalkyl , or 3 - to 7 - membered
`each R13 is independently D , ( C , - C6 ) alkyl , ( C , - C6 )
`heterocycloalkyl comprising 1 to
`3 heteroatoms
`alkoxy , ( C , - Co ) haloalkyl , ( C , - Co ) haloalkoxy , halo
`selected from O , N , and S , wherein in the alkyl , aryl ,
`gen , CN ,
`OH ,
`- NH2 ,
`C ( O ) ( C / - C ) alkyl , 25
`heteroaryl , cycloalkyl , and heterocycloalkyl are option
`- S ( O ) , ( C1 - C . ) alkyl , ( C , - C . ) alkylamino , di ( C , - C . )
`ally substituted with one to three Ris ;
`alkylamino , ( C . - C14 ) aryl , 5 . or 6 - membered het
`each R18 is independently ( CZ - C6 ) alkyl , ( C , - C . ) alkoxy ,
`eroaryl comprising 1 to 3 heteroatoms selected from 0 ,
`( C2 - C ) haloalkyl ,
`( C , - C ) haloalkoxy , halogen ,
`N , and S , ( C3 - C2 ) cycloalkyl , 3 - to 7 - membered het
`- C ( O ) ( C1 - C6 ) alkyl , - S ( O ) , ( C , - Co ) alkyl , - NH2 ,
`erocycloalkyl comprising 1 to 3 heteroatoms selected 30
`( C1 - Co ) alkylamino , di ( C - C . ) alkylamino , OH , or
`from O , N , and S ,
`0
`C - C14 ) aryl ,
`0 - 5 - or
`CN ;
`6 - membered heteroaryl comprising 1 to 3 heteroatoms
`each R19 is independently at each occurrence ( C7 - C )
`selected from
`O , N , and S , — O - 3 - to 7 - membered
`alkyl , ( C , - C6 ) alkoxy , ( C . - C . ) haloalkyl , ( C , - C )
`heterocycloalkyl comprising 1 to
`3 heteroatoms
`haloalkoxy , halogen ,
`NR26C ( O ) R27 ,
`NR 26
`selected from O , N , and S ,
`O — ( Cz - C3 ) cycloalkyl , 35
`S ( O ) , R27 ;
`C ( O ) R26 - C ( O ) NR2R27 , — NR26R27 ,
`C ( O ) O ( C , - C )
`alkyl ,
`- C ( O ) NR26R27 ,
`- S ( O ) , R26
`S ( O ) , NR26R277
`— P ( O ) ( C1 - C6 )
`- S ( O ) , NR26R27 , — NR26R27 , — NR26C ( O ) NR26R27 ,
`alkyl ) 2 , — P ( O ) ( C6 - C14 ) aryl ) ,
`SiMe3 ,
`SF5 ,
`OH , or CN ;
`- NR26C ( O ) OR27 ,
`NR26S ( O ) , R279 - NR26C ( O )
`R27 , halogen , — P ( O ) ( ( C1 - C ) alkyl ) 2 , — P ( O ) ( ( Co
`each R20 is independently at each occurrence ( C2 - C6 )
`C14 ) aryl ) , ,
`SiMez , or
`SF5 , wherein in the alkyl , 40
`alkyl , ( C , - Co ) alkoxy , ( C , - C . ) haloalkyl , ( C , - C . )
`aryl , heteroaryl , cycloalkyl , and heterocycloalkyl are
`haloalkoxy , halogen , OH , - NH2 , or CN ;
`each R21 and R22 is independently H , ( C , - C ) alkyl ,
`optionally substituted with one to three R15 ;
`each R14 is independently D , ( C , - C . ) alkyl , ( C . - C . )
`( C2 - C . ) alkenyl , ( C2 - C . ) alkynyl , ( Co - C14 ) aryl , 5 - or
`alkoxy , ( C . - C . ) haloalkyl , ( C , - C ) haloalkoxy , halo
`6 - membered heteroaryl comprising 1 to 3 heteroatoms
`gen , CN ,
`OH ,
`- NH2 ,
`C ( O ) ( C / - C ) alkyl , 45
`selected from O , N , and S , ( C3 - C3 ) cycloalkyl , or 3 - to
`- S ( O ) , ( C , - C . ) alkyl , ( C , - C6 ) alkylamino , di ( C1 - C )
`7 - membered heterocycloalkyl comprising 1 to 3 het
`alkylamino , ( Co - C14 ) aryl , 5 . or 6 - membered het
`eroatoms selected from O , N , and S , wherein the alkyl ,
`eroaryl comprising 1 to 3 heteroatoms selected from 0 ,
`aryl , heteroaryl , cycloalkyl and heterocycloalkyl are
`N , and S , ( C2 - C3 ) cycloalkyl , 3 - to 7 - membered het
`optionally substituted with one to three Ros ;
`erocycloalkyl comprising 1 to 3 heteroatoms selected 50
`each R23 and R24 is independently H , ( C . - C . ) alkyl ,
`from O , N , and S ,
`O - ( C8 - C14 ) aryl ,
`O - 5 - or
`( C2 - C . ) alkenyl , ( C2 - C . ) alkynyl , ( C6 - C14 ) aryl , 5 - or
`6 - membered heteroaryl comprising 1 to 3 heteroatoms
`6 - membered heteroaryl comprising 1 to 3 heteroatoms
`selected from O , N , and S , - 0 - 3 - to 7 - membered
`selected from O , N , and S , ( C5 - C3 ) cycloalkyl , or 3 - to
`heterocycloalkyl comprising 1
`to
`3 heteroatoms
`7 - membered heterocycloalkyl comprising 1 to 3 het
`selected from O , N , and S ,
`0
`( C3 - C3 ) cycloalkyl , 55
`eroatoms selected from O , N , and S , wherein the alkyl ,
`C ( O ) O ( C1 - C6 )
`alkyl ,
`- C ( O ) NR26R27 ,
`aryl , heteroaryl , cycloalkyl and heterocycloalkyl are
`- S ( O ) , NR26R27 , - NR26R27 , - NR26C ( O ) NR26R27
`optionally substituted with one to three Ros ;
`- NR26C ( O ) OR27 ,
`NR2S ( O ) , R27 ,
`NR26C ( 0 )
`each R25 is independently at each occurrence ( C1 - C6 )
`alkyl , ( C , - Co ) alkoxy , ( C1 - C . ) haloalkyl , ( C , - C . )
`R27 , halogen , — P ( O ) ( C - C . ) alkyl ) 2 , — P ( O ) ( ( C
`C14 ) aryl ) 2 ,
`SiMez , or SF5 , wherein in the alkyl , 60
`haloalkoxy , halogen , OH , or CN ;
`aryl , heteroaryl , cycloalkyl , and heterocycloalkyl are
`each R26 and R27 is independently at each occurrence H ,
`( C . - C . ) alkyl , ( C2 - C . ) alkenyl , ( C2 - C . ) alkynyl , ( C6
`optionally substituted with one to three Ris ;
`each R15 is independently ( C , - C6 ) alkyl , ( C . - C . ) alkoxy ,
`C14 ) aryl , 5 - or 6 - membered heteroaryl comprising 1 to
`3 heteroatoms selected from O , N , and S , ( C5 - C3 )
`( C , - C ) haloalkyl ,
`( C - C ) haloalkoxy , halogen ,
`- C ( O ) ( C - Co ) alkyl , - S ( O ) , ( C , - C . ) alkyl , - NH2 , 65
`cycloalkyl , or 3 - to 7 - membered heterocycloalkyl com
`( C . - C . ) alkylamino , di ( C , - C . ) alkylamino , OH , or
`prising 1 to 3 heteroatoms selected from O , N , and S ,
`wherein the alkyl , alkenyl , alkynyl , aryl , heteroaryl ,
`CN ;
`
`Post-Grant Review Petition for US 9,840,491
`EXHIBIT 1028
`Page 2
`
`

`

`US 9 , 840 , 491 B2
`
`10
`
`cycloalkyl and heterocycloalkyl are optionally substi
`tuted with one to three substituents independently
`selected from ( C , - C ) alkyl , ( C , - C . ) alkoxy , ( C - C )
`haloalkyl , ( C , - C . ) haloalkoxy , - NH2 , ( C , - C . ) alky
`lamino , or di ( C , - C . ) alkylamino ;
`each R28 is independently at each occurrence ( C . - C . )
`alkyl , ( C , - C6 ) alkoxy , ( C , - C ) haloalkyl , ( C , - C . )
`haloalkoxy , halogen , - C ( O ) ( C1 - C6 ) alkyl ,
`S ( O ) ,
`( C , - C . ) alkyl , - NH2 , ( C , - C . ) alkylamino , di ( C - C . )
`alkylamino , OH , or CN ;
`m is 0 , 1 , 2 , 3 , or 4 ;
`n is 0 , 1 , 2 , or 3 ;
`q is independently at each occurrence 0 , 1 , or 2 ; and
`provided that when R2 is optionally substituted alkyl , Rs 16
`is H , and R , is H , then Ro is not chloro .
`2 . The compound of claim 1 , wherein X? is C .
`3 . The compound of claim
`1 , wherein R , is OH .
`4 . The compound of claim 1 , wherein R , is ( C1 - C6 ) alkyl
`or ( Co - C14 ) aryl , wherein the alkyl and aryl are optionally 20
`substituted with one to three Rg .
`5 . The compound of claim 1 , wherein R4 is H .
`6 . The compound of claim 1 , wherein R4 is H .
`7 . The compound of claim 1 , wherein is Y , is N or CR ,
`and R , is H .
`8 . The compound of claim 1 , wherein Yz is N or CR , and
`Ro is H , ( C , - C . ) alkyl , ( C , - C . ) alkoxy , - NH2 , - NHC ( O )
`( CZ - C6 ) alkyl , or ( Co - C14 ) aryl , wherein the alkyl , and aryl
`are optionally substituted with one to three R13 .
`9 . The compound of claim 1 , wherein Y4 is N or CR , and
`R , is H , ( CZ - C . ) alkyl , ( C6 - C14 ) aryl , or - O
`( Co - C14 ) aryl ,
`wherein the alkyl and aryl are optionally substituted with
`one to three R14
`10 . The compound of claim
`1 , wherein n is 1 .
`11 . The compound of claim
`1 , having Formula ( la ) ,
`Formula ( lb ) , or Formula ( Ic ) :
`
`30
`
`35
`
`wherein :
`X , is C , S , or S ( O ) ;
`R2 is ( C1 - C6 ) alkyl , ( C6 - C14 ) aryl , 5 . or 6 - membered
`heteroaryl comprising 1 to 3 heteroatoms selected from
`O , N , and S , ( C3 - C3 ) cycloalkyl , 3 - to 7 - membered
`heterocycloalkyl comprising 1 to
`3 heteroatoms
`selected from O , N , and S , or - NR R11 , wherein the
`alkyl , aryl , heteroaryl , cycloalkyl , and heterocycloalkyl
`are optionally substituted with one to three Rei
`each Rz is independently at each occurrence selected from
`D , ( C , - C . ) alkyl , ( Co - C14 ) aryl , 5 - or 6 - membered
`heteroaryl comprising 1 to 3 heteroatoms selected from
`O , N , and S , ( Cz - C3 ) cycloalkyl , or 3 - to 7 - membered
`heterocycloalkyl comprising 1 to
`3 heteroatoms
`selected from
`O , N , and S , wherein the alkyl , aryl ,
`heteroaryl , cycloalkyl , and heterocycloalkyl are option
`ally substituted with one to three R20 ; or
`two R , together when on adjacent carbons form a ( C2 - C . )
`cycloalkyl optionally substituted with one to three R20 ;
`or two Rz together when attached to the same carbon
`atom form a ( Cz - C . ) spirocycloalkyl optionally substi
`tuted with one to three R20 ; or two Rz together when
`attached to the same carbon atom form a 3 - to 7 - mem
`bered spiroheterocycloalkyl comprising 1 to 3 heteroa
`toms selected from O , N , and S optionally substituted
`with one to three Rzo ; or two Rz together when on
`adjacent carbons form a ( C6 - C14 ) aryl ring optionally
`substituted with one to three R20 ; or two Rz together
`when on adjacent carbons form
`a 5 - or 6 - membered
`heteroaryl ring comprising 1 to 3 heteroatoms selected
`from O , N , and S optionally substituted with one to
`three R2o ;
`R? is H , ( C . - C . ) alkyl , ( C2 - Co ) alkenyl , ( C2 - Co ) alkynyl ,
`( C - C . ) haloalkyl , halogen , NO2 , or CN , wherein the
`alkyl , alkenyl , and alkynyl are optionally substituted
`with one to three R12 ;
`Ro is H , D , ( C , - C6 ) alkyl , ( C2 - Cd ) alkenyl , ( C2 - Co )
`alkynyl , ( C , - C ) alkoxy , ( C - C ) haloalkyl , ( C , - C . )
`haloalkoxy , halogen , CN , NO2 , - NH2 , — NHC ( O )
`( CZ - C6 ) alkyl , ( Co - C14 ) aryl , 5 - or 6 - membered het
`eroaryl comprising 1 to 3 heteroatoms selected from 0 ,
`N , and S , ( C3 - Cg ) cycloalkyl , or 3 - to 7 - membered
`heterocycloalkyl comprising 1
`to
`3 heteroatoms
`selected from
`O , N , and S , wherein the alkyl , aryl ,
`heteroaryl , cycloalkyl , and heterocycloalkyl are option
`ally substituted with one to three R13 ;
`R , is H , ( C , Co ) alkyl , ( C6 - C14 ) aryl , 5 - or 6 - membered
`heteroaryl comprising 1 to 3 heteroatoms selected from
`O , N , and S , ( C3 - C3 ) cycloalkyl , 3 - to 7 - membered
`heterocycloalkyl comprising 1 to
`3 heteroatoms
`selected from O , N , and S ,
`O
`( C6 - C14 ) aryl ,
`0 - 5
`or 6 - membered heteroaryl comprising 1 to 3 heteroa
`toms selected from O , N , and S , — N ( ( C / - C . ) alkyl )
`( CG - C14 ) aryl , — NH — ( CG - C14 ) aryl ,
`— N ( ( C / - C )
`alkyl ) - 5 - or 6 - membered heteroaryl comprising 1 to 3
`heteroatoms selected from O , N , and S , or - NH - 5 - or
`6 - membered heteroaryl comprising 1 to 3 heteroatoms
`selected from
`O , N , and S , wherein the alkyl , aryl ,
`heteroaryl , cycloalkyl , and heterocycloalkyl are option
`ally substituted with one to three R14 ;
`wherein Rs , R , and R , are not all simultaneously H ;
`each Rg is independently D , ( C , - C . ) alkyl , ( CZ - C )
`alkoxy , ( C , - C . ) haloalkyl , ( C , - C . ) haloalkoxy , halo
`gen , CN ,
`( C , - C3 ) - alkylene - O
`( C , - Co ) alkyl ,
`- ( Co - C4 ) - alkylene - ( C6 - C14 ) aryl ,
`( Co - C4 ) - alky
`lene - 5 - or 6 - membered heteroaryl comprising 1 to 3
`heteroatoms selected from
`O , N , and S , ( C3 - C10 )
`
`( Ia ) 40
`
`45 45
`
`50
`
`( Ib )
`
`55
`
`( Ic )
`
`60
`
`65
`
`R7
`
`or a pharmaceutically acceptable salt , stereoisomer , and
`tautomer thereof ,
`
`RS
`
`R6
`
`R5
`
`RS Ro
`
`Ro
`
`OH
`
`( R3 ) m
`
`OH
`
`( R3
`
`N
`
`R2 ,
`
`or
`
`??
`
`( R3 ) m
`
`R2
`
`N sont R2 ,
`och
`
`Post-Grant Review Petition for US 9,840,491
`EXHIBIT 1028
`Page 3
`
`