United States Patent
`(12)
`(10) Patent No.:
`US 9,795,604 B2
`
`Byrd et a].
`(45) Date of Patent:
`Oct. 24, 2017
`
`US009795604B2
`
`(54) METHODS OF TREATING AND
`PREVENTING GRAFT VERSUS HOST
`DISEASE
`.
`.
`(71) Appl1cant: Pharmacycllcs LLC, Sunnyvale, CA
`(US)
`
`(72)
`
`Inventors: John C. Byrd, Columbus, OH (US);
`Jason A_ DubovskyS CohunbusS OH
`.
`-
`gibviataégang/T'uglriisalflydohnson
`.
`y,
`,
`_ y _
`Dubhn, OH (US); DaVld Mlkloss
`Stanford, CA (US)
`
`,
`
`8,067,395 B2 *
`8 088 781 B2 *
`,
`,
`
`8,476,284 B2
`8,501,751 B2
`8,552,010 B2
`8,790,662 B2*
`
`89875421 B2 *
`2012/0071497 A1
`2013/0178483 A1
`2015/0086507 A1*
`
`2015/0157634 A1*
`
`11/2011 Jankowski
`1/2012 H ' b
`on1g erg .............
`
`........... C07D 471/04
`1:6IFTI/{231/03
`514/2621
`
`et a1.
`7/2013 Honi ber
`8/2013 Honigberg et al.
`10/2013 Honigberg et a1.
`7/2014 Spellberg ............. C12N 5/0642
`424/937
`3/2015 Chang ~~~~~~~~~~~~~~~~~~~~ C07K16/18
`424/1301
`3/2012 Buggy et a1.
`7/2013 Buggy et a1.
`3/2015 Izumi
`................... A61K 31/519
`424/937
`6/2015 Blazar .................. A61K 31/519
`
`(73) Assignee: Pharmacyclics LLC, Sunnyvale, CA
`(US)
`
`2016/0256397 A1*
`
`424/937
`9/2016 Chong ................. A6lK 9/2009
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U30 1540)) by 0 day5~
`
`21
`
`PP
`A 1. No.: 14/523,650
`
`(22)
`
`Filed:
`
`Oct. 24, 2014
`
`(65)
`
`Prior Publication Data
`
`US 2015/0118209 A1
`
`A r 30 2015
`p i
`a
`.
`.
`Related U'S' Application Data
`(60) Provisional application No. 61/895,981, filed on Oct.
`25, 2013, provisional application No. 61/910,945,
`filed on Dec. 2: 2013a provisional application No.
`61/973,173,
`filed on Mar. 313 20143 provisional
`application No. 61/973,176, filed on Mar. 31: 2014.
`
`(51)
`
`Int. Cl.
`A61K 31/519
`A61K 38/13
`A 61K 35” 7
`
`(2006.01)
`(2006 01)
`201 501
`(
`‘
`)
`(200601)
`(200601)
`(2006.01)
`(2015.01)
`
`A61K 45/06
`A61K 31/5377
`A61K 31/56
`A61K 35/28
`(52) US. Cl.
`CPC ........ A61K 31/519 (2013.01). A61K 31/5377
`,
`a
`,
`881381? $21; jg??? 88381? $21; 3:35;
`(2013.01); A61K 35/28 (2013.01)
`(58) Field of Classification Search
`CPC ............ A6lK 2300/00; A6lK 31/5377; A6lK
`31/56; A61K 38/13; A61K 31/519; A61K
`35/17; A61K 35/28; A61K 45/06
`USPC ......... 514/205, 171, 233.5, 262.1; 424/937,
`
`FOREIGN PATENT DOCUMENTS
`101674834 A
`3/2010
`WO-2002/080926
`10/2002
`wo—2011/153514 A2
`12/2011
`WO-2012/l71007 A2
`12/2012
`WO-2015/06l751 Al
`4/2015
`
`CN
`W0
`W0
`WO
`WO
`
`OTHER PUBLICATIONS
`
`Chang-Ki Min, “The pathophysiology of chronic graft-versus-host
`disease: the unveiling of an enigma”, Jun. 2011, The Korean Journal
`of Hematology, vol. 46, No. 2, pp. 80-87.*
`Magenau et a1., “Advances in understanding the pathogenesis of
`graft-versushost disease”, 2016, British Journal of Haematology,
`V01. 173, Issue 2,1313. 190-205.*
`Dubovsky et a1. Ibrutinib treatment ameliorates murine chronic
`graft-versus-host disease, The Journal of Clinical Investigation, J
`Clin Invest. Oct 1, 2014. D01:10.1172/JCI75328 (10 pgs.).
`Kapur et a1. B-cell involvement in chronic graft-versus-host disease.
`
`Haematologica. Nov. 2008;93(11):1702-11. (Epub Aug. 25, 2008).
`Jacobson et a1. B-cell-directed therapy for chronic graft-versus-host
`
`disease. Haematologica. Nov. 2010;95(11):1811-3.
`Srinivasan et a1. Donor B-cell alloantibody deposition and germinal
`center formation are required for the development ofmurine chronic
`GVHD and bronchiolitis obliterans. Blood. Feb.
`9, 2012;
`119(6):1570—80 (Epub Nov. 9, 2011).
`Treister. How we treat oral chronic graft-versus-host disease. Blood
`2012 120:3407-3418.
`Pharmacyclics: Study of the Bruton’s Tyrosine Kinase Inhibitor in
`Subjects With Chronic Graft Versus Host Disease. ClinicalTrials.
`gov [Internet]. Bethesda (MD): National Library of Medicine (US).
`Available from: http://clinica1tria1s.gov/show/NCT02195869.
`(Continued)
`
`Primary Examiner i My-Chau T Tran
`(74) Attorney Agent or Firm 7 Foley Hoag LLP
`’
`’
`
`.424/9371
`.
`.
`See appllcat1on file for complete search hlstory.
`
`(57)
`
`ABSTRACT
`
`(56)
`
`_
`References Clted
`
`US PATENT DOCUMENTS
`7,514,444 B2
`4/2009 Honigberg et a1.
`7,625,880 B2* 12/2009 Jankowski
`........... C07D 471/04
`514/252.13
`
`8,008,309 B2
`
`8/2011 Honigberg et a1.
`
`Described herein are methods for treating and preventing
`graft versus host disease using ACK inhibitors. The methods
`include administering to an individual in need thereof an
`ACK inhibitor such as ibrutinib for treating and preventing
`graft Versus 11051 dlsease
`
`55 Claims, 23 Drawing Sheets
`
`SAN EX 1001, Page 1
`
`SAN EX 1001, Page 1
`
`

`

`US 9,795,604 B2
`
`Page 2
`
`(56)
`
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`OTHER PUBLICATIONS
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`PCT/US2014/062277 International Search Report and Written
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`Burger et al. High-Level Expression of the T-Cell Chemokines
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`2013].
`Available
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`http://clinicaltrials. gov/ct2/show/
`NCT01325701 NLM Identifier: NCT01325701.
`Ponader et al. The Bruton tyrosine kinase inhibitor PCI-32765
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`for European Application No. EP
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`Dubovsky et al., “Ibrutinib can reverse established chronic graft-
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`immune-mediated
`Lehmann, “Pathogenesis and treatment of
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`
`* cited by examiner
`
`SAN EX 1001, Page 2
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`SAN EX 1001, Page 2
`
`

`

`U.S. Patent
`
`Oct. 24, 2017
`
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`US 9,795,604 B2
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`U.S. Patent
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`Oct. 24, 2017
`
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`U.S. Patent
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`U.S. Patent
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`U S. Patent
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`U.S. Patent
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`Oct. 24, 2017
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`Oct. 24, 2017
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`U.S. Patent
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`Oct. 24, 2017
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`SAN EX 1001, Page 13
`
`SAN EX 1001, Page 13
`
`

`

`U.S. Patent
`
`Oct. 24, 2017
`
`Sheet 12 of 23
`
`US 9,795,604 B2
`
`mm»: g
`
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`SAN EX 1001, Page 14
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`

`

`U.S. Patent
`
`Oct. 24, 2017
`
`Sheet 13 of 23
`
`US 9,795,604 B2
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`SAN EX 1001, Page 15
`
`SAN EX 1001, Page 15
`
`

`

`U.S. Patent
`
`Oct. 24, 2017
`
`Sheet 14 0f 23
`
`US 9,795,604 B2
`
`FIG. 9
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`SAN EX 1001, Page 16
`
`SAN EX 1001, Page 16
`
`

`

`U.S. Patent
`
`Oct. 24, 2017
`
`Sheet 15 of 23
`
`US 9,795,604 B2
`
`FIG. 9 (cont’d)
`
`B
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`SAN EX 1001, Page 17
`
`SAN EX 1001, Page 17
`
`

`

`U.S. Patent
`
`Oct. 24, 2017
`
`Sheet 16 of 23
`
`US 9,795,604 B2
`
`FIG. 9 (cont’d)
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`SAN EX 1001, Page 18
`
`SAN EX 1001, Page 18
`
`

`

`U.S. Patent
`
`Oct. 24, 2017
`
`Sheet 17 of 23
`
`US 9,795,604 B2
`
`FIG. 9 (cont’d)
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`SAN EX 1001, Page 19
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`SAN EX 1001, Page 19
`
`

`

`U.S. Patent
`
`Oct. 24, 2017
`
`Sheet 18 of 23
`
`US 9,795,604 B2
`
`FIG. 9 (cont’d)
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`SAN EX 1001, Page 20
`
`SAN EX 1001, Page 20
`
`

`

`U.S. Patent
`
`Oct. 24, 2017
`
`Sheet 19 0f 23
`
`US 9,795,604 B2
`
`FIG. 10
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`SAN EX 1001, Page 21
`
`SAN EX 1001, Page 21
`
`

`

`U.S. Patent
`
`Oct. 24, 2017
`
`Sheet 20 of 23
`
`US 9,795,604 B2
`
`FIG. 10 (cont’d)
`
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`SAN EX 1001, Page 22
`
`SAN EX 1001, Page 22
`
`

`

`U.S. Patent
`
`Oct. 24, 2017
`
`Sheet 21 of 23
`
`US 9,795,604 B2
`
`FIG. 10 (cont’d)
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`SAN EX 1001, Page 23
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`SAN EX 1001, Page 23
`
`

`

`U.S. Patent
`
`Oct. 24, 2017
`
`Sheet 22 of 23
`
`US 9,795,604 B2
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`SAN EX 1001, Page 24
`
`SAN EX 1001, Page 24
`
`

`

`U.S. Patent
`
`Oct. 24, 2017
`
`Sheet 23 of 23
`
`US 9,795,604 B2
`
`FIG. 10 (cont’d)
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`SAN EX 1001, Page 25
`
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`

`

`US 9,795,604 B2
`
`1
`METHODS OF TREATING AND
`PREVENTING GRAFT VERSUS HOST
`DISEASE
`
`CROSS-REFERENCE
`
`Formula (A)
`
`2
`
`R3\
`
`/R2
`
`N
`
`R1
`
`N \
`|
`
`N/
`
`\A
`N/\
`R4;
`
`This application claims the benefit of priority of US.
`Provisional Application No. 61/895,981, filed Oct. 25, 2013;
`US. Provisional Application No. 61/910,945, filed Dec. 2,
`2013; US. Provisional Application No. 61/973,173, filed
`Mar. 31, 2014; and US. Provisional Application No. 61/973,
`176 filed Mar. 31, 2014, each of which is incorporated herein
`by reference.
`
`10
`
`15
`
`SEQUENCE LISTING
`
`The instant application contains a Sequence Listing which
`has been submitted in ASCII format via EFS-Web and is
`
`20
`
`hereby incorporated by reference in its entirety. Said ASCII
`copy, created on Oct. 20, 2014, is named 25922-885-201SE-
`Q.txt and is 633 bytes in size.
`
`BACKGROUND OF THE INVENTION
`
`Chronic graft versus host disease (cGVHD) is the most
`common long-term complication following allogeneic stem
`cell transplant (SCT), affecting 30-70% of patients who
`survive beyond the first 100 days. cGVHD and its associated
`immune deficiency have been identified as a leading cause
`of non-relapse mortality (NRM) in allogeneic SCT survi-
`vors. SCT survivors with cGVHD are 4.7 times as likely to
`develop severe or life-threatening health conditions com-
`pared with healthy siblings, and patients with active cGVHD
`are more likely to report adverse general health, mental
`health, functional impairments, activity limitation, and pain
`than allo-SCT survivors with no history of cGVHD. Any
`organ system can be affected, and further morbidity is
`frequently caused by long-term exposure to the corticoster-
`oids and calcineurin inhibitors required to treat the condi-
`tion.
`
`SUMMARY OF THE INVENTION
`
`Disclosed herein, in some embodiments, are methods of
`preventing the occurrence of graft versus host disease
`(GVHD) or reducing the severity of GVHD occurrence in a
`patient requiring cell transplantation comprising administra-
`tion of a therapeutically effective amount of an ACK inhibi-
`tor (e.g., an ITK or BTK inhibitor). In some embodiments,
`disclosed herein are methods of reducing the severity of
`GVHD occurrence in a patient requiring cell transplantation
`comprising administration of a therapeutically effective
`amount of an ACK inhibitor (e. g., an ITK or BTK inhibitor).
`In some embodiments the ACK inhibitor is a compound of
`Formula (A). In some embodiments, disclosed herein are
`methods of preventing the occurrence of graft versus host
`disease (GVHD) or reducing the severity of GVHD occur-
`rence in a patient requiring cell transplantation, comprising
`administration of a therapeutically effective amount of a
`compound of Formula (A) having the structure:
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`wherein:
`Ais N;
`R1 is phenyl-O-phenyl or phenyl-S-phenyl;
`R2 and R3 are independently H;
`R4 is L3-X-L4-G, wherein,
`L3 is optional, and when present is a bond, optionally
`substituted or unsubstituted alkyl, optionally substituted or
`unsubstituted cycloalkyl, optionally substituted or unsubsti-
`tuted alkenyl, optionally substituted or unsubstituted alky-
`nyl;
`
`X is optional, and when present is a bond, 407
`
`
`
` C(:O) , S , S (:0) , S (:0)2 ,
`
`
`
`NH ,
`NR9
`,
`NHC(O)
`,
`C(O)NH ,
`NR9C(O)7,
`4C(O)NR97,
`Si(:O)2NH7,
`iNHS(:O)27,
`Si(:O)2NR97,
`iNRQS(:O)27,
`40C(O)NH7,
`iNHC(O)Oi,
`iOC(O)NR97,
`7NR9C(O)07,
`4CH:NOi, gON:CH7, 7NR10C(O)NR107, het-
`eroaryl-,
`aryl-,
`7NR10C(:NR11)NR107,
`iNRloC
`(:NR11)7, *C(:NR11)NR10*5 *OC(:NR11)*5 01'
`4C(:NR11)07;
`L4 is optional, and when present is a bond, substituted or
`unsubstituted alkyl, substituted or unsubstituted cycloalkyl,
`substituted or unsubstituted alkenyl, substituted or unsub-
`stituted alkynyl, substituted or unsubstituted aryl, substi-
`tuted or unsubstituted heteroaryl, substituted or unsubsti-
`tuted heterocycle;
`or L3, X and L4 taken together form a nitrogen containing
`heterocyclic ring;
`G is
`
`0
`
`R6
`
`0
`
`WR” WM,
`
`R8
`
`R6
`
`R6
`
`0
`0
`0
`\\S//
`Q
`Iii / R7, iii / R7, or
`(fi
`R6
`i
`/ WAR.
`S
`
`R8
`
`R8
`
`R20
`
`R8
`
`wherein,
`R6, R7 and R8 are independently selected from among H,
`halogen, CN, OH, substituted or unsubstituted alkyl or
`substituted or unsubstituted heteroalkyl or substituted or
`unsubstituted cycloalkyl, substituted or unsubstituted het-
`erocycloalkyl, substituted or unsubstituted aryl, substituted
`or unsubstituted heteroaryl;
`each R9 is independently selected from among H, substi-
`tuted or unsubstituted lower alkyl, and substituted or unsub-
`stituted lower cycloalkyl;
`
`SAN EX 1001, Page 26
`
`SAN EX 1001, Page 26
`
`

`

`US 9,795,604 B2
`
`3
`each R10 is independently H, substituted or unsubstituted
`lower alkyl, or substituted or unsubstituted lower cycloalkyl;
`or
`
`two Rlo groups can together form a 5-, 6-, 7-, or 8-mem-
`bered heterocyclic ring; or
`R10 and R11 can together form a 5-, 6-, 7-, or 8-membered
`heterocyclic ring; or each R1 1 is independently selected from
`H or substituted or unsubstituted alkyl; or a pharmaceuti-
`cally acceptable salt thereof. In some embodiments, L3, X
`and L4 taken together form a nitrogen containing heterocy-
`clic ring. In some embodiments, the nitrogen containing
`heterocyclic ring is a piperidine group. In some embodi-
`ments, G is
`
`In some embodiments, the compound of Formula (A) is
`1-[(3 R)-3- [4-amino-3-(4 -phenoxyphenyl)pyrazolo[3 ,4-d]
`pyrimidin-l-yl]piperidin-1-yl]prop-2-en-1-one.
`In
`some
`embodiments, the patient has cancer. In some embodiments,
`the patient has a hematological malignancy.
`In some
`embodiments, the patient has a relapsed or refractory hema-
`tological malignancy. In some embodiments, the patient has
`a B-cell malignancy. In some embodiments, the patient has
`a T—cell malignancy. In some embodiments, the patient has
`a leukemia, a lymphoma, or a myeloma. In some embodi-
`ments,
`the B-cell malignancy is a non-Hodgkin’s lym-
`phoma. In some embodiments,
`the B-cell malignancy is
`chronic lymphocytic leukemia (CLL).
`In some embodi-
`ments,
`the B-cell malignancy is a relapsed or refractory
`B-cell malignancy. In some embodiments, the B-cell malig-
`nancy is a relapsed or refractory non-Hodgkin’s lymphoma.
`In some embodiments, the B-cell malignancy is a relapsed
`or refractory CLL. In some embodiments, the patient has
`high risk CLL. In some embodiments, the patient has a 17p
`chromosomal deletion. In some embodiments, the patient
`has 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or
`greater CLL as determined by bone marrow biopsy. In some
`embodiments, the patient has received one or more prior
`anticancer agents. In some embodiments,
`the anticancer
`agent is selected from among alemtuzumab, bendamustine,
`bortezomib, CAL-101, chlorambucil, cyclophosphamide,
`dexamethasone, docetaxel, doxorubicin, endostatineveroli-
`mus, etoposide, fludarabine, fostamatinib, hydroxydaunoru-
`bicin, ibritumomab, ifosphamide, lenalidomide, mesalazine,
`ofatumumab, paclitaxel, pentostatin, prednisone, rituximab,
`temsirolimus, thalidomide, tositumomab, vincristine, or a
`combination thereof. In some embodiments, the anticancer
`agent is rituximab. In some embodiments, the anticancer
`agent is alemtuzumab. In some embodiments, the anticancer
`agent
`is
`fludarabine, cyclophosphamide, and rituximab
`(FCR). In some embodiments, the anticancer agent is oxa-
`liplatin, fludarabine, cytarabine, rituximab (OFAR). In some
`embodiments, the amount of the ACK inhibitor compound
`(e.g., a compound of Formula (A)) prevents or reduces
`GVHD while maintaining a graft-versus-leukemia (GVL)
`reaction effective to reduce or eliminate the number of
`
`cancerous cells in the blood of the patient. In some embodi-
`ments, the cell transplantation is a hematopoietic cell trans-
`plantation.
`In some embodiments,
`the GVHD is acute
`GVHD.
`In some embodiments,
`the GVHD is chronic
`
`4
`GVHD. In some embodiments, the GVHD is scleroderma-
`tous GVHD. In some embodiments, the GVHD is steroid
`resistant GVHD.
`In some embodiments,
`the GVHD is
`cyclosporin-resistant GVHD.
`In some embodiments,
`the
`GVHD is refractory GVHD. In some embodiments,
`the
`GHVD is oral GVHD.
`In some embodiments,
`the oral
`GVHD is reticular oral GVHD. In some embodiments, the
`oral GVHD is erosive oral GVHD. In some embodiments,
`the oral GVHD is ulcerative oral GVHD. In some embodi-
`
`ments, the oral GVHD is GVHD of the oral cavity. In some
`embodiments, the oral GVHD is GVHD of the oropharyn-
`geal region.
`In some embodiments,
`the oral GVHD is
`GVHD of the pharyngeal region. In some embodiments, the
`oral GVHD is GVHD of the esophageal region. In some
`embodiments, the oral GVHD is acute oral GVHD. In some
`embodiments, the oral GVHD is chronic oral GVHD. In
`some embodiments, the patient exhibits one or more symp-
`toms of GVHD. In some embodiments, the patient has or
`will receive an allogeneic bone marrow or hematopoietic
`stem cell transplant. In some embodiments, the ACK inhibi-
`tor compound (e.g., a compound of Formula (A)) is admin-
`istered concurrently with an allogeneic bone marrow or
`hematopoietic stem cell transplant. In some embodiments,
`the ACK inhibitor compound (e.g., a compound of Formula
`(A)) is administered prior to an allogeneic bone marrow or
`hematopoietic stem cell transplant. In some embodiments,
`the ACK inhibitor compound (e.g., a compound of Formula
`(A)) is administered subsequent to an allogeneic bone mar-
`row or hematopoietic stem cell transplant. In some embodi-
`ments, the patient is a candidate for receiving HLA-mis-
`matched hematopoietic stem cells. In some embodiments,
`the patient
`is a candidate for receiving unrelated donor
`hematopoietic stem cells, umbilical vein hematopoietic stem
`cells, or peripheral blood stem cells. In some embodiments,
`the ACK inhibitor compound (e.g., a compound of Formula
`(A)) is administered orally. In some embodiments, the ACK
`inhibitor compound (e.g., a compound of Formula (A)) is
`administered at a dosage of between about 0.1 mg/kg per
`day to about 100 mg/kg per day. In some embodiments, the
`ACK inhibitor compound (e.g., a compound of Formula
`(A)) is administered at a dosage of about 40 mg/day, about
`140 mg/day, about 280 mg/day, about 420 mg/day, about
`560 mg/day, or about 840 mg/day. In some embodiments,
`the ACK inhibitor compound (e.g., a compound of Formula
`(A)) is administered in combination with other prophylactic
`agents. In some embodiments, the ACK inhibitor compound
`(e.g., a compound of Formula (A)) is administered from day
`1
`to about day 120 following allogeneic bone marrow or
`hematopoietic stem cell transplant. In some embodiments,
`the ACK inhibitor compound (e.g., a compound of Formula
`(A)) is administered from day 1 to about day 1000 following
`allogeneic bone marrow or hematopoietic stem cell trans-
`plant. In some embodiments, the ACK inhibitor compound
`(e.g., a compound of Formula (A))
`is administered in
`combination with one or more additional therapeutic agents.
`In some embodiments, the additional therapeutic agent is a
`corticosteroid. In some embodiments, the therapeutic agent
`is cyclosporine (CSA), mycophenolate mofetil (MMF) or a
`combination thereof. In some embodiments, the patient has
`or will receive a donor lymphocyte infusions (DLI). In some
`embodiments, the patient is administered one or more DLIs.
`In some embodiments, the patient is administered two or
`more DLIs. In some embodiments, the DLI comprises CD3+
`lymphocytes. In some embodiments, the patient is admin-
`istered one or more donor lymphocyte infusions (DLI)
`following an allogeneic bone marrow or hematopoietic stem
`cell transplant. In some embodiments, the ACK inhibitor
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`SAN EX 1001, Page 27
`
`SAN EX 1001, Page 27
`
`

`

`US 9,795,604 B2
`
`5
`compound (e.g., a compound of Formula (A)) is adminis-
`tered concurrently with a DLI following allogeneic bone
`marrow or hematopoietic stem cell
`transplant. In some
`embodiments, the ACK inhibitor compound (e.g., a com-
`pound of Formula (A)) is administered prior to a DLI
`following an allogeneic bone marrow or hematopoietic stem
`cell transplant. In some embodiments, the ACK inhibitor
`compound (e.g., a compound of Formula (A)) is adminis-
`tered following a DLI following an allogeneic bone marrow
`or hematopoietic stem cell transplant. In some embodiments,
`the ACK inhibitor compound (e.g., a compound of Formula
`(A)) is ibrutinib.
`Disclosed herein, in some embodiments, are methods of
`treating a patient for alleViation of a bone marrow mediated
`disease, comprising administering to the patient allogeneic
`hematopoietic stem cells and/or allogeneic T—cells, and a
`therapeutically effective amount of an ACK inhibitor (e.g.,
`an ITK or BTK inhibitor). In some embodiments, disclosed
`herein are methods of treating a patient for alleViation of a
`bone marrow mediated disease, with alleViation of conse-
`quently developed graft versus host disease (GVHD), com-
`prising administering to the patient allogeneic hematopoietic
`stem cells and/or allogeneic T—cells, and a therapeutically
`effective amount of a compound of Formula (A):
`
`Formula (A)
`
`R3\
`
`/R2
`
`N
`
`R1
`
`N \
`|
`
`N/
`
`\A
`N/\
`R4;
`
`wherein:
`
`Ais N;
`
`R1 is phenyl-O-phenyl or phenyl-S-phenyl;
`R2 and R3 are independently H;
`R4 is L3-X-L4-G, wherein,
`L3 is optional, and when present is a bond, optionally
`substituted or unsubstituted alkyl, optionally substituted or
`unsubstituted cycloalkyl, optionally substituted or unsubsti-
`tuted alkenyl, optionally substituted or unsubstituted alky-
`nyl;
`
`X is optional, and when present is a bond, 407,
`
`
` C(:O) , S , S (:0) , S (:O)2 ,
`
`
`
`
`NH ,
`NR9
`,
`NHC(O)
`,
`C(O)NH ,
`NR9C(O)7,
`7C(O)NR97,
`Si(:O)2NH7,
`iNHS(:O)27,
`Si(:O)2NR97,
`7NR9S(:O)27,
`40C(O)NH7,
`iNHC(O)Oi,
`40C(O)NR97,
`7NR9C(O)Oi,
`iCH:NOi, iON:CH7, 7NR10C(O)NR107, het-
`eroaryl-,
`aryl-,
`7NR10C(:NR11)NR107,
`iNRIOC
`(:NR11)75 *C(:NR11)NRiois *OC(:NR11)*s 0r
`iC(:NR1 00*;
`L4 is optional, and when present is a bond, substituted or
`unsubstituted alkyl, substituted or unsubstituted cycloalkyl,
`substituted or unsubstituted alkenyl, substituted or unsub-
`stituted alkynyl, substituted or unsubstituted aryl, substi-
`tuted or unsubstituted heteroaryl, substituted or unsubsti-
`tuted heterocycle;
`or L3, X and L4 taken together form a nitrogen containing
`heterocyclic ring;
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Gis
`
`0
`
`R6
`
`0
`
`W1“, W1“,
`
`R8
`
`R
`
`R6
`
`0
`Q
`5
`O\\S//O
`iii / R7, if / R7, or
`(fi
`R6
`
`R8
`
`R8
`
`i R20
`S/ \KkRp
`
`R8
`
`wherein,
`R6, R7 and R8 are independently selected from among H,
`halogen, CN, OH, substituted or unsubstituted alkyl or
`substituted or unsubstituted heteroalkyl or substituted or
`unsubstituted cycloalkyl, substituted or unsubstituted het-
`erocycloalkyl, substituted or unsubstituted aryl, substituted
`or unsubstituted heteroaryl,
`each R9 is independently selected from among H, substi-
`tuted or unsubstituted lower alkyl, and substituted or unsub-
`stituted lower cycloalkyl;
`each R10 is independently H, substituted or unsubstituted
`lower alkyl, or substituted or unsubstituted lower cycloalkyl;
`or
`
`two R10 groups can together form a 5-, 6-, 7-, or 8-mem-
`bered heterocyclic ring; or R10 and R11 can together form a
`5-, 6-, 7-, or 8-membered heterocyclic ring; or each R11 is
`independently selected from H or substituted or unsubsti-
`tuted alkyl, or a pharmaceutically acceptable salt thereof, is
`administered prior to, concurrently with, or following the
`allogeneic hematopoietic stem cells and/or allogeneic
`T—cells. In some embodiments, L3, X and L4 taken together
`form a nitrogen containing heterocyclic ring.
`In some
`embodiments, the nitrogen containing heterocyclic ring is a
`piperidine group. In some embodiments, G is
`
`In some embodiments, the compound of Formula (A) is
`1-[(3 R)-3- [4 -amino -3 -(4 -phenoxyphenyl)pyrazolo[3,4-d]
`pyrimidin-l-yl]piperidin-1-yl]prop-2-en-1-one.
`In
`some
`embodiments, the patient has cancer. In some embodiments,
`the patient has a hematological malignancy.
`In some
`embodiments, the patient has a relapsed or refractory hema-
`tological malignancy. In some embodiments, the