(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)~
`
`(19) World Intellectual Property
`~~
`Organization
`International Bureau
`
`(43) International Publication Date
`4 February 2016 (04.02.2016) Wi
`
`POIPCT
`
`ANY
`
`(10) International Publication Number
`WO 2016/019237 A2
`
`Designated States (unless otherwise indicated, for every
`kind 6 national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,
`BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,
`DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU,ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG,
`MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM,
`PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC,
`SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN,
`TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ,
`TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU,
`TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE,
`DK, EE, ES, FI, FR, GB, GR, HR, HU,IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, KM, ML, MR, NE, SN, TD, TG).
`
`(31)
`
`International Patent Classification:
`A6I1K 31/53 (2006.01)
`A61K 31/522 (2006.01)
`
`(81)
`
`(21)
`
`International Application Number:
`
`PCT/US20 15/043 102
`
`(22)
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`International Filing Date:
`
`Filing Language:
`
`Publication Language:
`
`31 July 2015 (31 .07.2015)
`
`English
`
`English
`
`Priority Data:
`62/03 1,658
`
`31 July 2014 (31.07.2014)
`
`(84)
`
`US
`
`(25)
`
`(26)
`
`(30)
`
`(71)
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`(72)
`
`Applicant: PHARMACYCLICS LLC [US/US]; 995 E.
`Arques Avenue, Sunnyvale, CA 94085-4521 (US).
`
`Inventors: CHEN, Wei; 1668 Walden Court, Fremont,
`CA 94539 (US). WANG, Longcheng; 4294 Wilkie Way -
`Apt. L, Palo Alto, CA 94306 (US). JIA, Zhaozhong, J.;
`3416 Leafwood Court, San Mateo, CA 94403
`(US).
`PALMER, James, T.; 3-100 Parker Street, Templestowe,
`VIC 3106 (AU).
`
`Published:
`
`(74)
`
`Agent: JACKSON, David, A.; Klauber & Jackson L.L.C.,
`25 Fast Spring Valley Avenue - Suite 160, Maywood, NJ
`07607 (US).
`
`without international search report and to be republished
`upon receipt f that report (Rule 48.2(g))
`
`(54)
`
`Title: INHIBITORS OF BRUTON'S TYROSINE KINASE
`
`(57) Abstract: Described herein are cyano containing heteroaryl compounds as kinase inhibitors. Methods for synthesizing such in -
`hibitors, and methods for using such inhibitors in the treatment of diseases described.
`
`
`
`wo2°16/6192372|IMTINNNNAITOTT
`
`

`

`WO 2016/019237
`
`PCT/US2015/043102
`
`INHIBITORS OF BRUTON'S TYROSINE KINASE
`
`CROSS-REFERENCE TO RELATED APPLICATION
`
`[0001] This application claims the benefit of U.S. Provisional Application No. 62/03 1,658, filed July 31,
`
`2014, which is incorporated herein by reference in its entirely.
`
`FIELD OF THE INVENTION
`
`[0002] Described herein are compounds, methods of making such compounds, pharmaceutical
`
`compositions and medicaments containing such compounds, and methods of using such compounds and
`
`compositions to inhibit the activity 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 akey regulator of B-cell development, activation, signaling, and survival (Kurosaki, Curr
`
`Op Imm, 2000, 276-281; Schaefter and Schwartzberg, Curr Op Imm 2000, 282-288). In addition, Btk
`
`plays arole in anumber of other hematopoetic cell signaling pathways, e.g., Toll like receptor (TLR) and
`
`cytokine receptor-mediated TNF-a production in macrophages, IgE receptor (FcepsilonRI) signaling in
`
`Mastcells, inhibition of Fas‘/APO-1 apoptotic signaling in B-lineage lymphoid cells, and collagen-
`
`stimulated platelet aggregation. See, e.g., C. A. Jeffries, et al., (2003), Journal o Biological Chemistry
`
`278:26258-26264; N.J. Horwood, et al,
`
`(2003), The Journal o Experimental Medicine 197: 1603-161 1;
`
`Iwaki et al. (2005), Journal o Biological Chemistry 280(48):40261-40270; Vassilev et al. (1999), Journal
`
`& Biological Chemistry 274(3): 1646-1656, and Quek et al. (1998), Current Biology 8(20): 1137-1 140.
`
`SUMMARY OF THE INVENTION
`
`[0005] Described herein are inhibitors of Bruton's tyrosine kinase (Btk). Also described herein are
`irreversible inhibitors of Btk. Also described herein are reversible inhibitors of Btk.
`
`[0006] 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").
`
`[0007] Further described are irreversible inhibitors of Btk that form a covalent bond with a serine residue
`
`on C4818 mutated Btk. Specifically described are irreversible inhibitors of Btk that form a covalent bond
`
`with a serme481 residue on C481 S mutated Btk (Woyach, ef ai. Resistance mechanisms for the Bruton's
`
`tyrosine kinase inhibitor Ibrutimb, N Engl J Med. 2014, 12;370(24):2286-94). Further described herein are
`
`

`

`WO 2016/019237
`
`PCT/US2015/043102
`
`irreversible inhibitors of other tyrosine kinases, wherein the other tyrosine kinases share homology with
`
`C481 S mutated Btk by having a serine residue Gncluding a homologous resisdue to BTK C481 S residue)
`that can form a covalent bond with the inhibitor.
`
`[0008] Further described herein are reversible inhibitors of C481 S mutated Btk.
`
`[0009] Further described herein are reversible inhibitors of other tyrosine kinases, wherein the other
`
`tyrosine kinases share homology with Btk.
`
`[0010] Also described herein are methods for synthesizing such reversible or irreversible inhibitors,
`
`methods for using such reversible or irreversible inhibitors in the treatment of diseases (including diseases
`
`wherein irreversible inhibition of Btk provides therapeutic benefit to a patient having the disease). Further
`
`described are pharmaceutical formulations that include a reversible or irreversible inhibitor of Btk.
`
`[0011] Thus, in one specific aspect, the present invention provides methods for preventing, treating or
`
`ameliorating in amammal a disease or condition that is causally related to the aberrant activity of a
`
`tyrosine kinase receptor in vivo, which comprises administering to the mammalan effective disease-
`
`treating or condition-treating amount of a compound according to Formula (1D having the structure:
`
`
`
`wherein:
`
` is aheterocyclic moiety that binds to the active site of a tyrosine kinase;
`
`1) Y is substituted or unsubstituted alkylene, heteroalkylene, arylene, heteroarylene,
`
`heterocycloalkylene, or cycloalkylene; and L, is NR,,; or
`
`h) Y is N containing substituted or unsubstituted heterocycloalkylene; and L, is a bond; provided
`
`that the L,-CN groupis attached to Y through the ring N;
`
`L, is abond or alkylene; and
`
`Rj, 1s H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or
`
`unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
`
`unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a protecting group;
`
`or
`
`ametabolite, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof.
`
`[0012]
`
`In one embodiment, the tyrosine kinase receptor is Btk receptor.
`
`[0013]
`
`In onc embodiment, the active site is a cavity in which the compound or the moicty binds to the
`
`tyrosine kinase.
`
`

`

`WO 2016/019237
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`PCT/US2015/043102
`
`[0014]
`
`In one embodiment, the the disease or condition is an autoimmune disease, a heteroimmune
`
`disease, a cancer, mastocytosis, osteoporosis or bone resorption disorder, or an inflammatory disease.
`
`In anotheraspect, the present invention provides a compound according to Formula (1) having the
`[0015]
`structure:
`
`
`
`
`[|L
`
`4;—— CN
`
`wherein:
`
`@
`
` is aheterocyclic moiety that binds to the active site of a tyrosine kinase;
`
`1) Y is substituted or unsubstituted alkylene, heteroalkylene, arylene, heteroarylene,
`
`heterocycloalkylenc, or cycloalkylenc; and L; is NR,,; or
`
`h) Y is N containing substituted or unsubstituted heterocycloalkylene; and L, is a bond; provided
`
`that the L,-CN groupis attached to Y through the ring N;
`
`L, is abond or alkylene; and
`
`R,,1s H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or
`
`unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
`
`unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a protecting group;
`
`or
`
`ametabolite, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof.
`
`
`wd wy
`ot Kang"
`
`ra
`
`we
`
`N~
`WJ
`
`/
`
`N
`Pp
`
`ok
`
`/
`
`\
`Nw
`Re LU ys
`
`we
`
`NH2
`N~ |
`
`=~
`N
`
`pe
`
`N
`
`N
`\
`Te
`
`oO
`
`2
`
`NH>
`N oo
`~~
`N
`
`|
`
`we
`Y—Ro
`N
`\
`we
`
`or
`
`NH2
`N on
`|
`
`ww
`N
`
`Wi
`8
`yN
`N
`\
`po
`
`,
`
`and wherein Wg is CR,, and R, is as described herein; and Rg is H, alkyl, CN,or halo.
`-3-
`
`

`

`WO 2016/019237
`
`PCT/US2015/043102
`
`[0017]
`
`In another particular embodiment, Wg is CR,; and R, is phenyl substituted with substituted or
`
`unsubstituted benzyl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenthioxy, or
`
`substituted or unsubstituted phenylammo.
`
`[0018]
`
`In another aspect, the present invention provides pharmaceutical compositions comprising a
`
`therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable
`
`excipient.
`
`In one embodiment, the pharmaceutical composition comprising the compound of Formula (I)
`
`is formulated for aroute of administration selected from oral administration, parenteral administration,
`
`buccal administration, nasal administration, topical administration, or rectal administration.
`
`In another
`
`aspect is a method for treating an autoimmune disease or condition comprising administering to a patient
`
`in need a therapeutically effective amount of a compound of Formula (1).
`
`In one embodiment the
`
`autoimmune disease is selected from rheumatoid arthritis or lupus.
`
`In a further aspect is a method for
`
`treating a heteroimmunedisease or condition comprising administering to a patient in need a
`
`therapeutically effective amount of a compound of Formula (1).
`
`In yet another embodiment is a method
`
`for treating a cancer comprising administering to a patient in need a therapeutically effective amountof a
`
`compound of Formula (1).
`
`In one embodiment the cancer is a B-cell proliferative disorder.
`
`[0019]
`
`In another embodiment the B-cell proliferative disorder is diffuse large B cell lymphoma,
`
`follicular lymphoma or chronic lymphocytic leukemia.
`
`[0020]
`
`In yet a further aspect is a method for treating mastocytosis comprising administering to a patient
`
`in need a therapeutically effective amount of a compound of Formula (1).
`
`[0021]
`
`In another aspect, a method is provided for treating osteoporosis or bone resorption disorders
`
`comprising administering to a patient in need a therapeutically effective amount of a compound of
`
`Formula (1).
`
`[0022]
`
`In a further aspect, a method is provided for treating an inflammatory disease or condition
`
`comprising administering to a patient in need a therapeutically effective amount of a compound of
`
`Formula (1.
`
`[0023] Any combination of the groups described above for the various variables is contemplated herein.
`
`It is understood that substitucnts and substitution pattcrns on the compounds provided herein can be
`
`selected by one of ordinary skill in the art to provide compoundsthat are chemically stable and that can be
`
`synthesized by techniques knowninthe art, as well as those set forth herein.
`
`[0024]
`
`In afurther aspect, pharmaceutical compositions are provided which include a therapeutically
`
`effective amountof at least one of any of the compoundsherein, or a pharmaceutically acceptable salt,
`
`pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable
`
`solvate. In certain embodiments, compositions 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, prevention, or amelioration
`
`of one or more symptoms of dieases, 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
`-4-
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`WO 2016/019237
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`PCT/US2015/043102
`
`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 pharmaceutical composition containing:
`
`1) a
`
`physiologically acceptable carrier, diluent, and/or excipient; and ii) one or more compounds provided
`herein.
`
`[0027]
`
`In one aspect, provided herein are methodsfor treating a patient by administering a compound
`
`provided herein. In some embodiments, provided herein is a method of inhibiting the activity of tyrsome
`
`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, 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, disorder, or condition, which
`
`would benefit from inhibition of Bruton's tyrosine kinase (Btk) activity.
`
`[0029]
`
`In some embodiments, compounds provided herein are administered to a human.
`
`[0030]
`
`In some embodiments, compounds provided herein are orally administered.
`
`[0031]
`
`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, compounds provided herein are
`
`used for the formulation of a medicamentfor the inhibition of Bruton's tyrosine kinase (Btk) activity.
`
`[0032] Articles of manufacture including packaging material, a compound or composition or
`
`pharmaceutically acceptable derivative thereof provided herein, whichis 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 acceptable salt, pharmaceutically active metabolite,
`
`pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for inhibiting
`
`the activity of tyrosine kinase(s), such as Btk, are provided.
`
`[0033]
`
`In afurther aspect, provided hercin 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
`
`amountof at least one compound having the structure of Formula (D.
`
`In some embodiments, the subject
`
`in need is suffering from an autoimmunedisease, 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 Sjogren's syndrome, multiple
`
`sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-
`
`myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia,
`
`autoimmunehepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura,
`
`optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, Lemporal
`
`arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis,
`
`Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia,
`
`scleroderma, or vulvodynia.
`
`-5-
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`WO 2016/019237
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`PCT/US2015/043102
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`[0034]
`
`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 rhinitis, or atopic dermatitis.
`
`[0035]
`
`In certain embodiments, the subject in need is suffering from an inflammatory disease, e.g.,
`
`asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis,
`
`colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis,
`
`endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,
`
`gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis,
`
`myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis,
`
`pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis,
`
`salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.
`
`[0036]
`
`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 leukemia,
`
`lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, 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 lymphoma, 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 agentis an inhibitor of mitogen-activated protein kinase signaling, e.g., UV0126, PD98059,
`
`PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannm, or
`LY294002.
`
`[0037]
`
`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, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral
`
`artcrial occlusive disorder, pulmonary cmbolism, or decp venous thrombosis.
`
`[0038]
`
`In afurther aspect, provided herein is a method for treating an autoimmunedisease by
`
`administering to a subject in need thereof a composition containing a therapeutically effective amount of
`
`at least one compound having the structure of Formula Formula (D, (Ila)-dIp, (la)-dII), (Va)-dVp,
`
`(Va)-(Vf), (Vla)-CVIN, CVila)-(VII), (VHIa)-CVIIIf), (7Xa)-(EXf), CXa)-CXf), CXTa)-CXTf), (XTla)-CcT),
`
`(X1lla)-CXT),
`
`(X1Va)-CXIVA), (XVa)-(XVE), OCVIa)-CXVID, (XVITa)-(XVITA), OCVIa)- XVII),
`
`(X)X%a)-(X1Xf), (XXa)-(XXf), (XXla)-(XXI1f), or CXXTla)-C<XIIf).
`
`In one embodiment, the autoimmune
`
`disease is arthritis. In another embodiment, the autoimmunedisease is lupus. In some embodiments, the
`
`autoimmunedisease is inflammatory bowel disease (including Crohn's disease and ulcerative colitis),
`
`rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Sull's disease, juvenile arthritis, lupus, diabetes,
`
`myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease Sjogren's syndrome, multiple
`
`sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-
`
`myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia,
`-6-
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`WO 2016/019237
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`PCT/US2015/043102
`
`autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, 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, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia,
`
`scleroderma, or vulvodynia.
`
`[0039]
`
`In afurther 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 therapeutically effective amount
`
`of at least one compound having the structure of (D, (la)-CIIf), (la)-dUf, (Va)-dVf), (Va)-(Vf), (Vla)-
`
`(VID, CVila)-CVILD, ~CVilla)-CVOID, (xa)-dxD, (Xa)-CXD, CXla)-CXID, CXlla)-CXIID, Cxla)-CXTI),
`
`(x1Va)-CXIVf),
`
`(XVa)-CXVf), CXVIa)-CXVIN, CxVIa)-CXVITN, OsVIa)-CXVITA, ~CXxEXa)-CXTxf),
`
`(XXa)-(XXf), CXXTa)-CXXIAF, or COCXTIa)-CCXTIA).
`
`In some embodiments, the heteroimmune conditiom
`
`or disease is graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I
`
`hypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopic dermatitis.
`
`[0040]
`
`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 Formula (1, (Ma)-dT, (lla)-dIIP), (Va)-dVf), CVa)-CVA,
`
`(Vla)-C(VIf), (Vlla)-CVIIf), CVUla)-CVOIf, doxa)-(xf), (Xa)-Cxf), (xla)-CxIf), Cxlla)-CXIIf), Cxla)-
`
`CX, C1Va)-COTIVA), OCVa)-XVI), OOVIa)-(XVIf), OVIa)-XVOf), OCVIa)-OOVOTA,
`
`(XTXa)-
`
`(XIX), (XXa)-(XXE), OCXTa)-COCXTA), or CXXTa)-CXILf).
`
`In some embodiments, the inflammatory
`
`disease is asthma, inflammatory bowel disease (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, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,
`
`gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis,
`
`myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis,
`
`pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis,
`
`salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uvcitis, 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 amountof at least one
`
`compound having the structure of Formula (1, (a)-(ITf), (a)-(IIIf), (Wa)-(IVf, (Va)-(Vf), (Vla)-CVID,
`
`(Vila)-CVIf), CVilla)-CVINA,
`
`(xXa)-(Xf), (Xa)-CXf), CXla)-CXT, Cclla)-OIH, Ccla)-CXTTf, CdVa)-
`
`(XIVf), (XVa)-(XVE), (XVIa)-COVIF), (XV Ia)-CXVOf), CXVITTa)-COVITED), CXXa)-CXTX£),
`
`(XX a)-(XXf),
`
`(XXTa)-(XXIf), or (XXTla)-(XXII).
`
`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 leukemia, lymphoplasmacytic lymphoma/W aldenstrom
`
`macroglobulinemia, 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
`
`lymphoma, burkitt lymphoma/leukemia, or lymphomatoid granulomatosis. In some embodiments, where
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`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, ARR Y-142886,
`
`$B239063, SP600125, BAY 43-9006, wortmannm, 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 therapeutically effective amountof
`
`at least one compoundhaving the structure of Formula (I, (Ila)-dIf), (la)-dHf), (7Va)-dVf), (Va)-(Vf),
`
`(Vla)-CVIf), CVila)-(VII), (Villa)-CVTIf), (-Xa)-(-Xf), CXa)-(Xf), CXla)-CXT, Cxla)-CXTI), CXllla)-
`
`CXUIA, CX)Va)-CXTV#), CXVa)-(XV1), CXVIa)-(XVIN, CXVIa)-CXVO), CXVIa)-CXVOI), CXLXa)-
`
`CXTXf), CXXa)-COX), CXXKTa)-CXXIN, or CXXTIa)-CXXIIf).
`
`In some embodiments, the thromboembolic
`
`disorder is myocardial infarct, 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.
`
`[0043]
`
`In afurther aspect, provided herein is a method for treating an autoimmunedisease 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 compound
`
`forms a covalent bound with the activated form of Bruton's tyrosine kinase. In further or alternative
`
`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.
`
`[0044]
`
`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 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 compoundirreversibly inhibits the Bruton’s tyrosine kinase to whichit is
`
`covalently bound.
`
`In a further or alternative embodiment, the compound forms a covalent bond with a
`
`cystcine residuc on Bruton's tyrosine kinasc.
`
`[0045]
`
`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 amountof a
`
`compoundthat 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 irreversibly inhibits the Bruton's tyrosine kinase to which it is covalently
`
`bound.
`
`In afurther 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 composition 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 irreversibly inhibits the Bruton’s tyrosine kinase to whichit is
`
`covalently bound. In a further or alternative embodiment, the compound forms a covalent bond with a
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`cysteine residue on Bruton's tyrosine kinase.
`
`[0046]
`
`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 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 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.
`
`[0047]
`
`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 comprising administering to the mammal at least once an
`
`effective amount ofat least one compound having the structure of Formula (D, Cla)-d1, Clla)-dUf),
`
`(Va)-dVf), (Va)-(V, CVla)-CVID, CVla)-CVIIA), CVilla)-CVTIA), (-Xa)-(2Xf), (Xa)-CXf), CXla)-CXT£),
`
`CXlla)-CXTI, CXIa)-CXTA, CXTWa)-(XTVA), (XVa)-CXVH), CXVIa)-XVID, CXVIIa)-COVITD, OXVIITa)-
`
`CXVTTTA, CX Xa)-CXTX1), COXa)-CXXD), CXOXKTa)-CXXTP) or CX®KTTa)-CXXTIP). Tn another aspect are
`
`methods for modulating, including including reversibly or 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 Formula (1), dla)-dIf), Ula)-dII, (Va)-dV), (Va)-(V, (Vla)-CVID,
`
`(Vila)-(VIIf), (Villa)-CVIIA, (Xa)-(2xf), (Xa)-CXf), CXla)-CXTf), CXIla)-CXTIA), Cxia)-CXTO), Cx1Va)-
`
`CX1Vf), (XVa)-(XV£), CXVIa)-CXVID, CXVIla)-CXVIL), (XVIa)-CXVOIA), (XTXa)-(XTXf), (XKa)-CxXf),
`
`(XXIa)-CXXIf), or (xXTla)-COCXTIf).
`
`In another aspect are methods for treating Btk-dependent or Btk
`
`mediated conditions or diseases, comprising administering to the mammalat least once an effective
`
`amountof at least one compound havingthe structure of Formula (D, dla)-dIf, dlla)-d0N, (Va)-dvp,
`
`(Va)-(Vf), (Vla)-CVID), CVila)-(VIIf), CVilla)-C(VI), (Xa)-(-Xf), (Xa)-CXf), CXla)-CXTD, CxTla)-CXTIA),
`
`(Xilla)-CSMT, xlVa)-CXIVi), (Va)-(XVE), CXVIa)-CXVID, CXVIa)-CXVID), (XVIa)-(XVITA),
`
`CX1X%a)-CXTX#), OXXa)-OOXK), CXXTa)-COCXTA), or CXXTIa)-CCXTL).
`
`[0048]
`
`In another aspect are methods for treating inflammation comprising administering to the mammal
`
`al least once an effective amountof al least one compound having the structure of Formula (D, (a)-dIf,
`
`(ila)-d0f), (Va)-dVfi), (Va)-(Vf), (Vla)-CVIN), CVila)-CVIID,
`
`(VHIa)-(VIIf), (Xa)-(Exf), CXa)-Cxf),
`
`(Xla)-CXTf), CXla)-CCTI, ~Cxila)-CXTIA), CXTVa)-CXTVf), CXVa)-CXV), CXVIa)-CXVIf), (XVIIa)-
`
`(XVIIf), OSVIITa)-CXVITID, CX1Xa)-CXTXA), (XXa)-OOXKT), OXXTa)-OCXTA), or OCKTIa)-OCXIIf).
`
`[0049] A further aspect are methods for the treatment of cancer comprising administering to the mammal
`
`at least once an effective amountof at least one compound having the structure of Formula (1D, dla)-dIf,
`
`(la)-d0f), (Va)-(Vif), (Va)-(Vf), (Vla)-CVID, CVla)-(VHf, (VIlla)-CVOIf,
`
`(2Xa)-(Zxf), (Xa)-CXf),
`
`(Xla)-CXTN, CXTla)-CXTID, ~CXM1a)-CXTITN, ~CXTVa)-CXTVI), CXVa)-(XVI, CXVIa)-CXVIN, CXVTTa)-
`
`CXVIIf), CSVIIJa)-CXVIIA), CxTXa)-(XTXf), (XXa)-Ockt), CXXTa)-OCXT£), or OCKTIa)-OCXIIf). The type
`
`of cancer may include, but is not limited to, pancreatic cancer and other solid or hematological tumors.
`
`[0050]
`
`In another aspect are methodsfor treating respiratory diseases comprising administering to the
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`WO 2016/019237
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`PCT/US2015/043102
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`mammal at least once an effective amountof at least one compound havingthe structure of Formula (1),
`
`(Ila)-dIf), dHa)-dIIf), (VWa)-dVf), CVa)-(Vf), CVla)-CVIf), (Vla)-CVIIf), (VHIa)-CVHIf), (TXa)-Cxf),
`
`(Xa)-(Xf), (Xla)-CXTf), CXTla)-CXTIf), CXMa)-CXTMf), CXTWa)-CXTV£), CXVa)-CX VP), CXVTa)-(XVIF),
`
`(XVila)-CXVIIf), OXVIIa)-CXVITIF), CXTXa)-CXTX£), OCKa)-OCXf), (XXTa)-CCKI£), or OCKTIa)-OCXTf).
`
`In a further embodiment of this aspect, the respiratory disease is asthma.
`
`In a further embodimento