(12)
`
`United States Patent
`Verner
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,732,454 B2
`Jun. 8, 2010
`
`US007732454B2
`
`(54) INHIBITORS OF BRUTON'S TYROSINE
`KNASE
`
`(75) Inventor: Erik Verner, San Mateo, CA (US)
`
`(73) Assignee: Pharmacyclics, Inc., Sunnyvale, CA
`(US)
`
`(*) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 112 days.
`
`(21) Appl. No.: 11/692,870
`1-1.
`(22) Filed:
`
`(65)
`
`Mar. 28, 2007
`O
`O
`Prior Publication Data
`US 2008/0076921 A1
`Mar 27, 2008
`ar. Z. f.
`Related U.S. Application Data
`inn-in-
`(63) States E" application No. 1 1/617,645,
`ed. On Dec. ZS,
`(60) Provisional application No. 60/826,720, filed on Sep.
`22, 2006, provisional application No. 60/828,590,
`filed on Oct. 6, 2006
`• as
`
`(51) Int. Cl.
`(2006.01)
`AOIN 43/90
`(2006.01)
`AOIN 25/00
`(2006.01)
`A 6LX 3/59
`(2006.01)
`A6 IK 47/00
`(2006.01)
`CO7D 487/00
`(2006.01)
`CO7D 487/12
`(2006.01)
`CO7D 49/00
`C Ee C
`(
`.01)
`CI2N 9/12
`(2006.01)
`(52) U.S. Cl. .................... 514/262.1: 514/789: 544/184:
`544/262:544/350; 435/194
`(58) Field of Classification Search ....................... None
`See application file for complete search history.
`References Cited
`
`(56)
`
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`
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`
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`OTHER PUBLICATIONS
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`vol. 5, Jul. 2006, pp. 564-576.
`Burchat et al., “Pyrazolo 3,4-dipyrimidines Containing an Extended
`3-Substituent as Potent Inhibitors of Lck—a Selectivity Insight.”
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`Cohen, M.S. et al., “Structural Bioinformatics-Based Design of
`Selective, Irreversible Kinase Inhibitors.” Science, vol.308, May 27,
`2005, pp. 1318-1321.
`-- - 9
`Desiderio. S., “Role of Btk in B cell develo
`a
`pment 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
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`324 (Jul. 2002).
`Horwood, Nicole J. et al., “Bruton's Tyrosin Kinase Is Required for
`Lipopolysaccharide—induced Tumor Necrosis Factor O. Produc
`tion.” 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).
`
`(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 imidazo 1.5-f1.2.4 triazine com
`pounds that form covalent bonds with Bruton's tyrosine
`kinase (Btk). The imidazo 1.5-f1.2.4 triazine compounds
`described are irreversible inhibitors of Btk. Methods for the
`preparation of the imidazo 1.5-f1.2.4 triazine compounds
`are disclosed. Also disclosed are pharmaceutical composi
`tions that include the imidazo 1.5-f1.2.4 triazine com
`pounds. Methods of using the imidazo 1.5-f1.2.4 triazine
`Btk inhibitors 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.
`
`12 Claims, 7 Drawing Sheets
`
`SANDOZ INC.
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`IPR2023-00478
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`

`

`US 7,732.454 B2
`Page 2
`
`OTHER PUBLICATIONS
`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).
`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).
`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).
`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.
`15.
`“Tyrosine Kinase Inhibitors.
`al.,
`et
`Smaill, J.B.
`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).
`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).
`PCT/US06/49626 Search Report dated Apr. 9, 2008.
`Vippagunta et al., “Crystalline Solids.” Advanced Drug Delivery
`Reviews 48:3-26 (2001).
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`Weinheim p. IX of Preface, Wiley-VCH, Verglag GmbH & Co.
`KGaA (2005).
`U.S. Appl. No. 1 1/964,285, filed Dec. 26, 2007, Honigberg.
`* cited by examiner
`
`SANDOZ INC.
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`

`

`U.S. Patent
`
`Jun. 8, 2010
`
`Sheet 1 of 7
`
`US 7,732.454 B2
`
`
`
`- - - - O - - - A - D - Z.
`
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`
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`
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`
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`
`T. T. r. T Cy Cy Cy T. T. T. T. T.
`
`|- H|-| H. L. H. HE-Id - H -->
`
`HD D > D H > D > D H H >
`
`s: 322; 332;
`
`SANDOZ INC.
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`

`U.S. Patent
`U.S. Patent
`
`Jun. 8, 2010
`
`Sheet 2 of 7
`
`US 7,732.454 B2
`US 7,732,454 B2
`
`
`
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`
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`
`SANDOZINC.
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`

`

`U.S. Patent
`
`Jun. 8, 2010
`
`Sheet 3 of 7
`
`US 7,732.454 B2
`
`
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`
`SANDOZ INC.
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`

`

`U.S. Patent
`
`Jun. 8, 2010
`
`Sheet 4 of 7
`
`US 7,732.454 B2
`
`
`
`intensity, cps
`
`
`
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`
`SANDOZ INC.
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`

`

`U.S. Patent
`
`Jun. 8, 2010
`
`Sheet 5 of 7
`
`US7,732,454 B2
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`
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`

`

`U.S. Patent
`
`Jun. 8, 2010
`
`Sheet 6 of 7
`
`US 7,732.454 B2
`
`
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`SANDOZ INC.
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`

`

`U.S. Patent
`
`US 7,732.454 B2
`
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`

`

`1.
`INHIBITORS OF BRUTON'S TYROSINE
`KNASE
`
`RELATED APPLICATIONS
`
`This application is a continuation-in-part patent applica
`tion of U.S. patent application Ser. No. 1 1/617,645 filed Dec.
`28, 2006, which claims benefit of U.S. Provisional Applica
`tion No. 60/826,720 entitled “INHIBITORS OF BRUTON'S
`TYROSINE KINASE filed Sep. 22, 2006; and U.S. Provi
`sional Application No. 60/828,590 entitled “INHIBITORS
`OF BRUTONSTYROSINE KINASE filed Oct. 6, 2006, all
`of which are herein incorporated by reference.
`
`FIELD OF THE INVENTION
`
`10
`
`15
`
`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
`kinases.
`
`BACKGROUND OF THE INVENTION
`
`25
`
`30
`
`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-lin
`eage lymphoid cells, and collagen-stimulated platelet aggre
`gation. See, e.g., C. A. Jeffries, et al., (2003), Journal of 40
`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.
`
`45
`
`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
`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 (A1-A6), Formula (B1-B6), For
`
`50
`
`55
`
`60
`
`65
`
`US 7,732,454 B2
`
`2
`mula (C1-C6), or Formula (D1-D6), and pharmaceutically
`acceptable salts, Solvates, esters, acids and prodrugs thereof.
`In certain embodiments, isomers and chemically protected
`forms of compounds having a structure represented by any of
`Formula (A1-A6). Formula (B1-B6), Formula (C1-C6), or
`Formula (D1-D6), are also provided.
`In one aspect, provided herein are compounds of Formula
`(D1-D6). Formula (D1-D6) are as follows:
`
`Air
`
`I-1
`
`Formula (D1)
`
`NH2
`
`N1 N C.
`
`2
`
`Y.
`n Z
`
`R6
`
`R8
`
`R7
`
`I-Ar
`
`Formula (D2)
`
`NH2
`
`CC)
`N - Y.
`
`n Z
`
`R6
`
`R8
`
`R7
`
`I-Ar
`
`Formula (D3)
`
`NH2 C
`ls l/
`
`N 2
`
`N
`
`N
`
`Y.
`n Z
`
`R6
`
`Rs
`
`R
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`

`3
`
`-continued
`
`NH2
`
`4N2
`N
`ls NN /
`N1 sy
`
`Y.
`N Z
`
`R6
`
`Rs
`
`R
`
`NH2
`
`N4Y-2
`
`N
`
`N- s/
`
`Y.
`n Z
`
`R6
`
`R8
`
`R7
`
`Formula (D.6)
`
`35
`
`NH2
`
`N
`N21
`S N
`
`Y.
`n Z
`
`R6
`
`R8
`
`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
`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:
`R7 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
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`US 7,732,454 B2
`
`Formula (D4)
`
`Formula (D5)
`
`10
`
`15
`
`25
`
`30
`
`unsubstituted
`Substituted
`
`4
`C-Cacycloalkyl,
`stituted
`C-Cheterocycloalkyl,
`and
`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).
`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 form 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-Csheteroalkyl). In some
`other embodiments, R is H, substituted or unsubstituted
`C-C alkyl, Substituted or unsubstituted C-Cheteroalkyl,
`C-Calkoxyalkyl, C-C alkyl-N(C-C alkyl), C-C alkyl
`(aryl),
`C-C alkyl(heteroaryl),
`C-C alkyl (C-
`Cscycloalkyl), or C-C alkyl (C-Csheterocycloalkyl). In yet
`other embodiments, R is H, substituted or unsubstituted
`C-C alkyl, —CH2—O—(C-C alkyl), —CH2—N(C-
`Calkyl), C-C alkyl(phenyl), or C-C alkyl(5- or 6-mem
`bered heteroaryl). In yet other embodiments, R is H, substi
`tuted or unsubstituted C-C alkyl, —CH2—O—(C-
`Calkyl), —CH2—(C-Calkylamino), C-C alkyl(phenyl),
`or C-C alkyl(5- or 6-membered heteroaryl). In some
`embodiments, R is H, substituted or unsubstituted
`C-C alkyl, —CH2—O—(C-C alkyl), —CH2—N(C-
`Calkyl), C-C alkyl(phenyl), or C-C alkyl(5- or 6-mem
`bered heteroaryl containing 1 or 2 Natoms), 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
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1025, p. 11 of 76
`
`

`

`5
`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-dipyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one
`(Compound 4); (E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-
`1H-pyrazolo 3,4-dpyrimidin-1-yl)piperidin-1-yl)but-2-en
`1-one (Compound 5): 1-(3-(4-amino-3-(4-phenoxyphenyl)-
`1H-pyrazolo 3,4-dpyrimidin-1-yl)piperidin-1-yl)
`sulfonylethene (Compound 6):
`1-(3-(4-amino-3-(4-
`phenoxyphenyl)-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 3,4-
`dpyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one (Com
`pound 11): 1-((S)-3-(4-amino-3-(4-phenoxyphenyl)-1H
`30
`pyrazolo 3,4-dipyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-
`O
`(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-dipyrimidin
`1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 14); and
`(E)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo 3,4-
`dpyrimidin-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 for ameliorating 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
`
`6
`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
`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 structures:
`
`Air
`
`11
`
`NH2
`
`N1 N C.
`
`2
`
`Y.
`NZ
`
`R6
`
`R8
`
`R
`7 s
`
`US 7,732,454 B2
`
`10
`
`15
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1025, p. 12 of 76
`
`

`

`US 7,732,454 B2
`
`7
`
`-continued
`
`-continued
`- Ar
`
`NH2
`
`N -
`
`Y R6
`
`R
`w
`
`R8
`I-Ar
`
`NH2 C)
`ls
`/
`
`N21
`
`N
`
`N
`
`Y R6
`
`Rs
`
`R
`w
`
`NH
`
`4N2
`N
`ls NN /
`N1 sy
`Ya,
`
`R6
`
`Rs
`
`R
`w
`
`NH2
`
`N4Y-2
`
`N
`
`N--
`
`Y R6
`
`R8
`
`R
`7
`
`10
`
`15
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`NH2
`
`N
`N21
`N N
`
`Y.
`NZ
`
`Rs
`
`R6
`
`R7
`
`, wherein v
`
`wherein indicates the point of attachment between the inhibi
`tor 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 (A1-A6). Formula
`(B1-B6), Formula (C1-C6), or Formula (D1-D6). In some
`embodiments, the subject in need is suffering from an autoim
`mune 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 syndrome, multiple sclerosis, Guillain-Barré syn
`drome, acute disseminated encephalomyelitis, Addison's dis
`ease,
`opSoclonus-myoclonus
`syndrome,
`ankylosing
`spondylitisis, antiphospholipid antibody syndrome, aplastic
`anemia, autoimmune hepatitis, coeliac disease, Goodpas
`ture's syndrome, idiopathic thrombocytopenic purpura, optic
`neuritis, Scleroderma, primary biliary cirrhosis, Reiter's Syn
`drome, Takayasu's arteritis, temporal arteritis, warm autoim
`mune hemolytic anemia, Wegener's granulomatosis, psoria
`sis, alopecia universalis, Behcet’s disease, chronic fatigue,
`dysautonomia, endometriosis, interstitial cystitis, neuromyo
`tonia, 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
`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.
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1025, p. 13 of 76
`
`

`

`US 7,732,454 B2
`
`10
`
`15
`
`30
`
`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, lymphoplasmacytic 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 (A1-A6), Formula (B1-B6), Formula (C1-C6), or
`Formula (D1-D6). In one embodiment, the autoimmune dis
`ease is arthritis. In another embodiment, the autoimmune
`disease is lupus. In some embodiments, the autoimmune dis
`ease is inflammatory bowel disease (including Crohn's dis
`ease and ulcerative colitis), 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, mul
`40
`tiple sclerosis, Guillain-Barré syndrome, acute disseminated
`encephalomyelitis, Addison's disease, opSoclonus-myoclo
`nus syndrome, ankylosing spondylitisis, antiphospholipid
`antibody syndrome, aplastic anemia, autoimmune hepatitis,
`coeliac disease, Goodpasture's syndrome, idiopathic throm
`bocytopenic 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,
`Behget's
`disease,
`chronic
`fatigue,
`dysautonomia,
`endometriosis, interstitial cystitis, neuromyotonia, Sclero
`derma, 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 (A1-A6), Formula (B1-B6), For
`mula (C1-C6), or Formula (D1-D6). In some embodiments,
`the heteroimmune condition or disease is graft versus host
`disease, transplantation, transfusion, anaphylaxis, allergy,
`type I hyperSensitivity, allergic conjunctivitis, allergic rhini
`tis, or atopic dermatitis.
`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 (A1-A6). Formula (B1-B6), Formula (C1-C6), or
`
`10
`Formula (D1-D6). In some embodiments, the inflammatory
`disease is asthma, inflammatory bowel disease (including
`Crohn's disease and ulcerative colitis), appendicitis, ble
`p