Inhibitors of bruton`s tyrosine kinase

Bruton Tyrosine Kinase Inhibitors

FIELD OF INVENTION

Described herein are compounds, methods for making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using the same compounds and compositions for inhibiting tyrosine kinase activity.

BACKGROUND OF THE INVENTION

Bruton's tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, is a key signaling enzyme expressed on all hematopoietic cell types except T lymphocytes and natural killer cells. Btk plays an essential role in the B cell signaling pathway that links stimulation of B cell cell surface receptors (BCR) with downstream intracellular responses.

Btk is a key regulator of B cell development, activation, signaling and survival (Kurosaki, Curr Op Imin, 2000, 276-281; ​​Schaeffer and Schwartzberg, Curr Op Imm

2000, 282-288). In addition, Btk has a role in several other hematopoietic cell signaling pathways, for example in the production of cytokine receptors and Toll-like receptors (TLR) in macrophages, in IgE receptor signaling (FcepsilonRI). ) in mast cells, inhibition of Fas / APO-1 apoptotic signaling in strain B lymphoid cells, and collagen-stimulated platelet aggregation. Take, for example, CA Jeffries et al. (2003), Journal of Biological Chemistry 278: 26258-26264; NJ Horwood, et al. (2003), The

Journal of Experimental Medicine 197: 1603-1611; Iwali et al. (2005), Journal of Biological Chemistry 280 (48): 40261-40270; Vassilev et al. (1999), Journal of Biological Chemistry 274 (3): 1646-1656; and Quek et al. (1998), Current Biology 8 (20): 1137-1140. Some pyrazolopyrimidines

Substituted 2 201 840 / foram were disclosed as tyrosine kinase inhibitors in US 2004/006083.

SUMMARY OF THE INVENTION

Bruton tyrosine kinase (Btk) inhibitors are described herein. Also described herein are irreversible Btk inhibitors. Irreversible Btk inhibitors that form a covalent bond with a cysteine ​​residue at Btk are further described. Further described herein are irreversible inhibitors of other tyrosine kinases, wherein the other tyrosine kinases share homology with Btk in that they have a cysteine ​​residue (including a Cys 481 residue) that can form a covalent bond with the irreversible inhibitor. (such tyrosine kinases are referred to herein as Btk tyrosine kinase cysteine ​​homologues). Also described herein are methods for synthesizing these irreversible inhibitors, methods for using these irreversible inhibitors in the treatment of diseases (including diseases where irreversible inhibition of Btk provides therapeutic benefits to a patient with the disease). Further described are pharmaceutical formulations including an irreversible Btk inhibitor.

Described herein is a compound of Formula (D). Formula (D) is as follows:

<img file="PT2201840E_D0001.tif" />

Formula (D) wherein:

L_The it's CH₂O, NH or S;

201 2 201 840 / ΡΤ

THE_r is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

Y is an optionally substituted group selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

is C (= 0), OC (= O), NHC (= 0), C (= S),

NHS (= O)_Xwhere x is 1 or 2;

S (= O)_X, OS (= O)_X,

R₇ and Rg are independently selected from H, C1 alkyl₇-Ç₄ unsubstituted, C-alkyl₇-Ç₄ substituted, unsubstituted C1-C4 heteroalkyl, C-heteroalkyl₇-Ç₄ substituted, unsubstituted C3 -C6 cycloalkyl, substituted C3 -C6 cycloalkyl, C heterocycloalkyl₂Unsubstituted -C6 and heterocycloalkyl C₂-C6 substituted; or

R₇ and Rg taken together form a bond;

R6 is H, substituted or unsubstituted C1 -C4 alkyl, C heteroalkyl₇-Ç₄ substituted or unsubstituted, C1 -C6 alkoxyalkyl, C1 -C6 alkylaminoalkyl, substituted or unsubstituted C3 -C6 cycloalkyl, substituted or unsubstituted aryl, C heterocycloalkyl₂Substituted or unsubstituted -C6, substituted or unsubstituted heteroaryl, C1-6 alkyl₂-Ç₄(aryl), C-alkyl₂Ç₄(heteroalkyl), alkyl (C cycloalkyl)₃-Ç₈), or C-alkyl₂-Ç₄ (heterocycloalkyl C₂-Ç₈); and pharmaceutically acceptable solvates thereof or pharmaceutically acceptable salts thereof.

The compounds of Formula D wherein R is H and R₇ and Rg are H or taken together form a bond are embodiments of the invention.

For each and every embodiment, substituents may be selected from a subset of the stated alternatives. For example, in some embodiments, L_The it's CH₂, O or NH. In other embodiments, L_The is O or NH. And in still other embodiments, L_The it's the.

In some embodiments, Ar is a substituted or unsubstituted aryl. In yet other embodiments, Ar is a 6 membered aryl. In some other embodiments, Ar is phenyl.

201 2 201 840 / ΡΤ

In some embodiments, x is 2. In still other embodiments, Z is C (= 0), OC (= 0), NHC (= 0), S (= 0)_x, 0S (= 0)_x or NHS (= O)_X. In some other embodiments, Z is C (= 0), NHC (= 0) or S (= 0) 2.

Described herein are compounds wherein R₇ and Rg are independently selected from H, unsubstituted C1-C4 alkyl, substituted C1-C4 alkyl, unsubstituted C1-C4 heteroalkyl and substituted C1-C4 heteroalkyl; or R 7 and R 8 taken together form a bond. In one embodiment, each of R 7 and R c is H; or R 7 and R 6 taken together form a bond.

R is H, alkyl heteroalkyl alkoxyalkyl

C1-C4

C1-C4

Ci-Cg

Described herein are compounds wherein substituted or unsubstituted, substituted or unsubstituted, C1 -C6 alkylaminoalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1 -C6 alkyl₄ (aryl), C1 -C6 alkyl₄ (heteroaryl), C1 -C6 alkyl₄ (cycloalkyl C₃-Ç₈) or C1 -C6 alkyl₄(heterocycloalkyl C₂Ç₈). In some cases R₆ is H, C1 -C6 alkyl₄ substituted or unsubstituted, C6 -C heteroalkyl₄ substituted or unsubstituted, C1 -C6 alkoxyalkyl₆Cg-C alkyl₂-N (C1 -C6 alkyl)₃)₂Cg-C alkyl₄(aryl), C1 -C6 alkyl₄ (cycloalkyl C₃-Ç₈)

Ç₄ (heterocycloalkyl C₂-Ç₈). In other examples, R₆ is H, C1 -C6 alkyl₄ replaced or unsubstituted, -CH₂-O- (C1 -C6 alkyl)₃)₂Cg-C alkyl₄(phenyl) or 5 or 6 membered). In other examples, R is H, substituted or unsubstituted C1-C4 alkyl, -CH₂-O- (C1-C3 alkyl), -CH₂- (Cg-Cg alkylamino), C1-C4 alkyl (phenyl) or C1-C4 alkyl (5 or 6 membered heteroaryl). In some embodiments, Rg is H, substituted or unsubstituted C1-C4 alkyl, -CH₂-O- (C1 -C6 alkyl)₃), -CH₂Cg-C alkyl₄(heteroaryl), or C1 -C6 alkyl₃), -CH₂-N (C1-C4 alkyl alkyl (heteroaryl

N (alkyl or C1 -C6 alkyl)

Ci_C₃)₂Cg-C alkyl₄(phenyl)

C4 (5 or 6 membered heteroaryl containing 1 or 2 N atoms), or C1-C4 alkyl (5 or 6 membered heterocycloalkyl containing 1 or 2 N atoms).

In some substituted embodiments, selected from

Y is a group optionally alkyl, heteroalkyl,

Cycloalkyl and heterocycloalkyl. In other embodiments, Y is an optionally substituted group selected from C1 -C6 alkyl, C1 -C6 heteroalkyl, 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 C1 -C6 alkyl₆C 1 -C 6 heteroalkyl, 5 or 6 membered cycloalkyl and 5 or 6 membered heterocycloalkyl containing 1 or N atoms. In some other embodiments, Y is a 5 or 6 membered cycloalkyl or 1 or 5 membered heterocycloalkyl containing 1 or 2 N atoms. In some embodiments, Y is a 4-, 5-, 6- or 7-membered cycloalkyl ring; or Y is a 4, 5, 6 or membered heterocycloalkyl ring.

Any combination of the groups described above for the various variables is described herein. It is understood that substituents and substitution patterns may be selected by one of ordinary skill in the compounds provided herein to provide compounds which are chemically stable and which may be synthesized by techniques known in the prior art, as well as those set forth herein. .

In one aspect there is provided herein a compound selected from:

1- (3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one (Compound 4 ); (E) —1- (3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1yl) piperidin-1-yl) but-2-en-1-one one (Compound 5); 1- (3- (4-amino3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) sulfonylene (Compound 6); 1- (3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-yl) prop-2-yn-1-one (Compound 8); 1- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-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-d] pyrimidin-1-yl) pyrrolidin-1yl) prop-2-en-1-one ( Compound 11); 1 - ((S) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) prop-2-en-1-one ( Compound 12); 1 - ((R) -3- (4-amino-3- (4,2020,840 / β-phenoxyphenyl) -β-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1yl) prop-2- en-1-one (Compound 13); 1 - ((S) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1yl) prop-2-en-1-one ( Compound 14); and (E) -1- (3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1yl) -4- (dimethylamino) but-2 -en-1-one (Compound 15).

In another aspect they are pharmaceuticals, which are therapeutically acceptable compounds herein, or an effective of said solvate compositions. In any of the certain embodiments, those provided include at least one of or a pharmaceutically acceptable salt. In compositions provided herein further include a pharmaceutically acceptable diluent, excipient and / or binder.

Pharmaceutical compositions formulated for administration by an appropriate route and means containing effective concentrations of one or more compounds provided herein which deliver effective amounts for the treatment, prevention, or amelioration of one or more symptoms of diseases, disorders or conditions that are modulated, are provided. or otherwise affected by tyrosine kinase activity, or where tyrosine kinase activity is implicated. Effective amounts and concentrations are effective in ameliorating any of the symptoms of any of the diseases, disorders or conditions disclosed herein.

In certain embodiments, there is provided herein a pharmaceutical composition containing: i) a physiologically acceptable carrier, diluent and / or excipient; and ii) one or more compounds provided herein.

Described herein are methods of treating a patient by administering a compound provided herein. Also described herein is a method for inhibiting tyrosine kinase (s) activity, such as Btk, or for treating a disease, disorder or condition, which benefits inhibition of tyrosine kinase (s) such as

Btk, in a patient, which includes administering to the patient a therapeutically effective amount of any of the effective compounds of at least one of these or salts thereof.

Pharmaceutically acceptable or pharmaceutically acceptable solvates.

In one aspect, there is provided herein a compound disclosed herein for use in inhibiting Bruton's tyrosine kinase (Btk) activity or for treating a disease, disorder or condition that benefits from inhibiting tyrosine kinase activity of Bruton (Btk).

In some embodiments, the compounds provided herein are administered to a human.

In some embodiments, the compounds provided herein are administered orally.

In other embodiments, the compounds provided herein are used in the formulation of a medicament for inhibiting tyrosine kinase activity. In some other embodiments, the compounds provided herein are used for the formulation of a medicament for inhibiting Bruton tyrosine kinase (Btk) activity.

Industrial articles including packaging material, a pharmaceutically acceptable compound or composition or derivative thereof provided herein which are effective for inhibiting tyrosine kinase (s) activity such as Btk within the packaging material and a label indicating that the compound or composition, or pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate thereof, is used to inhibit tyrosine kinase (s) activity, such as Btk.

In another aspect are inhibited tyrosine kinases comprising a Bruton tyrosine kinase, a Bruton tyrosine kinase homologue or a Btk tyrosine kinase cistern homologue thereof, convalently linked to an inhibitor of the structure:

EP 2 201 840 / EN

<img file="PT2201840E_D0002.tif" />

, _{on what} wv 'indicates the point between the inhibitor and tyrosine kinase. In one embodiment, the inhibitor is conveniently linked to the cysteine ​​residue on tyrosine kinase.

union another to one

Described herein is a method for inhibiting Bruton tyrosine kinase in a subject in need thereof by administering to the same subject a composition containing a therapeutically effective amount of at least one compound having the structure of any one of Formula (A). ), Formula (B), Formula (C), or Formula (D). The individual in need may suffer from an autoimmune disease, for example 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-Barré syndrome, Acute disseminated encephalomyelitis, Addison's disease, Opsoclonia-myoclonia syndrome, Ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu arteritis, temporal arteritis, autoimmune hemolytic anemia warm type, Wegener's granulomatosis, psoriasis, universal alopecia, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma or vulvar vestibulitis.

The individual in need of heteroimmune disease, by host, transplant, may suffer from a condition or example, transfusion graft disease, anaphylaxis, allergy,

201 2 201 840 / ΡΤ Type I hypersensitivity, allergic conjunctivitis, allergic rhinitis or atopic dermatitis.

The inflammatory individual, bronchiolitis, cholecystitis, dermatitis, endometritis, needy may suffer from a disease for example asthma, appendicitis, blepharitis, cervicitis, cholangitis, cystitis, dacrioadenitis, endocarditis, epicondylitis, gastroenteritis, bronchitis, bursitis, colitis, conjunctivitis, dermatitis encephalitis, enteritis, enterocolitis, fasciitis, fibrositis, gastritis, epididymitis, hepatitis, suppurative hydadadenitis, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, ovaritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vasitis vulvitis.

In some cases, the individual in need suffers from cancer. The cancer may be a proliferative B-cell disorder, for example, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, prolymphocytic B-cell leukemia / Waldenström macroglobulinemia, splenic marginal zone lymphoma , multiple myeloma, plasmocytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, large B cell (thymic) mediastinal lymphoma, large B cell intravascular lymphoma, primary effusion lymphoma, Burkitt leukemia / lymphoid or lymphomatoid granulomatosis. When the subject suffers from cancer, the subject may be administered an anticancer agent in addition to one of the above compounds. In one example, the anticancer agent is an inhibitor of mitogen-activated protein kinase signaling of, for example, U0126, PD98059, PD184352, PD0325901, ARRY142886, SB239063, SP600125, BAY 43-9006, wortmannin or LY294002.

The individual in need may suffer from a thromboembolic, for example myocardial infarction, chest, reocclusion after angioplasty, restenosis and angina disorder after

201 2 201 840 / ΡΤ angioplasty, reocclusion after aorton coronary bypass, restenosis after aorton coronary bypass, stroke, transient ischemia, an occlusive disorder of peripheral arteries, pulmonary embolism, or deep vein thrombosis.

Described herein is a method of treating an autoimmune disease by administering to a subject in need a composition containing a therapeutically effective amount of at least one compound having the structure of any one of Formula (A), Formula (B), Formula (C) or Formula (D). Autoimmune disease may be arthritis. In other cases, the autoimmune disease is lupus. In some cases, autoimmune disease is inflammatory bowel disease (including Crohn's disease 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, Sjogren's syndrome, Multiple sclerosis, Guillain-Barré syndrome, Acute disseminated encephalomyelitis, Addison's disease, Opsoclonia-myoclonia syndrome, Ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu arteritis, temporal arteritis, autoimmune hemolytic anemia warm type, Wegener's granulomatosis, psoriasis, universal alopecia, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma or vulvar vestibulitis.

Also described herein is a method of 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 any one of Formula (A). ), Formula (B), Formula (C) or Formula (D). The heteroimmune condition or disease is for example graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis or atopic dermatitis.

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Described herein is a method of 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 one of Formula (A),

Formula (B), Inflammatory formula may be (including disease disease appendicitis, cervicitis, cystitis, encephalitis, blepharitis, cholangitis, dacrioadenitis, endocarditis, (C) or Formula (D). asthma, Crohn's inflammatory bowel disease and ulcerative colitis), bronchiolitis, bronchitis, bursitis, cholecystitis, colitis, conjunctivitis, dermatitis, dermatomyositis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hepatitis suppurative, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, ovaritis, orchitis, osteitis, otitis, pancreatitis, pharyngitis, pleuritis, proctitis, prostatitis, sinusitis, stomatitis, parotitis, pericarditis, phlebitis, pneumonitis, pyelonephritis, rhinitis, synovitis, tendonitis, peritonitis, pneumonia, salpingitis, tonsillitis, uveitis, vaginitis, vasculitis or vulvitis,

Described 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 one of Formula (A), Formula (B). ), Formula (C) or Formula (D). In one example, cancer is a proliferative B-cell disorder, for example, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, prolymphocytic B-cell leukemia / Waldenstrom macroglobulinemia, splenic lymphoma of the marginal zone, multiple myeloma, plasmocytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, large B cell (thymic) mediastinal lymphoma, large B cell intravascular lymphoma, primary effusion lymphoma, Burkitt leukemia / lymphoid or lymphomatoid granulomatosis. In some cases where the individual suffers from cancer, the individual is given an anti-cancer agent in

Addition to one of the above-mentioned compounds. In one case, the anticancer agent is an inhibitor of mitogen-activated protein kinase signaling, for example U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin or LY294002.

Described 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 at least one compound having the structure of any one of Formula (A), Formula ( B), Formula (C) or Formula (D). Thromboembolic disorder may be myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortonary coronary bypass, restenosis after aorta-coronary bypass, apoplexy, transient ischemia, an occlusive disorder peripheral arteries, pulmonary embolism or deep vein thrombosis.

Also described herein is a method for treating an autoimmune disease by administering to a subject in need 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 bond with the activated form of Bruton tyrosine kinase. In a further or alternative embodiment, it irreversibly inhibits Bruton tyrosine kinase to which it is covalently linked. In a further or alternate embodiment, the compound forms a covalent bond with a cysteine ​​residue in Bruton's tyrosine kinase.

Described herein is a method of treating a heteroimmune disease or condition 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 bond with the activated form of Bruton tyrosine kinase. In additional or alternative embodiments, the compound irreversibly inhibits Bruton's tyrosine kinase to which it is

Covalently linked. In yet another additional or alternative embodiment, the compound forms a covalent bond with a cistern residue in Bruton tyrosine kinase.

Also described is a method for treating an inflammatory 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 bond with the activated form of Bruton tyrosine kinase. In other additional or alternative embodiments, the compound irreversibly inhibits the Bruton tyrosine kinase to which it is covalently linked. In a further or alternative embodiment, the compound forms a covalent bond with a cistern residue in Bruton tyrosine kinase. In yet another aspect, there is provided herein a composition containing a therapeutically effective amount of a compound that forms a covalent bond with Bruton's tyrosine kinase for the treatment of cancer. In one embodiment, the compound forms a covalent bond with the activated form of Bruton tyrosine kinase. In other additional or alternative embodiments, the compound irreversibly inhibits Bruton tyrosine kinase to which it is covalently linked. In a further or alternative embodiment, the compound forms a covalent bond with a cistern residue in Bruton tyrosine kinase. Described herein is a method of treating a thromboembolic disorder by administering to a subject in need a composition containing a therapeutically effective amount of a compound that forms a covalent bond with Bruton's tyrosine kinase. In one case, the compound forms a covalent bond with the activated form of Bruton tyrosine kinase. In other additional or alternative cases, the compound irreversibly inhibits the Bruton tyrosine kinase to which it is covalently linked. The compound may form a covalent bond with a cistern residue in Bruton tyrosine kinase.

Described herein are methods for modulating, including irreversibly inhibiting, the activity of Btk or other tyrosine kinases, wherein the other tyrosine kinases

Share homology to Btk in that they have 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 administration to the mammal at least once of an effective amount of at least one compound having the structure of any one of Formula (A), Formula (B), Formula (C) or Formula (D). Methods are described for modulating, including irreversibly inhibiting Btk activity in a mammal, comprising administering to the mammal at least once an effective amount of at least one compound having the structure of any one of Formula (A). ), Formula (B), Formula (C) or Formula (D). Methods for treating Btk-dependent or Btk-mediated diseases or conditions are described, comprising administering to the mammal at least once an effective amount of at least one compound having the structure of any one of Formula (A), Formula (B), Formula (C) or Formula (D).

Also described are methods for treating inflammation comprising administering to the mammal at least once an effective amount of at least one compound of the structure of Formula (A), (B), (C) or (D).

Also described herein are methods for treating cancer comprising administering to the mammal at least once an effective amount of at least one compound of the structure of Formula (A), (B), (C) or (D) . The type of cancer may include, but is not limited to, pancreatic cancer or other solid or haematological tumors.

Described herein are methods for treating respiratory diseases comprising administering to the mammal at least once an effective amount of at least one compound of the structure of Formula (A), (B), (C) or (D). Respiratory disease may be asthma. Respiratory disease may include, but is not limited to, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, severe acute asthma, chronic asthma, clinical asthma, night asthma, allergen-induced asthma, aspirin-sensitive asthma, asthma-induced asthma

201 2 201 840 / ΡΤ exercise, eucapnic hyperventilation, childhood-onset asthma, adult-onset asthma, cough variant of asthma, occupational asthma, steroid-resistant asthma, seasonal asthma.

There are methods described for preventing rheumatoid arthritis and osteoarthritis comprising administering to the mammal at least once an effective amount of at least one compound of the structure of Formula (A), (B), (C) or (D ).

Also described are methods for treating inflammatory skin responses comprising administering to the mammal at least once an effective amount of at least one compound of the structure of Formula (A), (B), (C) or (D) . Such inflammatory skin responses include, for example, dermatitis, contact dermatitis, eczema, urticaria, rosacea and scarring. Methods for reducing psoriatic lesions on the skin, joints or other tissues or organs are described, comprising administering to the mammal an effective amount of a first compound having the structure of Formula (A), (B), (C) or (D).

Described herein is the use of a compound of Formula (A), (B), (C) or (D) in the manufacture of a medicament for treating an inflammatory disease or condition in an animal in which the activity of Btk or other tyrosine kinases, wherein the other tyrosine kinases share homology to Btk in that they have a cysteine ​​residue (including a Cys 481 residue) that can form a covalent bond with at least one of the irreversible inhibitors described herein, contributes to the pathology and / or symptoms of the disease or condition. The protein tyrosine kinase may be Btk. Inflammatory conditions or diseases may be respiratory, cardiovascular or proliferative diseases.

Administration may be enteral, parenteral or both, and wherein (a) the effective amount of the compound is systemically administered to the mammal; (b) the effective amount of the compound is orally administered to the mammal; (c) the effective amount of the compound is administered to the mammal intravenously; (d) the effective amount of the compound is administered by inhalation; (e) the effective amount of the compound is administered

By nasal administration; or (f) the effective amount of the compound is administered by injection to the mammal; (g) the effective amount of the compound is topically (dermal) administered to the mammal; (h) the effective amount of the compound is administered by ophthalmic administration; or (i) the effective amount of the compound is administered rectally to the mammal.

Described herein are single administrations of the effective amount of the compound, including when (i) the compound is administered once; (ii) the compound is administered to the mammal multiple times over a day; (iii) continuously; or (iv) continuously.

Multiple administrations of the effective amount of the compound are described herein , including when (i) the compound is administered in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours. The method may comprise a pause of medication wherein administration of the compound is temporarily suspended or the dose of the compound to be administered is temporarily reduced; At the end of the break, the dosage of the compound is resumed. The length of the medication break may range from 2 days to 1 year.

Described herein is the treatment of proliferative disorders, including cancer, comprising administering at least one additional agent selected from the group consisting of alemtuzumab, arsenic trioxide, asparaginase (pegylated or not), bevacizumav, cetuximab, platinum such as cisplatin, cladribine, daunorubicin / doxorubicin / idarubicin, irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate, paclitaxel ™, taxol, temozolomide, thioguanine, or classes of drugs including hormones (an antiestrogen, antiandrogen or gonadotropin-releasing hormone analogs, interferons such as interferon alfa, nitrogen mustards such as busulfan or melphalan or mechlorethamine, retinoids such as tretinoin, topoisomerase inhibitors irinotecan or topotecan, tyrosine kinase inhibitors such as gefinitinib or imatinib, or agents to treat signs or symptoms induced by this

Therapy including allopurinol, filgastrim, granisetrone / ondasetrone / palonosetron, dronabinol.

Also described herein is the identification of patients by screening for a tyrosine kinase gene haplotype. The tyrosine kinase gene haplotype can be a tyrosine kinase pathway gene or a Btk haplotype.

The compounds of Formula (A), (B), (C) or (D) may be irreversible Bruton tyrosine kinase (Btk) inhibitors. These irreversible inhibitors may be selective for Btk. These inhibitors may have an IC50 below 10 microM in an enzyme assay. An irreversible Btk inhibitor having an IC 50 of less than 1 microM, for example less than 0.25 microM is described.

Compounds of Formula (A), (B), (C) or (D) which are selective irreversible inhibitors for Btk over Itk are described. Also disclosed are compounds of Formula (A), (B), (C) or (D) which are selective irreversible inhibitors for Btk over Lck. Compounds of Formula (A), (B), (C) or (D) which are selective irreversible inhibitors for Btk over GLA are described. The compound of Formula (A), (B), (C) or (D) may be a selective irreversible inhibitor for Btk over CMET. The compound of Formula (A), (B), (C) or (D) may be an irreversible selective inhibitor for Btk over EGFR. The compound of Formula (A), (B), (C) or (D) may be an irreversible selective inhibitor for Btk over Lyn.

Irreversible Btk inhibitors may also be EGFR inhibitors.

Other objects, features and advantages of the methods and compositions described herein will become more apparent from the following detailed description. The detailed description and concrete examples are given for illustrative purposes only. The section titles used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

201 2 201 840 / ΡΤ

Some terminology

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. Where there are a plurality of definitions for the terminology used herein, those in this section prevail. Where reference is made to a URL or any other identifier or address, it should be understood that such identifiers may change and particular information on the internet may come and go, but equivalent information may be found by searching the internet. Its reference highlights the availability and public dissemination of that information.

It will be understood that the above generic description and the following detailed description are merely exemplary and explanatory and are not restrictive of any claimed subject matter. In this application, the use of the singular includes the plural unless expressly stated otherwise. It should be noted that, as used in the description and the appended claims, the singular forms of one, one and or include the corresponding plural forms unless the context clearly states otherwise. In this application, the use of or means and / or unless otherwise stated. In addition, the use of the term including as well as in other ways such as include, include and included is not limiting.

The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All documents, or parts of documents, cited in the application, including but not limited to patents, patent applications, articles, books, manuals and treaties, are hereby expressly incorporated by reference in their entirety for any purpose.

The definition of standard chemical terms can be found in reference works including Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4TH ED. , Vol. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional mass spectroscopy methods are employed,

201 2 201 840 / ΡΤ

NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technique techniques. The specific, procedures and analytical, pharmaceutical chemistry, here and pharmacology, which are part of the state unless definitions are given to the nomenclature employed in connection with, and the laboratory techniques of synthetic organic chemistry and medical chemistry described are known. of the state of the art. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical preparations, formulation and delivery, and patient care. Standard techniques for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection) may be used. Reactions and purification techniques may be performed, for example, using manufacturer's specification kits or as commonly done in the prior art or as described herein. Said techniques and procedures may generally be performed by conventional methods well known in the art and as described in various generic and more specific references which are cited and discussed throughout the present description.

It will be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs and reagents described herein and, as such, may vary. It is also to be understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to limit the scope of the methods and compositions described herein, which will be limited only by the appended claims.

An alkyl group refers to an aliphatic hydrocarbon group. The alkyl moiety may be a saturated alkyl group, meaning that it does not contain any alkene or alkyne moiety. The alkyl moiety may also be an unsaturated alkyl moiety, which means it contains at least one alkene or alkyne moiety. An alkene moiety refers to a group that has at least one carbon-carbon double bond, and an alkene moiety refers to a group that has at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be

201 2 201 840 / ΡΤ branched, straight chain or cyclic. Depending on the structure, an alkyl group may be a monoradical or a diradical (e.g., an alkylene group. The alkyl group may also be a lower alkyl of 1 to 6 carbon atoms.

As used herein, Ci-C_x includes Ci-C₂, C1-C3 ... C1-C_x.

The alkyl moiety may have from 1 to 10 carbon atoms (where it appears herein, a numerical range, such as 1 to 10, refers to each integer in the given range; for example, 1 to 10 carbon atoms means that the alkyl group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also contemplates the occurrence of the term alkyl without any numerical range being designated. ). The alkyl group of the compounds described herein may be referred to as C1-C4 alkyl or similar designations. By way of example only, C1 -C4 alkyl indicates that there are from one to four carbon atoms in the alkyl chain, that is, the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec. butyl and t-butyl. Thus, C1-C4 alkyl includes C1-C4 alkyl₂ and alkyl Οχ-Ο₃. The alkyl groups may be substituted or unsubstituted. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and others.

As used herein, the term non-cyclic alkyl refers to a non-cyclic alkyl (i.e. a straight or branched chain containing at least one carbon atom). Non-cyclic alkyls may be fully saturated or may contain non-cyclic alkenes and / or alkynes. Non-cyclic alkyls may optionally be substituted.

The term alkenyl refers to a type of alkyl group in which the first two atoms of the alkyl group form a double bond that is not part of an aromatic group. This

That is, an alkenyl group begins with the -C (R) = C (R) -R atoms, where R refers to the remaining portions of the alkenyl group, which may be the same or different. The alkenyl moiety may be branched, straight or cyclic (in which case it would also be known as a cycloalkenyl group). Depending on the structure, an alkenyl group may be a monoradical or a diradical (i.e. an alkenylene group). Alkenyl groups may be optionally substituted. Non-limiting examples of an alkenyl group include -CH = CH₂, -C (CH₃) = CH₂, -CH = CHCH₃, -C (CH₃) = CHCH₃. Alkenylene groups include, but are not limited to, -CH = CH-, -C (CH₃) = CH-, -CH = CHCH₂-, -CH = CHCH₂CH₂- and -C (CH₃) = CHCH₂-. Alkenyl groups may have 2 to 10 carbon atoms. The alkenyl group may also be a lower alkenyl of 2 to 6 carbon atoms.

The term alkynyl refers to a type of alkyl group in which the first two atoms of the alkyl group form a triple bond. That is, an alkynyl group begins with -C = CR, where R refers to the remaining portions of the alkynyl group, which may be the same or different. The R portion of the alkynyl moiety may be branched, straight chain or cyclic. Depending on the structure, an alkynyl group may be a monoradical or diradical (i.e. an alkynylene group). Alkynyl groups may optionally be substituted. Non-limiting examples of an alkynyl group include, but are not limited to, -C = CH, -C = CCH₃, -C = CCH₂CH₃, -C = C- and -C = CCH₂. Alkynyl groups may have 2 to 10 carbon atoms. The alkynyl group may also be a lower alkynyl of 2 to 6 carbon atoms.

An alkoxy group refers to an (alkyl) O- group, where alkyl is as defined herein.

Hydroxyalkyl refers to an alkyl radical, as defined herein, substituted with at least one hydroxy group. Non-limiting examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4hydroxybutyl, 2,3-dihydroxybutyl. hydroxypropyl, 1- (hydroxymethyl) -2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl.

Alkoxyalkyl refers to an alkyl radical as defined herein substituted with an alkoxy group as defined herein.

An alkenyloxy group refers to an (alkenyl) O- group, wherein alkenyl is as defined herein.

The term alkylamine refers to the group -N (alkyl) _xH_ywhere x and y are selected from x = 1, y = lex = 2, y = 0.

When x = 2, alkyl groups together with the N atom to which they are attached may optionally form a cyclic ring system.

Alkylaminoalkyl refers to an alkyl radical as defined herein substituted with an aquylamine as defined herein.

An amide is a chemical moiety of Formula -C (O) NHR or -NHC (O) R wherein R is selected from alkyl, cycloalkyl, aryl, heteroaryl (attached via a ring carbon) and heteroalicyclic (attached) through a ring carbon). An amide moiety may form a bond between an amino acid or peptide molecule and a compound described herein, thereby forming a prodrug. Any carboxyl or amine side chain in the compounds described herein may be amidified. Specific procedures and groups for forming these amides are known to those skilled in the art and can easily be found in reference sources such as Green and Wuts, Protective Groups in Organic Synthesis, 3.^The Ed., John Wiley &amp; Sons, New York, NY, 1999.

The term ester refers to a chemical moiety of the formula -COOR wherein R is selected from alkyl, cycloalkyl, aryl, heteroaryl (attached via a ring carbon) and heteroalicyclic (attached via a ring carbon) . Any carboxyl or hydroxy side chain in the compounds described herein may be esterified. The specific procedures and groups for making such

2,201,840 / esters are known to those skilled in the art and can easily be found in reference sources such as Green and Wuts, Protective Groups in Organic Synthesis, 3.^TheEd., John Wiley &amp; Sons, New York, NY, 1999.

As used herein, the term ring refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyl), heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatic (e.g., aryls and heteroaryls), non-aromatic (e.g., cycloalkyls and non-aromatic heterocycles). ). The rings may optionally be replaced. The rings may be monocyclic or polycyclic.

As used herein, the term ring system or ring system refers to one or more than one ring.

The terms member ring or membered ring may include any cyclic structure. The terms members or members are intended to translate the number of skeleton atoms that make up the ring. Thus, for example, cyclohexyl, pyridine, pyran and thiopyran are 6 membered rings, and cyclopentyl, pyrrole, furan and thiophene are 5 membered rings.

The term fused refers to structures in which two or more rings share one or more bonds.

The terms carbocyclic or carbocycle refers to a ring wherein each of the ring-forming atoms is a carbon atom. The carbocycle includes aryl and cycloalkyl. The term thus distinguishes heterocycle carbocycle (heterocyclic) wherein the ring backbone contains at least one atom that is different from carbon (i.e. a heteroatom). Heterocycle includes heteroaryl and heterocycloalkyl. Carbocycles and heterocycles may optionally be substituted.

The term aromatic refers to a planar ring having a delocalized π electron system containing 4n + 2 n electrons, where n is an integer. Aromatic rings can be formed from five, six, seven,

Eight, nine or more than nine atoms. Aromatics may optionally be substituted. The term aromatic includes both carbocyclic aryl (e.g. phenyl) and heterocyclic (or heteroaryl or heteroaromatic) aryl (e.g. pyridine) groups. The term includes fused ring monocyclic or polycyclic groups (i.e. rings that share pairs of adjacent carbon atoms).

As used herein, the term aryl refers to an aromatic ring wherein each of the ring-forming atoms is a carbon atom. Aryl rings may be formed of five, six, seven, eight, nine or more than nine carbon atoms. Aryl groups may optionally be substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, phenanthrenyl, anthrancenyl, fluorenyl and idenyl. Depending on the structure, an aryl group may be a monoradical or diradical (i.e. an arylene group).

An aryloxy group refers to an (aryl) O- group, wherein aryl is as defined herein.

Aralkyl means an alkyl radical as defined herein substituted with an aryl group. Non-limiting aralkyl groups include benzyl, phenethyl and the like.

Aralkenyl means an alkenyl radical as defined herein substituted with an aryl group as defined herein.

The term cycloalkyl refers to a monocyclic or polycyclic radical containing only carbon and hydrogen, and which may be saturated, partially unsaturated, or fully unsaturated. Cycloalkyl groups include groups of 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include the following portions:

<img file="PT2201840E_D0003.tif" />

201 2 201 840 / ΡΤ

Ο&gt; · τΛ Ο Ο Ο

<img file="PT2201840E_D0004.tif" />

&lt;IT

<img file="PT2201840E_D0005.tif" />

<img file="PT2201840E_D0006.tif" />

/ and others. Depending on the structure, a cycloalkyl group may be a monoradical or a diradical (e.g., a cycloalkylene group). The cycloalkyl group may also be a lower cycloalkyl of 3 to 8 carbon atoms.

Cycloalkylalkyl means an alkyl radical as defined herein substituted with a cycloalkyl group. Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like.

The term heterocycle refers to heteroaromatic and heteroalicyclic groups containing one to four heteroatoms, each selected from 0, S and N, wherein each heterocyclic group has from 4 to 10 atoms in its ring system, and provided that the ring of the said group does not contain two adjacent 0 or S atoms. Here, whenever the number of carbon atoms in a heterocycle is indicated (e.g., C1 -C6 heterocycle), at least one other atom (the heteroatom) must be present in the ring. Designations such as heterocycle Οχ-Οβ refer only to the number of ring carbon atoms and do not refer to the total number of ring atoms. It is understood that the heterocyclic ring may have additional ring heteroatoms. Designations such as 4-6 membered heterocycle refer to the total number of atoms that are contained in the ring (i.e. a four, five or six membered ring wherein at least one atom is a carbon atom, at least one atom is a heteroatom and the remaining two to four atoms are carbon atoms or heteroatoms). In heterocycles having two or more heteroatoms, these two or more atoms may be the same or different from each other. Heterocycles may optionally be substituted. Bonding to a heterocycle may be on a heteroatom or through a carbon atom. Non-aromatic heterocyclic groups include groups that have only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least

Hydrofuranyl, hydropyranyl, atoms in their ring system. Heterocyclic groups include benzo fused ring systems. An example of a 4-membered heterocyclic group is azetidinyl (azetidine derivative). An example of a 5 membered heterocyclic group is thiazolyl. An example of a 6 membered heterocyclic group is pyridyl, and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetradihydrofuranyl, tetrahydrothienyl, tetradihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, oxyidanyl, oxetanyl, oxetanyl, oxetanyl diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, 3Hindolyl and quinozylyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazinyl, tetrazolyl, furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, isoquinolinyl, indolyl, benzimidazolyl, cinolinyl, indazolyl, indolizinyl, triazinyl, triazinyl, triazoleyl quinolinyl, benzofuranyl, phthalazinyl, pteridinyl, purinyl, thiadiazolyl, benzothiazolyl, oxadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. The foregoing groups, as derived from the groups listed above, may be C-linked or N-linked where possible. For example, a pyrrole-derived group may be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Further, an imidazole-derived group may be imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-4-yl or imidazol-5-yl (all Heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or two oxo (= O) moieties such as pyrrolidin-2-one Depending on the structure, a heterocyclic group may be monoradical or diradical (i.e. heterocyclene).

C-linked imidazol-2-yl).

a group

EP 2 201 840 / EN

The terms heteroaryl or, alternatively heteroaromatic, refer to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An N-containing heteroaromatic or heteroaryl moiety refers to an aromatic group in which at least one of the ring backbone atoms is a nitrogen atom. Illustrative examples of heteroaryl groups include the following portions:

<img file="PT2201840E_D0007.tif" />

and others. Depending on the structure, a heteroaryl group may be a monoradical or diradical (i.e. a heteroarylene group).

As used herein, the terms nonaromatic heterocycle, heterocycloalkyl or heteroalicyclic refer to a nonaromatic ring wherein one or more ring-forming atoms are heteroatoms. A non-aromatic heterocycle or heterocycloalkyl group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. The radicals may be fused to an aryl or a heteroaryl. Heterocycloalkyl rings may be formed of three, four, five, six, seven, eight, nine, or more than nine atoms. Aromatic substituted heterocycloalkyl rings may optionally be In certain embodiments, heterocycles do not contain one or more carbonyl or thiocarbonyl groups such as, for example, oxo-containing groups include, but not cyclic imides,

Examples of are limited to cyclic thioimides, tetrahydrothiopyran, 4H-pyran, piperidine, 1,3-dioxane, 1,3-dioxane, dioxane, piperazine, 1,3-oxathian, heterocycloalkyl lactams, lactones, cyclic carbamates, tetra -hydropyran, 1,4-dioxin, 1,41,4-oxathyne, 1,4ΕΡ2,2020,840 / ΡΤ oxatian, tetrahydro-1,4-thiazine, 2Η-1,2-oxazine, maleimide, succinimide, acid barbituric, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidone, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3dioxole, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine and 1,3-oxathiolane. Illustrative examples of heterocycloalkyl groups, also referred to as nonaromatic heterocycles, include:

<img file="PT2201840E_D0008.tif" />

and others. The term heteroalicyclic also includes all carbohydrate ring forms, including but not limited to monosaccharides, disaccharides and oligosaccharides. Depending on the structure, a heterocycloalkyl group may be monoradical or diradical (i.e. a heterocycloalkylene group).

The term halogen- or alternatively halogen or halide means fluorine, chlorine, bromine and iodine.

The terms haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy include alkyl, alkenyl, alkynyl and alkoxy structures in which at least one hydrogen is substituted by a halogen atom. In certain embodiments in which two or more hydrogen atoms are substituted by halogen atoms, the halogen atoms are all the same. In other embodiments in which two or more hydrogen atoms

201 2 201 840 / por are replaced by halogen atoms, halogen atoms are not all equal to each other.

The term fluoroalkyl as used herein refers to an alkyl group in which at least one hydrogen is substituted by a fluorine atom. Examples of fluoroalkyl groups include, but are not limited to, -CF 3, -CH 2 CF 3, -CF 2 CF 3, -CH 2 CH 2 CF 3 and the like.

As used herein, the terms heteroalkyl, heteroalkenyl, heteroalkynyl include optionally substituted alkyl, alkenyl and alkynyl radicals in which one or more main chain atoms are heteroatoms, for example oxygen, nitrogen, sulfur, silicon, phosphorus or combinations thereof. The heteroatom (s) may be placed at any position within the heteroalkyl group or at the position at which the heteroalkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH₂-O-CH₃, -CH₂-CH₂-O-CH₃, -CH₂-NH-CH₃, -CH₂-CH₂NH-CH₃, -CH₂-N (CH₃) -CH₃, -CH 2 -CH 2 -NH-CH 3, -CH 2 -CH 2 -N (CH₃) -ch₃, -CH2-S-CH2-CH3, -CH2-CH2, -S (O) -CH₃, -CH2-CH2-S (o)₂-ch₃, -ch = ch0-CH3, -Si (CH₃)₃, -CH₂-CH = N-OCH₃ and -CH = CH-N (CH₃) -CH₃. In addition, up to two heteroatoms may be consecutive, such as, for example, -CH₂-NH-OCH₃ and -CH₂-O-Si (CH₃) ₃.

The term heteroatom refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from oxygen, sulfur, nitrogen, silicon and phosphorus, but are not limited to these atoms. In embodiments in which two or more atoms are present, the two or more heteroatoms may all be the same, or some or all of the two or more heteroatoms may each be different from the others.

The term single bond or bond refers to a chemical bond between two atoms, or two portions when the atoms joined by the bond are considered as part of a larger structure.

An isocyanate group refers to an -NCO group.

An isothiocyanate group refers to a -NCS group.

201 2 201 840 / ΡΤ

The term portion refers to a specific segment or functional group of a molecule. Chemical portions are often recognized chemical entities incorporated or attached to a molecule.

<td>a</td><td>group</td><td>sulfinyl</td><td>refers</td><td>to one</td><td>-S (= 0) -R.</td>

<td>a</td><td>group</td><td>sulfonyl</td><td>refers</td><td>to one</td><td>-s (= o)₂-r.</td>

<td>a</td><td>group</td><td>thioalkoxy</td><td colspan="2">or alkylthio</td><td>refers to a group -S</td>

alkyl.

An alkylthioalkyl group refers to an alkyl group substituted with an -S-alkyl group.

As used herein, the term O-carboxy or acyloxy refers to a group of Formula RC (= O) O-.

Carboxy means a -C (O) OH radical.

As used herein, the term acetyl refers to a group of Formula -C (= O) CH₃.

Acyl refers to the group -C (O) R.

<td>As here</td><td>used, 0</td><td>term</td><td> tri-</td>

<td>halogenomethanesulfonyl Formula X₃CS (O) 2^_ where X</td><td>refers to It is a halogen.</td><td>a group</td><td>in</td>

<td>As used herein, Formula -CN group.</td><td>, 0 cyan term</td><td>refers</td><td>to one</td>

<td>Cyanoalkyl means defined, substituted with</td><td>an alkyl radical, at least one group</td><td>such as cyan.</td><td>on here</td>

As used herein, the term N-sulfonamido or sulfonylamino refers to a group of Formula RS (= O) 2 NH-.

As used herein, the term O-carbamyl refers to a group of Formula -OC (= O) NR 2.

EP 2 201 840 / EN

As used herein, the term N-carbamyl refers to a group of Formula ROC (= O) NH-.

As used herein, the term O-thiocarbamyl refers to a group of Formula -OC (= S) NR 2.

As used herein, the term N-thiocarbamyl refers to a group of Formula ROC (= S) NH-.

<td>Such as</td><td>used here,</td><td> 0</td><td>term</td><td>C-starch</td><td>refers to a</td>

<td>group of</td><td>Formula -C (= O) NR₂.</td><td></td><td></td><td></td><td></td>

<td colspan="2">Aminocarbonyl refers to</td><td>cL</td><td colspan="2">a radical -CONH₂</td><td> •</td>

<td>Such as</td><td>used here,</td><td>O</td><td>term</td><td>N-starch</td><td>refers to a</td>

<td>group of</td><td>Formula RC (= O) NH-</td><td> •</td><td></td><td></td><td></td>

As used herein, the substituent R which appears by itself and without a numerical designation refers to a substituent selected from alkyl, cycloalkyl, aryl, heteroaryl (linked by a ring carbon) and non-aromatic heterocycle (linked by a ring carbon).

The term optionally substituted or substituted means that the referenced group may be substituted with one or more additional groups individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, cyano, halogen, acyl, nitro, haloalkyl, fluoroalkyl, amino, including mono- and disubstituted groups, and its protected derivatives. By way of example an optional substituent may be L_sR_s where each L_s is independently selected from a bond, -O-, -C (= O) -, -S-, -S (= O) -, -S (= O)₂-, -NH-, -NHC (O) -, -C (O) NH-, S (= O)₂NH-, -NHS (= O)₂, -OC (O) NH-, -NHC (O) O-, - (C1 -C6 alkyl₆ substituted or unsubstituted) or -alkenyl C₂Substituted or unsubstituted -C6); and each R_s is independently selected from H, - (substituted or unsubstituted C1 -C4 alkyl), (substituted or unsubstituted C3 -C6 cycloalkyl), heteroaryl or heteroalkyl. The protecting groups that

No. 2,201,840 may form the protective derivatives of the above substituents are known to those skilled in the art and may be found in references such as Green and Wuts mentioned above.

The term Michael acceptor moiety refers to a functional group that can participate in a Michael reaction, in which a new covalent bond is formed between a portion of the Michael acceptor moiety and the donor moiety. Michael's acceptor moiety is an electrophile and the donor moiety is a nucleophile. G groups in any of Formula (A), Formula (B) or Formula (C) are non-limiting examples of Michael acceptor moieties.

The terms nucleophilic or nucleophilic refer to an electron rich compound or a portion thereof. An example of a nucleophile includes, but is by no means limited to, a cysteine ​​residue of a molecule, such as, for example, Cys 481 or Btk.

The terms electrophilic or electrophilic refer to an electron poor or electron deficient molecule, or a portion thereof. Examples of electrophiles include, but are not in any way limited to, Michael acceptor moieties.

The terms acceptable or pharmaceutically acceptable with respect to a formulation, composition or ingredient as used herein means to have no persistent detrimental effect on the overall health of the subject being treated or to nullify the biological activity or properties of the compound and to be relatively non toxic.

As used herein, the term agonist refers to a compound, the presence of which results in a biological activity of a protein that is the same as the biological activity that results from the presence of a naturally occurring ligand for the protein, such as example, Btk.

As referred to herein, the term partial agonist to a compound whose presence results in a biological of a protein that is of the same type.

That which results from the presence of a natural but minor protein ligand.

As used herein, the term antagonist refers to a compound whose presence results in a decrease in the magnitude of a biological activity of a protein. In certain embodiments, the presence of an antagonist results in complete inhibition of a biological activity of a protein, such as, for example, Btk. In certain embodiments, an antagonist is an inhibitor.

As used herein, amelioration of the symptoms of a particular disease, disorder or condition by the administration of a particular pharmaceutical compound or composition refers to any decrease in severity, delayed onset, slower progression, or shortening of the condition. duration, whether permanent or temporary, lasting or transient, which may be attributed or associated with the administration of the compound or composition.

Bioavailability refers to the weight percent of the compounds disclosed herein, such as compounds of any of Formula (A), Formula (B), Formula (C) or Formula (D), which is delivered to the general circulation of the animal or human being under study. Total exposure of a drug (AUC₍o- j) when administered intravenously is usually defined as 100% bioavailable (F%). Oral bioavailability refers to the extent to which the compounds disclosed herein, such as compounds of any one of Formula (A), Formula (B), Formula (C) or Formula (D), are absorbed into general circulation when Pharmaceutical composition is taken orally compared to intravenous injection.

Blood plasma concentration refers to the concentration of the compounds disclosed herein, such as compounds of any one of Formula (A), Formula (B), Formula (C) or Formula (D), in the blood plasma component of an individual. It is understood that the plasma concentration of compounds of any one of Formula (A), Formula (B), Formula (C) or Formula (D) may vary significantly between individuals due to the variability.

201 2 201 840 / ΡΤ as regards metabolism and / or possible interactions with other therapeutic agents. According to one embodiment disclosed herein, the blood plasma concentration of the compounds of any one of Formula (A), Formula (B), Formula (C) or Formula (D) may vary from individual to individual. Similarly, values ​​such as maximum plasma concentration (C_max) or the time to reach the maximum plasma concentration (T_max) or the total area under the plasma concentration curve over time (AUC (o- j), may vary from individual to individual. Due to this variability, the amount required to constitute a therapeutically effective amount of a compound of any One of Formula (A), Formula (B), Formula (C), or Formula (D) may vary from individual to individual.

Bruton tyrosine kinase, as used herein, refers to Homo Bruton tyrosine kinase as disclosed, for example, in U.S. Patent 6,236,469 (GenBank Accession No. : NP 000052).

The homologous expression of Bruton tyrosine kinase, as used herein, refers to Bruton tyrosine kinase orthologs, for example, mouse (GenBank Accession No. AAB47246), dog (Art. GenBank access code XP_549139), mouse (GenBank access number

NP_001007799), the hen (GenBank accession No. NP_989564), or the zebrafish (GenBank accession No.

XP_698117), and fusion proteins of any of the above which exhibit kinase activity with respect to one or more Bruton tyrosine kinase substrates (e.g., a peptide substrate with the amino acid sequence AVLESEEELYSSARQ).

By coadministration or the like as used herein is intended to encompass single patient administration of the selected therapeutic agents, and is intended to include treatment regimens in which the agents are administered by the same or different routes of administration. administration at the same time or at different times.

201 2 201 840 / ΡΤ

The terms therapeutically refer to one or an amount used herein to administer a disease symptoms without excessive. An effective effective amount, such as sufficient amount of the agent or a compound, which will alleviate to some extent one or more of the symptoms of the disease or condition being treated. The result may be reduction and / or relief of the signs, symptoms or causes of a disease, or any other desired alteration of a biological system. For example, an amount effective for therapeutic use is the amount of the composition, including a compound as disclosed herein, necessary to provide a clinically significant decrease in appropriate effective adverse side effects in any individual case may be determined using techniques such as a study of the subject. dose increase. The term therapeutically effective amount includes, for example, a prophylactically effective amount. An effective amount of a compound disclosed herein is an amount effective to achieve a desired pharmacological effect or therapeutic improvement without excessive adverse side effects. It is understood that an effective amount or a therapeutically effective amount may vary from individual to individual due to variations in compound metabolism of either Formula (A), Formula (B), Formula (C) or Formula (D) , the age, weight, general condition of the individual, the condition to be treated, the severity of the condition to be treated and the opinion of the prescribing physician. By way of example only, therapeutically effective amounts may be determined by routine experimentation, including, but not limited to, a dose escalation clinical trial.

The terms improve or improve mean increasing or prolonging a desired effect, in potency or duration. By way of example, improving the effect of therapeutic agents refers to the ability to increase or prolong the potency or duration of therapeutic agents during the treatment of a disease, disorder or condition. An ameliorating amount as used herein refers to an amount suitable for ameliorating the effect of a therapeutic agent in treating a disease, disorder or condition. When used in a patient, the effective amounts for this use will depend on the severity and progression.

201 2 201 840 / ΡΤ disease, disorder or condition, prior therapy, patient's health status and drug response, and physician's assessment.

The term homologous cysteine, as used herein, refers to a cysteine ​​residue found at a position in the sequence that is homologous to that of Bruton tyrosine kinase 481 as defined herein. For example, cysteine ​​482 is the homologous cysteine ​​of the Bruton tyrosine kinase mouse ortholog; cysteine ​​479 is the homologous cysteine ​​of the chicken ortholog; and cysteine ​​481 is the homologous cysteine ​​in the zebrafish ortholog. In another example, the homologous TXK cysteine, a member of the Bruton tyrosine related Tec family of kinases, is Cys 350. Other examples of homologous cysteine ​​kinases are shown in Fig. 1. Also see the sequence alignments. tyrosine kinases (TK) published on the world wide web in kinase. coitt / huittan / kinoitte / phylogeny. htrnl.

The identical term as used herein refers to two or more sequences or subsequences that are the same. Additionally, the substantially identical expression as used herein refers to two or more sequences that have a percentage of sequential units that are equal when compared and aligned for maximum match over a comparison window, or region designated as measured using comparison algorithms or by manual alignment and visual inspection. By way of example only, two or more sequences may be substantially identical if the sequence units are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 80% identical. 85% identical, about 90% identical or about 95% identical over a specified region. These percentages describe the percent identity of two or more sequences. The identity of a sequence may exist over a region that is at least about 75100 sequential units long, over a region that is about 50 sequential units long, or, when unspecified, throughout the entire sequence. sequence. This definition also refers to the complement of a test sequence. Just by way of example, two or

2 201 840 / ΡΤ more polypeptide sequences are identical when amino acid residues are equal, while two or more polypeptide sequences are substantially identical if amino acid residues are about 60% identical, about 65% identical, about 70% identical, about 75% identical, about 80% identical, about 85% identical, about 90% identical or about 95% identical over a specified region. Identity may exist along a region that is at least about 75-100 amino acids long, along a region that is about 50 amino acids long, or, when unspecified, throughout the sequence, of a polypeptide sequence. Additionally, by way of example only, two or more polynucleotide sequences the nucleic acid residues are or more identical polynucleotide sequences if the nucleic acid residues are about 60% identical, about 65% identical, about 70% identical, about 70% identical. 75% identical, about 80% identical, about 85% identical, about 90% identical or about 95% identical over a specified region. Identity may exist over a region that is at least about 75-100 nucleic acids in length, over a region that is about 50 nucleic acids in length, or, when unspecified, throughout the whole. sequence of a polynucleotide sequence.

are identical when equal while two are substantially

The terms inhibit, inhibit or inhibitor of a kinase as used herein refer to the inhibition of phosphotransferase enzyme activity.

The term irreversible inhibitor as used herein refers to a compound which upon contact with a target protein (e.g., a kinase) causes a new covalent bond to form within or within the protein, whereby a or more of the biological activities of the target protein (e.g. phosphotransferase activity) is diminished or abolished regardless of the subsequent presence or absence of the irreversible inhibitor.

The term irreversible Btk inhibitor as used herein refers to a Btk inhibitor that can form a

Covalently bonding to an amino acid residue from Btk. In one embodiment, the irreversible Btk inhibitor may form a covalent bond with a Btk Cys residue. In particular embodiments, the irreversible inhibitor may form a covalent bond with a Btk Cys 481 residue (or homologue thereof) or a cysteine ​​residue at the corresponding homologous position of another tyrosine kinase, as illustrated in Fig. 1.

The term isolated as used herein refers to the separation and removal of a component of interest from components of interest. The isolated substances may be in a dry or semi-dry state, or in solution, including but not limited to an aqueous solution. The isolated component may be homogeneous or the isolated component may be part of a pharmaceutical composition comprising additional pharmaceutically acceptable carriers and / or excipients. By way of example only, nucleic acids or proteins are isolated when such nucleic acids or proteins are free from at least some of the cellular components with which they are naturally associated, or when the nucleic acid or protein has been concentrated to a certain level. higher than the concentration of its production in vivo or in vitro. Also by way of example, a gene is isolated when separated from open reading frames flanking the

<td>gene and code interest.</td><td>an</td><td>protein</td><td>what</td><td>don't be the</td><td>of</td><td>gene</td><td>in</td>

<td>A metabolite of</td><td>one</td><td>compound</td><td>on here</td><td>disclosed is</td><td>one</td><td colspan="2">derivative</td>

<td>of this compound</td><td>what</td><td colspan="2">It is formed</td><td>when the</td><td colspan="2">compound</td><td>is</td>

metabolized. The term active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term metabolized as used herein refers to the sum of processes (including but not limited to hydrolysis reactions and enzyme catalyzed reactions such as oxidation reactions) whereby a particular substance is modified by a body. Thus, enzymes may produce specific structural changes in a compound. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions while uridine diphosphatoglucorinyltransferases catalyze the transfer of a

Activated glucuronic acid molecule for aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. More information on metabolism can be obtained from The Pharmalogical Basis of Therapeutics, 9.^The Edition, McGraw Hill (1996). The metabolites of the disclosed compounds can be identified by administering the compounds to a host and analyzing tissue samples from the host, by incubating the compounds with liver cells in vitro and analyzing the resulting compounds. Both methods are well known in the prior art. In some embodiments, the metabolites of a compound are formed by oxidative processes and correspond to the corresponding hydroxy containing compound. In some embodiments, a compound is metabolised to pharmacologically active metabolites.

The term modular as used herein means interacting with a target, direct war indirectly, in order to alter the activity of the target, including, by way of example only, improving the activity of the target, inhibiting the activity of the target, limiting the activity of the target. target activity or increase target activity.

As used herein, the term modulator refers to a compound that alters an activity of a molecule. For example, a modulator may cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor, such as decreasing the magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor completely prevents one or more activities of a molecule. In certain embodiments, a modulator is an activator, such as increasing the magnitude of at least one activity of a molecule. In certain embodiments, the presence of a modulator results in activity that does not occur in the absence of the modulator.

The term prophylactically effective amount as used herein refers to the amount of a composition applied to a patient that will to some extent alleviate one or more

201 2 201 840 / ΡΤ more of the symptoms of an illness, condition or disorder being treated. In such prophylactic applications, such amounts may depend on the patient's health, weight, and the like. It is considered within the skill of the art to determine these prophylactically effective amounts by routine experimentation, including, but not limited to, dose escalation clinical trials.

As used herein, the term selective binding compound refers to a compound that selectively binds to any portion of one or more target proteins.

As used herein, the term "selectively binding" refers to the ability of a selective binding compound to bind to a target protein, such as, for example, Btk, with greater affinity than to a non-target protein. . In certain embodiments, specific binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, 1000 or more times the affinity for a non-target.

As used herein, the term selective modulator refers to a compound that modulates a target activity selectively with respect to a non-target activity. In certain embodiments, specific modulator refers to modulating a target activity at least 10, 50, 100, 250, 500, 1000 times more than a non-target activity.

Substantially purified expression as used herein refers to a component of interest that may be substantially or essentially free of other components that normally accompany or interact with the component of interest prior to purification. By way of example only, a component of interest may be substantially purified when the preparation of the component of interest contains less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% (by dry weight) of contaminating components. Thus, a substantially purified component of interest may have a level of

Purity about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or greater.

The term individual as used herein refers to an animal that is the subject of treatment, observation or experiment. By way of example only, an individual may be, but is not limited to, a mammal, including, but not limited to, a human.

As used herein, the term target activity refers to a biological activity that can be modulated by a selective modulator. Some exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzyme activity, tumor growth, inflammation or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or condition.

As referred to herein one is susceptible to selective. In certain Btk.

used, the molecule or to be a target protein of an expression protein a moiety bound by a binding compound embodiments, a target protein is the

The terms treat or treatment as used herein include alleviating, diminishing or ameliorating the symptoms of a disease or condition, preventing additional symptoms, ameliorating or preventing the metabolic causes underlying the symptoms, inhibiting the disease or condition, i.e. development of the disease or condition, alleviate the disease or condition, cause regression of the disease or condition, alleviate a condition caused by the disease or condition, or stop the symptoms of the disease or condition. The terms treat or treatment include, but are not limited to, prophylactic and / or therapeutic treatments.

As used herein, the IC 50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as Btk inhibition, in an assay that measures that response.

201 2 201 840 / ΡΤ

As used herein, the EC 50 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response to 50% of the maximum expression of a particular response that is induced, elicited or potentiated by the compound. private test.

Brief Description of the Figures

Figure 1 shows a sequence comparison of Btk with other tyrosine kinases.

Figure 2 shows illustrative cellular data for inhibition of B cell receptor-induced phospholipase-CY phosphorylation by compound 4. In this example, there were 2E6 Ramos cells / well in serum free media; Cells were pretreated with compound for 1.5 h. B cell receptor was stimulated with anti-IgM for 3 min; 10X lysis buffer containing DNase was added directly to the cells. Sample buffer was added and loaded directly onto the gel. Samples were analyzed by phosphorylated Western blot - Btk and PLCyI and total Btk and PLCyI. Blot image was obtained on ChemiDoc CCD and quantified with ImageQuant. The phosphorylated band was normalized to the total band and the CI₅₀ has been calculated.

Figure 3 shows illustrative cellular data showing that compound 4 and compound 15 inhibit DHL-6 cell growth. In this example, there were 3E4 DHL-6 cells / well in complete medium. Cells were treated for the time indicated with the compound at 0.1% final concentration in DMSO. Cell number was measured using an Alamar Blue assay in accordance with the standard protocol.

Figure 4 shows illustrative mass spectra showing that compound 4 covalently modifies Btk. In this example, incubate 30uM compound 4 with 6-7uM recombinant Btk (Y-&gt; D mutant, kinase domain only) overnight at RT. Desalinate the protein-inhibitor complex by reverse phase HPLC and analyze directly on the mass spectrometer to determine molecular weight. &gt; 99% of recombinant Btk protein is covalently modified by compound 4.

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Figure 5 shows the illustrative inhibition of arthritis development in a mouse model by compound 4.

Figure 6 shows illustrative data demonstrating that the efficacy of compound 4 is associated with reduction of Rheumatoid Factor and anti-citrullinated cyclic peptide antibodies in the CAIA model. In these examples, * p &lt;0.01; ** p &lt;0.001 vs vehicle or saline treatment.

Figure 7 shows illustrative data regarding the inhibition of arthritis development in a mouse model by compound 13. This enantiomer of compound 4 completely inhibited arthritis development in the CAIA model at dosage levels of 10 and 30 mg / kg. For comparison, data regarding inhibition of arthritis development in the same mouse model are presented for dexamethasone.

Detailed Description of the Invention

The methods described herein include administering to a subject in need thereof a composition containing a therapeutically effective amount of one or more irreversible Btk inhibitor compounds described herein. Without being bound by theory, the various roles played by Btk signaling in various hematopoietic cell functions, for example, activation of B cell receptors, suggest that small molecule Btk inhibitors are useful for reducing the risk of, or for treating, a variety of diseases affected by or affecting many types of hematopoietic lineage cells including, for example, autoimmune diseases, heteroimmune diseases or conditions, inflammatory diseases, cancer (e.g., B cell proliferative disorders) and thromboembolic disorders. Further, the irreversible Btk inhibitor compounds described herein may be used to inhibit a small subset of other Btk homology tyrosine kinases in that they have a cysteine ​​residue (including a Cys 481 residue) that can form a bond. covalent with the irreversible inhibitor. See, for example, protein kinases in Figure 1. Thus, a subset of tyrosine kinases, other than Btk, are expected to

2 201 840 / ΡΤ are also useful as therapeutic targets in a number of health conditions.

The methods described herein may be used to treat an autoimmune disease, including but not limited to rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis , Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barré syndrome, Acute disseminated encephalomyelitis, Addison's disease, opsoclonia-myoclonia syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu arteritis, temporal arteritis, autoimmune hemolytic anemia warm type, Wegener's granulomatosis, psoriasis, universal alopecia, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma or vulvar vestibulitis.

transplantation, transfusion, pollen allergies of the

The methods described herein may be used to treat autoimmune diseases or conditions that include, but are not, graft versus host disease, anaphylaxis, allergies (e.g., plants, latex, drugs, foods, insects, animal skins, animal dander, mites or chalice cockroaches), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis or atopic dermatitis.

The methods described herein may be used to treat an inflammatory disease, including but not limited to asthma, inflammatory bowel disease, appendicitis, blepharitis, cervicitis, cholangitis, cystitis, dacrioadenitis, endocarditis, epicondylitis, gastroenteritis, mastitis, ovaritis, bronchiolitis, bronchitis, bursitis, cholecystitis, colitis, conjunctivitis, dermatitis, dermatomyositis, encephalitis, endometritis, enteritis, enterocolitis, epididymitis, fasciitis, fibrositis, gastritis, hepatitis, suppurative hydadenitis, laryngitis, meningitis, myelitis, myocarditis, myositis, nephritis,

201 2 201 840 / ΡΤ orchitis, osteitis, otitis, pancreatitis, peritonitis, pharyngitis, pleuritis, pneumonia, proctitis, prostatitis, salpingitis, sinusitis, stomatitis, tonsillitis, uveitis, vaginitis, vasculitis parotitis, pericarditis, phlebitis, pneumonitis, pyelitis, pyelitis , synovitis, tendonitis, or vulvitis.

The methods described herein may be used to treat cancer, for example B cell proliferative disorders, which include, but are not limited to, diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, leukemia. prolymphocytic B-cell, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma, plasmocytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, large B cell mediastinal (thymic) lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt leukemia / lymphoma and lymphomatoid granulomatosis.

The methods described herein may be used to treat including but not limited to myocardial infarction, angina pectoris (including unstable angina), reocclusion or restenosis after angioplasty or bypass coronary bypass, stroke, transient ischemia, occlusions of peripheral arteries, pulmonary embolism or deep vein thrombosis.

Symptoms, diagnostic tests and prognostic tests for each of the above conditions are known from the prior art. See for example, Harrison's Principles of International Medicine ©, 16.^The ed., 2004, The McGrawHill Companies, Inc. Dey et al. (2006), Cytojournal 3 (24), and the Revised European American Lymphoma (REAL) rating system (see, for example, the website of the National Cancer Institute).

Various animal models are useful for establishing a therapeutically effective dose range of irreversible Btk inhibitor compounds for treating any of the above diseases.

EP 2 201 840 / EN

For example, the dosage of irreversible Btk inhibitor compounds for treatment of an autoimmune disease may be determined in a mouse model of rheumatoid arthritis. In this model, arthritis is induced in Balb / c mice by administration of anti-collagen and lipopolysaccharide antibodies. See Nandakumar et al. (2003), Am. J. Pathol 163: 1827-1837.

In another example, the dosage of irreversible Btk inhibitors for the treatment of B cell proliferative disorders may be examined in, for example, a human-to-mouse xenograft model in which human B-cell lymphoma cells (e.g. Ramos) immunodeficient mouse (e.g., described, for example, in Pagel et al Res 11 (13): 4857-4866.

are implanted in the nude mouse) as (2005), Clin Cancer

Animal models for the treatment of thromboembolic disorders are also known.

The therapeutic efficacy of the compound for one of the aforementioned diseases may be optimized during the course of treatment. For example, the subject under treatment may be subjected to a diagnostic evaluation to correlate relief of disease symptoms or conditions with inhibition of Btk activity in vivo achieved by administering a certain dose of an irreversible Btk inhibitor. Cellular assays known in the art may be used to determine in vivo Btk activity in the presence or absence of an irreversible Btk inhibitor. For example, since activated Btk is phosphorylated on tyrosine 223 (Y223) and tyrosine 551 (Y551), phospho-specific immunocytochemical staining of P-Y223 or P-Y551 positive cells can be used to detect or quantify activation of Btk in a cell population (e.g., by FACS analysis of stained vs unstained cells). See, for example, Nisitani et al. (1999), Proc. Natl. Acad. Sci., USA 96: 22212226. Thus, the amount of the Btk inhibitor compound that is administered to an individual may be increased or decreased as necessary to maintain a level of inhibition of Btk.

EP 2 201 840 / EN

Optimal btk for treating the disease state of the individual.

Compounds

In the following description of irreversible Btk inhibitor compounds suitable for use in the methods described herein, definitions of the standard chemical terms referred to can be found in reference works (if not defined herein), including Carey and Sundberg, Advanced Organic Chemistry 4.^The Ed., Vol. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, which are within normal skill in the art, are used. Additionally, they are known from the prior art, as disclosed, for example, in US 6,326,469, amino acid and nucleic acid sequences for Btk (e.g., human Btk). Unless specific definitions are provided, the nomenclature employed with respect to and the laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard techniques may be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and patient care.

The Btk inhibitor compounds described herein are selective for Btk and kinases with a cysteine ​​residue at a position in the tyrosine kinase amino acid sequence that is homologous to the position in the amino acid sequence of cysteine ​​481 in Btk. See, for example, the kinases in Fig. 1. Inhibitor compounds described herein include a Michael acceptor moiety.

In general, an irreversible Btk inhibitor compound used in the methods described herein is identified or characterized in an in vitro assay, for example, an acellular biochemical assay or a cellular functional assay. Such assays are useful for determining an in vitro IC50 for an irreversible Btk inhibitor compound.

201 2 201 840 / ΡΤ

For example, an acellular kinase assay can be used to determine Btk activity after incubation of kinase in the absence or presence of a concentration range of an irreversible Btk inhibitor candidate compound. If the candidate compound is in fact an irreversible Btk inhibitor, Btk kinase activity will not be recovered by repeated washing with inhibitor-free medium. See, for example, JB Smaill, et al. (1999), J. Med. Chem. 42 (10): 1803-1815. Further, the formation of covalent complexes between Btk and an irreversible Btk inhibitor candidate is a useful indicator of irreversible Btk inhibition that can be readily determined by various methods known in the art (e.g., mass spectrometry). For example, some irreversible Btk inhibitor compounds may form a covalent bond with Btk Cys 481 (e.g., through a Michael reaction).

Cellular functional assays for Btk inhibition include measuring one or more cell endpoints in response to stimulation of a Btk-mediated pathway in a cell line (e.g., BCR activation in Ramos cells) in the absence or presence of a concentration range of an irreversible Btk inhibitor candidate compound. Useful endpoints for determining a response to BCR activation include, for example, Btk autophosphorylation, phosphorylation of a Btk target protein (e.g.

<td>PLC-γ), and the</td><td>flow</td><td>of calcium</td><td colspan="2">cytoplasmic.</td>

<td>Tests of</td><td>high</td><td>Yield</td><td>for many trials</td><td>biochemicals</td>

<td>acellular</td><td>(per</td><td>example,</td><td>kinase assays)</td><td>and rehearsals</td>

Functional cells (eg, calcium flux) are well known to those skilled in the art. In addition, high throughput screening systems are commercially available (see, for example, Zymark Corp., Hopkinton, MA; Air Technical Industries, Mentor, OH; Beckman Instruments, Inc. Fullerton, CA; Precision Systems, Inc., Natick, MA, etc.). These systems typically automate entire procedures including pipetting all samples and reagents, dispensing liquids, timed incubations, and final microplate readings at the appropriate detector (s) for the assay. The automated systems

201 2 201 840 / ΡΤ thus permit the identification and characterization of a large number of irreversible Btk inhibitor compounds without undue strain.

Irreversible Btk inhibitor compounds may be used for the manufacture of a medicament for the treatment of any of the foregoing conditions (for example autoimmune diseases, inflammatory diseases, allergic disorders, B cell proliferative disorders or thromboembolic disorders).

The irreversible Btk inhibitor compound used for the methods described herein may inhibit the activity of Btk kinase or a Btk homologue with an in vitro IC50 of less than 10 μΜ (for example, less than 1 μΜ, less than 5 μΜ less than 0.4 μΜ, less than 0.3 μΜ, less than 0.1 μΜ, less than less than 0.06 μΜ, less than 0.05 μΜ, less than

0.08 μΜ, 0.04 μΜ, minus minus minus less than 0.03 μΜ, less than 0.02 μΜ, less than 0.01, of

0,008 μΜ minus 0,004 μΜ minus 0,001 less than 0,00097 μΜ of 0,006 μΜ less than 0,005 μΜ, 0,003 μΜ less than 0,002 μΜ,

0.00099 μΜ, less than 0.00098 μΜ, less than 0, 00096 μΜ, less than

0.00095 μΜ, less than 0.00094 μΜ, less than 0.00093 μΜ, less than 0.00092, or less than 0.00090 μΜ).

The irreversible Btk inhibitor compound can selectively and irreversibly inhibit an activated form of its target tyrosine kinase (e.g., a phosphorylated form of tyrosine kinase). For example, activated Btk is transphosphorylated to tyrosine 551. For example, the irreversible Btk inhibitor can inhibit target kinase in cells only when target kinase is activated by signaling events.

any one of (D). Also acceptable, metabolites

Described herein are compounds of

Formula (A), Formula (B), Formula (C) or Formula described herein are pharmaceutically acceptable pharmaceutically acceptable, pharmaceutically active salts and pharmaceutically acceptable prodrugs of such compounds. Pharmaceutical compositions comprising at least one of these compounds or a pharmaceutically acceptable salt, a solvate or a

Pharmaceutically acceptable 2 201 840 /, a pharmaceutically active metabolite or a pharmaceutically acceptable prodrug of these compounds. Where the compounds described herein contain an oxidizable nitrogen atom, the hydrogen atom may be converted to an N-oxide by methods well known in the art. Chemically protected isomers and forms of compounds having a structure represented by any one of Formula (A), Formula (B), Formula (C) or Formula (D), are also described.

Pharmaceutically acceptable compounds of Formula (A) and acceptable solvates are described. Formula (A) is as follows:

and their pharmaceutically salts

<img file="PT2201840E_D0009.tif" />

on what:

A is independently selected from N or CR5;

Ri no no it's not H, L₂- (unsubstituted or substituted alkyl L₂- (unsubstituted or substituted cycloalkyl L₂- (substituted alkenyl or L₂- (substituted cycloalkenyl or L₂- (substituted heterocycle or L₂- (substituted heteroaryl

L₂- (aryl substituted or not a bond, O, S, -S (= 0), -S (= O)₂, C (= O), - (C1 -C6 alkyl)₆ substituted or unsubstituted), or - (alkenyl C₂-Ç₆substituted or unsubstituted);

substituted), substituted), substituted), substituted), substituted), or unsubstituted) or substituted), where L₂ is

R₂ and R₃ are independently selected from H, lower alkyl or substituted lower alkyl;

R₄ it's L₃-XL₄-G, where,

L₃ is optionally and, when present, is a bond, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted alkenyl or

Unsubstituted, optionally substituted or unsubstituted alkynyl;

is optional and, when present, is a bond, O, -C (= O), S, -s (= 0), -S (= O)₂, -NH, -NR₉, -NHC (O),

-C (O) NH, -NRgC (O), -C (O) NRg, -S (= 0) ₂NH, -NHS (= O)₂,

-S (= O)₂NRg-, -OC (O) NRg-, -NR₁₀C (O) NR₁₀-NR₁₀C (= NR_no) -C (= NRn) 0-;

-NRgS (= O)₂, -NRgC (O) O-, heteroaryl,

-C (= NRn) NR_K

-OC (O) NH-, -CH = NO-, aryl,

-NHC (O) O-, -ON = CH-, NR₁₀C (= NRn) NR₁₀-,

OC (= NR_no) - or is it a bond,

Optionally substituted and, when present, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted alkynyl, substituted heteroaryl substituted aryl or substituted or unsubstituted heterocycle;

replaced or not or not replaced, not replaced, or L

L₄taken together form a nitrogen-containing heterocyclic ring;

OR_and

<img file="PT2201840E_D0010.tif" />

<img file="PT2201840E_D0011.tif" />

R₇

Rg

OR_s tt | ** ,s

OR wherein, selected from lower lower alkyl or

R 6, R 7 and R 6 are independently from H, lower or substituted alkyl, substituted heteroalkyl lower heteroalkyl, substituted or unsubstituted lower cycloalkyl and substituted or unsubstituted lower heterocycloalkyl;

R₅ is H, halogen, -L₆- (0χ-0 alkyl)₃ replaced replaced), -L₆- (alkenyl C₂-Ç₄ replaced replaced), -L₆- (substituted heteroaryl or -L₆- (aryl where Le is a substituted) substituted), whether or not substituted or not or not bonded, 0, S, -S (= 0),

EP 2 201 840 / EN

S (= O)₂NH, C (O), -NHC (O) O, -OC (O) NH, -NHC (O) or -C (O) NH;

each R 9 is independently selected from H, substituted or unsubstituted lower alkyl and substituted or unsubstituted lower cycloalkyl;

each R 10 is independently H, substituted or unsubstituted lower alkyl or substituted or unsubstituted lower cycloalkyl; or two groups Rio may, taken together, form a ring

<td>heterocyclic</td><td>in</td><td> 5,</td><td> 6, 7</td><td>or</td><td>8 members;</td><td>or</td>

<td>Rg and Rio can,</td><td></td><td colspan="2">taken</td><td>in</td><td>set,</td><td>form a ring</td>

<td>heterocyclic</td><td>in</td><td> 5,</td><td> 6, 7</td><td>or</td><td>8 members;</td><td>or</td>

each Rn is independently selected from H, -S (= O)₂R₈, -S (= O)₂NH₂, -COLOR₈, -CN, -NO₂heteroaryl or heteroalkyl; and pharmaceutically acceptable solvates or pharmaceutically acceptable salts thereof.

Described herein is the compound of Formula (A) which has the following structure of Formula (B):

<img file="PT2201840E_D0012.tif" />

Formula (B) wherein:

Y is alkyl or substituted alkyl, or a 4-, 5- or 6-membered cycloalkyl ring;

each R_The is independently H, halogen, -CF₃, -CN, -NO₂OH OH₂, -L_The- (substituted or unsubstituted alkyl), -L_The(substituted or unsubstituted alkenyl), -L_The(Substituted or unsubstituted heteroaryl) or -L_The(substituted or unsubstituted aryl), where L_The is a bond, O, S, -S (= 0), -S (= O)₂NH, C (O) CH₂-NHC (O) O, -NHC (O) or -C (O) NH;

<img file="PT2201840E_D0013.tif" />

what,

R₆R 7 and R 6 are independently selected from H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl and substituted or unsubstituted lower heterocycloalkyl;

R12 is H or lower alkyl; or

Y and R 12 taken together form a 4-, 5- or 6-membered heterocyclic ring; and their pharmaceutically acceptable active metabolites, pharmaceutically acceptable solvates, pharmaceutically acceptable salts or pharmaceutically acceptable prodrugs.

be selected from

<img file="PT2201840E_D0014.tif" />

G can

<img file="PT2201840E_D0015.tif" />

<img file="PT2201840E_D0016.tif" />

y-_no.R «can be selected from

<img file="PT2201840E_D0017.tif" />

EP 2 201 840 / EN

A compound of Formula (Β) which has the following structure of Formula (C) is described:

<img file="PT2201840E_D0018.tif" />

t

G

Formula (C)

Y is alkyl or substituted alkyl or a 4-, 5- or 6-membered cycloalkyl ring;

R12 is H or lower alkyl; or

Y and R 12 taken together form a 4-, 5-, or 6-membered heterocyclic ring;

<img file="PT2201840E_D0019.tif" />

where Rê R₇ and R6 are independently selected from H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl and substituted or unsubstituted lower heterocycloalkyl; and pharmaceutically acceptable solvates thereof or pharmaceutically acceptable salts thereof.

In the described components, the group G of any one of Formula (A), Formula (B) or Formula (C) is any group that is used to tailor the physical and biological properties of the molecule. Such hoisting / modifications are accomplished using groups that modulate Michael acceptor chemical reactivity, acidity, basicity, lipophilicity, solubility and other physical properties of the molecule. The physical and biological properties modulated by these modifications to G include, by way of example only, improving the chemical reactivity of the group.

Michael acceptor, solubility, absorption in vivo, metabolism in vivo. Further, in vivo metabolism may include, by way of example only, controlling in vivo pharmacokinetic (PK) properties, off-target activities, potential toxicities associated with cypP450 interactions, drug interactions and the like. In addition, modifications in G allow to tailor the in vivo efficacy of the compound by modulating, by way of example, specific and non-specific binding to plasma and lipid proteins and tissue distribution in vivo.

Described herein are compounds of the structure of Formula (D):

<img file="PT2201840E_D0020.tif" />

Formula (D) wherein

La is CH₂O, NH or S;

Ar is an optionally substituted aromatic carbocycle or aromatic heterocycle;

Y is an optionally substituted alkyl, heteroalkyl, carbocycle, heterocycle, or a combination thereof;

Z is C (O), OC (O), NHC (O), C (S), S (O)_X, OS (O)_XNHS (O)_Xwherein x is 1 or 2; and

R 6, R 7 and R 6 are independently selected from H, alkyl, heteroalkyl, carbocycle, heterocycle or combinations thereof.

In a further or alternative embodiment, La is O.

In a further or alternative embodiment, Ar is phenyl.

201 2 201 840 / ΡΤ

In a further or alternative embodiment, Z is C (O).

In a further or alternative embodiment each of R 1, R₂ and R₃ it's H.

Described herein is a compound of Formula (D). Formula (D) is as follows:

<img file="PT2201840E_D0021.tif" />

Formula (D) wherein:

L_The it's CH₂O, NH or S;

Ar is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;

is a group optionally substituted by alkyl, heteroalkyl, heterocycloalkyl, aryl and heteroaryl;

selected from cycloalkyl, is C (= 0)

NHS (= 0) x,

OC (= 0), where x is

NHC (= 0), 1 or 2;

C (= S),

S (= 0)_x, 0S (= 0)_x,

R₇ and Rg are independently selected from H, unsubstituted C1-C4 alkyl, substituted C1-C4 alkyl, unsubstituted C1-C4 heteroalkyl, substituted C1-C4 heteroalkyl, C-cycloalkyl₃Unsubstituted -C6, cycloalkyl C₃Substituted -C6, heterocycloalkyl C₂Unsubstituted -C6 and heterocycloalkyl C₂-C6 substituted; or

R₇ and Rg taken together form a bond;

R 6 is H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 alkylaminoalkyl₇-Cg,

201 2 201 840 / substituído substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-Cg heterocycloalkyl, substituted or unsubstituted heteroaryl, C1-C4 alkyl (aryl), C1-C4 alkyl ( heteroaryl), C1 -C4 alkyl (C cycloalkyl₃Ç₈) or C1-C4 alkyl (C heterocycloalkyl₂-Ç₈); and or pharmaceutically acceptable solvates or pharmaceutically acceptable salts thereof. The compounds of Formula (D) wherein R 6 is H and R 7 and R 8 are H or taken together form a bond are embodiments of the invention.

For each and every embodiment, substituents may be selected from a subset of the stated alternatives. For example, in some embodiments, L_The it's CH₂, O, or NH. In other embodiments, L_The is O or NH. And in still other embodiments, L_The it's the.

In some embodiments, Ar is 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 still other embodiments, Z is C (= 0), OC (= 0), NHC (= 0), S (= 0)_x, OS (= 0) _x, or NHS (= O)_X. In some other embodiments, Z is C (= 0), NHC (= 0) or S (= 0)₂.

Compounds are described wherein R₇ and R 6 are independently selected from H, unsubstituted C 1 -C 4 alkyl, substituted C 1 -C 4 alkyl, unsubstituted C 1 -C 4 heteroalkyl and substituted C 1 -C 4 heteroalkyl; or R₇ and Rg taken together form a bond. In one embodiment, each of R₇ and Re is H; or R₇ and Rg taken together form a bond.

Compounds are described wherein substituted or unsubstituted Rr, substituted or unsubstituted C1-C2-N alkyl (alkyl is H, C1-C4 alkyl heteroalkyl C1-C4 alkoxyalkyl Οχ-Οβ, substituted or unsubstituted, substituted,

Ci-C₃) 2, substituted aryl, substituted heteroaryl C1-C4 alkyl (aryl), C1-C4 alkyl (heteroaryl), C-alkyl₇Ç₄(cycloalkyl C₃-Cg) or C1 -C4 alkyl (C2 -C6 heterocycloalkyl). In some cases, R is H, unsubstituted or substituted C1-C4 alkyl

201 2 201 840 / ΡΤ substituted, substituted or unsubstituted C1-C4 heteroalkyl, C1-C6 alkoxyalkyl, C1-C2-N alkyl (C1C-alkyl₃) 2z C1-C4 alkyl (aryl), C1-C4 alkyl (heteroaryl), C1-C4 alkyl (C-cycloalkyl)₃-Cg) or C1-6 alkyl₃Ç₄ (C 2 -C 6 heterocycloalkyl). In other cases, R 6 is H, substituted or unsubstituted C 1 -C 4 alkyl, -CH₂-O- (C1 -C6 alkyl)₃), -CH₂-N (C1 -C6 alkyl)₃) 2 / · C1-C4 alkyl (phenyl) or C1 -C4 alkyl₄ (5 or 6 membered heteroaryl). In some cases R 6 is H, substituted or unsubstituted C 1 -C 4 alkyl, -CH 2 -O- (C 1 -C 6 alkyl)₃), -CH₂-N (C1 -C6 alkyl)₃) 2 / · C1-C4 alkyl (phenyl) or C1-C4 alkyl (5 or 6 membered heteroaryl containing 1 or 2 N atoms), or C1-C4 alkyl (5 or 6 membered heterocycloalkyl containing 1 or 2 N atoms) substituted heteroalkyl

In some embodiments, Y is a group optionally substituted from alkyl, heteroalkyl, cycloalkyl and heterocycloalkyl. In other embodiments, Y is an optionally substituted group selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, 4, 5, 6 or membered cycloalkyl, and 4, 5, 6 or 7 membered heterocycloalkyl.

In yet other embodiments, Y is a group optionally selected from C1 -C6 alkyl₆, Cq-C₆5 or 6 membered cycloalkyl, 5 or 6 membered heterocycloalkyl containing 1 or 2 N atoms. In some other embodiments, Y is a 5 or 6 membered cycloalkyl or 5 or 6 membered heterocycloalkyl containing 1 or 2 N atoms.

Any combination of the groups described above for the various variables is described herein. It is understood that substituents and substitution patterns may be selected by one of ordinary skill in the compounds provided herein to provide compounds which are chemically stable and which may be synthesized by techniques known in the prior art, as well as those set forth herein. .

Some examples of compounds of Formula (A), Formula (B), Formula (C), Formula (D) described herein include:

201 2 201 840 / ΡΤ

<img file="PT2201840E_D0022.tif" />

EP 2 201 840 / EN

<img file="PT2201840E_D0023.tif" />

EP 2 201 840 / EN

<img file="PT2201840E_D0024.tif" />

In one aspect there is provided herein a compound selected from:

1- (3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one (Compound 4 ); (E) —1- (3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1yl) piperidin-1-yl) but-2-en-1-one one (Compound 5); 1- (3- (4-amino3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) sulfonylene (Compound 6); 1- (3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-yl) prop-2-yn-1-one (Compound 8); 1- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-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-d] pyrimidin-1-yl) pyrrolidin-1yl) prop-2-en-1-one ( Compound 11); 1 - ((S) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1yl) prop-2-en-1-one ( Compound 12); 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-lil) prop-2-en-1-one ( 13); 1 - ((S) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-lil) prop-2-en-1-one ( Compound 14); and (E) -1- (3- (4-amino-3- (4EP 2 201 840 / phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1yl) -4- (dimethylamino) but-2-en-1-one (Compound 15).

Throughout the specification, groups and their substituents may be selected by one skilled in the art to provide stable compounds and moieties.

The compounds of any of Formula (A) or Formula (B) or Formula (C) or Formula (D) described herein may irreversibly inhibit Btk and may be used to treat patients suffering from dependent diseases or conditions. Bruton's tyrosine kinase or Bruton's tyrosine kinase mediated, including, but not limited to cancer, autoimmune diseases and other inflammatory diseases.

Compound Preparation

Compounds of any one of Formula (A), Formula (B), Formula (C) or Formula (D) may be synthesized using standard synthesis techniques known to those skilled in the art or using methods known in the prior art in combination. with methods described herein. Additionally, solvents, temperatures and other reaction conditions herein may vary according to those skilled in the art.

In addition, synthetic ones may also be used.

As guidance following methods

The reactions may be employed in a linear sequence to provide the compounds described herein or may be used to synthesize fragments which are subsequently assembled by the methods described herein and / or known in the art.

Formation of Covalent Bonds by Electrophile Reaction with a Nucleophile of a

The compounds described herein may be use of various nucleophilic or electrophilic modified to form new functional groups or substituents. Table 1 entitled Examples of Covalent Bonds and Their Precursors lists selected examples of covalent bonds precursor functional groups which give rise to,

201 2 201 840 / ΡΤ may be used as a guide for the variety of electrophile and nucleophil combinations available. Precursor functional groups are presented as electrophilic groups and nucleophilic groups.

Table 1: Examples of Covalent Bonds and Their Precursors

<td>IPL / Gllgie</td><td>§1ΐ11ΐ111β ^</td><td></td>

<td>Carboxamides</td><td>Esters enabled</td><td>amines / anilines</td>

<td>Carboxamides</td><td>acylazides</td><td>amines / anilines</td>

<td>Carboxamides</td><td>acyl halides</td><td>amines / anilines</td>

<td>Esters</td><td>acyl halides</td><td>alcohols / phenols</td>

<td>Esters</td><td>acylnitriles</td><td>alcohols / phenols</td>

<td>Carboxamides</td><td>acylnitriles</td><td>amines / anilines</td>

<td>Imines</td><td>Aldehydes</td><td>amines / anilines</td>

<td>Hydrazones</td><td>aldehydes or ketones</td><td>Hydrazines</td>

<td>Oximes</td><td>aldehydes or ketones</td><td>Hydroxylamines</td>

<td>Alkylamines</td><td>alkyl halides</td><td>amines / anilines</td>

<td>Esters</td><td>alkyl halides</td><td>carboxylic acids</td>

<td>Thioethers</td><td>alkyl halides</td><td>Thiols</td>

<td>Ethers</td><td>alkyl halides</td><td>alcohols / phenols</td>

<td>Thioethers</td><td>alkylsulfonates</td><td>Thiols</td>

<td>Esters</td><td>alkylsulfonates</td><td>carboxylic acids</td>

<td>Ethers</td><td>alkylsulfonates</td><td>alcohols / phenols</td>

<td>Esters</td><td>Anhydrides</td><td>alcohols / phenols</td>

<td>Carboxamides</td><td>Anhydrides</td><td>amines / anilines</td>

<td>Thiophenols</td><td>aryl halides</td><td>Thiols</td>

<td>Aarilamines</td><td>aryl halides</td><td>Amines</td>

<td>Thioethers</td><td>azindins</td><td>Thiols</td>

<td>Boronate Esters</td><td>boronates</td><td>Glycols</td>

<td>Carboxamides</td><td>carboxylic acids</td><td>amines / anilines</td>

<td>Esters</td><td>carboxylic acids</td><td>Alcohols</td>

<td>hydrazines</td><td>Hydrazides</td><td>carboxylic acids</td>

<td>W-Acylureas or Anhydrides</td><td>carbodiimides</td><td>carboxylic acids</td>

<td>Esters</td><td>diazoalkanes</td><td>carboxylic acids</td>

<td>Thioethers</td><td>epoxides</td><td>Thiols</td>

<td>Thioethers</td><td>halogenoacetamides</td><td>Thiols</td>

<td>Aminotriazines</td><td>halogenotriazines</td><td>amines / anilines</td>

<td>Ethers of triazinyl</td><td>halogenotriazines</td><td>alcohols / phenols</td>

<td>Amidines</td><td>imidoesters</td><td>amines / anilines</td>

<td>Urea</td><td>Isocyanates</td><td>amines / anilines</td>

<td>Urethanes</td><td>Isocyanates</td><td>alcohols / phenols</td>

201 2 201 840 / ΡΤ

<td>Thiourea</td><td>isothiocyanates</td><td>amines / anilines</td>

<td>Thioethers</td><td>Maleimides</td><td>Thiols</td>

<td>Phosphite Esters</td><td>phosphoramidites</td><td>Alcohols</td>

<td>Silylethers</td><td>Silyl halides</td><td>Alcohols</td>

<td>Alkylamines</td><td>sulfonate esters</td><td>amines / anilines</td>

<td>Thioethers</td><td>sulfonate esters</td><td>Thiols</td>

<td>Esters</td><td>sulfonate esters</td><td>carboxylic acids</td>

<td>Ethers</td><td>sulfonate esters</td><td>Alcohols</td>

<td>Sulfonamides</td><td>sulfonyl halides</td><td>amines / anilines</td>

<td>Sulfonate Esters</td><td>sulfonyl halides</td><td>Phenols / Alcohols</td>

<td>Alkylthiol</td><td>a, β-unsaturated ester</td><td>thiols</td>

<td>Alkyl ethers</td><td>a, β-unsaturated ester</td><td>alcohols</td>

<td>Alkylamines</td><td>a, β-unsaturated ester</td><td>amines</td>

<td>Alkylthiol</td><td>Vinylsulfone</td><td>thiols</td>

<td>Alkyl ethers</td><td>Vinylsulfone</td><td>alcohols</td>

<td>Alkylamines</td><td>Vinylsulfone</td><td>amines</td>

<td>Vinyl Sulphide</td><td>propargylamide</td><td>Thiol</td>

Use of Protective Groups

In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, when desired in the final product, to avoid their unwanted participation in the reactions. Protecting groups are used to block some or all of the reactive moieties and prevent these groups from participating in chemical reactions until the protecting group is removed. Each protecting group may be removable by different means. Protecting groups that are cleaved under totally disparate reaction conditions meet the differential removal requirements. Protecting groups may be removed by acid, base and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups which are removable by hydrogenolysis and Fmoc groups which are base labile. . Reactive carboxylic acid and hydroxy moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl and acetyl, in the presence of amine blocked with acid labile groups such as t-butyl carbamate or with carbamates which may are

201 2 201 840 / ΡΤ stable in the presence of acids and bases but are hydrolytically removable.

Reactive carboxylic acid and hydroxy moieties may also be blocked with hydrolytically removable protecting groups such as the benzyl group, while amino groups capable of forming hydrogen bonds with acids may be blocked with base labile groups such as Fmoc. Reactive carboxylic acid moieties may be protected by conversion to simple ester compounds as exemplified herein, or may be blocked with oxidative-removable protecting groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with silyl carbamates while fluoride.

Allyl blocking groups are useful in the presence of acid and base protecting groups as they are stable and may subsequently be removed by metal or β-acid catalysts. For example, an allyl blocked carboxylic acid may be deprotected by a Pd catalyzed reaction in the presence of acid labile t-butyl carbamate protecting groups or base labile aminoacetate. Yet another form of protecting group is a resin to which a compound or an intermediate may be attached. As long as the residue is bonded to the resin, this functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.

Typically, the protecting / blocking groups may be selected from:

HjC *

H₂

HjC ''

H .C

<img file="PT2201840E_D0025.tif" />

allyl

<img file="PT2201840E_D0026.tif" />

El

Bn

H₂

Ct-Butyl

<img file="PT2201840E_D0027.tif" />

H₃ç_x , CH, {H3CbC '^s&lt;

(CW

<img file="PT2201840E_D0028.tif" />

TBDMS

Teoc

201 2 201 840 / ΡΤ

<img file="PT2201840E_D0029.tif" />

trityl acetyl

<img file="PT2201840E_D0030.tif" />

Fmoc

Other protecting groups, as well as a detailed description of techniques applicable to the creation of protecting groups and their removal, are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3.^The Ed., John Willey &amp; Sons, New York, NY, 1999, and in Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994.

Compound Synthesis

Described herein are production methods and methods of using tyrosine kinase inhibiting compounds described herein. The compounds described herein may be synthesized using the following synthesis schemes. The compounds may be synthesized using methodologies analogous to those described below by use of suitable alternative starting materials.

Described herein are compounds that inhibit tyrosine kinase activity, such as Btk, and processes for their preparation. Also described herein are pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites and pharmaceutically acceptable prodrugs of those compounds. Further described are pharmaceutical compositions comprising at least one of those compounds or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a pharmaceutically active metabolite or a pharmaceutically acceptable prodrug of those compounds.

The starting material used for the synthesis of the compounds described herein may be synthesized or may be obtained from commercial sources such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, California), or Sigma. Chemical Co. (St. Louis, Mo.). The compounds described herein, and other related compounds containing different substituents, may be synthesized.

Using techniques and materials known to those skilled in the art, as described, for example, in March, Advanced Organic Chemistry 4.^th Ed. (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4^th Ed., Vol. A and B (Plenum 2000, 2001); Green and Wuts, Protective Groups in Organic Synthesis

3^rd Ed., (Wiley 1999); Fieser and Fieser, Reagents for Organic Synthesis, Volumes 1-17 (John Wiley &amp; Sons, 1991); Rodd, Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); and Larock, Comprehensive Organic Transformations (VCH Publishers Inc., 1989). Other methods for the synthesis of compounds described herein can be found in International Patent Application Publication WO 01/01982901, Arnold et al., Bioorganic &amp; Medicinal Chemistry Letters 10 (2000) 21672170; Burchat et al., Bioorganic &amp; Medicinal Chemistry Letters 12 (2002) 1687-1690. General methods for preparing compounds as disclosed herein may be derived from reactions known in the art, and the reactions may be modified by use of appropriate conditions and reagents, as will be appreciated by one of skill, for the introduction of the various portions found. in the formulas as provided herein. As a guide, the following synthesis methods may be used.

Reaction products may be isolated and purified, if desired, using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography and the like. These materials may be characterized using conventional means, including physical constants and spectral data.

The compounds described herein may be prepared using the synthetic methods described herein as a single isomer or a mixture of isomers.

An example of a synthetic approach to the preparation of compounds of any of Formulas (A), (B), (C) or (D) is shown in Scheme 1.

201 2 201 840 / ΡΤ

Scheme 1

<img file="PT2201840E_D0031.tif" />

Halogenation of commercially available β-pyrazolo [3,4-d] pyrimidin-4-amine provides an input for the synthesis of compounds of Formulas (A), (B), (C) and / or (D). 1H-pyrazolo [3,4-d] pyrimidin-4-amine is treated with Niosuccinamide to give 3-iodo-1H-pyrazolo [3,4-d] pyrimidin4-amine. Metal catalyzed cross coupling reactions are then performed with 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine. Palladium-mediated cross-coupling of a suitably substituted phenylboronic acid under basic conditions yields intermediate 2. Intermediate 2 is coupled with N-Boc-3-hydroxypiperidine (as an example) via the Mitsunobu reaction to give intermediate 3 protected with Boc (tert-butyloxycarbonyl). After deprotection with acid, coupling with, for example, an acid chloride, such as acryloyl chloride, completes the synthesis to give compound 4.

known from the tyrosine kinase state such as good yields and purity

Using the synthesis methods described herein as well as the art, inhibitors described herein are obtained with the compounds prepared by the methods disclosed herein are purified by conventional means in the art, such as, for example, filtration, recrystallization, chromatography, distillation and combinations thereof.

EP 2 201 840 / EN

Any combination of the groups described above for the various variables is described herein. It is understood that substituents and substitution standards may be selected by persons skilled in the art from the compounds provided herein to provide compounds which are chemically stable and which may be synthesized by techniques known in the art as well as those set forth herein.

Other Forms of Compounds

Compounds having a structure of any one of Formula (A), Formula (B), Formula (C) or Formula (D) are described. It is understood that when reference is made to the compounds described herein, it is intended to include compounds of any one of Formula (A), Formula (B), Formula (C) or Formula (D), as well as all compounds specific formulas falling within these generic formulas unless otherwise indicated.

The compounds described herein may have one or more stereocenters and each center may exist in the R or S configuration. The compounds disclosed herein include all diastereoisomeric, enantiomeric and epimeric forms as well as their appropriate mixtures. Stereoisomers may be obtained, if desired, by methods known in the art, such as separation of stereoisomers by chiral column chromatography.

Diastereoisomeric mixtures may be separated into their individual diastereoisomers based on their physicochemical differences by known methods, for example by chromatography and / or fractional crystallization. Enantiomers may be separated by chiral column chromatography. Enantiomers may also be separated by converting the enantiomeric mixture into a diastereoisomeric mixture by reaction with an appropriate optically active compound (e.g. alcohol), separation of diastereoisomers and conversion (e.g. hydrolysis) of individual diastereoisomers to the corresponding pure enantiomers. All of these isomers, including diastereoisomers, enantiomers and mixtures thereof,

Are considered to be an integral part of the compositions described herein.

The methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs) or pharmaceutically acceptable salts of the compounds described herein. In some situations the compounds may exist as tautomers. All tautomers are included within the scope of the compounds disclosed herein. Additionally, the compounds described herein may exist in both unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. Solvated forms of the compounds disclosed herein are also considered to be described herein.

Compounds of any one of Formula (A), Formula (B), Formula (C) or Formula (D) in unoxidized form may be prepared from N-oxides of compounds of any one of Formula. (A), Formula (B), Formula (C) or Formula (D) by treatment with a reducing agent such as, but not limited to, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium hydride, phosphorus trichloride, tribromide or the like in a suitable inert organic solvent, such as acetonitrile, ethanol, aqueous dioxane, or the like, from 0 ° to 80 ° C.

Also described herein are prodrugs. A prodrug refers to an agent that is converted to the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be more easily administered than the parent drug. They may, for example, be bioavailable by oral administration while the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions relative to the parent drug. An example of a prodrug would be a compound that is administered as an ester (the prodrug) to facilitate transmission across a cell membrane where water solubility is detrimental to mobility, but is then metabolically hydrolyzed to carboxylic acid, the active entity, once inside the cell where water solubility is

Beneficial. Another example of a prodrug may be a short peptide (polyamino acid) attached to an acidic group where the peptide is metabolized to reveal the active moiety. In certain cases, upon administration in vivo, a prodrug is chemically converted to the biological, pharmaceutical or therapeutically active form of the compound. A prodrug may also be metabolised enzymatically by one or more steps or processes in the biological, pharmaceutical or therapeutically active form of the compound. To produce a prodrug, a pharmaceutically active compound is modified such that the active compound is regenerated upon administration in vivo. The prodrug may be designed to alter the metabolic stability or transport characteristics of a drug, to mask side effects or toxicity, to improve the taste of a drug, or to alter other characteristics or properties of a drug. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those skilled in the art, once a pharmaceutically active compound is known, may designate prodrugs of the compound, (see, for example, Nogrady (1985), Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392); Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pages 352-401; Saulnier et al. (1994), Rioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).

Prodrugs are often useful because, in some situations, they may be more easily administered than the parent drug. They may, for example, be bioavailable by oral administration while the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions relative to the parent drug. Prodrugs may be designed as derivatives of reversible drugs for use as modifiers to enhance transport of drugs to site-specific tissues. In some embodiments, the design of a prodrug increases effective water solubility. See, for example, Fedorak et al., Am. J. Physiol, 269: G210-218 (1995); McLeod et al., Gastroenterol, 106: 405-413 (1994); Hochhaus and Others, Biomed

201 2 201 840 / ΡΤ

Chrom., 6: 283-286 (1992); J. Larsen and Η. Bundgaard, Int. J.

Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J.

Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm.

Sci., 64: 181, 210 (1975); T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.

Locations in the aromatic ring portion of the compounds of any one of Formula (A), Formula (B), Formula (C) or Formula (D) may be susceptible to various metabolic reactions, whereby the incorporation of appropriate substituents into the structures of the compounds. Aromatic ring, such as, by way of example only, halogens, may reduce, minimize or eliminate this metabolic pathway.

The above described compounds include isotopically labeled compounds which are identical to those recited in the various above-described formulas and structures except that one or more atoms are replaced by an atom with a different atomic mass or mass number than atomic mass or mass number normally found in nature. Examples of isotopes which may be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine such as ²H, ³H, ¹³Ç, ¹⁴Ç, ¹⁵N ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F ³⁶C1, respectively. described here,

Certain isotopically-labeled compounds, for example, those in which they are incorporated are radioactive isotopes such as ³H e ¹⁴C, are useful in tissue distribution assays of drugs and / or substrates. Further, substitution with isotopes such as deuterium, that is,²H may provide certain therapeutic advantages resulting from increased metabolic stability, for example, increased in vivo half-life or reduced dosing requirements.

The above-described compounds may be metabolised upon administration to an organism in need thereof to produce a metabolite which is then used to produce a desired effect, including a desired therapeutic effect.

201 2 201 840 / ΡΤ

The compounds described herein may be formed, and / or used, as pharmaceutically acceptable salts. Pharmaceutically acceptable salt types include, but are not limited to: (1) acid addition salts formed by reacting the free base form of the compound with a pharmaceutically acceptable acid such as hydrobromic acid, sulfuric acid, inorganic hydrochloric acid nitric, phosphoric acid, metaphosphoric acid, and the like; or acetic acid, cyclopentanopropionic acid, lactic acid, acid with an organic acid such as propionic, hexanoic acid, glycolic acid, pyruvic acid, malonic, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, acid citric, benzoic acid, 3- (4hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2naphthalenesulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene1-carbocylic acid, glucoheptonic acid, 4,4'-methylenobis (3-hydroxy-2-ene-1-yl) carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, (tertiary butyl) acetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example an alkali metal ion (eg lithium, sodium, potassium), an alkaline earth ion (eg magnesium or calcium), or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, triethanolamine, the like. The bases aluminum, diethanolamine, methylglucamine, and include potassium hydroxide, sodium hydroxide and the like.

Tromethamine, acceptable Ninorganic calcium hydroxide, sodium carbonate,

Corresponding counterions of pharmaceutically acceptable salts may be analyzed and identified using various methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma,

Atomic absorption spectroscopy, mass spectrometry, or any combination thereof.

The salts are recovered by using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, lyophilization.

It will be appreciated that a reference to a pharmaceutically acceptable salt includes its solvent addition forms or its crystalline forms, in particular solvates and polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of a solvent and may be formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein may be conveniently prepared or formed during the processes described herein. Additionally, the compounds provided herein may exist in both unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

It should be understood that a reference to a salt includes its solvent-added forms or its crystalline forms, in particular solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystalline packaging arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shapes, optical and electrical properties, stability and solubility. Several factors, such as the recrystallization solvent, the rate of

Crystallization and storage temperature may lead to mastery of a single crystalline form.

The compounds described herein may be in various forms, including but not limited to, amorphous forms, ground forms and nanoparticle forms. Additionally, the compounds described herein include crystalline forms also known as polymorphs. Polymorphs include the different crystalline packaging arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shapes, optical and electrical properties, stability and solubility. Various factors, such as the recrystallization solvent, the crystallization rate and the storage temperature, may lead to the domain of a single crystalline form.

Acceptable screening using limited spectroscopy, and characterization of pharmaceutically polymorph salts and / or solvates can be performed in a variety of techniques including, but not limited to, thermal analysis, X-ray diffraction, vapor sorption, and microscopy. Thermal analysis methods target thermochemical or thermophysical degradation processes including but not limited to polymorphic transitions, and these methods are used to analyze relationships between polymorphic forms, determine weight losses, to find glass transition temperature or for studies. compatibility of excipients. Such methods include, but are not limited to, differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA), and thermogravimetric and infrared (TG / IV) analysis. X-ray diffraction methods include, but are not limited to, single crystal and powder diffractometers and synchrotron sources. The various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid state). Various microscopy techniques include, but are not limited to, polarized light microscopy, electron microscopy (SEM) with x-ray scattering energy analysis (EDX), EDX environmental scanning electron microscopy (in

Gaseous or water vapor atmosphere), IR microscopy and Raman microscopy.

Throughout the specification, groups and their substituents may be selected by one skilled in the art to provide stable compounds and moieties.

Pharmaceutical Composition / Formulation

Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into pharmaceutically usable preparations. The correct formulation depends on the route of administration selected. Any of the well known techniques, carriers and excipients may be used as appropriate and as understood in the art. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19.^The Ed. (Easton, Pa .: Mack Publishing Company, 1995); Hoover and John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, HA and Lachman, L., Pharmaceutical Dosage Forms, Eds. Mareei Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, i.^The Ed. (Lippincott Williams &amp; Wilkins 1999).

A pharmaceutical composition as used herein refers to a mixture of a compound described herein, such as, for example, compounds of any one of Formula (A), Formula (B), Formula (C) or Formula (D), with other chemical components such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents and / or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of the compounds described herein are administered in a pharmaceutical composition to a mammal with a disease, disorder or condition to be treated. Preferably, the mammal is a human being. A therapeutically effective amount may vary widely depending upon the severity of the

201 2 201 840 / ΡΤ disease, the age and relative health of the individual, the potency of the compound used and other factors. The compounds may be used alone or in combination with one or more therapeutic agents as components of mixtures.

The compositions may also include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and trishydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. These acids, bases and buffers are included in an amount necessary to maintain the pH of the composition in an acceptable range.

The compositions may also include one or more salts in an amount necessary to bring the osmolality of the composition to an acceptable range. These salts include those containing sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; Suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

The term pharmaceutical combination as used herein means a product which results from the mixing or combination of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term fixed combination means that the active ingredients, for example, a compound described herein and a co-agent, are both administered simultaneously to a patient in the form of a single entity or dosage. The term non-fixed combination means that the active ingredients, for example a compound described herein and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially without specific time limit limits, in that such administration provides effective levels of the two compounds to the patient's body. The latter is also applicable to cocktail therapy, for example the administration of three or more active ingredients.

201 2 201 840 / ΡΤ

The pharmaceutical formulations described herein may be administered to an individual by multiple routes of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal or transdermal administration routes. Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, dissolution formulations. tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations and mixed immediate and controlled release formulations.

Pharmaceutical compositions including a compound described herein may be manufactured in conventional manner, as by way of example only, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, holding or compressing processes .

The pharmaceutical compositions described herein include at least one compound described herein, such as, for example, a compound of any one of Formula (A), Formula (B), Formula (C) or Formula (D) as an ingredient. active in a free acid or free base form, or in a pharmaceutically acceptable salt form. Additionally, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs) as well as active metabolites of these compounds, with the same type of activity. In some situations, the compounds may exist as tautomers. All tautomers are included within the scope of the compounds disclosed herein. Additionally, the compounds described herein may exist in unsolvated as well as solvated form with pharmaceutically acceptable solvents such as water, ethanol and the like. The solvated forms of

No. 2,201,840 / ΡΤ compounds disclosed herein are also considered to be disclosed herein.

Defoamers reduce foaming during processing which may result in coagulation of aqueous dispersions, bubbles in the finished film or generally impair processing. Exemplary defoaming agents include silicon or sorbitan sesquiolate emulsions.

Antioxidants include, butylated (BHT), sodium metabisulfite ascorbate and embodiments, the chemical antioxidants where required.

for example sodium hydroxytoluene, ascorbic acid, tocopherol improve

In some stability activities include one or more microbial substances. that contains

Preservative compositions for inhibiting suitable preservatives include mercury such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetylpyridinium chloride bromide.

cetyltrimethylammonium

The formulations described herein may benefit from antioxidants, metal chelating agents, thiol-containing compounds, and other stabilizing agents in general. Examples of such stabilizing agents include, but are not limited to: (a) about 0.5% to about 2% w / v of glycerol, (b) about 0.1% to about 1% w / v of methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003 % to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate , (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) bivalent cations such as magnesium and zinc, or (n) combinations thereof.

Binders impart cohesive qualities and include, for example, alginic acid and its salts; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g.

EP 2 201 840 / EN

Methocel®), hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g. Ethocel®), and microcrystalline cellulose (e.g. Avicel®); microcrystalline dextrose; amylose; aluminum magnesium silicate, polysaccharide acids; bentonites; gelatine; polyvinylpyrrolidone / vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, a sugar such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®) and lactose; a natural or synthetic gum such as gum arabic, gum tragacanth, ghatti gum, isapol shell mucilage, polyvinylpyrrolidone (e.g. Polyvidone® CL, Kollidon® CL, Polyplasdone® XL-10), larch arabinogalactans, Veegum® 'polyethylene glycol , waxes, sodium alginate and the like.

A carrier or carrier materials include any excipients commonly used in pharmaceuticals and should be selected based on compatibility with those disclosed herein, such as compounds of any one of Formula (C) or Formula (D), release of the carrier form. binders, disintegration, solubilizers, Formula (A), Formula (B), and the properties of the desired dosage profile. Exemplary materials include, for example, surfactants, suspending agents, fillers, stabilizers, lubricants, wetting agents, diluents and the like. Pharmaceutically compatible carrier materials may include, but are not limited to, gum arabic, gelatin, colloidal silicon dioxide, calcium glycerophosphate, lactate maltodextrin, glycerine, polyvinylpyrrolidone (PVP) cholesterol, calcium magnesium silicate, cholesterol esters , sodium caseinate, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sodium stearoyl lactylate from sugars, carrageenan, monoglycerides, diglycerides, pregelatinized starch and the like. See, for example, Remington: The Science and Practice of Pharmacy, 19.^The Ed. (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,

EP 2 201 840 / EN

Pennsylvania 1975; Liberman, HA and Lachman, L., Pharmaceutical Dosage Fornis, Eds. Mareei Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7.^The Ed. (Lippincott Williams &amp; Wilkins 1999).

HPC-L),

K100, HPMC K4M, carboxymethylcellulose hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose

Dispersing (or dispersing) agents and / or viscosity modulating agents include materials that control the diffusion and homogeneity of a drug in liquid media or a granulation method or a mixing method. In some embodiments, these agents also facilitate the effectiveness of an erosion coating or matrix. Exemplary dispersing agents / diffusion facilitators include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and carbohydrate-based dispersing agents such as for example hydroxypropylcelluloses (e.g. HPC, HPC-SL and hydroxypropyl methylcelluloses (e.g. HPMC

HPMC K15M and HPMC K100M), Sodium, Methylcellulose, Hydroxypropylcellulose, Stearate-Acetate Phthalate (HPMCAS), Non-triethanolamine Cellulose, Crystalline Ethylene 4-Polymer Copolymer, Polyvinyl Alcohol (PVA) , vinylpyrrolidone / vinyl acetate (S630), (1,1,3,3-tetramethylbutyl) phenol with formaldehyde oxide (also known as tiloxapol), poloxamers (e.g. Pluronics F68®, F88® and F108®, which are block copolymers of ethylene oxide and propylene oxide);

poloxamines (e.g. Tetronic 908¹¹ also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippanny, NJ)), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K17, polyvinylpyrrolidone / vinyl acetate copolymer (S-630), polyethylene glycol, for example, polyethylene glycol may have a molecular weight of from about 300 to about 6000, or from about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose,

Carbomeric monolaurate, polysorbate-80, sodium alginate, gums such as, for example, gum and arabic gum, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, for example , sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan, povidone, polyvinyl alcohol (PVA), alginates, chitosans and combinations thereof. Plasticizers such as cellulose or triethylcellulose may also be used as dispersing agents. Particularly useful dispersing agents in liposome dispersions and self-emulsifying dispersions are dimyristoylphosphatidylcholine, natural egg phosphatidylcholine, natural egg phosphatidylglycerol, cholesterol and isopropyl myristate.

Combinations of one or more erosion facilitators with one or more diffusion facilitators may also be used in the present compositions.

The term diluent refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffer solutions (which may also provide pH control or maintenance) are used in the art as diluents, including but not limited to a phosphate buffered saline. In certain embodiments, the diluents increase the mass of the composition to facilitate compression or create sufficient mass for a homogeneous mixture to fill the capsule. These compounds include, for example, lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®; dibasic calcium phosphate, dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray dried lactose / pregelatinized starch, compressible sugar such as Di-Pac® (Amstar); mannitol, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose stearateacetate, sucrose-based diluents, icing sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrates; cereal solids

Hydrolysed, amylose; powder cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite and the like.

The term disintegrate includes both dissolution and dispersion of the dosage form when in contact with gastrointestinal fluid. Disintegrating or disintegrating agents facilitate the disruption or disintegration of a substance. Examples of disintegrating agents include a starch, for example a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as sodium starch. Promogel® or Explotab®, a cellulose such as a wood product, crystalline methylcellulose, for example Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia® and SolkaFloc®, methylcellulose, croscarmellose, or a cross-linked cellulose such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethyl cellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrrolidone, an alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum® HV (aluminum magnesium silicate), a gum such as carob, agar, of Karaya, pectin or tragic acid, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation exchange resin, citrus pulp, sodium lauryl sulfate, starch lauryl sulfate, and the like .

Drug absorption or absorption typically refers to the process of drug movement from the site of drug administration, through a barrier, into a blood vessel or to the site of action, for example, a drug moving from the intestinal tract into the portal vein or lymphatic system.

An enteric coating is a substance that remains substantially intact in the stomach but dissolves and releases the drug in the small intestine or colon. In general, the enteric coating comprises a material

Which prevents release into the low pH environment of the stomach but ionizes at a higher pH, typically at a pH of 6 to 7, and thus dissolves sufficiently in the small intestine or colon to release it. the active agent.

Erosion facilitators include materials that control the erosion of a particular material in the gastrointestinal fluid. Erosion facilitators are generally known to those skilled in the art. Exemplary erosion enhancers include, for example, hydrophilic polymers, electrolytes, proteins, peptides and amino acids.

Fillers include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, microcrystalline, cellulose powder dextrates, cellulose sulfate, dextrose, dextran, starches, pregelatinized starch, sucrose, xylitol. , lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

Flavoring and / or sweetening agents useful in the formulations described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, bavarian cream, blackberry, butterscotch , calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, chewing gum, citrus fruit, citrus punch, citrus cream, cotton candy, cocoa, cola, fresh cherry, fresh citrus, cyclamate, cilamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrretinate, Glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate (MagnaSweet®), maltol, mannitol, oak, marshmallow , menthol, mint cream, berries, neo-hesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® Powder, raspberry, sherry, rum, saccharin, safrol, sorbitol mint green, cream mint green, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, taline, silitol,

201 2 201 840 / ΡΤ sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tutti frutti, vanilla, hazelnut, watermelon, wild cherry, wintergreen, xylitol or any combination of these flavoring ingredients, for example anise menthol , anise-cherry, cinnamon-orange, cinnamon-cherry, mint-chocolate, lemon-honey, lime-lemon, mint-lemon, mentoleucalyptus, cream-orange, vanilla-mint, and mixtures thereof.

Lubricants and sliders are compounds that prevent, reduce or inhibit adhesion or friction of materials. Exemplary lubricants include, for example, stearic acid, calcium hydroxide, talc, sodium stearyl fumarate, a hydrocarbon such as mineral oil or hydrogenated vegetable oil such as hydrogenated soybean oil (Sterotex®), higher fatty acids and their alkali metal salts. and alkaline earth metals such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol (e.g. PEG-4000) or a methoxypolyethylene glycol such as Carbowax ™, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, silica colloidal such as Syloid ™, Cab-O-Sil®, a starch such as cornstarch, silicone oil, a surfactant, and the like.

A measurable serum concentration or measurable plasma concentration describes the concentration in blood serum or blood plasma, typically measured in mg, pg or ng, of therapeutic agent per ml, dl or 1 of blood serum absorbed into the bloodstream after administration. As used herein, measurable plasma concentrations are typically measured in ng / ml or pg / ml.

Pharmacodynamics refers to the factors that determine the observed biological response to drug concentration at a site of action.

Pharmacokinetics refers to the factors that determine the attainment and maintenance of the appropriate drug concentration at a site of action.

EP 2 201 840 / EN

Plasticizers are compounds used to soften microencapsulation material or film coatings and make them less brittle. Suitable plasticizers include, for example, polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350 and PEG 800, stearic acid, propylene glycol, oleic acid, triethylcellulose and triacetin. In some embodiments, plasticizers may also function as dispersing agents or wetting agents.

Solubilizers include compounds such as triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium docusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylhydroxypropylmethylethanol, n-butanol, bile salts, transcutol, pyrrolidone, polyvinylpyrrolidone, cellulose, hydroxypropylcyclodextrins, isopropyl alcohol, cholesterol, polyethylene glycol 200-600, glycofurol, propylene glycol and dimethyl isosorbide and the like

Stabilizers include compounds such as any antioxidant agents, buffers, acids, preservatives and the like.

Steady state, as used herein, is when the amount of drug administered is equal to the amount of drug eliminated within a dosage range, which results in constant or plateau drug exposure.

Suspending agents include compounds such as polyvinylpyrrolidone, for example, polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone / vinyl acetate copolymer (S630), polyethylene glycolol, for example, molecular weight glycol terenol, e.g. from 300 to about 6000, or from about 3350 to about 4000, or from about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxymethylcellulose stearate-acetate, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums such as gum and arabic gum, guar gum, xanthans including xanthan gum, sugars, cellulose such as, for example,

201 2 201 840 / ΡΤ carboxymethylcellulose carboxymethylcellulose hydroxyethylcellulose, sodium, methylcellulose, sodium, hydroxypropyl methylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan, povidone and the like,

Surfactants include compounds such as sodium lauryl sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate ethylene oxide and propylene oxide copolymers, for example, Pluronic® (BASF), and the like. Some other surfactants include polyoxyethylene fatty acid glycerides and example oils, hydrogenated castor oil with (60); and polyoxyethylene alkyl ethers, alkylphenyl ethers, for example Octoxynol 10, Octoxynol 40. In some embodiments, surfactants may be included to increase physical stability or for other purposes.

vegetables, by polyoxyethylene

Viscosity enhancing agents include, for example, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose stearate acetate, hydroxypropyl methylcellulose phthalate, carbomer, polyvinyl alcohol, alginates, gum arabic, combinations thereof.

Wetting agents include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, sodium docusate, sodium oleate, lauryl sulfate. sodium, sodium docusate, triacetin, Tween 80, vitamin E TPGS, ammonium salts and the like.

Dosage Forms

The compositions described herein may be formulated for administration to an individual by any conventional means including, but not limited to oral, parenteral (e.g. intravenous, subcutaneous or intramuscular), buccal, intranasal, rectal or

2 201 840 / transdermal. As used herein, the term individual is used to mean an animal, preferably a mammal, including a human or non-human. The terms patient and individual may be used interchangeably.

In addition, the pharmaceutical compositions described herein, which include a compound of any one of Formula (A), Formula (B), Formula (C) or Formula (D), may be formulated in any suitable dosage form including but not limited to aqueous oral dispersions, liquids, gels, syrups, elixirs, pastes, suspensions and the like for oral ingestion by a patient to be treated, oral solid dosage forms, aerosols, controlled release formulations, fast dissolving formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragées, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multi-particle formulations, and immediate release mixed formulations controlled.

Pharmaceutical preparations for oral use may be obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally by milling the resulting mixture, and processing the granule mixture, after adding suitable auxiliaries, if desired, to obtaining tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate may be added.

Dragee cores are provided with suitable coatings. For this purpose solutions may be used

2 201 840 / de sugar concentrates, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the dragee or tablet coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical preparations which may be used orally include snap caps made of gelatin as well as soft, sealed caps made of gelatin and a plasticizer such as glycerol or sorbitol. Snap-in capsules may contain the active ingredients in a filled mixture such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and optionally stabilizers. In soft capsules, the active compounds may be dissolved or suitable, such as fatty oils, or liquid polyethylene glycols.

suspended in liquids liquid paraffin

Additionally, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

Solid dosage forms which may take the form of a tablet (including a suspension tablet, a rapidly dissolving tablet, a chewable tablet, a rapidly disintegrating tablet, an effervescent tablet or a capsule tablet) are described, of a pill, a powder (including a sterile packaged powder, a dispensable powder or an effervescent powder), a capsule (including soft or hard capsules, for example capsules made from animal gelatin or plant-derived HPMC or sprinkle capsules), solid dispersions, solid solutions, bioerodible dosage forms, controlled release formulations, pulsatile release dosage forms, dosage forms in multi-particles, pellets, granules, or an aerosol. The pharmaceutical formulation may be in powder form. In still other cases, the pharmaceutical formulation is in tablet form, including but not limited to a rapidly dissolving tablet. Additionally, the formulations

The pharmaceutical compositions described herein may be administered in a single or multiple capsule dosage form. The pharmaceutical formulation may be administered in two, or three, or four, tablets or capsules.

Solid dosage forms, for example tablets, effervescent tablets and capsules, prepared by mixing particles of a compound of any one of Formula (A), Formula (B), Formula (C) or Formula (D) are disclosed. , with one or more pharmaceutical excipients to form a dough mix composition. By referring to these dough mix compositions as homogeneous, it is meant that the particles of the compound of any one of Formula (A), Formula (B), Formula (C) or Formula (D) are uniformly dispersed throughout. composition so that the composition can be readily subdivided into equally effective unit doses such as tablets, pills and capsules. Individual unit doses may also include film coatings, which disintegrate upon oral ingestion or upon contact with diluents. These formulations may be manufactured by conventional pharmacological techniques.

Conventional pharmacological techniques include, for example, one or a combination of methods: (1) dry blending, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, for example, spray drying, drum coating, melt granulation, granulation, coating or fluid bed spray drying (e.g. Wurster coating), tangential coating, top spraying, tabletting, extrusion and alike.

The solid pharmaceutical dosage forms described herein may include a compound described herein and one or more pharmaceutically acceptable additives such as a carrier, a binder, a filler, a suspending agent, a flavoring, disintegrating agent, a lubricant, a coloring agent, sweetening agent, dispersing agent, surfactant, diluent, solubilizer,

2 201 840 / hum a wetting agent, a plasticizer, a stabilizer, a penetration enhancer, a wetting agent, a defoaming agent, an antioxidant, a preservative, compatible, or one or more combinations thereof. In still other aspects, the use of standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20.^The Ed. (2000), a film coating is provided around the formulation of the compound of any one of Formula (A), Formula (B), Formula (C) or Formula (D). In one embodiment, some or all of the compound particles of any one of Formula (A), Formula (B), Formula (C) or Formula (D) are coated.

In another embodiment, some or all of the compound particles of any of the microencapsulated Formulas. Further particles of the compound Formula (A), Formula (B), (A), (B), in another of any Formula (C) (C) or (D), are embodiments, either of Formula (D) or ) are not microencapsulated and uncoated.

Carriers suitable for use in the solid dosage forms described herein include, but are not limited to, gum arabic, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate , soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl-lactylate, carrageenan, monoglyceride, diglyceride, pregelatinised starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose stearate acetate, sucrose, microcrystalline cellulose, lactose, mannitol and the like.

Suitable fillers for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose powder, dextran, starches, hydroxypropyl methylcellulose hydroxypropyl methylcellulose, hydroxypropyl methylcellulose lactitol, mannitol, sorbitol, polyethylene glycol, and the like.

cellulose, dextrose, dextrates, pregelatinized starch (HPMC), stearate acetate (HPMCAS) phthalate, sucrose, xylitol, sodium chloride,

201 2 201 840 / ΡΤ

In order to free the compound of any one of Formula (A), Formula (B), Formula (C) or Formula (D) from a matrix of solid dosage forms as efficiently as possible, disintegrants are often used. in the formulation, especially when the dosage forms are pressed with a binder. Disintegrants assist in disintegration of the dosage form matrix by swelling or capillary action when moisture is absorbed by the dosage form. Disintegrants suitable for use in solid dosage forms described herein include, but are not limited to, natural starch such as cornstarch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or starch glycolate. sodium such as Promogel® or Explotab®, a cellulose such as a wood product, methylcrystalline cellulose, for example Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emocel®, Vivacel®, Ming Tia® and Solka-Floc®, methylcellulose, croscarmellose, or a cross-linked cellulose such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®, cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrrolidone, an alginate such as alginic acid or an alginic acid salt such as sodium alginate, a clay such as Veegum® HV (aluminum magnesium silicate), a gum such as agar, guar, locust bean, Karaya, pectin or anadrag, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation exchange resin, citrus pulp, sodium lauryl sulphate, sodium lauryl sulphate in combination with starch, and the like.

Binders impart cohesiveness to oral solid dosage form formulations: in the formulation of powder-filled capsules, they aid in the formation of the plug that can be filled into hard or soft shell capsules, and in tablet formulation, ensure that the tablet remains intact. after pressing and help to ensure uniformity of the mixture prior to a pressing or filling step. Suitable materials for use as binders in the solid dosage forms described herein include, but are not limited to,

EP 2 201 840 / EN

Klucel®), ethylcellulose (eg Ethocel®), and microcrystalline (eg microcrystalline, amylose, polysaccharide acids are not limited to carboxymethylcellulose, methylcellulose (eg Methocel®), hydroxypropyl methylcellulose (eg Hypromellose USP Pharmacoat-603) , hydroxypropyl methylcellulose stearate acetate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., cellulose example, Avicel '), magnesium aluminum silicate dextrose, bentonites, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tarring, dextrin, a sugar such as sucrose (eg Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol ( (eg Xylitab®), lactose, a synthetic or natural gum such as gum arabic, gum tragacanth, ghatti gum, isapol shell mucilage, starch, polyvinylpyrrolidone (e.g. Povidone® CL, Kollidon® CL, Polypladone® XL -10, and Povidone® K12), larch arabinogalactans, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like.

In general, binder levels of 20-70% are used in the formulation of powder filled gelatin capsules. Levels of use of binders in the tablet formulation range from direct compression, wet granulation, roller compaction, or use of other excipients such as fillers which in themselves may act as moderate binders. Those skilled in the art may determine the level of binder for the formulations, but up to 70% binder utilization is common in the tablet formulation.

Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, maize starch, sodium stearyl fumarate, alkali and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxy polyethylene glycol such as Carbowax ™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate,

Glyceryl, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate and the like.

Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol and sorbitol), cyclodextrins and others.

The term non-water soluble diluent represents compounds typically used in the formulation of medicaments such as calcium phosphate, calcium sulfate, starches, modified starches and microcrystalline cellulose, and microcellulose (for example with a density of about 0.45 g / kg). cm³(e.g. Avicel, cellulose powder) and talc.

Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate quaternary ammonium compounds (e.g. Polyquat 10®), sodium oleate, sodium lauryl sulphate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and the like.

Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, oxide copolymers ethylene and propylene oxide, for example Pluronic® (BASF) and the like.

Suitable suspending agents for use in the solid dosage forms described herein include, but are not limited to, polyvinylpyrrolidone, for example polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone, e.g. molecular weight from about 300 to about 6000, or from about 3350 to about 4000, or from about 7000 to about 5400, vinylpyrrolidone /

Vinyl acetate (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums such as, for example, gum arabic, gum gum, xanthans, including xanthan gum, sugars, cellulosics such as, for example, sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like.

Suitable antioxidants for use in the solid dosage forms described herein include, for example, butylated hydroxytoluene (BHT), sodium ascorbate and tocopherol.

It will be appreciated that there is considerable overlap between additives used in the solid dosage forms described herein. Thus, the additives listed above should be taken as merely exemplary, not limiting, of the types of additives that may be included in solid dosage forms described herein. The amounts of these additives may be readily determined by one skilled in the art according to the particular desired properties.

In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, a plasticizer is usually a solid or a high boiling liquid. Suitable plasticizers may be added from about 0.01% to about 50% by weight (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, sterol, stearate and oil.

Pressed tablets are solid dosage forms prepared by compacting the bulk mixture of the formulations described above. In various embodiments, compressed tablets, which are designed to dissolve in the mouth, will include one or more flavoring agents. In others

In the release between embodiments, the compressed tablets will include a film around the final compressed tablet. Film coating may provide a retard of the compound of any of the following

Formula (A), Formula (B), Formula (C) or Formula (D) from the formulation. In other situations, film coating aids patient acceptance (eg Opadry® coatings or sugar coatings). Film coatings including Opadry® typically range from about 1% to about 3% of the tablet weight. Pressed tablets may include one or more excipients.

A capsule may be prepared, for example, by placing the bulk mixture of the compound formulation of any of Formula (A), Formula (B), Formula (C) or Formula (D) described above into a capsule. In some cases, the formulations (suspensions and non-aqueous solutions) are placed in a soft gelatin capsule. In other cases, the formulations are enclosed in standard gelatin capsules or non-gelatin capsules, such as capsules comprising HPMC. In other cases, the formulation is placed in a sprinkling-openable capsule, wherein the capsule may be swallowed whole or may be opened and the contents sprinkled on the food prior to ingestion. In some cases, the therapeutic dose is divided into multiple capsules (e.g., two, three or four). In some cases, the full dose of the formulation is delivered in capsule form.

In various instances, the particles of the compound of any one of Formula (A), Formula (B), Formula (C) or Formula (D), and one or more excipients are dry mixed and pressed into a dough such as a tablet of sufficient hardness to provide a pharmaceutical composition which disintegrates substantially by less than about 30

<td>minutes</td><td>any less</td><td>in</td><td>about</td><td> 35</td><td>minutes</td><td>any less</td><td>in</td><td>fence</td><td>in</td><td> 40</td>

<td>minutes</td><td>any less</td><td>in</td><td>about</td><td> 45</td><td>minutes</td><td>any less</td><td>in</td><td>fence</td><td>in</td><td> 50</td>

<td>minutes</td><td>any less</td><td>in</td><td>about</td><td> 55</td><td>minutes</td><td colspan="2">or less</td><td colspan="2">about</td><td>in</td>

<td colspan="2">60 minutes,</td><td>after</td><td colspan="3">oral intake,</td><td>like this</td><td colspan="3">freeing</td><td>The</td>

formulation in the gastrointestinal fluid.

201 2 201 840 / ΡΤ

Dosage forms including microencapsulated formulations are described. In some examples, one or more compatible materials are present in the microencapsulation material. Exemplary materials include, but are not limited to, pH modifiers, erosion enhancers, defoamers, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegrating agents, fillers, surfactants, solubilizers, stabilizers, lubricants, wetting agents and thinners.

Materials useful for the above described microencapsulation include materials compatible with compounds of any one of Formula (A), Formula (B), Formula (C) or Formula (D) which sufficiently isolate the compounds of any one of the following. Formula (A), Formula (B), Formula (C) or Formula (D), of other non-compatible excipients. Materials compatible with the compounds of any one of Formula (A), Formula (B), Formula (C) or Formula (D) are those which delay the release of the compounds of any one of Formula (A), Formula (B), Formula (C) or Formula (D) in vivo.

Exemplary microencapsulation materials useful for retarding the release of formulations which include the above described compounds include, but are not limited to, hydroxypropylcellulose ethers (HPC) such as Klucel® or In that HPC, poorly substituted hydroxypropylcellulose ethers (L-HPC), hydroxypropyl methylcellulose (HPMC) ethers such as Seppifilm-LC, Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, Benecel MP824 and Benecel MP843, methylcellulose polymers such as Methocel®-A, Agoat hydroxypropyl methylcellulose stearate-acetate (HF-LS, HF-LG, HF-MS) and Metolose®, ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel®, Agualon®- EC, Surelease®, polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcellulose such as Natrosol®, carboxymethylcelluloses and carboxymethylcelluloses (CMC) salts such as Aguolon®-CMC, poly (vinyl alcohol) and polyethylene glycol copolymers such as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as

EP 2 201 840 / EN

Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100, Eudragit® L12.5, Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, cellulose acetate phthalate, Seppifilms such as mixtures of HPMC and stearic acid, cyclodextrins and mixtures of these materials.

The use of plasticizers such as polyethylene glycols, for example PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350 and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin, which are incorporated into the microencapsulation material, are described. In other cases, the microencapsulation material useful for retarding the release of pharmaceutical compositions is from USP or National Formulary (NF). In still some other embodiments, the microencapsulation material is Klucel. In still other embodiments, the microencapsulation material is Methocel.

The microencapsulated compounds of any one of Formula (A), Formula (B), Formula (C) or Formula (D) may be formulated by methods known to one of ordinary skill in the art. These known methods include, for example, spray drying processes, rotary disc solvent processes, forward melting processes, spray cooling, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, interface polymerization processes. gas or solid gas, pressure extrusion or solvent extraction bath. In addition to these various chemical techniques, for example complex coacervation, solvent evaporation, polymer-polymer incompatibility, interfacial liquid polymerization, in situ polymerization, liquid drying and liquid desolvation can also be used. In addition, other methods such as roller compaction, extrusion / spheronization, coacervation or coating of nanoparticles can also be used.

In one case, the particles of any one of Formula (A), Formula (B), Formula (C) or Formula (D) compounds are microencapsulated before being formulated into one of the above forms. In another embodiment, some or most of

2,201,840 / part of the particles are coated prior to being further formulated using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20. ^The Edition (2000).

Solid dosage forms of the compounds of any one of Formula (A), Formula (B), Formula (C) or Formula (D), which are plasticized (coated) with one or more layers are described. Illustratively, a plasticizer is generally a high boiling solid or liquid. Suitable plasticizers may be added from about 0.01% to about 50% (w / w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, sterol, stearate and oil.

Also described are powders including formulations with a compound of any one of Formula (A), Formula (B), Formula (C) or Formula (D) formulated to include one or more pharmaceutical and flavoring excipients. These powders may be prepared, for example, by mixing the formulation with optional pharmaceutical excipients to form a bulk mix composition. A suspending agent and / or wetting agent are also described. This bulk mixture is evenly subdivided into unit dose or multi dose packs.

The preparation of effervescent powders is also described. Effervescent salts have been used to disperse medicaments in water for oral administration. Effervescent salts are coarse granules or powders that contain a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid and / or tartaric acid. When salts of the compositions described herein are added to water, the acids and base react to release carbon dioxide gas, thereby causing effervescence. Examples of effervescent salts include, for example, the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and / or tartaric acid. Any

201 2 201 840 / ΡΤ

100 The acid-base combination resulting in carbon dioxide release may be used instead of the combination of sodium bicarbonate and citric or tartaric acids, provided that the ingredients are suitable for pharmaceutical use and result in a pH of about 6.0 or more. .

The formulations described herein include a compound of Formula (A) as solid dispersions. Methods of producing such solid dispersions are known in the art and include, but are not limited to, for example, U.S. Pat. 4,343,789, 5,340,591, 5,456,923,

5,700,485, 5,723,269, and US Pub Application 2004/0013734.

Formulations in the form of solid solutions are also described. The solid solutions incorporate a substance together with the active agent and other excipients, so that heating of the mixture results in dissolution of the drug, and the resulting composition is then cooled to provide a solid mixture which may be further formulated or directly added to a mixture. capsule or pressed into a tablet. Methods for producing these solid solutions are known in the art and include, but are not limited to, for example, U.S. Pat. 4,151,273, 5,281,420, and 6,083,518.

Oral solid pharmaceutical dosage forms include formulations described herein which include a compound of any one of Formula (A), Formula (B),

Formulated Formula (C) compound of Formula (A) release Formula (A), or Formula (D) may be to provide additional controlled release of the

Controlled release refers to

<td>of the compound</td><td>of any</td><td>an</td><td>in between</td><td>at</td>

<td>), Formula (B),</td><td>Formula (C)</td><td>or</td><td>Formula (D)</td><td>The</td>

<td colspan="2">a dosage form in which</td><td>it is</td><td>incorporated,</td><td>in</td>

according to the desired profile over an extended period of time. Controlled release profiles include sustained release delayed release. immediate

In examples, sustained release, pulsatile release profiles and contrast with controlled release composition compositions allow delivery of an agent to an individual over an extended period of time according to a predetermined profile. These release speeds can provide levels

EP 2 201 840 / EN

101 therapeutically effective agent agents over an extended period of time and thus provide a longer period of pharmacological response while minimizing side effects compared to conventional rapid release dosage forms. These longer response times provide many inherent benefits that are not achieved with the corresponding short acting immediate release preparations.

The solid dosage forms described herein may be formulated as enteric coated delayed release oral dosage forms, that is, as an oral dosage form of a pharmaceutical composition as described herein which uses an enteric coating to affect the small intestine release of gastrointestinal tract. The enteric coated dosage form may be a pressed or molded or extruded (coated or uncoated) tablet / mold containing granules, powders, pellets, beads or particles of the active ingredient and / or other components of the composition, which are themselves own, coated or uncoated. The enteric coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier of the composition, which are themselves coated or uncoated.

The term delayed release as used herein refers to delivery so that release can be performed at a predetermined location in the most distal intestinal tract from which it would have been performed if there were no delayed release changes. In some embodiments, the method for retarding release is coating. Any coatings should be applied with sufficient thickness so that the entire coating will not dissolve in gastrointestinal fluids at a pH of less than about 5, but will dissolve at a pH of about 5 and above. Any anionic polymer exhibiting a pH dependent solubility profile is expected to be used as an enteric coating in the methods and compositions described herein for delivery to the lower gastrointestinal tract. In some cases, the polymers described herein are anionic carboxylic polymers. In others

EP 2 201 840 / EN

102 In such cases, the compatible polymers and their mixtures, and some of their properties, include, but are not limited to:

Shellac, also called purified shellac, a refined product obtained from the resinous secretion of an insect. This coating dissolves in a medium with pH&gt; 7;

Acrylic polymers. The performance of acrylic polymers (especially their solubility in biological fluids) may vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. The Eudragit E, L, S, RL, RS and NE series (Rohm Pharma /) are available in solubilized form in organic solvent, aqueous dispersion or dry powders. The Eudragit RL, NE and RS series are insoluble in the gastrointestinal tract but are permeable and are mainly used for colon targeting. The Eudragit E series dissolves in the stomach. The Eudragit L, L-30D and S series are insoluble in the stomach and dissolve in the intestine.

Cellulose derivatives. Examples of suitable cellulose derivatives are: ethylcellulose; reaction mixtures of cellulose acetate partial esters with phthalic anhydride. Performance may vary based on degree and type of replacement. Cellulose acetate phthalate (CAP) dissolves at pH&gt; 6. Aquateric (FMC) is an aqueous based system and is a spray-dried CAP pseudolatex with particle size &lt;lpm. Other components in Aquateric may include Pluronics, Tweens and acetylated monoglycerides. Other suitable cellulose derivatives include: cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose succinate-acetate (e.g., AQOT (Shin Etsu)). Performance may vary based on degree and type of replacement. For example, HPMCPs such as quality HP-50, HP-55, HP-55S, HP-55F are suitable. Performance may vary based on degree and type of replacement. For example, suitable qualities of hydroxypropyl methylcellulose succinateacetate include, but are not limited to, AS-LG (LF) dissolving at pH5, AS-MC (MF) dissolving at pH 5.5, and AS-HG (HF ) that dissolves at a pH

201 2 201 840 / ΡΤ

103 higher These polymers are offered in granules or as fine powders for aqueous dispersions;

Poly (Vinyl Phthalate Acetate) (PVAP). PVAP dissolves at pH&gt; 5 and is much less permeable to water vapor and gastric fluids.

The coating may contain, possibly as dyes, plasticizers and coating such magnesium, which plasticizers often contain other suitable talc and / or stearate excipients are well known in the prior art, including triethyl citrate (Citroflex 2). , triacetin (glyceryl triacetate), acetyltriethyl citrate (Citrotlex A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers will usually contain 10-25% by weight of a plasticizer, in particular dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. Conventional coating techniques such as spraying or drum coating are employed to apply coatings. The thickness of the coating will need to be sufficient to ensure that the oral dosage form remains intact until the desired intestinal tract site for topical delivery is reached.

Flavorings, anti-adhesives, surfactants, defoaming agents, lubricants (eg carnauba wax or PEG) may be added to coatings in addition to plasticizers to solubilize or disperse the coating material and to improve the performance of the coating and the coated product. .

Described herein are formulations which include a compound of Formula (A) which are delivered using a pulsatile dosage form. A pulsatile dosage form is capable of providing one or more immediate release pulses at predetermined time points after a controlled period of time or at specific locations. Pulsable dosage forms including the formulations described herein which include a compound of any of Formulas (A),

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104 (Β), (C) and (D) may be administered using a variety of pulsatile formulations known in the art. For example, such formulations include, but are not limited to, those described in US Patents 5,011,692, 5,017,381, 5,229,135 and 5,840,329. Other pulsatile release dosage forms include, for example, U.S. Patent Nos. 4,871,549, 5,260,068, 5,260,069, 5,508,040, 5,567,441 and 5,837,284. The controlled release dosage form can be a pulsatile release solid oral dosage form comprising at least two particle groups (i.e. multiparticles), each containing the formulation described herein. The first particle group provides a substantially immediate dose of the compound of any one of Formula (A), Formula (Β), Formula (C) or Formula (D) upon ingestion by a mammal. The first group of particles may be uncoated or include a coating and / or a sealant. The second group of particles includes coated particles which include from about 2% to about 75%, from about 2.5% to about 70%, or from about 40% to about 70% by weight. of the total dose of the compound of any one of Formula (A), Formula (Β), Formula (C) or Formula (D) in said formulation in a mixture with one or more binders. The coating includes a pharmaceutically acceptable ingredient in an amount sufficient to provide a delay of about 2 hours to about 7 hours after ingestion prior to the release of the second dose. Suitable coatings include one or more differentially degradable coatings, such as, by way of example, pH-sensitive coatings (enteric coatings) such as

Eudragit® EPO, Eudragit® L100, Eudragit® RD100, Eudragit® S 12.5 as

Eudragit

Eudragit® Acrylic Reams (for

L30D-55, Eudragit

Eudragit® Eudragit® example, FS 30D,

S100, L12.5, Eudragit NE 40D) of cellulose by enteric release

L100-55,

Eudragit¹ E100, and Eudragit® NE30D, alone or in admixture with example derivatives, ethyl cellulose, or coatings of varying thicknesses to provide differentiated formulation comprising a compound of any one of Formula (A), Formula (Β), Formula (C) or Formula (D).

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105

Many other types of controlled release systems known to those skilled in the art are suitable for use with the formulations described herein. Examples of such delivery systems include, for example, polymer based systems such as polyglycolic and polylactic acid, polyanhydrides and polycaprolactone; porous matrices, non-polymer based systems that are lipid, including sterols such as cholesterol, cholesterol esters and neutral fatty acids or fats such as mono-, di- and tri-glycerides; hydrogel release systems; silastic systems; peptide based systems; wax coatings, bioerodible dosage forms, compressed tablets using conventional binders and the like. Take, for example, Liberman and others,

Pharmaceutical Dosage Fornis, 2.^The Ed., Vol. 1, p. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2.^The Ed., P. 751-753 (2002); U.S. Patents 4,327,725, 4,624,848, 4,968,509, 5,461,140,

5,516, 527, 5, 622,721, 5, 686, 105,

6,465,014 and 6,932,983.

5,456,923, 5,977,175,

5,700,410, which are compounds of Formula (B), a

Pharmaceutical formulations are provided which include particles of any one of Formula (A),

Formula (C) or Formula (D), and at least dispersion or suspending agent for oral administration to an individual. The formulations may be powder and / or suspension granules, and upon mixing with water, a substantially uniform suspension is obtained.

Liquid formulation dosage forms for oral administration may be aqueous suspensions selected from the group including, but not limited to, dispersions, emulsions, solutions, pharmaceutically acceptable aqueous oral, elixirs, gels and syrups. See, for example, Singh et al., Encyclopedia of Pharmaceutical Technology, 2.^The Ed., P. 754-757 (2002). In addition to the particles of the compound of Formula (A), liquid dosage forms may include additives such as: (a) disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) at least one preservative, (e) viscosity increasing agents, (f) at least one sweetening agent, and (g) at least one flavoring agent. In some

EP 2 201 840 / EN

106 In embodiments, the aqueous dispersions may further include a crystalline inhibitor.

The aqueous suspensions and dispersions described herein may remain homogeneous as defined in The USP Pharmacists' Pharmacopeia (2005 edition, chapter 905) for at least 4 hours. Homogeneity may be determined by a consistent sampling method with respect to determining the homogeneity of the entire composition. An aqueous suspension may be resuspended in a homogeneous suspension by physical agitation lasting less than 1 minute. An aqueous suspension may be resuspended in a homogeneous suspension by physical agitation lasting less than 45 seconds. For example, an aqueous suspension may be resuspended in a homogeneous suspension by physical agitation lasting less than 30 seconds. In other cases, no agitation is required to maintain a homogeneous aqueous dispersion.

Examples of disintegrating agents for use in aqueous suspensions and dispersions include, but are not limited to, a starch, for example a natural starch such as cornstarch or potato starch, a pregelatinised starch such as National 1551 or Amijel. ®, or sodium starch glycolate such as Promogel® or Explotab®; a cellulose such as a wood product, crystalline methylcellulose, for example Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tie® and Solka-Floc®, methylcellulose croscarmellose, or a cross-linked cellulose such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose; a cross-linked starch such as sodium starch glycolate; a cross-linked polymer such as cross-linked polyvinylpyrrolidone; an alginic acid or an alginic acid salt such as sodium alginate; a clay such as Veegum® HV (aluminum magnesium silicate); a gum such as agar, guar, locust bean, Karaya, pectin or tragacanth; sodium starch glycolate; bentonite; a natural sponge; a surfactant; a resin such as a cation exchange resin; citrus pulp; Sodium lauryl sulfate; sodium lauryl sulphate in combination with starch; and others.

crospovidone; an alginate such as

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107

Suitable dispersing agents for aqueous suspensions and dispersions known in the art are described and include, for example, hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG, polyvinylpyrrolidone (PVP, commercially known as Plasdone®), and dispersing agents. carbohydrate-based such as, for example, hydroxypropylcellulose and hydroxypropylcellulose (e.g. HPC, hydroxypropyl methylcellulose and hydroxypropyl methylcellulose (e.g. HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose stearate-acetate, aluminum magnesium silicate, triethanolamine, polyvinylpyrrolidone (PVA) copolymer vinyl acetate (Plasdone®, eg S-630), tetramethylbutyl polymer) phenol with ethylene oxide and

HPC-SL, and HPC-L), de

4- (1,1,3,3formaldehyde (also known as tiloxapol), poloxamers (e.g.,

F88® and F108®, which are propylene oxide copolymers); and 908® poloxamines, also known as ethylene diamine oxide sequential block copolymer (BASF

Pluronics F68®, oxide blocks (e.g. Poloxamine 908®, tetrafunctional ethylene and Tetronic which is derived from and a propylene addition and ethylene oxide Corporation, Parsippanny, NJ)). In other embodiments, the dispersing agent is selected from a group that does not comprise one of the following agents: hydrophilic polymers; electrolytes; Tween® 60 or 80; PEG; polyvinylpyrrolidone (PVP); hydroxypropylcellulose and hydroxypropylcellulose ethers (e.g., HPC, HPC-SL and HPC-L); hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M, and Pharmacoat® USP 2910 (Shin-Etsu)); sodium carboxymethylcellulose; methylcellulose;

hydroxyethylcellulose; hydroxypropyl methylcellulose phthalate; hydroxypropyl methylcellulose stearate acetate; non-crystalline cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl alcohol (PVA); 4- (1,1,3,3tetramethylbutyl) phenol polymer with ethylene oxide and formaldehyde; poloxamers (for example, Pluronics F68®, F880®, and F108®, the

EP 2 201 840 / EN

108 which are block copolymers of ethylene oxide and propylene oxide); or poloxamines (for example, Tetronic 908®, also known as Poloxamine 908®).

Suitable wetting agents for the aqueous suspensions and dispersions described herein are known in the art and include, but are not limited to, cetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fatty acid esters (e.g., commercially available Tweens® such as, for example, Tween 20® and Tween 80® (ICI Specialty Chemicals)), and polyethylene glycols (e.g. Carbowaxs 3350® and 1450®, and Carbopol 934® (Union Carbide)), oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium docusate, triacetin, vitamin E Tocolate TPGS, sodium, simethicone, phosphatidylcholine and the like.

Suitable preservatives for the aqueous dispersions and suspensions described herein include, for example, potassium sorbate, parabens (e.g. methylparaben and propylparaben), benzoic acid and its salts, other parahydroxybenzoic acid esters such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. Preservatives as used herein are incorporated into the dosage form in a concentration sufficient to inhibit microbial growth.

Suitable viscosity enhancers for the aqueous suspensions and dispersions described herein include, but are not limited to, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, Plasdon® S-630, carbomer, polyvinyl alcohol, alginates. , gum arabic, chitosans and their combinations. The concentration of the viscosity increasing agent will depend on the agent selected and the desired viscosity.

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109

Examples of suitable sweetening agents for aqueous acacia, banana, aspartame syrup suspensions or dispersions described herein, acesulfame K, Bavarian cream include, for example, alitame, anise, apple, blackberry, butterscotch , calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, citrus chewing gum, citrus punch, citrus cream, cotton candy, cocoa, cola, fresh cherry, fresh citrus, cyclamate, cilamate , dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrretinate, Glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glycyrrhizinate (MagnaSweet®), maltol, mannitol , oak, marshmallow, menthol, mint cream, berries, neo-hesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum saccharin, safrol, sorbitol, mint, mint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, taline, silitol, sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tutti frutti, vanilla, hazelnut, watermelon, wild cherry, wintergreen, xylitol or any combination of these flavoring ingredients, for example anise menthol, cherry, cinnamon orange, cherry cinnamon, mint chocolate, mellimão, lime , mint lemon, eucalyptus menthol, orange oranges, vanilla mint, and mixtures thereof. The liquid aqueous dispersion may comprise a sweetening or flavoring agent in a concentration ranging from about 0.001% to about 1.0% of the volume of the aqueous dispersion. In another situation, the liquid aqueous dispersion may comprise a sweetening or flavoring agent in a concentration ranging from about 0.005% to about 0.5% of the volume of the aqueous dispersion. In still another case, the liquid aqueous dispersion may comprise a sweetening or flavoring agent in a concentration ranging from about 0.01% to about 1.0% of the volume of the aqueous dispersion.

In addition to the additives listed above, liquid formulations may further include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers. They are emulsifiers

201 2 201 840 / ΡΤ

110 ο ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, sodium lauryl sulfate, sodium docusate, cholesterol, cholesterol esters, taurocholic acid, phosphatidylcholine, oils such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, sorbitan fatty acid esters, or mixtures thereof, and the like.

The pharmaceutical formulations described herein may be self-emulsifying drug delivery systems (SEDDS). Emulsions are dispersions from one immiscible phase to another, usually in the form of droplets. Generally, emulsions are created by vigorous mechanical dispersion. SEDDS, as opposed to emulsions and microemulsions, form emulsions spontaneously when added to excess water without any external mechanical dispersion or agitation. An advantage of SEDDS is that they only require a slight mixture to distribute the droplets throughout the solution. Additionally, water or the aqueous phase may be added just prior to administration, which ensures the stability of an unstable or hydrophobic active ingredient. Thus, SEDDS provide an effective delivery system for oral or parenteral delivery of hydrophobic active ingredients. SEDDS may provide improvements in the bioavailability of hydrophobic active ingredients. Methods for producing self-emulsifying dosage forms are known in the art and include, but are not limited to, for example, U.S. Patent Nos. 5,858,401, 6,667,048 and 6,960,563.

It should be noted that there is an overlap between the above additives used in the aqueous dispersions or suspensions described herein since a given additive is often classified differently by different professionals in the field, or is commonly used for any of several different functions. . Thus, the additives listed above should be construed as merely exemplary, and not limiting, of the types of additives that may be included in the formulations described herein. At

EP 2 201 840 / EN

111 The amounts of these additives may be readily determined by one skilled in the art in accordance with the particular desired properties.

Intranasal Formulations

Intranasal formulations are known in the prior art and are described, for example, in US Patents 4,476,116, 5,116,817 and 6,391,452. Formulations comprising a compound of any one of Formula (A), Formula (B), Formula (C) or Formula (D), which are prepared according to these and other techniques well known in the art, are prepared. as saline solutions using benzyl alcohol or other suitable preservatives, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. See, for example, Ansel, HC et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6.^TheEd. (1995). Preferably, these compositions and formulations are prepared with suitable non-toxic pharmaceutically acceptable ingredients. These ingredients are known to those skilled in the preparation of nasal dosage forms and some of them can be found in Remington: The Science and Practice of Pharmacy, 21.^The Ed., 2005, a standard reference in the area. The choice of suitable carriers is highly dependent on the exact nature of the desired nasal dosage form, for example solutions, suspensions, ointments or gels. Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Lower amounts of others such as pH adjusters, surfactants, ingredients, emulsifiers or dispersants, preservatives, gelling agents, buffers and other stabilizing and solubilizing agents may also be present. The nasal dosage form should be isotonic with nasal secretions.

For administration by inhalation, the compounds of any of Formula (A), Formula (B), Formula (C) or Formula (D) described herein may be in the form of an aerosol, a mist or a powder. The pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray dispenser from pressurized packs or a nebulizer using a

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112 suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve for delivery of a metered amount. Capsules and cartridges, such as, by way of example, of gelatin for use in an inhaler or insufflator apparatus may be formulated containing a powder mixture of the compound described herein and a suitable powder base such as lactose or starch.

Mouth formulations

Buccal formulations which include compounds of any one of Formula (A), Formula (B), Formula (C) or Formula (D) may be administered using a variety of formulations known in the art. For example, such formulations include, but are not limited to, U.S. Patent Nos. 4,229,447, 4,596,795, 4,755,386 and 5,739,136. In addition, the buccal dosage forms described herein may also include a bioerodible (hydrolysable) polymeric carrier which also serves to adhere the dosage form to the buccal mucosa. The buccal dosage form is manufactured to gradually erode over a predetermined period of time over which delivery of the compound of any of Formulas (A), (B), (C), or (D) , is essentially provided in it all. Oral delivery of drugs, as will be appreciated by those skilled in the art, avoids the disadvantages encountered with oral drug administration, for example, slow absorption, degradation of the active agent by fluids in the gastrointestinal tract and / or first-time inactivation. passage in the liver. With respect to the bioerodible (hydrolyzable) polymeric carrier, it should be noted that virtually any of these carriers may be used provided that the desired drug delivery profile is not compromised, and the carrier is compatible with the compound of any one of the following. Formula (A), Formula (B), Formula (C) or Formula (D) and any other components which may be present in the oral dosage unit. Generally, the polymeric carrier comprises hydrophilic (water soluble and water expandable) polymers that adhere to the wetted surface of the

201 2 201 840 / ΡΤ

113 buccal mucosa. Examples of polymeric carriers useful herein include polymers of acrylic acid and co, for example, those known as carbomers (Carbopol®, which can be obtained from BF Goodrich, one of these polymers). Other components, which may also be incorporated into limited oral dosage forms, lubricants, include, but are not limited to, diluents, binders described herein, disintegrants, flavorants, colorants, preservatives, and the like. For buccal and sublingual administration, the compositions may take the form of conventionally formulated tablets, candies or gels.

Transdermal Formulations

The transdermal formulations described herein may be administered using a variety of devices which have been described in the prior art. For example, such devices include, but are not limited to, U.S. Patent Nos. 3,598,122, 3,598,123, 3,710,795,

<td> 3,</td><td> 731,683,</td><td> 3,742,951,</td><td> 3,814,097,</td><td> 3,921,636,</td><td> 3,972,995,</td>

<td> 3,</td><td> 993,072,</td><td> 3, 993, 073,</td><td> 3,996,934,</td><td> 4,031,894,</td><td> 4,060,084,</td>

<td> 4,</td><td> 069,307,</td><td> 4,077,407,</td><td> 4,201,211,</td><td> 4,230,105,</td><td> 4,292,299,</td>

<td> 4,</td><td> 292,303,</td><td> 5,336,168,</td><td> 5,665,378,</td><td> 5,837,280,</td><td> 5,869,090,</td>

<td> 6,</td><td> 923,983,</td><td>6,929,801 and</td><td> 6, 946, 144 .</td><td></td><td></td>

<td>At</td><td>forms</td><td>Dosing</td><td>transdermal</td><td colspan="2">described herein may</td>

certain pharmaceutically acceptable excipients conventional in the prior art. In one embodiment, the transdermal formulations described herein include at least three components: (1) an incorporating formulation which is a compound Formula (B), penetration; additional gelling formulations of either Formula (C) or Formula and (3) a transdermal adjuvant may such as, but not creamed and between Formula (A), (D); (2) an aqueous promoter. include limited ointments,

In addition, the components a, agents and the like. At ; Transdermal formulation bases may further include a tissue or nonwoven backing material to improve absorption and prevent removal of the transdermal formulation from the skin. Transdermal formulations that may maintain a saturated or supersaturated state to promote diffusion in the skin are also described.

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114

Formulations suitable for transdermal administration of the compounds described herein may employ transdermal delivery devices and transdermal delivery packages and may be lipophilic or buffered emulsions, aqueous solutions, dissolved and / or dispersed in a polymer or an adhesive. These packages may be designed for continuous, pulsed, or as needed delivery of pharmaceutical agents. Moreover, transdermal delivery of the compounds described herein may be accomplished via iontophoretic patches and the like. Additionally, transdermal patches may provide controlled delivery of the compounds of any of Formula (A), Formula (Β), Formula absorption rate may be compound speed control membranes within a matrix of (C) or Formula ( D). decreased by use

A is either trapping the polymer or gel.

Conversely, to increase absorption carrier or absorbable absorption enhancers may be used. An enhancer may include pharmaceutically acceptable solvents to aid passage through the skin. For example, transdermal patches are in the form of a patch comprising a support member, a reservoir containing the compound optionally with carriers, optionally a rate control barrier to deliver the compound to the skin of the host at a controlled and predetermined rate during an extended period of time, and means for attaching the device to the skin.

Injectable Formulations

Formulations comprising a compound of any one of Formula (A), Formula (Β), Formula (C) or Formula (D) suitable for intramuscular, subcutaneous or intravenous injection may include solutions, dispersions, suspensions or emulsions. aqueous or non-aqueous, sterile, physiologically acceptable, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, Cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as oleate. of ethyl. The correct flowability can be

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115 maintained, for example, by the use of a coating such as lecithin, by maintaining the proper particle size in case of dispersions and by the use of surfactants. Formulations suitable for subcutaneous injection may also contain additives such as preservatives, wetting agents, emulsifiers and dispensing agents. Prevention of microorganism growth can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form may be achieved by the use of absorption retarding agents such as aluminum monostearate and gelatin.

For intravenous injections, the compounds described herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution or physiological saline buffer. For transmucosal administration, suitable penetrants for the permeate barrier are used in the formulation. These penetrants are generally known in the prior art. For other parenteral injections, appropriate formulations may include aqueous or non-aqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally known in the prior art.

Parenteral injections may involve bolus injection or continuous infusion. Formulations for injection may be presented as unit doses, for example, in ampoules, or in multi-dose containers, with an added preservative. The pharmaceutical composition described herein may be suitable for parenteral injection such as sterile oily vehicle solutions or emulsions and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate as oily injection suspensions. Lipophilic solvents or a suspensions or aqueous form,

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116 Suitable carriers include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which compound to enable highly concentrated ones.

increase the solubility of solution preparation

Alternatively, the active ingredient may be in powder form for constitution with an appropriate carrier, for example sterile pyrogen-free water, prior to use.

Other Formulations

Delivery systems for pharmaceutical compounds such as, for example, liposomes and emulsions are described herein. Also described are compositions comprising a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), polypeptide (methyl methacrylate), polyacrylamide, polycarbophile, butyl acrylate acrylic copolymer, sodium alginate and dextran.

The compounds described herein may be administered topically and may be formulated in a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, ointments, sticks, balms, creams or ointments. These pharmaceutical compounds may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

The compounds described herein may also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG and the like. In the suppository forms of the combinations, a low melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.

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117

Examples of Dosage and Treatment Regime Methods

The compounds described herein may be used in the preparation of medicaments for inhibiting Btk or a homologue thereof, or for treating diseases or conditions that would benefit at least in part from inhibiting Btk or a homologue thereof. Additionally, a method for treating any of the diseases or conditions described herein in an individual in need of such treatment involves administering pharmaceutical compositions containing at least one compound of any one of Formula (A), Formula (B), Formula (C) or Formula (D) described herein, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable N-oxide or a pharmaceutically acceptable solvate, in therapeutically effective amounts, to that individual.

Compositions containing the compound (s) described herein which may be administered for prophylactic and / or therapeutic treatment are described. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in amounts sufficient to cure or at least partially arrest the symptoms of the disease or condition. Effective amounts for this use will depend upon the severity and progression of the disease or condition, prior therapy, health status, weight and drug response of the patient, and the judgment of the attending physician. It is considered within the skill of the person skilled in the art to determine therapeutically effective amounts by routine experimentation (including, but not limited to, a dose escalation clinical trial).

In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of contracting a particular disease, disorder or condition. These amounts are defined as being prophylactically effective amounts or doses. In this use, the precise amounts also depend on the patient's health, weight, and the like. It is considered within the skill of the person skilled in the art to determine these prophylactically effective amounts by routine experimentation (e.g., dose escalation clinical trial). When

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118 When applied to a patient, the effective amounts for such use will depend upon the severity and progression of the disease, disorder or condition, prior therapy, health status and drug response of the patient, as well as the judgment of the attending physician.

In cases where the patient's condition does not improve, at the physician's discretion, the administration of the compounds may be chronic, that is, over an extended period of time, including throughout the patient's life, in order to improve, or otherwise control or limit the symptoms of the patient's disease or condition.

In cases where the patient's condition improves, at the physician's discretion, administration of the compounds may be continued continuously; alternatively, the dose of the drug to be administered may be temporarily reduced or temporarily discontinued for a certain period of time (ie, medication pause). The length of the medication break may range from 2 days to 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days. days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dose reduction during a medication break may be 10% -100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

Once the patient's condition improves, a maintenance dose is given if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, depending on the symptoms, to a level at which improvement in the disease, disorder or condition is maintained. Patients may, however, require long-term intermittent treatment if symptoms recur.

The amount of a given agent which will correspond to such amount will vary depending on factors such as the specific compound, the disease or condition and its severity, the identity (e.g., weight) of the individual or host that

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119 requires treatment, but may in any case be routinely determined in a known manner in the prior art according to the particular circumstances surrounding the case, including, for example, the specific agent to be administered, the route of administration, the condition to be treated and the individual or host to be treated. In general, however, the doses employed for the treatment of an adult human typically range from 0.02-5000 mg per day, or about 1-1500 mg per day. The desired dose may conveniently be presented in a single dose or in divided doses administered simultaneously (or over a short period of time) or at suitable intervals, for example, in two, three, four or more daily sub-doses.

unit may have the discrete quantities

The pharmaceutical compositions described herein may be in unit dosage form suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The dosage forms a pack containing the formulation. Non-limiting examples are packaged tablets or capsules and powders in vials or ampoules. The aqueous suspension compositions may be packaged in non-resealable single dose containers. Alternatively, multiple dose resealable containers may be used, in which case the inclusion of a preservative in the composition is typical. By way of example only, parenteral injection formulations may be presented in unit dose form which includes but is not limited to ampoules or multi-dose containers with an added preservative.

The above ranges are only suggestive because the number of variables in relation to an individual treatment regimen is large, and considerable deviations from these recommended values ​​are not uncommon. Such dosages may be altered depending upon a number of variables, not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the individual subject's requirements, the severity of the disease or condition being treated and the physician's judgment.

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120

The toxicity and therapeutic efficacy of these therapeutic regimens may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to determination of LD.₅₀ (lethal dose for 50% of the population) and ED₅₀ (therapeutically effective dose in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio between LD₅oe ED₅O. Compounds having high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used in formulating a dosage range for use in humans. The dosage of these compounds is preferably in a range of circulating concentrations including ED₅o with minimal toxicity. The dosage may vary within this range depending on the dosage form employed and the route of administration used.

Combination Treatments

The irreversible Btk inhibitor compositions described herein may also be used in combination with other well-known therapeutic reagents which are selected for their therapeutic value for the condition to be treated. In general, the compositions described herein and, in embodiments in which combination therapy is employed, other agents need not be administered in the same pharmaceutical composition and may, because of their different physical and chemical characteristics, have to be administered by different routes. Determination of the mode of administration and the desirability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled practitioner. Initial administration may be in accordance with established protocols known in the prior art and then, based on the observed effects, may be changed by the skilled practitioner, the dosage, the modes of administration and the times of administration.

In certain cases, it may be appropriate to administer at least one irreversible Btk inhibitor compound described herein in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by the patient after receiving one of the inhibitor compounds

EP 2 201 840 / EN

121 irreversible effects of Btk described herein are nausea, so it may be appropriate to administer an anti-nausea agent in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic efficacy of one of the compounds described herein may be enhanced by the administration of an adjuvant (i.e. the adjuvant alone may have minimal therapeutic benefits but, in combination with another therapeutic agent, the benefit joint therapy for the patient is improved). Or, by way of example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) which also has therapeutic benefits. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive to both therapeutic agents or the patient may experience a synergistic benefit.

The particular choice of compounds used will depend upon the diagnosis of the attending physicians and their assessment of the patient's condition and the appropriate treatment protocol. The compounds may be administered concurrently (e.g. simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending on the nature of the disease, disorder or condition, the condition of the patient and the actual choice of compounds used. Determination of the order of administration and the number of repetitions of administration of each therapeutic agent during the treatment protocol is well within the knowledge of the skilled practitioner upon assessment of the disease to be treated and the condition of the patient.

It is well known to those skilled in the art that therapeutically effective dosages may vary when the drugs are used in combination treatments. Methods for experimentally determining therapeutically effective dosages of drugs and other agents for use in combination treatment regimens are described in the literature. For example, the use of metronomic dosing, that is, more often providing lower doses in order to minimize toxic side effects, has been

201 2 201 840 / ΡΤ

122 exhaustively described in the literature. Combination treatment also includes periodic treatments that begin and end several times to aid clinical management of the patient.

For the combination therapies described herein, the dosages of the co-administered compounds will certainly vary depending on the type of co-drugs employed, the specific drug employed, the disease or condition to be treated, and so on. Additionally, when co-administered with one or more biologically active agents, the compounds provided herein may be administered either simultaneously with the biologically active agent (s) or sequentially. If administered sequentially, the attending physician will decide on the appropriate protein administration sequence in combination with the biologically active agent (s).

In either case, the multiple therapeutic agents (one of which is a compound of Formula (A), (B), (C) or (D) described herein) may be administered in any order or even simultaneously. If simultaneously, multiple therapeutic agents may be provided in one unified form or in multiple forms (by way of example only, as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneously, the time interval between multiple doses may range from more than zero weeks to less than four weeks. Additionally, combination methods, compositions and formulations should not be limited to the use of only two agents; The use of multiple therapeutic combinations is also envisaged.

It is understood that the dosage regimen for treating, preventing or ameliorating the conditions for which relief is sought may be modified according to a variety of factors. These factors include the disorder from which the individual suffers as well as the age, weight, gender, diet and medical condition of the individual. Thus, the actual dosage regimen employed may vary widely and thus depart from the dosage regimens set forth herein.

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123

The pharmaceutical agents comprising the combination therapy disclosed herein may be in a combined dosage form or in separate dosage forms intended for substantially simultaneous administration. The pharmaceutical agents that make up the combination therapy may also be administered sequentially, each therapeutic compound being administered by a regimen requiring two administration steps. The two-step administration regimen may require sequential administration of the active agents or spaced administration of the active agents separately. The time between the various administration steps may range from a few minutes to several hours depending on the properties of each pharmaceutical agent such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmaceutical agent. Circadian variation in target molecule concentration may also determine the optimal dose range.

Additionally the compounds described herein may also be used in combination with procedures which may provide additional or synergistic benefits to the patient. By way of example only, patients are expected to derive therapeutic and / or prophylactic benefits from the methods described herein, wherein the pharmaceutical compositions of a compound disclosed herein and / or combinations with other therapies are combined with genetic testing to determine if that individual is. a carrier of a mutant gene known to correlate with certain diseases or conditions.

The compounds described herein and combination therapies may be administered before, during or after the occurrence of a disease or condition, and the time of administration of the composition containing a compound may vary. Thus, for example, the compounds may be used as prophylactics and may be administered continuously to individuals prone to develop conditions or diseases to prevent the occurrence of the disease or condition. The compounds and compositions may be administered to an individual during or as soon as possible after the onset of symptoms. Administration of the compounds may be initiated in the first few

EP 2 201 840 / EN

124 hours after the onset of symptoms, the first 6 hours after the onset of symptoms, or within 3 hours after the onset of symptoms. Initial administration may be by any practicable route such as, for example, intravenous injection, bolus injection, infusion over 5 minutes to about 5 hours, a pill, a capsule, a transdermal patch, and buccal delivery, and the like, or combinations thereof. A compound should be administered as soon as practicable after the onset of a disease or condition has been detected or suspected, and for a period of time necessary to treat the disease, such as, for example, from about 1 month to about 3 months. months. Duration of treatment may vary for each individual, and the extent may be determined using known criteria. For example, the compound or compound-containing formulation may be administered for at least 2 weeks, from about 1 month to about 5 years, or from about 1 month to about 3 years.

Exemplary Therapeutic Agents For Use In Combination With An Irreversible Btk Inhibitor Compound

In cases where the individual suffers or is at risk for an autoimmune disease, an inflammatory disease or an allergic disease, an irreversible Btk inhibitor compound may be used with one or more of the following therapeutic agents in any combination: immunosuppressants (eg tacrolimus, cyclosporine, rapamycin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, or FTY720), glucocorticoids (eg prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, betamethasone, betamethasone, fluorocortisone, deoxycorticosterone acetate, aldosterone), non-steroidal anti-inflammatory drugs (eg salicylates, arylalkanoic acids, 2-arylpropionic acids, N-aryl anthranilic acids, oxicams, coxibes or sulfonanilides), Cox-2 specific inhibitors (eg valdecoxib, celecoxib or rofecoxib), leflunomide, gold thioglycosis, gold thiomalate, aurophine, sulfasclazine, hydroxylamine, INF-α binding proteins (eg infliximab, etanercept or adalimumab), abatacept, anakinra, interferon-α, interferon-γ, interleukin-2, allergy vaccines, antihistamines,

201 2 201 840 / ΡΤ

125 antileukotrienes, beta-agonists, theophylline or anticholinergics.

In cases where the individual suffers or is at risk of proliferative B cell disorder (eg plasma cell myeloma), the individual may be treated with an irreversible Btk inhibitor compound in any combination with one or more other anticancer agents. In some embodiments, one or more of the anticancer agents are pro-apoptotic agents. Examples of anticancer agents include, but are not limited to, any of the following: gossypol, Genasense, polyphenol E, chlorofusine, (all trans) -retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, acid (all trans ) retinoic, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin, 17-Nalylamino-17-desmethoxygeldanamycin (17-AAG), flavopyridol, LY294002, bortezomib, trastuzumab2, PDK-11 Taxol ™ also referred to as paclitaxel which is a well known anti-cancer drug that acts by increasing and stabilizing microtubule formation, and Taxol ™ analogs such as Taxotere ™. Compounds having the base taxane backbone as a common structural feature have also been shown to be able to arrest cells in the G2-M phases due to stabilized microtubules and may be useful for treating cancer in combination with the compounds described herein.

Further examples of anticancer agents for use in combination with an irreversible Btk inhibitor compound include mitogen activated protein kinase signaling inhibitors, for example U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY43-9006 , wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors and antibodies (e.g. rituxan).

Other anticancer agents that may be employed in combination with an irreversible Btk inhibitor compound include: Adriamycin, Dactinomycin, Bleomycin, Viblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine;

201 2 201 840 / ΡΤ

126 ambomycin;

amsacrine;

asperlin;

benzodepa;

ametantrone acetate; aminoglutethimide; anastrozole; antramycin; asparaginase;

azacytidine; azetepa; azotomycin; batimastat; bicalutamide; bisantrene hydrochloride;

bisnafide dimesylate; bizelesine; bleomycin sulfate; breguine sodium; bropyrimine; busulfan; cactinomycin;

calusterone; caracemide; carbetimer;

carmustine; carubicin hydrochloride;

cedefingol; chlorambucil; cirolemycin; cladribine; chrysnatol mesylate; cyclophosphamide; cytarabine; dacarbazine;

daunorubicin; decitabine; dexormaplatin; carboplatin hydrochloride mesylate;

carzelesin;

dezaguanine hydrochloride; doxorubicin;

droloxifene citrate;

duazomycin; elsamitrucin; esorubicin hydrochloride;

edatrexate; enloplatin; epirubicin; estramustine;

dezaguanine; diaziguone; doxorubicin; droloxifene; dromostalonone propionate; eflornithine hydrochloride;

prototype; erbulozole;

epipropidine phosphate; estramustine sodium hydrochloride; ethanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; farabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil;

fosguidone; sodium fostriecin; gemcitabine; gemcitabine; hydroxyurea; ifosfamide hydrochloride; iimophosine; interleukin II flurocytabine; idarubicin hydrochloride; (including recombinant, or rIL2), interleukin II interferon alfa-2a; interferon alfa-2b; interferon alpha-nl; interferon alpha-n3; interferon beta it; gamma-1b interferon; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol; loxometrol sodium; lomustine;

losoxantrone hydrochloride; masoprocol; maytansine;

mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaryl; mercaptopurine;

methotrexate; sodium methotrexate; metoprine; meturedepa;

mitindomide; mitocarcin; mitochromine;

mytomalcin; mitomycin; mitosper; mitotane; mitoxantrone; mycophenolic acid; nocodazole;

pegaspargase;

peplomycin; ormaplatin hydrochloride; oxisurane;

pentamustine; pipobroman sulfate; piposulfan;

plicamycin; plomestane; porfimer sodium; prednimustine; procarbazine hydrochloride;

mitogiline; ngalamycin hydrochloride;

peliomycin; perfosfamide; pyroxantrone; porphyromycin; puromycin;

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127 puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sodium sparphosate; sparsomycin; spirogermonium hydrochloride; spiromustine; spiroplatin; streptonigrine; streptozocin; sulofenur; talisomycin; thecogalan sodium; tegafur; temoporfin hydrochloride; teniposide; teroxyrone; thiamiprine; thioguanine; thiotepa; thiazofurin;

teloxantrone; testolactone; tirapazamine;

toremifene citrate; trestolone acetate; trimethrexate phosphate; triciribine sulfate mustard; trimethrexate; tryptorelin glucuronate; tubulozole hydrochloride; uracil; uredepa; vapreotida; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglicinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostanthin; zorubicin hydrochloride.

Other anticancer agents that may be employed in combination with an irreversible Btk inhibitor compound include: 20-epi-1,2,5-dihydroxyvitamin D 3; 5etinyluracil; abiraterone; aclarubicin; acylfulveno; adecipenol; adozelesin; aldesleukin; ALLTK antagonists; altretamine; ambamustine; starch; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrografolide; angiogenesis inhibitors; antagonist D; G antagonist; antelelix; anti-dorsalizing morphogenetic protein 1; antiandrogen; prostate carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicoline glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrin; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatirosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorines; benzo! lestaurosporin; beta lactam derivatives; betaaletin; betacyclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinilespermine; bisnafide; bistranene A; bizelesine; breflate; bropyrimine; budotitan; sulfoximine butionine; calcipotriol; calfostine C; camptothecin derivatives; Canaripox IL-2;

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128 capeeitabine; carboxamido-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanopermines; Cecropin B; cetrorelix; chlorins;

cis-porphyrin; clotrimazole;

chloroquinoxaline sulfonamide; cicaprost;

cladribine; clomiphene analogs; colimycin A; collimycin B; combrestastatin A4; combrestastatin analogue; conagenin; crambescidine 816; chrysnatol; cryptophycin 8; cryptophycin A derivatives;

cycloplatam; cytolytic factor;

cyclopentatetraquinones; cytarabine octophosphate; dacliximab; decitabine; dehydrodidemnin B; dexamethasone; dexiphosphamide; dexrazoane;

curachma A; cypemycin; cytostatin; of sloreiin; dexverapamil;

diaziquone; didemnin B; didox; diethylnorespermine; dihydro-5-azacytidine; 9-dioxamycin; diphenylspiromustine;

docosanol; dronabinol; edelfosine; epirubicin;

dolasetrone; doxifluridine; droloxifene; duocarmycin SA; ebselene; ecomustine; edrecolomab; eflornithine; elemene; emitsfur; epristeride; estramustine analog;

farabine; f1avop iri do1; estrogen agonist hydrochloride; estrogen antagonists; ethanidazole; etoposide phosphate; exemestane; fadrozole;

fenretinide; filgrastim; finasteride;

flezelastine; fluasterone; fludarabine;

fluorodaunorunicine; forfenimex; formestane;

fostriecin; photemustine; gadolinium texaphyrin; gallium nitrate; galocytabine; ganirelix; gelatinase inhibitors; gememeitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; oxyphene; idramantona;

ilmophosine; ilomastat; imidazoacridones; imiquimod; immunostimulatory peptides; insulin-like growth factor receptor 1 inhibitor; interferon agonists; interferons; interleukins; iobenguan; iododoxorubicin; 4-ipomeanol; iroplact; irsogladina;

isobengazole; isohomohalicondrin B; itasetron;

jasplaquinolide; caalalide F; N-lamellarin triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukocyte interferon alpha inhibitory factor; leuprolide + progesterone; leuprorelin; Levamisole; liarozole; linear polyamine analog; lipophilic disaccharide peptide; lipophilic platinum compounds; lysoclinamide 7;

of leukemia; estrogen +

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129 lobaplatin; lombricin; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysophylline; lytic acids; maytansine; manostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; Mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogs; mitonafide; mitotoxin fibroblast growth factor - saporin; mitoxantrone; mopharotene; molgramostim; monoclonal antibody, human chorionic gonadotropin; monophosphorylipid A + sk of mycobacterial cell wall; mopidamol; multidrug resistance gene inhibitor; multiple tumor suppressor-based therapy 1; mustard anti-cancer agent; micaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyl dinaline; N-substituted benzamides; naphtarrelin; nagrestip; naloxone + pentazocine; napavine; naphterpine; nartograstim; nedaplatin; nemorubicin; nerhydronic acid; neutral endopeptidase; nitulamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrulin; Benzylguanine; octreotide; oquicenone; oligonucleotides;

oracin;

onapristone; cytokines; pamidronic oxaunomycin; pazeliptin;

ondansetron; ormaplatin; palauamine; panaxitriol; pegaspargase;

oral osaterone inducer; oxaliplatin;

palmitoylrizoxine; panomifene acid; parabactin;

peldesin; sodium pentosan polysulfate; pentostatin; pentrozole; perflubron; perfosfamide; peryl alcohol; phenazinomycin; phenylacetate;

phosphatase inhibitors; pilocarpine; pirarrubicin; placetin B; picibanil inhibitor; pyritrexim;

placetin A hydrochloride activator; plasminogen;

platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porphyromcin;

prednisone; protein A inhibitors;

propyl bis-acridone; prostaglandin J2;

proteasome; protein kinase C inhibitor-based immunomodulator; microalgae protein kinase C inhibitors; protein tyrosine phosphatase inhibitors; purine nucleosidophosphorylase inhibitors; glitter; pyrazoloacridine; pyridoxylated hemoglobin-polyoxyethylene conjugate; antagonists of

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130 raf; raltitrexed; ramosetrone; rasfarnesyltransferase protein inhibitors; ras inhibitors; ras-GAP inhibitor; demethylated reteliptin; ribozyme etidronate; rhenium retinamide Re 186;

rhizoxin;

roituquine;

romurtide;

safingol; saintopine; Sdi 1 mimetics;

rogletimide;

RII;

roquinimex; rubiginone Bl; ruboxyl; SarCNU; sarcophytol A; sargramostim; semustine; senescence-derived inhibitor 1; sense oligonucleotides;

signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizopyrane; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedine binding protein; sonermin; sparphosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitors; stipiamide; stromelysin inhibitors;

surfer vasoactive intestinal peptide antagonist; suramine; swainsonine;

sulfinosine; super active;

synthetic glycosaminoglycans; talimustine; tamoxifen methiodide; tauromustine; tegafur; tellurium;

tazarotene; sodium tecogalane; telomerase inhibitors; temoporphine; temozolomide; teniposide; tetrachlorodeca oxide; tetrazomine; taliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetics; thymalfasine; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl thiopurpurin; tirapazamine; titanocene dichloride; topsentin; toreminfene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimethrexate; triptorelin; tropisetrone; turosteride; tyrosine kinase inhibitors; tirphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotida; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; green vegetables; verteporfin; vinorelbine; vinxaltin; vitaxine; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin estimator.

Still other employed in irreversible anti-cancer agents in combination with de Btk include that inhibiting compounds, antimetabolites, natural products or hormones, for example, may also be a compound.

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131 cyclophosphamide mustards, (eg nitrogen (eg, mecloroetamine, chlorambucil, etc.), alkylsulfan sulfonates), nitrosureas (eg triazenes (decarbazine, include, but are not folic (eg, (e.g., carmustine, lomustine, etc.), etc.) Examples of limited antimetabolites, methotrexate acid analogs, or pyrimidine cytarabine analogs), mercaptopurine, thioguanine, pentostatin purine analogs).

Examples of useful natural products in combination with an irreversible Btk inhibitor compound include, but are not limited to, vinca alkaloids (eg vinblastine, vincristine), epipodophyllotoxins (eg etoposide), antibiotics (eg daunorubicin, doxorubicin). , bleomycin), enzymes (e.g., L-asparginase), or biological response modifiers (e.g., interferon alpha).

Examples of alkylating agents that may be employed in combination with an irreversible Btk inhibitor compound include, but are not limited to, nitrogen mustards (e.g. mecloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimines and methylmelamines (e.g. , hexamethylmelamine, thiotepa), alkyl sulfonates (e.g. busulfan), nitrosureas (e.g. carmustine, lomustine, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g. methotrexate), or pyrimidine analogs (e.g. fluorouracil, floxouridine, cytarabine), purine analogs (e.g. mercaptopurine, thioguanine, pentostatin) .

Examples of hormones and antagonists useful in combination with an irreversible Btk inhibitor compound include, but are not limited to, adrenocorticosteroids (e.g. prednisone), progestins (e.g. hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens. (e.g. diethylstilbestrol, ethinyl estradiol), antiestrogen (e.g. tamoxifen), androgens (e.g.

EP 2 201 840 / EN

132 testosterone, fluoxymestrone), anti-androgen (eg flutamide), gonadotropin-releasing hormone analog (eg leuprolide). Other agents that may be used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (e.g. cisplatin, caboplatin), anthracenedione (e.g. mitoxantrone), substituted urea (e.g. hydroxyurea), methylhydrazine derivative (e.g., procarbazine), adrenocortical suppressors (e.g., mitotane, aminoglutethimide).

Examples of anti-cancer agents that act to sustain cells in the G2-M phases due to stabilized microtubules and which may be used in combination with an irreversible Btk inhibitor compound include, without limitation, the following marketed drugs and developing drugs: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC639829, Discodermolide (also known as NVP-XX- A-296), ABT-751 (Abbott, also known as E-7010), Altorirtins (such as Altorirtin A and Altorirtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 4, Spongistatin 5,

Spongistatin 7, Spongistatin 8 and Cemadotine Hydrochloride (also known as LU-103793 and NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as deoxyiepotilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB and deoxyiepotilone Β), Epothilone E, Epothilone F, Epothilone B N-oxide, Epotilone A N-oxide,

Spongistatin 3, Spongistatin 6, Spongistatin 9)

16-aza-epothilone B, 21-aminoepothilone as BMS-310705), 21-hydroxyepotilone as Deoxyiepotilone F and dEpoF),

Auristatin Soblidotine (Pharmacia, (Pharmacia, (Pharmacia),

PE (Also Known (Also Known As Also Known As

LS-4559 by (Pharmacia),

B (also known D (also known 26-fluoroepothilone) as NSC-654663), TZT-1027), LS-4559-P

LS-4577), LS-4578

LS-477-P), LS-4477

RPR-112378 (Aventis), Vincristine, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda),

GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences),

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133

BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM97 (Armad / Kyowa Hakko), AM-132 (Armad) , AM-138 (Armad / Kyowa)

Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as

AVE-8063A and CS-39.HC1), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HC1 and RPR-258062A),

Vitilevuamide, Tubulisin A, Canadensol, Centaureidine (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1 (Parker

Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin Al (also known as ΒΊΌ-956 and DIME), DDE-313 (Parker Hughes Institute) , Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D24851 (Asta Medica), A-105972 (Abbott), Hemiasterlina, 3BAABU (Cytoskeleton / Mt. Sinai known as MF -191), Vanadocene TMPN Acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocin (also known as NSC-698666), 3-1AABE (Cytoskeleton / Mt. Sinai School of Medicine), A-204197 also known as T- 900607),

School of Medicine, also (Arizona Ste University), (Abbott), T-607 (Tuiarik,

RPR-115781 (Aventis),

Desmethyleleuterobine, Desaethyleleuterobine, and Z-Eleuterobine), Caribaeosida,

Eleuterobines (such as

Isoeleuterobin A

Caribaeolina,

Halicondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), (Abbott), (Aventis),

NPI-2350

A-259754 (Nereus), (Abbott), such as NSCLDiazonamide A, A-293620 Tacalonolide A, TUB-245

Diozostatin, (-) - Phenylistine (also known as

96F037), D-68838 (Asta Medica), D-68836 (Asta Medica),

Myoseverine B, D-43411 (Zentaris, also known as D81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known SPA-110, Trifluoroacetate Salt) (Wyeth), D-82317 ( Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin Sodium Phosphate, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

In cases where the individual suffers or is suffering from a thromboembolic disorder (for example,

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134 apoplexy), the individual may be treated with an irreversible Btk inhibitor compound in any combination with one or more other antithromboembolic agents. Examples of antithromboembolic agents include, but are not limited to, any of the following: thrombolytic agents (e.g., alteplase, anistreplase, streptokinase, urokinase or tissue plasminogen activator), heparin, tinzaparin, warfarin, dabigratane (eg, ethaxylate dabigratane), factor Xa inhibitors (eg fondaparinux, draparinux, draparinux DX-9065a, otamixaban, LY517717 or YM150), ticlopidine, clopidogrel, CS-747 (prasugrel, LY640315), ximelagratane or BIBR 1048.

Kits! Manufacturing Articles

For use in the therapeutic applications described herein, kits and articles of manufacture are also described herein. These kits may include a compartmentalized holder, package or container for receiving one or more containers such as vials, tubes and the like, each container including one of the separate elements for use in a method described herein. Suitable containers include, for example, bottles, vials, syringes and test tubes. Containers may be made of various materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials. Packaging materials for use in pharmaceutical packaging are well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of packaging materials include, but are not limited to, blisters, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected and one mode of administration and intended. . A wide range of formulations of the compounds and compositions provided herein are contemplated, as well as a variety of treatments for any disease, disorder or condition that benefits from Btk inhibition, or in which Btk is a mediator or contributor to symptoms or treatment formulation. the cause.

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For example, the container (s) may include one or more of the compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container (s) optionally have a sterile access port (for example, the container may be an intravenous solution bag or a vial with a cap pierced by a hypodermic injection needle). These kits optionally comprise a compound with a description or label or identifying instructions related to its use in the methods described herein.

Typically, a kit may include one or more additional containers, each containing one or more miscellaneous materials (such as reagents, optionally in concentrated form, and / or devices), commercially or user desirable, for use with the compound herein. described. Non-limiting examples of these materials include, but are not limited to, tampons, diluents, filters, needles, syringes; media labels, packages, containers, vials and / or tubes, which contain contents and / or instructions for use, and package inserts with instructions for use. Typically, an instruction set will also be included.

A label may be affixed or attached to the container. A label may be on the container when letters, numbers or other characters forming the label are affixed, molded or engraved on the container itself; A label may be associated with a container when it is present within a receptacle or holder which also contains the container, for example as a package insert. A label may be used to indicate that the contents are intended to be used for a specific therapeutic application. The label may also indicate guidelines for use of the contents, as in the methods described herein.

The pharmaceutical compositions may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing a compound provided herein. The package may, for example, contain a metal or plastic wrap such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The packaging or

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136 The dispensing device may also be accompanied by a warning associated with the container as prescribed by the government entity regulating the manufacture, use, or sale of pharmaceutical products, which reflects the entity's approval of the drug form for human or veterinary administration. Such a warning, for example, may be the US Food and Drug Administration approved labeling for prescription forms, or the approved product labeling. Compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in a suitable container, and labeled for treatment of an indicated condition.

Examples

The following specific and non-limiting examples should be construed as illustrative only and do not in any way limit the present disclosure. Without further elaboration, it is believed that one skilled in the art may, based on the present disclosure, make full use of the present disclosure. Where reference is made to a URL or other identifier or address, it should be understood that such identifiers may change and particular information on the Internet will come and go, but equivalent information may be found by searching the internet. Its reference highlights the availability and public dissemination of that information.

Example 1: Compound Synthesis

Preparation of 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate 2)

4-Amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate 2) is prepared as disclosed in International Patent Publication WO 01/019829. Briefly, 4-phenoxybenzoic acid (48 g) is added to thionyl chloride (100 mL) and heated at gentle reflux for 1 hour. Thionyl chloride is distilled off, residual oil is dissolved in toluene and volatile material is removed at 80 ° C / 20 mbar. The resulting acid chloride is dissolved in toluene (200 mL) and tetrahydrofuran (35 mL). Malononitrile (14.8 g) is added and the solution is stirred at -10 ° C while diisopropylethylethylamine (57.9 g) in toluene (150 mL) is added while maintaining the temperature below 0 ° C.

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After 1 hour at 0 ° C, the mixture is stirred at 20 ° C overnight. The amine hydrochloride is filtered off and the filtrate is evaporated in vacuo. The residue is taken up in ethyl acetate and washed with 1.25 M sulfuric acid, and then brine, and dried over sodium sulfate. Evaporation of the solvents yields a semi-solid residue which is treated with a little ethyl acetate to give 4.1 g of 1,1-dicyano-2-hydroxy-2- (4-phenoxyphenyl) ethylene as a solid. a white solid (mp 160-162 ° C). Evaporate the filtrate to 56.58 (96%) of 1,1-dicyano-2-hydroxy-2- (4-phenoxyphenyl) ethane as a tan solid which is pure enough for further use.

1,1-Dicyano-2-hydroxy-2- (4-phenoxyphenyl) ethane (56.5 g) in acetonitrile (780 mL) and methanol (85 mL) is stirred under nitrogen at 0 ° C while diisopropylethylamine ( 52.5 mL) followed by 2M trimethylsilyldiazomethane (150 mL) in THF. The reaction mixture is stirred for 2 days at 20 ° C, and 2 g of silica (for chromatography) are then added. The reddish-brown solution is evaporated in vacuo, the residue is dissolved in ethyl acetate and washed well with water, then brine, dried and evaporated. The residue is extracted with diethyl ether (3x250 mL), decanting the insoluble oil. Evaporation of ether extracts gives 22.5 g of 1,1-dicyano-2-methoxy-2- (4-phenoxyphenyl) ethane as a pale orange solid. The insoluble oil is purified by flash chromatography to give 15.0 g of an orange-red oil.

1,1-dicyano-2-methoxy-2- (4-phenoxyphenyl) ethane (22.5 g) and 1,1-dicyano-2-methoxy-2- (4-phenoxyphenyl) etene oil (15 g ) are treated with a solution of hydrazine hydrate (18 mL) in ethanol (25 mL) and heated on the steam bath for one hour. Ethanol (15 mL) is added followed by water (10 mL). The precipitated solid is collected and washed with ethanol: water (4: 1) and then air dried to give 3-amino-4-cyano-5- (4-phenoxyphenyl) pyrazole as a pale orange solid. .

3-Amino-4-cyano-5- (4-phenoxyphenyl) pyrazole (29.5 g) is suspended in formamide (300 mL) and heated under nitrogen to 180 ° C

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138 for 4 hours. The reaction mixture is cooled to 30 ° C and water (300 mL) is added. The solid is collected, washed well with water, then methanol, and air dried to give 4-amino- 3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine.

Example 1a: Synthesis of 1- (3- (4-Amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1 -one (Compound 4)

Scheme 1.

<img file="PT2201840E_D0032.tif" />

3 4

Synthesis of compound 4; a) polymer bound triphenylphosphine (TPP), diisopropyl diazodicarboxylate (DIAD), tetrahydrofuran (THF); b) HCl / dioxane; then acryloyl chloride, triethylamine (TEA).

The compounds described herein were synthesized following the steps outlined in Scheme 1. A detailed illustrative example of the reaction conditions shown in Scheme 1 is described for the synthesis of 1-3- (4-amino-3- (4-phenoxyphenyl) -1Hpyrazole. [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one (Compound 4).

101 mg of 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine and 330 mg of polymer-bound triphenylphosphine (TPP) (PolymerLab polymer) were mixed together with 5 mL of tetrahydrofuran. hydrofuran (THF). tert-Butyl 3-hydroxypiperidine-1-carboxylate (200 mg, 2.0 equivalents) was added to the mixture followed by the addition of diisopropyl diazodicarboxylate (0.099 mL). The reaction mixture was kept at room temperature overnight. The reaction mixture was filtered to remove

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139 resins and the reaction mixture was concentrated and purified by flash chromatography (pentane / ethyl acetate = 1/1) to give intermediate 3 (55 mg).

Intermediate 3 (48.3 mg) was treated with 1 mL of 4N HCl in dioxane for 1 hour and then concentrated to dryness. The residue was dissolved in dichloromethane and triethylamine (0.042 mL) was added followed by acrylic chloride (0.010 mL). The reaction was stopped after 2 hours. The reaction mixture was washed with 5 wt% aqueous citric acid and then brine. The organic layer was dried with MgSO 4 and concentrated. Flash chromatography (with CfhH ^ Me / MeOH = 25/1) gave 22 mg of compound 4 as a white solid. MS (M + 1): 441.2;¹1 H NMR (400 MHz): 8.26, s, 1H; 7.65, m, 2H;

7.42, m, 2H; 7.1-7.2, m, 5H; 6.7-6.9, m, 1H; 6.1, m, 1H; 5.55.7, m, 1H; 4.7, m, 1H; 4.54, m, 0.5H; 4.2, m, 1H; 4.1, m, 0.5H; 3.7, m, 0.5H; 3.2, m, 1H; 3.0, m, 0.5H; 2.3, m, 1H;

2.1, m, 1H; 1.9, m, 1H; 1.6, m, 1H.

Example 1b: Synthesis of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) propyl 2-en-tarpaulin (Compound 13).

<img file="PT2201840E_D0033.tif" />

Synthesis of compound 13 was performed using a procedure analogous to that described in Example 1a. MS (calc.):

440.2; MS (ESI) m / e (M + 1H)⁺ : 441.1, (δ-1H) ': 439.2.

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Example 1c: Synthesis of 1 - ((S) -3- (4-amino-3- (4-phenoxyphenyl) 1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) propyl 2-en-tarpaulin (Compound 14).

pG

<img file="PT2201840E_D0034.tif" />

Synthesis of compound 14 was performed using a procedure analogous to that described for Example 1a. MS (calcd): 440.2; MS (ESI) m / e (M + 1H)⁺: 441.5, (M-1H) ': 439.2.

Example 1d: Synthesis of 1 - ((S) -3- (4-amino-3- (4-phenoxyphenyl) 1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) propyl 2-en-tarpaulin (Compound 12).

<img file="PT2201840E_D0035.tif" />

The synthesis of this compound was performed using a procedure analogous to that described for Example 1a. MS (calc.): 426.18; MS (ESI) m / e (M + 1H)⁺: 427.2, (M-1H) ':

425,2 .

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Example 1e: Synthesis of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) propyl 2-en-tarpaulin (Compound 11).

<img file="PT2201840E_D0036.tif" />

The synthesis of this compound was performed using a procedure analogous to that described for Example 1a. MS (calc.): 426.18; MS (ESI) m / e (M + 1H)⁺: 427,2.

Example 1f: Synthesis of N - ((1s, 4s) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexyl) acrylamide (Compound 10).

<img file="PT2201840E_D0037.tif" />

The synthesis of this compound was performed using a procedure analogous to that described for Example 1a.

MS (calcd): 454.21; MS (ESI) m / e (M + 1H) +: 455.1, (M-1H) -:

453, 1.

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Example 1g: Synthesis of 1- (3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) sulfonylene (compound 6).

<img file="PT2201840E_D0038.tif" />

Synthesis of compound 6 was performed using a procedure analogous to that described for Example 1a. MS (calc.): 476.16; MS (ESI) m / e (M + 1H)⁺: 478.0, (M-1H) ': 475.3.

Example 1h: Synthesis of 1- (3- (4-amino-3- (phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-yn-1-one (Compound 8).

<img file="PT2201840E_D0039.tif" />

Synthesis of compound 8 was performed using a procedure analogous to that described for Example 1a. MS (calc.): 438.18; MS (ESI) m / e (M + 1H)⁺: 439.2, (M-1H) ': 437.2.

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Example II: Synthesis of (E) -1- (3- (4-amino-3- (4-phenoxyphenyl) 1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) -4 (dimethylamino) but-2-en-1-one (Compound 15). (not according to the invention)

<img file="PT2201840E_D0040.tif" />

Synthesis of compound 15 was performed using a procedure analogous to that described for Example 1a. MS (Cal.): 497.25; MS (ESI) m / e (M + 1H)⁺: 498.4, M-1H) ": 496.

Example 2: In vitro Btk Inhibitory Activity

IC50s for Btk of the compounds disclosed herein were determined either in an acellular kinase assay or in a BCR-induced cellular calcium flux functional assay as described below.

Btk kinase activity was determined using a time resolved fluorescence resonance energy transfer (TR-FRET) methodology. Measurements were made in a 50 µl reaction volume using 96-well assay plates.

The enzyme kinase, inhibitor, ATP (at K_m for kinase), and 1 μΜ peptide substrate (Biotin-AVLESEEELYSSARQ-NH₂) were incubated in a reaction buffer composed of 20 mM Tris, 50 mM NaCl, MgCl 2 (5-25 mM depending on kinase), MnCl₂ (010 mM), 1 mM DTT, 0.1 mM EDTA, 0.01% bovine serum albumin, 0.005% Tween-20 and 10% DMSO at pH 7.4 for one hour. The reaction was quenched by the addition of 1.2 equivalents EDTA (relative to divalent cation) in 25 µl Lance 1x buffer (Perkin-Elmer). Streptavidin-APC (Perkin-Elmer) and Eu-labeled p-Tyr100 antibody (Perkin-Elmer) in Lance 1x buffer were added in a volume of 25 pL to give

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144 final concentrations of 100 nM and 2.5 nM, respectively, and the mixture was allowed to incubate for one hour. The TR-FRET signal was measured on a multimodal plate reader with an excitation wavelength (λ_Εχ) at 330 nm and detection wavelengths_In) at 615 and 665 nm. Activity was determined by the ratio of fluorescence at 665 nm to 615 nm. For each compound, enzymatic activity was measured at various concentrations of the compound. Negative control reactions were performed in the absence of inhibitor in six replicates and two non-enzyme controls were used to determine baseline fluorescence levels. Inhibition constants, Ki (app) were obtained using the BatchKi program (Kuzmic et al. (2000), Anal. Biochem. 286: 45-50). IC50 values ​​were obtained according to the equation:

IC50 = {K_i(app) / (l + [ATP] / K_m^ATP)} + [E] total / 2;

For all kinases, [ATP] = K_m^ATP, [Btk]_I'mtai = 0.5 nM and [Lck]_totai = 6 nM.

Calcium flux fluorescence-based assays were performed on a FlexStation II384 fluorometric imaging plate reader (Molecular Devices) according to the manufacturer's instructions. Briefly, actively growing Ramos (ATCC) cells in RPMI medium supplemented with 10% FBS (Invitrogen) were washed and replated in low serum medium at approximately 5 x 10 6.⁵ cells per 100 µl per well in a 96-well plate. Test compounds were dissolved in DMSO and then diluted in low serum medium at final concentrations ranging from 0 to 10 μΜ (with a dilution factor of 0.3). Diluted compounds were then added to each well (final DMSO concentration was 0.01%) and incubated at 37 degrees in a 5% CO 2 incubator for one hour. Thereafter, 100 µl of a calcium sensitive dye (from the Calcium 3 Assay Kit, Molecular Devices) was added to each well and incubated for an additional hour. Compound-treated cells were stimulated with a goat anti-human IgM antibody (80ug / ml; Jackson ImmunoResearch) and read on FlexStation II384 using λ_Εχ = 485 nm and Ã_In = 538 nm

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145 for 200 seconds. Relative fluorescence unit (RFU) and IC50 were recorded and analyzed using an internal SoftMax program (Molecular Devices).

Table 2: Assay Data for Representative Compounds

<td colspan="4">oO</td>

<td></td><td>NH ll N</td><td colspan="2">ΖΛ 2 Λ ν ' R</td>

<td>Compound N.⁰</td><td>R</td><td>BTK IC₅₀ (ηΜ)</td><td>Ca Flow in Ramos IC Cells₅₀ (nM)</td>

<td> 4</td><td>&lt;Amw Λ Ο</td><td> 0,72</td><td> 10</td>

<td> 5*</td><td>Λ ο</td><td> 20</td><td> 89</td>

<td> 6</td><td>Λ &lt;Α</td><td> 0,52</td><td> 92</td>

<td> 7*</td><td>Λ 0</td><td> 0,58</td><td> 9</td>

<td> 8</td><td>ο</td><td> 0,72</td><td> 9</td>

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<td> 9</td><td>WWW O Λ</td><td> 3, 6</td><td> 48</td>

<td> 10</td><td>mwv Φ^HnY ^ 0</td><td> 0,58</td><td> 3</td>

<td> 11</td><td>H</td><td> 1,6</td><td> 24</td>

<td> 12</td><td>v&gt; wv ά</td><td> 1,9</td><td> 90</td>

<td> 13</td><td>&lt;VW Λ O</td><td> &lt;0,5</td><td> 10</td>

<td> 14</td><td>&gt; &lt;wv O</td><td> 1,4</td><td> 7</td>

<td> 15*</td><td>The The 1</td><td> 2,5</td><td> 36</td>

* not according to the present invention

Two lines of evidence demonstrated irreversible inhibition of Btk by these compounds. First, after recombinant Btk was pretreated with compounds, its activity was not recovered by repeated washing with inhibitor-free media (see, for example, JB Smaill, et al., J. Med. Chem. 1999, 42, 1803). Second, a major mass peak was observed by

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147 mass corresponding to the molecular weight of a 1: 1 covalent complex between compound 4 and Btk (Compound 4: 440 Da, recombinant Btk kinase domain: 33,487 Da; Complex: expected 33,927 Da, observed 33,927 Da).

These compounds are highly potent inhibitors of Btk kinase activity with single digit subnanomolar to nanomolar IC 50 values ​​for in vitro kinase activity. Your IC50 in Ca flow test²⁺(Ramos cells) ranged from 3 to 92 nM.

It should be noted that we found that three types of Michael acceptors, acrylamide, vinylsulfonamide and propargylamide, exhibited strong interactions with Btk. The addition of a trans-oriented methyl group to the vinyl group decreased potency as shown by compound 5, which was 28 times less potent than 4. This presumably relates to the reduced electrophilicity of the more substituted olefin. Compound 15 with a tertiary amino group regained some potency compared to compound 5, although it still suffered from a power loss from compound 13. Compound 10 was about 6 times more potent than compound 9, presumably due to the difference in electrophile orientation. Finally, the R configuration was determined as the slightly preferred absolute stereochemical configuration by two sets of enantiomers (11 vs. 12 and 13 vs. 14).

Example 3: Btk Inhibition

Additionally, we characterized the properties of these compounds by assaying a number of biochemical and functional cell endpoints. In particular, we sought to analyze the selectivity of these compounds for inhibition of Btk versus closely related protein kinases Lck, Lyn and Syk. In anti-IgM stimulated Ramos cells (a human B cell line), we analyzed PLC-γΙ Btk-dependent phosphorylation; Lyn and Syk's dependent phosphorylation of tyrosine 551 on Btk; and BCR-activated calcium flux. We also measured the effect of compound 4 on Jurkat cells, a human T cell line in which Lck and Itk, but not Btk, are required for Ca flow.²⁺mediated by T cell receptors.

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As shown in Table 3, compound 4 showed significant selectivity for Btk in cell assays. In anti-IgM stimulated Ramos cells, compound 4 inhibited PLC-γΙ phosphorylation with an IC50 = 0.014 μΜ, while Lyn and Syk dependent phosphorylation of tyrosine 551 in Btk was weakly inhibited (IC₅&gt; 7.5 μΜ). Thus, compound 4 shows&gt; 500-fold selectivity between Btk and Lyn or Syk in cells. Further, compound 4 was 11 times less active in inhibiting Ca flow.²⁺ gue in Ramos cells, supporting the expected selectivity for B cells versus T cells.

Table 3. Cell Assay Data for Compound 4

<td rowspan="2">Comp.</td><td colspan="5">BTK^The Lck^The Lyn^The Btk p551^B pPLC-yl^B</td><td rowspan="2">Ca flow in branches^B(μΜ)</td><td rowspan="2">Ca Flow in Jurkat^B(μΜ)</td>

<td>(nM)</td><td>(nM)</td><td>(nM)</td><td>(μΜ)</td><td>(μΜ)</td>

<td> 4</td><td> 0, 72^B</td><td> 97</td><td> 14</td><td> &gt;7,5</td><td> 0,014</td><td> 0,0405</td><td> 0,466</td>

[a] Ki (app) [b] IC₅₀

Example 4: Using Compound 4 to Treat Rheumatoid Arthritis

The in vivo efficacy of compound 4 was evaluated in a mouse model of rheumatoid arthritis. Arthritis was induced in a Balb / c mouse by administration of anti-collagen and lipopolysaccharide (LPS) antibodies. See Nandakumar et al. (2003), Am. J. Pathol. 163: 1827-1837.

Female Balb / c mice were treated with 100 mg / kg of Chemicon mAb cocktail against type II collagen intravenously on day 0 and 1.25 mg / kg of intraperitoneal LPS on day 1. Compound 4 was administered orally in a 1, 3, 10 methylcellulose formulation and 30 mg / kg aqueous suspension once daily starting on day 2 to day 12. Blood samples were taken 0.5 and 2 hours after dosing of compound 4 on day 12 (see Table 4). Serum concentrations of compound 4 were guaranteed by LC / MS / MS. Twenty-four hours after the dose, compound 4 levels were below the guantification level.

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Table 4. Dose and Temporal Dependence on Plasma Concentration of Compound 4

<td rowspan="2">Dose (mg / kg / day)</td><td rowspan="2">Harvest Time (h)</td><td colspan="2">Cone. (μΜ)</td>

<td>Average</td><td>DP</td>

<td rowspan="2"> 1</td><td> 0,5</td><td> 0,0657</td><td> 0,0153</td>

<td> 2</td><td> 0,0485</td><td> 0,0200</td>

<td rowspan="2"> 3</td><td> 0,5</td><td> 0,250</td><td> 0,019</td>

<td> 2</td><td> 0,135</td><td> 0,059</td>

<td rowspan="2"> 10</td><td> 0,5</td><td> 0, 635</td><td> 0,053</td>

<td> 2</td><td> 0,670</td><td> 0,190</td>

<td rowspan="2"> 30</td><td> 0,5</td><td> 1,72</td><td> 0,15</td>

<td> 2</td><td> 1,10</td><td> 0,19</td>

Inhibition of arthritis by compound 4 was dose dependent, with a maximal effect (&gt; 95% inhibition) at dose levels of 10 and 30 mg / kg. The plasma concentrations of compound 4 which induced this maximal effect ranged from 0.61.7 μΜ to T_max (2 h) and did not need to be sustained at high levels for 24 hours to be effective, which is not surprising for an irreversible inhibitor. Based on sequence analysis and molecular modeling, it is proposed that the irreversible inhibitors described herein form a covalent bond with the Btk Cys 481 residue (e.g., the Michael reaction acceptor portion of the compounds described herein reacts with the residue Bys Cys 481). Based on sequence homology analysis (Figure 1), the compounds disclosed herein are also expected to act as irreversible kinase inhibitors with a Cys 481 residue or homologous cysteine ​​residue, but to reversibly bind to kinases with an amino acid different at position 481 within the sequence of a catalytic domain that is otherwise homologous to that of Btk. Take, for example, the sequences listed in Figure 1. See also tyrosine kinase (TK) sequence alignments published on the world wide web at kinase.com/human/kinome/phylogeny.html.

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Example 5: Inhibition of mast cell degranulation

Human CD34 + cells differentiated 9 weeks in culture in the presence of 50 ng / ml IL-6, 100 ng / ml SCF.

in mast cells per 1 ng / ml IL-3,

The cells were incubated with IgE + IL-4 for 4 days and was then degranulated induced. Degranulation hexosaminidase degranulation did not affect the Alamar assay by cross-linking with an anti-IgE. A was guantified using the compound's assay. The compound did not inhibit Ca ++ ionophore-induced ionomycin and cell viability as determined by Blue. Compound 4 has an IC50 in the lowest MC degranulation of 100 nanomolar. As such, the above-described compounds may be used for the treatment of inflammatory diseases such as asthma.

Example 6: Pharmaceutical Compositions:

The compositions described below are presented with a compound of Formula (A) for illustrative purposes; Any of the compounds of any one of Formula (A), Formula (B), Formula (C) or Formula (D) may be used in such pharmaceutical compositions.

Example 6a: Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable for injection, 100 mg of a water-soluble salt of a compound of Formula (A) is dissolved in DMSO and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into an appropriate dosage unit form for administration by injection.

Example 6b: Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mL of a compound of Formula (A) is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule, which is suitable for oral administration.

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Example 6c: Sublingual Composition (Hard Candies)

To prepare a buccal delivery pharmaceutical composition such as a hard candy, 100 mg of a compound of Formula (A) is mixed with 420 mg of mixed sugar powder, with 1.6 ml of light corn syrup, 2, 4 mL of distilled water and 0.42 mL of mint extract. The mixture is gently mixed and poured into a mold to form a candy suitable for buccal administration.

Example 6d: Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound of Formula (A) is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit such as a nebulizer which is suitable for administration by inhalation.

Example 6e: Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of a compound of Formula (A) is mixed with 2.5 g methylcellulose (1500 mPa), 100 mg methylparaben, 5 g glycerin and 100 ml purified water. The resulting gel mixture is then incorporated into rectal delivery units, such as syringes, which are suitable for rectal administration.

Example 6f: Topical Gel Composition

To prepare a topical gel pharmaceutical composition, 100 mg of a compound of Formula (A) is mixed with 1.75 g of hydroxypropylcellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified USP alcohol. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.

Example 6g: Ophthalmic Solution Composition

To prepare an ophthalmic solution pharmaceutical composition, 100 mg of a compound of Formula (A) is

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152 mixed with 0.9 g NaCl in 100 mL purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.