Attorney Docket No.: 055112-5002-PR-02
`
`each R2 is independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,
`arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl,
`
`sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, or carbonate;
`
`)-, -C(=O)-N(R9)-(CHR9
`Y is -N(R9)-C(=O)-, -C(=O)-N(R9
`-S(=O)rN(R9
`)-, -N(R9)-C(=O)-N(R9
`) or -N(R9)S(=O)r;
`
`)-, -N(R9)-S(=O)-, -S(=O)-N(R9
`
`)-,
`
`z is an integer of 1, 2, 3, or 4;
`
`R 3 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, fluoroalkyl, heteroalkyl, alkoxy, amido,
`
`amino, acyl, acyloxy, sulfinyl, sulfonyl, sulfoxide, sulfone, sulfonamido, halo, cyano, aryl,
`
`heteroaryl, hydroxyl, or nitro;
`
`each R 5 is independently alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxy, amido, amino,
`
`acyl, acyloxy, sulfonamido, halo, cyano, hydroxyl, or nitro;
`
`each R 9 is independently hydrogen, alkyl, cycloalkyl, heterocyclyl, or heteroalkyl; or two
`adjacent occurrences of R9 together with the atoms to which they are attached form a 4- to 7-
`
`membered ring;
`
`W d is heterocyclyl, aryl, cycloalkyl, or heteroaryl, each of which is substituted with one or more
`d
`
`,
`,
`
`
`R IO Rll Rl2 Rl3 or , an
`
`RIO, R 11
`
`, R 12 and R 13 are each independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl,
`
`cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocyclyloxy,
`
`amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxyl, nitro,
`
`phosphate, urea, carbonate or NR'R" wherein R' and R" are taken together with nitrogen to form
`
`a cyclic moiety.
`
`14. The method of paragraph 14, wherein the PBK inhibitor is:
`
`DBl/ 80293456.1
`
`125
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`Ex. 1004, p. 483 of 1432
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`

`

`Attorney Docket No.: 055112-5002-PR-02
`
`or its pharmaceutically acceptable salt thereof, wherein
`
`Bis:
`
`wherein We is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and
`
`q is an integer of 0, 1, 2, 3, or 4;
`
`Xis a bond or -(CH(R9)}c, and z is an integer of 1;
`
`Wd is:
`
`DBI/ 80293456.1
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`126
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`Ex. 1004, p. 484 of 1432
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`

`

`Attorney Docket No.: 055112-5002-PR-02
`
`l~
`Xi
`,✓-:;:.
`'x,
`
`i Rbr"1R"
`~~X,y---Ru
`
`R'l
`
`DBI/ 80293456.1
`
`127
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`Attorney Docket No.: 055112-5002-PR-02
`
`0
`
`.
`
`R_ll
`
`t X5
`
`0
`
`x~
`
`Rw~N#
`
`N >-R·ll,
`
`N
`H
`
`NXR.ll;
`X-: R1~
`
`DBI/ 80293456.1
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`128
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`Ex. 1004, p. 486 of 1432
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`

`

`Attorney Docket No.: 055112-5002-PR-02
`
`X 1, X 2 and X 3 are each independently C, CR13 or N; and X 4, X 5 and Xe, are each independently
`N, NH, CR13
`, Sor O;
`
`R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amido, alkoxycarbonyl, sulfonamido, halo,
`cyano, or nitro;
`
`R 2 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl,
`alkoxy, amino, halo, cyano, hydroxy or nitro; R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
`
`heterocycloalkyl, alkoxy, amido, amino, alkoxycarbonyl sulfonamido, halo, cyano, hydroxy or
`
`nitro; and
`
`each instance of R9 is independently hydrogen, alkyl, or heterocycloalkyl.
`
`15. The method of paragraph 14, wherein the PBK inhibitor is
`
`Formula (Ill)
`
`NH
`
`or a pharmaceutically acceptable salt thereof.
`
`16. The method of paragraph 14, wherein the PBK inhibitor is
`
`DBl/ 80293456.l
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`129
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`Attorney Docket No.: 055112-5002-PR-02
`
`Formula (IV)
`
`or a pharmaceutically acceptable salt thereof.
`
`17. The method of paragraph 1, wherein the BTK inhibitor is:
`
`or a pharmaceutically acceptable salt thereof, wherein
`
`Xis CH, N, 0 or S;
`
`Y is C(R6), N, 0 or S;
`
`DBI/ 80293456.1
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`130
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`Ex. 1004, p. 488 of 1432
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`

`

`Attorney Docket No.: 055112-5002-PR-02
`
`Z is CH, N or bond;
`
`A is CH orN;
`
`B4 is Nor C(R10);
`
`R1 is R11C(O), R12S(O), RuSO2 or (1-6C)alkyl optionally substituted with R14;
`
`R2 is H, (1-3C)alkyl or (3-7C)cycloalkyl;
`
`R 3 is H, (1-6C)alkyl or (3-7C)cycloalkyl); or
`
`R 2 and R3 form, together with the N and C atom they are attached to, a (3- 7C)heterocycloalkyl
`optionally substituted v.rith one or more fluorine, hydroxyl, (l-3C)alkyl, (l-3C)alkoxy or oxo;
`
`~ is Hor (1-3C)alkyl;
`
`R 5 is H, halogen, cyano, (1-4C)alkyl, (1-3C)alkoxy, (3-6C)cycloalkyl, any alkyl group of which
`is optionally substituted with one or more halogen; or R 5 is ( 6-1 0C)aryl or (2-
`
`6C)heterocycloalkyl;
`
`~ is Hor (1-3C)alkyl; or
`
`Rs and R6 together may form a (3-7C)cycloalkenyl, or (2-6C)heterocycloalkenyl; each optionally
`
`substituted with (1-3C)alkyl, or one or more halogen;
`
`R7 is H, halogen, CF3 , (1-3C)alky1 or (1-3C)alkoxy;
`
`Rs is H, halogen, CF3 , (1-3C)alkyl or (1-3C)alkoxy; or
`
`R7 and Rs together with the carbon atoms they are attached to, form (6-lOC)aryl or (1-
`
`9C)heteroaryl;
`
`DB1/ S0293456.l
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`131
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`Attorney Docket No.: 055112-5002-PR-02
`
`R 9 is H, halogen, (1-3C)alkyl or (1-3C)alkoxy;
`
`R 10 is H, halogen, (1-3C)alkyl or (1-3C)alkoxy;
`
`R 11 is independently selected from a group consisting of (1-6C)alkyl, (2-6C)alkenyl and (2-
`
`6C)alkynyl each alkyl, alkenyl or alkynyl optionally substituted with one or more groups
`
`selected from hydroxyl, (l-4C)alkyl, (3-7C)cycloalkyl, [(1-4C)alkyl]amino, di[(l-
`
`4C)alkyl]amino, (1-3C)alkoxy, (3-7C)cycloalkoxy, (6-IOC)aryl or (3-7C)heterocycloalkyl; or
`
`R 11 is (1-3C)alkyl-C(0)-S-(l-3C)alkyl; or
`
`R 11 is (1-5C)hcteroaryl optionally substituted with one or more groups selected from halogen or
`
`cyano;
`
`R 12 and R 13 are independently selected from a group consisting of (2-6C)alkenyl or (2-
`6C)alkynyl both optionally substituted with one or more groups selected from hydroxyl, (1-
`
`4C)alkyl, (3-7C)cycloalkyl, [(1-4C)alkyl]amino, di[(l-4C)alkyl]amino, (1-3C)alkoxy, (3-
`
`7C)cycloalkoxy, (6-l0C)aryl or (3-7C)heterocycloalkyl; or
`
`(1-5C)heteroaryl optionally substituted with one or more groups selected from halogen or cyano;
`
`and
`
`Rl 4 is independently selected from a group consisting of halogen, cyano or (2-6C)alkenyl or (2-
`
`6C)alkynyl both optionally substituted with one or more groups selected from hydroxyl, (1-
`
`4C)alkyl, (3-7C)cycloalkyl, (1-4C)alkylamino, di[(l-4C)alkyl]amino, (1-3C)alkoxy, (3-
`
`7C)cycloalkoxy, ( 6-1 0C)aryl, ( l-5C)heteroaryl or (3-7C)heterocycloalkyl.
`
`18. The method of paragraph 1, wherein the BTK inhibitor is:
`
`DBI/ 80293456.1
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`

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`
`~Ar
`a
`
`or a pharmaceutically acceptable salt thereof, wherein
`
`La is CH2, 0, NH or S;
`
`Ar is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;
`
`Y is an optionally substituted group selected from the group consisting of alkyl, heteroalkyl,
`
`cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
`
`Z is C(=O), OC(=O), NRC(=O), C(=S), S(=O)x, OS(=O)x, NRS(=O)x, where xis 1 or 2;
`
`R7 and R 8 are each H; or R7 and R 8 taken together form a bond;
`
`~ is H; and
`
`19. The method of paragraph 1, wherein the BTK inhibitor is:
`
`DBI/ 80293456.1
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`133
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`Ex. 1004, p. 491 of 1432
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`

`Attorney Docket No.: 055112-5002-PR-02
`
`~Ar
`a
`
`or a pharmaceutically acceptable salt thereof, wherein
`
`La is CH2, 0, NH or S;
`
`Ar is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;
`
`Y is an optionally substituted group selected from the group consisting of alkyl, heteroalkyl,
`
`cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
`
`Z is C(=O), OC(=O), NRC(=O), C(=S), S(=O)x, OS(=O)x, NRS(=O)x, where xis 1 or 2;
`
`R7 and R 8 are each H; or R7 and R 8 taken together form a bond;
`
`~ is H; and
`
`20. The method of paragraph 1, wherein the BTK inhibitor is:
`
`DBI/ 80293456.1
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`134
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`Ex. 1004, p. 492 of 1432
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`

`Attorney Docket No.: 055112-5002-PR-02
`
`~Ar
`a
`
`or a pharmaceutically acceptable salt thereof, wherein
`
`La is CH2, 0, NH or S;
`
`Ar is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;
`
`Y is an optionally substituted group selected from the group consisting of alkyl, heteroalkyl,
`
`cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
`
`Z is C(=O), OC(=O), NRC(=O), C(=S), S(=O)x, OS(=O)x, NRS(=O)x, where xis 1 or 2;
`
`R7 and R 8 are each H; or R7 and R 8 taken together form a bond;
`
`~ is H; and
`
`21. The method of paragraph 1, wherein the BTK inhibitor is:
`
`DBI/ 80293456.1
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`135
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`Ex. 1004, p. 493 of 1432
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`

`

`Attorney Docket No.: 055112-5002-PR-02
`
`~Ar
`a
`
`or a pharmaceutically acceptable salt thereof, wherein
`
`La is CH2, 0, NH or S;
`
`Ar is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;
`
`Y is an optionally substituted group selected from the group consisting of alkyl, heteroalkyl,
`
`cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
`
`Z is C(=O), OC(=O), NRC(=O), C(=S), S(=O)x, OS(=O)x, NRS(=O)x, where xis 1 or 2;
`
`R7 and R 8 are each H; or R7 and R 8 taken together form a bond;
`
`~ is H; and
`
`22. The method of paragraph 1, wherein the BTK inhibitor is:
`
`DBI/ 80293456.1
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`Ex. 1004, p. 494 of 1432
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`Attorney Docket No.: 055112-5002-PR-02
`
`or a pharmaceutically acceptable salt thereof,
`
`wherein:
`
`Q 1 is aryl 1, heteroaryl 1, cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl, any of
`which is optionally substituted by one to five independent G 1 substituents;
`
`R 1 is alkyl, cycloalkyl, bicycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, or
`heterobicycloalkyl, any of which is optionally substituted by one or more independent G 11
`
`substituents;
`
`G 1 and G41 are each independently halo, oxo, -CF3, -OCF3, -OR2, -NR2R3(R3a)j 1, -C(O)R2,
`-CO2R2, -CONR2R3, -NO2, -CN, -S(O)j1R2, -SO2NR2R3, NR2(C=O)R3
`, NR2(C=O)OR3
`NR2(C=O)NR2R3, NR2S(O)j1R3, -(C=S)OR2, -(C=O)SR2, -NR2(C=NR3)NR2aR3\
`-NR2(C=NR3)OR2\ -NR2(C=NR3)SR3
`\ -O(C=O)OR2, -O(C=O)NR2R3, -O(C=O)SR2,
`-S(C=O)OR2, -S(C=O)NR2R3, C0 _10alkyl, Cz-10alkenyl, Cz-10alkynyl, Ci-i0alkoxyC 1- 10alkyl, C 1-
`10alkoxyC2-10alkenyl, C1-10alkoxyC2-10alkynyl, C 1-10alkylthioC1 -10alkyl, C1-10alkylthi0Cz-
`
`,
`
`10alkenyl, C 1- 10alkylthioC2-10alkynyl, cycloC3- 8alkyl, cycloC3- 8alkenyl, cycloC 3- 8alkylC 1- 10alkyl,
`eye loC 3-3alkenyl C 1-10alkyl, cycloC 3-salkyl Cz-1 oalkenyl, cycloC 3-salkenyl C2-1 oalkenyl, cycloC 3-
`
`galky l C2-1 oalkyny l, cycloC3-galkenylC2-1oalkynyl, heterocyclyl-Co-1oalkyl, heterocyclyl-Cz-
`
`10alkenyl, or heterocyclyl-C2-10alkynyl, any of which is optionally substituted with one or more
`· d
`d
`h l
`C
`OC
`O 222
`222 333( 333 )
`C(O) 222 CO
`222
`, -NR R R
`a jla, - . R
`,
`1n epen ent a o, oxo, - F3, -
`F3, - R
`, - . 2R
`-CONR222R333' -NO2, -CN, -S(O)j1aR222, -SO2NR222R333' NR222(C=O)R333' NR222(C=O)OR333'
`
`NR222(C=O)NR222R333, NR222S(O)j1aR333, -(C=S)OR222, -(C=O)SR222,
`
`-NR222(C=NR333)NR222aR333a, -NR222(C=NR333)OR222a, -NR222(C=NR333)SR333a, -O(C=O)OR222,
`-O(C=O)NR222R333, -O(C=O)SR222, -S(C=O)OR222, or -S(C=O)NR222R333 substituents; or -(X1)n-
`(Y1)m-R4; or aryl-C0_10alkyl, aryl-Cz- 10alkenyl, or aryl-Cri 0alkynyl, any of which is optionally
`substituted with one or more independent halo, -CF3, -OCF3 , -OR222, -NR222R333(R333a)j2a,
`-C(O)R222, -CO2R222, -CONR222R333, -NO2, -CN, -S(O)j2aR222, -SO2NR222R333, NR222(C=O)R333,
`
`NR222(C=O)OR333' NR222(C=O)NR222R333' NR z22S(O)j2aR333, -(C=S)OR 222' -(C=O )SR222'
`
`-NR222(C=NR333)NR222aR333a, -NR222(C=NR333)OR222a, -NR222(C=NR333)SR333a, -O(C=O)OR222,
`-O(C=O)NR222R333, -O(C=O)SR222, -S(C=O)OR222, or -S(C=O)NR222R 333 substituents; or
`hetaryl-C0 _10alkyl, hetaryl-C2-10alkenyl, or hetaryl-Cz-10alkynyl, any of which is optionally
`
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`

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`
`substituted with one or more independent halo, -CF3, -OCF3, -OR222, -NR222, R 333(R333a)j3a,
`-C(O)R222, -CO2R222, -CONR222R333' -NO2, -CN, -S(O)j3aR222, -SO2NR222R333, NR222(C=O)R333,
`
`NR222(C=O)OR333, NR222(C=O)NR222R333, NR222S(O)j3aR333, -(C=S)OR222, -(C=O)SR222,
`
`-NR222(C=NR333)NR222aRu3a, -NR222(C=NR333)OR222a, -NR222(C=NR333)SR333a,
`-O(C=O)OR222, -O(C=O)NR222R333, -O(C=O)SR222, -S(C=O)OR222, or -S(C=O)NR222R333
`substituents;
`
`a
`
`a
`
`1,
`
`a
`
`G 11 is halo, oxo, -CF3, -OCF3, -OR21 , -NR21R31(R3a1)j4, -C(O)R21 , -CO2R21 , -CONR21R 31, -NO2,
`-CN, -S(O)j4R21 , -S02NR21R31 , NR21(C=O)R31 , NR21 (C=O)OR31, NR21 (C=O)NR21R31 ,
`1R3
`NR21 S(O)j4R31 , -(C=S)OR21 , -(C=O)SR21 , -NR21 (C=NR31)NR2
`1, -NR21 (C=NR31)0R2
`-NR21 (C=NR31 )SR3
`1, -O(C=O)OR21 , -O(C=O)NR21R31 , -O(C=O)SR21 , -S(C=O)OR21 ,
`-S(C=O)NR21R31 , -P(O)OR21 0R31 , Co-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10alkoxyC1-10alkyl,
`C1-10alkoxyC2-1oalkenyl, C1-10alkoxyCr10alkynyl, C1-10alkylthioC1-1oalkyl, C1-10alkylthioC2-
`
`a
`
`1oalkenyl, C1-1oalkylthioC2-10alkynyl, cycloC3-galkyl, cycloC3-galkenyl, cycloC3-galkylC1-10alkyl,
`
`cycloC 3-galkenyl C 1 -1 oalkyl, cycloC3-galkyl Cr 1 oalkenyl, cycloC3-galkenyl Cr 1 oalkenyl, cycloC 3-
`
`galky l Cr 10alkynyl, cycloC3-salkcnylCr 10alkynyl, hctcrocyclyl-Co-10alkyl, hctcrocyclyl-Cr
`
`10alkenyl, or heterocyclyl-C2-10alkynyl, any of which is optionally substituted with one or more
`independent halo, oxo, -CF3, -OCF 3, -OR2221 , -NR2221R 3331(R333a1)j4a, -C(O)R2221 , -CO2R 2221 ,
`-CONR2221R3331, -NO2, -CN, -S(O)j4aR2221, -SO2NR2221R3331, NR2221(C=O)R3331,
`NR2221(C=O)OR3_131, NR2221(C=O)NR2221R3331, NR2221S(O)j4aR3331, -(C=S)OR2221, -(C=O)SR2221,
`-NR222l(C=NR333l)NR222alR333al, -NR222l(C=NR333l)OR222al, -NR222l(C=NR333l)SR333al,
`-O(C=O)OR2221, -O(C=O)NR2221R 3331, -O(C=O)SR2221 , -S(C=O)OR2221 , -P(O)OR2221 OR3331 , or
`-S(C=O)NR2221R3331 substituents; or aryl-C0-10alkyl, aryl-C2-10alkenyl, or aryl-C2-10alkynyl, any
`of which is optionally substituted with one or more independent halo, -CF3, -OCF3, -OR2221 ,
`-NR2221R3331(R333a1)jsa, -C(O)R2221, -CO2R2221, -CONR2221R3331, -NO2, -CN, -S(O)jsaR2221,
`-SO2NR2221R3331, NR2221(C=O)R3331, NR2221(C=O)OR3331, NR2221(C=O)NR2221R3331,
`NR2221S(O)jsaR3331, -(C=S)OR2221, -(C=O)SR2221, -NR2221(C=NR3331)NR222a1R333a1,
`
`-NR222l(C=NR333l)OR222al, -NR222l(C=NR333l)SR333al, -O(C=O)OR2221' -O(C=O)NR2221R3331'
`-O(C=O)SR2221 , -S(C=O)OR2221 , -P(O)OR2221R3331 , or -S(C=O)NR2221R3331 substituents; or
`hetaryl-Co-10alkyl, hetaryl-Cr10alkenyl, or hetaryl-Cr10alkynyl, any of which is optionally
`substituted with one or more independent halo, -CF3, -OCF3, -OR2221 , -NR2221 R3331(R333a1\ 6a,
`-C(O)R2221, -CO2R2221, -CONR2221R3331, -NO2, -CN, -S(O)j6aR2221, -SO2NR2221R3331,
`
`DBI/ 80293456.1
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`138
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`

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`
`NR2221(C=O)R3331, NR2221(C=O)OR3m, NR2221(C=O)NR2221R3331, NR2221S(O)j 6aR3331,
`-(C=S)OR2221, -(C=O)SR2221, -NR222l(C=NR333l)NR222alR333al, -NR2221(C=NR333l)OR222al,
`
`-NR2221(C=NR3331)SR333a1, -O(C=O)OR2221, -O(C=O)NR2221R3331, -O(C=O)SR2221,
`-S(C=O)OR2221 , -P(O)OR2221 ORB31 , or -S(C=O)NR2221 R3331 substituents; or G 11 is taken
`together with the carbon to which it is attached to form a double bond which is substituted with
`R 5 and G111 · ,
`
`each independently equal to Co-10alkyl, C2-10alkenyl, C2-1oalkynyl, C1-10alkoxyC1-10alkyl, C1-
`
`10alkoxyC2-10alkenyl, C 1-10alkoxyC2-10alkynyl, C1 -10alkylthioC1 -10alkyl, C1 -10alkylthi0Cr
`
`10alkcnyl, Cn 0alkylthioCr 10alkynyl, cycl0Cn1alkyl, cycloC3-8alkcnyl, cycloC .nalkylC1 - 10alkyl,
`cycloC3-salkenylC1-10alkyl, cycloC3-salkylC2-10alkenyl, cycloC3-salkenylC2-10alkenyl, cycloC3-
`
`salkylC2-1oalkynyl, cycloC3-salkenylC2-1oalkynyl, heterocyclyl-Co-1oalkyl, heterocyclyl-C2-
`
`10alkenyl, or heterocyclyl-C2-10alkynyl, any of which is optionally substituted by one or more
`G 111 substituents; or aryl-C0-10alkyl, aryl-Cr10alkenyl, or aryl-Cr 10alkynyl, hetaryl-C0-10alkyl,
`hetaryl-Cr10alkenyl, or hetaryl-Cr 10alkynyl, any of which is optionally substituted by one or
`more G 111 substituents; or in the case of -NR2R3(R3a)j 1 or -NR222R333(R333a)j1a or
`-NR222R333(R333a)j2 a or -NR2221R333l(R333al)j3a or -NR2221R3331(R333al)j 4a or -NR2221R333I(R333al)jsa
`or -NR2221R3331(R333a1)j6a, R2 and R3 or R222 and R3333 or R 2221 and R3331 taken together with the
`nitrogen atom to which they are attached form a 3-10 membered saturated ring, unsaturated ring,
`
`heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring is optionally
`
`substituted by one or more Gm substituents;
`
`X 1 and Y 1 are each independently-O-, -NR7
`)-, -N(C(O)R7
`-, -N(C(O)OR7
`-, -S(O)j7-, -CR5R6
`)-, -CH(NR7
`-N(SO2R 7
`)-, -CH2O-, -CH2S-, -CH2N(R7
`)-, -CH2N(C(O)R7
`)-, -CH2N(C(O)OR7
`)-, -CH(NHC(O)OR7
`-CH2N(SO2R 7
`)-, -CH(NHR7
`)-, -CH(NHC(O)R7
`)-, -CH(NHSO2R 7
`-CH(OC(O)R7
`)-, -CH(OC(O)NHR7
`)-, -CH=CH-, -C.ident.C-, -C(=NOR7
`)-, -C(O)-, -CH(OR7
`)-, -N(R7)C(O)-, -N(R7)S(O)-, -N(R7)S(O)2- -OC(O)N(R7
`)-, -N(R7)C(O)N(R7
`-C(O)N(R7
`)-,
`-NR7C(O)O-, -S(O)N(R7
`)-, -N(C(O)R7)S(O)-, -N(C(O)R7)S(O)r,
`)-, -S(O)2N(R7
`-N(R7)S(O)N(R7
`)-, -N(R7)S(O)2N(R7
`)-, -C(O)N(R7)C(O)-, -S(O)N(R7)C(O)-, -S(O)2N(R7)C(O)-,
`-OS(O)N(R7
`)-, -OS(O)2N(R7
`)-, -N(R7)S(O)O-, -N(R7)S(O)2O-, -N(R7)S(O)C(O)-,
`-N(R7)S(O)2C(O)-, -SON(C(O)R7
`)-, -N(R7)SON(R7
`)-, -SO2N(C(O)R7
`)-, -N(R7)SO2N(R7
`
`DBI/ 80293456.1
`
`139
`
`)-,
`
`)-,
`
`)-,
`
`)-,
`
`)-,
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`
`

`

`Attorney Docket No.: 055112-5002-PR-02
`
`)-,
`
`)-,
`
`)-,
`
`)-, -N(R7)P(O)(OR8)O-, -N(R7)P(O)(OR8
`-C(O)O-, -N(R7)P(OR8)O-, -N(R7)P(OR8
`)-,
`-N(C(O)R7)P(OR8)O-, -N(C(O)R7)P(OR8
`)-, -N(C(O)R7)P(O)(OR8)O-, -N(C(O)R7)P(OR8
`)-,
`)-, -CH(R7)N(C(O)R7
`-CH(R7)S(O)-, -CH(R7)S(O)2-, -CH(R7)N(C(O)OR7
`)-, -CH(R7)N(SO2R 7
`-CH(R7)O-, -CH(R7)S-, -CH(R7)N(R7
`)-, -CH(R7)N(C(O)R7
`)-, -CH(R7)N(C(O)OR7
`)-, -CH(R7)C(=NOR7
`-CH(R7)N(SO2R 7
`)-, -CH(R7)C(O)-, -CH(R7)CH(OR7
`)-,
`-CH(R7)C(O)N(R7
`)-, -CH(R7)N(R7)C(O)-, -CH(R7)N(R7)S(O)-, -CH(R7)N(R7)S(O)r,
`-CH(R7)OC(O)N(R7
`)-, -CH(R7)N(R7)C(O)N(R7
`)-, -CH(R7)NR7C(O)O-, -CH(R7)S(O)N(R7
`)-, -CH(R7)N(C(O)R7)S(O)-, -CH(R7)N(C(O)R7)S(O)-,
`-CH(R7)S(O)2N(R7
`-CH(R7)N(R7)S(O)N(R7
`)-, -CH(R7)N(R7)S(O)2N(R7
`)-, -CH(R7)C(O)N(R7)C(O)-,
`-CH(R 7)S(O)N(R 7)C(O)-, -CH(R 7)S(O)2N(R 7)C(O)-, -CH(R 7)OS(O)N(R 7
`)-,
`-CH(R7)OS(O)zN(R7
`)-, -CH(R7)N(R7)S(O)O-, -CH(R7)N(R7)S(O)2O-, -CH(R7)N(R7)S(O)C(O)-,
`-CH(R7)N(R7)S(O)2C(O)-, -CH(R7)SON(C(O)R7
`)-, -CH(R7)SO 2N(C(O)R7
`)-,
`)-, -CH(R7)N(R7)SO2N(R7
`-CH(R7)N(R7)SON(R7
`)-, -CH(R7)C(O)O-, -CH(R7)N(R7)P(OR8)O-,
`)-, -CH(R7)N(R7)P(O)(OR8)O-, -CH(R7)N(R7)P(O)(OR8
`-CH(R7)N(R7)P(OR8
`)-,
`-CH(R7)N(C(O)R7)P(OR 8)O-, -CH(R 7)N(C(O)R7)P(OR8
`)-, -CH(R7)N(C(O)R7)P(O)(OR8)O-, or
`-CH(R7)N(C(O)R7)P(OR8
`
`)-; or
`
`X 1 and Y 1 are each independently represented by one of the following structural formulas:
`
`\_,,-
`
`----
`
`O-R10
`I
`0,1
`P-N
`o
`,,,,,
`
`II x,,-
`
`,
`
`O-R10
`I
`\
`I
`\ P-N
`,,,
`,,
`
`\ 0
`'
`
`x ii x--
`
`,-
`
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`
`

`

`Attorney Docket No.: 055112-5002-PR-02
`
`R 10, taken together with the phosphinamide or phosphonamide, is a 5-, 6-, or 7-membered aryl,
`heteroaryl or heterocyclyl ring system;
`
`Rs, R6
`
`, and G 111 are each independently a C0 - 10alkyl, C2-1oalkenyl, C2-10alkynyl, C 1-10alkoxyC 1-
`10alkyl, C1-10alkoxyC2-10alkenyl, C1-10alkoxyC2-10alkynyl, C1-1oalkylthioC1-10alkyl, C1-
`
`10alkylthi0Cr10alkenyl, C1-10alkylthi0Cr10alkynyl, cycloC3-salkyl, cycloC3-salkenyl, cycloC3-
`
`salkylC,-,oalkyl. cycloC_nalkenylC1-1oalkyl, cycloCrsalkylCr1oalkenyl, cycloC3-salkenylCr
`
`1oalkenyl, cycloC3-salkylCz-10alkynyl, cycloC3-salkenylCz-10alkynyl, heterocyclyl-Co-10alkyl,
`
`,
`
`,
`
`heterocyclyl-C2-10alkenyl, or heterocyclyl-C2-10alkynyl, any of which is optionally substituted
`, -NR77R87, -C(O)R77, -CO2R 77
`with one or more independent halo, -CF3, -OCF3, -OR77
`-CONR77R87, -NO2, -CN, -S(O)jsaR77, -SO2NR77R87, NR77(C=O)R87, NR77(C=O)OR87,
`NR77(C=O)NR78R87, NR77S(O)jsaR87, -(C=S)OR77
`, -(C=O)SR77, -NR71(C=NR87)NR78R88,
`, -O(C=O)OR77
`-NR77(C=NR87)OR78
`, -NR77(C=NR87)SR78
`, -O(C=O)NR77R87
`, -O(C=O)SR77
`87
`77 87
`.
`r'
`,.,,.,
`-S(C=O)OR ', -P(O)OR' 'OR , or -S(C=O)NR R
`substituents; or aryl-C0- 10alkyl, aryl-C2-
`10alkenyl, or aryl-Cr10alkynyl, any of which is optionally substituted with one or more
`, -NR77R87, -C(O)R77, -CO2R 77, -CONR77R87, -NO2, -CN,
`independent halo, -CF3, -OCF3, -OR77
`, -SO2NR77R87, NR77(C=O)R87, NR77(C=O)OR87, NR77(C=O)NR78R87,
`-S(O)jsaR77
`NR77 S(O)jsaR87, -(C=S)OR77
`, -NR 77 (C=NR 87)NR78R 88, -NR77 (C=NR 87)OR78,
`, -(C=O)SR77
`-NR7'(C=NR87)SR78
`, -O(C=O)OR77, -O(C=O)NR77R87, -O(C=O)SR77, -S(C=O)OR77,
`-P(O)OR77R87, or -S(C=O)NR77R87 substituents; or hetaryl-Co-10alkyl, hetaryl-Cz-10alkenyl, or
`hetaryl-Cr10alkynyl, any of which is optionally substituted with one or more independent halo,
`77
`s1 C(O) 77 CO n CO
`77 87
`0
`C
`S(o·
`C Oc F3, - R O n
`n
`
`
`, -NR R
`, -
`R
`, -
`2R
`, - NR R
`, -N 2, - N, -
`)jsaR
`- F3, -
`-SO2NR77R87, NR77(C=O)R87, NR77(C=O)OR87, NR77(C=O)NR78R 87, NR77S(O)jsaR87,
`, -NR77(C=NR87)NR78R88, -NR77(C=NR87)OR78, -NR77(C=NR87)SR78,
`-(C=S)OR77
`, -(C=O)SR77
`-O(C=O)OR77, -O(C=O)NR77R87, -O(C=O)SR77
`, -S(C=O)OR77, -P(O)OR77OR87, or
`-S(C=O)NR77R87 substituents; or Rs with R6 taken together with the respective carbon atom to
`which they are attached, form a 3-10 membered saturated or unsaturated ring, wherein said ring
`is optionally substituted with R69; or R 5 with R 6 taken together with the respective carbon atom
`to which they are attached, form a 3-10 membered saturated or unsaturated heterocyclic ring,
`wherein said ring is optionally substituted with R 69;
`
`,
`
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`
`

`

`Attorney Docket No.: 055112-5002-PR-02
`
`R7 and R8 are each independently H, acyl, alkyl, alkenyl, aryl, heteroaryl, heterocyclyl or
`cycloalkyl, any of which is optionally substituted by one or more 0 111 substituents;
`
`R4 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl. cycloalkenyl, or
`heterocycloalkenyl, any of which is optionally substituted by one or more 0 41 substituents;
`
`R69 is equal to halo, -OR78, -SH, -NR78R88, -CO2R78, -CONR78R88, -NO2, -CN, -S(O)j8R78,
`-SO2NR78R88, C 0- 10alkyl, Cr10alkenyl, Cr10alkynyl, Ci-i 0alkoxyCi-i 0alkyl, Ci-i 0alkoxyCr
`1 oalkenyl, C 1-1 oalkoxyCr10alkynyl, C 1-10alkylthioC1 -1oalkyl, C1-10alkylthioC2-1 oalkenyl, C1 -
`
`10a1ky1thioC2-10a1kyny1, cyc10C3-galkyl, cyc10C3-galkeny1, cyc10C3-galky1C1-10alkyl, cyc10C3-
`
`salkcnylC 1-10alkyl, cycloC 3-galkylCr 10alkcnyl, cycloC 3-salkcnylCr walkcnyl, cycloC3-salkylCr
`
`10alkynyl, cycloC3-8alkenylCr10alkynyl, heterocyclyl-C0 - 10alkyl, heterocyclyl-Cr 10alkenyl, or
`heterocyclyl-Cr10alkynyl, any of which is optionally substituted with one or more independent
`halo, cyano, nitro, -OR778, -SO2NR778R888, or -NR778R888 substituents; or aryl-C0- 10alkyl, aryl-C2-
`10alkenyl, or aryl-C2-10alkynyl, any of which is optionally substituted with one or more
`independent halo, cyano, nitro, -OR778, C 1- 10alkyl, Cr10alkenyl, Cr10alkynyl, haloC 1- 10alkyl,
`haloC2-10alkenyl, haloC2-10alkynyl, -COOH, C1-4alkoxycarbonyl, -CONR778R888, -SO2NR778R888,
`or -NR778R888 substituents; or hetaryl-C 0- 10alkyl, hetaryl-Cr10alkenyl, or hetaryl-C2-10alkynyl,
`any of which is optionally substituted with one or more independent halo, cyano, nitro, -OR778,
`C1-10alkyl, Cr10alkenyl, Cr10alkynyl, haloCi-ioalkyl, hal0Cr1oalkenyl, hal0Cr10alkynyl,
`-COOH, C 1- 4alkoxycarbonyl, -CONR778R888, -SO2NR778R888, or -NR778R888 substituents; or
`mono( C 1-6alkyl )arninoC 1-6alkyl, di( C 1-6alky 1 )arninoC 1-6alky 1, mono( aryl )aminoC 1-6alkyl,
`
`di(aryl)aminoC1-6alkyl, or -N(C1-6alkyl)-C1-6alkyl-aryl, any of which is optionally substituted
`with one or more independent halo, cyano, nitro, -OR778, C1-10alkyl, Cr10alkenyl, C2- 10alkynyl,
`haloCnoalkyl, hal0Cr10alkenyl, haloCr 10alkynyl, -COOH, C 1-4alkoxycarbonyl, -CONR778R888
`SO2NR778R888, or -NR778R888 substituents; or in the case of -NR78R88, R78 and R88 taken together
`with the nitrogen atom to which they are attached form a 3-10 membered saturated ring,
`
`unsaturated ring, heterocyclic saturated ring, or heterocyclic unsaturated ring, wherein said ring
`
`is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, Ci-i 0alkoxy,
`-SO2NR778R888, or -NR778R888 substituents;
`
`DBl/ 80293456.l
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`

`Attorney Docket No.: 055112-5002-PR-02
`
`888
`d
`778
`88
`87
`78
`77
`R
`, R
`, R
`, R
`, R
`, an R
`
`1
`1 C
`1 C
`lk
`lk
`lkvl C
`d
`h . d
`are eac m epen ent y o-10a
`. , 2-1oa eny, 2-10a yny,
`
`C1-10alkoxyC1-1oalkyl, C1-10alkoxyCr10alkenyl, Ci-ioalkoxyCr10alkynyl, C1-10alkylthioC1-
`
`10alkyl, C1 -10alkylthioC2-10alkenyl, C1 -10alkylthioC2-10alkynyl, cycloC3-3alkyl, cycloC3-salkenyl,
`
`cycloC3-3alkylC1-10alkyl, cycloC3-3alkenylC1-1oalkyl, cycloC3-3alkylC2-1oalkenyl, cycloC3-
`
`3alkenylC2-1oalkenyl, cycloC3-salkylCr1oalkynyl, cycloC:,-salkenylC2-10alkynyl, heterocyclyl-Co-
`
`10alkyl, heterocyclyl-Cr10alkenyl, heterocyclyl-Cr10alkynyl, C 1 -10alkylcarbonyl, Cr
`1 oalkenylcarbonyl, C2-1 oalkynylcarbonyl, C1 -1 oalkoxycarbonyl, C1 -1 oalkoxycarbonylC1 -1 oalkyl,
`
`monoC1 -6alkylaminocarbonyl, di C 1-6alkylaminocarbonyl, mono( aryl)aminocarbonyl,
`di(aryl)aminocarbonyl, or C 1-10alkyl(aryl)aminocarbonyl, any of which is optionally substituted
`with one or more independent halo, cyano, hydroxy, nitro, Ci-i 0alkoxy, -SO2N(C0-4alkyl)(C0-
`4alkyl), or -N(Cu-4alkyl)(Ctr4alkyl) substituents; or aryl-Cu-walkyl, aryl-Cz-walkenyl, or aryl-Cz-
`
`10alkynyl, any of which is optionally substituted with one or more independent halo, cyano, nitro,
`
`-O(Crr4alkyl), C1-10alkyl, C2-10alkenyl, C2-10alkynyl, haloC1-10alkyl, haloC2-10alkenyl, haloCr
`
`10alkynyl, -COOH, Cnalkoxycarbonyl, -CON(C0 - 4alkyl)(C0 - 10alkyl), -SO2N(C0 - 4alkyl)(C0 -
`4alkyl), or -N(Co-4alkyl)(Co-4a]kyl) substituents; or hetaryl-Co-10alkyl, hetaryl-Cr10alkenyl, or
`
`hetaryl-Cr10alkynyl, any of which is optionally substituted with one or more independent halo,
`cyano, nitro, -O(Co-4alkyl), C1-10alkyl, C2-10alkenyl, C2-10alkynyl, haloC1-10alkyl, haloC2-
`
`10alkenyl, haloCz- 10alkynyl, -COOH, C 1-4alkoxycarbonyl, -CON ( C0-4alkyl)( C0 - 4alkyl),
`-SO2N(C0-4alkyl)(C0-4alkyl), or -N(C0- 4alkyl)(C0 - 4alkyl) substituents; or mono(C1-
`6alkyl)aminoC 1-6alkyl, di( C 1-6alkyl)aminoC1 -6alky 1, mono( aryl)aminoC 1-6alkyl,
`
`di(aryl)aminoCi-6alkyl, or -N(C1-6alkyl)-C 1- 6alkyl-aryl, any of which is optionally substituted
`with one or more independent halo, cyano, nitro, -O(Co-4alkyl), C1-10alkyl, C2-10alkenyl, Cr
`10alkynyl, haloC1- 10alkyl, haloCz- 10alkenyl, haloCz-10alkynyl, -COOH, C1-4alkoxycarbonyl,
`-CON(Co-4alkyl)(Co-4alkyl), -SO2N(Co-4alkyl)(Co-4alkyl), or -N(Co-4alkyl)(Co-4alkyl)
`
`substituents; and
`
`n, m,jl,jla,j2a,j3a,j4,j4a,j5a,j6a,j7, andj8 are each independently equal to 0, 1, or 2.
`
`23. The method of paragraphs 1, 2, or 3, wherein the BTK inhibitor is:
`
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`Attorney Docket No.: 055112-5002-PR-02
`
`9 NH
`
`NH2
`
`or a pharmaceutically-acceptable salt thereof, and the PI3K inhibitor is:
`
`HN~N
`
`N
`
`lN
`
`r
`
`F
`
`or a pharmaceutically-acceptable salt thereof.
`
`24. The method of paragraphs 1, 2, or 3, wherein the BTK inhibitor is (S)-4-(8-amino-3-(1-
`
`(but-2-ynoyl)pyrrolidin-2-yl)imidazo[ 1,5-a ]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide or
`
`apharmaceutically-acceptable salt thereof, and the PI3K inhibitor or PBK-8 inhibitor is
`
`(S)-N-( 1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine or a
`
`pharmaceutically-acceptable salt thereof.
`
`25. A method of treating a solid tumor cancer m a human compnsmg administering a
`
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`
`therapeutically effective dose of a BTK inhibitor and a PI3K inhibitor, wherein the dose
`
`is effective to inhibit signaling between the cells of the solid tumor cancer and at least
`
`one microenvironment selected from the group consisting of macrophages, monocytes,
`
`mast cells, helper T cells, cytotoxic T cells, regulatory T cells, natural killer cells,
`
`myeloid-derived suppressor cells, regulatory B cells, neutrophils, dendritic cells, and
`
`fibroblasts.
`
`26. The method of Claim 25, wherein the cancer is a solid tumor cancer, and wherein the
`
`solid tumor cancer is selected from the group consisting of colon carcinoma, pancreatic
`
`carcinoma, breast cancer, lung cancer, colorectal cancer, thyroid cancer, bone sarcoma,
`
`and stomach cancer.
`
`27. The method of any of Claims 25-26, wherein the dose is further effective to increase
`
`immune system recognition and rejection of the solid tumor by the human.
`
`28. The method of any of Claims 25-27, wherein the PI3K inhibitor is a PBK-8 inhibitor.
`
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`
`ABSTRACT
`
`[00323] In some embodiments, the invention
`
`includes a therapeutic combination of a
`
`phosphoinositidc 3-kinasc (PBK) inhibitor, including PBK inhibitors selective for the y- and 8-
`
`isoforms and selective for both y- and 6-isoforms, and a Bruton's tyrosine kinase (BTK)
`
`inhibitor. In some embodiments, the invention includes therapeutic methods of using a BTK
`
`inhibitor and a PBK-8 inhibitor to treat solid tumor cancers by modulation of the tumor
`
`microenvironment, including macrophages, monocytes, mast cells, helper T cells, cytotoxic T
`
`cells, regulatory T cells, natural killer cells, myeloid-derived suppressor cells, regulatory B cells,
`
`neutrophils, dendritic cells, and fibroblasts.
`
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`

`

`Electronic Acknowledgement Receipt
`
`EFS ID:
`
`Application Number:
`
`19829023
`
`62035777
`
`International Application Number:
`
`Confirmation Number:
`
`2633
`
`Title of Invention:
`
`Therapeutic Combination of a Pl3K Inhibitor and a BTK Inhibitor
`
`First Named Inventor/Applicant Name:
`
`Ahmed Hamdy
`
`Customer Number:
`
`28977
`
`Filer:
`
`Frederick Vogt
`
`Filer Authorized By:
`
`Attorney Docket Number:
`
`055112-5002-02-PR
`
`Receipt Date:
`
`11-AUG-2014
`
`Filing Date:
`
`Time Stamp:
`
`Application Type:
`
`Payment information:
`
`Submitted with Payment
`
`Payment Type
`
`Payment was successfully received in RAM
`
`RAM confirmation Number
`
`Deposit Account
`
`Authorized User
`
`16:38:24
`
`Provisional
`
`yes
`
`Deposit Account
`
`$660
`
`3466
`
`500310
`
`The Director of the USPTO is hereby authorized to charge indicated fees and credit any overpayment as follows:
`
`Charge any Additional Fees required under 37 C.F.R. Section 1.16 (National application filing, search, and examination fees)
`
`Charge any Additional Fees required under 37 C.F.R. Section 1.17 (Patent application and reexamination processing fees)
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1004, p. 505 of 1432
`
`

`

`Charge any Additional Fees required under 37 C.F.R. Section 1.19 (Document supply fees)
`
`Charge any Additional Fees required under 37 C.F.R. Section 1.21 (Miscellaneous fees and charges)
`
`File Listing:
`
`Document
`Number
`
`Document Description
`
`File Name
`
`File Size(Bytes)/
`Message Digest
`
`Multi
`Part/.zip
`
`Pages
`(if appl.)
`
`1477553
`
`1
`
`Provisional Cover Sheet (SBl 6)
`
`ProvisionalSB.pdf
`
`no
`
`4
`
`9bd6c35d9&26fad81658799c3ddaf2d98f.l
`6ef6
`
`Warnings:
`
`Information:
`
`2
`
`Drawings-only black and white line
`drawings
`
`DWGS.pdf
`
`no
`
`41
`
`655240
`
`5td8dbd989f7457 38bc5b5Jefl41003355ft
`acbf
`
`Warnings:
`
`Information:
`
`3
`
`Warnings:
`
`Information:
`
`SPEC.pdf
`
`yes
`
`146
`
`1118854
`
`3dca9991 cd9 I dbbf08057728e0c879d6e3a
`e750c
`
`Multipart Description/PDF files in .zip description
`
`Document Description
`
`Specification
`
`Claims
`
`Abstract
`
`End
`
`119
`
`145
`
`146
`
`Start
`
`1
`
`120
`
`146
`
`31180
`
`4
`
`Fee Worksheet (SB06)
`
`fee-info.pdf
`
`no
`
`2
`
`d859e36 7 e5 f1 dbS aOS 34 52 4d082593db01 c
`.524eb
`
`Warnings:
`
`Information:
`
`Total Files Size (in bytes)
`
`3282827
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1004, p. 506 of 1432
`
`

`

`This Acknowledgement Receipt evidences receipt on the noted date by the USPTO of the indicated documents,
`characterized by the applicant, and including page counts, where applicable. It serves as evidence of receipt similar to a
`Post Card, as described in MPEP 503.
`
`New Applications Under 35 U.S.C. 111
`If a new application is being filed and the application includes the necessary components for a filing date (see 37 CFR
`1.53(b)-(d) and MPEP 506), a Filing Receipt (37 CFR 1.54) will be issued in due course and the date shown on this
`Acknowledgement Receipt will establish the filing