(12) United States Patent
`Honigberg et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8.476,284 B2
`*Jul. 2, 2013
`
`USOO8476284B2
`
`(54) INHIBITORS OF BRUTON'S TYROSINE
`KNASE
`(75) Inventors: Lee Honigberg, San Francisco, CA
`(US); Erik Verner, Belmont, CA (US);
`Zhengying Pan, Austin, TX (US)
`(73) Assignee: Pharmacyclics, Inc., Sunnyvale, CA
`(US)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`This patent is Subject to a terminal dis-
`claimer.
`(21) Appl. No.: 13/328,718
`(22) Filed:
`Dec. 16, 2011
`
`(*) Notice:
`
`e J. V.9
`
`(65)
`
`Prior Publication Data
`US 2012/O108612 A1
`May 3, 2012
`Related U.S. Application Data
`(60) Continuation of application No. 13/312,606, filed on
`Dec. 6, 2011, which is a continuation of application
`No. 13/249,066, filed on Sep. 29, 2011, which is a
`continuation of application No. 12/356,498, filed on
`Jan. 20, 2009, now Pat. No. 8,088,781, which is a
`division of application No. 1 1/617,645, filed on Dec.
`28, 2006, now Pat. No. 7,514,444.
`(60) Provisional application No. 60/826,720, filed on Sep.
`22, 2006, provisional application No. 60/828,590,
`filed on Oct. 6, 2006.
`(51) Int. Cl
`AOIN 43/90
`A 6LX3/59
`(52) U.S. Cl.
`USPC ....................................................... 51.4/262.1
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(2006.01)
`(2006.01)
`
`(56)
`
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`Primary Examiner — Jeffrey Murray
`(74) Attorney, Agent, or Firm — Wilson, Sonsini, Goodrich
`& Rosati
`ABSTRACT
`(57)
`Disclosed herein are compounds, including compounds hav
`ing the Formula (A)
`
`Formula (A)
`
`R3 NN -R2
`
`R
`
`1N-\
`l
`A
`2 N
`N
`V
`R4
`
`where A, R1, R2, R3, and R4 are as defined in the specifi
`cation, that form covalent bonds with Bruton's tyrosine
`kinase (Btk). Also described are irreversible inhibitors
`of Btk. Methods for the preparation of the compounds
`are disclosed. Also disclosed are pharmaceutical com
`positions that include the compounds. Methods of using
`the Btkinhibitors are disclosed, alone or in combination
`with other therapeutic agents, for the treatment of
`autoimmune diseases or conditions, heteroimmune dis
`eases or conditions, cancer, including lymphoma, and
`inflammatory diseases or conditions.
`11 Claims, 8 Drawing Sheets
`
`SAN EX 1018, Page 1
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`SAN EX 1018, Page 5
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`

`

`US 8,476,284 B2
`
`1.
`INHIBITORS OF BRUTON'S TYROSINE
`KNASE
`
`RELATED APPLICATIONS
`
`This application is a continuation of U.S. application Ser.
`No. 13/312,606 entitled “INHIBITORS OF BRUTONS
`TYROSINE KINASE filed Dec. 6, 2011; which is a con
`tinuation of U.S. application Ser. No. 13/249,066 entitled
`INHIBITORS OF BRUTONS TYROSINE KINASE filed
`Sep. 29, 2011; which is a continuation of U.S. application Ser.
`No. 12/356,498, now U.S. Patent No. 8,088,781 entitled
`INHIBITORS OF BRUTONS TYROSINE KINASE filed
`Jan. 20, 2009; which is a divisional of U.S. application Ser.
`No. 1 1/617,645, now U.S. Pat. No. 7,514,444 entitled
`INHIBITORS OF BRUTONS TYROSINE KINASE filed
`Dec. 28, 2006; which claims benefit of U.S. Provisional
`Application No. 60/826,720 entitled “INHIBITORS OF
`BRUTON'S TYROSINE KINASE filed Sep. 22, 2006; and
`U.S. Provisional Application No. 60/828,590 entitled
`INHIBITORS OF BRUTON'S TYROSINE KINASE filed
`Oct. 6, 2006, all of which are herein incorporated by refer
`CCC.
`
`10
`
`15
`
`2
`inhibitor (such tyrosine kinases, are referred herein as “Btk
`tyrosine kinase cysteine homologs'). Also described herein
`are methods for synthesizing such irreversible inhibitors,
`methods for using such irreversible inhibitors in the treatment
`of diseases (including diseases wherein irreversible inhibi
`tion of Btk provides therapeutic benefit to a patient having the
`disease). Further described are pharmaceutical formulations
`that include an irreversible inhibitor of Btk.
`Compounds described herein include those that have a
`structure of any of Formula (A), Formula (B), Formula (C), or
`Formula (D), and pharmaceutically acceptable salts, Solvates,
`esters, acids and prodrugs thereof. In certain embodiments,
`isomers and chemically protected forms of compounds hav
`ing a structure represented by any of Formula (A). Formula
`(B), Formula (C), or Formula (D), are also provided.
`In one aspect, provided herein is a compound of Formula
`(D). Formula (D) is as follows:
`
`Air
`I-1
`
`Formula (D)
`
`FIELD OF THE INVENTION
`
`25
`
`NH2
`
`Described herein are compounds, methods of making Such
`compounds, pharmaceutical compositions and medicaments
`containing Such compounds, and methods of using Such com
`pounds and compositions to inhibit the activity of tyrosine
`30
`kinases.
`
`BACKGROUND OF THE INVENTION
`
`35
`
`Bruton's tyrosine kinase (Btk), a member of the Tec family
`of non-receptor tyrosine kinases, is a key signaling enzyme
`expressed in all hematopoietic cells types except T lympho
`cytes and natural killer cells. Btk plays an essential role in the
`B-cell signaling pathway linking cell Surface B-cell receptor
`(BCR) stimulation to downstream intracellular responses.
`Btk is a key regulator of B-cell development, activation,
`signaling, and survival (Kurosaki, Curr Op Imm, 2000, 276
`281; Schaeffer and Schwartzberg, Curr Op Imm 2000, 282
`288). In addition, Btk plays a role in a number of other
`hematopoetic cell signaling pathways, e.g., Toll like receptor
`(TLR) and cytokine receptor mediated TNF-C. production
`in macrophages, IgE receptor (FcepsilonRI) signaling in
`Mast cells, inhibition of Fas/APO-1 apoptotic signaling in
`B-lineage lymphoid cells, and collagen-stimulated platelet
`aggregation. See, e.g., C. A. Jeffries, et al., (2003), Journal of 50
`Biological Chemistry 278:26258-26264; N. J. Horwood, et
`al., (2003), The Journal of Experimental Medicine 197:1603
`1611; Iwaki et al. (2005), Journal of Biological Chemistry
`280(48):40261-40270; Vassilev et al. (1999), Journal of Bio
`logical Chemistry 274(3):1646-1656, and Quek et al. (1998),
`Current Biology 8(20): 1137-1140.
`
`40
`
`45
`
`55
`
`SUMMARY OF THE INVENTION
`
`Described herein are inhibitors of Bruton's tyrosine kinase
`(Btk). Also described herein are irreversible inhibitors of Btk.
`Further described are irreversible inhibitors of Btk that form
`a covalent bond with a cysteine residue on Btk. Further
`described herein are irreversible inhibitors of other tyrosine
`kinases, wherein the other tyrosine kinases share homology
`with Btk by having a cysteine residue (including a Cys 481
`residue) that can form a covalent bond with the irreversible
`
`60
`
`65
`
`N1 N O 2 M
`
`N
`
`Y
`NZ
`
`Rs
`
`R6
`
`R7
`
`wherein:
`L is CH, O, NH or S:
`Ar is a substituted or unsubstituted aryl, or a substituted or
`unsubstituted heteroaryl;
`Y is an optionally substituted group selected from among
`al