Inhibitors of Bruton's Tyrosine Kinase

[0001] Compounds, methods for preparing these compounds, pharmaceutical compositions and drugs containing these compounds, and methods for using these compounds and compositions for inhibiting tyrosine kinase activity are described herein.

BACKGROUND OF THE INVENTION [0002] Bruton tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, is a key signaling enzyme expressed in all hematopoietic cell types except T lymphocytes and natural cytotoxic (NK) cells. Btk plays a central role in the B cell signaling pathway combining stimulation of the surface cell B cell receptor with a cascade of intracellular responses.

[0003] Btk is a key regulator of B cell development, stimulation, activation, signaling and survival (Kurosaki, Curr Op Imm, 2000, 276-281; ​​Schaeffer and Schwartzberg, Curr Op Imm 2000, 282-288). In addition, Btk plays a role in many other hematopoietic cell signaling pathways, for example, in the production of TNF-α in macrophages stimulated by Toll like receptors (TLRs) and cytokine receptor, signal transduction by IgE receptor (FcepsilonRI) in mast cells, Fas / APO inhibition -1 apoptotic signal transduction in white blood cell B cells and collagen stimulated platelet aggregation. See, 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; lwaki 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 substituted pyrazolopyrimidines as tyrosine kinase inhibitors are disclosed in US 2004/006083.

SUMMARY OF THE INVENTION [0004] Bruton tyrosine kinase (Btk) inhibitors are described herein. Irreversible Btk inhibitors have also been described. In addition, irreversible Btk inhibitors have been described which form a covalent bond with the Btk cysteine ​​residue. In addition, irreversible inhibitors of other tyrosine kinases in which other tyrosine kinases share homology with Btk by possessing a cysteine ​​residue (including Cys 481 residues) are described so that they can form a covalent bond with an irreversible inhibitor (such as tyrosine kinases, referred to herein as "cysteine ​​homologues Btk tyrosine kinase "). Also described are methods of making such irreversible inhibitors, methods of using such irreversible inhibitors for the treatment of diseases (including diseases in which an irreversible Btk inhibitor provides a therapeutic benefit to a sick patient). In addition, pharmaceutical formulations containing an irreversible Btk inhibitor have been described.

[0005] A compound of formula (D) is described herein. Formula (D) is as follows:

<img file="PL2201840T3_D0001.tif" />

N

Ar in which:

La is CH2, O, NH or S;

<img file="PL2201840T3_D0002.tif" />

EP 2 201 840 B1

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

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

Z means C (= O), OC (= O), NHC (= O), C (= S), S (= O) x, OS (= O) x, NHS (= O) x, where x is 1 or 2;

R7 and R8 are independently selected from H, unsubstituted C1-C4alkyl, substituted C1-C4alkyl, unsubstituted C1-C4heteroalkyl, substituted C1-C4heteroalkyl, unsubstituted C3-C6cycloalkyl, substituted C3-C6cycloalkyl, unsubstituted C2-C6heterocycloalkyl and substituted or

R7 and R8 taken together form a bond;

R6 is H, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C1-C4heteroalkyl, C1-C6alkoxyalkyl, C1-C8alkylaminoalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8heterocycloalkyl, substituted or unsubstituted C1-C4alkyl (aryl),

C1-C4alkyl (heteroaryl), C1-C4alkyl (C3-C8cycloalkyl) or C1-C4alkyl (C2-C8 heterocycloalkyl); and pharmaceutically acceptable solvates or pharmaceutically acceptable salts thereof. Compounds of formula D in which R6 is H and R7 and R8 are H or taken together form a bond, are embodiments of the invention.

[0006] For each and all embodiments, substituents can be selected from a subset of the alternatives set forth. For example, in some embodiments, La is CH2, O or NH. In other embodiments, La is O or NH. In yet other embodiments, La is O.

[0007] In some embodiments, Ar is substituted or unsubstituted aryl. In yet other embodiments, Ar is a 6 membered aryl. In some other embodiments, Ar is phenyl.

[0008] In some embodiments, x is 2. In yet other embodiments, Z is C (= O), OC (= O), NHC (= O), S (= O) x, OS (= O) x or NHS (= O) x. In some other embodiments, Z is C (= O), NHC (= O) or S (= O) 2.

[0009] Compounds described herein are wherein R7 and R8 are independently selected from H, unsubstituted C1-C4 alkyl, substituted C1-C4alkyl, unsubstituted C1-C4heteroalkyl and substituted C1C4heteroalkyl; or R7 and R8 taken together form a bond. In one embodiment, each of R7 and R8 is H; or R7 and R8 taken together form a bond.

[0010] Compounds described herein, wherein R6 is H, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C1-C4heteroalkyl, C1-C6alkoxyalkyl, C1-C8alkylaminoalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C4alkyl (aryl) , C1-C4alkyl (heteroaryl), C1-C4alkyl (C3-C8cycloalkyl) or C1-C4alkyl (C2-C8 heterocycloalkyl). In some cases, R6 is H, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C1-C4heteroalkyl, C1-C6alkoxyalkyl, C1-C2alkyl-N (C1-C3alkyl) 2, C1-C4alkyl (aryl), C1-C4alkyl (heteroaryl) , C1-C4alkyl (C3-C8cycloalkyl) or C1-C4alkyl (C2-C8 heterocycloalkyl). In other examples, R6 is H, substituted or unsubstituted C1-C4alkyl, -CH2-O- (C1-C3alkyl), -CH2-N (C1-C3alkyl) 2, C1-C4alkyl (phenyl) or C1-C4alkyl (5 or 6- membered heteroaryl). In other examples, R6 is H, substituted or unsubstituted C1-C4alkyl, -CH2-O- (C1-C3alkyl), -CH2- (C1-C6alkylamino), C1-C4alkyl (phenyl) or C1-C4alkyl (5- or 6- membered heteroaryl). In some embodiments, R6 is H, substituted or unsubstituted C1-C4alkyl, -CH2-O- (C1-C3alkyl), -CH2-N (C1-C3alkyl) 2, C1-C4alkyl (phenyl) or C1-C4alkyl (5- or 6-membered heteroaryl containing 1 or 2 N atoms) or C1-C4alkyl (5- or 6-membered heterocycloalkyl containing 1 or 2 N atoms).

[0011] In some embodiments, Y is an optionally substituted group selected 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 7-membered cycloalkyl and 4-, 5-, 6- or 7-membered heterocycloalkyl. In yet other embodiments, Y is an optionally substituted group selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, 5- or 6-membered cycloalkyl, and 5- or 6-membered heterocycloalkyl containing 1 or 2 N atoms. In some other embodiments, Y is 5- or A 6 membered cycloalkyl or a 5- or 6-membered heterocycloalkyl containing 1 or 2 N. In some embodiments, Y is a 4-, 5-, 6-, or 7-membered cycloalkyl ring; or Y is a 4-, 5-, 6- or 7-membered heterocycloalkyl ring.

[0012] Any combinations of the groups described above for the various variables are described herein. It is understood that the substituents and examples of substitutions in the compounds provided herein can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and can be synthesized by using known methods in the art as well as those specified herein.

[0013] In one aspect, the invention provides a compound selected from the following:

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-1-yl) piperidin-1-yl) but-2-en-1- he (Compound 5); 1- (3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) sulfonylethene (Compound 6); 1- (3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-yn-1-one (Compound 8 ); 1- (4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3.4d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one (Compound 9) ; N - ((1s, 4s) -4- (4-amino-3- (4-phenoxyphenyl) 1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexyl) acrylamide (Compound 10); 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) prop-2-en-1- he (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- he (Compound 12); 1 ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1 -on (Compound 13); 1 - ((S) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1- he (Compound 14); and (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).

[0014] In a further aspect, the invention provides pharmaceutical compositions that comprise a therapeutically effective amount of at least one of any of the compounds of the invention, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof. In some embodiments, the compositions provided herein further include a pharmaceutically acceptable diluent, excipient and / or binder.

[0015] Pharmaceutical compositions provided for administration by an appropriate route and agents are provided comprising effective concentrations of one or more compounds provided herein providing an effective amount to treat, prevent or ameliorate one or more symptoms of the disease, disorder or condition1) that are modulated or otherwise treated with tyrosine kinase or mediated by tyrosine kinase. Effective amounts and concentrations are sufficient to alleviate any symptoms of any disease, disorder or condition disclosed herein. [0016] In some embodiments, the invention provides a pharmaceutical composition comprising: i) a pharmaceutically acceptable carrier, diluent and / or excipient; and ii) one or more compounds provided herein.

[0017] Described herein are methods for treating patients comprising administering a compound provided herein. Also described are methods of inhibiting the activity of tyrosine kinase (s), such as Btk, or treating diseases, disorders or conditions in which inhibition of tyrosine kinase (s), such as Btk, can be beneficial in a patient comprising administering to a patient a therapeutically effective amount of at least one of any of the compounds of the invention, or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate.

[0018] In one aspect, the invention provides a compound for inhibiting Bruton tyrosine kinase (Btk) activity or for treating a disease, disorder or condition in which inhibition of Bruton tyrosine kinase (Btk) activity can be benefited.

[0019] In some embodiments, the compounds of the invention are administered to a human.

[0020] In some embodiments, the compounds of the invention are administered orally.

[0021] In other embodiments, the compounds of the invention are used in the preparation of medicaments for inhibiting tyrosine kinase activity. In certain other embodiments, the compounds of the invention are used in the preparation of medicaments for inhibiting Bruton's tyrosine kinase (Btk) activity.

[0022] Manufactured articles include packaging materials, a compound or composition, or pharmaceutically acceptable derivatives of the invention that are effective for inhibiting the activity of tyrosine kinases (s), such as Btk, inside the packaging and an indication that indicates the compound or composition. or a pharmaceutically acceptable salt or pharmaceutically acceptable solvate, used to inhibit the activity of tyrosine kinase (s), such as Btk.

[0023] In another aspect, the invention relates to inhibited tyrosine kinases, including Bruton tyrosine kinase, Bruton tyrosine kinase homolog, or Btk tyrosine kinase homolog covalently linked to an inhibitor having the structure:

EP 2 201 840 B1

<img file="PL2201840T3_D0003.tif" />

wherein '^{/ vvv}'indicates the connection point between the inhibitor and the tyrosine kinase. In a further embodiment, the inibitor is covalently linked to a cysteine ​​residue tyrosine kinase.

[0024] Described herein is a method of inhibiting Bruton tyrosine kinase in a subject in need thereof by administering to that subject a composition comprising a therapeutically effective amount of at least one compound having a structure having one of the formulas selected from formula (A), formula (B), formula (C) or formula (D). The subject in need may suffer from autoimmune disease such as inflammation of the face, arthritis, systemic lupus, rheumatoid arthritis, psoriatic arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's disease, inflammation thyroid gland, Graves' disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, myoclonus and opsoclonia syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasturea syndrome, idiopathic purpura, optic neuritis, systemic sclerosis, cirrhosis, primary cholera syndrome Takayasua arteries, temporal arteritis, heat autoimmune hemolytic anemia, Wegener's granuloma, psoriasis, full body hair loss or absence, Behęet's disease, chronic fatigue syndrome, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, systemic sclerosis or vulvodynia.

[0025] The subject in need may suffer from a heteroimmunological condition or disease, for example, host immune response against transplantation, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis or atopic dermatitis.

[0026] A subject in need may suffer from an inflammatory disease, for example, asthma, appendicitis, eyelid inflammation, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, tear dermatitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epicondylitis, fasciitis, musculo-tendonitis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis cerebral myelitis, myocarditis, myositis, nephritis, ovary inflammation, orchitis, osteomyelitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebtitis, pneumonia, pneumonia, proctitis, proctitis, pyelonephritis, rhinitis, otitis, sinusitis, gangrene, synovitis, Achilles tendonitis, tonsillitis, uveitis, vaginitis, vasculitis or vulvitis.

[0027] In some cases, the needy suffers from cancer. The tumor may be a B cell proliferative disease, for example, spreading large B cell lymphoma, nodular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, chronic B cell prolymphocytic leukemia, lymphoplasmic lymphoma / Waldenstrom's macroglobulinemia, marginal zone lymphoma , plasmacytoma, extra-node lymphoma of the marginal zone, nodal lymphoma of the marginal zone, mantle zone cell lymphoma, large lymphoma primary mediastinum of large B cells, intravascular large B cell lymphoma, primary exudative lymphoma, Burkitt's lymphoma / leukemia or lymphoid granulomatosis. When a subject suffers from cancer, the drug may be administered in combination with one of the above compounds

Anti-cancer agent. For example, the cancer drug is a mitogen activated protein kinase inhibitor, for example, U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin or LY294002.

[0028] A subject in need may suffer from thromboembolic disorders, such as, for example, myocardial infarction, angina pectoris, angioplasty reocclusion, angioplasty recurrence after vasoconstriction, reocclusion after coronary artery bypass grafting, recurrence of aortic coronary artery stenosis bypass, stroke, transient ischemia, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis.

[0029] Described herein is a method of treating autoimmune diseases comprising administering to a subject in need a composition comprising a therapeutically effective amount of at least one compound having a structure of any formula selected from formula (A), formula (B), formula (C) or formula (D). An autoimmune disease can be arthritis. In another case, autoimmune disease is systemic lupus. In some cases, the autoimmune disease is enteritis (including Crohn's disease and ulcerative colitis), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, arthritis, Still's disease, juvenile arthritis, systemic lupus, diabetes, myasthenia gravis, Hashimoto's disease, Ord's thyroiditis, Graves's disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, myoclonus and opsoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic purpura, optic neuritis, systemic sclerosis primary biliary, Reiter's syndrome, Takayasua arteritis, temporal arteritis, heat autoimmune hemolytic anemia, Wegener's granuloma, psoriasis, loss of or lack of hair all over the body, Behęet's disease, chronic fatigue syndrome, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, systemic sclerosis or vulvodynia.

[0030] Also described herein is a method of treating a heteroimmunological condition or disease by administering to a subject in need a composition comprising a therapeutically effective amount of at least one compound having a structure of any formula selected from Formula (A), Formula (B), Formula (C) or Formula (D ). The heteroimmunological condition or disease may, for example, be a host immune response against transplantation, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis or atopic dermatitis.

[0031] Described herein is a method of treating an inflammatory disease comprising administering a composition comprising a therapeutically effective amount of at least one compound having a structure of any formula selected from formula (A), Formula (B), Formula (C) or Formula (D). The inflammatory disease can be asthma, enteritis (Crohn's disease and ulcerative colitis), appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis. , conjunctivitis, cystitis, tear dermatitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, supranitis, fasciitis, musculo-tendonitis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis meningitis, myelitis, myocarditis, myositis, nephritis, ovary inflammation, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, pneumonia, proctitis, proctitis, pyelonephritis, rhinitis, trumpitis auditory disease, sinusitis, gangrene, synovitis, Achilles tendonitis, tonsillitis, uveitis, vaginitis, vasculitis or vulvitis.

[0032] Described herein is a method of treating cancer comprising administering to a subject in need a composition comprising a therapeutically effective amount of at least one compound having a structure of any formula selected from Formula (A), Formula (B), Formula (C) or Formula (D). In one example, the cancer is a B cell proliferative disease, such as, for example, large B cell spreading lymphoma, nodular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, chronic B cell prolymphocytic leukemia, lymphoplasmic lymphoma / Waldenstrom's macroglobulinemia, lymphoma zone , plasma cell myeloma, plasmacytoma, extra-node marginal zone lymphoma, nodal marginal zone lymphoma, mantle zone cell lymphoma, primary large B cell mediastinal lymphoma, intravascular large B cell lymphoma, primary exudative lymphoma, Burkitt's lymphoma / leukemia or lymphoid granulomatosis. In some cases, when a subject suffers from cancer, an anti-cancer agent is administered to the subject in combination with the above-mentioned compounds. In one case, the anti-cancer agent is an inhibitor of mitogen activated protein kinase, for example,

EP 2 201 840 B1

U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin or LY294002.

[0033] Described herein is a method of treating thromboembolic disorders comprising administering to a subject in need a composition comprising a therapeutically effective amount of at least one compound having a structure of any formula selected from Formula (A), Formula (B), Formula (C) or Formula (D) . Thromboembolism may include myocardial infarction, angina pectoris, angioplasty after angioplasty, recurrence of vasoplasty after angioplasty, rheocele after aorto-coronary artery bypass grafting, recurrence of narrowing after aortic-coronary artery bypass grafting, stroke, transient ischemia, peripheral arterial occlusive disease. pulmonary embolism or deep vein thrombosis.

[0034] Also described herein is a method of treating an autoimmune disease comprising administering to a subject in need a composition comprising a therapeutically effective amount of a compound forming a covalent bond with Bruton's tyrosine kinase. In one embodiment, the compound forms a covalent bond with an activated form of Bruton's tyrosine kinase. In a further alternative embodiment, the compound irreversibly inhibits Bruton's tyrosine kinase, to which it is covalently bound. In a further or alternative embodiment, the compound forms a covalent bond with a cysteine ​​residue on Bruton's tyrosine kinase.

[0035] A method of treating a heteroimmunological condition or disease is described herein comprising administering to a subject in need a composition comprising 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's tyrosine kinase. In further or alternative embodiments, the compound irreversibly inhibits Bruton's tyrosine kinase, to which it is covalently bound. In a further or alternative embodiment, the compound forms a covalent bond with a cysteine ​​residue on Bruton's tyrosine kinase.

[0036] Also described herein is a method of treating an inflammatory disease comprising administering to a subject in need a composition comprising 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's tyrosine kinase. In further or alternative embodiments, the compound irreversibly inhibits Bruton's tyrosine kinase, to which it is covalently bound. In a further or alternative embodiment, the compound forms a covalent bond with a cysteine ​​residue on Bruton's tyrosine kinase. In yet another aspect, the invention provides a composition comprising a therapeutically effective amount of a compound that forms a covalent bond with Bruton's tyrosine kinase for treating cancer. In one embodiment, the compound forms a covalent bond with the activated form of Bruton's tyrosine kinase. In further or alternative embodiments, the compound irreversibly inhibits Bruton's tyrosine kinase, to which it is covalently bound. In a further or alternative embodiment, the compound forms a covalent bond with a cysteine ​​residue on Bruton's tyrosine kinase. Described herein is a method of treating thromboembolic disorders comprising 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's tyrosine kinase. In further or alternative cases, the compound irreversibly inhibits Bruton's tyrosine kinase, to which it is covalently bound. The compound may form a covalent bond with a cysteine ​​residue on Bruton's tyrosine kinase.

[0037] Described herein are methods for modulating, including irreversibly inhibiting the activity of Btk or other tyrosine kinases, wherein other tyrosine kinases share homology with Btk by having a cysteine ​​residue (including Cys 481 residue) so that they can form a covalent bond with at least one irreversible an inhibitor disclosed herein, in a mammal comprising administering to the mammal at least once an effective amount of at least one compound having a structure of any formula selected from formula (A), Formula (B), Formula (C) or Formula (D). Modulating methods are disclosed, 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 a structure of any formula selected from Formula (A), Formula (B), Formula (C) or Formula (D ). Disclosed are methods of treating conditions or diseases mediated by Btk or mediated by Btk, comprising administering to the mammal at least once an effective amount of at least one compound having a structure of any formula selected from Formula (A), Formula (B), Formula (C) or Formula (D).

[0038] Also disclosed are methods of treating inflammation comprising administering to the mammal at least once an effective amount of at least one compound having a structure of any formula selected from formula (A), (B), (C) or (D).

[0039] Also described herein are methods of treating cancer comprising administering to the mammal at least once an effective amount of at least one compound having a structure of any formula selected from formula (A), (B), (C) or (D). The type of cancer may include, but is not limited to, pancreatic cancer and other solid or hematological tumors.

[0040] Also described herein are methods of treating respiratory diseases comprising administering to the mammal at least once an effective amount of at least one compound having a structure of any formula selected from formula (A), (B), (C) or (D). Respiratory disease can be

Asthma. Respiratory diseases may include, but are not limited to, adult acute stress respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (congenital) asthma, acute severe asthma, chronic asthma, clinical asthma, acute asthma, allergen-induced asthma, aspirin sensitive asthma , exercise-induced asthma, hyperventilation, childhood onset asthma, adult onset asthma, cough asthma, occupational asthma, steroid-resistant asthma, seasonal asthma.

[0041] Methods for preventing rheumatoid arthritis and osteoarthritis are disclosed comprising administering to a mammal at least once an effective amount of at least one compound having a structure of any formula selected from formula (A), (B), (C) or (D).

[0042] Also disclosed are methods of treating an inflammatory skin response comprising administering to a mammal at least once an effective amount of at least one compound having a structure of any formula selected from 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 and organs are disclosed, comprising administering to a mammal an effective amount of a first compound having a structure of any formula selected from formula (A), (B), (C) or (D).

[0043] Described herein is the use of a compound of formula (A), (B), (C) or (D) in the manufacture of a medicament for the treatment of an inflammatory disease or condition in an animal in which the activity of Btk or other tyrosine kinases, wherein other tyrosine kinases share homology with Btk by having a cysteine ​​residue (including Cys 481 residue) so that they can form a covalent bond with at least one irreversible inhibitor disclosed herein, contributes to the pathology and / or symptoms of the disease or condition. The protein tyrosine kinase may be Btk. The inflammatory disease or condition may be respiratory, cardiovascular or proliferative diseases.

[0044] Administration may be by enteral or parenteral route or both, and in which (a) (a) an effective amount of the compound is administered systemically to the mammal; (b) an effective amount of the compound is administered orally to the mammal; (c) an effective amount of the compound is administered to the mammal intravenously; (d) an effective amount of the compound is administered by inhalation; (e) an effective amount of the compound is administered to the nose; or (f) an effective amount of the compound is administered to an mammal by injection; (g) an effective amount of the compound is administered to the mammal topically (through the skin); (h) an effective amount of the compound is administered by the onamic route; or (i) an effective amount of the compound is administered to the mammal rectally.

[0045] Described herein is a separate administration of an effective amount of a compound in which (i) the compound is administered once; (ii) the compound is administered to the mammal repeatedly during one day; (iii) continually; or (iv) continuously.

[0046] Multiple administration of an effective amount of a compound is described herein wherein (i) the compound is administered in a single dose; (ii) the time between repeated administrations is 6 hours; (iii) the compound is administered to the mammal every 8 hours. The method may comprise a drug withdrawal period during which administration of the compound is temporarily suspended or the dose of the compound administered is temporarily reduced; at the end of the drug withdrawal period, dosing of the compound resumes. The withdrawal period may vary from 2 days to 1 year.

[0047] Described herein is the treatment of proliferative diseases, including cancer, comprising the administration of an additional agent selected from the group consisting of alemtuzumab, arsenic trioxide, asparaginase (pegylated or non-), bevacizumab, cetuximab, platinum-based compounds such as cisplatin, cladribine, daunorubicin / doxorubicin / idarubicin, irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate, Paclitaxel ™, taxol, temozolomide, thioguanine or a class of drugs including hormones (anti-estrogen, antiandrogen or gonadotropin analogues, interferons such as alpha interferon, nitrogen mustards such as busulfan or melphalan or mechlorethamine, retinoids such as tretinoin, topoisomerase inhibitors such as irinotecan or topotecanone inhibitors imatinib or agents for the treatment of signs and symptoms caused by such therapy including allopurinol, filgrastim, granisetron / ondansetron / palonosetron, dronabinol.

[0048] Patient identification by monitoring the tyrosine kinase gene haplotype is also described herein. The tyrosine kinase gene haplotype may be the tyrosine kinase gene pathway or the Btk haplotype.

[0049] Compounds of formula (A), (B), (C) or (D) may be irreversible inhibitors of Bruton tyrosine kinase (Btk). Such irreversible inhibitors may be selective for Btk. Such inhibitors may have an IC 50 below 10 microM in the enzymatic activity assay. An irreversible Btk inhibitor is disclosed that exhibits an IC50 of less than 1 microM, for example less than 0.25 microM.

[0050] The compounds of formula ((A), (B), (C) or (D) that are selective and irreversible inhibitors for Btk better than for ltk are disclosed. The compounds of formula (A), (B) are also disclosed ( C) or (D) which are selective irreversible inhibitors for Btk better than for Lck. Compounds of formula (A), (B), (C) or (D) are disclosed which are selective irreversible inhibitors for Btk better than for ABL . The compound of formula (A), (B), (C) or (D) may be a selective irreversible inhibitor for Btk better than for CMET. The compound of formula (A), (B), (C) or (D) may be a selective irreversible inhibitor for Btk better than for

EP 2 201 840 B1

EGFR. The compound of formula (A), (B), (C) or (D) may be a selective irreversible inhibitor for Btk better than for Lyn.

[0051] Irreversible Btk inhibitors may also be EGFR inhibitors.

[0052] Other objects, features and benefits of the methods and compositions disclosed herein will become apparent in the context of the following detailed description. The detailed description and specific examples are given only to illustrate the invention.

Section headers are for organizational purposes only and are not intended to limit the subject matter.

Selected terminology [0053] Unless otherwise specified, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which the subject of the present invention belongs. In the event of different definitions, the ones in this section apply. If the links are given according to the URL system or other such identifiers or addresses, it is understood that such identifiers may change and detailed information on the internet can be updated or deleted, but equivalent information can be found by searching the internet. The links provided here attest to the availability and public dissemination of such information.

[0054] It is understood that the following general description and detailed description are exemplary and explanatory only and do not constitute a limitation on any of the objects of the present disclosure. In this application, the use of the singular includes the plural, unless specifically stated otherwise. It should be noted that in the description and in the appended claims, singular designators also refer to the plural, unless the context expressly indicates otherwise. In this application, the use of the term "or" means "and / or" unless otherwise indicated. In addition, the term 'including', like other forms, is 'include', 'includes' and 'covered' not a limiting term.

[0055] The section headings are given here for organizational purposes only and are not intended to limit the subject matter of the invention described. All documents and parts of documents cited in this application, including but not limited to patents, patent applications, articles, books, textbooks and scientific papers are specifically included as references in their entirety for any purpose.

[0056] Definitions of standard chemical terms can be found in reference works, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology methods are used according to average skill in the art. Unless specific terms are provided, the relevant nomenclature for laboratory technique and procedure, analytical chemistry, synthesis of organic chemistry, and medical and pharmaceutical chemistry is known in the art. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical preparations, formulation preparation, administration and treatment of patients. Standard techniques can be used for recombination DNA, oligonucleotide synthesis and organ culture and transformations (e.g., electroporation, lipofection). Reactions and purification techniques can be carried out, for example, using kits from commercial listings or as customarily performed in the art or as described herein. The above techniques and procedures may generally be carried out according to customary methods well known in the art or as described in various general and more detailed references that are cited or discussed in this specification.

[0057] It is understood that the methods and compositions described herein are not limited to the specific methodology, rules of procedure, cell lines, constructs and reagents described herein and may be different. It is also understood that the terminology used herein is only for the purpose of describing specific embodiments and is not intended to limit the scope of methods and compositions that are limited only by the scope of the appended claims.

[0058] The term "alkyl" refers to an aliphatic hydrocarbon group. The alkyl moiety may be a "saturated alkyl" group, which means it does not contain any alkene or alkyne moieties. The alkyl moiety may also be an "unsaturated alkyl" moiety, which means it contains at least one alkene or alkyne moiety. The "alkene" moiety refers to a group that has at least one carbon-carbon double bond, the term "alkyne" refers to a group that has at least one carbon-carbon triple bond. The alkyl moiety, when saturated or unsaturated, can be branched, straight or cyclic. Depending on the structure

The alkyl group may be a monoradical or a diradical (i.e., an alkylene group). The alkyl group may be "lower alkyl" having 1 to 6 carbon atoms.

[0059] As used herein, C1-Cx includes C1-C2, C1-C3 ... C1-Cx.

[0060] An "alkyl" moiety may have 1 to 10 carbon atoms (whenever a numeric range such as "1 to 10" occurs here refers to any integer in the range given; for example, "1 to 10 carbon atoms" means that alkyl has 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although this definition also includes the term "alkyl" where the number range is not indicated). The alkyl group in the compounds disclosed herein may be designated "C1-C4 alkyl" or the like. For example, "C1-C4 alkyl" indicates that one to four carbon atoms exist in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl hydroperoxide. Thus, C1-C4 alkyl includes C1-C2 alkyl and C1-C3 alkyl. Alkyl groups can 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 the like.

[0061] As used herein, the term "non-cyclic alkyl" refers to alkyl that is not cyclic (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 be optionally substituted.

[0062] 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. That is, the alkenyl group begins with -C (R) = C (R) -R, where R refers to the remaining parts of the alkenyl group that may be the same or different. The alkenyl moiety may be a branched, straight chain or cyclic (in which case it may be called a "cycloalkenyl" group). Depending on the structure, the alkenyl group can be monoradical or diradical (i.e., alkenylene). Alkenyl groups may be optionally substituted. Non-limiting examples of alkenyl groups 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 can have 2 to 10 carbon atoms. Alkenyl groups can be "lower alkenyls" having 2 to 6 carbon atoms.

[0063] 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, the alkynyl group begins with -C = CR, where R refers to the remaining parts of the alkynyl group that can be the same or different. The "R" portion of the alkynyl moiety may be branched, straight chain or cyclic. Depending on the structure, the alkynyl group can be monoradical or diradical (i.e., alkynylene). Alkynyl groups may be optionally substituted. Non-limiting examples of alkynyl groups include, but are not limited to, -Cech, -ChCCH₃, -ChCCH₂CH₃, -ChC- and -CeCCH₂-. Alkynyl groups may have 2 to 10 carbon atoms. Alkynyl groups may be "lower alkynyls" having 2 to 6 carbon atoms. [0064] The term "alkoxy" refers to the group (alkyl) O-, wherein alkyl is as defined above. [0065] The term "hydroxyalkyl" refers to an alkyl radical, as defined herein, substituted with at least one hydroxy group. Non-limiting examples of hydroxyalkyl include hydroxymethyl,

2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl,

3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1- (hydroxymethyl) -2-hydroxyethyl,

2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl.

[0066] The term "alkoxyalkyl" refers to an alkyl radical, as defined herein, substituted with an alkoxy group, as defined herein.

[0067] The term "alkenyloxy" refers to the group (alkenyl) O-, wherein alkenyl is as defined herein.

[0068] The term "alkylamine" refers to the group -N (alkyl) xHy, where x and y are selected from x = 1, y = 1 and x = 2, y = 0. When x = 2, the alkyl groups together with the N atom to which they are attached may optionally form a cyclic ring system.

[0069] The term "alkylaminoalkyl" refers to an alkyl radical, as defined herein, substituted with an alkylamine, as defined herein.

[0070] The term "amide" means a chemical moiety of the formula -C (O) NHR or -NHC (O) R, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (carbon bonded ring) and heteroalicyclic (bonded via ring carbon). The amide moiety may form a bond between the amino acid or peptide molecule and the compound described herein to form a prodrug. Any amine or

A carboxy group in a chain in a compound disclosed herein may be subject to amidation. Procedures and specific groups for obtaining such amides are known to the skilled artisan and can easily be found in reference references such as Greene and Wuts, Protective Grups in Organic Synthesis, 3rd Ed., John Wiley &amp; Sons, New York, NY, 1999.

[0071] The term "ester" refers to a chemical moiety of the formula -COOR, where R is selected from alkyl, cycloalkyl, aryl, heteroaryl (carbon-bonded ring and heteroalicyclic (carbon-bonded ring). Any hydroxyl or carboxyl group anywhere the chain in the compounds disclosed herein can be esterified. Procedures and specific groups for obtaining such esters are known to the person skilled in the art and can easily be found in reference references such as Greene and Wuts, Protective Grups in Organic Synthesis, 3rd Ed., John Wiley &amp; Sons, New York, NY, 1999.

[0072] As used herein, the term "ring" refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatic rings (e.g., aryls and heteroaryls), and non-aromatic rings (e.g., cycloalkyl and non-aromatic heterocycles). The rings may be optionally substituted. The rings can be monocyclic or polycyclic.

[0073] As used herein, the term "ring system" refers to one or more than one ring.

[0074] The term "membered ring" may refer to any cyclic structure. The term "membered" is intended to indicate 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.

[0075] The term "fused" refers to structures in which two or more rings share one or more bonds.

[0076] The term "carbocyclic" or "carbocycle" refers to a ring in which each of the atoms forming the ring is a carbon atom. Carbocycle includes aryl and cycloalkyl. The term therefore distinguishes a carbocycle from a heterocycle ("heterocycle") in which the ring backbone contains at least one atom that is different from a carbon atom (i.e., a heteroatom). Heterocycles include heteroaryls and heterocycloalkyls. Carbocycles and heterocycles can be optionally substituted.

[0077] The term "aromatic" refers to a flat ring having a delocalized π electron system containing 4n + 2 π electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine or more than nine atoms. The aromatic rings may be optionally substituted. The term "aromatic" includes both carbocyclic aryl groups (e.g., phenyl) and heterocyclic aryl groups (or "heteroaryls" or "heteroaromatics") (e.g. pyridine). The term includes monocyclic or fused polycyclic ring (i.e., rings that share common adjacent pairs of carbon atoms).

[0078] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. Aryl rings can be formed from five, six, seven, eight, nine or more than nine carbon atoms. Aryl groups may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, phenantrenyl, anthracenyl, fluorenyl and indenyl. Depending on the structure, the aryl group can be monoradical or diradical (i.e., arylene).

[0079] The term "aryloxy" refers to the group (aryl) O-, where aryl is as defined herein.

[0080] The term "aralkyl" means an alkyl radical, as defined herein, substituted with an aryl group. Without limitation, aralkyl groups include benzyl, phenethyl and the like.

[0081] The term "aralkenyl" means an alkenyl radical, as defined herein, substituted with an aryl group, as defined herein.

[0082] The term "cycloalkyl" refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and can be saturated, partially unsaturated, and completely unsaturated. Cycloalkyl groups can have from 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include the following moieties:

Λ.π&gt;, Α.οοΌο&gt;. □ 0.0 · OO CO

EP 2 201 840 B1

<img file="PL2201840T3_D0004.tif" />

and similar. Depending on the structure, the cycloalkyl group may be monoradical or diradical (e.g. cycloalkylene). The cycloalkyl group may be a "lower cycloalkyl" having 3 to 8 carbon atoms.

[0083] The term "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.

[0084] The term "heterocycle" refers to heteroaromatic and heteroalicyclic groups containing one to four heteroatoms, each selected from O, S and N, in which each heterocyclic group has from 4 to 10 atoms in the ring system, and provided that the ring this group does not contain two adjacent O or S. In this specification, whenever the number of carbon atoms in a heterocycle (e.g., C1-C6 heterocycle) is indicated, at least one other atom (heteroatom) must be present in the ring. A designation such as "C1-C6 heterocycle" only refers to the number of ring carbon atoms and does not refer to the total number of ring atoms. It is understood that the heterocylic ring may contain additional ring heteroatoms. A designation such as "4-6 membered heterocycle" refers to the total number of atoms contained in a ring (ie, a four, five or six membered ring in which at least one atom is a carbon atom, at least one atom is a heteroatom and the others two to four atoms are carbon or heteroatoms). In heterocycles having two or more heteroatoms, these two or more heteroatoms may be the same or different. Heterocycles can be optionally substituted. The bond to the heterocycle can be via a heteroatom or via a carbon atom. Non-aromatic heterocyclic groups include groups having only 4 atoms in the ring system, but heterocyclic aromatic groups must have at least 5 atoms in the ring system. Heterocyclic groups include benzene ring fused ring systems. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl. An example of a 6-membered heterocyclic group is pyridyl and for example a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidine, morpholino, thiomorpholine, thioxanyl, piperazinyl, azetidinyl, octyanynyl, octyanyl , 3,6-tetrahydropyridinyl, 2-pyrolinyl, 3-pyrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithanyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzimurazolyl , pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. The above groups are derived from the groups mentioned above, they can be C-attached or N-attached if possible. For example, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). In addition, the group derived from imidazole may be imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached) . Heterocyclic groups include benzo-fused ring systems and a ring system substituted with one or two oxo (= O) moieties such as pyrrolidin-2-one. Depending on the structure, the heterocyclic group may be a monoradical or a diradical (i.e., a heterocyclic group).

[0085] The terms "heteroaryl" or, alternatively, "heteroaromatic" refer to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen or sulfur. An "heteroaromatic" or "heteroaryl" containing N group 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 moieties:

<img file="PL2201840T3_D0005.tif" />

EP 2 201 840 B1

<img file="PL2201840T3_D0006.tif" />

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

[0086] As used herein, the term "non-aromatic heterocycle", "heterocycloalkyl" or "heteroalicyclic (s)" refers to a non-aromatic ring in which one or more of the atoms forming the ring is a heteroatom. The term "non-aromatic heterocycle" or "heterocycloalkyl" refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen or sulfur. Radicals can be condensed with aryl or heteroaryl. Heterocycloalkyl rings can be formed from three, four, five, six, seven, eight, nine or more than nine atoms. Heterocycloalkyl rings may be optionally substituted. In some embodiments, non-aromatic heterocycles contain one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups. Examples of heterocycloalkyls include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxine, 1,4 -dioxane, piperazine, 1,3-oxatate, 1,4-oxatin, 1,4-oxatate, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine , hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidion, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxol, 1,3-dioxolane, 1,3-dithiol, 1,3-dithiolane, isoxazoline, isoxazolidine, oxo oxazolidine, oxazolidinone, thiazoline, thiazolidine and 1,3-oxathiolane. Illustrative examples of heterocycloalkyl groups also depicted as non-aromatic heterocycles include:

<img file="PL2201840T3_D0007.tif" />

and similar. The term heteroalicyclic also includes all hydrocarbon ring forms, including but not limited to monosaccharides, disaccharides and oligosaccharides. Depending on the structure, the heterocycloalkyl group may be monoradical or diradical (such as a heterocycloalkylene group). [0087] The term "halo" or, alternatively, "halogen" or "halogen" means fluoro, chloro, bromo and iodo. [0088] The term "haloalkyl," "haloalkenyl," "haloalkynyl" and "haloalkoxy" includes alkyl, alkenyl, alkynyl and alkoxy structures in which at least one hydrogen atom is replaced by a halogen atom. In some embodiments in which two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms are all the same or different. In other embodiments in which two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms are not all the same. [0089] The term "fluoroalkyl," as used herein, refers to an alkyl group in which at least one hydrogen atom is replaced by a fluorine atom. Examples of fluoroalkyl groups include, but are not limited to,

-CF3, -CH2CF3, -CF2CF3, -CH2CH2CF3 and the like.

[0090] As used herein, the terms "heteroalkyl" "heteroalkenyl" and "heteroalkynyl" include optionally substituted alkyl, alkenyl and alkynyl radicals in which one or more of the chain backbone atoms is a heteroatom, e.g. oxygen, nitrogen, sulfur, silicon, phosphorus or combinations thereof (combinations). The heteroatom (s) can be located in any position within the heteroalkyl group or in a position where the group

Heteroalkyl 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-CH2-NH-CH3, -CH2-N (CH3) -CH3, -CH2- CH2-NH-CH3,

-CH2-CH2-N (CH3) -CH3, -CH2-S-CH2-CH3, - CH2-CH2, -S (O) -CH3, -CH2-CH2-S (O) 2-CH3, -CH = CH-O-CH3, -Si (CH3) 3, -CH2-CH = N-OCH3 and -CH = CH-N (CH3) -CH3. In addition, two atoms can be sequentially, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si (CH3) 3.

[0091] The term "heteroatom" refers to an atom other than carbon or hydrogen. Heteroatoms are usually independently selected from oxygen, sulfur, nitrogen, silicon and phosphorus, but are not limited to these atoms. In embodiments in which there are two or more heteroatoms, two or more heteroatoms may be all the same or some or each of two or more heteroatoms may be different from the others.

[0092] The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties when the atoms connected by the bond are considered to be part of a larger substructure.

[0093] The term "isocyanate" refers to the group -NCO.

[0094] The term "isothiocyanate" refers to the group -NCS.

[0095] The term "moiety" refers to a specific part or functional group of a molecule. Chemical moieties are often recognized as chemical units embedded in or attached to a molecule.

[0096] The term "sulfinyl" refers to -S (= O) -R.

[0097] The term "sulfonyl" refers to -S (= O) 2-R.

[0098] The term "thioalkoxy" or "alkylthiol" refers to a -S-alkyl group.

[0099] The term "alkylthioalkyl" refers to an alkyl group substituted with a -Salkyl group.

[0100] As used herein, the term "O-carboxy" or "acyloxy" refers to groups of the formula RC (= O) O-.

[0101] The term "carboxy" means the -C (O) OH radical.

[0102] As used herein, the term "acetyl" refers to a group of formula -C (= O) CH3.

[0103] The term "acyl" refers to the group -C (O) R.

[0104] As used herein, the term "trihalomethanesulfonyl" refers to a group of formula X3CS (O) 2 where X is halogen.

[0105] As used herein, the term "cyano" refers to a group of formula -CN.

[0106] The term "cyanoalkyl" means an alkyl radical, as defined herein, substituted with at least one cyano group.

[0107] As used herein, the term "N-sulfonamido" or "sulfonylamino" refers to groups of the formula RS (= O) 2NH-.

[0108] As used herein, the term "O-carbamyl" refers to a group of formula -OC (= O) NR2.

[0109] As used herein, the term "N-carbamyl" refers to a group of formula ROC (= O) NH-.

[0110] As used herein, the term "O-thiocarbamyl" refers to a group of formula -OC (= S) NR2.

[0111] As used herein, the term "N-thiocarbamyl" refers to a group of formula ROC (= S) NH-.

[0112] As used herein, the term "C-amido" refers to a group of formula -C (= O) NR2.

[0113] The term "aminocarbonyl" refers to the -CONH2 radical.

[0114] As used herein, the term "N-amido" refers to a group of formula RC (= O) NH-.

[0115] As used herein, the term "R" occurring as such or without a reference number refers to a substituent selected from alkyl, cycloalkyl, aryl, heteroaryl (ring-linked carbon) and a non-aromatic heterocycle (ring-linked carbon).

[0116] The term "optionally substituted" or "substituted" means that the reference group may be substituted by one or more additional group (s) 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 di-substituted amino and protected derivatives thereof. Examples of optional substituents may be: LsRs, where each Ls 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-,

- (substituted or unsubstituted C 1 -C 6 alkyl) or - (substituted or unsubstituted C 2 -C 6 alkenyl); and each Rs is independently selected from H, (substituted or unsubstituted C1-C4alkyl), (substituted or unsubstituted C3-C6cycloalkyl), heteroaryl or heteroalkyl. Protecting groups that can form protected derivatives of the above substituents are known to the person skilled in the art and can be found in references such as Greene and Wuts, supra. [0117] 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 part of the Michael acceptor moiety and the donor moiety. The Michael acceptor moiety is an electrophile and the "donor moiety" is a nucleophile. The "G" groups present in any compound of formula (A), Formula (B) or Formula (C) are non-limiting examples of Michael acceptor moieties.

[0118] The term "nucleophile" or "nucleophilic" refers to compounds or electron rich moieties thereof. For example, the nucleophile is, but is not limited to, a cysteine ​​residue of the molecule, for example Cys 481 in Btk.

[0119] The term "electrophile" or "electrophilic" refers to a molecule or electron-deficient or electron deficient moiety thereof. For example, electrophiles include, but are not limited to, Michael acceptor moieties.

[0120] The term "acceptable" or "pharmaceutically acceptable", when used in reference to a preparation, composition or ingredient as used herein, means not showing any permanent adverse health effects on the subject being treated or those that abolish the biological activity or properties of the compound or relatively toxic effects.

[0121] As used herein, the term "agonist" refers to a compound whose presence induces the same biological protein activity as the biological activity of a protein caused by the presence of a naturally occurring protein ligand, such as, for example, Btk.

[0122] As used herein, the term "partial agonist" refers to a compound whose presence induces a biological activity of a protein that is of the same type as caused by the presence of a naturally occurring protein ligand, but to a lesser extent.

[0123] As used herein, the term "antagonist" refers to a compound whose presence causes a decrease in the degree of biological activity of a protein. In some embodiments, the presence of the antagonist causes complete inhibition of the biological activity of the protein, such as, for example, Btk. In some embodiments, the antagonist is an inhibitor.

[0124] As used herein, the term "alleviating" the symptoms of a particular disease, disorder or condition by administering a specific compound or pharmaceutical composition refers to reducing the severity, delaying onset, slowing of progress, or shortening of duration, whether permanently or temporarily, stable or for a short time, which may be assigned to or associated with the administration of the compound or composition.

[0125] The term "bioavailable" refers to the weight percent of the compound disclosed herein, such as a compound of any formula (A), Formula (B), Formula (C) or Formula (D), so that it is provided into the circulatory system of the animal or human being examined. Total exposure (AUC₀ &lt;_:) per drug when administered intravenously is usually determined as 100% bioavailability (F%). "Oral bioavailability" refers to the extent of absorption of a compound disclosed herein, such as a compound of any formula (A), Formula (B), Formula (C) or Formula (D), in the circulatory system when the com position is taken orally compared to intravenous injections.

[0126] The term "plasma concentration" refers to the concentration of compounds disclosed herein, such as compounds of any formula (A), Formula (B), Formula (C) or Formula (D), in plasma as a blood component in entity. It is understood that the plasma concentration of compounds of formula (A), Formula (B), Formula (C) or Formula (D) may vary significantly by subject, due to different metabolism and / or possible interactions with other therapeutic agents. According to one embodiment disclosed herein, the plasma concentration of compounds of any formula (A), Formula (B), Formula (C) or Formula (D) may be different for different subjects. Similarly, values ​​such as maximum plasma concentration (Cmax) or time to maximum plasma concentration (Tmax) or total area under the plasma concentration versus time curve (auC (₀_ ")) May be different for different entities. Because of these differences, the amount needed that is the "therapeutically effective amount" of a compound of any formula (A), Formula (B), Formula (C) or Formula (D) may vary for different entities.

[0127] The term "Bruton tyrosine kinase," as used herein, refers to Bruton tyrosine kinase from Homo sapiens, as disclosed, for example, in US Patent US 6,326,469 (GenBank Accession No. NP_000052).

[0128] The term "Bruton tyrosine kinase homolog," as used herein, refers to Bruton tyrosine kinase orthologists, for example, orthologs derived from mice (GenBank Acession No. AAB47246), dog (GenBank Acession No. XP_549139.), Rat (GenBank Acession No. NP_001007799), chicken (GenBank Acession No. NP_989564) or zebrafish (zebra fish) (GenBank Acession No. XP_698117), and fusion proteins of any of the previous ones which have kinase activity on one or more Bruton tyrosine kinase substrates (for example, a peptide substrate having the amino acid sequence "AVLESEEELYSSARQ").

[0129] The terms "co-administration" or similar, as used herein, mean the administration of selected therapeutic agents to one patient, and are intended to include modes of treatment in which the agents are administered by the same or different route, or at the same or different times.

[0130] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient amount of an agent or compound being administered that to some extent relieves one or more symptoms of the disease, disorder or condition being treated. The result may be reduction and / or relief of signs, symptoms or effects of the disease, or any other improvement in the biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition containing a compound as disclosed herein required to provide a clinically significant reduction in disease symptoms without

Excessive undesirable side effects. The appropriate "effective amount" in any particular case may be determined using techniques such as dose escalation studies. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. The "effective amount" of a compound disclosed herein is an amount effective to achieve the desired pharmacological effect or therapeutic improvement without undue undesirable side effects. It is understood that the "effective amount" or "therapeutically effective amount" may be different for different subjects due to differences in the metabolism of a compound of any formula (A), Formula (B), Formula (C) or Formula (D), age , body weight, general condition of the subject, severity of the condition being treated and assessment of the treating physician. For example, therapeutically effective amounts can be determined experimentally, including without limitation clinical dose escalation.

[0131] The terms "enhance" or "enhance" mean improvement or extension of either potency or duration of the desired effect. For example, "enhancing" the result of a therapeutic agent refers to the ability to improve or extend or potency, or the duration of the result of a therapeutic agent during the treatment of a disease, disorder or condition. The term "enhancing effective amount," as used herein, refers to an amount corresponding to an enhancement of a therapeutic agent in the treatment of a disease, disorder or condition. The effective amounts used will depend on the severity and course of the disease, disorder or condition, previous therapies, the patient's health and response to medications, as well as the judgment of the treating physician.

[0132] The term "homologous cysteine," as used herein, refers to a cysteine ​​residue occurring at the sequence position such that it is homologous to Bruton's tyrosine kinase 481 cysteine, as defined herein. For example, cysteine ​​482 is a homologous cysteine ​​of a Bruton tyrosine kinase rat orthologist; cysteine ​​479 is a homologous cysteine ​​of a chicken ortholog; and cysteine ​​481 is homologous to the cysteine ​​ortholog in zebrafish. Another example is homologous cysteine ​​TXK, a member of the Bruton tyrosine-related Tec kinase family, Cys 350. Other examples of kinases having homologous cysteines are shown in FIG. 1. See also tyrosine kinase (TK) sequence alignments published at kinase.com/human/kinome/phylogeny.html.

[0133] The term "identical" as used herein refers to two or more sequences or sub-sequences that are the same. In addition, the term "substantially identical," as used herein, refers to two or more sequences that have the same percentage of consecutive units when compared or adjusted for maximum response when comparing in a comparison window or a designated measurement region using comparative algorithms or by manual adjustment or visual inspection. By way of example only, two or more sequences may be "substantially identical" if the subsequent units in a particular region are approximately 60% identical, approximately 65% ​​identical, approximately 70% identical, approximately 75% identical, approximately 80% identical , about 85% identical, about 90% identical, or about 95% identical. Such percentages describe the "percent identity" of two or more sequences. Sequence identity may occur in a region whose length is at least about 75-100 consecutive units, in a region whose length is about 50 consecutive units, or if it is not specified in the entire sequence. This definition also refers to the complement of the test sequence. By way of example only, two or more polypeptide sequences may be identical if the amino acid residues are the same, while two or more polypeptide sequences are "substantially identical" if the amino acid residues in a particular region are approximately 60% identical, approximately 65% ​​identical , approximately 70% identical, approximately 75% identical, approximately 80% identical, approximately 85% identical, approximately 90% identical, or approximately 95% identical. Identity can exist in a region that is at least about 75-100 amino acids long, in a region that is about 50 amino acids long, or if it is not specified in the entire polypeptide sequence. In addition, for example, two or more polynucleotide sequences are identical when the nucleic acid residues are the same, while two or more polynucleotide sequences are "substantially identical" if the nucleic acid residues in a particular region 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. Sequence identity may occur in a region whose length is at least about 75-100 nucleic acids, in a region whose length is about 50 nucleic acids, or if it is not specified in the entire polynucleotide sequence.

[0134] The terms "inhibits", "inhibiting" or "inhibitor" kinases, as used herein, refer to inhibition of phosphotransferase enzymatic activity.

[0135] The term "irreversible inhibitor," as used herein, refers to a compound that, when in contact with a target protein (e.g., kinase), causes the formation of a new covalent binding to a protein or through a protein, resulting in one or more biological activity of the target protein (e.g., phosphotransferase activity) is reduced or abolished despite the subsequent presence or absence of an irreversible inhibitor.

[0136] The term "irreversible Btk inhibitor," as used herein, refers to a Btk inhibitor that can form a covalent bond with an amino acid residue of Btk. In one embodiment, an irreversible inhibitor

EP 2 201 840 B1

Btk can form a covalent bond with the Cys Btk residue; in specific embodiments, an irreversible inhibitor may form a covalent bond with the Cys 481 residue (or homologue thereof) Btk or with the cysteine ​​residue at the homologously corresponding position of another tyrosine kinase, as shown in Fig. 1.

[0137] The term "isolated" as used herein refers to the separation of a preferred component and the removal of components of non-interest therefrom. The isolated substances may be solid or semi-solid or in solution, including without limitation, an aqueous solution. The isolated component may be in a homogeneous state or the isolated component may be part of a pharmaceutical composition that contains 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 that accompany them in their natural state or the nucleic acids or proteins are concentrated to such an extent that their concentration is greater than produced in vivo or in vitro. Also, for example, a gene is isolated when it is separated from an open reading frame that places the gene and encodes a protein other than the gene of interest.

[0138] The term "metabolite" of a compound disclosed herein is a derivative of that compound that forms when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when that compound is metabolized. The term "metabolized," as used herein, refers to the sum of processes (including, without limitation, hydrolysis reactions and enzyme-catalyzed reactions, such as oxidation reactions), in which a particular substance is transformed in the body. Thus, enzymes can cause specific structural changes in a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphoglucuronic transferases catalyze the transition of molecules activated by glucuronic acid into aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. Further information on metabolism can be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). The metabolites of the compounds disclosed herein can be identified by administering the compounds to the host and analyzing tissue samples taken from the host, or by incubating the compounds with liver cells in vitro and analyzing the resulting compounds. Both methods are well known in the art. In some embodiments, the metabolites of the compound are formed by oxidative processes and correspond to the corresponding hydroxy compounds. In some embodiments, the compound is metabolized to pharmacologically active metabolites.

[0139] The term "modulate" as used herein means interaction with a target, direct or indirect, so as to alter the activity of the target, including, for example, increasing the activity of the target, inhibiting the activity of the target, limiting the activity of the target or expanding the activity of the target.

[0140] As used herein, the term "modulator" refers to a compound that changes the activity of a molecule. For example, a modulator may cause an increase or decrease in the amount of some activity of a molecule compared to the amount of activity in the absence of a modulator. In some embodiments, the modulator is an inhibitor that reduces the amount of one or more activity of the molecule. In some embodiments, the inhibitor completely inhibits one or more activities of the molecule. In some embodiments, the modulator is an activator that increases the amount of at least one activity of the molecule. In some embodiments, the presence of a modulator affects the activity that does not occur in the absence of the modulator.

[0141] The term "prophylactically effective amount," as used herein, refers to an amount of a composition that is used in a patient that will ameliorate to some extent one or more symptoms of the disease, disorder or condition being treated. In prophylactic applications, such amounts may depend on the patient's state of health, weight and the like. Determination of such a prophylactically effective dose is assessed by a specialist through routine experimentation, including without limitation, clinical dose escalation.

[0142] As used herein, the term "selective binding of a compound" refers to a compound that selectively binds to any portion of one or more target proteins.

[0143] As used herein, the term "selectively binds" refers to the ability to selectively bind a compound to attach a target protein, such as, for example, Btk, with greater affinity than its binding to a non-target protein. In some embodiments, specific binding refers to binding to a target with an affinity of at least 10, 50, 100, 250, 500, 1000 or more times greater than off-target affinity.

[0144] As used herein, the term "selective modulator" refers to a compound that selectively modulates a target activity relative to a non-target activity. In some embodiments, a specific modulator is responsible for modulating the target activity at least 10, 50, 100, 250, 500, 1000 times greater than modulating the non-target activity.

[0145] The term "substantially pure" as used herein refers to a component of interest that may be substantially or substantially free of other components typically associated with or interacting with the component of interest prior to purification. For example, the component of interest may be "substantially pure" when the formulation 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% (in dry matter) of the impurity components. Thus, the "substantially pure" component of interest may have a purity of about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99% or more.

[0146] The term "subject" as used herein refers to an animal that is the object of treatment, observation or experiment. For example, the subject may be a mammal, including but not limited to a human.

[0147] As used herein, the term "target activity" refers to biological activity that is susceptible to modulation by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, inflammation or inflammatory diseases, and improvement of one or more symptoms associated with the disease or condition.

[0148] As used herein, the term "target protein" refers to a molecule or portion of a protein susceptible to binding by a selective binding compound. In some embodiments, the protein is ultimately a Btk.

[0149] The terms "treat," "treatment" or "treatment" as used herein include alleviating, weakening or reducing the symptoms of a disease or condition, preventing further symptoms, reducing or preventing hidden metabolic causes of the symptoms, inhibiting the disease or condition, for example, arresting the development of a disease or condition, alleviating the disease or condition, causing regression of the disease or condition, relieving the condition caused by the disease or condition or stopping the symptoms of the disease or condition. The terms "treat," "treatment" or "treatment" include, but are not limited to, prophylactic and / or therapeutic treatment.

[0150] As used herein, the IC50 value refers to the amount, concentration or dosage of a particular test compound that achieves 50% inhibition of maximal response, such as Btk inhibition, in a test in which such response is determined.

[0151] As used herein, EC50 refers to the dosage, concentration or amount of a particular test compound that causes a dose-dependent response at 50% of the maximum expression of a specific response that is elicited, provoked, or amplified by a particular test compound.

BRIEF DESCRIPTION OF THE FIGURES [0152] Fig. 1 shows a comparison of Btk sequences with those of other tyrosine kinases.

[0153] Fig. 2 illustrates cell data pertaining to inhibition of B cell receptor induced by phospholipase-γγ phosphorylation by compound 4. In this example, 2E6 Ramos cells / well in serum free medium was used; cells were pre-treated with the compound for 1.5 hours. The B cell receptor was stimulated with anti-IgM for 3 minutes; 10X lysis buffer containing DNAse was added directly to the cells. Sample buffer was added and applied directly to the gel. Samples were analyzed by western blot - phosphorylated Btk and PLCyI and total Btk and PLCyI. The blot was imaged with ChemiDoc CCD and assayed with ImageQuant. The phosphorylated band was normalized to the total band and the IC50 was calculated.

[0154] Figure 3 illustrates cellular data showing that compound 4 and compound 15 inhibit DHL-6 cell growth. In this example, 3E4 DHL-6 cells / well in complete medium was used. cells

For the indicated time, was treated with a compound having a final concentration of 0.1% in DMSO. The number of cells was measured by the Alamar Blue test according to a standard protocol.

[0155] Fig. 4 is a mass spectrum image showing that compound 4 covalently modifies Btk. In this example, 30uM of compound 4 was incubated with 6-7uM of recombinant BTK (Y-&gt; D mutation, kinase domains only) overnight at room temperature. The protein-inhibitor complex was desalted by reverse phase HPLC and analyzed directly by mass spectrometry to determine molecular weight. &gt; 99% of the recombinant Btk protein is covalently modified by compound 4.

[0156] Fig. 5 illustrates graphically the inhibition of compound 4 in the development of arthritis in a mouse model.

[0157] Fig. 6 illustrates data showing that the efficacy of compound 4 is associated with the reduction of rheumatoid factor and anti-cyclic citrullinated peptide antibody in the CAIA model. In these examples, * p &lt;0.01; ** p &lt;0.001 compared to vehicle and saline treatment.

[0158] Fig. 7 illustrates results of compound 13 inhibition of arthritis development in a mouse model. This enantiomer of compound 4 completely inhibits the development of arthritis in the CAIA model at dose levels of 10 and 30 mg / kg. For comparison, data relating to inhibition of arthritis development in the same mouse model is presented for dexamethasone.

DETAILED DESCRIPTION OF THE INVENTION [0159] The methods described herein include administering to a subject in need a composition comprising a therapeutically effective amount of one or more irreversible Btk inhibitor compounds described herein. Without being bound by theory, the different roles of signaling Btk in various hematopoietic cell functions, for example, activation of the B cell receptor, suggests that small molecules of Btk inhibitors are useful for reducing risk or for treating various diseases affecting or affecting many cell types the hematopoietic pathway, including, for example, autoimmune diseases, heteroimmunological conditions or diseases, inflammatory diseases, cancers (e.g., B cell proliferative disorders) and thromboembolic disorders. In addition, the irreversible Btk inhibitor compounds described herein may be useful for inhibiting a small subset of other tyrosine kinases that share homology with Btk by having a cysteine ​​residue (including Cys 481 residue) so that they can form a covalent bond with an irreversible inhibitor. See, for example, the kinase protein in FIG. 1. Thus, a subset of non-Btk tyrosine kinases is anticipated to also be useful as a therapeutic target in many health conditions.

[0160] The methods described herein can be used to treat autoimmune diseases, which include, but are not limited to, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, systemic lupus, diabetes, myasthenia gravis, Hashimoto's disease, thyroiditis Orda, Graves disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, myoclonic and opsoclonial syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasturea syndrome, idiopathic purpura, optic neuritis, systemic sclerosis, primary biliary cirrhosis, reiter arteriosus, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granuloma, psoriasis, body hair loss or lack, Behęet's disease, chronic fatigue syndrome, dysautonomy, endometriosis, interstitial cystitis, neuromyotonia, systemic sclerosis and vulvodynia.

[0161] The methods described herein can be used to treat heteroimmunological diseases and conditions including, but not limited to, host anti-transplant immune response, transplantation, transfusion, anaphylaxis, allergies (e.g., pollen pollen allergies, latex, drugs, food, insect venom, animal hair, exfoliated animal skin, house dust mites or cockroach armor), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis and atopic dermatitis.

[0162] The methods described herein can be used to treat inflammatory diseases, including but not limited to asthma, enteritis, appendicitis, eyelid inflammation, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis , colitis, conjunctivitis, cystitis, tear dermatitis, dermatitis, dermatomyositis, encephalitis,

Endocarditis, endometritis, enterocolitis, enterocolitis, epicondylitis, epididymitis, fasciitis, musculo-tendonitis, gastritis, gastroenteritis, hepatitis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, ovarian inflammation, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, proctitis, proctitis, pyelonephritis, rhinitis, inflammation eustachian tube, sinusitis, gangrene, synovitis, Achilles tendonitis, tonsillitis, uveitis, vaginitis, vasculitis and vulvitis.

[0163] The methods described herein can be used to treat cancer, which includes, but is not limited to, for example, B cell proliferative disorders, which includes, but is not limited to, spreading large B cell lymphoma, nodular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, chronic B cell prolymphocytic leukemia, lymphoplasmic lymphoma / Waldenstrom macroglobulinemia, splenic marginal lymphoma, plasma cell myeloma, plasmacytome, extra-node marginal zone lymphoma, marginal nodal lymphoma, mantle zone cell lymphoma, primary B-large mediastinal lymphoma, large B-cell endovascular lymphoma, primary exudative lymphoma, Burkoid lymphoma / lymphoma.

[0164] The methods described herein can be used to treat thromboembolic disorders, including, but not limited to, myocardial infarction, angina pectoris (including unstable angina), reocclusion and recurrence of narrowing after angioplasty or after aortic-coronary bypass grafting, stroke, transient ischemia , peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis.

[0165] Symptoms, diagnostic tests and prognostic tests for each of the above-mentioned conditions are known in the art. See, for example, Harrison's Principles of Internal Medicine®, "16th ed., 2004, The McGraw-Hill Companies, Inc. Dey et al. (2006), Cytojourmal 3 (24) and the "Revised European American Lymphoma" (REAL) classification system (see, for example, the National Cancer Institute website).

[0166] Many animal models are useful for establishing a range of therapeutically effective doses of irreversible Btk inhibitor compounds for the treatment of the aforementioned diseases.

[0167] For example, dosing of irreversible Btk inhibitor compounds for the treatment of autoimmune disease can be determined in an animal model of rheumatoid arthritis in mice. In this model, arthritis is induced in Balb / c mice by administration of anti-collagen antibodies and lipopolysaccharides. See Nandakumar et al. (2003), Am. J. Pathol 163: 1827-1837.

[0168] In another example, the dosage of irreversible Btk inhibitors for the treatment of B cell proliferative disorders can be tested experimentally, for example, in a human guess xenograft model in which human B cell lymphoma cells (e.g. Ramos cells) are implanted in deficient mice immunity (for example, nude nude mice) as described in, for example, Pagel et al. (2005), Clin Cancer Res 11 (13): 4857-4866.

[0169] Animal models for the treatment of thromboembolic disorders are also known.

[0170] The therapeutic effectiveness of a compound for the treatment of one of the aforementioned diseases can be optimized throughout the duration of treatment. For example, the subject being treated may be subjected to a diagnostic evaluation to correlate symptom relief or disease pathology with in vivo inhibition of Btk activity achieved by administering given doses of an irreversible Btk inhibitor. Cellular assays known in the art can be used to determine in vivo Btk activity in the presence or absence of an irreversible Btk inhibitor. For example, because activated Btk is phosphorylated on tyrosine 223 (Y223) and tyrosine 551 (Y551), phosphospecific immunocytochemical staining of P-Y223 or P-Y551 positive cells can be used to detect or quantify Bkt activation in a population of cells (e.g. , by FACS assay for stained or unstained cells). See, for example, Nisitani et al. (1999), Proc. Natl. Acad. Sci, USA 96: 2221-2226. Thus, the amount of Btk inhibitor compound that is administered to a subject can be increased or decreased so as to maintain an optimal level of Btk inhibition for treating the subject's disease state.

EP 2 201 840 B1

Compounds [0171] In the following description of irreversible Btk inhibitor compounds suitable for use in accordance with the methods described herein, terms referring to standard chemical terms can be found in reference publications (unless otherwise defined herein), including Carey and Sundberg "Advanced Organic Chemistry 4th Ed." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology methods are used in accordance with prior art skills. In addition, the nucleic acid and amino acid sequences for Btk (e.g., human Btk) are known in the art as disclosed in United States Patent US 6,326,469. Unless specific definitions are provided, the relevant nomenclature, laboratory procedures and techniques used, analytical chemistry, organic chemical synthesis, and medical and pharmaceutical chemistry, described herein are known in the art. Standard methods can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, drug formulation, administration and treatment of patients.

[0172] The Btk inhibiting compounds described herein are selective for Btk and kinases having cysteine ​​residues at the position of the tyrosine kinase amino acid sequence such that it is homologous to the position of the amino acid sequence of cysteine ​​481 in Btk. See, for example, the kinases in FIG. 1. Inhibitor compounds described herein include the Michael acceptor moiety.

[0173] Generally, the irreversible Btk inhibitor compound used in the methods described herein is assayed or characterized in an in vitro assay, for example, in a biochemical cell-free or functional cell assay. Such assays are useful for determining in vitro IC50 for an irreversible Btk inhibitor compound.

[0174] For example, a cell-free assay can be used to determine Btk activity after incubation of the kinase in the presence or absence of a candidate irreversible Btk inhibitor compound concentration range. If the candidate compound is in fact an irreversible Btk inhibitor, Btk kinase activity will not be restored after washing again with the inhibitor-free medium. See, for example, JB Smaill, et al. (1999), J. Med. Chem. 42 (10): 1803-1815. In addition, the formation of a covalent complex between Btk and an irreversible Btk inhibitor candidate is a useful indicator of irreversible Btk inhibition, so that they can easily be determined by a variety of methods known in the art (e.g., mass spectrometry). For example, some compounds irreversible Btk inhibitors can form a covalent bond with Cys 481 in Btk (for example, by Michael reaction).

[0175] Functional cell tests for assessing Btk inhibition include measuring one or more endpoints in response to stimulation of the Btk mediated pathway in a cell line (e.g., BCR activation in Ramos cells) in the absence or in the range of irreversible candidate compound concentrations Btk inhibitor. Useful endpoints to determine a response to BCR activation include, for example, Btk autophosphorylation, Btk phosphorylation of the target protein (e.g., PLC-γ), and cytoplasmic calcium transition.

[0176] High-performance biochemical cell-free assay (for example, kinase assays) and functional cell tests (for example, calcium ion influx) are well known to the skilled artisan. In addition, high performance 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 usually automate the entire procedure, including pipetting all samples and reagents, dispersing liquids, synchronizing incubations, and final reading of the microplates in the detector (s) suitable for the assay. Automated systems therefore allow the identification and characterization of a large number of irreversible inhibitor compounds without undue effort.

[0177] Compounds irreversible Btk inhibitors can be used in the manufacture of a medicament for the treatment of any of the aforementioned conditions (e.g., autoimmune disease, inflammatory disease, allergic disorder, B cell proliferative disorder or thromboembolic disorder).

[0178] A compound irreversible Btk inhibitor, used according to the method described herein, may inhibit in vitro Btk kinase activity or Btk kinase homolog at IC₅₀ less than 10 μΜ, (for example, less than 1 μM, less than 0.5 μM, less than 0.4 μM, less than 0.3 μM, less than 0.1, less than 0.08 μΜ, less than 0.06 μΜ, less than 0.05 μΜ, less than 0.04 μΜ, less than 0.03 μΜ, less than less than 0.02 μΜ, less than 0.01, less than 0.008 μΜ, less

EP 0.002 μΜ, less than 0.005 μΜ, less than 0.004 μΜ, less than 0.003 μΜ, less than 0.002 μΜ, less than 0.001, less than 0.00099 μΜ, less than 0.00098 μΜ, less than 0 , 00097 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).

[0179] A compound irreversible Btk inhibitor can selectively and irreversibly inhibit the activated form of a target tyrosine kinase (e.g., a phosphorylated form of a tyrosine kinase). For example, activated Btk is transphosphorylated on tyrosine 551. For example, an irreversible Btk inhibitor can inhibit target kinase in cells only when the target kinase is activated by signal transduction process events.

[0180] Compounds of any formula (A), Formula (B), Formula (C) or Formula (D) are described herein. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites and pharmaceutically acceptable prodrugs of these compounds are also described. Pharmaceutical compositions are described which contain at least one such compound or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a pharmaceutically active metabolite or a pharmaceutically acceptable prodrug of such a compound. When the compounds described herein contain a nitrogen susceptible to oxidation, the nitrogen atom may be converted to an N-oxide according to methods well known in the art. Isomers and chemically protected forms of compounds having a structure represented by any formula selected from Formula (A), Formula (B), Formula (C) or Formula (D) have also been described.

[0181] Compounds of formula (A) and pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof are described. Formula (A) is as follows:

wherein

<img file="PL2201840T3_D0008.tif" />

A is independently selected from N or CR5;

Formula (A)

R1 is H, L2- (substituted or unsubstituted alkyl), L2- (substituted or unsubstituted cycloalkyl), L2- (substituted or unsubstituted alkenyl), L2- (substituted or unsubstituted cycloalkenyl), L2- (substituted or unsubstituted heterocycle), L2 - (substituted or unsubstituted heteroaryl) or L2- (substituted or unsubstituted aryl), where L2 is a bond, O, S, -S (= O), -S (= O) 2, C (= O), - (substituted or unsubstituted C 1 -C 6 alkyl) or - (substituted or unsubstituted C 2 -C 6 alkenyl);

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

R4 is L3-X-L4-G, wherein

L3 is optionally (optionally), and when present is a bond, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl;

X is optionally, and when present is a bond, O, -C (= O), S, -S (= O), -S (= O) 2, -NH, -NR9, -NHC (O), -C (O) NH, -NR9C (O), -C (O) NR9, -S (= O) 2NH, -NHS (= O) 2, -S (= O) 2NR9-, -NR9S (= O) 2 , -OC (O) NH-, -NHC (O) O-, -OC (O) NR9-, -NR9C (O) O-, -CH = NO-, -ON = CH-, -NR10C (O) NR10-, heteroaryl, aryl, - NR10C (= NR11) NR10-, -NR10C (= NR11) - -C (= NR11) NR10-, -OC (= NR11) - or -C (= NR11) O-;

L4 is optionally, and when present, is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle;

Or L3, X and L4 together form a nitrogen-containing heterocyclic ring;

G means

<img file="PL2201840T3_D0009.tif" />

wherein

R6, R7 and R8 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;

R5 is H, halogen, -L6- (substituted or unsubstituted C1-C3 alkyl), -L6- (substituted or unsubstituted C2-C4 alkenyl), -L6- (substituted or unsubstituted heteroaryl) or -L6 (substituted or unsubstituted aryl) where L6 is a bond, O, S, -S (= O), S (= O) 2, NH, C (O), NHC (O) O, -OC (O) NH, -NHC (O) or -C (O) NH;

each R9 is independently selected from H, substituted or unsubstituted lower alkyl and substituted or unsubstituted lower cycloalkyl;

each R10 is independently H, substituted or unsubstituted lower alkyl or substituted or unsubstituted lower cycloalkyl; or two R10 groups can together form a 5-, 6-, 7- or 8-membered heterocyclic ring; or R9 and R10 may together form a 5-, 6-, 7- or 8-membered heterocyclic ring; or each R11 is independently selected from H, -S (= O) 2R8, -S (= O) 2NH2, -C (O) R8. -CN, -NO2, heteroaryl or heteroalkyl; and their pharmaceutically acceptable solvates or pharmaceutically acceptable salts.

[0182] Described herein is a compound of formula (A) which has the following structure of formula (B):

<img file="PL2201840T3_D0010.tif" />

G Formula B in which:

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

each Ra is independently H, halogen, -CF3, -CN, -NO2, OH, NH2, -La- (substituted or unsubstituted alkyl), -La- (substituted or unsubstituted alkenyl), -La- (substituted or unsubstituted heteroaryl) or -La- (substituted or unsubstituted aryl), where La is a bond, O, S, -S (= O), -S (= O) 2, NH, C (O), CH2, -NHC (O) O , -NHC (O) or -C (O) NH;

EP 2 201 840 B1

G means

<img file="PL2201840T3_D0011.tif" />

wherein,

R6, R7 and R8 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 R12 together form a 4-, 5- or 6-membered heterocyclic ring; and pharmaceutically acceptable active metabolites thereof, pharmaceutically acceptable solvates, pharmaceutically acceptable salts or pharmaceutically acceptable prodrugs. [0183] G may be selected from

<img file="PL2201840T3_D0012.tif" />

<img file="PL2201840T3_D0013.tif" />

, and [0184]

<img file="PL2201840T3_D0014.tif" />

<img file="PL2201840T3_D0015.tif" />

[0185] A compound of formula (B) has been described which has the following structure of formula (C):

<img file="PL2201840T3_D0016.tif" />

G Formula (C)

EP 2 201 840 B1

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

R12 is H or lower alkyl; or

Y and R12 together form a 4-, 5- or 6-membered heterocyclic ring;

G means

<img file="PL2201840T3_D0017.tif" />

<img file="PL2201840T3_D0018.tif" />

<img file="PL2201840T3_D0019.tif" />

wherein,

R6, R7 and R8 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 or pharmaceutically acceptable salts thereof.

[0186] In the components described, the group "G" of any formula (A), Formula (B) or Formula (C) is any group that is used to match the physical and biological properties of the molecule. Such alignment / modification is achieved using groups that modulate the Michael acceptor chemical reactivity, acidity, alkalinity, lipophilicity, solubility and other physical properties of the molecule. Physical and biological properties modulated by such G group modifications include, for example, an increase in the Michael acceptor chemical reactivity, solubility, in vivo absorption and in vivo metabolism. In addition, in vivo metabolism may include, for example, controlling in vivo PK properties, off-target activities, potential toxicity associated with cypP450 interactions, drug-drug interactions, and the like. In addition, G group modifications allow the in vivo efficiency of the compound to be adjusted by modulating, for example, specific and non-specific protein binding to plasma proteins and to lipids and distribution in tissues in vivo.

[0187] Described herein are compounds having the structure of formula (D):

<img file="PL2201840T3_D0020.tif" />

* Formula (D) in which

La is CH2, O, NH or S;

Ar is an optionally substituted aromatic carbocycle or aromatic heterocycle;

Y is optionally substituted alkyl, heteroalkyl, carbocycle, heterocycle or combinations thereof;

Z is C (O), OC (O), NHC (O), C (S), S (O) x, OS (O) x, NHS (O) x, where x is 1 or 2; and

R6, R7, and R8 are independently selected from H, alkyl, heteroalkyl, carbocycle, heterocycle or combinations thereof.

[0188] In a further or alternative embodiment, La is O.

[0189] In a further or alternative embodiment, Ar is phenyl.

[0190] In a further or alternative embodiment, Z is C (O).

[0191] In a further or alternative embodiment, each of R1. R2, and R3 is H. [0192] Described herein is a compound of formula (D) as follows:

<img file="PL2201840T3_D0021.tif" />

La is CH2, O, NH or S;

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

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

Z means C (= O), OC (= O), NHC (= O), C (= S), S (= O) x, OS (= O) x, NHS (= O) x, where x is 1 or 2;

R7 and R8 are independently selected from H, unsubstituted C1-C4alkyl, substituted C1-C4alkyl, unsubstituted C1-C4heteroalkyl, substituted C1-C4heteroalkyl, unsubstituted C3-C6cycloalkyl, substituted C3-C6cycloalkyl, unsubstituted C2-C6heterocycloalkyl and substituted or

R7 and R8 together form a bond;

R6 is H, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C1-C4heteroalkyl, C1-C6alkoxyalkyl, C1-C8alkylaminoalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C2-C8heterocycloalkyl, substituted or unsubstituted C1-C4alkyl (aryl), C1-C4alkyl (heteroaryl), C1-C4alkyl (C3-C8cycloalkyl) or C1-C4alkyl (C2-C8heterocycloalkyl); and or pharmaceutically acceptable solvates or pharmaceutically acceptable salts thereof. Embodiments of the invention are compounds of formula (D) wherein R6 is H and R7 and R8 are H or together form a bond.

[0193] For any or all of the embodiments, the substituents may be selected from a subset of the listed alternatives. For example, in some embodiments, La is CH2, O or NH. In other embodiments, La is O or NH. In yet other embodiments, La is O.

[0194] In some embodiments, Ar is substituted or unsubstituted aryl. In yet other embodiments, Ar is 6-membered aryl. In some other embodiments, Ar is phenyl.

[0195] In some embodiments, x is 2. In yet other embodiments, Z is C (= O), OC (= O), NHC (= O), S (= O) x, OS (= O) x or NHS (= O) x. In some other embodiments, Z is C (= O), NHC (= O) or S (= O) 2.

[0196] Compounds wherein R7 and R8 are independently selected from H, unsubstituted C1-C4 alkyl, substituted C1-C4alkyl, unsubstituted C1-C4heteroalkyl and substituted C1-C4heteroalkyl are described; or R7 and R8 together form a bond. In one embodiment, each of R7 and R8 is H; or R7 and R8 together form a bond.

[0197] Compounds wherein R6 is H, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C1-C4heteroalkyl, C1-C6alkoxyalkyl, C1-C2alkyl-N (C1-C3alkyl) 2, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C1-C4alkyl (aryl), C1-C4alkyl (heteroaryl),

EP 2 201 840 B1

C1-C4alkyl (C3-C8cycloalkyl) or C1-C4alkyl (C2-C8 heterocycloalkyl). In some cases, R6 is H, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C1-C4heteroalkyl, C1-C6alkoxyalkyl, C1-C2alkyl-N (C1-C3aklyl) 2, C1-C4alkyl (aryl), C1-C4alkyl (heteroaryl ), C1-C4alkyl (C3-C8cycloalkyl) or C1-C4alkyl (C2-C8 heterocycloalkyl). In other cases, R6 is H, substituted or unsubstituted C1-C4alkyl, -CH2-O- (C1-C3alkyl), -CH2-N (C1-C3alkyl) 2, C1-C4alkyl (phenyl) or C1-C4alkyl (5 or 6 - member heteroaryl). In some cases, R6 is H, substituted or unsubstituted C1-C4alkyl, -CH2-O- (C1-C3alkyl), -CH2-N (C1-C3alkyl) 2, C1-C4alkyl (phenyl) or C1-C4alkyl (5- or a 6-membered heteroaryl containing 1 or 2 N atoms) or a C1-C4alkyl (5- or 6-membered heterocycloalkyl containing 1 or 2 N atoms).

[0198] In some embodiments, Y is an optionally substituted group selected 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 7-membered cycloalkyl and 4-, 5-, 6- or 7-membered heterocycloalkyl. In yet other embodiments, Y is an optionally substituted group selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, 5- or 6-membered cycloalkyl, and 5- or 6-membered heterocycloalkyl containing 1 or 2 N atoms. In some other embodiments, Y is 5 - or a 6-membered cycloalkyl or a 5- or 6-membered heterocycloalkyl containing 1 or 2 N atoms.

[0199] For various variants, any combinations of the groups described above have been described. It is understood that the substituents and method of substitution in the compounds provided herein can be selected by one of skill in the art to provide compounds that are chemically stable and can be synthesized by methods known in the art or as described herein.

[0200] Some examples of compounds of formula (A), Formula (B), Formula (C), Formula (D) described herein include:

<img file="PL2201840T3_D0022.tif" />

EP 2 201 840 B1 and

<img file="PL2201840T3_D0023.tif" />

<img file="PL2201840T3_D0024.tif" />

<img file="PL2201840T3_D0025.tif" />

[0201] Also described herein is:

EP 2 201 840 B1

<img file="PL2201840T3_D0026.tif" />

<img file="PL2201840T3_D0027.tif" />

and

<img file="PL2201840T3_D0028.tif" />

[0202] In one aspect, the invention provides a compound selected from the following:

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-1-yl) piperidin-1-yl) but-2-en-1- he (Compound 5); 1- (3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) sulfonylethene (Compound 6); 1- (3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4d] pyrimidin-1-yl) piperidin-1-yl) prop-2-yn-1-one (Compound 8 ); 1- (4- (4-amino-3- (4-phenoxyphenyl) 1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one (Compound 9); N - ((1S, 4S) -4- (4 amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) cyclohexyl) acrylamide (Compound 10); 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) pyrrolidin-1-yl) prop-2-en- 1on (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- he (Compound 12); 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1- he (Compound 13); 1 - ((S) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1- he (Compound 14); and (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).

[0203] Throughout the present disclosure, groups and their substituents may be selected by one skilled in the art to provide stable moieties and compounds.

[0204] Compounds of any formula (A) or Formula (B) or Formula (C) or Formula (D) described herein can irreversibly inhibit Btk and can be used to treat patients suffering from Bruton's tyrosine kinase-related conditions or diseases mediated by Bruton's tyrosine kinase including, but not limited to, cancer, autoimmune diseases, and other inflammatory diseases.

EP 2 201 840 B1

Preparation of Compounds [0205] Compounds of any formula (A), (B), (C) or (D) can be synthesized using standard synthetic techniques known to a person skilled in the art or using methods known in the art in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions set out herein may be changed according to the state of the art. The synthesis methods outlined in the description below may be helpful for preparing compounds.

[0206] To provide the compounds described herein, the reactions can be used in sequential order or synthesized fragments that can then be combined using methods described herein and / or known in the art.

Formation of a covalent coupling by the reaction of an electrophile with a nucleophile [0207] The compounds described herein can be modified using different electrophiles or nucleophiles to form new functional groups or substituents. Table 1 entitled "Examples of covalent linkages and their precursors" lists selected examples of covalent coupling products and precursor functional groups from which they can be obtained and which can be used as a guide to the variety of available electrophile and nucleophile combinations. Precursor functional groups are represented as electrophilic groups or nucleophilic groups.

Table 1: Examples of covalent linkages and their precursors [0208]

<td>Product of covalent coupling</td><td>electrophile</td><td>nucleophile</td>

<td>carboxamides</td><td>Activated esters</td><td>amines / anilines</td>

<td>carboxamides</td><td>Acyl Azides</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>acyl nitrile</td><td>alcohols / phenols</td>

<td>carboxamides</td><td>acyl nitrile</td><td>amines / anilines</td>

<td>imines</td><td>aldehydes</td><td>amines / anilines</td>

<td>hydrazones</td><td>aldehydes or ketones</td><td>hydrazine</td>

<td>oximes</td><td>aldehydes or ketones</td><td>hydroxylamine</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>alkyl</td><td>thiols</td>

<td>esters</td><td>alkyl</td><td>carboxylic acids</td>

<td>ethers</td><td>alkyl</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>arylamine</td><td>Aryl halides</td><td>amines</td>

<td>thioethers</td><td>Azyndyny</td><td>thiols</td>

EP 2 201 840 B1

<td>Product of covalent coupling</td><td>electrophile</td><td>nucleophile</td>

<td>Boronic acid esters</td><td>boronates</td><td>glycols</td>

<td>carboxamides</td><td>Carboxylic acids</td><td>Amine / aniline</td>

<td>esters</td><td>Carboxylic acids</td><td>Alcohols</td>

<td>hydrazine</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>epoxies</td><td>thiols</td>

<td>thioethers</td><td>Fluorowcoacetamidy</td><td>thiols</td>

<td>aminotriazine</td><td>Fluorowcotriazyny</td><td>Amine / aniline</td>

<td>Triazinyl ethers</td><td>Fluorowcotriazyny</td><td>Alcohols / phenols</td>

<td>amidines</td><td>imidoesters</td><td>Amine / aniline</td>

<td>ureas</td><td>isocyanates</td><td>Amine / aniline</td>

<td>urethanes</td><td>isocyanates</td><td>Alcohols / phenols</td>

<td>thioureas</td><td>isothiocyanates</td><td>Amine / aniline</td>

<td>thioethers</td><td>maleimides</td><td>thiols</td>

<td>Phosphinic acid esters</td><td>Fosforamidyty</td><td>Alcohols</td>

<td>silyl</td><td>Silyl halides</td><td>Alcohols</td>

<td>alkylamines</td><td>Sulfonic acid esters</td><td>Amine / aniline</td>

<td>thioethers</td><td>Sulfonic acid esters</td><td>thiols</td>

<td>esters</td><td>Sulfonic acid esters</td><td>Carboxylic acids</td>

<td>ethers</td><td>Sulfonic acid esters</td><td>Alcohols</td>

<td>sulfonamides</td><td>Sulfonyl halides</td><td>Amine / aniline</td>

<td>Sulfonic acid esters</td><td>Sulfonyl halides</td><td>Phenols / alcohols</td>

<td>alkylthio</td><td>α, β-unsaturated ester</td><td>thiols</td>

<td>alkyl ethers</td><td>α, β-unsaturated ester</td><td>Alcohols</td>

<td>alkylamines</td><td>α, β-unsaturated ester</td><td>amines</td>

<td>alkylthio</td><td>vinyl sulfone</td><td>thiols</td>

<td>alkyl ethers</td><td>vinyl sulfone</td><td>Alcohols</td>

<td>alkylamines</td><td>vinyl sulfone</td><td>amines</td>

<td>Winylosiarczek</td><td>propargylamide</td><td>thiol</td>

Use of protecting groups [0209] In the reactions described, it may be necessary to protect reactive functional groups, for example, hydroxyl, amino, imino, thiol or carboxyl groups desired in

In the final product to protect them from reacting. Protecting groups are used to block some or all reactive moieties and protect such groups from participating in chemical reactions before removal of the protecting group. Each protecting group can be removed using a variety of methods. Protecting groups that undergo cleavage under completely different reaction conditions require a different removal method. Protecting groups can be removed by acid, base and by hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid sensitive and can be used to protect reactive carboxyl and hydroxyl moieties in the presence of amino groups protected by Cbz groups that are removable by hydrogenolysis, and by Fmoc groups that are sensitive on the rules. Reactive carboxylic acid and hydroxyl groups can be blocked by base sensitive groups such as, but not limited to, methyl, ethyl and acetyl in the presence of an amine blocked by acid sensitive groups such as t-butyl carbamate or carbamates, which are both basic and acid-stable, but can be removed hydrolytically.

[0210] Reactive carboxylic acid and hydroxy acid moieties can also be blocked by hydrolytically removable protecting groups, such as a benzyl group, while amino groups capable of forming a hydrogen bond with acids can be blocked by base sensitive groups such as Fmoc. Reactive carboxylic acid moieties can be protected by conversion to a simple ester of a compound, as exemplified herein, or can be blocked by oxidative removable groups such as 2,4-dimethoxybenzyl, while co-existing amino groups can be blocked by fluorolabile silylcarbamates.

[0211] Allyl blocking groups are useful in the presence of acid and base protecting groups because they are stable and can be removed later with metal catalysts and quasi-acid catalysts. For example, allyl blocked carboxylic acids may be deprotected in Pd catalyzed reactions⁰- in the presence of protecting groups sensitive to acid t-butyl carbamates or sensitive to bases aminoacetates. Still another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residues are attached to the resin, the functional groups are blocked and cannot react. When released from the resin, functional groups are able to participate in the reaction.

[0212] Typical blocking / protecting groups may be selected from:

<img file="PL2201840T3_D0029.tif" />

<img file="PL2201840T3_D0030.tif" />

[0213] Other protecting groups and detailed descriptions of the techniques applicable to the creation of protecting groups as well as their removal are found in Greene and Wuts, Protective Grups in Organic Synthesis, 3rd Ed., John Wiley &amp; Sons, New York, NY, 1999, and Kocienski, Protective Grups, Thieme Verlag, New York, NY, 1994.

Synthesis of Compounds [0214] Methods for the preparation and methods of using tyrosine kinase inhibitor compounds are described herein. according to the invention. The compounds described herein can be synthesized using the following synthesis schemes. compounds

EP 2 201 840 B1 can be synthesized using methods analogous to those described below using suitable alternative starting materials.

[0215] Described herein are compounds that inhibit the activity of tyrosine kinases (s), such as Btk, and methods for their preparation. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites and pharmaceutically acceptable prodrugs of these compounds are also described. Pharmaceutical compositions are described which contain at least one such compound or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a pharmaceutically active metabolite or a pharmaceutically acceptable prodrug of such a compound.

[0216] Starting materials 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 having other substituents can be synthesized using methods and materials known to the skilled person, such as those described, for example, in March, ADVANCED ORGANIC CHEMISTRY 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed., Vols. A and B (Plenum 2000, 2001); Green and Wuts, PROTECTIVE GRUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999); Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's 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's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). Other methods for synthesizing the compounds described herein can be found in International Patent Application Publication Number WO 01/01982901, Arnold et al. Bioorganic &amp; Medicinal Chemistry Letters 10 (2000) 2167-2170; Burchat et al. Bioorganic &amp; Medicinal Chemistry Letters 12 (2002) 1687-1690. General methods for preparing the compounds disclosed herein can be modeled on reactions known in the art and can be modified by using appropriate reagents and conditions as recognized by one skilled in the art to incorporate various moieties found in the formulas as provided herein. As a guide, synthetic methods can be used which are presented later in this description.

[0217] Reaction products can, if desired, be isolated and purified using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography and the like. Such products can be characterized by customary means, including physical constants and spectral data.

[0218] The compounds described herein can be prepared using the synthetic methods described herein as single isomers or as a mixture of isomers.

[0219] An example of a systematic approach to the preparation of compounds of any formula (A), (B), (C) or (D) is provided in Scheme I.

<img file="PL2201840T3_D0031.tif" />

[0220] Halogenation of the commercially available 1H-pyrazolo [3,4-d] pyrimidin-4-amine is an introduction to the synthesis of compounds of formula (A), (B), (C) and / or (D). 1H-Pyrazolo [3,4-d] pyrimidin-4-amine is reacted with N-iodosuccinimide to give 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine. Then metal-catalyzed cross coupling of 3-iodo-1H-pyrazolo [3,4-d] pyrimidin-4-amine is performed. Cross coupling mediated by palladium of appropriately substituted phenyl boronic acid under basic conditions yields intermediate 2. Then intermediate 2 is coupled with N-Boc-3-hydroxypiperidine (for example) in the Mitsunobu reaction to give Boc (tert-butyloxycarbonyl) ) protected intermediate 3. After deprotection with acid, and after

By coupling with, for example, an acid chloride such as acryloyl chloride, the synthesis is completed to give compound 4.

[0221] Using the synthetic methods described herein, as well as known to the skilled person, tyrosine kinase inhibitors as described herein are obtained in good yield and purity. Compounds prepared by the methods disclosed herein are purified by conventional methods known in the art, such as, for example, filtration, recrystallization, chromatography, distillation and combinations thereof.

[0222] For various variants, any combinations of the groups described above are described. It is understood that the substituents and method of substitution in the compounds provided herein can be selected by one of skill in the art to provide compounds that are chemically stable and can be synthesized by methods known in the art or as described herein.

Further forms of the compounds [0223] Compounds having a structure having any formula selected from formula (A), Formula (B), Formula (C) or Formula (D) have been described. It is understood that when reference is made to the compounds described herein, it refers to compounds of any formula (A), Formula (B), Formula (C) or Formula (D), as well as all specific compounds that fall within the scope of the formula general, unless otherwise indicated.

[0224] The compounds described herein may have one or more asymmetric centers, and each of these centers may be in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric and epimeric forms as well as their respective mixtures. Stereoisomers can be obtained, if desired, by methods known in the art, for example, by separating stereoisomers on chiral chromatographic columns.

[0225] Diasteromeric mixtures can be separated into individual diastereomers based on differences in their physico-chemical properties by known methods, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated on chiral chromatographic columns. Enantiomers may also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g. by hydrolysis) individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomers, enantiomers and mixtures thereof, are considered to be part of the compositions described herein.

[0226] The methods and formulations described herein include the use of N-oxides, crystal forms (also known as polymorphs), or pharmaceutically acceptable salts of the compounds described herein. In some cases, the compounds may exist as tautomers. All tautomers are within the scope of the present invention. In addition, the compounds described herein may be present in unsolvated forms as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. Solvated forms of the compounds described herein are also considered within the scope of the invention.

[0227] Compounds of any formula (A), Formula (B), Formula (C) or Formula (D) in non-oxidized form can be prepared from N-oxides of compounds of any formula (A), Formula (B), Formula (C ) or Formula (D) by treatment with a reducing agent such as, without limitation, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, phosphorus tribromide or the like in a suitable organic aprotic solvent such as acetonitrile, ethanol . dioxane or similar at 0 to 80 ° C.

[0228] Prodrugs have also been described. The term "prodrug" refers to an agent that is converted in vivo to the parent drug. Prodrugs are often used because, in some cases, they may be easier to administer than the parent drug. For example, they may be bioavailable after oral administration as opposed to parent drugs. The prodrug may also have improved solubility in the pharmaceutical composition compared to the parent drug. For example, a prodrug may be a compound that is administered as an ester ("prodrug") to facilitate penetration through the cell membrane when water solubility is a determinant of mobility, but which is then metabolically hydrolysed to the carboxylic acid, the active entity, when inside the cell, where the water solubility is good. A further example of a prodrug may be a short peptide (polyamino acid) attached to acidic groups, where the peptide is metabolized to release the active moiety. In some cases, when administered in vivo, the prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. The prodrug may also be metabolized enzymatically by one- or multi-stage processes into a biologically, pharmaceutically or therapeutically active form of the compound. To produce a prodrug, the pharmaceutically active compound is modified to be regenerated after in vivo administration. A prodrug may be designed to alter metabolic stability, drug distribution characteristics, screening for side effects or toxicity, to improve the taste of the drug, or change other characteristics or properties of the drug. According to the principles of knowledge in the field of pharmacodynamic processes and drug metabolism in vivo, a specialist knowing a pharmaceutically active compound can design prodrugs of this compound (see, on

Example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pp. 388-392; Silverman (1992), The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego, pp. 352-401, Saulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. .

1985).

[0229] Prodrugs are often useful in some cases because they may be easier to administer than the parent compound. For example, they may be bioavailable after oral administration as opposed to parent drugs. The prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug. Prodrugs can be designed as reversible drug derivatives, for use as modifiers to improve drug transport to specific tissue. In some embodiments, the prodrug design increases the effective water solubility. See, for example, Fedorak et al., Am. J. Physiol., 269: G210-218 (1995); McLoed et al., Gastroenterol, 106: 405-413 (1994); Hochhaus et al., Biomed. Chrom., 6: 283-286 (1992); J. Larsen and H. 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.

[0230] Sites in the aromatic ring in a portion of a compound of any formula (A), Formula (B), Formula (C) or Formula (D) can be very sensitive to various metabolic reactions, therefore the introduction of appropriate substituents into ring structures such as for example, halogens can reduce, minimize or eliminate these metabolic pathways.

[0231] The compounds described herein include isotope-labeled compounds that are indentional as represented herein by various formulas and structures, except that one or more atoms are replaced by other atoms having an atomic mass or atomic number other than the atomic mass or number atomic usually present in nature. Examples of isotopes that can be incorporated into compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as²H ³H, ή ο ή λ ηε 1 Q 17 QR 1 R RR ¹³C ¹⁴C ¹⁵N ¹⁸ABOUT, ¹⁷ABOUT, ³⁵S ¹⁸F ³⁶Cl. Some isotope-labeled compounds described herein, for example, those into which radioactive isotopes have been incorporated, such as³H and ¹⁴C are useful for determining drug and / or substrate tissue distribution. In addition, substitution by isotopes, such as deuterer, i.e.²H, may provide some therapeutic benefits resulting from greater metabolic stability, for example an increase in vivo half-life or a reduction in the required dose.

[0232] The compounds described herein can be metabolized after administration to a needy organism in which the desired effect is then produced, including the desired therapeutic effect.

[0233] The compounds described herein may be prepared and / or used in the form of pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts formed by reacting the free base compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid and the like; or with an organic acid such as acetic acid, propionic acid, hexanoic acid, cyclopentanopropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, acid, citric, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptenoic acid, 4,4'-methylene bis- (3-hydroxy-2-eno -1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic 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 is present in the parent compound or is replaced by a metal ion, for example, an alkali metal (e.g. lithium, sodium, potassium), an alkaline earth metal ion (e.g. magnesium or calcium), or an aluminum ion ; or coordinating relationships with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide and the like.

[0234] Corresponding counterions of pharmaceutically acceptable salts can be analyzed and identified using various methods, including but not limited to ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively excited plasma spectrometry, atomic absorption spectroscopy, mass spectrometry and combinations thereof.

[0235] Salts can be recovered using at least one of the following techniques: filtration, solvent-free precipitation followed by filtration, solvent evaporation or, in the case of aqueous solutions, lyophilization.

[0236] It should be understood that reference to a pharmaceutically acceptable salt includes solvent addition forms or crystalline forms thereof, in particular solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvents, and can be formed during processes

Crystallization with pharmaceutically acceptable solvents such as water, ethanol and the like. Hydrates are formed when the solvent is water and alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can conveniently be prepared or formulated during the processes described herein. In addition, the compounds provided herein may exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the compounds and methods provided herein.

[0237] It should be understood that reference to salts includes solvent addition forms or their crystalline forms, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvents, and can be formed during crystallization processes with pharmaceutically acceptable solvents such as water, ethanol and the like. Hydrates are formed when the solvent is water and alcoholates are formed when the solvent is alcohol. Polymorphs include different methods of crystal packing of the same elemental composition of the compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal habit, optical and electrical properties, stability and solubility. Various factors such as recrystallization solvents, recrystallization rate and storage temperatures can cause a single crystalline form to dominate.

[0238] The compounds described herein may take various forms, including but not limited to amorphous forms, ground forms, and nano-particles. In addition, the compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include different methods of crystal packing of the same elemental composition of the compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal habit, optical and electrical properties, stability and solubility. Various factors such as recrystallization solvents, recrystallization rate and storage temperatures can cause a single crystalline form to dominate.

[0239] Scanning and characterization of pharmaceutically acceptable salts, polymorphs and / or solvates can be performed using a variety of methods, including but not limited to, thermal analysis, X-ray diffraction, spectroscopy, vapor sorption and microscopy. Thermal analysis methods use thermochemical decay or thermophysical processes, including, but not limited to, polymorphic transformations, and these methods are used to analyze the relationship between polymorphic forms, mass loss determination, glass transition temperature determination, or compatibility testing with excipients. Such methods include, but are not limited to, differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA) and infrared analysis in combination with thermogravimetric analysis (TG / IR). X-ray diffraction methods relate, without limitation, to single crystal or powder diffractometry and synchrotron radiation sources. Various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS and NMR (liquid and solid state). Various microscopic techniques include, but are not limited to, polarized light microscopy, scanning electron microscopy (SEM) with X-ray energy dispersion (EDX), environmental scanning electron microscopy with EDX (in a gas or steam atmosphere), IR microscopy and Raman microscopy.

[0240] To provide stable moieties and compounds throughout the description of the group and their substituents may be selected by one of ordinary skill in the art.

Pharmaceutical composition / formulation [0241] Pharmaceutical compositions may be prepared in a conventional manner using one or more physiologically acceptable carriers including excipients and excipients, facilitating the processing of the active ingredients into preparations which can be used pharmaceutically. The correct formulation depends on the chosen route of administration. Any well known techniques, carriers and excipients may be used as appropriate and as understood in the art. A brief description of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, ed. IX (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; ed. Liberman, HA and Lachman, L., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, ed. VII (Lippincott Williams &amp; Wilkins 1999).

[0242] A pharmaceutical composition, as understood herein, refers to a mixture of a compound described herein, such as, for example, compounds of any of formulas (A), (B), (C) or (D), with other ingredients chemicals, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients. The pharmaceutical composition facilitates administration of the compound into the body. In the practice of the methods of treatment or use provided herein, therapeutically effective amounts of the compounds described herein are administered in a pharmaceutical composition

A mammal having a disease, disorder or condition to be treated. Preferably, the mammal is a human. A therapeutically effective amount may vary significantly depending on the severity of the disease, age and condition, and the subject's appropriate health, strength of the compound used, and other factors. The compounds can be used alone or in combination with one or more therapeutic agents included in the mixtures.

[0243] The compositions may also contain one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. These acids, bases and buffers are introduced in an amount required to maintain the pH of the composition within an acceptable range.

[0244] The compositions may further contain one or more salts in an amount required to bring the osmolarity of the composition to an acceptable range. Such salts include those having sodium, potassium or ammonium cation and chloride, citrate, ascorbic, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anion; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0245] The term "pharmaceutical combination" as used herein means a product obtained by mixing or combining more than one active ingredient, and includes both combinations of the fixed and unsteady compositions of the active ingredients. The term "fixed combination" means that the active ingredients, e.g., the compound described herein and the accompanying agent, are administered to the patient simultaneously as a single unit or dose. "Combination of unknown composition" means that the active substances, e.g. the compound described herein and the accompanying agent, are administered to the patient simultaneously as separate units or in parallel, simultaneously or sequentially without specific time restrictions between them, this administration providing effective levels of two compounds in the patient's body. The latter also applies to therapy in the form of a drug cocktail, e.g. the administration of three or more active substances.

[0246] The pharmaceutical formulations described herein may be administered to a subject by various routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal or transdermal administration. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid suspensions, self-emulsifying suspensions, solid solutions, liposomal suspensions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melting formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multi-particle formulations, and mixed direct and controlled release formulations.

[0247] Pharmaceutical compositions containing the compound described herein can be prepared in a traditional manner, such as by way of example only, using traditional mixing, dissolving, granulating, dragee-making, milling and fractionating (pulverizing), emulsifying, encapsulating, sealing or encapsulating processes. compression (ironing).

[0248] The pharmaceutical compositions described contain at least one compound described herein, such as, for example, a compound of any of formulas (A), (B), (C) or (D) as the active substance in the form of the free acid or free base or in the form of a pharmaceutically acceptable salt. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystal forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. In some situations, the compounds may exist as tautomers. All tautomers fall within the scope of the compounds described herein. In addition, the compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0249] "Anti-foaming agents" reduce foaming during processing that can coagulate aqueous suspensions, drug bubbles (in the film formed ), or generally adversely affect processing. Exemplary anti-foaming agents include silicone emulsions or sorbitan sesquihydrate.

[0250] "Antioxidants" include, for example, butylated hydroxytoluene (BHT), sodium ascorbate,

Ascorbic acid, sodium metabisulfite and tocopherol. Antioxidants that increase chemical stability have been required in some embodiments.

[0251] Compositions that contain one or more preservatives to inhibit bacterial (microbial) activity are described. Suitable preservatives include mercury-containing substances such as merfen and thimerosal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridine chloride.

[0252] The formulations described herein may use antioxidants, metal chelating agents, thiol containing compounds and other general stabilizing agents. Examples of such stabilizing agents include, but are not limited to: (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol , (d) about 1 πΜ to about 10 πΜ 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) cyclodextrin, (1) pentosan polysulfate and other heparinides, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0253] "Binders" give the composition coherence and include, for example, alginic acid and its salts; cellulose derivatives such as carboxymethyl cellulose, methyl cellulose (e.g. Methocel^®), hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel^®), ethyl cellulose (e.g., Ethocel^®) And microcrystalline cellulose (e.g. Avicel^®); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acids; bentonites; gelatin; polyvinylpyrrolidone / vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, sugar such as sucrose (e.g., Dipac^®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g. Xylitab^®) and lactose; natural or synthetic rubber such as acacia, tragacanth, ghatti gum, cereal husk mucus, polyvinylpyrrolidone (e.g. Polyvidone^® CL, Kollidon^® CL, Polyplasdone^® KSL-10), arabinogalactan from larch bark, Veegum^®, polyethylene glycol, waxes, sodium alginate and the like.

[0254] "Carrier" or "carrier materials" include any customary pharmacy excipients and should be selected in accordance with the compounds disclosed herein, such as compounds of any of formulas (A), (B), (C) or (D), and the release profile of the desired dosage form. Exemplary carrier materials include, e.g. binders, dispersing agents, disintegrants, bulking agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents and the like. "Pharmaceutically compatible carrier materials" may include, but are not limited to, acacia gum, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol, cholesterol esters, sodium caseinate , soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dibasic phosphate, cellulose and cellulose conjugates, sugars, sodium stearoyl lactate, carrageenan, monoglyceride, diglyceride, pregelatinized starch and the like. See, e.g., Remington: The Science and Practice of Pharmacy, Ed. nineteenth (Easton, Pa .: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; ed. Liberman, HA and Lachman, L., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, ed. VII (Lippincott Williams &amp; Wilkins 1999).

[0255] "Dispersing agents" and / or "viscosity modifying agents" include materials that control the diffusion and homogeneity of a drug in a liquid medium or granulation method or blend method. In some embodiments, these agents also increase the coating efficiency or eroding of the matrix. Exemplary diffusion / dispersants include, e.g., hydrophilic polymers, electrolytes, Tween^® 60 or 80, PEG, polyvinylpyrrolidone (PVP; known commercially as Plasdone^®) and carbohydrate-based dispersants, such as, for example, hydroxypropyl cellulose (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcellulose (e.g. HPMC K100, HPMC K4M, HPMC K15M and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethyl cellulose, polypropylmethyl cellulose, HPLC, polypropylmethanol, vinyl acetate (S630), polymer 4- (1,1,3,3-tetramethylbutyl) phenol with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g. Pluronics F68^®, F88^® and F108^®which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908^®, also known as Poloksamine 908^®, which is a four-function block copolymer derived from the gradual attachment of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ)), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, polyvinylpyrrolidone K30, polyethylene glycol, e.g. glycol

The polyethylene may have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethyl cellulose, methyl cellulose, polysorbate-80, sodium alginate, gums, e.g., gum tragacanth and acacia gum, guar gum, xanthanes, including xanthan gum, sugars, celluloses, such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxysorbitan monolaurate, povidone, carbomers, polyvinyl alcohol (PVA), alginates and their combinations. Emollients such as cellulose or triethyl cellulose can also be used as dispersing agents. Dispersants that are particularly useful in liposome suspensions and self-emulsifying suspensions are dimrististoyl phosphatidylcholine, natural egg phosphatidylcholine, natural egg phosphatidylglycerol, cholesterol and isopropyl myristate.

[0256] Combinations of one or more erosion facilitators with one or more diffusion facilitators can also be used in the present compositions.

[0257] The term "diluent" refers to chemical compounds that are used to dilute the subject compound prior to its delivery. Thinners can also be used to stabilize compounds as they can provide a more stable environment. Salts dissolved in buffered solutions (which may also provide control or maintenance of pH), including, but not limited to, phosphate buffered saline solutions are used as diluents in this field. In some embodiments, diluents increase the volume of the composition by facilitating their compression or form a sufficiently large mass of a homogeneous capsule filling mix. Such 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 sugars such as Di-Pac^® (Amstar); mannitol, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose-based diluents, confectionary sugars; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrans; hydrolysed cereal solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite and the like.

[0258] The term "disintegrate" includes both dissolution and dispersion of the dosage form upon contact with the gastrointestinal fluid. "Disintegrating or disintegrating agents" facilitate the disintegration or fragmentation of substances. Examples of disintegrating agents include starch, e.g., natural starch such as starch corn or potato starch, pregelatinized starch such as National 1551 or Amijel^®or sodium starch glycolate such as Promogel^® or Eksplotab^®, cellulose such as wood cellulose, microcrystalline cellulose, e.g. Avicel^®, Avicel^® PH101, Avicel^® PH102, Avicel^® PH105, Elcema^® P100, Emcocel^®, Vivacel^®, Ming Tia^® and Solka-Floc^®, methylcellulose, croscarmellose or cross-linked cellulose, such as cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol^®), crosslinked carboxymethylcellulose or crosslinked croscarmellose, crosslinked starch such as sodium starch glycolate, crosslinked polymer such as crospovidone, crosslinked polyvinylpyrrolidone, alginate such as alginic acid or alginic acid salt such as sodium alginate, clay such as Veeg^® HV (magnesium aluminum silicate), gum such as agar, guar, locust bean gum, Karaya, pectin or tragacanth, sodium starch glycolate, bentonite, natural sponge, surfactant, resin such as cation exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch and the like.

[0259] "Drug absorption" (absorption) or "absorption" typically refers to the process of the drug moving from the drug administration site through a barrier to a blood vessel or to the site of action, e.g. a drug moving from the gastrointestinal tract into the portal vein or lymphatic system.

[0260] 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. Generally, the enteric coating contains a polymeric material that prevents release in the gastric environment of low pH but is ionized at higher pH, usually pH 6 to 7, and thus dissolves sufficiently in the small intestine or colon to release the active substance.

[0261] "Erosion promoters" include materials that control the erosion of specific material in gastrointestinal fluid. Agents that promote erosion are well known to those skilled in the art. Exemplary erosion promoters include, e.g., hydrophilic polymers, electrolytes, proteins, peptides and amino acids.

[0262] "Fillers" include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose,

Dextrose, dextrans, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol and the like.

[0263] "Flavorings" and / or "sweeteners" useful in the formulations described herein include, e.g., acacia syrup, acesulfame K, Alitame, anise, apple, aspartame, banana, whipped cream (Bavarian cream), blueberry, blackcurrant, caramel (ang. butterscotch), calcium citrate, camphor, caramel, cherry, Cherry cream, chocolate, cinnamon, chewing gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, kola, refreshing cherry, refreshing citrus, cyclamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycretinate, licorice root syrup (licorice), grape, grapefruit, honey, isomalt, lemon, lime (lime), lemon cream, ammonium glycisinate (MagnaSweet^®), maltol, mannitol, clone, marshmallow, menthol, mint cream, mixed berry, DC neohesperidin, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet^® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, mint, mint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, silylitol, sucralose, sorbitol , Swiss cream, tagatose, tangerine, taumatin, tutti frutti, vanilla, walnut, watermelon, wild cherry, pear (wintergreen), xylitol or any combination of these flavor ingredients, e.g. anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint and mixtures thereof.

[0264] "Lubricants" and "glidants" are compounds that prevent, reduce, or inhibit adhesion or friction of materials. Exemplary lubricants include, e.g., 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 salts with alkali and alkaline earth metals such as aluminum, calcium, magnesium, zinc stearates, stearic acid, sodium stearates, glycerol, talc, waxes, Stearowet^®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (e.g., PEG-4000) or methoxypolethylene 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^®, starch such as corn starch, silicone oil, surfactant and the like.

[0265] "Measurable plasma concentration" or "measurable serum concentration" means the concentration in blood plasma or serum, usually measured in mg, μg or ng of the drug per ml, dl or l plasma absorbed into the blood stream after administration . As used herein, measurable plasma concentrations are typically measured in ng / ml or μg / ml.

[0266] "Pharmacodynamics" refers to factors that determine the biological response observed with respect to drug concentration at the site of action.

[0267] "Pharmacokinetics" refers to factors that determine the achievement and maintenance of an appropriate concentration of a drug at the site of action.

[0268] "Emollients" are compounds used to soften microencapsulation material or film coatings to make them less brittle. Suitable softeners include, e.g., polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350 and PEG 800, stearic acid, propylene glycol, oleic acid, triethyl cellulose and triacetin. In some embodiments, emollients may also act as dispersing agents or wetting agents.

[0269] "Solubilizers" include compounds such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium docusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxyethylpropyl hydroxy isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol and dimethylisosorbide and the like.

[0270] "Stabilizers" include compounds such as antioxidants, buffers, acids, preservatives and the like.

[0271] "Steady state", as it stands today, occurs when the amount of drug administered is equal to the amount of drug eliminated during one dosing interval, resulting in plateau or constant drug exposure in plasma.

[0272] "Dispersing agents" include compounds such as polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, a vinylpyrrolidone / vinyl acetate copolymer (S630), polyethylene glycol, which can be polyethylene glycol, e.g.

To about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxymethylcellulose acetate stearate, polysorbate-80, hydroxyethyl cellulose, such as sodium, gums, such as sodium, tragacanth and acacia gum, guar gum, xanthanes, including xanthan gum, sugars, celluloses, such as sodium carboxymethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, similar hydroxypropyl methyl cellulose, hydroxyethyl cellulose, polysorbate sodium, polysorbate, monoxysolate 80 .

[0273] "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, oxyethylene glycolate propylene, e.g. Pluronic^® (BASF) and similar. Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene hydrogenated castor oil (60); and polyoxyethylene alkyl ether and alkyl phenylethers, e.g. octoxynol 10, octoxynol 40. In some embodiments, surfactants may be included to increase physical stability or for other purposes.

[0274] "Viscosity enhancing agents" include, e.g., methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, hydroxypropyl methylcellulose phthalate, and polyalkyl alcohol, carboxylate, polyethylene glycol, carboxymethylcellulose, polyethylene glycol, carboxymethylcellulose, polyethylene glycol, carboxymethylcellulose, polyethylene glycol, carboxymethylcellulose, polyethylene glycol, carboxymethylcellulose, polyethylene glycol, carboxymethylcellulose, carboxymethylcellulose, polyethylene glycol, carboxymethylcellulose, polyethylene glycol, carboxymethylcellulose.

[0275] "Wetting agents" include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium docaurate, sodium lithosinate, sodium oleate E TPGS, ammonium and similar salts.

Dosage Forms [0276] The compositions described herein can be formulated for administration to a subject by any conventional means including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous or intramuscular), buccal, intranasal, rectal or transdermal. The term "subject" as used herein is used in the sense of an animal, preferably a mammal, including human and non-human beings. The terms patient and subject may be used interchangeably.

[0277] In addition, the pharmaceutical compositions described herein that contain a compound of any formula (A), (B), (C) or (D) may be formulated at any suitable dosage form, including, but not limited to, aqueous oral suspensions, liquids, gels, syrups, elixirs, suspensions, suspensions and the like, for oral consumption by the patient to be treated, solid oral dosage forms, aerosols, controlled release formulations, fast melting formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, sustained release formulations, pulse release formulations, multi-particle formulations and mixed direct and controlled release formulations .

[0278] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture and processing the mixture of granules after adding suitable excipients, if necessary, to obtain tablet 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 tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium or others, such as: polyvinylpyrrolidone or sodium If desired, disintegrants such as cross-cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar or alginic acid or a salt such as sodium alginate may be added.

[0279] Dragee cores may be provided with appropriate coatings. For this purpose, concentrated sugar solutions may be used, 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 tablet and dragee coatings to identify or characterize different combinations of active compound doses.

[0280] Pharmaceutical preparations that can be used orally include snap capsules made of gelatin, as well as flexible, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The snap-on capsules may contain the active ingredients in admixture with a filler such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In flexible capsules, the active compounds can be dissolved or dispersed in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

[0281] Solid dosage forms are described, which may be in the form of tablets (including dispersible tablet, fast dissolving tablet, biting disintegrating tablet, fast disintegrating tablet, effervescent tablet or caplet), pills, powder (including sterile packaged powder, metered powder or effervescent powder), capsules (including both soft and hard capsules, e.g. capsules made of animal gelatin or HPMC of plant origin or sprinkle capsules, solid dispersion, solid solution, bioerodible dosage forms, controlled release formulations, pulsatile release dosage forms, multi-particle dosage forms, pellets , granules or aerosol. The pharmaceutical formulations may be in the form of powder. In yet other cases, the pharmaceutical formulation is in the form of a tablet, including, but not limited to said fast dissolving tablet. In addition, the pharmaceutical formulations described herein may be administered as a single capsule or in the form of multiple capsules. The pharmaceutical formulations can be administered in two or three or four capsules or tablets.

[0282] Solid dosage forms, e.g., tablets, effervescent tablets and capsules, prepared by mixing the particles of a compound of any of formulas (A), (B), (C) or (D) with one or more pharmaceutical substances are described auxiliary to form a mass of composition blends. Referring to these masses of the composition of mixtures as homogeneous, it is assumed that the particles of the compound of any of formulas (A), (B), (C) or (D) are dispersed evenly within the composition, so that the composition can easily be divided into equal effective unit dosage forms such as tablets, pills and capsules. Individual dosage units may also contain coatings that disintegrate when ingested or on contact with a diluent. These preparations can be produced using traditional pharmacological techniques.

[0283] Traditional pharmacological techniques include, e.g., one or a combination of the following methods: (1) dry mixing, (2) direct tabletting, (3) milling, (4) dry or without water granulation, (5) wet granulation , or (6) melting. See, e.g., Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, spray drying or fluid bed coating (e.g. Wurster coating), cone drum coating, spraying, tableting, extrusion and the like.

[0284] The pharmaceutical solid dosage forms described herein may contain the compound described herein and one or more pharmaceutically acceptable excipients, such as a compatible (compatible) carrier, binder, bulking agent, suspending agent, flavoring agent, sweetener, disintegrant, agent dispersing, surfactant, lubricant, dye, diluent, solubilizer, wetting agent, emollient, a stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative or one or more combinations thereof. In yet other aspects, using conventional coating procedures such as those described in Remington's Pharmaceutical Sciences, 4th ed. XX (2000), a coating is applied around the compound formulation of any of formulas (A), (B), (C) or (D). In one embodiment, some or all of the compound particles of any of formulas (A), (B), (C) or (D) are coated. In another embodiment, some or all of the compound particles of any of formulas (A), (B), (C) or (D) are encapsulated in microcapsules. In yet another embodiment, the particles of the compound of any of formulas (A), (B), (C) or (D) are not encapsulated or coated.

[0285] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia gum, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate,

Soy lecithin, lecithin, sodium chloride, tricalcium phosphate, dibasic phosphate, sodium stearoyl lactate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropyl methylcellulose, manostearate, microsolactose acetate, stearyl cellulose, hydroxyl cellulose.

[0286] Suitable bulking agents 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, powdered cellulose, dextrose, dextrans, dextran, starches, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol and the like.

[0287] To release a compound of any of formulas (A), (B), (C) or (D) from the solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulations, especially when the dosage forms are pressed from binder. Disintegrants facilitate the disintegration of the matrix of the dosage form as a result of swelling or capillary effect when moisture is absorbed into the dosage form. Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starches such as corn starch or potato starch, pregelatinized starches like National 1551 or Amijel^®or sodium starch glycolate such as Promogel^® or Eksplotab^®, celluloses such as (R) (R) (R) (R) wood cellulose, microcrystalline cellulose, e.g. Avicel^®, Avicel^® PH101, Avicel^® PH102, Avicel^® PH105, Elcema^® P100, Emcocel^®, Vivacel^®, Ming Tia^® and Solka-Floc^®, methyl cellulose, croscarmellose or cross-linked cellulose, such as cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol^®), cross-linked carboxymethyl cellulose or cross-linked cross-croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, alginate such as alginic acid or alginic acid salt such as sodium alginate, clay such as Veegum^® HV (magnesium aluminum silicate), gum such as agar, guar, locust bean gum, Karaya, pectin or tragacanth, sodium starch glycolate, bentonite, natural sponge, surfactant, resin such as cation exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch and the like.

[0288] Binders give sticky oral formulations to formulations: in powder filled capsule formulations, they facilitate the formation of a cork that can be used to fill soft or hard gelatin capsules or tablet formulations, ensure that the tablet remains intact after tableting and give homogeneity to the tablet compound before pressing or filling step. Materials suitable for use as binders in the solid oral forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel^®), hydroxypropyl methyl cellulose (e.g. Hypromellose USP Pharmacoat-603), hydroxypropyl methyl cellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel^®), ethyl cellulose (e.g., Ethocel^®) And microcrystalline cellulose (e.g. Avicel^®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, such as dextrin, sugar^®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g. Xylitab^®), lactose, natural or synthetic gums such as acacia, tragacanth, ghatti gum, cereal husk gruel, starch, polyvinylpyrrolidone (e.g. Povidone^® CL, Kollidon^® CL, Polyplasdone^® KSL10 and Povidone^® K-12), arabogalactan from larch bark, Veegum^®, polyethylene glycol, waxes, sodium alginate and the like.

[0289] Generally, the amounts of binder used in powder filled gelatin capsule formulations are in the range of 20-70%. The level of use of the binder in tablet formulations varies, depending on whether the tablet is obtained by direct tabletting, wet granulation, roller compaction or the use of other excipients such as fillers, which can themselves act as a moderate binder. Those skilled in the art can determine the level of binder for the formulation, but the binder use level commonly used in tablet formulation is up to 70%.

[0290] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, cornstarch, sodium stearyl fumarate, alkali and alkaline earth metal salts such as aluminum , calcium, magnesium, zinc, stearic acid, sodium stearate, magnesium stearate, zinc stearate, waxes, Stearowet^®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol or methoxypolyethylene glycol such as Carbowax ™, PEG 4000, PEG 5000, PEG 6000, glycol

Propylene, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate and the like.

[0291] 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 dextrans and maltodextrin), polyols (including mannitol, xylitol and sorbitol), cyclodextrins and the like.

[0292] The term "water insoluble diluent" means compounds typically used in pharmaceutical formulation such as calcium phosphate, calcium sulfate, starches, modified starches and microcrystalline cellulose, and microcellulose (e.g., having a density of about 0.45 g / cm³e.g. Avicel, cellulose powder) and talc.

[0293] Suitable wetting agents for use in the solid oral dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate,^®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and the like.

[0294] Suitable surfactants for use in the solid oral dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monoleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide, e.g. propylene oxide^® (BASF) and similar.

[0295] Suitable suspending agents for use in the solid dosage forms described herein include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone

K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, polyethylene glycol, e.g. polyethylene glycol which may have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, vinylpyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polysorbate-80 cellulose, hydroxylate sodium, gums such as, e.g., tragacanth and acacia, guar gum, xanthanes, including xanthan gum, sugars, cellulosics such as e.g. sodium carboxymethyl cellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, after lisorbate-80, sodium alginate, polyethoxysorbitan monolaurate, polyethoxysorbitan monolaurate, povidone and the like.

[0296] Suitable antioxidants for use in the solid dosage forms described herein include, e.g., butylated hydroxytoluene (BHT), sodium ascorbate and tocopherol.

[0297] Note the overlapping of excipients used in the solid dosage forms described herein. Therefore, the above-mentioned excipients should be considered as exemplary, and not limiting, types of excipients that may be present in the solid dosage forms described herein. The amounts of these excipients can be easily determined by those skilled in the art according to the specific properties desired.

[0298] In other embodiments, one or more layers of the pharmaceutical formulation are softened. Illustratively, the emollient is generally a solid or liquid body with a high boiling point. Suitable emollients can be added in an amount of from about 0.01% to about 50% by weight (w / w) of the coating composition. Emollients 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, stearol oil, stearate.

[0299] The compressed tablets are solid dosage forms made by compressing the mass of the formulation blend described above. In various embodiments, compressed tablets intended to dissolve in the mouth will contain one or more flavoring agents. In other embodiments, compressed tablets will contain a film surrounding the final compressed tablet. The coating may provide delayed release from the formulation of a compound of any of formulas (A), (B), (C) or (D). In other situations, the coating helps the patient follow the doctor's instructions (e.g. Opadry coating)^®or sugar coatings). Coatings containing Opadry^® they usually make up from about 1% to about 3% of the weight of the tablet. Compressed tablets may contain one or more excipients. [0300] A capsule can be made, for example, by placing a mass of 43 compound compound formulation

Any of the formulas (A), (B), (C) or (D) described above inside the capsule. In some cases, the formulations (non-aqueous suspensions and solutions) are placed in a soft gelatin capsule. In other cases, the formulations are placed in typical gelatin or non-gelatin capsules, such as capsules containing ΗΡΜΟ In other cases, the formulation is placed in a sprinkle capsule, which capsule can be swallowed whole or opened, and the contents sprinkle food before eating. In some cases, the therapeutic dose is divided into many (e.g., two, three or four) capsules. In some cases, the entire dose of the formulation is delivered in the form of a capsule.

[0301] In various cases, particles of a compound of any of formulas (A), (B), (C) or (D), and one or more excipients are dry mixed and pressed into a mass, such as a tablet, having sufficient hardness to undergo major disintegration in less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes or less than about 60 minutes, after oral administration thereby releasing the formulation into the gastrointestinal fluid.

[0302] Solid dosage forms having microcapsule formulations are described. In some cases, one or more (compatible) compatible substances are embedded in the surrounding material. Exemplary substances include, but are not limited to, pH modifiers, erosion promoters, anti-foaming agents, antioxidants, flavors and carrier materials such as binders, disintegrants, bulking agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents and thinners.

[0303] Materials suitable for micro-encapsulation described herein include (compatible) materials compatible with compounds of any of formulas (A), (B), (C) or (D) that sufficiently isolate a compound of any of formulas (A), ( B), (C) or (D) from other incompatible excipients. Materials compatible with compounds of any of formulas (A), (B), (C) or (D) are those that delay the release of compounds of any of formulas (A), (B), (C) or (D) , in vivo.

[0304] Exemplary microencapsulation materials useful for delaying the release of formulations containing the compounds described herein include, but are not limited to, hydroxypropyl cellulose (HPC) ethers such as Klucel^® or Nisso HPC, low substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat^®, Metolose SR, Metocel^®-E, Opadry YS, PrimaFlo, Benecel MP824 and Benecel MP843, methyl cellulose polymers such as Methocel^®-A, hydroxypropyl methylcellulose acetate stearate Aqoat (HF-LS, HFLG, HF-MS) and Metolose^®, ethyl cellulose (EC) and mixtures thereof such as E461, Ethocel^®, Aqualon^®-EC, Surelease^®, polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethyl cellulose such as Natrosol^®, carboxymethyl cellulose and carboxymethyl cellulose (CMC) salts such as Aqualon^®-CMC, polyvinyl alcohol and polyethylene glycol copolymers such as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLKS), polyethylene glycols, modified edible starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit^® EPO, Eudragit^® L30D-55, Eudragit^® FS 30D, Eudragit^®L100-55, Eudragit^® L100, Eudragit^® S100, Eudragit^® RD100, Eudragit^® E100, Eudragit^® L12.5, Eudragit^®S12.5, Eudragit^® NE30D and Eudragit^® NE 40D, cellulose acetate phthalate, Sepifilm such as mixtures of HPMC and stearic acid, cyclodextrin and mixtures of these materials.

[0305] The use of softeners such as polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350 and PEG 800, stearic acid, propylene glycol, oleic acid and triacetin, which are incorporated in the microencapsulating material, are described . In other cases, microencapsulation material useful for delaying the release of pharmaceutical compositions is known from USP or National Formulary (NF). In yet other embodiments, the microencapsulation material is Klucel. In yet other embodiments, the microencapsulation material is Methocel.

[0306] The microencapsulation of compounds of any of formulas (A), (B), (C) or (D) can be carried out by methods known to those skilled in the art. Such known methods include, for example, spray drying processes, solvent processes using a rotary cone, hot melting processes, cold spray methods, fluidized bed, electrostatic deposition, centrifugal extrusion, suspension separation (suspension) by rotary method, phase-bound polymerization. liquid-gas or solid-gas, pressure extrusion or solvent spray extraction bath. In addition to these, several chemical techniques may also be used, e.g., complex coacervation, solvent evaporation, induction of polymer-polymer incompatibility, interfacial polymerization in a liquid medium, in situ polymerization, liquid drying and desolvation in a liquid medium. In addition, others may also be used

Methods such as roller compacting, extrusion / spheronization, coacervation or coating of nanoparticles.

[0307] In one case, the particles of the compounds of any of formulas (A), (B), (C) or (D) are microencapsulated before being formulated in one of the above forms. In yet another embodiment, some or most of the particles are coated prior to further formulation using conventional coating procedures such as those described in Remington's Pharmaceutical Sciences, ed. XX (2000).

[0308] Solid oral formulations of compounds of any of formulas (A), (B), (C) or (D) which are softened (coated) with one or more layers are described. For illustration, the emollient is generally a solid or liquid body with a high boiling point. Suitable emollients are added in an amount of from about 0.01% to about 50% by weight (w / w) of the coating composition. Emollients 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, stearol oil, stearate.

[0309] Also described are powders containing formulations of compounds of any of formulas (A), (B), (C) or (D), formulated to contain one or more pharmaceutical excipients and flavors. Such powders can be prepared, for example, by mixing formulations and optional pharmaceutical excipients to form a bulk blend of the composition. A dispersing and / or wetting agent is also described. This mass of the mix is ​​uniformly distributed into unit dose packaging or multiple unit dose packaging.

[0310] Effervescent powders are also described. Effervescent salts are used to disperse drugs in water for oral administration. Effervescent salts are granules or coarse powders containing the therapeutic agent in a dry mix, usually consisting of sodium bicarbonate, citric acid and / or tartaric acid. When the salts of the compositions described herein are added to water, the acids and bases react with each other to release carbon dioxide gas, thus causing "effervescence". Examples of effervescent salts include, e.g., the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and / or tartaric acid. Instead of a combination of sodium bicarbonate and citric and tartaric acids, any acid-base combinations that release carbon dioxide may be used, provided the ingredients are suitable for pharmaceutical use and provide a pH of about 6.0 or higher.

[0311] The formulations described herein contain a compound of formula (A) in the form of solid dispersions. Methods for making solid dispersions are known in the art and include, but are not limited to, for example, US Patent Nos. 4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269 and US Publication No. 2004/0013734. Formulations in the form of solid solutions are also described. In solid solutions, the substance is included along with the active substance and other auxiliaries, which causes the drug to dissolve when the mixture is heated, after which the resulting composition is cooled, obtaining a solid mixture, which can be further formulated or added directly to the capsule or compressed into a tablet. Methods for making such solid solutions are known in the art and include, but are not limited to, for example, US Patent Nos. 4,151,273, 5,281,420 and 6,083,518.

[0312] Pharmaceutical solid oral dosage forms including formulations described herein that contain a compound of any of formulas (A), (B), (C) or (D) may be further developed to provide controlled release of the compound of formula (A ). Controlled release refers to the release of a compound of any of formulas (A), (B), (C) or (D) from the dosage form in which it is introduced, according to a fixed profile over an extended period. Controlled release profiles include, for example, sustained release, sustained release, pulsed release and delayed release. In contrast to direct release compositions, controlled release compositions allow the agent to be delivered to a subject over a prolonged period according to a predetermined profile. Such release rates can provide therapeutically effective levels of the agent for a longer period of time, thereby providing a longer period of pharmacological response while minimizing adverse effects compared to traditional rapid release dosage forms. These extended response periods provide a number of inherent benefits that are not obtained with corresponding short-acting direct release formulations.

[0313] The solid dosage forms described herein can be formulated as enteric coated oral delayed release dosage forms, i.e. as the oral dosage form of the pharmaceutical composition described herein that uses the enteric coating to achieve release in the small intestine of the gastrointestinal tract. The enteric coated dosage form may be a compressed or molded or extruded tablet / form (form) (coated or uncoated)

EP 2 201 840 B1 containing granules, powder, pellets, beads or particles of the active substance and / or other components of the composition which are coated or uncoated on their own. The enteric coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules of a solid support, or compositions that are themselves coated or uncoated.

[0314] The term "delayed release" as used herein refers to such delivery in which release can be achieved at some generally predictable location of the intestinal system more distant than would be achieved if no change in release delay were achieved. In some embodiments, the method of obtaining delayed release is coating. Any coating should be applied to a suitable thickness so that the entire coating does not dissolve in gastrointestinal fluids at a pH below about 5, while it dissolves at a pH of about 5 and above. It can be expected that any anionic polymer having a pH-dependent dissolution profile can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower sections of the gastrointestinal tract. In some cases, the polymers described herein are anionic carboxyl polymers. In other cases, polymers and their (compatible) compatible mixtures, and some of their properties, include, but are not limited to:

[0315] Shellac, also called purified lacquer, a refined product obtained from resinous secretions of insects. This coating dissolves in an environment with a pH&gt; 7;

[0316] Acrylic polymers. The characteristics of acrylic polymers (mainly their solubility in biological fluids) may vary depending on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymer. Eudragity series E, L, S, RL, RS and NE (Rohm Pharma) are available in dissolved form in an organic solvent, as aqueous suspensions or dry powders. Eudragits of the RL, NE and RS series are insoluble in the gastrointestinal tract, but are permeable and are mainly used for targeted delivery to the colon. Eudragity E series dissolve in the stomach. Eudragits of the L, L-30D and S series are insoluble in the stomach and dissolve in the intestine;

[0317] Cellulose derivatives. Examples of suitable cellulose derivatives are: ethyl cellulose; reaction mixtures of partial cellulose esters with phthalic anhydride. Their characteristics may vary depending on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves at pH&gt; 6. Aquateric (ΡΜΟ) is a water-based system and is a spray dried CAP psuedolatex with a particle size &lt;1 μm. Other components of Aquateric may include Pluronic, Tween and acetylated monoglycerides. Other suitable cellulose derivatives include: cellulose acetate trimellitate (Eastman); methyl cellulose (Pharmacoat, Methocel); hydroxypropyl methylcellulose phthalate (ΗΡΜΦΡ); hydroxypropyl methylcellulose succinate (HPMCS); and hydroxypropyl methylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). Their characteristics may vary depending on the degree and type of substitution. For example, gatunki grades are suitable, such as HP-50, HP-55, HP-55S, HP-55F. Their characteristics may vary depending on the degree and type of substitution. For example, suitable species of hydroxypropyl methylcellulose acetate phthalate include, but are not limited to, AS-LG (LF), which dissolves at pH 5, AS ^ G ^ F), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH. These polymers are offered as granules or fine powders for aqueous suspensions;

[0318] Polyvinyl acetate phthalate (PVAP). PVAP dissolves at pH&gt; 5 and is much less permeable to water vapor and gastrointestinal fluids.

[0319] The coating may, and usually contains, a softener and is likely to contain other coating auxiliaries, such as dyes, talc and / or magnesium stearate, which are well known in the art. Suitable emollients include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), triethyl acetyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, propylene glycol ester dibutyl phthalate. In particular, anionic carboxylic acrylic polymers will usually contain 10-25% by weight of softeners, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. Traditional coating techniques, such as spray or pan coating, are used to apply the coatings. The coating thickness must be sufficient to ensure that the oral dosage form will remain intact until the desired intestinal delivery site is reached.

[0320] In addition to softeners, dyes, detoxifying agents, surfactants, anti-foaming agents, lubricants (e.g. wax, may be added to coatings)

(Carnauba or PEG), aimed at solubilizing or dispersing the coating material and improving the characteristics of the coating and the coated product.

[0321] The formulations described herein that contain a compound of formula (A) are provided using a pulsatile release dosage form. The pulsatile release dosage form has the ability to deliver one or more direct release pulses at scheduled time points after a controlled delay period or at specific locations. Pulse-release dosage forms including formulations described herein that contain a compound of any of formulas (A), (B), (C) or (D) can be administered using a variety of pulse-release formulations known in the art. For example, such formulations include, but are not limited to, those described in US Patent Nos. 5,011,692, 5,017,381, 5,229,135 and 5,840,329. Other pulsatile release dosage forms include, for example, US Patent Nos. 4,871,549, 5,260,068, 5,260,069, 5,508,040, 5,567,441 and 5,837,284. Controlled release dosage forms may be solid oral pulsatile release dosage forms comprising at least two groups of particles (i.e., multiparticulates), each containing the formulation described herein. The first group of particles provides essentially immediately a dose of a compound of any of formulas (A), (B), (C) or (D), after ingestion by a mammal. The first group of particles may be either uncoated or include a coating and / or a sealing shell. The second group of particles includes coated particles that contain 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 a compound of any of formulas (A), ( B), (C) or (D) in said formulation, mixed with one or more binders. The coating contains a pharmaceutically acceptable component in an amount sufficient to provide a delay of from about 2 hours to about 7 hours after ingestion before the second dose is released. Suitable coatings include one or more coatings that are degraded in a variety of ways, such as, by way of example only, pH-sensitive coatings (enteric coatings), such as acrylic resins (e.g. Eudragit^® EPO, Eudragit^® L30D-55, Eudragit^® FS 30D Eudragit^® L100-55, Eudragit^® L100, Eudragit^® S100, Eudragit^® RD100, Eudragit^® E100, Eudragit^® L12.5, Eudragit^® S 12.5 and Eudragit^® NE30D, Eudragit^® NE 40D^®) alone or in admixture with cellulose derivatives, e.g. ethyl cellulose or non-enteric coatings having different thicknesses to provide differential release of a formulation containing a compound of any of formulas (A), (B), (C) or (D).

[0322] 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 administration systems include, e.g., polymer-based systems such as polylactic and polyglycolic acid, polyanhydrides and polycaprolactone; porous matrices, non-polymeric systems that are lipids, including sterols such as cholesterol, cholesterol and fatty acid esters or neutral fats such as mono-, di- and triglycerides; hydrogel release systems; Silastic silicone elastomer systems, peptide based systems; wax coatings, bioerodible dosage forms, compressed tablets using traditional binders and the like. See, e.g., Liberman et al., Pharmaceutical Dosage Forms, ed. 2, vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, ed. 2, pp. 751-753 (2002); U.S. Patent Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,40, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014 and 6,932,983.

[0323] Pharmaceutical formulations comprising particles of compounds of any of formulas (A), (B), (C) or (D) and at least one dispersing or suspending agent for oral administration to a subject are described. The formulations can be in the form of powder and / or granules for suspension, and when mixed with water, a substantially uniform suspension forms.

[0324] Liquid dosage forms of oral administration formulations may be aqueous suspensions selected from the group consisting of, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, ed. 2, pp. 754-757 (2002). In addition to the particles of the compound of formula (A), liquid dosage forms may contain auxiliary substances such as: (a) disintegrants; (b) dispersing agents; (c) wetting agents; (d) at least one preservative, (e) viscosity enhancers, (f) at least one sweetener, and (g) at least one flavoring agent. In some embodiments, the aqueous dispersions may further include a crystallization inhibitor.

[0325] The aqueous suspensions and dispersions described herein may remain homogeneous as defined in Pharmacopoeia St. United States (2005 edition, chapter 905) for at least 4 hours. Homogeneity should be assessed by sampling in accordance with the method for determining the homogeneity of the entire composition. The aqueous suspension can be re-suspended into a homogeneous suspension by physical mixing for less than a minute. The aqueous suspension can be re-suspended into a homogeneous suspension by physical agitation for less than 45 seconds. For example, the aqueous suspension may be re-suspended into a homogeneous suspension by physical means

Mixing for less than 30 seconds. In other cases, no mixing is needed to maintain a homogeneous aqueous suspension.

[0326] Examples of disintegrants for use in aqueous suspensions and dispersions include, but are not limited to, starches, e.g., natural starch such as corn starch or potato starch, pregelatinized starch such as National 1551 or Amijel^® or sodium starch glycolate such as Promogel^® or Eksplotab^®; cellulose such as wood cellulose, microcrystalline cellulose, e.g. Avicel^®, Avicel^® PH101, Avicel^®PH102, Avicel^® PH105, Elcema^® P100, Emcocel^®, Vivacel^®, Ming Tie^® and Solka-Floc^®, methyl cellulose, croscarmellose or cross-linked cellulose, such as cross-linked carboxymethyl cellulose (Ac-Di-Sol^®), cross-linked carboxymethyl cellulose or cross-linked croscarmellose; cross-linked starch such as sodium starch glycolate; a cross-linked polymer such as crospovidone; cross-linked polyvinylpyrrolidone; alginate such as alginic acid or a salt of alginic acid such as sodium alginate; clay like Veegum^® HV (magnesium aluminum silicate); gum such as agar, guar, locust bean gum, Karaya, pectin or tragacanth; sodium starch glycolate; bentonite; natural sponge; surfactant; a resin such as a cation exchange resin; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate in combination with starch and the like.

[0327] Dispersants suitable for aqueous suspensions and dispersions known in the art are described, for example, hydrophilic polymers , electrolytes, Tween^® 60 or 80, PEG, polyvinylpyrrolidone (PVP; known commercially as Plasdone^®) and carbohydrate-based dispersants such as, for example, hydroxypropyl cellulose and hydroxypropyl cellulose ethers (e.g. HPC, HPC-SL and HPC-L), hydroxypropyl methyl cellulose and hydroxypropyl methyl cellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate phthalate, non-crystalline cellulose, polyvinylmethanol, polyvinylmethanol,^®, e.g. S-630), polymer of 4- (1,1,3,3-tetramethylbutyl) -phenol with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g. Pluronics F68^®, F88^® and F108^®which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908^®, also known as Poloxamine 908^®, which is a four-function block copolymer derived from the subsequent attachment of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, NJ). In other embodiments, the dispersant is selected from the group not including one of the following: hydrophilic polymers, electrolytes, Tween^® 60 or 80, PEG, polyvinylpyrrolidone (PVP) and hydroxypropyl cellulose and hydroxypropyl cellulose ethers (e.g. HPC, HPC-SL and HPC-L), hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g. HPMC K100, HPMC K4M and HPMC K100M HPMC100)^® USP 2910 (Shin-Etsu)); sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate, non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylidone copolymer^®, e.g. S-630), polymer of 4 (1,1,3,3-tetramethylbutyl) -phenol with ethylene oxide and formaldehyde, poloxamers (e.g. Pluronics F68^®, F88^® and F108^®which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908^®, also known as Poloxamine 908^®.

[0328] Wetting agents suitable 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 Tween^® such as, e.g., Tween 20^® and Tween 80^® (ICI Specialty Chemicals)), and polyethylene glycols (e.g., Carbowax 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 lauryl sulfate, sodium trioxylate, sodium tococholate

[0329] Suitable preservatives for the aqueous suspensions and suspensions or dispersions described herein include, for example, potassium sorbate, parabens (e.g., methylparaben and propylparaben), benzoic acid and its salts, other para-hydroxybenzoic acid esters such as butylparaben, such 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 added to the dosage form in a concentration sufficient to inhibit the growth of microorganisms.

[0330] Suitable viscosity enhancing agents for the aqueous suspensions or dispersions described herein include, but are not limited to, methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, Plasdon^® S-630,

Carbomer, polyvinyl alcohol, alginates, acacia gum, chitosans and combinations thereof. The concentration of the viscosity increasing agent will depend on the agent selected and the viscosity required.

[0331] Examples of sweeteners suitable for the aqueous suspensions or dispersions described herein include, for example, acacia syrup, acesulfame K, Alitame, anise, apple, aspartame, banana, whipped cream (Bavarian cream), blueberry, black currant, caramel , calcium citrate, camphor, caramel, cherry, Cherry cream, chocolate, cinnamon, chewing gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, kola, refreshing cherry, refreshing citrus, cyclamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycretinate, licorice root syrup (licorice), grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate (MagnaSweet^®), maltol, mannitol, clone, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet^® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, mint, mint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, potassium acesulfame, mannitol, talin, silyl, sucralose, sorbitol , Swiss cream, tagatose, mandarin, taumatin, tutti frutti, vanilla, walnut, watermelon, wild cherry, pear, xylitol or any combination of these flavor ingredients, e.g. anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime e, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint and mixtures thereof. The aqueous liquid dispersions may contain a sweetener or flavoring in a concentration ranging from about 0.001% to about 1.0% by volume of the aqueous dispersion. In another situation, the aqueous liquid dispersions may contain a sweetener or flavoring in a concentration ranging from about 0.005% to about 0.5% by volume of the aqueous dispersion. In yet another situation, the aqueous liquid dispersions may contain a sweetener or flavoring in a concentration ranging from about 0.01% to about 1.0% by volume of the aqueous dispersion.

[0332] In addition to the excipients mentioned above, the liquid formulations may further contain inert diluents commonly used in the art, such as water and other solvents, solubilizers and emulsifiers. Exemplary emulsifiers are 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 oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, esters of fatty acid and sorbitan or mixtures of these substances and the like.

[0333] The pharmaceutical formulations described herein may be self-emulsifying drug delivery systems (SEDDS). Emulsions are dispersions of the immiscible phase in another phase, usually in the form of drops. Generally, emulsions are formed by vigorous mechanical dispersion. SEDDS, unlike emulsions or microemulsions, creates emulsions spontaneously when added to excess water without any external mechanical dispersion or mixing. The advantage of SEDDS is that only gentle mixing is needed to disperse the drops throughout the solution. In addition, water or an aqueous phase may be added just prior to administration, which ensures the stability of the labile or hydrophobic active ingredient. Thus, SEDDS provides an effective delivery system for oral and parenteral administration of hydrophobic active substances. SEDDS can provide improved bioavailability of hydrophobic active substances. Methods for making self-emulsifying dosage forms are known in the art and include, but are not limited to, for example, US Patent Nos. 5,858,401, 6,667,048 and 6,960,563.

[0334] It should be noted that the above-mentioned excipients used in the aqueous dispersions or suspensions described herein partially overlap, as the substance is often classified differently by different practitioners in the field or is widely used due to several different functions. Thus, the above-mentioned excipients should be considered only as exemplary and non-limiting types of excipients that may be included in the formulations described herein. The amounts of these excipients can be easily determined by a person skilled in the art in accordance with the specific properties required.

Nasal Formulations [0335] Nasal formulations known in the art are described, for example, in US Patent Nos. 4,476,116,

5,116,817 and 6,391,452. Formulations containing a compound of any of formulas (A), (B), (C) or (D), which are prepared by these and other techniques well known in the art are prepared in the form of physiological 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, ed. 6

EP 2 201 840 B1 (1995). Preferably, these compositions and formulations are formulated with suitable non-toxic pharmaceutically acceptable ingredients. These ingredients are known to those skilled in the art in preparing a nasal dosage form, and some of them can be found in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, ed. 21, 2005, standard reference in this field. The choice of suitable carriers is highly dependent on the particular type of nasal dosage form desired, e.g. lotions, suspensions, ointments or gels. Nasal dosage forms generally contain, in addition to the active substance, large amounts of water. Small amounts of other ingredients may be present, such as pH adjusting agents, emulsifiers or dispersing agents, preservatives, surfactants, gelling or buffering agents, and other stabilizing and solubilizing agents. Nasal dosage forms should be isotonic with nasal secretions.

[0336] For administration by inhalation, compounds of any of formulas (A), (B), (C) or (D) described herein may be in the form of an aerosol, mist or powder. The pharmaceutical compositions described herein are traditionally provided in the form of an aerosol spray presentation from pressurized packages or nebulizers, using a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. In the case of a pressure aerosol, the dosage unit may be determined by connecting a valve to deliver a metered amount. Capsules and cartridges of (exemplified only) gelatin, for use in an inhaler or insufflator, containing a powdered mixture of the compound described herein and a suitable powder base such as lactose or starch may be developed.

Buccal Formulations [0337] Buccal formulations containing compounds of any of formulas (A), (B), (C) or (D) can be administered using a variety of formulations known in the art. For example, such formulations include, but are not limited to, US Patent Nos. 4,229,447, 4,596,795, 4,755,386 and 5,739,136. In addition, the buccal dosage forms described herein may further comprise a bioerodible (hydrolysable) polymeric carrier, which also serves to adhere the dosage form to the mucosa. The buccal dosage form is produced in such a way that it erodes gradually over a predetermined period in which the delivery of the compound of any of formulas (A), (B), (C) or (D) occurs mainly through the mucosa. The buccal delivery of the drug, as known by those skilled in the art, avoids the disadvantages encountered with oral drug administration, e.g. slow absorption, degradation of the active substance by fluids present in the gastrointestinal tract and / or deactivation due to the first pass effect in the liver. Regarding the bioerodible (hydrolysable) polymeric carrier, it should be understood that in fact such a carrier can be used as long as the desired drug release profile is not violated and the carrier is (compatible) compatible with a compound of any of formulas (A), B), (C) or (D) and other ingredients that may be present in the buccal dosage unit. Generally, polymeric carriers include hydrophilic polymers (water-soluble and water-swellable) that adhere to the wet surface of the cheek mucosa. Examples of polymeric carriers useful in this case include acrylic acid polymers and copolymers and, e.g., those known as "carbomers" (Carbopol^®, which can be obtained from BF Goodrich, is one such polymer). Other ingredients that may also be included in the buccal dosage form described herein include, but are not limited to, disintegrants, diluents, binders, lubricants, flavors, dyes, preservatives and the like. For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in conventional manner.

Transdermal formulations [0338] The transdermal formulations described herein may be administered using various products (devices) that have been described in the art. For example, such products include, but are not limited to, US patents Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084, 4,067,307 , 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and 6,946,144.

[0339] The transdermal dosage forms described herein may contain specific pharmaceutically acceptable excipients commonly known in the art. In one embodiments, the transdermal formulations described herein comprise at least three components: (1) a formulation of the compound of any of formulas (A), (B), (C) or (D); (2) a penetration enhancer; and (3) aqueous adjuvants. In addition, transdermal formulations may contain additional ingredients such as but not limited to

Confined to these, gelling agents, cream bases and ointments and the like. The transdermal formulation may additionally comprise woven or other undercoat to increase absorption and prevent removal of the transdermal formulation from the skin. Also described are transdermal formulations that may be saturated or supersaturated to facilitate diffusion into the skin.

[0340] Formulations suitable for transdermal administration of the compounds described herein can be used using transdermal delivery devices and transdermal delivery patches and may be lipophilic emulsions or buffered aqueous solutions dissolved and / or dispersed in a polymer or adhesive. Such patches may be constructed for continuous, pulsatile, or on-demand pharmaceutical administration. Further, transdermal delivery of the compounds described herein can be achieved by iontophoretic dressings and the like. In addition, transdermal patches may provide controlled delivery of compounds of any of formulas (A), (B), (C) or (D). The rate of absorption can be slowed down by using rate controlling membranes or by encapsulating the compound in a polymer matrix or gel. Conversely, absorption promoters can be used to increase absorption. The absorption promoter or carrier may contain absorbable pharmaceutically acceptable solvents to facilitate passage through the skin. For example, transdermal devices are in the form of a bandage comprising a primer component, a reservoir containing the compound, optionally with a carrier, optionally a speed controlling barrier to deliver the compound to the host skin at a controlled and predetermined speed for a longer period, and means for adhering the product to the skin .

Formulations for injection [0341] Formulations containing a compound of any of formulas (A), (B), (C) or (D) suitable for intramuscular, subcutaneous or intravenous injections may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders to reconstitute sterile injectable solutions or dispersions before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or media include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, Cremophor and the like), their respective mixtures, vegetable oils (such as olive oil) and organic esters for injection such as ethyl oleate. Adequate fluidity can be maintained, for example, by the use of a layer such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Formulations suitable for subcutaneous injection may also contain additives such as preserving, wetting, emulsifying and spreading agents. The use of various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid and the like, prevents the growth of microorganisms. 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 result in the use of absorption delaying agents such as aluminum monostearate and gelatin.

[0342] For intravenous injections, the compounds described herein may be formulated as aqueous solutions, preferably in physiologically compatible buffers, such as Hank's solution, Ringer's solution, or physiological saline buffer. For mucosal administration, penetrating agents suitable for crossing the barrier are used in the formulations. Such penetrants are generally known in the art. For other parenteral injections, suitable formulations may include aqueous or non-aqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally known in the art.

[0343] Parenteral injections may include bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampoules or in multiple-dose containers, with an added preservative. The pharmaceutical composition described herein may be in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulation ingredients such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active ingredients in water-soluble form. In addition, active substance suspensions may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or 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 carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspensions may also contain suitable stabilizers or agents to increase the solubility of the compounds, enabling the preparation of highly concentrated solutions. Alternatively, the active substance may

Be reconstituted with a suitable vehicle before use, e.g. sterile pyrogen-free water.

Other Formulations [0344] Described herein are delivery systems for pharmaceutical compounds such as, for example, liposomes and emulsions. Also described are compositions comprising a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly (methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate and dextran.

[0345] The compounds described herein can be administered topically and can be formulated in various compositions suitable for topical administration, such as solutions, suspensions, lotions, gels, pastes, drug impregnated rods, lotions, creams or ointments. Such pharmaceutical compositions may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0346] The compounds described herein can also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal sprays, suppositories, jelly suppositories, or suppressive enemas, containing conventional suppository bases such as cocoa butter or other glycerides, such as also synthetic polymers such as polyvinylpyrrolidone, PEG and the like. In suppository compositions, low melting waxes such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, are first melted.

Examples of dosing methods and modes of drug administration [0347] The compounds described herein can be used to prepare drugs for inhibiting Btk or homologues thereof, or for treating diseases or conditions in which Btk inhibition or homologues can be benefited, at least in part. In addition, a method of treating any disease or condition described herein in a subject in need of such treatment includes administering to the subject a pharmaceutical composition comprising at least one compound of any 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 a therapeutically effective amount.

[0348] Compositions comprising a compound (s) described herein that are administered for prophylactic and / or therapeutic treatment are described. For therapeutic uses, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for these uses will depend on the severity and course of the disease or condition, previous therapies, the patient's state of health, weight and response to drugs, as well as the judgment of the treating physician. Determination of such a prophylactically effective dose is assessed by a specialist through routine experimentation (including without limitation, clinical dose escalation).

[0349] For preventive uses, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a disease, disorder or condition. Such amounts are referred to as "prophylactically effective amounts or doses". In this application, the exact dose also depends on the patient's state of health, weight and the like. Determination of such a prophylactically effective dose is assessed by a specialist through routine experimentation (including without limitation, clinical dose escalation). Amounts effective for such use in a patient will depend on the severity and course of the disease, disorder or condition, previous therapies, the patient's state of health and response to medications, as well as the judgment of the treating physician.

[0350] In the event that the patient's condition does not improve after the physician has freely selected the dose, then the administration of the compounds may be prolonged, i.e. for a prolonged period of time, including the patient's entire life, to reduce or otherwise control or reduce symptoms patient's disease or condition.

[0351] In a case where the patient's condition does not improve after the physician has freely selected the dose, then administration of the compounds may be continuous; alternatively, the administered dose of the drug may be temporarily reduced or temporarily suspended for a certain period (ie, "drug holiday"). The withdrawal period may vary from 2 days to 1 year, including, for example, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days,

EP 2 201 840 B1

150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days or 365 days. The dose reduction during the drug withdrawal period may be in the range of 10% -100%, including, for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.

[0352] If an improvement in the patient's condition occurs, the maintenance dose is administered as needed. Thereafter, the dosage or frequency of administration, or both, can be reduced depending on the symptoms, to a level at which improvement in the disease, disorder or condition is maintained. Patients may require periodic treatment during periods of recurrence of disease symptoms.

[0353] The amount of a given agent will correspond to the amount that will vary depending on factors such as the particular compound, disease or condition and their severity, identity (e.g., body weight) of the subject or host in need of treatment, but may still be routine determined in a manner known in the art, in accordance with the specific circumstances of the case, including, for example, the specific agent being administered, by route of administration, the condition being treated, subject or host in need of treatment. Generally, however, doses used to treat adult humans will typically be in the range of 0.02-5000 mg per day, or from about 1-1500 mg per day. The desired dose may conveniently be present in the form of a single dose or in divided doses administered simultaneously (or over a short period) or at appropriate time intervals, for example, as two, three, four or more sub-doses per day.

[0354] The pharmaceutical composition described herein may be in unit dosage forms for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compounds. The dosage unit may be in the form of a package containing separate amounts of the formulation. Non-limiting examples are packaged tablets or capsules and powders in vials or ampoules. The aqueous suspension compositions can be packaged in single dose containers that are resealable. Alternatively, multi-dose resealable containers may be used in which the preservative is a typical additive to the composition. For example, parenteral injection formulations may be presented in unit dosage forms, which include, but are not limited to, ampoules or multi-dose containers with an added preservative.

[0355] The ranges given previously are only a suggestion because there are a large number of variables regarding individual treatment regimen and a significant departure from the recommended doses is not uncommon. Such dosages can be varied depending on many factors not limited to the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the particular subject and the severity of the disease or condition to be treated, as well as the medical judgment of the physician.

[0356] Toxicity and therapeutic efficacy of treatment can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, including LD50 (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 it can be expressed as the ratio LD50 to ED50. Compounds showing a high therapeutic index are more preferred. The results obtained from cell culture assays and animal studies can be used in determining the range of doses for human use. The dosage of such compounds is preferably within a circulating concentration range including ED50 with minimal toxicity. The dosage may vary in this regard depending on the dosage form and route of administration used.

Combination Therapy [0357] The irreversible Btk inhibitor compositions described herein can also be used in combination with other well-known therapeutic components selected in terms of therapeutic value for the treatment of relevant conditions. Generally, the compositions described herein and their embodiments, where combined treatment is used, other agents need not be administered in the same pharmaceutical composition and may, due to different physical and chemical characteristics, be administered by different routes. The determination of the mode of administration and the desirability of administration, if possible, in the same pharmaceutical composition, is well known to clinical specialists. Initial administration may be based on the principles established in the art, and then, after taking into account the effects observed, clinical specialists may vary the doses, modes and times of administration.

[0358] In some cases, it may be appropriate to administer at least one compound

An irreversible Btk inhibitor described herein in combination with another therapeutic agent.

For example, if one of the undesirable side effects experienced by a patient receiving an irreversible Btk inhibitor compound is nausea, it may be appropriate to co-administer with the first therapeutic agent an anti-nausea agent. Or, for example, the therapeutic effectiveness of one of the compounds described herein can be improved by administering an adjuvant (i.e., the adjuvant as such may have a therapeutic effect, but when combined with another therapeutic agent, the overall therapeutic benefit for the patient is improved). Or, for example, the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (also under the treatment regimen) that also has therapeutic benefit. In any case, regardless of the disease, disorder and condition being treated, the overall benefit experienced by the patient may be simply added from the two therapeutic agents or there may be a synergistic effect.

[0359] The specific choice of compounds will depend on the diagnosis of the attending physician and his assessment of the patient's condition, as well as on the appropriate therapeutic treatment methods. The compounds can be administered simultaneously (e.g., simultaneously or essentially simultaneously or in the same treatment regimen) or sequentially, depending on the type of disease, disorder or condition of the patient and the actual choice of compounds. The determination of the order of administration and the number of repetitions of administration of each therapeutic agent during the treatment period is well known to a clinical specialist in the state of the art after his assessment of the disease being treated and the patient's condition.

[0360] It is apparent to those skilled in the art that the therapeutically effective dosage can vary when the drug is administered in combination therapy. Methods for the experimental determination of therapeutically effective doses of drugs and other agents for use in combination therapy regimens have been described in the literature. For example, the use of synchronized dosing, i.e., delivery of frequent lower doses to minimize toxic side effects, is widely described in the literature. Combination therapy also includes temporary treatment that begins and ends at different times to support the patient's clinical management.

[0361] In the combination therapies described herein, the simultaneous dosing of the compounds will of course depend on the type of drug being administered simultaneously, the particular drug used, the disease or condition being treated and the like. In addition, when a compound provided herein is administered simultaneously with one or more biologically active agents, it may be administered simultaneously or sequentially with the biologically active agent (s). If administered sequentially, the attending physician will decide on the correct order for administering the protein in combination with the biologically active agent (s).

[0362] In any case, the administration of multiple therapeutic agents (one of which is a compound of formula (A), (B), (C), or (D) described herein) can be administered in any order or even simultaneously. If the administration is simultaneous, the multiple combination may be provided as a separate, combined or multi-dose form (for example, as one tablet or as two separate tablets). One of the therapeutic agents may be administered in multiple doses, or both may be administered in multiple doses. multiple doses. If not administered simultaneously, the time intervals between multiple doses may be different, counted from zero to less than four weeks. In addition, combination methods, compositions and formulations are not limited to the use of only two agents; the use of multiple therapeutic combinations (multiple therapeutic combinations) is also envisaged.

[0363] It is understood that the dosage regimen to treat, prevent or ameliorate the condition (s) in which relief is expected can be modified in accordance with a variety of factors. These factors include the disorder the subject is suffering from, as well as the age, weight, sex, diet and health of the subject. Thus, the dosage regimen actually used may vary widely and may be different from the regimen presented herein.

[0364] The pharmaceutical agents comprising the combination treatment disclosed herein may be in combined dosage forms or separate dosage forms intended for substantially simultaneous administration. Pharmaceutical agents that make up the combination treatment may also be administered sequentially with the therapeutic compound administered in a mode requiring two-stage administration. A two-stage mode of administration may be required for subsequent administration of active agents or administration of separate active agents at intervals. The interval between repeated administration steps may range from a few minutes to several hours, depending on the properties of each therapeutic agent such as strength, solubility, bioavailability, half-life and

Pharmaceutical kinetic profile. Circadian variation in target molecule concentration may determine optimal dose intervals.

[0365] In addition, the compounds described herein may also be used in combination with methods that may provide additional or synergistic benefit to a patient. For example, in patients expecting to obtain a therapeutic and / or prophylactic benefit by the methods described herein, in which the pharmaceutical composition of the compound disclosed herein and / or combination with other therapies is associated with genetic testing to determine if the subject is a carrier of a mutant gene that has been known as responsible for certain diseases or conditions.

[0366] The compounds described herein and combination therapy may be carried out before, during or after the occurrence of the disease or condition, and the timing of administration of the composition containing the compound may vary. Thus, for example, the compounds can be used prophylactically and can be administered continuously to subjects who are at risk of developing conditions or diseases to prevent the occurrence of diseases or conditions. The compounds and compositions can be administered to subjects during or as soon as possible after the onset of symptoms. Administration of compounds may be initiated within the first 48 hours of onset of symptoms, within the first 6 hours of onset of symptoms, or within 3 hours of onset of symptoms. Initial administration may be by any route of administration such as, for example, intravenous injections, high dose injections, continuous infusions for from 5 minutes to about 5 hours, pills, capsules, skin delivery patches, buccal formulations and the like, and combinations thereof . The compound should be administered as soon as practicable after the disease or condition is detected or expected to occur, and for a period of time required to treat the disease, such as, for example, from about 1 month to about 3 months. The length of treatment may vary for each subject and can be determined according to known criteria. For example, the compound or formulation containing the compound may be administered for at least 2 weeks, from 1 month to about 5 years, or from about 1 month to about 3 years.

Exemplary therapeutic agents for use in combination (combination) with an irreversible Btk inhibitor compound [0367] If the subject suffers or is at risk of developing an autoimmune disease, inflammatory disease or allergic disease, the irreversible Btk inhibitor compound may be used with one or more of the following therapeutic agents in any combination: immunosuppressants (for example: tacrolimus, ciclosporin, rapamycin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate or FTY720), glucocorticoids (for example: prednisone, cortisone acetate, prednisolone, methylprednisolone, dexamethasone, betamethasone, triklonzone nonsteroidal anti-inflammatory drugs (for example: salicylates, aryl propionic acids, 2-aryl propionic acids, N-arylantranilic acids, oxycams, coxibs or sulfonamides), specific COX-2 inhibitor (for example: valdecoxib, celecoxib, or rofecoxib), leflunomide, gold salts with thioglucosin, gold , sulfasalazine, hydroxychloroquine, minocycline, TNF-α binding protein (for example: infliximab, etanercept or adalimumab), abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergen vaccines, antihistamines, anti-leukotrienes, beta-agonists, theophylline or anticholinergics.

[0368] If the subject suffers from or is at risk of B cell proliferative disorder (plasma cell myeloma), the subject may be treated with an irreversible Btk inhibitor compound in any combination with one or more other anti-cancer agents. In some embodiments, one or more anti-cancer agents are proapoptotic drugs. Examples of anti-cancer agents include the following, but are not limited to: gossypol, genasens, polyphenol E, chlorofusine, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor - related to apoptosis - including ligands (TRAIL), 5-aza-2'-deoxycytidine, all trans retinoic acids, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin, 17-NAlloylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, Tax PKC412 also known as "paclitaxel" - a well-known anticancer drug that works by strengthening and stabilizing the formation of microtubules and Taxol ™ analogues, such as Taxotere ™. Compounds that have a basic taxane skeleton as a common feature of the structure have also shown the ability to retain cells in G2 phases -M due to the stabilization of microtubules and may be useful in the treatment of cancer in combination with the compounds described herein.

[0369] Further examples of anti-cancer drugs for use in combination with an irreversible Btk inhibitor compound include mitogen-activated protein kinase inhibitors, for example U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 439006, wortmanina or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituxan).

[0370] Other anti-cancer drugs that can be used in combination with the irreversible Btk inhibitor compound are Adriamycin, Daktinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin, aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase,; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brecquar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; Crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; desaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; Droloxifene Citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; etoprine; Fadrozole Hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; Gemcitabine Hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin II (including recombinant interleukin II or rlL2), interferon alfa-2a; interferon alfa-2b; alpha-n1 interferon; alpha-n3 interferon; interferon beta-1 a; interferon gamma-1 b; iproplatin; Irinotecan Hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; Mechloretamine Hydrochloride; megestrol sodium; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; sodium methotrexate; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamyin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; Puromycin Hydrochloride; pyrazofurin; riboprine; rogletimid; safingol; safingol hydrochloride; semustine; simtrazene; sodium sparfosate; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; sodium tecogalate; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; winepidine sulfate; winglicinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.

[0371] Other anti-cancer drugs that can be used in combination with the irreversible Btk inhibitor compound are: 20-epi-1, dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; G antagonist; antarelix; morphogenetic protein to prevent dorsalization 1; antiandrogen, prostate cancer; antiestrogen; antineoplaston; antisense oligonucleotides; afidycoline glycinate; apoptosis gene modulators; apoptosis regulators; apuric acid; ara-CDP-DLPTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinatin 1; axinatin 2; axinatin 3; azasetron; azatoxin; azatyrosine baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporine; beta-lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistraten A; bizelesin; breflate; bropirimine; budotitane; butionine sulfoximin; calcipotriol; calfostine C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; an inhibitor of cartilage origin; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorites; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine phosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnina B; didox; diethylnorspermine; dihydro-5-azacytidine; 9- dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duokarmycyna SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemen; emitefur;

Epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozol; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorubicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texafirin complex; gallium nitrate, galocytabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; iimofosine; ilomastat; imidazoacridones; imiquimod; immunostimulatory peptides; insulin-like growth factor 1 receptor inhibitor; interferon agonists; interferons; interleukin; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalid F; lamelarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide + estrogen + progesterone; leuprolide; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharidopeptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; complex of lutetium with texafirin; lysofylline; lytic peptides; maytansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor, mifepristone; miltefosine; mirimostim; double stranded RNA mismatch; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; Monoclonal antibodies, human chorionic gonadotropin; monophosphorylated lipid A + myobacterium cell wall sk monophosphorylated lipid A + myobacterium cell wall sk; mopidamol; multi-drug resistance gene inhibitor; therapy based on MTS1 suppressor (multiple tumor suppressor 1 -based therapy); mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone + pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; nerindronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitric oxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium salt; pentostatin; pentrozole; perflubron; perfosfamide; perilyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum with triamine complex; porfimer sodium; porfiromycin; prednisone; ropylobisakrydon; prostaglandin J2; proteasome inhibitors; protein A immunomodulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurin; pyrazoloacridine; hemoglobin conjugate with pyridoxal and polyoxyethylene; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; demethylated reteleptin; rhenium ethidronate Re 186; rhizoxin; ribozymes; retinamide RII; roglethimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophitol A; sargramostim; Sdi 1 mimetics; semustine; aging inhibitor 1; sense oligonucleotides; signal repetition inhibitors; transduction signal modulators; single chain protein binding antigen; sizofiran; sobuzoxane; sodium borocaptan; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfose acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; cell stream inhibitor; cell stream division inhibitor ;; stipiamide; stromelysin inhibitors; inhibitors; sulfmozyna; a superactive vasoactive peptide antagonist; suradista; suramin; swainsonine; synthetic synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor antagonist; thymotrinan; thyroid stimulating hormone; ethiopurpurine ethyl tin; tirapazamine; titanocene dichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; bicalutamide; tyrosine kinase inhibitors; tyrphostin; UBC inhibitors; ubenimex; urogenital sinus growth factor inhibitor; urokinase receptor antagonists; vapreotide; variolin B; erythrocyte gene therapy system vector; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilaskorb and zynostatin stimalamer.

Still other anti-cancer agents that can be used in conjunction with an irreversible Btk inhibitor compound include alkylating drugs, antimetabolites, natural products or hormones, e.g. nitrogen mustards (e.g. mechloretamine, cyclophosphamide, chlorambucil and others), alkyl sulfonates (e.g. busulfan), nitrosoureas (e.g. carmustine, lormustine and others) or triazenes (e.g. dacarbazine). Examples of anti-metabolites include, but are not limited to, folic acid analogues (e.g., methotrexate), or pyrimidine analogs (e.g., cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0373] Examples of natural products useful in combination with an irreversible Btk inhibitor compound include, but are not limited to, vinca alkaloids (e.g. vinblastine, vincristine), epipodophyllotoxin (e.g. etoposide), antibiotics (e.g. daunorubicin, doxorubicin , bleomycin), enzymes (e.g. L-asparaginase) or biological response modifiers (e.g. interferon alpha).

[0374] Examples of alkylating drugs that can be used in conjunction with an irreversible Btk inhibitor compound include, but are not limited to, nitrogen mustards (e.g., mechloretamine, cyclophosphamide, chlorambucil, melphalan, and others), ethyleneimine and methylmelamine (e.g. hexamethylmelamine, thiotepa) , alkyl sulfonates (e.g. busulfan), nitrosoureas (e.g. carmustine, lomustine, semustine, streptozotocin and others) or triazenes (dacarbazine etc.). Examples of anti-metabolites include, but are not limited to, folic acid analogues (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0375] Examples of hormones and antagonists useful in combination with the irreversible Btk inhibitor compound include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestin (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g. diethylstinbestrol estradiol), anti-estrogens (e.g. tamoxifen), androgens (e.g. testosterone propionate), anti-androgens (e.g. flutamide), gonadotropin-releasing hormone analogue (e.g. leuprolide). Other agents that can be used in the methods and compositions described herein for treating or preventing cancer include platinum coordination complexes (e.g. cisplatin, carboplatin), anthracenedione (e.g. mitoxantrone), substituted ureas (e.g. hydroxycarbamide), methylhydrazine derivatives (e.g. procarbazine) ), adrenocorticoid suppressants (e.g. mitotane, aminoglutethimide).

[0376] Examples of anti-cancer agents that act by retaining cells in the G2-M phase thereby stabilizing microtubules that can be used in conjunction with an irreversible Btk inhibitor compound include, but are not limited to, commercially available drugs and drugs in development: Erbulozol (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isithionate (also known as CI-980), vincristine, NSC-639829, Diskodermolid (also known as NVP-XX -A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtiny (just like Altorhyrtyn A and Altorhyrtyn C), Spongistatin (just like Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8 and Spongistatin 9), Cemadotine hydrochloride (also known as LU-103793 and NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyEpotylon A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB and desoxy Epotylon B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-Epothilone B, 21-aminoEpotylon B (also known as BMS-310705), 21-hydroxyEpotylon D (also known as DesoxyEpotylon F and dEpoF), 26-fluoroEpotylon), Auristatin PE (also known as NSC-654663), Soblidotine (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477- P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS- 164 (Takeda), GS198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (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.HCI), AC-7700 (Ajinomoto, also known as AVE8062, AVE-8062A, CS-39-L-Ser.HCI and RPR -258062A), Vitilevuamide, Tubulizine A, Canadensol, Kentaureidine (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (also known as BTO-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), Narcosin (also known as NSC-5366), Naskapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Lenanocin (also known as NSC-698666), 3-1AABE (Cytoskeleton / Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethylleuterobin, Desaethylethyluterobin, Isoeleuterobin A and Z-Eleuterobin), Caribaeoside, Karibaeolin, Halichondrin B, D64131 (Asta Medica), D-68144 (Asta Medica), Diazonamid A, A-293620 (Abbott), NPI-2350 (Nereus), Takalonolid A, TUB-245 (Aventis), A- 259754 (Abbott), Diosostatin, (-) - Fenylahistyn (also known as NSCL96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverine B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin sodium phosphate, BPROY-007 (National Health Research Institutes) and SSR-250411 (Sanofi).

[0377] If the subject suffers from or is at risk of developing thromboembolic disease (e.g., stroke), he may be treated with an irreversible Btk inhibitor in combination with

Any other anticoagulant. Examples of anticoagulants are, but are not limited to, the following: thrombolytic agents: (e.g., alteplase, anistreplase, streptokinase, urokinase or tissue plasminogen activator), heparin, tinzaparin, warfarin, dabigatran (e.g., dabigatran etexilate), e.g. fondaparinux, draparinux, rivaroxaban, DX-9065a, otamixaban, LY517717 or YM150), ticlopidine, clopidogrel, CS-747 (prasugrel, LY640315), ximelagatran or BIBR 1048.

Factory kits / articles [0378] For therapeutic use described herein are the kits and factory articles described herein. Such kits may include a carrier, packaging, or container that is divided into one or more containers, such as vials, tubes and the like, and each container (s) contains one of the separate components for use in accordance with as described here. Suitable containers include, for example, bottles, vials, syringes and test tubes. The containers can be made of various materials, such as glass or plastic.

[0379] The factory goods described herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those skilled in the art. See, e.g., US Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging include, but are not limited to, blister bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles and any packaging suitable for the chosen formulation and intended route of administration and treatment. The wide range of preparations of compounds and compositions provided herein are contemplated for various methods of treating any disease, disorder or condition in which Btk inhibition can be beneficial or mediated by Btk or is involved in symptoms or causes.

[0380] For example, the container (s) may contain one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container (s) may optionally have sterile access intravenous devices (for example, the container may be a bag with a solution for intravenous administration or a vial having a stopper that can be punctured with a hypodermic injection needle). Such kits optionally containing a connection to the identification description or labeling or instruction related to use in accordance with the methods described herein.

[0381] The kit typically includes one or more additional containers, each with one or more different materials (such as components, optionally in concentrated form and / or article (device)) desirable from a commercial and user standpoint to use the compounds described herein. For example, such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, carriers, packaging, vials and / or tubes with content designation and / or instructions for use and packaging containing instructions. A set of instructions will usually also be included.

[0382] The label may be on or attached to the packaging. The label may be on the packaging when letters, numbers or other characters forming the marking are associated, molded or inscribed on the container itself; the label may be attached to the container when it is placed in the package or in a bag in which the container is still present, for example as an insert. The label can be used to indicate how the components are to be used in specific therapeutic applications. The label can also indicate directions for using content such as the methods described here.

[0383] The pharmaceutical compositions may be in a dosage pack or device (s) that may contain one or more unit dosage forms containing the compound provided herein. For example, the packet may contain metal or plastic foil, such as a blister pack. The packet or product (dispensing device) may be accompanied by instructions for use. The package or dispenser may also be accompanied by a leaflet related to the container in the form of recommendations of a government agency regulating the manufacture, use or sale of medicinal products, which leaflet confirms registration by the agency of the form of the drug for human and animal administration. Such a note may be a mark of approval by the US Food and Drug Administration for prescription drugs. Compositions containing a compound provided herein prepared with a pharmaceutically compatible carrier may be prepared, placed in a suitable container, and labeled for the treatment of indicated conditions.

Examples [0384] The following specific and non-limiting examples are intended to be illustrative only and do not constitute a limitation of the present disclosure in any way. It is believed that without further development a person skilled in the art may, based on the description herein, apply the present disclosure in its entirety.

EP 2 201 840 B1

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Example 1: Synthesis of compounds

Preparation of 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine (intermediate 2) [0385] 4-Amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d] pyrimidine (intermediate 2) is prepared as disclosed in International Patent Application Publication No. WO 01/019829. Briefly, 4-phenoxybenzoic acid (48 g) is added to thionyl chloride (100 mL) and heated to reflux for 1 hour. Thionyl chloride is removed by distillation and the remaining oil is dissolved in toluene and the volatiles are removed at 80 ° C / 20 mbar. The resulting acid chloride is dissolved in toluene (200 ml) and tetrahydrofuran (35 ml). Malononitril (14.8 g) is added and the solution is stirred at -10 ° C followed by the addition of diisopropylethylamine (57.9 g) in toluene (150ml) keeping the temperature below 0 ° C. After 1 hour at 0 ° C, the mixture is stirred at 20 ° C overnight. The amine hydrochloride is removed before filtration and the filtrate is evaporated in vacuo. The residue is taken up in ethyl acetate and washed with 1.25 M sulfuric acid, then with brine and dried over sodium sulfate. Evaporation of the solvents gives a semi-solid residue, which is treated with a small amount of ethyl acetate to give 4.1 g of 1,1-dicyano-2-hydroxy-2- (4-phenoxyphenyl) ethene as a white solid (m.p. 160- 162 ° C). The evaporated filtrate gives 56.58 (96%) of 1,1-dicyano-2-hydroxy-2- (4-phenoxyphenyl) ethene in the form of a gray-brown body with sufficient purity for further use.

[0386] 1,1-Dicyano-2-hydroxy-2- (4-phenoxyphenyl) ethene (56.5 g) in acetonitrile (780 ml) and methanol (85 ml) are stirred under nitrogen at 0 ° C, followed by addition of diisopropylethylamine (52.5 mL) followed by 2M trimethylsilyl diazomethane (150 mL) in THF. The reaction is stirred for 2 days at 20 ° C, after which 2 g silica (for chromatography) is added. The brown-red solution is evaporated in vacuo, the residue is dissolved in ethyl acetate and washed with water, then with brine, dried and evaporated. The residue is extracted with diethyl ether (3x250 mL), decanted from insoluble oil. After evaporation of the ether, the extracts give 22.5 g of 1,1-dicyano-2-methoxy-2- (4-phenoxyphenyl) ethene in the form of a light orange solid. The insoluble oil is purified by flash chromatography to give 15.0 g of a red-orange oil.

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

[0388] 3-Amino-4-cyano-5- (4-phenoxyphenyl) pyrazole (29.5 g) is suspended in formamide (300 ml) and heated under nitrogen at 180 ° C 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- onu (Compound 4)

EP 2 201 840 B1 [0389]

Diagram 1

<img file="PL2201840T3_D0032.tif" />

3 4

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

[0390] The compounds described herein were synthesized according to the following steps in Scheme 1. A detailed example illustrating the reaction conditions of Scheme 1 is described for the 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).

[0391] 101 mg of 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidine and 330 mg of polymer-bound triphenylphosphine (TPP) (polymerlab) were mixed together with 5 ml of tetrahydrofuran (THF) . Tert-butyl 3-hydroxypiperidine-1-carboxylate (200 mg; 2.0 equivalents) was added to the mixture, followed by diisopropyl diazodicarboxylate (0.099 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered to remove the resin, concentrated and then purified by flash chromatography (pentane / ethyl acetate = 1/1) to give intermediate 3 (55 mg).

[0392] Intermediate 3 (48.3 mg) was treated with 1 mL of 4N HCl in dioxane for 1 hour, 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 completed after 2 hours. The reaction mixture was washed with 5 wt. aqueous citric acid solution followed by brine. The organic layer was dried with MgSO4, and concentrated. Flash chromatography (with CH2Cl2 / MeOH = 25/1) gave 22 mg of compound 4 as a white solid. MS (M + 1): 441.2;¹H-NMR (400MHz): 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; 5.5-5.7, 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) prop-2- en-1-one (Compound 13).

[0393]

<img file="PL2201840T3_D0033.tif" />

[0394] The synthesis of compound 13 was performed using procedures analogous to those described in Example 1a. EM (calculated): 440.2; MS (ESI) m / e (M + 1H)⁺: 441.1, (M-1H)^-: 439,2.

EP 2 201 840 B1

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

[0395]

<img file="PL2201840T3_D0034.tif" />

[0396] The synthesis of compound 14 was performed using procedures analogous to those described in Example 1a. EM (calculated): 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) prop-2- en-1-one (Compound 12).

[0397]

<img file="PL2201840T3_D0035.tif" />

[0398] The compound was synthesized using procedures analogous to those described in Example 1a. EM (calc.): 426.18; MS (ESI) m / e (M + 1H) +: 427.2, (M-1H) -: 425.2.

Example 1e: Synthesis of 1 - ((R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-120-yl) pyrrolidin-1-yl) prop-2 -en-1-one (Compound 11).

[0399]

<img file="PL2201840T3_D0036.tif" />

[0400] The compound was synthesized using procedures analogous to those described in Example 1a. EM (calc.): 426.18; MS (ESI) m / e (M + 1 H) +: 427.2.

Example 1f: Synthesis of N - ((1S, 4S) -4- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-15-yl) cyclohexyl) acrylamide (Compound 10).

[0401]

<img file="PL2201840T3_D0037.tif" />

[0402] Synthesis of this compound was performed using procedures analogous to those described in Example 1a. EM (calc): 454.21; MS (ESI) m / e (M + 1H) +: 455.1, (M-1H) -: 453.1.

Example 1g: Synthesis of 1- (3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) sulfonylethene (Compound 6) [0403]

<img file="PL2201840T3_D0038.tif" />

[0404] The synthesis of compound 6 was performed using procedures analogous to those described in Example 1a. EM 20 (calc.): 476.16; MS (ESI) m / e (M + 1H)⁺: 478.0, (M-1H)^-: 475,3.

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

[0405]

EP 2 201 840 B1

<img file="PL2201840T3_D0039.tif" />

[0406] The synthesis of compound 8 was performed using procedures analogous to those described in Example 1a. EM (calc): 438.18; MS (ESI) m / e (M + 1H)⁺: 439.2, (M-1H)^-: 437,2.

Example 1i: 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) (outside the scope of the present invention) [0407]

<img file="PL2201840T3_D0040.tif" />

[0408] The synthesis of compound 15 was performed using procedures analogous to those described in Example 1a. EM (calc): 497.25; MS (ESI) m / e (M + 1H)⁺: 498.4, M-1H)^-: 496.

Example 2: In Vitro Btk Inhibitory Activity [0409] The IC 50 values ​​for Btk of the compounds disclosed herein were determined in both the cell-free kinase assay and the BCR-induced calcium influx functional calcium cell test as described below.

[0410] Btk kinase activity was determined using time-resolved resonance fluorescence excitation energy transfer (TR-FRET) methodology. Measurements were carried out in a reaction volume of μΐ using 96-well assay plates.

[0411] Kinase enzyme, inhibitor, ATP (at K value_m for kinase), and 1 μM peptide substrate (BiotinAVLESEEELYSSARQ-NH2) was introduced into a reaction buffer composed of 20 mM Tris, 50 mM NaCl,

MgCl2 (5-25 mM depending on kinase), MnCl2 (0-10 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 (according to a divalent cation) in 25 μΐ 1x Lance buffer (Perkin-Elmer). Streptavidin-APC (Perkin-Elmer) and Eu-labeled p-Tyr100 antibody (PerkinElmer) in 1x Lance buffer in 25 μΐ volume were added to achieve 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 determined in a multi-detection plate reader at excitation wavelength (A_ex) 330 nm and detection wavelengths from 615 to 665 nm. Activity was determined by the ratio of fluorescence at 665 nm to that at 615 nm. For each compound, enzyme activity was determined at different compound concentrations. Negative control reactions were carried out in the absence of inhibitor in seven samples and two enzyme-free controls were used for

Determination of the baseline fluorescence level. Inhibition constants, Ki (app), were obtained using BatchKi software (Kuzmic et al. (2000), Anal. Biochem. 286: 45-50). IC50 values ​​were calculated according to the equation:

[0412]

ICso = {Kiiappyil + tATPyKn, ^)} + [E]_totol/2;

[0413] For all kinases, [ATP] = Km^ATP, [Btk] total = 0.5 nM and [Lck] total = 6 nM.

[0414] Calcium influx assays based on fluorescence were performed on a FlexStation

II384 fluorometric plate imaging reader (Μα ^ οα ^ ί · Devices) according to the manufacturer's instructions. Briefly, actively growing Ramos cell cultures (ATCC) in RPIW 1 medium enriched in 10% FBS (Invitrogen) were washed and transferred to plates in a low serum medium at a density of about 5 X 10⁵ cells per 100 μl per well in 96-well plates. The compounds to be assayed were dissolved in DIWSO and then diluted in low serum medium to final concentrations ranging from 0 to 10 μΜ (at a dilution factor of 0.3). The diluted compounds were then added to each well (final DMSO concentration was 0.01%) and incubated at 37 degrees in a 5% CO incubator₂ for one hour. Then 100 μl calcium sensitive dye (from Calcium 3 assay kit, Molecular Devices) was added to each well and incubated for an additional hour. Compound treated cells were stimulated with goat anti-human antibody (80ug / ml; Jackson ImmunoResearch) and read on a FlexStation II384 at A_ex = 485nm and A_Em = 538nm for 200 seconds. Relative fluorescence units (RFU) and IC50 values ​​were read and analyzed using the embedded SoftMax program (Molecular devices).

Table 2: Assay results for representative compounds

<td colspan="4">, ° "O NH₂ \ = / at JL.^NR</td>

<td>Union No.</td><td>R</td><td>Btk IC₅₀ (NM)</td><td>Ca influx to Ramos IC cell₅₀ (NM)</td>

<td> 4</td><td>ΛΛΛ / AND ABOUT</td><td> 0,72</td><td> 10</td>

<td> 5*</td><td>WW AND ABOUT</td><td> 20</td><td> 89</td>

<td> 6</td><td>WW Λ oo</td><td> 0,52</td><td> 92</td>

EP 2 201 840 B1

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

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

<td> 9</td><td>WW about ° A</td><td> 3,6</td><td> 48</td>

<td> 10</td><td>WW Φ^HNY ^ 0</td><td> 0,58</td><td> 3</td>

<td> 11</td><td>abovementioned ό</td><td> 1,6</td><td> 24</td>

<td> 12</td><td>abovementioned ά</td><td> 1,9</td><td> 90</td>

<td> 13</td><td>«MW AND ABOUT</td><td> &lt;0,5</td><td> 10</td>

<td> 14</td><td>Website Ο^Νγ ^ ABOUT</td><td> 1,4</td><td> 7</td>

<td> 15*</td><td>abovementioned AND ABOUT ¹</td><td> 2,5</td><td> 36</td>

<td colspan="4">* outside the scope of the present invention</td>

[0415] Two lines of evidence confirm irreversible inhibition of Btk by the compounds of the present

EP 2 201 840 B1. First, after treatment of the recombinant Btk with the compound, it does not recover its activity after repeated washing with an inhibitor-free medium (see, for example, JB Smaill, et al., J. Med. Chem. 1999, 42, 1803). Secondly, the main peak observed in mass spectrometry corresponds to the molecular weight of the 1: 1 covalent complex between compound 4 and Btk (Compound 4: 440 Da, recombinant Btk kinase domain: 33.448 Da; Complex: 33.927 Da expected, 33.927 Da observed).

[0416] These compounds are very potent Btk kinase inhibitors having activities with an IC 50 value in the range below nanomolar to single nanomolar to in vitro kinase activity. Their IC50 values ​​in the Ca inflow test²⁺ in cells (Ramos cell) are in the range of 3 to 92 nM.

[0417] In addition, three types of Michael acceptors, acrylamide, vinylsulfonamide and propargylamide, have been found to have strong interaction with Btk. By adding the methyl group in the trans position to the vinyl group, the activity of compound 5, which is 28 times weaker than 4, decreases. This is probably associated with a decrease in the electrophilicity of more substituted olefins. Compound 15 with a tertiary amine group gains power compared to compound 5, although it still has reduced potency compared to compound 13. Compound 10 is about 6 times more potent than 9, probably due to electrophilic orientation. Finally, the R configuration is defined as the slightly more preferred absolute configuration based on two pairs of enantiomers (11 vs. 12 and 13 vs. 14).

Example 3: Btk inhibition [0418] In addition, the properties of these compounds were characterized by determining the endpoints in many cell biochemical and functional assays. In particular, sought for selectivity assays for these compounds to inhibit Btk compared to closely related Lck, Lyn and Syk protein kinases. Anti-IgM stimulated Ramos (human B cell line) cells were evaluated for phosphorylation

PLC-γΙ dependent on Btk; Lyn and Syk dependent tyrosine 551 phosphorylation in Btk; and influx of activated BCR. Compound 4 was also assayed in Jurkat cells, a human T cell line in which Lck and Itk but not Btk are required for Ca influx.^{2+ in} mediated by the T cell receptor. As shown in Table 3, compound 4 shows significant Btk selectivity in cellular assays. In anti-IgM stimulated Ramos cells, compound 4 inhibited PLC-y1 phosphorylation with an IC value₅₀ = 0.014 μΜ, whereas Lyn and Syk dependent tyrosine phosphorylation of 551 in Btk was less inhibited (IC₅₀ &gt; 7.5 μΜ). Thus, compound 4 shows a&gt; 500-fold selectivity between Btk and Lyn or Syk in cells. In addition, compound 4 was 11-fold less active in inhibiting Ca influx²⁺ in Ramos cells, maintaining expected selectivity for B cells compared to T cells.

Table 3. Results of cellular assay of compound 4

<td>Relationship</td><td>Btk^and(NM)</td><td>Lck^and(NM)</td><td>Lyn^and(NM)</td><td>Btk p551^b(ΜΜ)</td><td>pPLC-yl^b(ΜΜ)</td><td>Ramos Ca inflow^b(ΜΜ)</td><td>Jurkat Ca inflow^b(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>

<td colspan="8">[a] Ki (app) [b] IC50</td>

Example 4: Use of compound 4 for the treatment of rheumatoid arthritis [0419] The in vivo efficacy of compound 4 was evaluated in a mouse model of rheumatoid arthritis. Arthritis was induced in Balb / c mice by administration of anti-collagen antibodies and lipopolysaccharides (LPS). See Nandakumar et al. (2003), Am. J. Pathol. 1 63: 1 827-1837.

[0420] Female Balb / c mice were treated with 100 mg / kg chemicon mAb type II collagen cocktail intravenously on day 0 and 1.25 mg / kg LPS intraperitoneally on day 1. Compound 4 was orally administered as an aqueous suspension based on methylcellulose at doses of 1 , 3, 10 and 30 mg / kg once daily starting on day 2 to day 12. Blood samples were collected on test day 12, 0.5 and 2 hours after dose of compound 4 (see Table 4). The concentration of compound 4 in the serum was determined by LC / MS / MS. Twenty-four hours after dosing, compound 4 levels were below the quantification level.

Table 4. Dose and plasma concentration of compound 4 as a function of time

EP 2 201 840 B1

<td rowspan="2">Dose (mg / kg / day)</td><td rowspan="2">Collection time (h)</td><td colspan="2">Conc. (ΜΜ)</td>

<td>Average</td><td>SD</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>

[0421] Inhibition of arthritis by compound 4 was dose-dependent, with maximum effect (&gt; 95% inhibition) at doses of 10 and 30 mg / kg. Compound 4 plasma concentrations that induce this maximal effect ranged from 0.6-1.7 μΜ at T_max (2 h) and to achieve efficacy it is not required to maintain them at high levels for 24 hours, which is not surprising with an irreversible inhibitor. Based on sequence analysis and cell modeling, it is suggested that the irreversible inhibitors described herein form covalent bonds with Cys 481 in Btk (e.g., Michael's acceptor, a portion of the compound described herein reacts with the rest of Cys 481 Btk). Based on sequence homology analysis (Fig. 1), it is anticipated that the compounds described herein act as irreversible inhibitors of kinases having Cys 481 or homologous cysteine ​​residues, but bind reversibly to kinases having other amino acids at position 481 in the catalytic domain sequence and which are otherwise homologous to Btk. See, for example, the sequences listed in Fig. 1. See also tyrosine kinase (TK) sequence alignments published at kinase.com/human/kinome/phylogeny.html.

Example 5: Inhibition of mast cell degranulation [0422] Human CD34 + cells were differentiated into mast cells within 9 weeks in culture in the presence of 1ng / ml IL-3, 50ng / ml IL-6, 100ng / ml SCF. Cells were incubated with IgE + IL-4 for 4 days, after which degranulation was induced by cross-linking with anti-IgE. Degranulations were determined using a hexosaminidase test. The compound did not inhibit ionomycin-induced Ca ++ ion phosphoration and did not affect cell viability as determined by the Alamar Blue assay. Compound 4 had an IC50 value in MC degranulation of less than 100 nanomolar. Thus, the compounds described herein can be used to treat inflammatory diseases such as asthma.

Example 6: Pharmaceutical compositions:

[0423] The compositions described below for purposes of illustration contain a compound of formula (A); any of the compounds of formulas (A), (B), (C) or (D) can be used to prepare such pharmaceutical compositions.

Example 6a: Parenteral compositions [0424] To prepare a parenteral pharmaceutical composition suitable for injection, 100 mg of a water soluble salt of the compound of formula (A) is dissolved in DMSO followed by mixing with 10 ml of 0.9% sterile salt physiological. The mixture is introduced into unit dosage forms suitable for administration by injection.

Example 6b: Oral compositions [0425] To prepare a pharmaceutical composition for oral administration, 100 mg of the compound of formula (A) is mixed with 750 mg of starch. The mixture is introduced into an oral dosage unit form, such as a hard gelatin capsule, which is suitable for oral administration.

EP 2 201 840 B1

Example 6c: Sublingual composition (hard lozenge) [0426] To prepare a pharmaceutical composition for sublingual delivery, such as a hard lozenge, 100 mg of compound of formula (A), 420 mg of powdered sugar mixture are mixed,

1.6 ml light corn syrup, 2.4 ml distilled water and 0.42 ml mint extract.

The mixture is gently mixed and poured into a casting mold to form lozenges suitable for sublingual administration.

Example 6d: Inhalation compositions [0427] To prepare a pharmaceutical composition for inhalation delivery, 20 mg of the 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 introduced into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.

Example 6e: Rectal gel composition [0428] To prepare a pharmaceutical composition for rectal administration, 100 mg of the compound of formula (A) is mixed with 2.5 g of methyl cellulose (1500 mPa), 100 mg of methylparapen, 5 g of glycerin and 100 ml of purified water. The resulting gel is then introduced into rectal delivery units, such as syringes, which are suitable for rectal administration.

Example 6f: Topical gel composition [0429] To prepare the topical gel pharmaceutical composition, 100 mg of the compound of formula (A) is mixed with 1.75 g of hydroxypropyl cellulose, 10 ml of propylene glycol, 10 ml of isopropyl myristate and 100 ml of purified USP alcohol. The resulting gel mixture is then introduced into containers, such as tubes, that are suitable for topical administration.

Example 6g: Ophthalmic Solution Composition [0430] To prepare an ophthalmic solution pharmaceutical composition, 100 mg of the compound of formula (A) is 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 introduced into ophthalmic delivery units, such as eye drop containers, which is suitable for ophthalmic administration.

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