(19) United States
`(12) Patent Application Publication (10) Pub. N0.2 US 2008/0139582 A1
`HONIGBERG et a].
`(43) Pub. Date:
`Jun. 12, 2008
`
`US 20080139582A1
`
`(54) INHIBITORS OF BRUTON’S TYROSINE
`KINASE
`
`(75) Inventors:
`
`Lee HONIGBERG, San Francisco,
`CA (Us); Erik VERNER,
`Belmont, CA (US); Zhengying
`PAN,A1pharetIa,GA(U$)
`
`Correspondence Address:
`WILSON SONSINI GOODRICH & ROSATI
`650 PAGE MILL ROAD
`PALO ALTO’ CA 943044050
`
`(73) Assignee:
`
`PHARMACYCLICS, INC.,
`Sunnyvale, CA (U S)
`
`(21) Appl NO .
`'
`ii
`22 F1 (12
`(
`)
`1 e
`
`11/964 285
`’
`D _ 26 2007
`ec
`’
`
`.
`.
`Related U's' Apphcatlon Data
`(63) Continuation-in-part of application No, 11/692,870,
`?led on Mar. 28, 2007, Which is a continuation-in-part
`ofapplication No. 11/617,645, ?led on Dec. 28, 2006.
`
`(60) Provisional application No. 60/826,720, ?led on Sep.
`22, 2006, provisional application No. 60/828,590,
`?led on Oct. 6, 2006.
`_
`_
`_
`_
`Publication Classi?cation
`
`(51) Int CL
`(2006.01)
`C07D 487/04
`(2006.01)
`A61K 31/519
`(200601)
`(‘121V 9/99
`(200601)
`A611) 35/00
`(2006.01)
`A61P 37/00
`(52) us. Cl. ..................... .. 514/262.1; 544/262; 435/184
`
`ABSTRACT
`
`(57)
`_
`_
`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 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 in?ammatory diseases or
`conditions.
`
`Irreversible Inhibitor
`
`%
`g
`
`7.5
`
`1.9
`
`algM
`Compound 4 (uM)
`.47
`.12
`.03
`
`E»
`DMSO 2
`
`.007
`
`pY551 Btk
`
`pY783 PLCy1
`
`Total Btk
`
`Total PLCy1
`
`Coalition for Affordable Drugs IV LLC – Exhibit 1003
`
`

`

`Patent Application Publication
`
`Jun. 12, 2008 Sheet 1 of 7
`
`US 2008/0139582 A1
`
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`

`Patent Application Publication
`
`Jun. 12, 2008 Sheet 2 0f 7
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`US 2008/0139582 A1
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`

`Patent Application Publication
`
`Jun. 12, 2008 Sheet 3 0f 7
`
`US 2008/0139582 A1
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`

`

`Patent Application Publication
`
`Jun. 12, 2008 Sheet 4 0f 7
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`US 2008/0139582 A1
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`Patent Application Publication
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`Jun. 12, 2008 Sheet 5 0f 7
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`US 2008/0139582 A1
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`Patent Application Publication
`
`Jun. 12, 2008 Sheet 6 0f 7
`
`US 2008/0139582 A1
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`

`Patent Application Publication
`
`Jun. 12, 2008 Sheet 7 0f 7
`
`US 2008/0139582 Al
`
`
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`

`

`US 2008/0139582 A1
`
`Jun. 12, 2008
`
`INHIBITORS OF BRUTON’S TYROSINE
`KINASE
`
`RELATED APPLICATIONS
`
`[0001] This application is a continuation-in-part patent
`application of Us. patent application Ser. No. 11/692,870
`?led Mar. 28, 2007 Which is a continuation-in-part of Us.
`patent application Ser. No. 11/617,645 ?led Dec. 28, 2006,
`the latter tWo of Which claim the bene?t of Us. Provisional
`Patent Application No. 60/826,720, ?led Sep. 22, 2006 and
`Us. Provisional PatentApplication No. 60/ 828,590 ?led Oct.
`6, 2006; all of Which are herein incorporated by reference.
`
`FIELD OF THE INVENTION
`
`[0002] Described herein are compounds, methods of mak
`ing such compounds, pharmaceutical compositions and
`medicaments containing such compounds, and methods of
`using such compounds and compositions to inhibit the activ
`ity of tyrosine kinases.
`
`BACKGROUND OF THE INVENTION
`
`[0003] 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
`lymphocytes 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.
`[0004] Btk is a key regulator of B-cell development, acti
`vation, signaling, and survival (Kurosaki, Curr Op [mm
`2000, 276-281; Schaeffer and SchWartZberg, Curr Op [mm
`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-ot pro
`duction in macrophages, IgE receptor (FcepsilonRI) signal
`ing in Mast cells, inhibition of Fas/APO-l apoptotic signaling
`in B-lineage lymphoid cells, and collagen-stimulated platelet
`aggregation. See, e.g., C.A. Jeffries, et al., (2003), Journal of
`Biological Chemistry 278:26258-26264; N. J. HorWood, et
`al., (2003), The Journal ofExperimentalMedicine 197: 1 603
`1611; IWaki et al. (2005), Journal ofBiological Chemistry
`280(48):40261-40270; Vassilev et al. (1999), Journal ofBio
`logical Chemistry 274(3): 1 646-1656, and Quek et al. (1998),
`Current Biology 8(20):1137-1140.
`
`SUMMARY OF THE INVENTION
`
`[0005] 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 bene?t to a patient having the
`disease). Further described are pharmaceutical formulations
`that include an irreversible inhibitor of Btk.
`[0006] Compounds described herein include those that
`have a structure of any of Formula (A1-A6), Formula (B1
`B6), Formula (C1-C6), or Formula (D1-D6), and pharmaceu
`tically acceptable salts, solvates, esters, acids and prodrugs
`thereof. In certain embodiments, isomers and chemically pro
`tected forms of compounds having a structure represented by
`any of Formula (A1-A6), Formula (Bl-B6), Formula (C1
`C6), or Formula (D1-D6), are also provided.
`[0007] In one aspect, provided herein are compounds of
`Formula (D1-D6). Formula (D1-D6) are as folloWs:
`
`AI
`
`La/
`
`Formula (Dl)
`
`NH2
`
`N \ \
`N
`L / /
`N
`l
`Y\Z
`
`NH2
`
`\
`N
`
`R8
`La/AI
`
`l
`Y\Z
`
`R8
`La/AI
`
`R6
`
`R7;
`
`R6
`
`R7;
`
`Formula (D2)
`
`Formula (D3)
`
`NH2 Q
`
`N/ l
`N
`L /
`
`N
`
`Y\Z
`
`R6
`
`R8
`
`R7;
`
`

`

`US 2008/0139582 A1
`
`Jun. 12, 2008
`
`-continued
`La/AI
`
`Formula (D4)
`
`Formula (D5)
`
`NH2
`
`/ /
`2
`
`N y
`
`H
`
`Formula (D 6)
`
`wherein:
`[0008] La is CH2, 0, NH or S;
`[0009] Ar is a substituted or unsubstituted aryl, or a
`substituted or unsubstituted heteroaryl;
`[0010] Y is an optionally substituted group selected from
`among alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,
`aryl, and heteroaryl;
`
`[0012] R7 and R8 are independently selected from among
`H, unsubstituted Cl-C4alkyl, substituted Cl-C4alkyl,
`unsubstituted
`Cl -C4heteroalkyl,
`substituted
`
`Cl-C4heteroalkyl, unsubstituted C3-C6cycloalkyl, sub
`stituted
`C3-C6cycloalkyl,
`unsubstituted
`C2-C6heterocycloalkyl,
`and
`substituted
`C2-C6heterocycloalkyl; or
`[0013] R7 and R8 taken together form a bond;
`[0014] R6 is H, substituted or unsubstituted C l-C4alkyl,
`substituted
`or
`unsubstituted
`Cl-C4heteroalkyl,
`Cl-C6alkoxyalkyl, Cl-Csalkylaminoalkyl, substituted
`or unsubstituted C3 -C6cycloalkyl, substituted or unsub
`stituted
`aryl,
`substituted
`or
`unsubstituted
`C2-C8heterocycloalkyl, substituted or unsubstituted het
`eroaryl,
`Cl-C4alkyl(aryl),
`Cl-C4alkyl(heteroaryl),
`C1-C4alkyl(C3-C8cycloalkyl),
`or
`Cl-C4alkyl(C2
`Csheterocycloalkyl); and
`pharmaceutically active metabolites, or pharmaceutically
`acceptable solvates, pharmaceutically acceptable salts, or
`pharmaceutically acceptable prodrugs thereof.
`[0015] For any and all of the embodiments, substituents can
`be selected from among from a subset of the listed altema
`tives. For example, in some embodiments, La is CH2, 0, or
`NH. In other embodiments, La is O or NH. In yet other
`embodiments, La is O.
`[0016] In some embodiments, Ar is a substituted or unsub
`stituted aryl. In yet other embodiments, Ar is a 6-membered
`aryl. In some other embodiments, Ar is phenyl.
`[0017] In some embodiments, X is 2. In yet other embodi
`ments, Z is C(:O), OC(:O), NHC(:O), S(:O)x,
`OS(:O)X, or NHS(:O)X. In some other embodiments, Z is
`C(IO), NHC(:O), or S(:O)2.
`[0018] In some embodiments, R7 and R8 are independently
`selected from among H, unsubstituted Cl-C4 alkyl, substi
`tuted Cl-C4alkyl, unsubstituted Cl-C4heteroalkyl, and sub
`stituted Cl-C4heteroalkyl; or R7 and R8 taken together form a
`bond. In yet other embodiments, each of R7 and R8 is H; or R7
`and R8 taken together form a bond.
`[0019] In some embodiments, R6 is H, substituted or unsub
`stituted
`Cl-C4alkyl,
`substituted
`or
`unsubstituted
`C 1 -C4heteroalkyl,
`C 1 -C6alkoxyalkyl,
`C l -C8alkylaminoalkyl, substituted or unsubstituted aryl, sub
`stituted or unsubstituted heteroaryl, C l-C4alkyl(aryl),
`Cl-C4alkyl(heteroaryl), C1-C4alkyl(C3-C8cycloalkyl), or
`Cl-C4alkyl(C2-C8heterocycloalkyl). In some other embodi
`ments, R6 is H, substituted or unsubstituted C l-C4alkyl, sub
`stituted
`or
`unsubstituted
`Cl -C4heteroalkyl,
`Cl-C6alkoxyalkyl, Cl-C2alkyl-N(Cl-C3alkyl)2, Cl-C4alkyl
`(aryl),
`C l -C4alkyl(heteroaryl),
`C l -C4alkyl(C3 -
`Cscycloalkyl), or C1-C4alkyl(C2-C8heterocycloalkyl). In yet
`other embodiments, R6 is H, substituted or unsubstituted
`Cl-C4alkyl, iCH2iOi(Cl-C3alkyl), iCH2iN(Cl
`C3alkyl)2, Cl-C4alkyl(phenyl), or Cl-C4alkyl(5- or 6-mem
`bered heteroaryl). In yet other embodiments, R6 is H, substi
`tuted or unsubstituted Cl-C4alkyl, 4CH24Oi(C1
`C3alkyl), 4CH2i(Cl-C6alkylamino), Cl-C4alkyl(phenyl),
`or Cl-C4alkyl(5- or 6-membered heteroaryl). In some
`embodiments, R6 is H, substituted or unsubstituted
`Cl-C4alkyl, iCH2iOi(Cl-C3alkyl), iCH2iN(Cl
`C3alkyl)2, Cl-C4alkyl(phenyl), or Cl-C4alkyl (5- or 6-mem
`bered heteroaryl containing 1 or 2 N atoms), or C l-C4alkyl(5
`or 6-membered heterocycloalkyl containing 1 or 2 N atoms).
`[0020] In some embodiments,Y is an optionally substituted
`group selected from among alkyl, heteroalkyl, cycloalkyl,
`and heterocycloalkyl. In other embodiments, Y is an option
`ally substituted group selected from among Cl-C6alkyl,
`Cl-C6heteroalkyl, 4-, 5-, 6-, or 7-membered cycloalkyl, and
`
`

`

`US 2008/0139582 A1
`
`Jun. 12, 2008
`
`4-, 5-, 6-, or 7-membered heterocycloalkyl. In yet other
`embodiments, Y is an optionally substituted group selected
`from among C l-C6alkyl, C l-C6heteroalkyl, 5- or 6-mem
`bered cycloalkyl, and 5- or 6-membered heterocycloalkyl
`containing 1 or 2 N atoms. In some other embodiments, Y is
`a 5- or 6-membered cycloalkyl, or a 5- or 6-membered het
`erocycloalkyl containing 1 or 2 N atoms. In some embodi
`ments, Y is a 4-, 5-, 6-, or 7-membered cycloalkyl ring; orY
`is a 4-, 5-, 6-, or 7-membered heterocycloalkyl ring.
`[0021] Any combination of the groups described above for
`the various variables is contemplated herein.
`[0022] In one aspect, provided herein is a compound
`selected from among:
`[0023] l-(3-(4-amino-3-(4-phenoxyphenyl)-lH-pyraZolo
`[3,4-d]pyrimidin- l -yl)piperidin-l -yl)prop-2-en- 1 -one
`(Compound 4); (E)-l -(3-(4-amino-3-(4-phenoxyphenyl)
`lH-pyraZolo [3 ,4-d]pyrimidin-l -yl)piperidin- l -yl)but-2 -en
`l-one (Compound 5); l-(3-(4-amino-3-(4-phenoxyphenyl)
`lH-pyraZolo [3 ,4-d]pyrimidin-l -yl)piperidin- l -yl)
`sulfonylethene
`(Compound 6);
`l-(3-(4-amino-3-(4
`phenoxyphenyl)- l H-pyraZolo [3 ,4-d]pyrimidin-l -yl)
`piperidin- l -yl)prop-2-yn-l -one (Compound 8); l-(4-(4
`amino -3 -(4-phenoXyphenyl) - l H-pyraZolo [3 ,4 -d] pyrimidin
`l-yl)piperidin-l -yl)prop-2-en-l -one (Compound 9); N-((ls,
`4s) -4-(4 -amino -3 -(4-phenoxyphenyl)- l H-pyraZolo [3 ,4-d]
`pyrimidin- l -yl)cyclohexyl)acrylamide (Compound 10);
`l-((R) -3 -(4-amino-3 -(4 -phenoxyphenyl)- l H-pyraZolo[3 ,4
`d]pyrimidin-l -yl)pyrrolidin-l -yl)prop -2 -en-l -one
`(Com
`pound II);
`l-((S)-3-(4-amino-3-(4-phenoXyphenyl)-lH
`pyraZolo [3 ,4-d]pyrimidin-l -yl)pyrrolidin- l -yl)prop-2-en-l -
`one
`(Compound
`12);
`l-((R)-3-(4-amino-3-(4
`phenoxyphenyl)- l H-pyraZolo [3 ,4-d]pyrimidin-l -yl)
`piperidin- l -yl)prop -2-en-l -one (Compound 13); l-((S)-3-(4
`amino -3 -(4-phenoXyphenyl) - l H-pyraZolo [3 ,4 -d] pyrimidin
`l-yl)piperidin-l-yl)prop-2-en-l-one (Compound 14); and
`(E)-l -(3 -(4-amino-3-(4 -phenoxyphenyl)- l H-pyraZolo[3 ,4
`d]pyrimidin-l -yl)piperidin-l -yl)-4-(dimethylamino)but-2
`en- 1 -one (Compound 15).
`[0024] In a further aspect are provided pharmaceutical
`compositions, Which include a therapeutically effective
`amount of at least one of any of the compounds herein, or a
`pharmaceutically acceptable salt, pharmaceutically active
`metabolite, pharmaceutically acceptable prodrug, or pharma
`ceutically acceptable solvate. In certain embodiments, com
`positions provided herein further include a pharmaceutically
`acceptable diluent, excipient and/or binder.
`[0025] Pharmaceutical compositions formulated for
`administration 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, pre
`vention, or amelioration of one or more symptoms of dis
`eases, 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 concentrations are effective for ameliorating
`any of the symptoms of any of the diseases, disorders or
`conditions disclosed herein.
`[0026] In certain embodiments, provided herein is a phar
`maceutical composition containing: i) a physiologically
`acceptable carrier, diluent, and/or excipient; and ii) one or
`more compounds provided herein.
`[0027] In one aspect, provided herein are methods for treat
`ing a patient by administering a compound provided herein.
`
`In some embodiments, provided herein is a method of inhib
`iting the activity of tyrosine kinase(s), such as Btk, or of
`treating a disease, disorder, or condition, Which Would bene?t
`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, or pharmaceutically acceptable salt, pharmaceutically
`active metabolite, pharmaceutically acceptable prodrug, or
`pharmaceutically acceptable solvate.
`[0028] 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, disor
`der, or condition, Which Would bene?t from inhibition of
`Bruton’s tyrosine kinase (Btk) activity.
`[0029]
`In some embodiments, compounds provided herein
`are administered to a human. In some embodiments, com
`pounds provided herein are orally administered.
`In other embodiments, compounds provided herein
`[0030]
`are used for the formulation of a medicament for the inhibi
`tion of tyrosine kinase activity. In some other embodiments,
`compounds 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 mate
`[0031]
`rial, a compound or composition or pharmaceutically accept
`able 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 prod rug, or pharmaceutically acceptable
`solvate thereof, is used for inhibiting the activity of tyrosine
`kinase(s), such as Btk, are provided.
`[0032]
`In another aspect are 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:
`
`Ar
`
`La/
`
`R6
`
`NH2
`
`N \ L \/N
`
`/
`N
`
`I
`Y
`\Z
`
`R8
`
`R
`7,
`
`

`

`US 2008/0139582 A1
`
`Jun. 12,2008
`
`4
`
`-continued
`Lei/AI
`
`-continued
`La/AI
`
`NHZ
`
`N /
`
`I \
`K N
`N
`|
`Y
`\Z
`
`R6
`
`R8
`
`R7 ,
`
`N
`
`NH
`2
`/ N
`l
`K /
`
`N
`
`Y
`\Z
`
`R6
`
`R8
`
`R
`7
`
`,
`
`zAr
`La
`
`NHZ
`
`N / /
`N
`K N /
`N/ \(
`Y\Z
`
`NH2
`
`N / /
`N
`\ N\(
`Y
`\z
`
`R6
`
`R8
`
`R
`7
`
`,
`
`La/Ar
`
`NH2
`
`N/ | \
`\ N
`l
`
`\z
`
`R8
`
`R6
`
`R
`7
`
`,
`
`wherein
`
`W
`
`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.
`[0033] In a further aspect, provided herein is a method for
`inhibiting 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 (Al-A6),
`Formula (B 1 -B6), Formula (Cl-C6), or Formula (D1 -D6). In
`some embodiments, the subject in need is suffering from an
`autoimmune disease, e.g., in?ammatory 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 Sjogren’s syndrome, multiple sclerosis, Guil
`lain-Barre 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,
`
`

`

`US 2008/0139582 A1
`
`Jun. 12, 2008
`
`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.
`[0034] In other embodiments, the subject in need is suffer
`ing from a heteroimmune condition or disease, e.g., graft
`versus host disease, transplantation, transfusion, anaphylaxis,
`allergy, type I hypersensitivity, allergic conjunctivitis, aller
`gic rhinitis, or atopic dermatitis.
`[0035] In certain embodiments, the subject in need is suf
`fering from an in?ammatory disease, e.g., asthma, appendi
`citis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,
`cholangitis, cholecystitis, colitis, conjunctivitis, cystitis,
`dacryoadenitis, dermatitis, dermatomyositis, encephalitis,
`endocarditis, endometritis, enteritis, enterocolitis, epi
`condylitis, epididymitis, fasciitis, ?brositis, 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.
`[0036] In further embodiments, the subject in need is suf
`fering from a cancer. In one embodiment, the cancer is a
`B-cell proliferative disorder, e.g., diffuse large B cell lym
`phoma, follicular lymphoma, chronic lymphocytic lym
`phoma, chronic lymphocytic leukemia, B-cell prolympho
`cytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom
`macroglobulinemia, splenic marginal Zone lymphoma,
`plasma cell myeloma, plasmacytoma, extranodal marginal
`Zone B cell lymphoma, nodal marginal Zone B cell lym
`phoma, mantle cell lymphoma, mediastinal (thymic) large B
`cell lymphoma, intravascular large B cell lymphoma, primary
`effusion lymphoma, burkitt lymphoma/leukemia, or lym
`phomatoid 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 sig
`naling, e.g., U0l26, PD98059, PD184352, PD0325901,
`ARRY-l42886, SB239063, SP600125, BAY 43-9006, Wort
`mannin, or LY294002.
`[0037] In further embodiments, the subject in need is suf
`fering from a thromboembolic disorder, e. g., myocardial inf
`arct, angina pectoris, reocclusion after angioplasty, restenosis
`after angioplasty, reocclusion after aortocoronary bypass,
`restenosis after aortocoronary bypass, stroke, transitory
`ischemia, a peripheral arterial occlusive disorder, pulmonary
`embolism, or deep venous thrombosis.
`[0038] 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 struc
`ture of any of Formula (Al-A6), Formula (Bl-B6), Formula
`(Cl-C6), or Formula (DI-D6). In one embodiment, the
`autoimmune disease is arthritis. In another embodiment, the
`autoimmune disease is lupus. In some embodiments, the
`autoimmune disease is in?ammatory boWel disease (includ
`ing Crohn’s disease and ulcerative colitis), rheumatoid arthri
`tis, psoriatic arthritis, osteoarthritis, Still’s disease, juvenile
`arthritis, lupus, diabetes, myasthenia gravis, Hashimoto’s
`thyroiditis, Ord’s thyroiditis, Graves’ disease Sjogren’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.
`[0039] In a further aspect, provided herein is a method for
`treating a heteroimmune condition or disease by administer
`ing 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 (Al-A6), Formula
`(Bl-B6), Formula (Cl-C6), or Formula (DI-D6). In some
`embodiments, the heteroimmune condition or disease is graft
`versus host disease, transplantation, transfusion, anaphylaxis,
`allergy, type I hypersensitivity, allergic conjunctivitis, aller
`gic rhinitis, or atopic dermatitis.
`[0040] In a further aspect, provided herein is a method for
`treating an in?ammatory disease by administering to a sub
`ject in need thereof a composition containing a therapeuti
`cally effective amount of at least one compound having the
`structure of any of Formula (Al -A6), Formula (Bl-B6), For
`mula (Cl-C6), or Formula (DI-D6). In some embodiments,
`the in?ammatory disease is asthma, in?ammatory boWel dis
`ease (including Crohn’s disease and ulcerative colitis),
`appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis,
`cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis,
`cystitis,
`dacryoadenitis,
`dermatitis,
`dermatomyositis,
`encephalitis, endocarditis, endometritis, enteritis, enterocoli
`tis, epicondylitis, epididymitis, fasciitis, ?brositis, gastritis,
`gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis,
`mastitis, meningitis, myelitis myocarditis, myositis, nephri
`tis, 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.
`[0041] 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 (Al -A6), Formula (B 1 -B6), Formula (C1 -C6), or
`Formula (D1 -D6). 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/Waldenstrom 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 lymphoma/leukemia, 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.,
`
`

`

`US 2008/0139582 A1
`
`Jun. 12, 2008
`
`U0126, PD98059, PD184352, PD0325901, ARRY-142886,
`SB239063, SP600125, BAY 43-9006, Wortmannin, or
`LY294002.
`[0042] In another aspect, provided herein is a method for
`treating a thromboembolic disorder 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 (Al -A6), Formula (Bl-B6), For
`mula (Cl-C6), or Formula (DI-D6). In some embodiments,
`the thromboembolic disorder is myocardial infarct, angina
`pectoris, reocclusion after angioplasty, restenosis after angio
`plasty, reocclusion after aortocoronary bypass, restenosis
`after aortocoronary bypass, stroke, transitory ischemia, a
`peripheral arterial occlusive disorder, pulmonary embolism,
`or deep venous thrombosis.
`[0043] 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 a compound that forms a covalent bond
`With Bruton’s tyrosine kinase. In one embodiment, the com
`pound forms a covalent bound With the activated form of
`Bruton’s tyrosine kinase. In further or alternative embodi
`ments, the compound irreversibly inhibits the Bruton’s
`tyrosine kinase to Which it is covalently bound. In a further or
`alternative embodiment, the compound forms a covalent
`bond With a cysteine residue on Bruton’s tyrosine kinase.
`[0044] In a further aspect, provided herein is a method for
`treating a heteroimmune condition or disease by administer
`ing to a subject in need thereof a composition containing a
`therapeutically effective amount of a compound that forms a
`covalent bond With Bruton’s tyrosine kinase. In one embodi
`ment, the compound forms a covalent bound With the acti
`vated form of Bruton’s tyrosine kinase. In further or alterna
`tive embodiments, the compound irreversibly inhibits the
`Bruton’s tyrosine kinase to Which it is covalently bound. In a
`further or alternative embodiment, the compound forms a
`covalent bond With a cysteine residue on Bruton’s tyrosine
`kinase.
`[0045] In a further aspect, provided herein is a method for
`treating an in?ammatory disease by administering to a sub
`ject in need thereof a composition containing a therapeuti
`cally effective amount of a compound that forms a covalent
`bond With Bruton’s tyrosine kinase. In one embodiment, the
`compound forms a covalent bound With the activated form of
`Bruton’s tyrosine kinase. In further or alternative embodi
`ments, the compound irreversibly inhibits the Bruton’s
`tyrosine kinase to Which it is covalently bound. In a further or
`alternative embodiment, the compound forms a covalent
`bond With a cysteine residue on Bruton’s tyrosine kinase. In
`yet another aspect, provided herein is a method for treating a
`cancer by administering to a subject in need thereof a com
`position containing a therapeutically effective amount of a
`compound that forms a covalent bond With Bruton’s tyrosine
`kinase. In one embodiment, the compound forms a covalent
`bound With the activated form of Bruton’s tyrosine kinase. In
`further or alternative embodiments, the compound irrevers
`ibly inhibits the Bruton’s tyrosine kinase to Which it is
`covalently bound. In a further or alternative embodiment, the
`compound forms a covalent bond With a cysteine residue on
`Bruton’s tyrosine kinase. In another aspect, provided herein is
`a method for treating a thromboembolic disorder by admin
`istering to a subject in need thereof a composition containing
`a therapeutically effective amount of a compound that forms
`a covalent bond With Bruton’s tyrosine kinase. In one embodi
`
`ment, the compound forms a covalent bound With the acti
`vated form of Bruton’s tyrosine kinase. In further or altema
`tive embodiments, the compound irreversibly inhibits the
`Bruton’s tyrosine kinase to Which it is covalently bound. In a
`further or alternative embodiment, the compound forms a
`covalent bond With a cysteine residue on Bruton’s tyrosine
`kinase.
`[0046] In another aspect are methods for modulating,
`including irreversibly inhibiting the activity of Btk or 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 at least
`one irreversible inhibitor described herein, in a mammal com
`prising administering to the mammal at least once an effective
`amount of at least one compound having the structure of any
`of Formula (Al -A6), Formula (B 1 -B6), Formula (C1 -C6), or
`Formula (DI-D6). In another aspect are methods for modu
`lating, including irreversibly inhibiting, the activity of Btk in
`a mammal comprising administering to the mammal at least
`once an effective amount of at least one compound having the
`structure of any of Formula (Al -A6), Formula (Bl-B6), For
`mula (Cl-C6), or Formula (DI-D6). In another aspect are
`methods for treating Btk-dependent or Btk mediated condi
`tions or diseases, comprising administering to the mammal at
`least once an effective amount of at least one compound
`having the structure of any of Formula (Al-A6), Formula
`(B 1 -B6), Formula (C1 -C6), or Formula (D1 -D6).
`[0047] In another aspect are methods for treating in?am
`mation comprising administering to the mammal at least once
`an effective amount of at least one compound having the
`structure of Formula (Al-A6), (Bl-B6), (Cl-C6), or (D1
`D6).
`[0048] A further aspect are methods for the treatment of
`cancer comprising administering to the mammal at least once
`an effective amount of at least one compound having the
`structure of Formula (Al-A6), (Bl-B6), (Cl-C6), or (D1
`D6). The type of cancer includes, but is not limited to, pan
`creatic cancer and other solid or hematological tumors.
`[0049] In another aspect are methods for treating respira
`tory diseases comprising administering to the mammal at
`least once an effective amount of at least one c