(12) United States Patent
`Honigberg et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7.514,444 B2
`*Apr. 7, 2009
`
`USOO751444.4B2
`
`(54) INHIBITORS OF BRUTON'S TYROSINE
`KNASE
`
`(75) Inventors: Lee Honigberg, San Francisco, CA
`(US); Erik Verner, San Mateo, CA
`(US); Zhengying Pan, Apharetta, GA
`(US)
`
`(73) Assignee: Pharmacyclics, Inc., Sunnyvale, CA
`(US)
`
`* 3f2OO1
`WOO1 19829
`WO
`WO-01-25238 A2
`4/2001
`WO
`WO-01-41754
`6, 2001
`WO
`WO-01-44258 A1
`6, 2001
`WO
`WO-02-387.97 A2
`5, 2002
`WO
`WO-02-080926
`10, 2002
`WO
`WO-03-000187
`1, 2003
`WO
`WO WO-2004-096.253
`11, 2004
`WO WO-2005-005429
`1, 2005
`WO WO-2005-O 14599
`2, 2005
`
`(*) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`This rent is subject to a terminal dis
`(21) Appl. No.: 11/617,645
`
`y x- - -
`
`9
`
`(22)
`(65)
`
`(60)
`
`(51)
`
`(52)
`
`(58)
`
`(56)
`
`Filed:
`
`Dec. 28, 2006
`
`Prior Publication Data
`US 2008/O108.636A1
`May 8, 2008
`
`Related U.S. Application Data
`Provisional application No. 60/826,720, filed on Sep.
`22, 2006, provisional application No. 60/828,590,
`filed on Oct. 6, 2006.
`
`Int. C.
`(2006.01)
`A 6LX 3/59
`(2006.01)
`AOIN 43/90
`(2006.01)
`CO7D 473/00
`U.S. Cl. .............................. 514/263.22; 514/263.2:
`544/277
`Field of Classification Search ....................... None
`See application file for complete search history.
`References Cited
`
`U.S. PATENT DOCUMENTS
`
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`7/2006 Uckun et al.
`2006.0167090 A1
`2008/0076921 A1* 3/2008 Honigberg et al. .......... 544, 184
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`Dorwald F. A. Side Reactions in Organic Synthesis, 2005, Wiley:
`VCH. Weinheimp. IX of Preface.*
`Browning, J.L., “B cells move to centre stage: novel opportunities for
`autoimmune disease treatment”. Nature Reviews/Drug Discovery
`vol. 5, Jul. 2006, pp. 564-576.
`Cohen, M.S. et al., “Structural Bioinformatics-Based Design of
`Selective, Irreversible Kinase Inhibitors.” Science, vol.308, May 27,
`2005, pp. 1318-1321.
`Desiderio, S., “Role of Btk in B cell development and signaling.”
`Curr, Op. in Immunology 1997, 9:534-540.
`Fruman, D.A., "Xid-like Phenotypes: A B Cell Signalosome Takes
`Shape.” Immunity 13: 1-3 (Jul. 2000).
`Gold, Michael R. "To make antibodies or not:signaling by the B-cell
`antigen receptor.” Trends in Pharmacological Sciences, 23(7):316
`324 (Jul. 2002).
`Horwood, Nicole J. et al., “Bruton's Tyrosin Kinase Is Required for
`Lipopolysaccharide-induced Tumor Necrosis Factor C. Production.”
`J. Exp. Med. 197(12):1603-1611 (Jun. 2003).
`Iwaki, Shokiet al., “Btk Plays a Crucial Role in the Amplification of
`FceRI-mediated Mast Cell Activation by Kit,” J. Biol. Chem.
`280(48):40261-40270 (Dec. 2, 2005).
`Jefferies, Caroline A. et al., “Bruton's Tyrosine Kinase Is a Toll?
`Interleukin-1 Receptor Domain-binding Protein That Participates in
`Nuclear Factor KBActivation by Toll-like Receptor 4.” J. Biol. Chem.
`278:26258-26264 (2003).
`Kawakami, Yuko et al., “Terreic acid, a quinone epoxide inhibitor of
`Bruton's tyrosine kinase.” PNAS USA96:2227-2232 (1999).
`(Continued)
`Primary Examiner James O Wilson
`Assistant Examiner Jeffrey H Murray
`(74) Attorney, Agent, or Firm Wilson Sonsini Goodrich &
`Rosati
`
`(57)
`
`ABSTRACT
`
`Disclosed herein are compounds that form covalent bonds
`with Bruton's tyrosine kinase (Btk). Also described are irre
`versible inhibitors of Btk. Methods for the preparation of the
`compounds are disclosed. Also disclosed are pharmaceutical
`compositions 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 diseases or conditions,
`cancer, including lymphoma, and inflammatory diseases or
`conditions.
`
`8 Claims, 7 Drawing Sheets
`
`SAN EX 1013, Page 1
`
`

`

`US 7.514.444 B2
`Page 2
`
`OTHER PUBLICATIONS
`Kuppers, R., “Mechanisms of B-cell lymphoma pathogenesis.”
`Nature Reviews/Cancer, vol. 5, Apr. 2005, pp. 251-262.
`Kurosaki, Tomohiro, “Functional dissection of BCR signaling path
`ways.” Curr. Op. Imm. 12:276-281 (2000).
`Mahajan, S. et al., “Rational Design and Synthesis of a Novel Anti
`leukemic Agent Targeting Bruton's Tyrosine Kinase (BTK), LFM
`A13 O-Cyano-B-Methyl-N-(2,5-Dibromophenyl)Propenamide).” J.
`of Biol. Chem., vol. 274, No. 14, Apr. 2, 1999, pp. 9587-9599.
`Mangla, Anita et al., “Pleiotropic consequences of Bruton tyrosin
`kinase deficiency in myeloid lineages lead to poor inflammatory
`responses.” Blood 104(4): 1191-1197 (2004).
`Niiro, Hiroaki and Clark, Edward A., “Regulation of B-Cell Fate by
`Antigen-Receptor Signals.” Nature Reviews 2:945-956 (2002).
`Oligino, Thomas J. and Dalrymple, Stacie A., “Targeting B cells for
`the treatment of rheumatoid arthritis.” Arthirits Res Ther 5(Suppl.
`4):S7-S11 (2002).
`Pan, Z. et al., “Discovery of Selectable Irreversible Inhibitors for
`Bruton's Tyrosine Kinase.” ChemMedChem 2006, 1, 1-5.
`Quek, L.S. et al., “A role for Bruton's tyrosine kinase (Btk) in platelet
`activation by collagen.” Curr. Biol. 8(20): 1137-1140 (1998).
`Sada, Kiyonao and Yamamura, Hirohei. “Protein-Tyrosine Kinases
`and Adaptor Proteins in FceRI-Mediated Signaling in Mast Cells.”
`Curr. Mol. Med. 3(1):85-94 (2003).
`Schaeffer, Edward M. and Schwartzberg, Pamela L., “Tec family
`kinases in lymphocyte signaling and function. Curr. Op. Imm.
`12:282-288 (2000).
`Science IP CAS Search, Sep. 5, 2006.
`Science IP CAS Search, Mar. 16, 2006.
`Merged Markush Service Search, Jun. 27, 2005.
`Shaffer, A.L.. et al., Lymphoid malignancies: the dark side of B-cell
`differentiation, Nature Reviews/Immunology, vol. 2, Dec. 2002, pp.
`920-932.
`Smith, C.I. Edvard et al., “The Tec family of cytoplasmic tyrosine
`kinases: mammalian Btk, Bmx. Itk, Tec, Txk and homologs in other
`species.” BioEssays 23:436-446 (2001).
`Smolen, Josef S. and Steiner, Gunter, “Therapeutic Strategies for
`Rheumatoid Arthritis.” Nature Reviews 2:473-488 (2003).
`Uckun, Fatih M. et al., “The Anti-leukemic Bruton's Tyrosin Kinase
`Inhibitor
`O-cyano-B-hydroxy-3-mehyl-N-(2,5-
`dibromophenyl)Propenamide
`(LFM-A13)Prevents
`Fatal
`Thromboembolism.” Leuk. Lymphoma 44(9): 1569-1577 (2003).
`
`Uckun, Fatih M. et al., “In Vivo Pharmacokinetic Features, Toxicity
`Profile, and Chemosensitizing Activity of C-Cyano-B-hydroxy-3-
`methyl-N-(2,5-dibromophenyl)propenamide (LFM-A13), a Novel
`Antileukemic Agent Targeting Bruton's Tyrosine Kinase.” Clin. Can
`cer Res. 8:1224-1233 (2002).
`Uckun, F.M., “Bruton's Tyrosin Kinase (BTK) as a Dual-Function
`Regulator of Apoptosis.” Biochem. Pharmacology, vol. 56, pp. 683
`691, 1998.
`Uckun, Fatih M. et al., “BTK as a Mediator of Radiation-Induced
`Apoptosis in DT-40 Lymphoma B Cells.”Science vol. 273 No. 5278,
`pp. 1096-1 100 (1996).
`Vassilev, A.O. and Uckun, F.M., “Therapeutic Potential of Inhibiting
`Bruton's Tyrosine Kinase, (BTK). Current Pharmaceutical Design,
`2004, 10, 1757-1766.
`Vassilev, Alexei et al., “Bruton's Tyrosine Kinase as an Inhibitor of
`the Fas/CD95 Death-inducing Signaling Complex.” J. Biol. Chem.
`274(3):1646-1656 (1999).
`Yamamoto, Noriyuki et al., “The Orally Available Spleen Tyrosine
`Kinase
`Inhibitor
`2-7-(3,4-Dimethoxyphenyl)-imidazol-2-
`cpyrimidin-5-ylamino-nicotinamide Dihydrochloride (BAY61
`3606) Blocks Antigen-Induced Airway Inflammation in Rodents.” J.
`Pharma. And Exp. Therapeutics 306(3): 1174-1181 (2003).
`Luskova, P. and Draber, P. “Modulation of the Fce Receptor I Sig
`naling by Tyrosin Kinase Inhibitors: Search for Therapeutic Targets
`of Inflammatory and Allergy Diseases. Curr. Pharmaceutical Design
`10:1727-1737 (2004).
`Arnold, L.D. et al., “Pyrrolo[2,3-dipyrimidines Containing an
`Extended 5-Substituent as Potent and Selective Inhibitors of lok 1.”
`Bioorg. Med. Chem. Ltrs. 10:2167-2170 (2000).
`Burchat et al., “Pyrazolo 3,4-dipyrimidines Containing an Extended
`3-Substituent as Potent Inhibitors of Lck—a Selectivity Insight.”
`Bioorg. Med. Chem. Ltrs. 12:1687-1690 (2002).
`Nisitani, S. et al., “In situ detection of activated Bruton's tyrosine
`kinase in the Ig signaling complex by phosphopeptide-specific
`monoclonal antibodies.” PNAS USA96:2221-2226 (1999).
`15.
`Smaill, J.B.
`et
`al.,
`“Tyrosine Kinase Inhibitors.
`and
`4-(Phenylamino)quinazoline
`4-(Phenylamino)pridodipyrimidine Acrylamides as Irresversible
`Inhibitors of the ATP Binding Site of the Epidermal Growth Factor
`Receptor.” J. Med. Chem. 42(10): 1803-1815 (1999).
`PCT/US06/49626 Search Report dated Apr. 9, 2008.
`* cited by examiner
`
`SAN EX 1013, Page 2
`
`

`

`U.S. Patent
`
`Apr. 7, 2009
`
`Sheet 1 of 7
`
`US 7.514.444 B2
`
`- - - O - - - A4 - D - Z.
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`
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`
`is, 3:2: 3:355
`
`
`
`SAN EX 1013, Page 3
`
`

`

`U.S. Patent
`U.S. Patent
`
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`90027,
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`SAN EX 1013, Page 4
`
`
`

`

`U.S. Patent
`
`Apr. 7, 2009
`
`Sheet 3 of 7
`
`US 7.514.444 B2
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`SAN EX 1013, Page 5
`
`

`

`U.S. Patent
`
`Apr. 7, 2009
`
`Sheet 4 of 7
`
`US 7.514.444 B2
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`SAN EX 1013, Page 6
`
`

`

`U.S. Patent
`
`Apr. 7, 2009
`
`Sheet 5 of 7
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`US 7,514,444 132
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`SAN EX 1013, Page 7
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`
`

`

`U.S. Patent
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`US 7.514.444 B2
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`SAN EX 1013, Page 8
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`

`

`U.S. Patent
`
`Apr. 7, 2009
`
`Sheet 7 Of 7
`
`US 7.514.444 B2
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`SAN EX 1013, Page 9
`
`

`

`US 7,514,444 B2
`
`1.
`INHIBITORS OF BRUTON'S TYROSINE
`KNASE
`
`RELATED APPLICATIONS
`
`This application claims benefit of U.S. Provisional Appli
`cation No. 60/826,720 entitled “INHIBITORS OF BRU
`TON'S TYROSINE KINASE filed Sep. 22, 2006; and U.S.
`Provisional Application No. 60/828,590 entitled “INHIBI
`TORS OF BRUTON'S TYROSINE KINASE filed Oct. 6, 10
`2006, both of which are herein incorporated by reference.
`
`5
`
`FIELD OF THE INVENTION
`
`Described herein are compounds, methods of making Such 15
`compounds, pharmaceutical compositions and medicaments
`containing Such compounds, and methods of using Such com
`pounds and compositions to inhibit the activity of tyrosine
`kinases.
`
`BACKGROUND OF THE INVENTION
`
`2O
`
`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- 25
`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- 30
`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 35
`cells, inhibition of Fas/APO-1 apoptotic signaling in B-lin
`eage lymphoid cells, and collagen-stimulated platelet aggre
`gation. See, e.g., C. A. Jeffries, et al., (2003), Journal of
`Biological Chemistry 278:26258-26264; N. J. Horwood, et
`al., (2003), The Journal of Experimental Medicine 197:1603- 40
`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.
`
`SUMMARY OF THE INVENTION
`
`45
`
`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 50
`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 55
`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- 60
`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 65
`Formula (D), and pharmaceutically acceptable salts, Solvates,
`esters, acids and prodrugs thereof. In certain embodiments,
`
`2
`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
`
`11
`
`Formula (D)
`
`NH2
`
`N1N DO 2
`
`Y.
`NZ
`
`Rs
`
`R6
`
`R
`
`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
`alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,
`and heteroaryl:
`Z is C(=O), OC(=O), NHC(=O), C(=S), S(=O),
`OS(=O), NHS(=O), where x is 1 or 2:
`R, and Rs are independently selected from among H.
`unsubstituted C-C alkyl, Substituted C-C alkyl,
`unsubstituted
`C-Cheteroalkyl,
`substituted
`C-Cheteroalkyl, unsubstituted C-Cacycloalkyl, Sub
`stituted
`C-Cacycloalkyl,
`unsubstituted
`C-Cheterocycloalkyl,
`and
`Substituted
`C-Cheterocycloalkyl, or
`R, and Rs taken together form a bond;
`R is H, substituted or unsubstituted C-C alkyl, substi
`tuted
`O
`unsubstituted
`C-Cheteroalkyl,
`C-Calkoxyalkyl, C-Calkylaminoalkyl, substituted
`or unsubstituted C-Cacycloalkyl, Substituted or unsub
`stituted
`aryl,
`substituted
`or
`unsubstituted
`C-Cheterocycloalkyl, substituted or unsubstituted het
`eroaryl, C-C alkyl(aryl), C-C alkyl(heteroaryl),
`C-C alkyl (C-Cacycloalkyl),
`or C-C alkyl (C-
`Cheterocycloalkyl); and
`pharmaceutically active metabolites, or pharmaceutically
`acceptable Solvates, pharmaceutically acceptable salts, or
`pharmaceutically acceptable prodrugs thereof.
`For any and all of the embodiments, substituents can be
`selected from among from a subset of the listed alternatives.
`For example, in some embodiments, L is CH, O, or NH. In
`other embodiments, L is O or NH. In yet other embodiments,
`L is O.
`In some embodiments, Aris a substituted or unsubstituted
`aryl. In yet other embodiments, Ar is a 6-membered aryl. In
`Some other embodiments, Ar is phenyl.
`In some embodiments, X is 2. In yet other embodiments, Z
`is C(=O), OC(=O), NHC(=O), S(=O), OS(=O), or
`NHS(=O). In some other embodiments, Z is C(=O), NHC
`(=O), O S(=O).
`
`SAN EX 1013, Page 10
`
`

`

`US 7,514,444 B2
`
`10
`
`15
`
`3
`In Some embodiments, R, and Rs are independently
`selected from among H. unsubstituted C-C alkyl, Substi
`tuted C-C alkyl, unsubstituted C-Cheteroalkyl, and Sub
`stituted C-Cheteroalkyl; or R, and Rs taken togetherform a
`bond. In yet other embodiments, each of R, and Rs is H; or R,
`and Rs taken together form a bond.
`In some embodiments, R is H, substituted or unsubstituted
`C-C alkyl, Substituted or unsubstituted C-Cheteroalkyl,
`C-Calkoxyalkyl, C-Calkylaminoalkyl, Substituted or
`unsubstituted aryl, substituted or unsubstituted heteroaryl,
`C-C alkyl(aryl), C-C alkyl(heteroaryl), C-C alkyl (C-
`Cscycloalkyl), or C-C alkyl(C-Csheterocycloalkyl). In
`some other embodiments, R is H, substituted or unsubsti
`tuted C-C alkyl,
`substituted
`or
`unsubstituted
`C-Cheteroalkyl, C-Calkoxyalkyl, C-C alkyl-N(C-
`Calkyl).
`C-C alkyl(aryl),
`C-C alkyl(heteroaryl),
`C-C alkyl (C-C scycloalkyl).
`O
`C-C alkyl (C-
`Cheterocycloalkyl). In yet other embodiments, R is H. Sub
`stituted or unsubstituted C-C alkyl, -CH2—O—(C-
`Calkyl), —CH2—N(C-C alkyl), C-C alkyl(phenyl), or
`C-C alkyl (5- or 6-membered heteroaryl). In yet other
`embodiments, R is H, substituted or unsubstituted
`C-C alkyl, -CH2—O—(C-C alkyl). —CH2—(C-
`Calkylamino), C-C alkyl(phenyl), or C-C alkyl(5- or
`6-membered heteroaryl). In some embodiments, R is H.
`25
`Substituted or unsubstituted C-C alkyl, -CH2—O—(C-
`Calkyl), —CH2—N(C-C alkyl), C-C alkyl(phenyl), or
`C-C alkyl (5- or 6-membered heteroaryl containing 1 or 2N
`atoms), or C-C alkyl (5- or 6-membered heterocycloalkyl
`containing 1 or 2 Natoms).
`In some embodiments, Y is an optionally substituted group
`selected from among alkyl, heteroalkyl, cycloalkyl, and het
`erocycloalkyl. In other embodiments, Y is an optionally sub
`stituted group selected from among C-Calkyl,
`C-Cheteroalkyl, 4-, 5-, 6-, or 7-membered cycloalkyl, and
`4-, 5-, 6-, or 7-membered heterocycloalkyl. In yet other
`embodiments, Y is an optionally Substituted group selected
`from among C-Calkyl, C-Cheteroalkyl, 5- or 6-mem
`bered cycloalkyl, and 5- or 6-membered heterocycloalkyl
`containing 1 or 2 Natoms. In some other embodiments, Y is
`a 5- or 6-membered cycloalkyl, or a 5- or 6-membered het
`erocycloalkyl containing 1 or 2 Natoms. In some embodi
`ments, Y is a 4-, 5-, 6-, or 7-membered cycloalkyl ring; or Y
`is a 4-, 5-, 6-, or 7-membered heterocycloalkyl ring.
`Any combination of the groups described above for the
`various variables is contemplated herein. It is understood that
`Substituents and Substitution patterns on the compounds pro
`vided herein can be selected by one of ordinary skill in the art
`to provide compounds that are chemically stable and that can
`be synthesized by techniques known in the art, as well as
`those set forth herein.
`In one aspect, provided herein is a compound selected from
`among:
`1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo 3,4-dpy
`rimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound
`4); (E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo
`3,4-dipyrimidin-1-yl)piperidin-1-yl)but-2-en-1-one
`(Compound 5): 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H
`pyrazolo 3,4-dipyrimidin-1-yl)piperidin-1-yl)sulfo
`nylethene (Compound 6): 1-(3-(4-amino-3-(4-phenox
`yphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl)piperidin-1-
`yl)prop-2-yn-1-one (Compound 8): 1-(4-(4-amino-3-(4-
`phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl)
`piperidin-1-yl)prop-2-en-1-one (Compound 9); N-(1S,
`4S)-4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo 3,4-d
`pyrimidin-1-yl)cyclohexyl)acrylamide (Compound 10);
`1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo.3,
`
`35
`
`4
`4-dpyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one
`(Compound 11): 1-((S)-3-(4-amino-3-(4-phenoxyphe
`nyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl)pyrrolidin-1-yl)
`prop-2-en-1-one (Compound 12): 1-((R)-3-(4-amino-3-
`(4-phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl)
`piperidin-1-yl)prop-2-en-1-one (Compound 13): 1-((S)-3-
`(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo 3,4-d
`pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one
`(Compound 14); and (E)-1-(3-(4-amino-3-(4-phenox
`yphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl)piperidin-1-
`yl)-4-(dimethylamino)but-2-en-1-one (Compound 15).
`In a further aspect are provided pharmaceutical composi
`tions, which include a therapeutically effective amount of at
`least one of any of the compounds herein, or a pharmaceuti
`cally acceptable salt, pharmaceutically active metabolite,
`pharmaceutically acceptable prodrug, or pharmaceutically
`acceptable solvate. In certain embodiments, compositions
`provided herein further include a pharmaceutically accept
`able diluent, excipient and/or binder.
`Pharmaceutical compositions formulated for administra
`tion by an appropriate route and means containing effective
`concentrations of one or more of the compounds provided
`herein, or pharmaceutically effective derivatives thereof, that
`deliver amounts effective for the treatment, prevention, or
`amelioration of one or more symptoms of diseases, disorders
`or conditions that are modulated or otherwise affected by
`tyrosine kinase activity, or in which tyrosine kinase activity is
`implicated, are provided. The effective amounts and concen
`trations are effective forameliorating any of the symptoms of
`any of the diseases, disorders or conditions disclosed herein.
`In certain embodiments, provided herein is a pharmaceu
`tical composition containing: i) a physiologically acceptable
`carrier, diluent, and/or excipient; and ii) one or more com
`pounds provided herein.
`In one aspect, provided herein are methods for treating a
`patient by administering a compound provided herein. In
`some embodiments, provided herein is a method of inhibiting
`the activity of tyrosine kinase(s). Such as Btk, or of treating a
`disease, disorder, or condition, which would benefit from
`inhibition of tyrosine kinase(s). Such as Btk, in a patient,
`which includes administering to the patient a therapeutically
`effective amount of at least one of any of the compounds
`herein, orpharmaceutically acceptable salt, pharmaceutically
`active metabolite, pharmaceutically acceptable prodrug, or
`pharmaceutically acceptable Solvate.
`In another aspect, provided herein is the use of a compound
`disclosed herein for inhibiting Bruton's tyrosine kinase (Btk)
`activity or for the treatment of a disease, disorder, or condi
`tion, which would benefit from inhibition of Bruton's
`tyrosine kinase (Btk) activity.
`In some embodiments, compounds provided herein are
`administered to a human.
`In some embodiments, compounds provided herein are
`orally administered.
`In other embodiments, compounds provided herein are
`used for the formulation of a medicament for the inhibition of
`tyrosine kinase activity. In some other embodiments, com
`pounds provided herein are used for the formulation of a
`medicament for the inhibition of Bruton's tyrosine kinase
`(Btk) activity.
`Articles of manufacture including packaging material, a
`compound or composition or pharmaceutically acceptable
`derivative thereof provided herein, which is effective for
`inhibiting the activity of tyrosine kinase(s). Such as Btk,
`within the packaging material, and a label that indicates that
`the compound or composition, or pharmaceutically accept
`able salt, pharmaceutically active metabolite, pharmaceuti
`
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`US 7,514,444 B2
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`5
`cally acceptable prodrug, orpharmaceutically acceptable sol
`vate thereof, is used for inhibiting the activity of tyrosine
`kinase(s). Such as Btk, are provided.
`In another aspectare inhibited tyrosine kinases comprising
`a Bruton's tyrosine kinase, a Bruton's tyrosine kinase
`homolog, or a Btk tyrosine kinase cysteine homolog thereof
`covalently bound to an inhibitor having the structure:
`
`6
`titis, meningitis, myelitis myocarditis, myositis, nephritis,
`oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis,
`pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,
`pneumonitis, pneumonia, proctitis, prostatitis, pyelonephri
`tis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, ten
`donitis, tonsillitis, uveitis, vaginitis, vasculitis, or Vulvitis.
`In further embodiments, the subject in need is suffering
`from a cancer. In one embodiment, the cancer is a B-cell
`proliferative disorder, e.g., diffuse large B cell lymphoma,
`follicular lymphoma, chronic lymphocytic lymphoma,
`chronic lymphocytic leukemia, B-cell prolymphocytic leuke
`mia, lymphoplanascytic lymphoma?Waldenström macroglo
`bulinemia, splenic marginal Zone lymphoma, plasma cell
`myeloma, plasmacytoma, extranodal marginal Zone B cell
`lymphoma, nodal marginal Zone B cell lymphoma, mantle
`cell lymphoma, mediastinal (thymic) large B cell lymphoma,
`intravascular large B cell lymphoma, primary effusion lym
`phoma, burkitt lymphomafleukemia, or lymphomatoid
`granulomatosis. In some embodiments, where the Subject is
`Suffering from a cancer, an anti-cancer agent is administered
`to the subject in addition to one of the above-mentioned
`compounds. In one embodiment, the anti-cancer agent is an
`inhibitor of mitogen-activated protein kinase signaling, e.g.,
`U0126, PD98059, PD184352, PD0325901, ARRY-142886,
`SB239063, SP600 125, BAY 43-9006, wortmannin, or
`LY2940O2.
`In further embodiments, the subject in need is suffering
`from a thromboembolic disorder, e.g., myocardial infarct,
`angina pectoris, reocclusion after angioplasty, restenosis after
`angioplasty, reocclusion after aortocoronary bypass, resteno
`sis after aortocoronary bypass, stroke, transitory ischemia, a
`peripheral arterial occlusive disorder, pulmonary embolism,
`or deep venous thrombosis.
`In a further aspect, provided herein is a method for treating
`an autoimmune disease by administering to a subject in need
`thereof a composition containing a therapeutically effective
`amount of at least one compound having the structure of any
`of Formula (A). Formula (B), Formula (C), or Formula (D). In
`one embodiment, the autoimmune disease is arthritis. In
`another embodiment, the autoimmune disease is lupus. In
`Some embodiments, the autoimmune disease is inflammatory
`bowel disease (including Crohn's disease and ulcerative coli
`tis), rheumatoid arthritis, psoriatic arthritis, osteoarthritis,
`Still's disease, juvenile arthritis, lupus, diabetes, myasthenia
`gravis, Hashimoto's thyroiditis, Ord’s thyroiditis, Graves
`disease Sjögren's syndrome, multiple Sclerosis, Guillain
`Barré syndrome, acute disseminated encephalomyelitis,
`Addison's disease, opSoclonus-myoclonus syndrome, anky
`losing spondylitisis, antiphospholipid antibody syndrome,
`aplastic anemia, autoimmune hepatitis, coeliac disease,
`Goodpasture's syndrome, idiopathic thrombocytopenic pur
`pura, optic neuritis, Scleroderma, primary biliary cirrhosis,
`Reiter's syndrome, Takayasu's arteritis, temporal arteritis,
`warm autoimmune hemolytic anemia, Wegener's granuloma
`tosis, psoriasis, alopecia universalis, Behcet’s disease,
`chronic fatigue, dysautonomia, endometriosis, interstitial
`cystitis, neuromyotonia, Scleroderma, or Vulvodynia.
`In a further aspect, provided herein is a method for treating
`a heteroimmune condition or disease by administering to a
`Subject in need thereof a composition containing a therapeu
`tically effective amount of at least one compound having the
`structure of any of Formula (A), Formula (B), Formula (C), or
`Formula (D). In some embodiments, the heteroimmune con
`dition or disease is graft versus host disease, transplantation,
`transfusion, anaphylaxis, allergy, type I hypersensitivity,
`allergic conjunctivitis, allergic rhinitis, or atopic dermatitis.
`
`Air
`
`11
`
`NH2
`
`N1 N C.
`
`2
`
`Y.
`NZ
`
`R8
`
`R6
`
`R7,
`
`10
`
`15
`
`25
`
`wherein viv indicates the point of attachment between the
`inhibitor and the tyrosine kinase. In a further embodiment, the
`inhibitor is covalently bound to a cysteine residue on the
`tyrosine kinase.
`In a further aspect, provided herein is a method for inhib
`iting Bruton's tyrosine kinase in a subject in need thereof by
`administering to the Subject thereof a composition containing
`a therapeutically effective amount of at least one compound
`having the structure of any of Formula (A). Formula (B),
`Formula (C), or Formula (D). In some embodiments, the
`Subject in need is suffering from an autoimmune disease, e.g.,
`inflammatory bowel disease, arthritis, lupus, rheumatoid
`arthritis, psoriatic arthritis, osteoarthritis, Still's disease,
`juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's
`thyroiditis, Ord’s thyroiditis, Graves disease Sjögren's syn
`drome, multiple sclerosis, Guillain-Barré syndrome, acute
`disseminated encephalomyelitis. Addison's disease, opSoclo
`nus-myoclonus syndrome, ankylosing
`spondylitisis,
`antiphospholipid antibody syndrome, aplastic anemia,
`autoimmune hepatitis, coeliac disease, Goodpasture’s Syn
`drome, idiopathic thrombocytopenic purpura, optic neuritis,
`Scleroderma, primary biliary cirrhosis, Reiter's syndrome,
`Takayasu's arteritis, temporal arteritis, warm autoimmune
`hemolytic anemia, Wegener's granulomatosis, psoriasis,
`alopecia universalis, Behcet’s disease, chronic fatigue, dys
`autonomia, endometriosis, interstitial cystitis, neuromyoto
`nia, Scleroderma, or Vulvodynia.
`In other embodiments, the subject in need is suffering from
`a heteroimmune condition or disease, e.g., graft versus host
`disease, transplantation, transfusion, anaphylaxis, allergy,
`type I hyperSensitivity, allergic conjunctivitis, allergic rhini
`tis, or atopic dermatitis.
`In certain embodiments, the Subject in need is Suffering
`from an inflammatory disease, e.g., asthma, appendicitis, ble
`pharitis, bronchiolitis, bronchitis, bursitis, cerviciitis, cholan
`gitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoad
`enitis,
`dermatitis,
`dermatomyositis,
`encephalitis,
`endocarditis, endometritis, enteritis, enterocolitis, epi
`condylitis, epididymitis, fasciitis, fibrositis, gastritis, gastro
`enteritis, hepatitis, hidradenitis Suppurativa, laryngitis, mas
`
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`7
`In a further aspect, provided herein is a method for treating
`an inflammatory disease by administering to a Subject in need
`thereof a composition containing a therapeutically effective
`amount of at least one compound having the structure of any
`of Formula (A). Formula (B), Formula (C), or Formula (D). In
`Some embodiments, the inflammatory disease is asthma,
`inflammatory bowel disease (including Crohn's disease and
`ulcerative colitis), appendicitis, blepharitis, bronchiolitis,
`bronchitis, bursitis, cerviciitis, cholangitis, cholecystitis, coli
`tis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, der
`matomyositis, encephalitis, endocarditis, endometritis,
`enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,
`fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis Sup
`purativa, laryngitis, mastitis, meningitis, myelitis myocardi
`tis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis,
`pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,
`pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, pros
`tatitis, pyelonephritis, rhinitis, Salpingitis, sinusitis, Stomati
`tis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, Vascu
`litis, or Vulvitis.
`In yet another aspect, provided herein is a method for
`treating a cancer by administering to a Subject in need thereof
`a composition containing a therapeutically effective amount
`of at least one compound having the structure of any of
`Formula (A). Formula (B), Formula (C), or Formula (D). In
`one embodiment, the cancer is a B-cell proliferative disorder,
`e.g., diffuse large B cell lymphoma, follicular lymphoma,
`chronic lymphocytic lymphoma, chronic lymphocytic leuke
`mia, B-cell prolymphocytic leukemia, lymphoplanascytic
`lymphoma?Waldenström macroglobulinemia, splenic