BR122021003286B1 - TYROSINE KINASE INHIBITOR COMPOUNDS, THEIR USES AND PHARMACEUTICAL COMPOSITION - Google Patents

Abstract

The present disclosure provides compounds that are tyrosine kinase inhibitors, in particular Bruton's tyrosine kinase ("BTK") inhibitors, and therefore are useful for treating diseases treatable by BTK inhibition such as cancer, autoimmune diseases, inflammatory and thromboembolic. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Description

[001] The present application claims the benefit of provisional application serial U.S. 62/170,547, filed June 3, 2015, and provisional application serial U.S. 62/271,689 filed December 28, 2015, each of which is incorporated into this document by reference in its entirety.

Field of Invention

[002] The present disclosure provides compounds that are inhibitors of tyrosine kinase, in particular inhibitors of Bruton's tyrosine kinase ("BTK") and are therefore useful for the treatment of diseases such as cancer, autoimmune, inflammatory and thromboembolic diseases. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Background

[003] BTK, a member of the Tec family of non-receptor tyrosine kinases, is essential for B cell signaling downstream of the B cell receptor. It is expressed on B cells and other hematopoietic cells, such as monocytes, macrophages and mast cells. It functions in several aspects of B cell function that maintain the B cell repertoire (see Gauld S. B. et al., B cell antigen receptor signaling: roles in cell development and disease. Science, 296:1641 to 1642. 2002.) B play a role in rheumatoid arthritis (see Perosa F., et al., CD20-depleting therapy in autoimmune diseases: from basic research to the clinic. J Intern Med. 267:260 to 277. 2010 and Dorner T, et al. Targeting B cells in immune-mediated inflammation: a comprehensive review of mechanisms of action and identification of biomarkers Pharmacol Ther. inhibitor PCI-32765 blocks B cell and mast cell activation and prevents mouse collagen indices Clin. , The role of B cells in lpr/lpr-induced autoimmunity.

[004] J. Exp Med. 180:1,295 to 1,306. 1994; Honigberg L. A., The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is effective in models of autoimmune disease and B-cell malignancy. Proc. Natl. Academic. Sci. 107:13,075 to 13,080. 2010; and Mina-Osorio P, et al., Suppression of glomerulonephritis in lupus-prone NZB x NZW mice by RN486, a selective inhibitor of Bruton's tyrosine kinase. Arthritis Rheum. 65: 2,380 to 2,391. 2013).

[005] There is also potential for BTK inhibitors to treat allergic diseases (see Honigberg, L., et. al., The selective BTK inhibitor PCI-32765 blocks B cell and mast cell activation and prevents mouse collagen indices arthritis. Clin. Immunol. 127 S1:S111. The irreversible inhibitor was observed to suppress IgE antigen complex-induced passive cutaneous anaphylaxis (PCA) in mice. These findings are in line with those noted with mast cells and BTK mutant knockout mice and suggest that BTK inhibitors may be useful for the treatment of asthma, an IgE-dependent allergic airway disease.

[006] Consequently, compounds that inhibit BTK would be useful in the treatment of diseases such as autoimmune diseases, inflammatory diseases and cancer.

summary

[007] In a first aspect, this disclosure is directed to a compound of Formula (I):

[008] where:

[009] R1 and R2 are independently hydrogen, alkyl, alkoxy, haloalkyl or halo;

[0010] X is -O-, -CONR-, -NRCO- or -NR-CO-NR' where R and R' are

[0011] independently hydrogen or alkyl;

[0012] Ar is heteroaryl or phenyl in which heteroaryl and phenyl are optionally substituted by one, two or three substituents independently selected from alkyl, halo, haloalkyl, alkoxy and hydroxy;

[0013] A is -N- or -CR3- where R3 is hydrogen, alkyl, cyclopropyl, halo, haloalkyl, haloalkoxy, alkoxy or cyano;

[0014] Y is bond or alkylene;

[0015] The Z ring is heterocycloamino optionally substituted by one or two substituents independently selected from alkyl, hydroxy, alkoxy and fluorine;

[0016] R5 is a group of formula (i), (ii), (iii) or (iv):

[0017] where:

[0018] Ra is hydrogen, fluorine or cyano; provided that when Ra is cyan, then Rb is hydrogen and Rc is not hydrogen;

[0019] Rb is hydrogen or alkyl; It is

[0020] Rc is hydrogen, hydroxyalkyl, alkoxyalkyl, alkyl (optionally substituted by one or two substituents independently selected from hydroxy, hydroxyalkyl, heteroaryl (optionally substituted by one or two substituents independently selected from alkyl and heterocyclyl in which heterocyclyl is optionally substituted by a or two substituents independently selected from halo and alkyl), and

[0021] -CONR9R10 (wherein R9 and R10 are independently hydrogen or alkyl or R9 and R10 together with the nitrogen atom to which they are attached form a heterocyclyl optionally substituted by one or two substituents selected from alkyl and heterocyclyl)), cycloalkyl (optionally substituted by one or two substituents independently selected from halo, alkyl, alkoxyalkyl and aryl; or wherein two adjacent cycloalkyl substituents together with the carbon atoms to which they are attached form a heterocyclyl group), heterocyclylalkyl, heterocyclyl ( wherein heterocyclyl and heterocyclyl in heterocyclylalkyl are optionally substituted by one, two or three substituents wherein two of the optional substituents are independently selected from alkyl, alkoxy, hydroxy, halo, amino and oxo, and one of the optional substituents is alkyl, hydroxyalkyl, alkoxy , alkoxyalkyl, acyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl or heterocyclyl, wherein the heterocyclyl is substituted by one or two substituents independently selected from hydrogen, alkyl, halo, hydroxy, and alkoxy), or -(alkylene)-NR6R7 (wherein R6 and R7 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl or heterocyclyl, wherein the heterocyclyl is optionally substituted by one or two substituents independently selected from alkyl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, acyl and alkoxycarbonyl; or R6 and R7 together with the nitrogen atom to which they are attached form

[0022] wherein one or two of X1, X2 and X3 are nitrogen and the rest are carbon and the ring is optionally replaced by one or two substituents independently selected from alkyl, haloalkyl and halo); and/or

[0023] a pharmaceutically acceptable salt thereof provided that:

[0024] when A is -N-, then Ra is cyano and Rc is heterocycloaminoalkyl, wherein the heterocycloamino in heterocycloaminoalkyl is optionally substituted by one or two substituents independently selected from alkyl, alkoxy, hydroxy, halo, amino and oxo, and the heterocycloamino nitrogen atom is replaced by heterocyclyl, wherein the heterocyclyl is replaced by one or two substituents independently selected from hydrogen, alkyl, halo, hydroxy and alkoxy.

[0025] In one embodiment, when R5 in the compounds of Formula (I) and/or a pharmaceutically acceptable salt thereof (and any embodiments thereof disclosed herein) is a group of formula (i), (ii) or (iii), where Ra is cyano, the compounds of the disclosure are reversible covalent inhibitors of BTK, that is, they can form a reversible covalent bond with a thiol group of a cysteine residue, in particular, with Cys481 of BTK.

[0026] [8] In another embodiment, when R5 in the compounds of Formula (I) and/or a pharmaceutically acceptable salt thereof (and any embodiments thereof disclosed herein) is a group of formula (i), ( ii) or (iii) where Ra is hydrogen or fluorine or R5 is

[0027] a group of formula (iv), the compounds of the disclosure are reversible covalent inhibitors of BTK, that is, they can form a reversible covalent bond with a thiol group of a cysteine residue, in particular with Cys481 of BTK.

[0028] In a second aspect, this disclosure is directed to a pharmaceutical composition comprising a compound of Formula (I), (or any of the embodiments thereof described herein), and/or a pharmaceutically acceptable salt thereof. ; and a pharmaceutically acceptable excipient. (a) In embodiment (a) of the second aspect, the formulation is a solid oral formulation comprising: (i) a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof (or any embodiment thereof disclosed herein): and (ii) means for releasing said compound and/or a pharmaceutically acceptable salt thereof in the intestine. (b) In embodiment (b) of the second aspect, the formulation is a solid oral formulation comprising means for delivering a therapeutically effective amount of a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof (or any modality thereof disclosed herein) from said oral formulation in the intestine.

[0029] Within embodiment (a) or (b), in one embodiment, the compound of Formula (I) and/or a pharmaceutically acceptable salt thereof (or any embodiment thereof disclosed in the present document) is released into the small intestine.

[0030] In yet another embodiment of modality (a) or (b) and modalities contained therein, wherein (i) the compound of Formula (I) and/or a pharmaceutically acceptable salt thereof (or modalities thereof disclosed in this document); and/or (ii) the dosage form comprising a compound of Formula (I) (or embodiments thereof disclosed herein); and/or a pharmaceutically acceptable salt thereof; is coated with at least one coating, wherein said coating is independently chosen from (when more than one coating is present) enteric coating and a non-enteric delayed release coating, preferably, the coating is one or more enteric coatings.

[0031] In one embodiment, when the compound of Formula (I) and/or a pharmaceutically acceptable salt thereof (or modalities thereof disclosed herein) and/or the dosage form comprising the compound of Formula (I) and/or a pharmaceutically acceptable salt thereof (or embodiments thereof disclosed herein) is coated with an enteric coating, the enteric coating is a polymer. In another embodiment, when the compound of Formula (I) and/or a pharmaceutically acceptable salt thereof and/or the dosage form comprising the compound of Formula (I) and/or a pharmaceutically acceptable salt thereof is coated with an enteric coating, the enteric coating is an anionic polymer selected from polymethacrylates (e.g., poly(methacrylic acid, methacrylate), poly(methacrylic acid, methyl methacrylate)); cellulose-based polymers (e.g., cellulose acetate phthalate CAP, cellulose acetate trimellitate CAT, cellulose acetate succinate CAS, hydroxypropylmethylcellulose acetate phthalate HPMCP, hydroxypropylmethylcellulose acetate succinate HPMCAS) and polyvinyl derivatives such as polyvinyl acetate phthalate PVAP . In yet another embodiment, the enteric coating wears off in the gastrointestinal tract which has a pH of about 4.5 to about 7 or of about 5 or 5.5 to about 7 to release the compound of Formula (I) and /or a pharmaceutically acceptable salt thereof (or embodiments thereof disclosed herein).

[0032] When a non-enteric coating is employed, non-enteric delayed-release dosage forms can be administered in the fasted state and the delayed-release coating can be designed to wear off, rupture or become highly permeable. in about 0.3 to about 3 hours or in about 0.5 to about 2 hours after administration to release the compound of Formula (I) (or embodiments thereof disclosed herein) and/or a pharmaceutically acceptable salt thereof.

[0033] In a third aspect, this disclosure is directed to a method for treating a disease treatable by inhibition of BTK in a mammal in need thereof, such method comprising administering to the mammal in need thereof, a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein) and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In one embodiment, the disease is cancer, autoimmune, inflammatory or thromboembolic diseases. In one embodiment, the disease is necrotizing hemorrhagic leukoencephalitis, acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, alopecia areata, alopecia universalis, amyloidosis, ankylosing spondylitis, anti-GBM/Anti-TBM nephritis, antiphospholipid syndrome (APS), antibody syndrome antiphospholipids, aplastic anemia, arthritis, autoimmune angioedema, autoimmune dysautonomia, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP ), autoimmune thyroid disease, autoimmune urticaria, autoimmune hemolytic anemia, axonal and neuronal neuropathies, Baló's disease, Behcet's disease, bullous pemphigoid, cardiomyopathy, Castleman's disease, celiac disease, Chagas disease, chronic fatigue syndrome, demyelinating polyneuropathy chronic inflammatory disease (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome, cicatricial pemphigoid/benign mucous pemphigoid, celiac disease, Cogans syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST disease, Crohn's disease, demyelinating neuropathies, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), diabetes, discoid lupus, Dressler's syndrome, dry eye, dysautonomia, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, syndrome of Evans, experimental allergic encephalomyelitis, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis (GPA) (formerly called Wegener's granulomatosis), Graves' disease , Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestativa, hypogammaglobulinemia, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-associated sclerosing disease, immunoregulatory lipoproteins, myositis of inclusion bodies, inflammatory bowel disease, interstitial cystitis, juvenile arthritis, juvenile diabetes (type 1 diabetes), juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, Linear IgA (LAD), lupus (SLE), lupus including lupus nephritis, Lyme disease, chronic Meniere's disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, membrane pemphigoid mucosa, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyotonia, neutropenia, ocular cicatricial pemphigoid, opsoclonus-myoclonus syndrome, optic neuritis, Ord's thyroiditis, osteoarthritis, palindromic rheumatism, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococci), degeneration paraneoplastic cerebellar disease, paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, pemphigus such as pemphigus vulgaris, pemphigus foliaceus, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, progesterone dermatitis, psoriasis, psoriatic arthritis, psoriaticarthritis, pure red cell aplasia, pyoderma gangrenous, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, recurrent polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, autoimmunity of sperm and testicular, stiff person syndrome, Still's disease, subacute bacterial endocarditis (SBE), Susac syndrome, sympathetic ophthalmia, Takayasu arteritis, temporal arteritis/giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome , transverse myelitis, autoimmune polyglandular syndromes Type I, II and III, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vesicobullous dermatosis, vitiligo, vulvodynia or lupus.

[0034] In an embodiment of the third aspect, the mammal is suffering from an autoimmune disease, for example, inflammatory bowel disease, arthritis, lupus, including lupus nephritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, granulomatosis with polyangiitis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, dry eye (including Sjogren's dry eye and non-Sjogren's dry eye), multiple sclerosis, Guillain's syndrome Barre, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arthritis, temporal arthritis, autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, pemphigus, such as pemphigus vulgaris and/or foliaceus, bullous pemphigoid, age-related macular degeneration (wet and dry), diabetic macular edema, corneal transplant, abdominal aortic aneurysm, mucous membrane pemphigoid or vulvodynia.

[0035] In another modality, the autoimmune disease is lupus, pemphigus vulgaris, myasthenia gravis, Sjogren's syndrome, dry eye, multiple sclerosis, Wegener's granulomatosis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, granulomatosis with po- liangitis or rheumatoid arthritis.

[0036] In another embodiment of the third aspect, the mammal is suffering from a heteroimmune disease or condition, for example, graft-versus-host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis and atopic dermatitis. In another embodiment, the disease is atopic dermatitis.

[0037] In yet another embodiment of the third aspect, the mammal is suffering from an inflammatory disease, for example, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis , dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis , nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis , uveitis, vaginitis, vasculitis or vulvitis. In another embodiment of this aspect, the mammal is suffering from an inflammatory skin disease that includes, by way of example, dermatitis, contact dermatitis, eczema, urticaria, rosacea and scarring psoriatic lesions on the skin, joints or other tissues or organs. . In another embodiment, the inflammatory disease is asthma or dermatitis.

[0038] In yet another embodiment of the third aspect, the mammal is suffering from inflammatory and/or autoimmune disease, including acute autoimmune and/or inflammatory disease, in which corticosteroid therapy is used as the first or second line therapy. or first- or second-line maintenance therapy. In one embodiment, the compound of Formula (I) (or any embodiments thereof disclosed herein) is used for the treatment of:

[0039] Endocrine Disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice: synthetic analogues can be used in conjunction with mineralocorticoids where applicable; in childhood mineralocorticoid supplementation is of particular importance); congenital adrenal hyperplasia; non-suppurative thyroiditis; hypercalcemia associated with cancer.

[0040] Rheumatic Disorders: As Adjunct Therapy for Short-Term Traction Management (For the Patient to Endure an Exacerbation or Acute Episode) In: Psoriatic Arthritis, Rheumatoid Arthritis, Including Juvenile Rheumatoid Arthritis (Selected Cases May Require Dose Maintenance Therapy Low), Ankylosing Spondylitis, Acute And Subacute Bursitis, Acute Non-Specific Tenosynovitis, Gout, Acute Gouty Arthritis, Post-traumatic Osteoarthritis, Osteoarthritis Synovitis, Epicondylitis.

[0041] Collagen Diseases: During an exacerbation or as maintenance therapy in selected cases of: systemic lupus erythematosus, systemic dermatomyositis (polymyositis), acute rheumatic carditis.

[0042] Dermatological diseases: Pemphigus; bullous herpetiform dermatitis; severe erythema multiforme (Stevens-Johnson syndrome); exfoliative dermatitis; mycosis fungoides; severe psoriasis; severe seborrheic dermatitis.

[0043] Allergic states: Control of disabling or severe intractable allergic conditions to adapt conventional treatment tests: perennial or seasonal allergic rhinitis; bronchial asthma; contact dermatitis; atopic dermatitis; serum disease; drug hypersensitivity reactions.

[0044] Ophthalmic diseases: Severe chronic and acute inflammatory and allergic processes involving the eye and its annex, such as: allergic marginal corneal ulcers, ophthalmic herpes zoster, anterior segment inflammation, diffuse posterior uveitis and choroiditis, ophthalmic - sympathetic mia, allergic conjunctivitis, keratitis, chorioretinitis, optic neuritis, iritis and iridocyclitis.

[0045] Respiratory diseases: Symptomatic sarcoidosis; Loeffler syndrome not manageable by other means; berylliosis; aspiration pneumonitis, disseminated or fulminant pulmonary tuberculosis when used simultaneously with appropriate antituberculosis chemotherapy

[0046] Hematological disorders: Idiopathic thrombocytopenic purpura in adults; secondary thrombocytopenia in adults; acquired hemolytic anemia (autoimmune); erythroblastopenia (RBC anemia); congenital hypoplastic anemia (erythroid).

[0047] Neoplastic diseases: For palliative management of: leukemias and lymphomas in adults, acute childhood leukemia.

[0048] Edematous states: To induce diuresis or remission of proteinuria in nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus.

[0049] Gastrointestinal diseases: For the patient to endure a critical period of the disease in: ulcerative colitis, regional enteritis.

[0050] Miscellaneous: Tuberculous meningitis with subarachnoid block or imminent block when used simultaneously with appropriate anti-tuberculosis chemotherapy; trichinosis with myocardial or neurological involvement.

[0051] The compound of Formula (I) and/or a pharmaceutically acceptable salt thereof can be used for the treatment of the diseases listed above optionally in combination with a corticosteroid, non-corticosteroid agents, immunosuppressants and/or anti-inflammatories. In one embodiment, the immunosuppressive agent is selected from interferon alpha, interferon gamma, cyclophosphamide, tacrolimus, mycophenolate mofetil, methotrexate, dapsone, sulfasalazine, azathioprine, an anti-CD20 agent (such as rituximab, ofatumumab, obinutuzumab or veltuzumab or a biologically similar version thereof), anti-TNFalpha agent (such as entanercept, infliximab, golilumab, adalimumab or Certolizumab pegol or a biologically similar version thereof), anti-IL6 agent targeting the ligand or its receptors (such as tocilizumab, sarilumab, olokizumab , elsililumab, or siltuximab), anti-IL17 agent for ligand or its receptors (such as secukinumab, ustekinumab, brodalumab, or ixekizumab), anti-IL1 agent for ligand or its receptors (such as rilonacept, canakinumab, or anakinra), anti-IL2 agent for ligand or its receptors (such as basiliximab or daclizumab), anti-CD2 agent such as alefacept, anti-CD3 agent such as muromonab-cd3, anti-CD80/86 agent such as abatacept or belatacept, anti-sphingosine-1-phosphate receptor agent such as fingolimod , anti-C5 agent such as eculizumab, anti-alpha 4 integrin agent such as natalizumab, anti-α4β7 agent such as vedolizumab, anti-mTOR agent such as sirolimus or everolimus, anti-calcineurin agent such as tacrolimus, and anti-BAFF/BlyS agent (such as belimumab , VAY736 or blisibimod), leflunomide and teriflunomide. Preferably, the immunosuppressive agent is rituximab, ofatumumab, obinutuzumab or veltuzumab or a biologically similar version thereof.

[0052] In yet another embodiment of the third aspect, the mammal is suffering from cancer. In one embodiment, the cancer is a B-cell proliferative disorder, e.g., diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma (CLL), chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia of B-cell (B-ALL), Philadelphia chromosome-positive B-ALL, B-cell prolymphocytic leukemia, small lymphocytic lymphoma (SLL), multiple myeloma, B-cell non-Hodgkin's lymphoma, lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia, lymphoma splenic marginal zone, plasma cell myeloma, plasma cytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphoma intravascular large B cell, primary effusion lymphoma, Burkitt's lymphoma/leukemia, or lymphomatoid granulomatosis.

[0053] In yet another embodiment, the mammal is suffering from a thromboembolic disorder, for example, myocardial infarction, angina pectoris, reocclusion after angioplasty, retenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke cerebral, transient ischemia, a peripheral artery occlusive disorder, pulmonary embolism or deep vein thrombosis.

[0054] In a fourth aspect, the disclosure is directed to a compound of Formula (I) (and any embodiments thereof described herein) and/or a pharmaceutically acceptable salt thereof for use as a medicament. In one embodiment, the use of the compound of Formula (I) and/or a pharmaceutically acceptable salt thereof is for the treatment of a BTK-mediated disease, e.g., the disease is an inflammatory disease, autoimmune disease, cancer, or thromboembolic diseases. described in the third aspect and modalities therein.

[0055] In a fifth aspect is the use of a compound of Formula (I) (or any of the modalities thereof described herein) and/or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament to treat a disease in a mammal in which BTK contributes to the pathology and/or symptoms of the disease. In one embodiment of this aspect, the disease is cancer, autoimmune, inflammatory or thromboembolic disease described in the third aspect and embodiments thereof.

[0056] In any of the aforementioned aspects involving the treatment of cancer, there are additional modalities that comprise administering the compound of Formula (I) (or any of the modalities thereof described herein) and/or a pharmaceutically acceptable salt of the even in combination with an anticancer agent. When combination therapy is used, the agents can be administered simultaneously (as a fixed combination pharmaceutical product) or sequentially.

[0057] In a sixth aspect, this revelation is directed to an intermediary of Formula (II):

[0058] where:

[0059] R1, R2, R3, X, Ar, Y and Z ring are as defined in the first aspect above;

[0060] or a salt thereof.

[0061] In a seventh aspect, a process for preparing is provided: (1). a compound of Formula (I) wherein Ra is cyano, A is -CR3- and other groups are as defined above: or a pharmaceutically acceptable salt thereof; comprising: (a) reacting a compound of Formula (II):

[0062] where:

[0063] R1, R2, R3, X, Ar, Y and Z ring are as defined in the first aspect above;

[0064] with an aldehyde of Formula RcCHO wherein Rc is as defined in the first aspect above; or (b) react a compound of Formula (III):

[0065] where:

[0066] R1, R2, R3, X, Ar, Y and Z are as defined in the first aspect above; with a compound of Formula RcCH=C(CN)COL wherein L is a leaving group under acylation reaction conditions, wherein Rc is as defined in the first aspect above; or

[0067] (2). a compound of Formula (I) wherein Ra is hydrogen, A is -CR3- and other groups are as defined in the first aspect above; or a pharmaceutical salt thereof; which comprises reacting a compound of Formula (III):

[0068] where:

[0069] R1, R2, R3, X, Ar, Y and Z ring are as defined in the first aspect above;

[0070] with a compound of Formula RcRbC=CHCOL in which L is a leaving group under acylation reaction conditions, in which Rb and Rc are as defined in the first aspect above; (c) optionally producing an acid addition salt of a compound obtained from Step (1) or (2) above; (d) optionally producing a free base of a compound obtained from Step (1) or (2) above.

Definitions:

[0071] Unless otherwise indicated, the terms used in the following specification and claims are defined for the purposes of this disclosure and have the following meaning:

[0072] "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, for example, methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms) and the like.

[0073] "Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise indicated, for example, methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0074] "Alkylsulfonyl" means a -SO2R radical in which R is alkyl as defined above, for example, methylsulfonyl, ethylsulfonyl and the like.

[0075] "Amino" means a -NH2.

[0076] "Alkoxy" means an -OR radical in which R is alkyl as defined above, for example, methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso- or tert-butoxy and the like.

[0077] "Alkoxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted by an alkoxy group (in one embodiment, one or two alkoxy groups), as defined above, for example, 2-methoxyethyl, 1-, 2- or 3-methoxypropyl, 2-ethoxyethyl and the like.

[0078] "Alkoxycarbonyl" means a -C(O)OR radical in which R is alkyl as defined above, for example, methoxycarbonyl, ethoxycarbonyl and the like.

[0079] "Acyl" means a -COR radical in which R is alkyl, haloalkyl or cycloalkyl, for example, acetyl, propionyl, cyclopropylcarbonyl and the like. When R is alkyl, the radical is also referred to herein as alkylcarbonyl.

[0080] "Cycloalkyl" means a cyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms in which one or two carbon atoms may be replaced by an oxo group, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and similar.

[0081] "Carboxy" means -COOH.

[0082] "Halo" means fluorine, chlorine, bromine or iodine; in one embodiment, fluorine or chlorine.

[0083] "Haloalkyl" means alkyl radical as defined above, which is substituted by one or one to five halogen atoms (in one embodiment, fluorine or chlorine) including those substituted by different halogens, for example, -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, and the like. When the alkyl is replaced only by fluorine, it may be referred to in this disclosure as fluoroalkyl.

[0084] "Haloalkoxy" means a -OR radical in which R is haloalkyl as defined above, for example, -OCF3, -OCHF2 and the like. When R is haloalkyl in which the alkyl is replaced only by fluorine, it may be referred to in this disclosure as fluoroalkoxy.

[0085] "Hydroxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted by one or two hydroxy groups, provided that if two hydroxy groups are present not are both on the same carbon atom. Representative examples include, but are not limited to, 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. Additional examples include, but are not limited to, 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(hydroxymethyl)-2-hydroxyethyl.

[0086] "Heterocyclyl" means a saturated or unsaturated monovalent bicyclic or monocyclic group (fused bicyclic or bridged bicyclic) of 4 to 10 ring atoms, wherein one or two ring atoms are heteroatoms selected from N, O or S( O)n, where n is an integer from 0 to 2, with the remaining ring atoms being C. Additionally, one or two ring carbon atoms in the heterocyclyl ring may be optionally replaced by a -CO group. More specifically, the term heterocyclyl includes, but is not limited to, oxetanyl, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, hexahydropyrrolo[1,2-a] pyrazin-6(2H)-one-yl, tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one-yl, 5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-a]pyrazine-yl, 3-oxa-8-azabicyclo[3.2.1]octane-yl and the like. When the heterocyclyl ring is unsaturated, it may contain one or two ring double bonds as long as the ring is non-aromatic.

[0087] "Heterocyclylalkyl" means a radical -(alkylene)-R in which R

[0088] is a heterocyclyl ring as defined above; for example, tetrahydrofuranylmethyl, piperazinylmethyl, morpholinylethyl and the like.

[0089] "Heterocycloamino" means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O or S(O)n, wherein n is a integer from 0 to 2, with the remaining ring atoms being C as long as at least one of the ring atoms is N. Additionally, one or two ring carbon atoms in the heterocycloamino ring may be optionally substituted by a group - CO-

[0090] When the heterocycloamino ring is unsaturated, it may contain one or two ring double bonds as long as the ring is not aromatic.

[0091] "Heterocycloaminoalkyl" means a radical -(alkylene)-R where R is heterocycloamino as described above.

[0092] "Heteroaryl" means a monocyclic or monovalent bicyclic aromatic radical of 5 to 10 carbon atoms in which one or more (in one embodiment, one, two or three) ring atoms are heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. .

[0093] "Mammal", for use herein, means domestic animals (such as dogs, cats and horses) and humans. In one embodiment, the mammal is a human being.

[0094] The present disclosure also includes prodrugs of compounds of Formula (I) (or any of the modalities thereof described herein) and/or a pharmaceutically acceptable salt thereof. The term prodrug is intended to represent covalently linked carriers that have the capacity to release the active ingredient of Formula (I) (or any of the embodiments thereof described herein), when the prodrug is administered to a mammal subject. The release of the active ingredient occurs in vivo. Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. Such appropriate functional groups however regenerate original functional groups in vivo or by routine manipulation. Prodrugs of compounds of Formula (I) (or any of the embodiments thereof described herein) include compounds in which a hydroxy, amino, carboxylic or similar group is modified. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxyl or amino functional groups in compounds of the Formula (I), amides (for example, trifluoroacetylamino, acetylamino and the like) and the like. Prodrugs of compounds of Formula (I) (or any of the embodiments thereof described herein) are also within the scope of this disclosure.

[0095] The present disclosure also includes polymorphic (amorphous as well as crystalline) forms and deuterated forms of compounds of Formula (I) (or any of the modalities thereof described herein) and/or a pharmaceutically acceptable salt thereof.

[0096] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that has the desired pharmacological activity of the parent compound. Such salts include:

[0097] acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanopropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, acid citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glycoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, acid lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like; or

[0098] salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference.

[0099] The compounds of the present disclosure may have asymmetric centers. Compounds of the present disclosure that contain an asymmetrically substituted atom can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolving materials. All chiral, diastereomeric, racemic forms, as individual forms and mixtures thereof, are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated.

[00100] Certain compounds of Formula (I) (or any of the modalities thereof described herein) and/or pharmaceutically acceptable salt thereof may also exist as tautomers and/or geometric isomers. All possible cis and trans tautomers and isomers, as well as individual forms and mixtures thereof, are within the scope of this disclosure. Additionally, as used herein, the term alkyl includes all possible isomeric forms of said alkyl group although only a few examples are presented. Additionally, when cyclic groups such as heteroaryl, heterocyclyl are substituted, they include all positional isomers although only a few examples are presented. Additionally, all hydrate forms of a compound of Formula (I) (or any of the embodiments thereof described herein) and/or a pharmaceutically acceptable salt thereof are encompassed within the scope of this disclosure.

[00101] "Oxo" or "carbonyl" means group =(O).

[00102] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes cases where the event or circumstance occurs and cases in which it does not occur. For example, "heterocyclyl group optionally substituted by an alkyl group" means that the alkyl may but need not be present, and that the description includes situations where the heterocyclyl group is replaced by an alkyl group and situations where the heterocyclyl group is not replaced by alkyl.

[00103] A "pharmaceutically acceptable carrier or excipient" means a carrier or an excipient that is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic or biologically or otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable carrier/excipient" as used in the specification and claims includes one or more than one such excipient.

[00104] The phrase "wherein two of the optional substituents are independently selected from alkyl, alkoxy, hydroxy, halo and oxo, and one of the optional substituents is alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, acyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl or heterocyclyl" in the definition of heterocyclyl for Rc in Formula (I) (and similar phrases elsewhere in the claim and/or specification) means that when the heterocyclyl is replaced by a substituent, the substituent may be any of the substituents options listed. When the heterocyclyl ring is substituted by two substituents, then either both substituents may be selected from alkyl, alkoxy, hydroxy, halo and oxo or one of the two substituents is selected from alkyl, alkoxy, hydroxy, halo and oxo and the other substituent is selected from alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, acyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl and heterocyclyl. And when the heterocyclyl ring is replaced by three substituents, then two substituents are selected from alkyl, alkoxy, hydroxy, halo and oxo and the third substituent is selected from alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, acyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl and heterocyclyl.

[00105] "Treating" or "treatment" of a disease includes: (1) preventing the disease, that is, causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but who does not yet experience or exhibit symptoms of the disease; (2) disease inhibition, that is, stopping or reducing the development of the disease or its clinical symptoms; or (3) alleviating the disease, i.e., causing regression of the disease or its clinical symptoms.

[00106] A "therapeutically effective amount" means the amount of a compound of Formula (I) (or any of the embodiments thereof described herein) that, when administered to a mammal for the treatment of a disease, is sufficient to carry out such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

Modalities

[00107] In embodiments 1 to 24 below and modalities or submodalities contained therein, the present disclosure includes: 1. A compound of Formula (I), as defined in the first embodiment of the first aspect above, including an E isomer or Z thereof and/or a pharmaceutically acceptable salt thereof. 2. The compound of embodiment 1 and/or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are independently hydrogen, alkyl, alkoxy, haloalkyl or halo;

[00108] X is -O-, -CONR-, -NRCO- or -NR-CO-NR' where R and R' are

[00109] independently hydrogen or alkyl;

[00110] Ar is heteroaryl or phenyl in which heteroaryl and phenyl are optionally substituted by one, two or three substituents independently selected from alkyl, halo, haloalkyl, alkoxy and hydroxy;

[00111] A is -N- or -CR3- where R3 is hydrogen, alkyl, cyclopropyl, halo, haloalkyl, haloalkoxy, alkoxy or cyano;

[00112] Y is bond or alkylene;

[00113] The Z ring is heterocycloamino optionally substituted by one or two substituents independently selected from alkyl, hydroxy, alkoxy and fluorine;

[00114] R5 is a group of formula (i), (ii), (iii) or (iv):

[00115] where:

[00116] Ra is hydrogen, fluorine or cyano; provided that when Ra is cyan, then Rb is hydrogen and Rc is not hydrogen;

[00117] Rb is hydrogen or alkyl; It is

[00118] Rc is hydrogen, alkyl optionally substituted by one or two substituents independently selected from OH, heteroaryl (optionally substituted by one or two substituents independently selected from alkyl and heterocyclyl in which the heterocyclyl is optionally substituted by one or two substituents independently selected from among halo and alkyl), and -CONR9R10 (where R9 and R10 are independently hydrogen or alkyl or R9 and R10 together with the nitrogen atom to which they are attached form a heterocyclyl optionally substituted by one or two substituents selected from alkyl and heterocyclyl ),

[00119] cycloalkyl optionally substituted by one or two substituents independently selected from halo, alkyl and aryl,

[00120] hydroxyalkyl, alkoxyalkyl,

[00121] heterocyclylalkyl, heterocyclyl (wherein heterocyclyl and heterocyclyl in heterocyclylalkyl are optionally substituted by one, two or three substituents wherein two of the optional substituents are independently selected from alkyl, alkoxy, hydroxy, halo, amino and oxo, and one of the substituents optional is alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, acyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl or heterocyclyl, wherein the heterocyclyl is replaced by one or two substituents independently selected from hydrogen, alkyl, halo, hydroxy and alkoxy), or

[00122] -(alkylene)-NR6R7 (wherein R6 and R7 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl or heterocyclyl, wherein the heterocyclyl is optionally substituted by one or two substituents independently selected from alkyl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, acyl and alkoxycarbonyl; or R6 and R7 together with the nitrogen atom to which they are attached form;

[00123] wherein one or two of X1, X2 and X3 are nitrogen and

[00124] the remainder is carbon and the ring is optionally substituted by one or two substituents independently selected from alkyl, haloalkyl and halo);

[00125] and/or a pharmaceutically acceptable salt thereof, provided that:

[00126] when A is -N-, then Ra is cyano and Rc is heterocycloaminoalkyl wherein the heterocycloamino in heterocycloaminoalkyl is optionally substituted by one or two substituents independently selected from alkyl, alkoxy, hydroxy, halo, amino and oxo, and the heterocycloamino nitrogen atom is replaced by heterocyclyl wherein the heterocyclyl is replaced by one or two substituents independently selected from hydrogen, alkyl, halo, hydroxy and alkoxy. 3. The compound of embodiments 1 to 2 and/or a pharmaceutically acceptable salt thereof, wherein A is -N-. 4. The compound of embodiments 1 to 2 and/or a pharmaceutically acceptable salt thereof wherein A is -CR3-. In one embodiment of embodiment 4, R3 is hydrogen, methyl, ethyl, isopropyl, fluorine or chlorine. In a second embodiment of embodiment 3, R3 is hydrogen. 5. The compound of any of embodiments 1 to 4 and embodiments contained therein and/or a pharmaceutically acceptable salt thereof, wherein -X-Ar is attached to carbon at position 4 of the phenyl ring, the carbon of which is phenyl ring attached to N of the cyclic urea ring is in position 1. 6. The compound of any one of embodiments 1 to 5 and embodiments contained therein and/or a pharmaceutically acceptable salt thereof,

[00127] where X is -O-. Within embodiment 6, in a fourth embodiment, Ar is heteroaryl or phenyl, wherein heteroaryl and phenyl are optionally substituted by one, two or three substituents independently selected from alkyl, halo, haloalkyl, alkoxy and hydroxy. Within modality 6, in a fifth modality, Ar is pyridinyl, pyrimidinyl, thienyl or pyrazinyl, optionally substituted by one, two or three substituents independently selected from alkyl, halo, haloalkyl, alkoxy and hydroxy. Within embodiment 6, in a sixth embodiment, Ar is phenyl in which phenyl is optionally substituted by one, two or three substituents independently selected from alkyl, halo, haloalkyl, alkoxy and hydroxy, preferably substituted by one or two fluorines. 7. The compound of any one of embodiments 1 to 6 and embodiments contained therein and/or a pharmaceutically acceptable salt thereof wherein X is -CONR- or -NRCO-. Within embodiment 6, in a fourth embodiment, Ar is heteroaryl or phenyl, in which heteroaryl and phenyl are optionally substituted by one, two or three substituents independently selected from alkyl, halo, haloalkyl, alkoxy and hydroxy. Within modality 7, in a fifth modality, Ar is pyridinyl, pyrimidinyl, thienyl or pyrazinyl, optionally substituted by one, two or three substituents independently selected from alkyl, halo, haloalkyl, alkoxy and hydroxy. Within modality 7, in a sixth modality, Ar is phenyl in which phenyl is optionally substituted by one, two or three substituents independently selected from alkyl, halo, haloalkyl, alkoxy and hydroxy, preferably, one or two fluorine. 8. The compound of any one of embodiments 1 to 7 and embodiments contained therein and/or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently hydrogen or halo, preferably hydrogen or fluorine, more preferably R1 and R2 are hydrogen or R1 is hydrogen and R2 is fluorine. 9. The compound of any one of embodiments 1 to 8 and embodiments contained therein and/or a pharmaceutically acceptable salt thereof, wherein Y is alkylene and ring Z is pyrrolidinyl, and in one embodiment, pyrrolidin-2-yl or azetidin -3-ila. Within embodiment 9, in one embodiment, Y is methylene. Within modality 9, in a second modality, the pyrrolidinyl ring fixed at C2 and the carbon stereochemistry of the pyrrolidinyl ring fixed at Y is (R) or (S). Within modality 9, there is another modality, in which R5 is a group of formula (i) or (iv). 10. The compound of any one of embodiments 1 to 9 and embodiments contained therein and/or a pharmaceutically acceptable salt thereof, wherein Y is a bond and ring Z is pyrrolidinyl or piperidinyl and is fixed to the cyclic urea nitrogen on the carbon C-3, the pyrrolidinyl or piperidinyl nitrogen atom is in the C-1 position. In one embodiment, the carbon stereochemistry of pyrrolidinyl or piperidinyl fixed to cyclic urea nitrogen is (R). 11. The compound of any one of embodiments 1 to 10 and embodiments contained therein and/or a pharmaceutically acceptable salt thereof, wherein Ra is hydrogen. Within embodiment 11, in one embodiment, R5 is a group of formula (i). Within embodiment 11, in a second embodiment, R5 is a group of formula (ii) or (iii). Within embodiment 11, in a third embodiment, R5 is a group of formula (iv). Within modalities one through three in modality 11, in a submodality, Rb and Rc are hydrogen. Within modalities one to three in modality 11, in another submodality, Rb is hydrogen and Rc is alkyl or -(alkylene)- NR6R7 (wherein R6 and R7 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl or heterocyclyl, wherein the heterocyclyl ring is optionally substituted by one or two substituents independently selected from alkyl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, acyl and alkoxycarbonyl), preferably, R6 and R7 are independently hydrogen or alkyl. 12. The compound of any one of modalities 1 to 11 and modalities contained therein or a pharmaceutically acceptable salt thereof, wherein Ra is cyano. Within embodiment 12, in one embodiment, R5 is a group of formula (i). Within embodiment 12, in a second embodiment, R5 is a group of formula (ii) or (iii). (a) Within embodiments one and two in embodiment 12, in a submodality, Rc is cycloalkyl, which is optionally substituted by one or two substituents independently selected from halo, alkyl, alkoxyalkyl and aryl; or wherein two adjacent cycloalkyl substituents together with the carbon atoms to which they are attached form a heterocyclyl group. In one embodiment, Rc is cyclopropyl, 1-methylcyclobutyl, 1-phenylcyclopropyl, 1-methylcyclopropyl, 2,2-difluorocyclopropyl, (B) . Within modalities one and two in modality 12, in a second submodality, Rc is unsubstituted alkyl. In one embodiment, Rc is isopropyl or tert-butyl. (w) . Within embodiments one and two in embodiment 11, in one submodality, Rc is -(alkylene)-NR6R7 (wherein R6 and R7 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl or heterocyclyl. In another submodality , Rc is -C(CH3)2NH2, -C(CH3)2NHCH3, -C(CH3)2N(CH3)2, - C(CH3)2NHCH2CH3, -C(CH3)2NHCH(CH3)2, -C(CH3 )2NHcyclopropyl, - C(CH3)2NH(CH2)2OCH3, -C(CH3)2OCH2CH3, - C(CH3)2N(CH2CH3)(oxetan-3-yl), -C(CH3)2N(CH3)(oxetan- 3-yl) or - C(CH3)2NH(oxetan-3-yl). (d) Within embodiments one and two in embodiment 12, in another submodality, Rc is heterocyclylalkyl in which the heterocyclyl in heterocyclylalkyl is optionally substituted by one, two or three substituents wherein two of the optional substituents are independently selected from alkyl, alkoxy, hydroxy, halo, amino and oxo, and one of the optional substituents is alkyl, hydroxyalkyl, alkoxyalkyl, acyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl or heterocyclyl, wherein the heterocyclyl is optionally substituted by one or two substituents independently selected from alkyl, halo, hydroxy and alkoxy.

[00128] In a submodality of submodality (d), Rc is - C(CH3)2morpholine-4-yl, -C(CH3)2-4-(2,2,2-trifluoroethyl)piperazin-1-yl, -C(CH3)2-4-(1-methyl)piperidin- 1-ila, , - C(CH3)2- 4-ethyl-3-oxopiperazin -1-yl, C(CH3)2tetrahydropyran-4-yl, - C(CH3)2-4- methoxycarbonylpiperazin-1-yl, -C( CH3)2-4-(oxetan-4-yl)piperazin-1-yl, - C(CH3)2-4-(3-methyloxetan-4-yl)piperazin-1-yl, -C(CH3)2- 4-t-butoxycarbonylpiperazin-1-yl, -C(CH3)2-4- acetylpiperazin-1-yl, -C(CH3)2-4- methoxycarbonylpiperazin-1-yl, , -C(CH3)2-piperazin- 1-yl, , -C(CH3)2-3,3- difluoropyrrolidin-1-yl, , - C(CH3)2-(S)-3-methoxypyrrolidin-1-yl, -C(CH3)2-( R)-3- methoxypyrrolidin-1-yl, -C(CH3)2-(S)-2-(methoxymethyl)pyrrolidin-1-yl, -C(CH3)2-(R)-2- (methoxymethyl)pyrrolidin -1-ila, , - C(CH3)2-4- methylpiperazin-1-yl, -C(CH3)2-4-ethylpiperazin-1-yl, -C(CH3)2-4- isopropylpiperazin-1-yl, - C(CH3 )2-4-(2-methoxyethyl)piperazin-1-yl, -C(CH3)2-4-acetylpiperazin-1-yl, -C(CH3)2-4-(3R,5S)-3,4, 5-trimethylpiperazin-1-yl, -C(CH3)2-4- (3R,5S)-3,5-dimethylpiperazin-1-yl, -C(CH3)2-4-(3R,5S)- dimethylmorpholin- 4-yl, -C(CH3)2-piperidin-1-yl, -C(CH3)2-pyrrolidin-1-yl, - C(CH3)2-3-oxo-piperazin-1-yl or -C( CH3)2-(3-oxo-4-methylpiperazin-1-yl). In a second submodality of submodality (d), Rc is heterocyclylalkyl, in which the heterocyclyl in heterocyclylalkyl is replaced by another heterocyclyl, in which the other heterocyclyl is replaced by alkyl on a carbon of the other heterocyclyl. (It is) . Within embodiments one and two in embodiment 12, in yet another submodality, Rc is heterocyclyl optionally substituted by one, two or three substituents, wherein two of the optional substituents are independently selected from alkyl, alkoxy, hydroxy, halo, amino and oxo, and one of the optional substituents is alkyl, hydroxyalkyl, alkoxyalkyl, acyl or heterocyclyl. In a submodality of submodality (e), Rc is 3-methyloxetan-3-yl, 3-ethyloxetan-3-yl, 3-fluoro-oxetan-3-yl, 3-amino-oxetan-3-yl, 4 -methylpiperidin-4-yl, 3-methylazetidin-3-yl, 1-methylazetidin-3-yl, 4-methyl-4-tetrahydropyranyl or 1,3-dimethylazetidin-3-yl. In another submodality (f), Rc is (g) In another submodality of embodiment 12, Rc is alkyl that is optionally substituted by one or two substituents independently selected from hydroxy, hydroxyalkyl, and heteroaryl that is substituted by one or two substituents independently selected from alkyl and heterocyclyl, in that the heterocyclyl is optionally substituted by one or two substituents independently selected from halo and alkyl. In another embodiment, Rc is alkyl that is substituted by one or two hydroxy substituents. In another embodiment, Rc is

[00129] In a submodality, Rc is alkyl that is substituted by a heteroaryl that is optionally substituted by one or two substituents independently selected from alkyl and heterocyclyl, wherein the heterocyclyl is optionally substituted by one or two independently selected substituents between halo and alkyl. Within this submodality, in another modality, Rc is

[00130] In another submodality, Rc is an alkyl that is substituted by -CONR9R10, in which R9 and R10 are independently hydrogen or alkyl or R9 and R10 together with the nitrogen atom to which they are attached form a heterocyclyl optionally substituted by one or two substituents selected from alkyl and heterocyclyl. Within this submodality is a modality in which R9 and R10 are both hydrogen or alkyl. In another embodiment, Rc is -C(CH3)2-CONH2 or -C(CH3)2-CON(CH3)2.

[00131] In another submodality, Rc is an alkyl that is substituted by -CONR9R10, in which R9 and R10 together with the nitrogen atom to which they are attached form a heterocyclyl optionally substituted by one or two substituents selected from alkyl and heterocyclyl . Within this submodality is a modality in which the heterocyclyl formed by R9 and R10 together with the nitrogen atom to which they are attached is 4-methylpiperazinyl or 4-(oxetan-3-yl)piperazin-1-yl. 13. The compounds of any of embodiments 3, 5, 6 and 8 to 10 (i.e., A is -N-; -X-Ar is attached to the carbon at position 4 of the phenyl ring, the carbon of the phenyl ring attached to the N of the cyclic urea ring is in position 1; or piperidinyl is C-1; the carbon stereochemistry of pyrrolidinyl or piperidinyl fixed to cyclic nitrogen is (R)), where R5 is a group of formula (i), Ra is cyano, Rb is hydrogen and Rc is heterocyclylalkyl , wherein the heterocyclyl in heterocyclylalkyl is optionally substituted by one, two or three substituents wherein two of the optional substituents are independently selected from alkyl, alkoxy, hydroxy, halo, amino and oxo, and one of the optional substituents is alkyl, hydroxyalkyl , alkoxy, alkoxyalkyl, acyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl or heterocyclyl, wherein the heterocyclyl is replaced by one or two substituents independently selected from hydrogen, alkyl, halo, hydroxy and alkoxy.

[00132] In a submodality of this modality, Rc is

[00133] Representative compounds are listed in Table I below: Table I

[00134] The E or Z isomer of any of the compounds in Table 1 and/or a pharmaceutically acceptable salt of any of these compounds are also included within the scope of the present invention.

[00135] The present invention is also directed to the following compounds: 4-amino-1-((3S)-1-(oxirane-2-carbonyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H- imidazo[4,5-c]pyridin-2(3H)-one; 4-amino-1-((3S)-1-(2,3-dihydroxypropanoyl)piperidin-3-yl)-3-(4-phenoxyphenyl)- 1H-imidazo[4,5-c]pyridin-2 (3H)-one; 4-amino-1-((3S)-1-(2-hydroxypropanoyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)- onea; (S)-4-amino-1-(1-(3-hydroxypropanoyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)- onea; 4-amino-1-(((2R)-1-(oxirane-2-carbonyl)pyrrolidin-2-yl)methyl)-3-(4-phenoxyphenyl)- 1H-imidazo[4,5-c]pyridin- 2(3H)-one; 4-amino-1-(((2R)-1-(2,3-dihydroxypropanoyl)pyrrolidin-2-yl)methyl)- 3-(4-phenoxyphenyl)-1H-imidazo[4,5-c] pyridin-2(3H)-one; 4-amino-1-(((2R)-1-(2-hydroxypropanoyl)pyrrolidin-2-yl)methyl)-3-(4-phenoxyphenyl)- 1H-imidazo[4,5-c]pyridin-2( 3H)-one; and (R)-4-amino-1-((1-(3-hydroxypropanoyl)pyrrolidin-2-yl)methyl)-3-(4-phenoxyphenyl)- 1H-imidazo[4,5-c]pyridin-2 (3H)-one; and/or a pharmaceutically acceptable salt thereof.

[00136] These compounds can be prepared according to Scheme 4 presented below and have the same usefulness as the compounds of Formula (I).

General Synthetic Scheme

[00137] The compounds of this disclosure can be made by the methods illustrated in the reaction schemes shown below.

[00138] The starting materials and reagents used in the preparation of these compounds are available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1 to 17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1 to 5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1 to 40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this disclosure may be synthesized, and various modifications to these schemes may be made and will be suggested to one skilled in the art having referred to this disclosure. Starting materials and intermediates, and final reaction products can be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

[00139] Unless otherwise specified, the reactions described herein occur at atmospheric pressure over a temperature range from about -78°C to about 150°C, from about 0°C to about 125°C or at about ambient (ambient) temperature, for example about 20°C.

[00140] Compounds of Formula (I) in which R5 is a group of formula (i) and other groups as defined in the Summary, can be prepared as illustrated and described in Scheme 1 below. Scheme 1

[00141] The reaction of a dihaloheteroaryl compound, such as 4,6-dichloro-5-nitropyrimidine, with an amine of Formula NH(PG)2 in which PG is a suitable amino protecting group, such as benzyl, provides a compound of Formula 1. The reaction is carried out in a suitable organic solvent, such as dioxane, dichloromethane and the like. Displacement of the second halo group by an amino compound of Formula 2, where Y and Z ring are as defined in the Summary and PG1 is a suitable amino protecting group, such as Boc, yields a compound of Formula 3. The reaction it is carried out in dichloromethane, dioxane, tetrahydrofuran and the like with an additional base such as triethylamine. The compounds of Formula 2, such as (R)-tert-butyl 3-aminopiperidine-1-carboxylate, (S)-tert-butyl 3-aminopiperidine-1-carboxylate, (R)-tert-butyl 3-(aminomethyl )pyrrolidine-1-carboxylate, (S)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate, (R)-tert-butyl 2-(aminomethyl)azetidine-1-carboxylate, and (S)-tert- butyl 2-(aminomethyl)azetidine-1-carboxylate, are commercially available or can be prepared by methods well known in the art. The nitro group of compounds of Formula 3 can be reduced with reagents such as Zn and ammonium chloride in EtOAc or with Fe or SnCl in a solvent such as acetic acid in EtOH to produce compounds of Formula 4.

[00142] The compounds of Formula 4 can be cyclized to form the benzimidazolones of Formula 5 by heating 4 in an organic solvent, such as dichloroethane and the like, with carbonyl diimidazole, phosgene or a phosgene equivalent (for example, di - phosgene or triphosgene), in the presence of a base such as triethylamine, diisopropylethyl amine and the like. Removal of the PG amino protecting group provides the compound of Formula 6. The reaction conditions used are based on the nature of the amino protecting group. For example, when PG is a benzyl group it can be removed by hydrogenation using a Pd/C catalyst and the like with an additive such as acetic acid to produce a compound of Formula 6. The reaction of 6 with an aryl boronic acid of Formula 7, wherein R1, R2, Ar and X are as defined in the summary, through a copper-mediated coupling (Chan-Lam coupling) using, for example, Cu(OAc)2 as a catalyst in a solvent such as DCM, with an additive such as TEMP or oxygen and a base such as pyridine or triethylamine, produces a compound of Formula 8. Compounds of Formula 7, for example, (4-phenoxyphenyl)boronic acid , 2-[4-(3-fluorophenoxy)-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 4-(4-fluorophenoxy)phenylboronic acid, 4-(3-fluorophenoxy) )phenylboronic acid, 4-(3,5-difluorophenoxy)-phenylboronic acid, 4-(4-chloro-2-fluorophenoxy)phenyl-boronic acid and 4-(3-(trifluoromethyl)phenoxy)phenyl boronic acid are commercially available or can be prepared from phenyl halide by lithium halogen exchange and quenching with triisopropyl borate.

[00143] Alternatively, compound 8 can be prepared by reacting compound 5 first with boronic acid 7, followed by removal of the amino protecting group under conditions described above. Removal of the PG1 amino protecting group in compound 8 provides the compound of Formula 9. The reaction conditions used are based on the nature of the amino protecting group. For example, when PG1 is Boc, it can be removed under acid hydrolysis reaction conditions such as treatment with an acid such as TFA, HCl and the like.

[00144] Compound 9 can then be converted into a compound of Formula (I) using methods well known in the art. For example, compounds of Formula (I) can be prepared by coupling compound 9 with an acid of Formula 10 or an acid derivative of compound 10, such as acid chloride, wherein Ra, Rb and Rc are as described. in the Summary, to generate a compound of Formula (I). When compound 10 is used, the reaction is carried out under standard amide coupling conditions, such as in the presence of HATU, DCC, carbon diimidazole (CDI) and the like. Compounds of Formula 10 or acid chloride derivatives thereof are commercially available (e.g., acryloyl chloride) or can be prepared by methods well known in the art, as the condensation product of cyanoacetic acid and an aldehyde, such as isobutyraldehyde or pivaldehyde.

[00145] The compound of Formula (I) in which Ra is cyano can also be prepared by first condensing compound 9 with 2-cyanoacetic acid under standard amide coupling conditions, such as carbon diimidazole (CDI) and the like. to generate a compound of Formula 11. The condensation of a compound of Formula 11 with an aldehyde of formula RcCHO wherein Rc is as defined above in the Summary, under standard condensation conditions, such as with the use of a base such as piperidine and the like, in the presence or absence of acetic acid and the like, in solvents such as ethanol and similar at temperatures in the ambient temperature range, reflux then provides a compound of Formula (I). Compounds of Formula RcCHO are commercially available or can be prepared by methods well known in the art, for example, acetaldehyde, cyclopropylaldehyde, isobutyraldehyde, 3-methyloxane-3-carbaldehyde, 2-(dimethylamino)-2-methylpropanal, 2-methyl- Tert-butyl 2-(1-piperidyl)propanal, (2S)-2-formylpyrrolidine-1-carboxylate and 2-methyl-2-(morpholin-4-yl)propanal are commercially available. Ethoxy-2-methylpropanal was prepared from isobutyraldehyde as described in international application PCT 2007142576. RCCHO compounds in which Rc is -(alkylene)-NR6R7 can be prepared by treating isobutyraldehyde with bromine to form bromoisobutyraldehyde followed by displacement of bromine through the addition of HNR6R7.

[00146] Alternatively, compound 11 can also be condensed with a RcCHO precursor group and then converted into a compound of Formula (I). For example, compound 11 can be condensed with tert-butyl 2-methyl-1-oxopropan-2-ylcarbamate followed by removal of the amino protecting group to generate a compound of Formula (I) in which Rc is 2- aminopropan-2-yl. The condensation reaction can also be carried out by adding the desired aldehyde RcCHO with a base such as pyrrolidine or piperidine with or without chlorotrimethylsilane in dichloromethane or other suitable solvent (e.g. dioxane and ethanol). Compounds of Formula (I) wherein R5 is a group of formula (ii) to (iv) can be prepared as described in Scheme 2. By following the procedure described above and replacing compound 9 with suitable starting materials , such as 2-butynoic acid, vinylsulfonyl chloride, (E)-prop-1-ene-1-sulfonyl chloride, 1-propyne-1-sulfonyl chloride, compounds of Formula (I) can be obtained.

[00147] Alternatively, to prepare the compounds of Formula (I) in which R5 is a group of formula (ii), the compounds of Formula 11 can be reacted with commercially available cyanomethane sulfonyl chloride to produce a cyanomethylsulfonamide that can be condensed with aldehydes of Formula 12 with TMSCl and pyrrolidine to produce structures of Formula (I). Scheme 2

[00148] Compounds of Formula (I) in which A=CH can be prepared as described in Scheme 3. 2,4-dichloro-3-nitropyridine can first be reacted with an amino compound of Formula 2, in which Y and Z ring are as defined in the Summary and PG1 is a suitable amino protecting group such as Boc. Subsequent reaction with an amine of Formula NH(PG)2 where PG is a suitable amino protecting group, such as 4-methoxybenzyl, in a solvent such as DMF produces a compound of Formula 14. Reduction of the nitro group through hydrogenation with Pd/C or through reduction with Zn, Fe or SnCl under standard conditions, produces a compound of Formula 15. Condensation with carbonyldiimidazole or a phosgene equivalent produces cyclic urea 16. Chan-Lam coupling can be carried out at this stage and the syntheses of compounds (I) completed as described in Scheme 1.

[00149] Alternatively, compound 17 can be prepared by first treating with an acid, such as TFA, to remove both protecting groups and subsequently installing the PG1 group (e.g., Boc). Subsequent treatment with dimethylformamide dimethyl acetal produces a compound of Formula 18. Reaction under Chan-Lam conditions as described above then produces compound 19. Subsequent deprotection by treatment of 19 with an acid such as HCl or TFA in solvents such as dichloromethane, dioxane, MeOH or EtOH produces a compound of Formula 20. The preparation of compounds of Formula (I) is then prepared in a manner analogous to the methods described in Schemes 1 and 2. Scheme 3 Scheme 4 below shows the preparation of compounds of Formula 21, 22, 24 and 25. Coupling a commercially available acid such as 3-hydroxypropanoic acid or 2-hydroxypropanoic acid (as a racemate or as the (S) or (R) isomer )) with compound 20 from Scheme 2 using a reagent such as HATU in a solvent such as DMF produces compounds of Formula 21 and 22, respectively. Acryloyl chloride can be added to compound 20 in a solvent such as DMF with a base such as trimethylamine or diisopropylethylamine to produce a compound of Formula 23. Oxidation with reagents such as osmium tetroxide and N-methyl morpholine oxide (NMO) in a mixture of acetone and water produces diols of Formula 24. Compound 25 can be prepared from a compound of Formula 23 by oxidation with an oxidant such as mCPBA in a solvent such as toluene or dichloromethane or by peroxide of tert-butyl hydrogen (TBHP) and a cinchona alkaloid catalyst (Sharpless epoxidation). Scheme 4

General Method A

[00150] Some other compounds can be prepared using the general method shown below.

Step 1

[00151] In a 100 ml round bottom flask purged and maintained with an O2 atmosphere, arylboronic acid (1.0 equiv.), TEA (4.0 equiv.), Cu(OAc)2 ( 0.50 equiv.), TEMPO (1.10 equiv.) and molecular sieves (4A) (500 mg) in dichloromethane (0.1 mM). The resulting solution was stirred for 30 min. and then arylboronic acid (2.00 equiv.) was added. The resulting solution was stirred overnight at rt. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column eluting with dichloromethane/methanol to produce the desired product A.

Step 2

[00152] To a solution of A (1.0 equiv.) in dioxane was added hydrogen chloride (12 M). The resulting solution was stirred for 3 h at 85°C in an oil bath. The reaction was then cooled abruptly by adding sodium bicarbonate (sat.). The resulting solution was extracted with DCM/MeOH (10:1) and the organic layers combined. The resulting mixture was washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 360 mg (100%) of B.

Step 3

[00153] In a 50 ml round bottom flask, B (1.0 equiv.), 2-cyanoacetic acid (1.0 equiv.), HATU (1.5 equiv.), TEA (3. 0 equiv.) and N,N-dimethylformamide (0.1 mMol). The resulting solution was stirred for 2 h at rt. The resulting solution was extracted with dichloromethane and the organic layers combined. The resulting mixture was washed with 6 x 100 ml of water. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane/methanol to produce compound C.

Step 4

[00154] In a round bottom flask, C (1.0 equiv.) was placed and dissolved in DCM at a concentration of 0.2 M. The solution was cooled to 0°C, and the aldehyde (3. 0 equiv.) was added followed by pyrrolidine (6.0 equiv.) and TMSCl (4.0 equiv.). The reaction was heated to rt and stirred for 3 h or until the sm was consumed. Water was added and the layers separated. The organic layer was dried with sodium sulfate, filtered and the solvent removed in vacuo. Purification by silica gel chromatography or preparative HPLC yielded the desired compounds D. Aldehydes were purchased commercially, using the method shown below or by methods known in the literature (i.e., oxidation of an alcohol through Swern conditions or with an oxidant such as PCC or DessMartin periodinane). General Method B Preparation of aldehydes from isobutyraldehyde

[00155] To a solution of 2-methylpropanal (1.0 equiv.) in DCM (0.2 M) cooled with an ice bath, bromine (1.0 equiv.) was added dropwise. After 1 h, most of the solvent was removed from the resulting 2-bromo-2-methylpropanal solution under vacuum. This material was diluted in DCM (8 ml) at rt and amine (2.0 equiv.) was added. After stirring overnight, the mixture was diluted with brine (30 ml) and the layers separated. The organic layer is dried (MgSO4), filtered and concentrated to isolate the desired aldehyde which is used directly in the next step or purified by silica gel chromatography before use.

Test

[00156] The BTK inhibitory activity, residence time of the inhibitory BTK-bound complex, and the ability of the compounds of the present disclosure to form an irreversible covalent bond or a reversible covalent bond with Cys 481 (UniprotKB sequence ID Q06187) of BTK may be tested using the in vitro and/or in vivo assays described in Biological Examples below.

[00157] The BTK inhibitory activity of the compound of Formula (I) and/or a pharmaceutically acceptable salt thereof of the present disclosure can be tested using the in vitro and/or in vivo assays described in Biological Examples 1, 3, 4 and 5 below. A determination of kinase inhibitory activity by any of these assays is considered to be kinase inhibitory activity within the scope of the present disclosure even if any or all of the other assays do not result in a determination of kinase inhibitory activity.

[00158] Without being bound by any specific mechanistic theory, in those embodiments in which the compound of the present disclosure is a reversible covalent inhibitor, it is believed that the cysteine sulfhydryl group and a carbon atom that form part of a carbon double bond - carbon in the R5 group in a compound of Formula (I), where R5 is a group of formula (i), (ii) or (iii) where Ra is cyano, (see Formula (I)) can form a reversible, i.e., labile, covalent bond, as in which Cys 481 of BTK attacks an electron-deficient carbon atom of the carbon-carbon double bond in the R5 groups listed above in the compound of the present disclosure to form a thiol adduct.

[00159] In some embodiments, the electron-deficient carbon atom of the olefin is distal to the carbon attached to the Ra group (where Ra is cyano) that is, the carbon atom attached to the Rb and Rc group (see Formula (I ) in the compounds of the present disclosure). Therefore, the combination of the Ra group (where Ra is cyano) and the "-N-CO-, -NSO2 or -N-SO-" chemical moieties and the olefinic chemical moiety to which they are attached in the compounds of the present disclosure can increase the reactivity of the olefin to form a thiol adduct with the active site cysteine residue in BTK.

[00160] The compounds of the present disclosure that are reversible covalent inhibitors can bind with BTK in two different ways. In addition to the labile covalent bond discussed above, they are also believed to form a non-covalent bond (e.g., via van der Waals bond, hydrogen bond, hydrophobic bond, hydrophilic bond, and/or electrostatic charge bond) with BTK. , the non-covalent bond being sufficient to at least partially inhibit the kinase activity of BTK.

[00161] As disclosed herein, the labile covalent bond occurs between the olefin in the inhibitor and the thiol side chain of cysteine residue 481 at or near the site where the inhibitor has the previously mentioned non-covalent bond with BTK.

[00162] As is evident, the compounds of the present disclosure that are reversible covalent inhibitors present both cysteine-mediated covalent binding and non-covalent binding to BTK. This is different from non-covalent reversible inhibitors that inhibit BTK only by non-covalent binding and do not feature cysteine-mediated covalent binding.

[00163] Binding the compounds of the present disclosure with BTK in the two different ways mentioned above provides a reversible covalent inhibitor that has a slow dissociation rate and a prolonged duration of action, in some cases comparable to an irreversible covalent inhibitor without formation of permanent irreversible protein adducts. The difference between irreversible and reversible covalent inhibitors, particularly the compounds disclosed herein, can be determined using the assays disclosed herein.

[00164] In general, the bond involved an inhibitor that forms a reversible covalent bond with BTK that is stable when BTK is in certain configurations and is susceptible to disruption when BTK is in different configurations (in both cases, under conditions physiological conditions), whereas the interaction between an inhibitor that forms an irreversible covalent bond with BTK is stable under physiological conditions even when BTK is in different configurations.

[00165] A reversible covalent bond often confers unique properties related to the compound's residence time within the cysteine-containing binding site. In this context, residence time refers to the temporal duration of the target compound complex under different conditions (see Copeland RA, Pompliano DL, Meek TD. Drug-target residence time and its implications for lead optimization. Nat. Rev. Drug Discov. 5(9), 730 to 739 (2006).

[00166] The presence of a reversible covalent bond in a reversible covalent inhibitor as disclosed herein may result in an extended residence time compared to a compound that does not form a covalent bond with BTK. In one embodiment disclosed herein, compounds of the present disclosure that are reversible covalent inhibitors have a residence time of at least about 1 h. Residence time can be measured using an occupancy assay in a biochemical or cellular environment (see Biological Example 2 and 9 below). Additionally, residence time can be measured using a functional assay after a certain washout period.

[00167] Compounds that form an irreversible covalent bond in an irreversible covalent inhibitor share these extended residence time properties, but can, however, be differentiated from a reversible covalent inhibitor using a reversibility assay. The ability of the compound of disclosure to form reversible or irreversible covalent bond with Cys481 of BTK can be determined by the assays described in Biological Examples 2, 6 to 8 below. Determination of the binding reversibility of the covalent bond between the cysteine residue and the olefinic bond of the compound of the disclosure by any of Biological Examples 2, 6 to 8 below is considered reversible binding within the scope of this disclosure even if one or both of the other methods do not result in a determination of binding reversibility.

Administration and Pharmaceutical Composition

[00168] In general, the compounds of the present disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of compounds of Formula (I) can range from about 0.01 to about 500 mg per kg of patient body weight per day, which can be administered in single or multiple doses. In one embodiment, the dosage level will be from about 0.1 to about 250 mg/kg per day. In another embodiment, the dosage level will be from about 0.5 to about 100 mg/kg per day. A suitable dosage may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. . Within this range the dosage may be about 0.05 to about 0.5, about 0.5 to about 5, or about 5 to about 50 mg/kg per day. For oral administration, the compositions may be provided in the form of tablets containing about 1.0 to about 1,000 milligrams of the active ingredient, particularly about 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1,000 milligrams of the active ingredient. The actual amount of the compound of this disclosure, that is, the active ingredient, will depend on numerous factors such as the severity of the disease being treated, the age and relative health of the subject, the potency of the compound being used, the route and form of administration, and other factors.

[00169] In general, the compounds of this disclosure will be administered as pharmaceutical compositions by any of the following routes: oral, systemic (e.g., transdermal, intranasal or suppository) administration, or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. . The preferred mode of administration is oral using an appropriate daily dosage regimen, which can be adjusted according to the degree of suffering. The compositions may take the form of tablets, pills, capsules, semisolids, powders, controlled-release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable compositions.

[00170] The choice of formulation depends on several factors such as the mode of administration of the drug (for example, for oral administration, formulations in the form of tablets, pills or capsules are preferred), and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based on the principle that bioavailability can be increased by increasing surface area, i.e., decreasing particle size. For example, U.S. Patent No. 4,107,288 describes a pharmaceutical formulation having particles in the size range of 10 to 1,000 nm in which the active material is supported in a cross-linked matrix of macromolecules. U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized into nanoparticles (average particle size 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits markedly high bioavailability. The bioavailability of drugs that decompose at stomach pH can be increased by administering such drugs in a formulation that releases the drug intraduodenally.

[00171] The compositions are comprised, in general, of a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient, such as binders, surfactants, diluents, buffering agents, non-stick agents, glidants, hydrophilic or hydrophobic polymers, retardants, stabilizing or stabilizing agents, disintegrators or superdisintegrators, antioxidants, antifoaming agents, fillers, flavorings, dyes, lubricants, sorbents, preservatives, plasticizers or sweeteners or mixtures thereof, which facilitate the processing of the compound of Formula ( I) (or embodiments thereof disclosed herein) and/or a pharmaceutically acceptable salt thereof in preparations that can be used pharmaceutically. Any of the well-known techniques and excipients may be used as appropriate and as understood in the art, see, for example, Remington: The Science and Practice of Pharmacy, Twenty-first edition, (Pharmaceutical Press, 2005); Liberman, H. A., Lachman, L., and Schwartz, J. B. Eds., Pharmaceutical Dosage Forms, Volume 1 and 2 Taylor & Francis 1990; and R.I. Mahato, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Second edition (Taylor & Francis, 2012).

[00172] In certain embodiments, the formulations may include one or more pH-adjusting agents or buffering agents, for example, acids such as acetic, boric, citric, fumaric, maleic, tartaric, malic, lactic, phosphoric and hydrochloric; 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, ammonium chloride and the like. Such buffers used as bases may have counterions other than sodium, for example, potassium, magnesium, calcium, ammonium or other counterions. Such acids, bases and buffers are included in an amount necessary to maintain the pH of the composition in an acceptable range.

[00173] In certain embodiments, the formulations may also include one or more salts in an amount to bring the osmolality of the composition to an acceptable range. Such salts include those having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfide anions; Suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfide and ammonium sulfate.

[00174] In certain embodiments, the formulations may also include one or more antifoaming agents to reduce foaming during processing that can result in coagulation of aqueous dispersions, bubbles in the finished film or generally impair processing. Exemplary defoaming agents include silicon emulsions or sorbitan sesquoleate.

[00175] In certain embodiments, the formulations may also include one or more antioxidants, such as non-thiol antioxidants, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid or its derivative, and tocopherol or its derivatives. In certain embodiments, antioxidants enhance chemical stability where necessary. Other agents such as citric acid or citrate salts or EDTA can also be added to slow down oxidation.

[00176] In certain embodiments, the formulations may also include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[00177] In certain embodiments, the formulations may also include one or more binders. Binders impart cohesive qualities and include, for example, alginic acid and salts thereof; cellulose derivatives, such as carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®); microcrystalline dextrose; amylose; magnesium and aluminum silicate; polysaccharide acids; bentonites; gelatin; polyvinylpyrrolidone/vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; Tragacanth, dextrin, a sugar such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and lactose; a natural or synthetic gum such as acacia, tragacanth, ghatti gum mucilage from isapol bark, polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL-10), larch arabogalactan, Veegum®, polyethylene glycol, oxide polyethylene, waxes, sodium alginate and the like.

[00178] In certain embodiments, the formulations may also include dispersing agents and/or viscosity modulating agents. Dispersing agents and/or viscosity modulating agents include materials that control the diffusion and homogeneity of a drug through liquid media or a granulation method or mixing method. In some embodiments, these agents also facilitate the effectiveness of an etching matrix or coating. Exemplary dispersing agents/diffusion facilitators include, for example, hydrophilic polymers, electrolytes, Tween®60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and carbohydrate-based dispersing agents such as, for example, hydroxypropyl celluloses (e.g., HPC, H-PC-SL, and HPCL), hydroxypropyl methylcelluloses (e.g., HPMC K100, RPMC K4M, HPMC K15M, and HPMC K100M), sodium carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose , hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), non-crystalline cellulose, polyethylene oxides, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinyl pyrrolidone/aluminum acetate copolymer vinyl (S630), 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 F10 ®8, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, also known as Poloxamine 908®, which is a tetrafunctional block copolymer derived from the sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, N.J.)), polyvinylpyrrolidone K12 , polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetate (S-630) copolymer, polyethylene glycol, for example, polyethylene glycol may have a molecular weight of about 300 to about 6,000 or about 3,350 to about 4,000 or about 7,000 to 5,400, sodium carboxymethylcellulose, methylcellulose, polysorbate-80, sodium alginate, gums, such as gum tragacanth and acacia gum, guar gum, xanthans, including xanthan gum, sugars, cellulosic materials, such as, for example, sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, povidone, carbomers, polyvinyl alcohol (PVA), alginates, chitosans and combinations thereof. Plasticizers such as cellulose or triethyl cellulose can also be used as dispersing agents. Particularly useful dispersing agents in liposomal dispersions and self-emulsification dispersions are dimyristoyl phosphatidyl choline, natural phosphatidyl choline from eggs, natural phosphatidyl glycerol from eggs, cholesterol and isopropyl myristate. In general, binder levels of about 10 to about 70% are used in powder-filled gelatin capsule formulations. The level of binder use in tablet formulations varies whether direct compression, wet granulation, cylinder compaction or use of other excipients such as fillers which themselves can act as a moderate binder. Formulators skilled in the art can determine the binder level for formulations, but binder usage level of up to 90% and more typically up to 70% in tablet formulations is more common.

[00179] In certain embodiments, the formulations may also include one or more diluents that refer to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize compounds due to the fact that they can provide a more stable environment. Salts dissolved in buffered solutions (which also provide pH maintenance or control) are used as diluents in the art, including, but not limited to, a phosphate buffered saline solution. In certain embodiments, the diluents increase the volume of the composition to facilitate compression or create sufficient volume for the homogeneous mixture for capsule filling. 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; pre-gelatinized starch, compressible sugar, such as Di-Pac® (Amstar); hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose-based diluents, icing sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrates; hydrolyzed cereal solids, amylose; cellulose powder, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite and the like.

[00180] In certain embodiments, the formulations may also include one or more disintegrators that include both dissolving and dispersing the dosage form when placed in contact with gastrointestinal fluids. Disintegrating agents or disintegrators facilitate the rupture or disintegration of a substance. Examples of disintegrating agents include a starch, for example, a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or sodium starch glycolate such as Promogel® or Explotab®, a cellulose such as a wood product, microcrystalline cellulose, for example, Avicel®, Avicel® PH101, Avicel® PH 102, Avicel® PH105, Elceme® P100, Emcocel®, Vivacel®, and Solka-Floc®, methylcellulose, croscarmellose or a cellulose cross-linked, such as cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol®), cross-linked carboxymethyl cellulose or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or an acid salt alginine, such as sodium alginate, a clay such as Veegum® HV (magnesium aluminum silicate), a gum such as agar, guar, carob, Karaya, pectin or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a ten - soactive, a resin such as a cation exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch and the like.

[00181] In certain embodiments, the formulations may also include erosion facilitators. Erosion facilitators include materials that control erosion of a particular material in gastrointestinal fluids. Erosion facilitators are generally known to those skilled in the art. Exemplary erosion facilitators include, for example, hydrophilic polymers, electrolytes, proteins, peptides and amino acids.

[00182] In certain embodiments, the formulations may also include one or more fillers that include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose , dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol and the like.

[00183] In certain embodiments, the formulations may also include one or more flavoring and/or sweetening agents, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, black currant, caramel. butter, calcium citrate, camphor, caramel, cherry, cherry cream chocolate, cinnamon, chewing gum, citrus, citrus drink, citrus cream, cotton candy, cocoa, cola, fresh cherry, fresh citrus, cyclamate, cilamate, dextrose , euca-lipto, eugenol, fructose, fruit drink, ginger, glycyrrhetinate, glycyrrhiza syrup (licorice), grape, grapefruit, honey, isomalt, lemon, lime, cream of lemon, monoammonium glyrrhizinate, maltol, mannitol, maple, marshmallow, menthol, creme de menthe, mixed cherry, neohesperidin DC, neotame, orange, pear, peach, peppermint, peppermint cream, powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, mint, cream of peppermint, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, aces-sulfame potassium, mannitol, talin, silitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti frutti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol or any combination of these flavoring agents, 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.

[00184] In certain embodiments, the formulations may also include one or more lubricants and glidants that are compounds that prevent, reduce or inhibit the adhesion or friction of materials. Exemplary lubricants include, for example, stearic acid, calcium hydroxide, talc, sodium stearyl lumerate, a hydrocarbon such as mineral oil or hydrogenated vegetable oil such as hydrogenated soybean oil, higher fatty acids and their alkali metal and metal salts. alkaline earth, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol (e.g. example, PEG4000) or a methoxypolyethylene glycol such as Carbowax®, sodium oleate, sodium benzoate, glyceryl benate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica such as Syloid®, Cab-O-Sil®, a starch such as starch corn, silicone oil, a surfactant and the like.

[00185] In certain embodiments, the formulations may also include one or more plasticizers which are compounds used to soften delayed-release or enteric coatings to make them less fragile. Suitable plasticizers include, for example, polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, triethyl citrate, dibutyl sebacate, triethyl cellulose and triacetin. In some embodiments, plasticizers may also function as dispersing agents or wetting agents.

[00186] In certain embodiments, the formulations may also include one or more solubilizers that include compounds such as triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium docusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone , N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cyclodextrins, e.g., Captisol®, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200 to 600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide and similar. In one embodiment, the solubilizer is vitamin E TPGS and/or Captisol® or β-hydroxypropylcyclodextrin.

[00187] In certain embodiments, the formulations may also include one or more suspending agents that include compounds such as polyvinylpyrrolidone, for example, polyvinylpyrrolidone K112, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, vinyl pyrrolidone/acetate copolymer vinyl (S630), polyethylene glycol, for example, polyethylene glycol may have a molecular weight of about 300 to about 6,000 or about 3,350 to about 4,000 or about 7,000 to about 5,400, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as gum gum tragacanth and acacia gum, guar gum, xanthans, including xanthan gum, sugars, cellulosic materials, such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monoleate, povidone and the like.

[00188] In certain embodiments, the formulations may also include one or more surfactants that include compounds such as sodium lauryl sulfate, sodium docusate, Tween 20, 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, mono- polyoxyethylene sorbitan oleate, polyoxyethylene sorbitan monolaurate, polysorbates, polaxomeres, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, for example, Pluronic® (BASF) and the like. Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, for example, polyoxyethylene hydrogenated castor oil (60); and polyoxyethylene alkyl ethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40. In some embodiments, surfactants may be included to enhance physical stability or for other purposes.

[00189] In certain embodiments, the formulations may also include one or more viscosity enhancing agents that include, for example, methyl cellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, hydroxypropylmethylcellulose phthalate, carbomer, polyvinyl alcohol alginates, acacia, chitosans and combinations thereof.

[00190] In certain embodiments, the formulations may also include one or more wetting agents that include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, sorbitan monolaurate polyoxyethylene sorbitan, sodium docusate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, Tween 80, vitamin E TPGS, ammonium salts and the like.

[00191] The pharmaceutical preparations disclosed in this document can be obtained by mixing one or more solid excipients such as carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersion, surfactant, lubricant, colorant, diluent, solubilizer, wetting agent, plasticizer, stabilizer, penetration enhancer, wetting agent, antifoam agent, antioxidant, preservative or one or more combinations thereof with one or more compounds described herein, optionally grinding the resulting mixture, and processing the granule mixture, after addition of suitable excipients, if desired, to obtain tablets.

[00192] The pharmaceutical preparations disclosed herein also include capsules produced from gelatin, as well as soft sealed capsules produced from gelatin and a plasticizer, such as glycerol or sorbitol. Capsules can also be produced from polymers such as hypromellose. The capsules may contain the active ingredients in mixture by addition with filler such as lactose, binders such as starches and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, lipids, solubilizers or liquid polyethylene glycols. Additionally, stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.

[00193] These formulations can be manufactured by conventional pharmacological techniques. Conventional pharmacological techniques include, for example, one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or nonaqueous granulation, (5) wet granulation, ( 6) fusion or (7) extrusion. See, for example, Lachman et al., The Theory and Practice of Industrial Pharmacy, 3rd edition (1986). Other methods include, for example, spray drying, multiple coating, melt granulation, granulation, coating or fluidized bed spray drying (e.g., wurster coating), tangential coating, top spraying, tableting, extrusion, extrusion/spheronization and the like.

[00194] It should be noted that there is considerable overlap between excipients used in the solid dosage forms described herein. Therefore, the additives listed above should be taken as merely exemplifying, and not limiting, the types of excipient that can be included in the solid dosage forms described herein. The type and amounts of such excipient can be readily determined by one skilled in the art, according to the particular properties desired.

[00195] In some embodiments, the solid dosage forms described herein are enteric-coated oral dosage forms, that is, as an oral dosage form of a pharmaceutical composition, as described herein, that utilizes an enteric coating. to effect the release of the compound in the intestine of the gastrointestinal tract. An "enterically coated" tablet and/or drug refers to a drug and/or tablet that is coated with a substance that remains intact in the stomach, but dissolves and releases the drug once the intestine (in one embodiment, small intestine) is reached. For use herein, "enteric coating", is a material, such as a polymeric material or materials that surround the therapeutically active agent core as a dosage form or as particles. Typically, a substantial amount of or all of the enteric coating material is dissolved before the therapeutically active agent is released from the dosage form in order to achieve delayed dissolution of the therapeutically active agent core or particles in the small intestine. and/or thick. Enteric coatings are discussed, for example, in Loyd, V. Allen, Remington: The Science and Practice of Pharmacy, Twenty-first edition, (Pharmaceutical Press, 2005; and P.J. Tarcha, Polymers for Controlled Drug Delivery, chapter 3, CRC Press , 1991. Methods for applying enteric coatings to pharmaceutical compositions are well known in the art and include, for example, U.S. patent publication 2006/0045822.

[00196] The enteric-coated dosage form may be an extruded, molded or compressed tablet (coated or uncoated) containing granules, powder, pellets, microspheres or particles of the compound of Formula (I) (or any modalities thereof) and/or a pharmaceutically acceptable salt thereof and/or other excipients, which are themselves coated or uncoated provided that at least the tablet or compound of Formula (I) is coated. The enteric-coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, microspheres or granules of the compound of Formula (I) (or any embodiments thereof) and/or a pharmaceutically acceptable salt thereof and /or other excipients, which are themselves coated or uncoated provided that at least one of them is coated. Some examples of coatings that were originally used as enteric coatings are beeswax and glyceryl monostearate; beeswax, shellac and cellulose; and cetyl alcohol, algae and shellac, as well as shellac and stearic acid (U.S. patent no. 2,809,918); polyvinyl acetate and ethyl cellulose (U.S. patent 3,835,221). More recently, the coatings used are neutral copolymers of polymethacrylic acid esters (Eudragit L30D). (F. W. Goodhart et al, Pharm. Tech., pages 64 to 71, April 1984); copolymers of methacrylic acid and methacrylic acid methyl ester (Eudragit S) or a neutral copolymer of methacrylic acid esters containing metal stearates (Mehta et al, patents in U.S. 4,728,512 and U.S. 4,794,001), acetate succinate cellulose and hypromellose phthalate.

[00197] Any anionic polymer that exhibits a pH-dependent solubility profile can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the intestine. In one embodiment, delivery to the small intestine. In another modality, delivery to the duodenum. In some embodiments, the polymers described herein are anionic carboxylic polymers. In other embodiments, compatible polymers and mixtures thereof, and some of their properties include, but are not limited to:

Shellac:

[00198] Also called purified lacquer, it is a refined product obtained from the resinous secretion of an insect. This coating dissolves in media with a pH>7;

Acrylic polymers:

[00199] The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. The Eudragit L, S and RS series (manufactured by Rohm Pharma and known as Evonik®) are available as solubilized in organic solvent, aqueous dispersion or dry powders. The Eudragit RL, NE and RS series are insoluble in the gastrointestinal tract but are permeable and are used primarily for colonic targeting. Eudragit L, L-30D and S series are insoluble in the stomach and dissolve in the intestine and can be selected and formulated to dissolve at a pH value greater than 5.5 or at a minimum greater than 5 or at a maximum greater than 7 .

Cellulose derivatives:

[00200] Examples of suitable cellulose derivatives are: ethyl cellulose; reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. Performance may vary based on degree and type of replacement. Cellulose acetate phthalate (CAP) dissolves at pH>6. Aquateric (FMC) is a water-based system and is a spray-dried CAP pseudo-latex with particles <1 μm. Other components in Aquateric may include pluronics, Tweens and acetylated monoglycerides. Other suitable cellulose derivatives include; cellulose trimethylate acetate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetate succinate (HPMCAS, e.g. AQOAT (Shin Etsu)). Performance may vary based on degree and type of replacement. For example, HPMCP like, classes HP-50, HP-55, HP-55S, HP-55F are suitable. Performance may vary based on degree and type of replacement. For example, classes of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH. These polymers are offered as granules or as fine powders for aqueous dispersions;

Polyvinyl acetate phthalate (PVAP):

[00201] PVAP dissolves at pH>5, and is much less permeable in water vapor and gastric fluids. Detailed description of the above polymers and their pH-dependent solubility can be found in the article entitled "Enteric coated hard gelatin capsules" by Professor Karl Thoma and Karoline Bechtold at http://pop.www.capsugel.com/media/library/ enteric-coated-hard-gelatin-capsules.pdf. In some embodiments, the coating can, and usually does, contain a plasticizer and possibly other coating excipients such as dyes, talc and/or magnesium stearate, which are well known in the art. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, acid esters acetic acid, propylene glycol and diethyl phthalate. In particular, anionic carboxylic acrylic polymers will typically contain 10 to 25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. Conventional coating techniques such as Wurster or fluid bed coaters or multiple or spray coating are employed to apply coatings. The thickness of the coating needs to be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the intestinal tract is reached.

[00202] Colorants, surfactants, anti-adhesion agents, anti-foaming agents, lubricants (e.g., carnauba wax or PEG) and other additives can be added to coatings in addition to plasticizers to solubilize or disperse the coating material, and to perfect the coating performance and the coated product.

[00203] To accelerate the dissolution of the enteric coating, a double coating of half the thickness of enteric polymer (e.g., Eudragit L30 D-55) can be applied and the inner enteric coating can be buffered up to pH 6.0 in the presence of 10% citric acid, followed by a final layer of standard Eudragit L 30 D-55. By applying two layers of enteric coating, each half the thickness of a typical enteric coating, Liu and Basit were able to accelerate the dissolution of enteric coating compared to a similar coating system applied, unbuffered, as a single layer (Liu , F. and Basit, A. Journal of Controlled Release 147 (2010) 242 to 245.)

[00204] The integrity of the enteric coating can be measured, for example, by the degradation of the drug within the micropellets. Enteric-coated dosage forms or pellets may be tested in a dissolution test primarily in gastric fluid and separately in intestinal fluid as described in USP to determine their function.

[00205] The formulation of enteric-coated capsules and tablets containing the disclosed compounds can be produced by methods well known in the art. For example, tablets containing a compound disclosed herein can be enteric coated with a coating solution containing Eudragit®, diethyl phthalate, isopropyl alcohol, talc and water using a side-vented dragee (Freund Hi- Coater).

[00206] Alternatively, a multiple unit dosage form comprising enteric-coated pellets that can be incorporated into a tablet or capsule can be prepared as set out below.

Core materials:

[00207] The core material for the individually enteric-coated layered pellets can be constituted according to different principles. Seeds layered with the active agent (i.e., the compound of Formula (I) (including embodiments disclosed herein) and/or a pharmaceutically acceptable salt thereof), optionally mixed with alkaline substances or buffer, can be used as the core material for further processing. The seeds that are to be layered with the active agent may be water-insoluble seeds comprising different oxides, celluloses, organic polymers and other materials, alone or in mixtures, or water-soluble seeds comprising different inorganic salts, sugars, pearls of sugar and other materials, alone or in mixtures. Additionally, the seeds may comprise the active agent in the form of crystals, agglomerates, compacts, etc. The size of the seeds is not essential to the present invention, but can vary between approximately 0.1 and 2 mm. Seeds layered with the active agent are produced by suspension/solution or powder layering using, for example, spray or granulation coating layering equipment.

[00208] Before the seeds are layered, the active agent can be mixed with additional components. Such components may be binders, surfactants, fillers, disintegrating agents, alkaline or other additives and/or pharmaceutically acceptable ingredients alone or in mixtures. Binders are, for example, polymers such as hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose, polyvinylpyrrolidone (PVP) or sugars, starches or other pharmaceutically acceptable substances with cohesive properties. Suitable surfactants are found in the groups of pharmaceutically acceptable ionic or non-ionic surfactants such as, for example, sodium lauryl sulfate.

[00209] Alternatively, the active agent optionally mixed with suitable constituents can be formulated into a core material. Said core material can be produced by extrusion/spheronization, ball forming or compression using conventional process equipment. The size of the formulated core material is approximately between 0.1 and 4 mm and, for example, between 0.1 and 2 mm. The manufactured core material may be further layered with additional ingredients comprising the active agent and/or used for further processing.

[00210] The active agent is mixed with pharmaceutical constituents to obtain preferred processing and handling properties and a suitable concentration of the active agent in the final preparation. Pharmaceutical constituents such as fillers, binders, lubricants, disintegrating agents, surfactants and other pharmaceutically acceptable additives can be used.

[00211] Alternatively, the aforementioned core material can be prepared using spray drying or spray freezing techniques.

Enteric coating layer (or layers):

[00212] Prior to applying the enteric coating layer (or layers) onto the core material in the form of individual pellets, the pellets may optionally be covered with one or more separating layers comprising pharmaceutical excipients which optionally include alkaline compounds as compounds. pH buffering. This separation layer (or layers) separates the core material from the outer layers which are the enteric coating layer (or layers). This separation layer (or layers) that protects the active agent core material should be water-soluble or rapidly disintegrating in water.

[00213] A separation layer (or layers) may optionally be applied to the core material through coating or layering procedures in suitable equipment such as a dragee, coating granulator or in a fluidized bed apparatus using of water and/or organic solvents for the coating process. As an alternative, the separation layer (or layers) can be applied to the core material using powder coating techniques. Materials for the separating layers are pharmaceutically acceptable compounds such as, for example, sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, water-soluble salts of polymers of enteric coating and others, used alone or in mixtures. Additives such as plasticizers, dyes, pigments, fillers, anti-static and non-stick agents, such as magnesium stearate, titanium dioxide, talc and other additives can also be included in the separation layer (or layers).

[00214] When the optional separation layer is applied to the core material, it may constitute a variable thickness. The maximum thickness of the separation layer (or layers) is normally only limited by the processing conditions. The separation layer can serve as a diffusion barrier and can act as a pH buffer zone. The optionally applied separation layer (or layers) is not essential to the invention. However, the separating layer (or layers) may improve the chemical stability of the active substance and/or the physical properties of the innovative multiple unit tablet dosage form.

[00215] Alternatively, the separation layer can be formed in situ by a reaction between an enteric coating polymer layer applied to the core material and an alkaline reaction compound in the core material. In this way, the separating layer formed comprises a water-soluble salt formed between the enteric coating layer polymer (or polymers) and an alkaline reaction compound that is in position to form a salt.

[00216] One or more enteric coating layers are applied to the core material or to the core material covered with separation layer (or layers) using a suitable coating technique. The enteric coating layer material can be dispersed or dissolved in water or suitable organic solvents. As the enteric coating layer polymers, one or more, separately or in combination, of the following may be used, for example, solutions or dispersions of copolymers of methacrylic acid, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate succinate. hydroxypropyl methylcellulose, polyvinyl acetate phthalate, cellulose acetate trimethylate, carboxymethyl ethyl cellulose, shellac or other suitable enteric coated polymer (or polymers).

[00217] The enteric coating layers contain pharmaceutically acceptable plasticizers to obtain the desired mechanical properties, such as flexibility and hardness of the enteric coating layers. Such plasticizers are, for example, but without limitation, triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates or other plasticizers.

[00218] The amount of plasticizer is optimized for each enteric coating layer formula, in relation to the selected enteric coating layer polymer (or polymers), selected plasticizer (or plasticizers) and the applied amount of said polymer (or polymers). , such that the mechanical properties, i.e., flexibility and hardness of the enteric coating layer (or layers), e.g., exemplified as Vickers hardness, are adjusted so that, if a tablet is desired, the acid resistance of the pellets covered with enteric coating layer (or layers) does not decrease significantly during compression of pellets into tablets. The amount of plasticizer is normally above 5% by weight of the enteric coating layer polymer (or polymers), such as 15 to 50% and additionally such as 20 to 50%. Additives such as dispersants, dyes, pigments, polymers, for example, poly(ethyl acrylate, methyl methacrylate), antifoaming agents and nonstick agents may also be included in the enteric coating layer (or layers). Other compounds can be added to increase film thickness and to decrease the diffusion of acidic gastric juices into the acid-susceptible material. The maximum thickness of the applied enteric coating is normally only limited by processing conditions and the desired dissolution profile.

External coating layer:

[00219] Pellets covered with an enteric coating layer (or layers) can optionally be additionally covered with one or more layers of external coating. The outer coating layer (or layers) should be water-soluble or rapidly disintegrating in water. The outer coating layer (or layers) may be applied to the enteric coated layered pellets through coating or layering procedures in suitable equipment such as a dragee, coating granulator or in a fluidized bed apparatus using of water and/or organic solvents for the layering or coating process. Materials for outer coating layers are chosen from pharmaceutically acceptable compounds such as sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and others. , used alone or in mixtures. Additives such as plasticizers, dyes, pigments, fillers, anti-static and non-stick agents, such as magnesium stearate, titanium dioxide, talc and other additives may also be included in the outer coating layer (or layers). The outer coating layer can further prevent potential agglomeration of pellets in enteric coated layers, additionally, it can protect the enteric coated layer from cracking during the compaction process and enhance the tableting process. The maximum thickness of the applied outer coating layer (or layers) is normally only limited by processing conditions and the desired dissolution profile. The outer coating layer can also be used as a tablet film coating layer.

[00220] The enteric coating of soft gelatin capsules may contain an emulsion, oil, microemulsion, self-emulsification system, lipid, triglycerides, polyethylene glycol, surfactants, other solubilizers and the like, and combinations thereof, to solubilize the agent active. The flexibility of the soft gelatin capsule is maintained by residual water and plasticizer. Furthermore, for gelatin capsules, the gelatin can be dissolved in water so that spraying needs to be carried out at a rate with relatively low relative humidity, as can be carried out in a fluid bed or Wurster. Furthermore, drying should be carried out without removing water or residual plasticizer that causes cracking of the capsule shell. Commercially available blends optimized for enteric coating of soft gelatin capsules, such as Instamodel EPD (enteric polymeric dispersion), available from Ideal Cures, Pvt. Ltd. (Mumbai, India). On a laboratory scale, enteric-coated capsules can be prepared by: a) rotating capsules in a vial or immersing capsules in a solution of enteric-coated material gently heated with plasticizer at the lowest possible temperature or b) in a laboratory scale spray/fluid bed and then drying.

[00221] For aqueous active agents, it may be especially desirable to incorporate the drug into the aqueous phase of an emulsion. Such a "water-in-oil" emulsion provides a suitable biophysical environment for the drug and can provide an oil-in-water interface that can protect the drug against adverse pH effects or enzymes that can degrade the drug. Additionally, such water-in-oil formulations can provide a lipid layer, which can interact favorably with lipids in body cells, and can increase the partitioning of the formulation onto cell membranes. Such splitting can increase the absorption of drugs in such formulations into the circulation and, therefore, can increase the bioavailability of the drug.

[00222] In some embodiments, the water-in-oil emulsion contains an oily phase composed of long- or medium-chain carboxylic acids or esters or alcohols thereof, a surfactant or a surface active agent, and an aqueous phase that contains primarily water and the active agent.

[00223] Long and medium chain carboxylic acids are those that lie in the range of C8 to C22 with up to three unsaturated bonds (also branching). Examples of saturated straight-chain acids are n-dodecanoic acid, n-tetradecanoic acid, n-hexadecanoic acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, montanic acid and melissic acid. Also useful are unsaturated monoolefin straight-chain monocarboxylic acids. Examples of these are oleic acid, gadoleic acid and erucic acid. Also useful are unsaturated straight-chain monocarboxylic acids (polyolefinic acids). Examples of these are linoleic acid, ricinoleic acid, linolenic acid, arachidonic acid and behenolic acid. Useful branched acids include, for example, diacetyl tartaric acid. Unsaturated olefin chains can also be hydroxylated or ethoxylated to prevent oxidation or to alter surface properties.

[00224] Examples of long-chain carboxylic acid esters include, but are not limited to, those from the group of: glyceryl monostearates; glyceryl monopalmitates; mixtures of glyceryl monostearate and glyceryl monopalmitate; glyceryl monolinoleate; glyceryl monooleate; mixtures of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate and glyceryl monolinoleate; glyceryl monolinolenate; glyceryl monogadoleate; mixtures of glyceryl monopalmitate, glyceryl monostearate, glyceryl monooleate, glyceryl monolinoleate, glyceryl monolinolenate and glyceryl monogadoleate; acetylated glycerides such as distilled acetylated monoglycerides; mixtures of propylene glycol monoesters, distilled monoglycerides, sodium steryl lactylate and silicon dioxide; d- alpha tocopherol polyethylene glycol 1000 succinate; mixtures of mono- and di-glyceride esters such as Atmul; calcium stearoyl lactylate; ethoxylated mono- and di-glycerides; lactated mono- and di-glycerides; lactylate carboxylic acid ester of glycerol and propylene glycol; lactyl esters of long-chain carboxylic acids; polyglycerol esters of long-chain carboxylic acids, propylene glycol mono- and di-esters of long-chain carboxylic acids; sodium stearoyl lactylate; sorbitan monostearate; sorbitan monooleate; other sorbitan esters of long chain carboxylic acids; succinylated monoglycerides; stearyl monoglyceryl citrate; stearyl heptanoate; cetyl esters of waxes; stearyl octanoate; C8-C30 cholesterol/lavosterol esters; and sucrose long-chain carboxylic acid esters. Examples of self-emulsifying long-chain carboxylic acid esters include those from the groups of stearates, pamitates, ricinoleates, oleates, behenates, ricinolenates, myristates, laurates, caprylates and caproates. In some embodiments, the oil phase may comprise a combination of 2 or more of long-chain carboxylic acids, esters or alcohols thereof. In some embodiments, medium chain surfactants may be used and the oil phase may comprise a mixture of caprylic/capric triglyceride and C8/C10 caprylic acid mono-/di-glycerides, glyceryl caprylate or propylene glycol monocaprylate. or mixtures thereof.

[00225] The alcohols that can be used are exemplified by the hydroxyl forms of the carboxylic acids exemplified above and also stearyl alcohol.

[00226] Surface active agents or surfactants are long-chain molecules that can accumulate at hydrophilic/hydrophobic interfaces (water/oil) and reduce surface tension at the interface. As a result, they can stabilize an emulsion. In some embodiments of this invention, the surfactant may comprise: The Tween® (polyoxyethylene sorbate) family of surfactants, Span® family (long-chain sorbitan carboxylic acid esters) of surfactants, Pluronic® family ( block copolymers of ethylene or propylene oxides) of surfactants, Labrasol®, Labrafil® and Labrafac® families (each polyglycolized glycerides) of surfactants, sorbitan esters of oleate, stearate, laurate or other long-chain carboxylic acids , poloxamers (block copolymers of polyethylene-polypropylene glycol or Pluronic®.), other long-chain carboxylic acid esters of sorbitan or sucrose, mono- and diglycerides, PEG derivatives of caprylic/capric triglycerides and mixtures thereof or mixture of two or more of those mentioned above. In some embodiments, the surfactant phase may comprise a mixture of Polyoxyethylene sorbitan (20) monooleate (Tween 80®) and sorbitan monooleate (Span 80®).

[00227] The aqueous phase may optionally comprise the active agent suspended in water and a buffer.

[00228] In some embodiments, such emulsions are thick emulsions, microemulsions and liquid crystal emulsions. In other embodiments, such emulsion may optionally comprise a permeation enhancer. In other embodiments, nanoparticles, microparticles, or spray-dried dispersions containing encapsulated microemulsion, thick emulsion, or liquid crystal may be used.

[00229] In some embodiments, the solid dosage forms described herein are non-enteric delayed-release dosage forms. The term "non-enteric delayed release" for use herein refers to delivery such that release of the drug can be accomplished at some generally predictable location in the intestinal tract more distal to that which would have been accomplished if there had been no alterations in release. retarded. In some embodiments, the method for delaying release is a coating that becomes permeable, dissolves, ruptures and/or is no longer intact after a designed duration. The coating on delayed-release dosage forms may have a fixed time for erosion after the drug is released (suitable coatings include polymeric coatings such as HPMC, PEO and the like) or have a core comprising a superdisintegrating agent (or agents). , osmotic or water attracting agent (or agents) such as a salt, hydrophilic polymer, typically polyethylene oxide or an alkylcellulose, salts such as sodium chloride, magnesium chloride, sodium acetate, sodium citrate, sugar such as glucose, lactose or sucrose or the like, which remove water through a semipermeable membrane or a gas generating agent such as citric acid and sodium bicarbonate, with or without an acid such as citric acid or any of the aforementioned acids incorporated into the dosage forms. The semipermeable membrane, although predominantly non-permeable to drug nor osmotic agent, is permeable to water which penetrates at a nearly constant rate to enter the dosage form to increase pressure and ruptures after the swelling pressure exceeds a certain threshold during a desired delay time. The permeability through this drug membrane should be less than 1/10 of water and in one embodiment less than 1/100 of water permeability. Alternatively, a membrane could be made porous by leaching an aqueous extract during a desired delay time.

[00230] Osmotic dosage forms have been described in Theeuwes US 3,760,984, and an osmotic breakthrough dosage form is described in Baker US 3,952,741. This osmotic breakthrough dosage form can provide a single pulse of release or multiple pulses if different devices with different timings are employed. The timing of osmotic disruption can be controlled by the choice of polymer and the thickness or area of the semipermeable membrane surrounding the core containing both the drug and the osmotic or attractant agent. As the pressure in the dosage form increases with additional permeate water, the membrane stretches to its breaking point and then the drug is released. Alternatively, specific areas of rupture in the membrane can be created by having a weaker, thinner area in the membrane or by adding a weaker material to an area of the coating membrane. Some preferred polymers with high water permeability that can be used as semipermeable membranes are cellulose acetate, cellulose acetate butyrate, cellulose nitrate, cross-linked polyvinyl alcohol, polyurethanes, nylon 6, nylon 6.6 and aromatic nylon. Cellulose acetate is an especially preferred polymer.

[00231] In another embodiment, the delayed coating that begins its delay to release the drug after the enteric coating is at least partially dissolved is comprised of erodible hydrophilic polymers that upon contact with water begin to erode gradually along the time. Examples of such polymers include cellulose polymers and derivatives thereof which include, but are not limited to, hydroxyalkyl celluloses, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, microcrystalline cellulose; polysaccharides and their derivatives; polyalkylene oxides, such as polyethylene oxide or polyethylene glycols, particularly high molecular weight polyethylene glycols; chitosan; poly(vinyl alcohol); xanthan gum; maleic anhydride copolymers; poly(vinyl pyrrolidone); starch and starch-based polymers; maltodextrins; poly(2-ethyl-2-oxazoline); poly(ethyleneimine); polyurethane; hydrogels; cross-linked polyacrylic acids; and combinations or mixtures of any of those mentioned above.

[00232] Some preferred hydrophilic erodible polymers suitable for forming the erodible coating are poly(ethylene oxide), hydroxypropyl methyl cellulose, and combinations of poly(ethylene oxide) and hydroxypropyl methyl cellulose. Poly(ethylene oxide) is used herein to refer to a linear unsubstituted ethylene oxide polymer. The molecular weight of poly(ethylene oxide) polymers may range from about 105 Daltons to about 107 Daltons. A preferred molecular weight range of poly(ethylene oxide) polymers is from about 2 times 105 to 2 times 106 Daltons and is commercially available from the Dow Chemical Company (Midland, Mich.) referred to as water-soluble resins. SENTRYR POLYOX™, NF (National Formulary) classification. When higher molecular weights of polyethylene oxide are used, other hydrophilic agents such as salts or sugars such as glucose, sucrose or lactose, which promote erosion or disintegration of this coating, are also included.

[00233] The delayed dosage form can be a mechanical pill such as an Enterion® capsule or pH-sensitive capsule that can release the drug after a pre-programmed time or when it receives a signal that can be transmitted or once the it comes out of the stomach.

[00234] The amount of the disclosure compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percentage (wt%) basis, from about 0.01 to 99.99% by weight of a compound of Formula (I) based on the total formulation, with the remainder is one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1 to 80% by weight.

[00235] The compounds of the present disclosure can be used in combination with one or more drugs in the treatment of diseases or conditions for which the compounds of the present disclosure or other drugs may be useful, where the combination of the drugs together is safer or less effective than either drug alone. Such other drug (or drugs) may be administered by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present disclosure. When a compound of the present disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present disclosure is preferred. However, combination therapy may also include therapies in which the compound of the present disclosure and one or more other drugs are administered at different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present disclosure and the other active ingredients may be used in smaller doses than when each is used singularly.

[00236] Consequently, the pharmaceutical compositions of the present disclosure also include those that contain one or more other active ingredients, in addition to a compound of the present disclosure.

[00237] The above combinations include combinations of a compound of the present disclosure not only with another active compound, but also with two or more other active compounds. Likewise, the compounds of the present disclosure can be used in combination with other drugs that are used in the prevention, treatment, control, improvement or reduction of the risk of diseases or conditions for which the compounds of the present disclosure are useful. Such other drugs can be administered by a route and in a commonly used amount, contemporaneously or sequentially with a compound of the present disclosure. When a compound of the present disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition, such as a fixed combination pharmaceutical product, which contains such other drugs in addition to the compound of the present disclosure is preferred. Accordingly, the pharmaceutical compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to a compound of the present disclosure. The weight ratio of the compound of the present disclosure in relation to the second active ingredient can be varied and will depend on the effective dose of each ingredient. Generally, an effective dose of each will be used.

[00238] Where the subject is suffering from or at risk of suffering from an autoimmune disease, an inflammatory disease or an allergy disease, a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof can be used with a or more of the following therapeutic agents in any combination: immunosuppressants (e.g., tacrolimus, cyclosporine, rapamycin, methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, or FTY720), glucocorticoids (e.g., prednisone, cortisone acetate, prednisone, nisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclomethasone, fludrocortisone acetate, deoxycortisone acetate, aldosterone), non-steroidal anti-inflammatory drugs (e.g. salicylates, arylalkanoic acids, 2-arylpropionic acids, N- arylanthranilic acids, oxicams, coxibs, or sulfonanilides), specific Cox-2 inhibitors (e.g., valdecoxib, celecoxib, or rofecoxib), leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline, binding of TNF-.alpha. (e.g., infliximab, etanercept, or adalimumab), abatacept, anakinra, interferon-beta, interferon-gamma, interleukin-2, allergy shots, antihistamines, antileukotrienes, beta-agonists, theophylline, or anticholinergics.

[00239] Where the subject is suffering from or at risk of suffering from a B cell proliferative disorder (e.g., plasma cell myeloma), the subject can be treated with a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof in any combination with one or more other anticancer agents. In some embodiments, one or more of the anticancer agents are pro-apoptotic agents. Examples of anticancer agents include, but are not limited to, any of the following: gossifol, genasense, polyphenol E, Chlorofusin, all-trans-retinoic acid (ATRA), bryostatin, apoptosis-inducing ligand related to tumor necrosis factor (TRAIL), 5-aza-2'-deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (GleevecTM), geldanamycin, 17-N-Allylamino-17- Demethoxygeldanamycin ( 17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352, TaxolTM, also referred to as "paclitaxel", which is a well-known anticancer drug that acts by enhancing and stabilizing microtubule formation , and Taxo-lTM analogues, such as TaxotereTM. It has also been shown that compounds that have the basic taxane skeleton as a common structural feature have the ability to retain cells in the G2-M phases due to stabilized microtubules and may be useful for treating cancer in combination with the compounds described herein. document.

[00240] Additional examples of anticancer agents for use in combination with a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof include inhibitors of mitogen-activated protein kinase signaling, for example, U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituxan).

[00241] Other anticancer agents that can be employed in combination with a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronin; adozelesin; aldesleukin; altretamine; ambomycin; amethantron acetate; aminoglutethimide; ansacrine; anastrozole; anthramycin; asparaginase; asperline; azacitidine; azetepa; nitrogen-mycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; sodium brequinar; bropyrimine; busulfan; cactinomycin; calusterone; characemid; carbetimer; carboplatin; carmustine; carubicin hydrochloride; - carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; chrysnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; empromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine sodium phosphate; ethanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabin; fenretinide; floxuridine; fludarabine phosphate; fluororouracil; flurocitabine; phosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide-; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; alpha-n1 interferon; alpha-n3 interferon; interferon beta-1a; interferon gamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitochromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxysuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosphamide; pipobroman; poposulfan; pyroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porphyromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprin; rogletimide; safingol; safingol hydrochloride; semustina; syntrazene; sodium sparfosate; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; sodium tecogalan; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; thiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesina; vindesine sulfate; vinepidine sulfate; vinglicinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.

[00242] Other anticancer agents that can be employed in combination with a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof include: 20-epi-1, 25 dihydroxy vitamin D3; 5-ethynyluracil; abiraterone; aclarrubicin; acylfulvene; adecipenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; anrubicin; ansacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; G antagonist; antarelix; antidorsalization morphogenetic protein-1; antiandrogen prostate carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-aletin; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafida; bistratene A; bizelesin; breflate; bropyrimine; budotitan; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canaripox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; MEAT 700; cartilage-derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogues; clotrimazole; colismycin A; colimycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; chrysnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentantraquinones; cycloplatam; cypemycin; cytarabine octophosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselene; ecomustina; edelfosine; edrecolomab; eflomitin; element; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; ethanidazole; etoposide phosphate; exemestane; fadrozole; fazarabin; fenretinide; filgrastim; fmasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; gallocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfan; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifen; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulating peptides; insulin-like growth factor 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplatt; irsogladine; isobengazole; iso-homohalychondrin B; itasetron; jasplaquinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; leukocyte interferon alpha; leuprolide+estrogen+progesterone; leuprorelin; Levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lumbricin; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysophilin; lytic peptides; maytansine; mannostatin A; marimastate; masoprocol; maspine; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double-stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafida; mitotoxin-saporin fibroblast growth factor; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotropin; monophosphoryl lipid A+ left myobacterium cell wall; mopidamol; multidrug resistance gene inhibitor; multiple tumor suppressor-based therapy 1; mustard anticancer agent; micaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavine; nafterpine; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric acid modulators; nitroxide antioxidant; nitrulin; O6- benzylguanine; octreotide; oquicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; Pazeliptin; pegaspargase; peldesine; sodium pentosan polysulfate; pentostatin; pentrozole; perflubrone; perfosphamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pyrarubicin; pyritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porphyromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; glitter; pyrazoloacridine; pyridoxylated hemoglobin and polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; farnesyl ras protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; demethylated reteliptin; rhenium etidronate Re 186; rhizoxin; ribozymes; retinamide R.sub.11; rogletimide; roituchin; ruptured; roquinimex; rubiginone B1; ruboxyl; safingol; saintopine; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustina; senescence derivative 1; sense oligonucleotide; signal transduction inhibitors; transduction signal modulators; single-chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermine; sparphosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitors; stipiamide; stromelysin inhibitors; sulfosine; superactive vasoactive intestinal peptide antagonist; suradist; suramin; swainsonine; synthetic glycosaminoglycans; talimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; taliblastin; thiocoralin; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; timotrinan; thyroid-stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosterea; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; candlelight; veramine; greens; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin estimamer.

[00243] Still other anticancer agents that may be employed in combination with a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof include alkylating agents, antimetabolites, natural products or hormones, for example, nitrogen mustards (e.g. , mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g. busulfan), nitrosoureas (e.g. carmustine, lomusitne, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites include but are not limited to folic acid analogues (e.g. methotrexate), or pyrimidine analogues (e.g. Cytarabine), purine analogues (e.g. mercaptopurine, thioguanine, pentostatin).

[00244] Examples of natural products useful in combination with a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof include, but are not limited to, vinca alkaloids (e.g., vimbastine, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., alpha interferon).

[00245] Examples of alkylating agents that can be employed in combination with a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof include, but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g. hexamethylmelamine, thiotepa), alkyl sulfonates (e.g. busulfan), nitrosoureas (e.g. carmustine, lomusitne, semustine, streptozocin, etc.) or triazenes (decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogues (e.g., methotrexate), or pyrimidine analogues (e.g., fluorouracil, floxuridine, Cytarabine), purine analogues (e.g., mercaptopurine, thioguanine, pentostatin - at.

[00246] Examples of hormones and antagonists useful in combination with a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g. flutamide), gonadotropin-releasing hormone analogue (e.g. leuprolide). Other agents that can be used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboplatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methylhydrazine derivative (e.g., procarbazine), andrenocortical suppressant (e.g., mitotane, aminoglutethimide).

[00247] Examples of anticancer agents that act by retaining cells in the G2-M phases due to stabilized microtubules and that can be used in combination with a BTK inhibitor compound of the disclosure include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin Isethionate (also known as CI980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A -296), ABT-751 (Abbott, also known as E-7010), Altorirtins (such as Altorirtin A and Altorirtin C), spongistatins (such as spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6 , spongistatin 7, spongistatin 8 and spongistatin 9), cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), epothilones (such as epothilone A, epothilone B, epothilone C (also known as deoxyepothilone A or dEpoA ), epothilone D (also mentioned as KOS-862, dEpoB and deoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS- 4559- P (Pharmacia, aka LS-4577), LS-4578 (Pharmacia, aka LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), sulfate of vincristine, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF- 223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad) , AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptoficina 52 (aka LY-355703), AC- 7739 (Ajinomoto, aka AVE-8063A and CS-39.HCl), AC -7700 (Ajinomoto, also known as AVE-8062, AVE- 8062A, CS-39-L-Ser.HCl, and RPR- 258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidine (also known as NSC- 106969), T -138067 (Tularik, aka T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, aka 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. Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D- 24851 (Asta Medica), A-105972 (Abbott), Hemiasterlina, 3-BAABU (Cytoskeleton/ Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene Acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocin (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 Desmethyleleutherobin, Desmethyleleutherobin, Isoeleutherobin A, and Z- Eleutherobin), Caribaeoside, Caribaeolin, Halicondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI- 2350 (Nereus), Tacalonolid A, TUB- 245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylhistine (also known as NSCL-96F037), D- 68838 (Asta Medica), D-68836 (Asta Medica), Mioseverin B, D43411 (Zentaris, aka D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (alias SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris) , D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

[00248] Where a subject is suffering from or at risk of suffering from a thromboembolic disorder (e.g., stroke), the subject can be treated with a compound of Formula (I) in any combination with one or more other agents antithromboembolic drugs. Examples of antithromboembolic agents include, but are not limited to, any of the following: thrombolytic agents (e.g., alteplase, anistreplase, streptokinase, urokinase, or tissue plasminogen activator), heparin, tinzaparin, warfarin, dabigatran (e.g., dabigatran), factor

Examples

[00249] The following preparations of compounds of Formula (I) and intermediates (References) are given to enable those skilled in the art to more clearly understand and practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof. The line on the alkene carbon in the compounds below denotes that the compounds are isolated as an undefined mixture of (E) and (Z) isomers.

Reference 1

[00250] Synthesis of (R,E)-3-(4-(((dimethylamino)methylene)amino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin- tert-butyl 1-yl)piperidine-1-carboxylate Step 1

[00251] In a 100 ml round bottom flask, 2,4-dichloro-3-nitropyridine (8 g, 41.45 mmol, 1.00 equiv.), N,N-dimethylformamide (50 ml) were placed. , tert-butyl (R)-3-aminopiperidine-1-carboxylate (8.3 g, 41.44 mmol, 1.00 equiv.) and TEA (6.29 g, 62.16 mmol, 1.50 equiv. .). The resulting solution was stirred overnight at 25°C. The resulting solution was diluted with H2O, extracted with ethyl acetate and the organic layers were combined. The resulting mixture was washed with saturated sodium chloride and dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate/petroleum ether (1:1) to generate 8 g (51%) of (R)-3-((2-chloro-3-nitropyridin tert-butyl -4-yl)amino)piperidine-1-carboxylate as a yellow oil. Step 2

[00252] In a 250 ml round bottom flask, tert-butyl (R)-3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (8 g) was placed , 22.42 mmol, 1.00 equiv.), i-propanol (100 ml), bis[(4-methoxyphenol)methyl]amine (5.78 g, 22.46 mmol, 1.00 equiv.) and TEA (2.955 g, 29.20 mmol, 1.30 equiv.). The resulting solution was stirred overnight at 95°C. The reaction mixture was cooled and concentrated under vacuum. This resulted in 12 g (92%) of tert-butyl (R)-3-((2-(bis(4-methoxybenzyl)amino)-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate as a yellow oil. Step 3

[00253] In a 250 ml round bottom flask, (R)- 3- ((2-(bis(4-methoxybenzyl)amino)-3-nitropyridin-4-yl)amino)piperidine-1- tert-butyl carboxylate (10 g, 17.31 mmol, 1.00 equiv.), AcOH/MeOH (1:1,100 ml), and Fe (9.69 g, 173.04 mmol, 10.00 equiv.) . The resulting solution was stirred overnight at 25°C and then concentrated under vacuum. The pH value of the solution was adjusted to 8.0 to 9.0 with sodium bicarbonate. The resulting solution was extracted with dichloromethane and the organic layers were washed with sodium bicarbonate, filtered and dried over anhydrous sodium sulfate, then concentrated in vacuo to give 8.8 g (92.8%) of (R)-3 tert-butyl -((3-amino-2-(bis(4-methoxybenzyl)-amino)pyridin-4-yl)amino)piperidine-1-carboxylate as yellow oil. Step 4

[00254] In a 250 ml round bottom flask, (R)- 3- ((3-amino-2-(bis(4-methoxy-benzyl)amino)pyridin-4-yl)amino)piperidine was placed - 1- tert-butyl carboxylate (12 g, 19.72 mmol, 1.00 equiv., 90%), CH3CN (100 ml), and CDI (5.336 g, 32.91 mmol, 1.50 equiv). The resulting solution was stirred overnight at 80°C. The reaction mixture was cooled and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate/petroleum ether (1:5) to generate 11 g (89%) of (R)-3- (4-[bis[(4- tert-butyl methoxy-phenyl)methyl]-amino]-2-oxo-1H,2H,3H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate as a yellow solid oil. Step 5

[00255] In a 50 ml round bottom flask, (R)-3- (4- [bis[(4-methoxyphenyl)-methyl]amino]-2-oxo-1H,2H,3H-imidazo[ tert-butyl 4,5-c]pyridin-1-yl)piperidine-1-carboxylate (1.5 g, 2.61 mmol, 1.00 equiv.), dichloromethane (30 ml), and trifluoroacetic acid (30 ml). The resulting solution was stirred for 4 h at 50°C. The pH value of the solution was adjusted to 9 with sodium bicarbonate. The resulting solution was extracted with dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The resulting mixture was concentrated in vacuo to give 0.45 g (73.7%) of (R)-4-amino-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[ 4,5- c]pyridin-2-one as a light yellow solid. Step 6

[00256] In a 100 ml round bottom flask, place (R)-4-amino-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c ]pyridin-2-one (1 g, 4.29 mmol, 1.00 equiv.), 1,4-dioxane/H2O (1:1, 50 ml), Boc2O (1.03 g, 4.72 mmol, 1.03 equiv) and sodium carbonate (1.5 g, 14.15 mmol, 1.50 equiv.). The resulting solution was stirred for 1 h at 25°C, then extracted with dichloromethane and the organic layers were combined. The resulting organic layer was washed with water and saturated sodium chloride and then concentrated in vacuo. The residue was applied to a silica gel column and eluted with dichloromethane/methanol (30:1) to generate 1.2 g (84%) of (R)-3-(4-amino-2-oxo- tert-butyl 2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate as a light yellow solid. Step 7

[00257] In a 100 ml round bottom flask, (R)-3- (4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine was placed tert-butyl -1-yl)piperidine-1-carboxylate (6.5 g, 19.50 mmol, 1.00 equiv.) and DMF-DMA (50 ml). The resulting solution was stirred for 1 h at 40 °C and then concentrated under vacuum. The resulting mixture was then dissolved with CH2Cl2 and washed with brine. The organic layers combined and concentrated under vacuum and washed with hexane. The solids were collected by filtration to generate 5.0289 g (66%) of (R,E)-3-(4-(((dimethylamino)methylene)amino)-2-oxo-2,3- tert-butyl dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate as a solid. LC-MS m/z: 389.2 (M+1)

Reference 2

[00258] Synthesis of 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-piperidin-3-yl]- 1H,2H,3H-imidazo[4,5-c]pyridin-2-one

Step 1

[00259] In a 250 ml round bottom flask, (R)- 3- (4-[bis[(4-methoxyphenyl)-methyl]amino]-2-oxo-1H,2H,3H-imidazo was placed tert-butyl [4,5-c]pyridin-1-yl)piperidine-1-carboxylate (10 g, 17.43 mmol, 1.00 equiv.), dichloromethane (100 ml), (4-phenoxyphenyl) acid boronic (7.5 g, 35.04 mmol, 2.00 equiv.), TEMPO (3 g, 19.20 mmol, 1.10 equiv.) and TEA (7 g, 69.18 mmol, 4.00 equiv. ), Cu(OAc)2 (1.6 g, 8.81 mmol, 0.50 equiv.). The resulting solution was stirred overnight at 25°C under ambient pressure oxygen atmosphere. (4-phenoxyphenyl)boronic acid (7.5 g, 35.04 mmol, 2.00 equiv.) was added and the resulting solution was allowed to react overnight at 25°C. The residue was applied to a silica gel column and eluted with ethyl acetate/petroleum ether (1:3) to generate 1.5 g (12%) of (R)-3-(4-[bis[( tert-butyl 4-methoxyphenyl)methyl]amino]-2-oxo-3-(4-phenoxyphenyl)-1H,2H,3H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate as a yellow solid. Step 6

[00260] In a 250 ml round bottom flask, (R)- 3- (4-[bis[(4-methoxyphenyl)-methyl]amino]-2-oxo-3-(4-phenoxyphenyl) was placed tert-butyl -1H,2H,3H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (5 g, 6.07 mmol, 1.00 equiv., 90%), dichloromethane (80 ml), and trifluoroacetic acid (80 ml). The resulting solution was stirred for 5 h at 50°C. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 9 with sodium bicarbonate. The resulting solution was extracted with dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The residue was applied to a silica gel column and eluted with dichloromethane/methanol (30:1) to generate 1 g (41%) of 4-amino-3-(4-phenoxyphenyl)-1-[(3R)- piperidin-3-yl]-1H,2H,3H-imidazo[4,5-c]pyridin-2-one as a light yellow solid.

Example 1

[00261] Synthesis of (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)- 2,3-dihydroimidazo[4,5-c]pyridin-1-yl )piperidine-1-carbonyl)-4,4-dimethylpent-2-enonitrile Step 1

[00262] In a 10 ml round bottom flask, 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-piperidin-3-yl]-1H,2H,3H-imidazo[4 ,5-c]pyridin-2-one (79 mg, 0.20 mmol, 1.00 equiv.), N,N-dimethylformamide (2 ml), TEA (0.082 ml, 1.50 equiv.), HATU ( 113 mg, 0.30 mmol, 1.50 equiv.), and 2-cyano-4,4-dimethylpent-2-enoic acid (46 mg, 0.30 mmol, 3.00 equiv.). The resulting solution was stirred for 2.5 h at room temperature and then quenched with the addition of water. The resulting solution was extracted with dichloromethane and the organic layers combined and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#- AnalyseHPLC-SHIMADZU(HPLC-10)): Column, Gemini-NX C18 AXAI packing, 21.2 x150 mm 5 µm 11 nm; mobile phase, Water with 0.05% TFA and ACN (20.0% ACN up to 50.0% in 8 min.); Detector, 254 nm to generate 50 mg (47%) of the title compound as a white solid. LC-MS m/z: 537.2 (M+1)

Example 2

[00263] Synthesis of (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)- 2,3-dihydroimidazo[4,5-c]pyridin-1-yl )piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enonitrile Step 1

[00264] In a 50 ml round bottom flask, (R,E)-3- (4-(((dimethylamino)-methylene)amino)-2-oxo-2,3-dihydro- tert-butyl 1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (200 mg, 0.51 mmol, 1.00 equiv.), dichloromethane (20 ml), TEA (208 mg, 2.06 mmol, 4.00 equiv.), TEMPO (88.5 mg, 0.57 mmol, 1.10 equiv.), and Cu(OAc)2 (46.7 mg, 0.26 mmol, 0.50 equiv.). The resulting solution was stirred for 0.5 h at 25°C. (4-phenoxyphenyl)boronic acid (220 mg, 1.03 mmol, 2.00 equiv.) was added and the resulting solution was allowed to react overnight at 25 °C. The residue was applied to a silica gel column and eluted with dichloromethane/ethyl acetate (5:1) to generate 150 mg (52%) of (R)-3-[4-[(E)-[(dimethylamino tert-butyl)methylidene]amino]-2-oxo-3-(4-phenoxyphenyl)-1H,2H,3H-imidazo[4,5-c]pyridin-1-yl]piperidine-1-carboxylate as a solid light yellow. Step 2

[00265] In a 25 ml round bottom flask, place (3R)-3- [4- [(E)-[(dimethylamino)-methylidene]-amino]-2-oxo-3-(4-phenoxyphenyl )- tert-butyl 1H,2H,3H-imidazo[4,5-c]pyridin-1-yl]piperidine-1-carboxylate (150 mg, 0.27 mmol, 1.00 equiv.), 1.4 -dioxane (6 ml) and hydrogen chloride (3 ml). The resulting solution was stirred overnight at 50°C. The reaction mixture was quenched with water. The pH of the solution was adjusted to 9 with sodium bicarbonate. The resulting solution was extracted with dichloromethane:CH3OH=10:1 and the organic layers were combined. The resulting mixture was washed with sodium chloride and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column and eluted with dichloromethane/methanol (30:1) to generate 80 mg (74%) of 4-amino-3-(4-phenoxyphenyl)- 1-[(3R )-piperidin-3-yl]-1H,2H,3H-imidazo[4,5-c]pyridin-2-one as a light yellow solid. Step 3

[00266] In a 50 ml round bottom flask, 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-piperidin-3-yl]-1H,2H,3H-imidazo[4 ,5-c]pyridin-2-one (2 g, 4.98 mmol, 1.00 equiv.), N,N-dimethylformamide (20 ml), 2-cyanoacetic acid (402.5 mg, 4.73 mmol , 0.95 equiv.), HATU (2.84 g, 7.47 mmol, 1.50 equiv.) and TEA (1.51 g, 14.92 mmol, 3.00 equiv.). The resulting solution was stirred for 1 h at room temperature and then quenched with water. The resulting solution was extracted with ethyl acetate and the organic layers combined. The organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane/methanol (30:1) to generate 1.3 g (56%) of 3-[(3R)- 3-[4-amino-2-oxo-3 -(4-phenoxyphenyl)-1H,2H,3H-imidazo[4,5-c]pyridin-1-yl]piperidin-1-yl]-3-oxopropanenitrile as a light yellow solid. Step 4

[00267] In a 50 ml round bottom flask, 3-[(3R)-3-[4-amino-2-oxo-3-(4-phenoxyphenyl)-1H,2H,3H-imidazo[4 ,5-c]pyridin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (800 mg, 1.71 mmol, 1.00 equiv.), dichloromethane (20 ml), 2-methyl-2-[ 4-(oxetan-3-yl)piperazin-1-yl]propanal (1.0875 g, 5.12 mmol, 3.00 equiv.), TMSCl (922 mg, 8.49 mmol, 4.97 equiv.) and pyrrolidine (0.607 g). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-TLC, then purified by Prep-HPLC under the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, Gemini-NX C18 AXAI packing, 21.2 x 150 mm 5 um 11 nm; mobile phase, water with 0.05% TFA and ACN (20.0% ACN up to 40.0% in 10 min.); Detector, UV 254 nm to generate 0.478 mg (42%) of the title compound as a light yellow solid. LC-MS m/z: 663.3 (M+1).

Example 3

[00268] Synthesis of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H )-one

[00269] In a 100 ml round bottom flask, (R)- 4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5- c]pyridin-2(3H)-one (150 mg, 0.37 mmol, 1.00 equiv.), DCM-CH3OH (6 ml), TEA (113 mg, 1.12 mmol, 3.00 equiv.) . This was followed by addition of prop-2-enoyl chloride (40.1 mg, 0.44 mmol, 1.20 equiv.) dropwise with stirring at 0°C in 5 min. The resulting solution was stirred for 2 h at 0°C. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane/methanol (30:1). The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column, XBridge Prep C18 OBD Column, 5 µm.19*150 mm; mobile phase, water with 0.05% TFA and ACN (25 .0% ACN to 45.0% in 8 min.) 54.5 mg of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl) product -1H-imidazo[4,5- c]pyridin-2(3H)-one were obtained as a white solid LC-MS m/z: 465.2 (M+1)

Example 4

[00270] Synthesis of (R)-4-amino-1-(1-(but-2-inoyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c] pyridin-2(3H)-one

[00271] In a 100 ml round bottom flask, (R)- 4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5- c]pyridin-2(3H)-one (150 mg, 0.37 mmol, 1.00 equiv.), N,N-dimethylformamide (15 ml), but-2-inoic acid (31.42 mg, 0. 37 mmol, 1.00 equiv.), HATU (213.2 mg, 0.56 mmol, 1.50 equiv.), TEA (113.4 mg, 1.12 mmol, 3.00 equiv.). The resulting solution was stirred for 2 hours at room temperature. The reaction was then cooled quickly with the addition of 50 ml of water. The resulting solution was extracted with 3 x 50 ml of dichloromethane and the organic layers combined. The resulting mixture was washed with 50 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane/methanol (30:1). The crude product (100 mg) was purified by Prep-HPLC as described in Example 3, to obtain 86.5 mg (50%) of (R)-4-amino-1-(1-(but-2-inoyl) piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one as a white solid. LC-MS m/z: 468.2 (M+1).

Example 5

[00272] Synthesis of (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine -1-yl)piperidin-1-carbonyl)-4-methyl-4-(1-methylpiperidin-4-yl)pent-2-enonitrile

Step 1

[00273] In a 250 ml 3-neck round-bottom flask, place methyl 2-(piperidin-4-yl)acetate hydrochloride (10 g, 51.63 mmol, 1.00 equiv.), dichloromethane ( 100ml). The resulting solution was stirred for 30 min at 0°C. Then triethylamine (15.65 g, 154.66 mmol, 3 equiv.), Boc2O (12.4 g, 56.82 mmol, 1.1 equiv.) was added. The resulting solution was allowed to react, with stirring, for an additional 14 h at 25 °C. The pH value of the solution was adjusted to 7.0 with citric acid (3%). The resulting mixture was washed with 2 x 100 ml of water and 2 x 100 ml of saturated brine. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 10 g (75.2%) of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate as colorless oil.

Step 2

[00274] In a 250 ml 3-neck round bottom flask, LDA (46.7 ml, 3.00 equiv.), tetrahydrofuran (80 ml), 4-(2-methoxy-2- tert-butyl oxoethyl)piperidine-1-carboxylate (8 g, 31.1 mmol, 1.00 equiv.). The resulting solution was stirred for 30 min. at -78°C. Then, CH3I (22 g, 155 mmol, 5.00 equiv.) was added. The resulting solution was allowed to react, with stirring, for an additional 1 h at -78°C. Additional LDA (46.7 ml, 3.00 equiv.) was added at -78°C and, after 0.5 h, CH3I (22 g, 155 mmol, 5.00 equiv.) was added. The reaction was stirred 16 h at r.t. The reaction was then cooled quickly with the addition of 200 ml of NH4Cl. The resulting solution was extracted with 2 x 200 ml of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2 x 200 ml of water and 2 x 200 ml of saturated sodium chloride. The residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:35). This resulted in 6 g (68%) of tert-butyl 4-(1-methoxy-2-methyl-1-oxopropan-2-yl)piperidine-1-carboxylate as light yellow oil.

Step 3

[00275] In a 100 ml 3-neck round bottom flask, LiAlH4 (1.6 g, 42.2 mmol, 4.00 equiv.), tetrahydrofuran (50 ml), 4-(1 tert-butyl-methoxy-2-methyl-1-oxopropan-2-yl)piperidine-1-carboxylate (3 g, 10.5 mmol, 1.00 equiv.). The resulting solution was stirred for 3 h at -78°C. The reaction mixture was heated to 0 °C. The reaction was then quenched with the addition of 1.6 ml of water, then 1.6 ml of 15% NaOH was added followed by 4.8 ml of H2O. The solids were filtered to yield 1.5 g (83%) of 2-methyl-2-(1-methylpiperidin-4-yl)propan-1-ol as a pink oil.

Step 4

[00276] In a 100 ml round bottom flask, oxalic dichloride (440 mg, 3.47 mmol, 1.20 equiv.), dichloromethane (50 ml) was placed at -78°C placed in DMSO (684 mg, 8.75 mmol, 3.00 equiv.), 2-methyl-2-(1-methylpiperidin-4-yl)propan-1-ol (500 mg, 2.92 mmol, 1.00 equiv. ), TEA (1.48 g, 14.6 mmol, 5.00 equiv.). The resulting solution was stirred for 30 min. at -78°C. The resulting solution was allowed to react, with stirring, for an additional 2 h at 25°C. The reaction was then cooled abruptly with the addition of water. The resulting solution was extracted with dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 385 mg (88%) of 2-methyl-2-(1-methylpiperidin-4-yl)propanal as yellow oil.

Step 5

[00277] In a 100 ml round bottom flask, (R)- 3- (3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro- 1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-yl)-3-oxopropanenitrile (100 mg, 0.19 mmol, 1.00 equiv., 90%), dichloromethane (50 ml) , 2-methyl-2-(1-methylpiperidin-4-yl)propanal (108 mg, 0.57 mmol, 3.00 equiv.), TMSCl (115 mg, 1.01 mmol, 5.00 equiv., 95 %), pyrrolidine (75.8 mg, 1.01 mmol, 5.00 equiv., 95%). The resulting solution was stirred for 16 h at rt. The crude product was purified by Prep-HPLC with the following conditions (Column, Gemini-NX C18 AXAI packing, 21.2 x 150 mm 5 µm 11 nm; mobile phase, water with 0.05% TFA and ACN ( 20.0% ACN to 50.0% in 8 min); Detector, 254 nm. This resulted in 15.5 mg (12%) of (R)-2-(3-(4-amino-2). -oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(1 -methylpiperidin-4-yl)pent-2-enonitrile as a light yellow solid LC-MS m/z: 620.3 (M+1).

[00278] Synthesis of (R)-2-(3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine -1-yl)piperidine-1-carbonyl)-6-hydroxy-4-(2-hydroxyethyl)hex-2-enonitrile

Step 1

[00279] In a 250 ml 3-neck round bottom flask purged and maintained with an inert nitrogen atmosphere, HMPA (6.0 ml) and LDA (16.8 mmol) in dry THF (20 ml) at -78 °C was treated with acetonitrile (690 mg, 16.8 mmol). The solution was stirred for 30 min. and (2-bromoethoxy)(tert-butyl)dimethylsilane (3.4 g, 14.3 mmol) in THF (15 ml) was added dropwise. Stirring continued for 2 h, after which a second portion of LDA (16.8 mmol in 20 ml of THF) was added. The solution was stirred for 30 min. and (2-bromoethoxy)(tert-butyl)dimethylsilane (3.4 g, 14.3 mmol) in THF (15 ml) was added dropwise. The reaction was allowed to proceed for 2 h. Saturated aqueous NH4Cl was added and the mixture was allowed to reach room temperature. Diethyl ether was added, the phases were separated and the aqueous layer was extracted with diethyl ether. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated. Column chromatography [silica, petroleum ether] produced a colorless oil (3.2 g, 53%).

Step 2

[00280] In a 250 ml 3-neck round bottom flask purged and maintained with an inert nitrogen atmosphere, 4-[(tert-butyldimethylsilyl)oxy]-2-[2-[(tert-butyldimethylsilyl) was placed oxy]ethyl]butanenitrile (1 g, 2.80 mmol, 1.00 equiv.) in toluene (15 ml). DIBAL-H (1M) (3.36 ml, 1.20 equiv) was added at -78°C and the resulting solution was stirred for 1 h at -78°C in a liquid nitrogen bath. Water (0.7 ml) was added and the mixture was allowed to reach RT. Aqueous NaOH (0.7 ml, 4 M) was added and stirring continued for 15 min. Water (2.1 ml) was added and the suspension was stirred for 15 min. additional. The mixture was dried with Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column with PE/EA (20:1). This resulted in 900 mg (89%) of 4-[(tert-butyldimethylsilyl)oxy]-2-[2-[(tert-butyldimethylsilyl)oxy]ethyl]butanal as colorless oil.

Step 3

[00281] In an 8 ml vial, 3-[(3R)-3-[4-amino-2-oxo-3-(4-phenoxyphenyl)-1H,2H,3H-imidazo[4,5 -c]pyridin-1-yl]piperidin-1-yl]- 3- oxopropanenitrile (150 mg, 0.32 mmol, 1.00 equiv.), 4-[(tert-butyldimethylsilyl)oxy]-2-2- [(tert-butyldimethylsilyl)oxy]ethylbutanal (346 mg, 0.96 mmol, 3.00 equiv.), TMSCl (173 mg, 1.59 mmol, 5.00 equiv.), pyrrolidine (114 mg, 1 .61 mmol, 5.00 equiv.), dichloromethane (2 ml). The resulting solution was stirred for 3 h at rt. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane/methanol (30:1). This resulted in 120 mg (46%) of 2-[[(3R)-3-[4-amino-2-oxo-3-(4-phenoxyphenyl)-1H,2H,3H-imidazo[4,5-c ]pyridin-1-yl]piperidin-1-yl]carbonyl]-6-[(tert-butyldimethylsilyl)oxy]-4-[2-[(tert-butyldimethylsilyl)oxy]ethyl]hex-2-enonitrile as a solid yellow.

Step 4

[00282] In a 25 ml round bottom flask, 2- [[(3R)- 3-[4-amino-2-oxo-3-(4-phenoxyphenyl)-1H,2H,3H-imidazo was placed [4,5-c]pyridin-1-yl]piperidin-1-yl]carbonyl]-6-[(tert-butyldimethylsilyl)oxy]-4-[2-[(tert-butyldimethylsilyl)oxy]ethyl]hex- 2-enonitrile (120 mg, 0.15 mmol, 1.00 equiv.), trifluoroacetic acid (1 ml), dichloromethane (5 ml). The resulting solution was stirred for 2 h at rt. The reaction was then quenched with the addition of saturated sodium bicarbonate. The resulting solution was extracted with 3 x 20 ml of DCM/MeOH (10:1) and the organic layers combined. The resulting mixture was washed with saturated sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by Prep-TLC with DCM/MeOH (15:1). The crude product was purified by Prep-HPLC with the following conditions (Atlantis Prep T3 OBD Column, 19*150 mm 5 µm 10 nm; mobile phase, water with 0.1% FA and MeCN (20.0% MeCN up to 50.0% in 10 min.); Detector, 254 nm This resulted in 7.9 mg (9%) of (R)-2-(3-(4-amino-2-oxo-3-(4). -phenoxyphenyl)- 2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carbonyl)-6-hydroxy-4-(2-hydroxyethyl)hex- 2- enonitrile as a white solid. LC-MS m/z: 583.2 (M+1).

[00283] Synthesis of (R)-2-(3-(4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[ 4,5-c]pyridin-1-yl)piperidin-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enonitrile

Step 1

[00284] In a 250 ml round bottom flask purged and maintained with an O2 atmosphere, Cu(OAc)2 (6.96 g, 38.3 mmol, 1.00 equiv.), pyridine (15 .2 g, 192 mmol, 5.00 equiv.) and 4A molecular sieves (5 g) in dichloromethane (100 ml). The resulting solution was stirred for 30 min. and then 2,6-difluorophenol (5 g, 38.4 mmol, 1.00 equiv.) and (4-bromophenyl)boronic acid (15.4 g, 76.6 mmol, 2.00 equiv.) were added. The resulting solution was stirred overnight at rt. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column and eluted with petroleum ether. This resulted in 5.5 g (50%) of 2-(4-bromophenoxy)-1,3-difluorobenzene as yellow oil.

Step 2

[00285] In a 250 ml 3-neck round bottom flask purged and maintained with an inert nitrogen atmosphere, 2(4-bromophenoxy)-1,3-difluorobenzene (5.5 g, 19.3 mmol) was placed , 1.00 equiv.) in tetrahydrofuran (100 ml). A 2.5 M solution of nBuLi in hexane (11.6 ml, 1.50 equiv.) was added at -78°C and the resulting solution was stirred for 30 min. and then trimethyl borate (4.03 g, 38.8 mmol, 2.00 equiv.) was added. The reaction was allowed to warm to RT and the resulting solution was stirred for 3 h at RT. The reaction was then quenched with the addition of hydrogen chloride (2 M). The resulting solution was extracted with 3 x 150 ml of ether and the organic layers combined. The resulting mixture was washed with 1 x 200 ml of sodium chloride (saturated). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane/methanol (50:1). This resulted in 2.15 g (45%) of [4-(2,6-difluorophenoxy)phenyl]boronic acid as a brown solid.

Step 3

[00286] In a 100 ml round bottom flask purged and maintained with an O2 atmosphere, 3-(4-(((dimethylamino)methylene)amino)-2-oxo-2,3-di was placed (R,E)-tert-butyl-hydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (500 mg, 1.29 mmol, 1.00 equiv.), TEA (521 mg, 5.15 mmol, 4.00 equiv.), Cu(OAc)2 (117 mg, 0.64 mmol, 0.50 equiv), TEMPO (221 mg, 1.41 mmol, 1.10 equiv) and Ms(4A) (500 mg) in dichloromethane (50 ml). The resulting solution was stirred for 30 min. and then [4-(2,6-difluorophenoxy)phenyl]boronic acid (644 mg, 2.58 mmol, 2.00 equiv.) was added. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with dichloromethane/methanol (30:1). This resulted in 490 mg of 3-(4- (((dimethylamino)methylene)amino)-2-oxo-3-(4- (R,E)-tert-butyl phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate as a brown solid.

Step 4

[00287] To a solution of 3-(4-(((dimethylamino)methylene)amino)-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)piperidine-1-(R,E)-tert-butyl carboxylate (490 mg, 0.83 mmol, 1.00 equiv.) in 30 ml of dioxane were added 15 ml of chloride hydrogen (12 M). The resulting solution was stirred for 3 h at 85°C in an oil bath. The reaction was then cooled abruptly by adding sodium bicarbonate (sat.). The resulting solution was extracted with 3 x 100 ml of DCM/MeOH (10:1) and the organic layers combined. The resulting mixture was washed with 1 x 100 ml of sodium chloride (sat.). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 360 mg (100%) of 4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H,2H,3H-imidazo [4,5-c]pyridin-2-one as a brown solid.

Step 5

[00288] In a 50 ml round bottom flask, 4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H was placed ,2H,3H-imidazo[4,5-c]pyridin-2-one (360 mg, 0.82 mmol, 1.00 equiv.), 2-cyanoacetic acid (70 mg, 0.82 mmol, 1.00 equiv.), HATU (470 mg, 1.24 mmol, 1.50 equiv.), TEA (250 mg, 2.47 mmol, 3.00 equiv.), N,N-dimethylformamide (10 ml). The resulting solution was stirred for 2 h at rt. The resulting solution was extracted with dichloromethane and the organic layers combined. The resulting mixture was washed with 6 x 100 ml of water. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane/methanol (30:1). This resulted in 260 mg (63%) of (R)-3-(3-(4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-2-oxo-2,3-dihydro -1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-yl)-3-oxopropanenitrile as a brown solid.

[00289] Following the protocol in step 4 of Example 2 produced (R)-2-(3-(4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-2-oxo-2,3 -dihydro- 1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl) pent-2-enenitrile. LC-MS m/z: 699.2 (M+1) Example 8

[00290] Synthesis of (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[ 4,5-c]pyridin-1-yl)piperidin-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enonitrile

Step 1

[00291] In a 250 ml round bottom flask purged and maintained with an O2 atmosphere, Cu(OAc)2 (6.96 g, 38.3 mmol, 1.00 equiv.), pyridine (15 .2 g, 192 mmol, 5.00 equiv.) and 4A molecular sieves (5 g) in dichloromethane (100 ml). The resulting solution was stirred for 30 min. and then 2,3-difluorophenol (5 g, 38.43 mmol, 1.00 equiv.) and (4-bromophenyl)boronic acid (15.4 g, 76.6 mmol, 2.00 equiv.) were added. The resulting solution was stirred overnight at rt. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with petroleum ether. This resulted in 3.17 g (29%) of 1-(4-bromophenoxy)-2,3-difluorobenzene as colorless oil.

Step 2

[00292] In a 250 ml 3-neck round bottom flask purged and maintained with an inert nitrogen atmosphere, 1(4-bromophenoxy)-2,3-difluorobenzene (3.17 g, 11.12 mmol) was placed , 1.00 equiv.) in tetrahydrofuran (100 ml). A 2.5 M solution of nBuLi (6.7 ml, 1.50 equiv.) was added at -78°C and the resulting solution was stirred for 30 min. and then trimethyl borate (2.32 g, 22.3 mmol, 2.00 equiv.) was added. The resulting solution was stirred for 3 h at rt. The reaction was then quenched with the addition of HCl (2 M). The resulting solution was extracted with 3 x 150 ml of ether and the organic layers combined. The resulting mixture was washed with 1 x 200 ml of sodium chloride (sat'd). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane/methanol (50:1). This resulted in 1 g (36%) of [4-(2,3-difluorophenoxy)phenyl]boronic acid as a white solid.

[00293] Following the protocols described in Example 2, but using [4-(2,3-difluorophenoxy)phenyl]boronic acid produced the title compound. LC-MS m/z: 699.2 (M+1).

Example 9

[00294] Synthesis of (R)-2-(3-(4-amino-3-(3-fluoro-4-phenoxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4.5 -c]pyridin-1-yl)piperidin-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enonitrile

[00295] Following the protocols described in Example 7, but with the use of (3-fluoro-4-phenoxyphenyl) boronic acid produced (the title compound with the use of the methods described in Example 2. LC-MS m/z : 681.4(M+1).

[00296] Synthesis of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4.5 -c]pyridin-1-yl)piperidin-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enonitrile

[00297] Following the protocols described in Example 7, but with the use of (2-fluoro-4-phenoxyphenyl) boronic acid (prepared as described in international application PCT 2012158764, November 22, 201, produced the title compound. LC -MS m/z: 681.2 (M+1). Example 11 Synthesis of (S)-2-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3- dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl )pent-2-enonitrile

Step 1

[00298] To a solution of 2,4-dichloro-3-nitropyridine (5 g, 25.9 mmol) in DMF (50 ml) were added Et3N (5.2 g, 51.8 mmol) and 2- (aminomethyl )(S)-tert-butylpyrrolidine-1-carboxylate (5.4 g, 27.2 mmol). The resulting mixture was stirred at rt overnight, then filtered and the filtrate was concentrated to dryness. The residue was treated with water (150 ml) and extracted with DCM (30 ml x 3). The combined organic phase was washed with brine (40 ml), dried with Na2SO4 and concentrated to dryness. The resulting 6.9 g of (S)-tert-butyl 2-(((2-chloro-3-nitropyridin-4-yl)amino)methyl)pyrrolidine-1-carboxylate were used in the next step without further purification.

Step 2

[00299] To a solution of (S)-tert-butyl 2-(((2-chloro-3-nitropyridin-4-yl)amino)methyl)pyrrolidine-1-carboxylate (6.9 g, 19.4 mmol) in i-PrOH (100 ml) bis(4-methoxybenzyl)amine (7.5 g, 29.1 mmol) and TEA (5.9 g, 58.2 mmol) were added. The mixture was refluxed overnight. After cooling to rt, the mixture was concentrated to dryness. The residue was purified by silica gel chromatography (eluent: petroleum ether / ethyl acetate 5:1 to 2:1) to generate 4.4 g of 2-(((2-(bis(4-methoxybenzyl) (S)-tert-butylamino)-3-nitropyridin-4-yl)amino)methyl)pyrrolidine-1-carboxylate as a light yellow solid.

Step 3

[00300] To a solution of 2-(((2-(bis(4-methoxybenzyl)amino)-3-nitropyridin-4-yl)amino)methyl)pyrrolidine-1-carboxylate of (S)-tert- butyl (4.4 g, 7.6 mmol) in EtOH (100 ml) were added NH4Cl (2.0 g, 38.1 mmol) and H2O (10 ml), followed by batch addition of Zn dust (2 .5 g, 38.1 mmol) with stirring. The resulting mixture was refluxed for 3 h before filtration through celite. The filtrate was concentrated to give a residue which was redissolved in water (50 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic phase was washed with brine (400 ml), dried with Na2SO4, concentrated to give 2.9 g of 2-(((3-amino-2-(bis(4-methoxybenzyl)amino)pyridin-4-yl (S)-tert-butyl)amino)methyl)pyrrolidine-1-carboxylate as a light yellow solid that was used directly in the next step.

Step 4

[00301] To a solution of 2-(((3-amino-2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)amino)methyl)pyrrolidine-1-carboxylate of (S)- tert - butyl (2.9 g, 5.3 mmol) in anhydrous acetonitrile (30 ml) CDI (2.6 g, 15.9 mmol) was added in portions. The resulting mixture was refluxed for 2 h before concentration to give a residue which was purified by silica gel chromatography with PE : EtOAc = 2 : 1 to yield 2.6 g of 2-((4-(bis(4- (S)-tert-butyl methoxybenzyl)amino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyrrolidine-1-carboxylate as a light yellow solid that was used directly in the next step.

Step 5

[00302] To a solution of 2-((4-(bis(4-methoxybenzyl)amino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl (S)-tert-butyl)methyl)pyrrolidine-1-carboxylate (7 g, 12.2 mmol) in anhydrous DCM (100 ml) was added Cu(OAc)2 (2.2 g, 12.4 mmol), TEMPO (2.1 g, 13.4 mmol), molecular sieves 4A (20 g) and Et3N (20 g, 196 mmol), followed by the addition in portions of 4-phenoxyphenylboronic acid (10.5 g, 48 .9 mmol) upon stirring. The mixture was stirred at rt for 78 h under O2 atmosphere. The solvent was concentrated and the residue was purified by silica gel column with PE:EtOAc = 2:1 to yield 2-((4-(bis(4-methoxybenzyl)amino)-2-oxo-3-(4- (S)-tert-butyl phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyrrolidine-1-carboxylate (3.2 g, 36% ) as a light yellow solid.

Step 5

[00303] 2-((4-(bis(4-methoxybenzyl)amino)-2-oxo-3-(4-phenoxyphenyl)- 2,3-dihydro-1H-imidazo[4,5-c] (S)-tert-Butyl pyridin-1-yl)methyl)pyrrolidine-1-carboxylate (2 g, 2.7 mmol) was dissolved in TFA (10 ml) and stirred at rt overnight. The reaction was concentrated and the residue was diluted with H2O (50 ml) and extracted with EtOAc. The aqueous phase was adjusted to pH = 13 with aqueous NaOH and extracted with EtOAc (2 x 100 ml) and the organic phase was concentrated to generate 870 mg of (S)-4-amino-3-(4-phenoxyphenyl)-1 - (pyrrolidin-2-ylmethyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one which was used in the next step without further purification.

Step 6

[00304] To a solution of (S)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazo[4,5-c]pyridin-2(3H)- ona (200 mg, 0.5 mmol) in DMF (10 ml) at 0°C were added Et3N (150 mg, 1.5 mmol), 2-cyanoacetic acid (47 mg, 0.55 mmol) and HATU (284 mg, 0.75 mmol). After stirring for 30 min. at 0 °C, the reaction was poured into water (20 ml) and extracted with EtOAc (30 ml twice), the organic phase was concentrated and the residue was purified by chromatography on silica gel eluting with PE: EtOAc = 1 : 1 to produce 70 mg of (S)-3-(2- ((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile as a white solid.

Step 7

[00305] To a solution of (S)-3-(2-((4-amino-2-oxo-3-(4-phenoxyphenyl)- 2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)methyl)pyrrolidin-1-yl)-3- oxopropanenitrile (80 mg, 0.17 mmol), 2-methyl-2-(4-(oxetan-3-yl)piperazin-1- il)propanal (72 mg, 0.34 mmol) and pyrrolidine (120 mg, 1.7 mmol) in DCM (2 ml) at room temperature was slowly added chloro(trimethyl)silane (69 mg, 0.68 mmol) by drip. After 30 min, the reaction was diluted with DCM (20 ml) and washed with aq. (20 ml). The organic layer was dried with anhydrous Na2SO4, filtered and concentrated to give a crude residue, which was purified by Prep-TLC to yield (S)-2-(2-((4-amino-2-oxo-3-(4 -phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl- 4-(4-(oxetan-3 -yl)piperazin-1-yl)pent-2-enonitrile as white solid (10 mg, 9%). LC-MS m/z: 662.8 (M+1). Example 12

[00306] Synthesis of (S)-1-((1-acryloylpyrrolidin-2-yl)methyl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2( 3H)-one

[00307] To a solution of (S)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazo[4,5-c]pyridin-2(3H)- ona (200 mg, 0.17 mmol) and DIPEA (129 mg, 1.0 mmol) in DCM (2 ml) were slowly added acryloyl chloride (45 mg, 0.50 mmol) dropwise at 0 °C. After 30 min, the reaction was diluted with DCM (20 ml) and washed with aq. (20 ml). The organic layer was dried with anhydrous Na2SO4, filtered and concentrated to give a crude residue which was purified by Prep-TLC to yield 70 mg of (S)-1-((1-acryloylpyrrolidin-2-yl)methyl)-4- amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one as white solid. LC-MS m/z: 455.9 (M+1). Example 13

[00308] Synthesis of (S)-4-amino-1-((1-(but-2-inoyl)pyrrolidin-2-yl)methyl)-3-(4-phenoxyphenyl)-1H-imidazo[4.5 -c]pyridin-2(3H)-one

[00309] To a solution of (S)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-2-ylmethyl)-1H-imidazo[4,5-c]pyridin-2(3H)- ona (200 mg, 0.17 mmol) and DIPEA (129 mg, 1.0 mmol) in DCM (10 ml) but-2-inoyl chloride (50 mg, 0.50 mmol) was slowly added dropwise at 0 °C. 0.5 h later, the reaction was diluted with DCM (20 ml) and washed with aq. (20 ml). The organic layer was dried with anhydrous Na2SO4, filtered and concentrated to give a crude residue which was purified by Prep-TLC to yield 50 mg of (S)-4-amino-1-((1-(but-2-inoyl) pyrrolidin-2-yl)methyl)-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one as white solid. LC-MS m/z: 467.9 (M+1).

Example 14

[00310] Synthesis of (R)-4-amino-1-(1-(2-fluoroacryloyl)piperidin-3-yl)- 3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin- 2(3H)-one

[00311] To a solution of (R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)- one (154 mg, 0.38 mmol, 1.0 equiv.) in 2 ml of DMF was added diisopropylethylamine (0.2 ml, 1.1 mmol). 2-Fluoroprop-2-enoic acid (51.8 mg, 0.580 mmol) was added followed by HATU (97 mg, 1.1 mmol). After stirring for 1 h, the material was purified directly by Prep HPLC (Shimadzu, C18 column; mobile phase, water with 0.05% TFA and ACN (10% to 90% for 20 min.). The purified fractions were diluted with saturated sodium bicarbonate and DCM and the layers separated. The organic layer was dried with MgSO4, filtered and concentrated. It was dissolved in a minimum of water and acetonitrile and lyophilized to obtain 65 mg of (R)-4-amino. -1-(1-(2-fluoroacryloyl)piperidin-3-yl)-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one as a white solid LC. - MS m/z: 474.1 (M+1).

Biological Examples Example 1 BTK enzyme activity assay

[00312] A Caliper-based kinase assay (Caliper Life Sciences, Hopkinton, MA) was used to measure the inhibition of BTK kinase activity of a compound of the present disclosure. Serial dilutions of test compounds were incubated with human recombinant BTK (0.5 nM), ATP (16 μM), and a phosphoacceptor peptide substrate FAM-GEEPLYWSFPAKKK-NH2 (1 μM) at room temperature for 3 h. The reaction was then terminated with EDTA, final concentration of 20 mM, and the phosphorylated reaction product was quantified on a Caliper Tabletop Profiling System (Caliper LabChip 3000). Percent inhibition was calculated for each compound dilution and the concentration that produced 50% inhibition was calculated. This value is presented as the IC50. IC50s for certain compounds of the disclosure are provided below.

Example 2 Measurement of BTK occupancy in human peripheral blood mononuclear cells

[00313] The potency of compounds for inhibiting BTK activity can be assessed by binding compounds to the target in human peripheral blood mononuclear cells (PBMCs) that contain BTK. The degree of BTK occupancy is measured after treating cells with the compounds and detecting unoccupied BTK through the occupancy bond of (R,E)-N-(2-(4-(4-(3-(4 -amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-oxobut-2-en-1-yl) piperazin-1-yl)ethyl)-3-(5,5-difluoro-7,9-dimethyl-5H-4H,5H-dipyrrolo[1,2-c:2',1'- f][1,3 ,2]diazaborinin-2-yl)propanamide as the probe.

[00314] Briefly, human blood was obtained from healthy volunteers and distributed at 5 ml each into 9 separate 15 ml tubes. Serial dilutions of the compound being tested for potency were added so that final concentrations started at 10 μM and were serially diluted 3 times for a total of 9 serial dilutions. The compounds were allowed to interact with the blood for 1 h. PBMC were then isolated from each tube using Ficoll. The isolated PBMCs were then resuspended in 1 ml of RPMI1640 medium and the occupancy probe was added at a concentration of 1 μM to each sample for 1 h. PBMCs were washed, lysed and evaluated by SDS-PAGE. In-gel fluorescence was used to measure the extent of inhibition of BTK occupancy probe binding to BTK. Subsequently, total BTK in each sample was determined by Western blotting with a BTK antibody (BD Bioscience catalog no. 611117).

[00315] This assay was also modified to measure the durability of BTK binding in CMSPs. Here, a 2 μM concentration of compound was added to human whole blood for 1 h. PBMCs were isolated using Ficoll, washed and resuspended in medium for 4 h or 18 h at 37°C. The occupancy probe was added at a concentration of 1 μM to each sample for 1 h, and BTK occupancy was then determined in the same manner as described above.

Example 3 Blocking CD69 expression in human whole blood samples

[00316] B cell receptor activation leads to BTK activity, calcium mobilization and increased B cell activation (see Honigberg L.A., et. al., Proc Natl Acad Sci U S A. 107:13075-80. 2010) . BTK inhibitors have been shown to block B cell activation as measured by CD69 expression (see Karp, R., et. al., "Inhibition of BTK with AVL-292 Translates to Protective Activity in Animal Models of Rheumatoid Arthritis." . Inflammation Research Association Meeting, September, 2010). CD69 was expressed following B cell activation as a measure of BTK activity in whole blood. Aliquots of whole blood were pre-incubated with serial dilutions of test compound for 30 min, followed by activation with anti-IgM (goat Fab'2, 50 μg/ml). Samples were incubated overnight at 37°C and then stained with PE-labeled anti-CD20 and APC-labeled anti-CD69 (BD Pharmingen) for 30 min. according to the manufacturer's directions. Whole blood was then lysed and cells selected for CD20 expression were quantified for CD69 expression by FACS. Percent inhibition was calculated based on a DMSO control for no inhibition and plotted as a function of test compound concentration from which an IC50 value was calculated.

Example 4 Inhibition of mouse collagen-induced arthritis

[00317] Murine collagen-induced arthritis inhibition (mCIA) is a standard animal disease model for rheumatoid arthritis. Previous studies have demonstrated that BTK inhibition is effective in blocking mCIA (see Honigberg L.A., et. al., Proc Natl Acad Sci U S A. 107:13075 to 13080. 2010). Starting on day 0, DBA/1 mice were injected with an emulsion of Type II collagen in Complete Freund's Adjuvant. The mice are boosted 21 days later to synchronize the development of the disease. After mild disease develops, the animals are enrolled in the study and randomized. Dosage is oral, Q.D. typically for 11 days with the test compound or dexamethasone (0.2 mg/kg) as a control. One group receives the vehicle alone. The clinical score (0 to 4) is based on the extent of swelling and severity of arthritis. Scores from all four paws are added for a maximum score of 16. Anti-collagen antibodies and total Ig are measured for each animal by Elisa at the end of the study (Bolder BioPath, Boulder, CO).

Example 5

[00318] Recovery of kinase activity upon dialysis to evaluate irreversible versus reversible covalent binding

[00319] A pharmaceutically acceptable compound and/or salt of the present disclosure in a concentration 10 times greater than its IC50 value is added to a protein kinase solution (5 nM) in a buffer containing 20 mM Hepes [ pH 7.5], 5 mM MgCl2, 0.01% Triton X-100 and 1 mM dithiothreitol. After 60 min. at 22°C, reactions were transferred to a dialysis cassette (0.1 to 0.5 ml Slide-A-Lyzer, 10 kDa PMC, Pierce) and dialyzed against 1 l of buffer (20 mM Hepes [pH 7.5], 5 mM MgCl2, 0.01% Triton X-100 and 1 mM dithiothreitol) at 22 °C. The dialysis buffer is changed twice a day until the end of the experiment. Aliquots are removed from the dialysis cassettes every 24 hours and analyzed for protein kinase activity. Kinase activity for each sample is normalized to the DMSO control for that time point and expressed as the mean ± SD. It will be observed that kinase activity will return on dialysis for a compound of the present disclosure, in which Ra is cyano and will not return for a compound of the present disclosure in which Ra is hydrogen or fluorine.

Example 6 Mass spectrum analysis

[00320] A protein kinase that is inhibited by a compound and/or a pharmaceutically acceptable salt of the present disclosure can be subjected to mass spectrum analysis to evaluate the formation of permanent and irreversible covalent adducts. Analytical methods suitable for examining intact total protein or peptide fragments generated under tryptic protein kinase cleavage are generally known in the art (see Lipton, Mary S., Ljiljana, Pasa-Tolic, Eds. Mass Spectrometry of Proteins and Peptides , Methods and Protocols, Second edition Humana Press 2009). Such methods identify permanent and irreversible covalent protein adducts by observing a mass peak that corresponds to the mass of a control sample plus the mass of an irreversible adduct. Two such methods are described below.

[00321] Mass spectrum analysis of intact whole kinase Method:

[00322] A protein kinase (5 μM) (such as BTK) is incubated with a compound of the present disclosure (25 μM, 5 equiv.) for 1 h at room temperature in buffer (20 mM Hepes [pH 8.0], 100 mM NaCl, 10 mM MgCl2). A control sample is also prepared which does not have a compound of the present disclosure. The reaction is stopped by adding an equal volume of 0.4% formic acid, and the samples are analyzed by liquid chromatography (Microtrap C18 Protein column [Michrom Bioresources], 5% MeCN, 0.4% formic acid. 2%, 0.25 ml/min.; eluted with 95% MeCN, 0.2% formic acid) and in-line ESI mass spectrometry (LCT Premier, Waters). The molecular masses of the protein kinase and any adducts can be determined with the MassLynx deconvolution software (see patent application no. WO2014 011900 and PCT/US2010/048916).

[00323] Results: High-resolution intact mass spectrometry analysis of protein kinases, such as BTK, that are inhibited by a compound of the present disclosure in which Ra is cyan will reveal a spectrum similar to the kinase in the absence of inhibitor (e.g. , control sample). There will be no formation of a new peak in the mass spectrum that corresponds to the molecular mass of the kinase plus the molecular mass of the compound. Conversely, high-resolution intact mass spectrometry analysis of a protein kinase that is inhibited by a compound of the present disclosure in which Ra is hydrogen or fluorine will reveal the formation of a new peak (e.g., a not present in the control sample without inhibitor) in the mass spectrum corresponding to the molecular mass of the kinase plus the molecular mass of the irreversible kinase inhibitor. Based on this experiment, an irreversible protein adduct will be evident to one skilled in the art.

[00324] Tryptic kinase digestion mass spectrum analysis Method:

[00325] A protein (10 to 100 pmols) is incubated with a compound and/or a pharmaceutically acceptable salt of the present disclosure (100 to 1,000 pmols, 10 equiv.) for 3 h before tryptic digestion. Iodoacetamide can be used as the alkylating agent after incubating the compound. A control sample is also prepared that does not utilize the compound and/or a pharmaceutically acceptable salt of the present disclosure. For tryptic digestions, a 1 μl (3.3 pmols) aliquot is diluted with 10 μl of 0.1% TFA prior to Zip Tipping micro C18 directly onto the MALDI target using alpha cyano-4-hydroxy cinnamic acid as the desorption matrix (5 mg/mol in 0.1% TFA:Acetonitrile 50:50) or Sinapinic acid as the desorption matrix (10 mg/mol in 0.1% TFA:Acetonitrile 50:50 ) (see document under no. PCT/US2010/048916).

[00326] Results: High resolution mass spectrometry analysis of the tryptic fragments of a kinase that is inhibited by a compound and/or pharmaceutically acceptable salt of the present disclosure in which Ra is cyano, will reveal a spectrum similar to the kinase in the absence of inhibitor (e.g. control sample). There will be no evidence of any modified peptides that are not present in the control sample. Based on this experiment, no permanent and irreversible protein adducts will be apparent to one skilled in the art.

[00327] In contrast, high-resolution mass spectrometry analysis of tryptic fragments of a kinase that is inhibited by compounds of the disclosure in which Ra is hydrogen or fluorine, will reveal a spectrum that contains modified peptides that are not present. in the control sample. Based on this experiment, irreversible protein adducts will be evident to one skilled in the art. Additionally, based on the exact mass and MS-MS fragmentation pattern, the sequence of the modified peptide can be verified by defining the cysteine residue that is the site of covalent modification.

Example 7 Determination of drug-kinase residence time

[00328] The following is a protocol that can be used to distinguish whether a compound exhibits a slow or no dissociation rate from BTK, as would typically occur if a covalent bond were formed between the compound and the target. The readout for slow dissociation is the ability of the compound of interest to block the binding of a high-affinity fluorescent tracer molecule to the active site of the kinase, as detected using time-resolved fluorescence resonance energy transfer (TR-FRET, from English "time-resolved fluorescence resonance energy transfer"). The experiment was conducted in a buffer consisting of 50 mM Hepes pH 7.5, 10 mM MgCl2, 0.01% Triton X-100 and 1 mM EGTA.

[00329] The first step of the procedure was the incubation of BTK at 500 nM (Invitrogen catalog no. PV3587) with 1.5 μM of a compound of the present disclosure for 30 min. in a volume of 10 μl. The mixture was then diluted 5-fold by adding 40 μl of buffer. A 10 μl volume of the diluted kinase/compound solution was then added to one well of a small volume 384-well plate (such as Greiner catalog no. 784076). In order to prove the reversibility of the kinase-compound binding interaction, a competition solution containing a high-affinity fluorescent tracer and an antibody coupled to Europium was prepared. For BTK, the competition solution contained 1.5 μM Tracer 178 (Invitrogen catalog no. PV5593), which is a patented high-affinity ligand for BTK coupled to the AlexaFluor 647 fluorophore. contained 80 nM of a Europium-coupled Anti-polyhistidine antibody (Invitrogen catalog no. PV5596) that was designed to bind to the polyhistidine purification tag on BTK.

[00330] After adding 10 μl of the competition solution to the Greiner plate, the mixture was incubated for an hour or more to allow time for dissociation of non-covalent inhibitors and binding of the high-affinity tracer. Covalent and slowly dissociating inhibitors are expected to block tracer binding while non-covalent inhibitors that dissociate rapidly do not. Tracer binding to BTK is detected using TR-FRET between the Europium moiety of the Anti-histidine antibody and the AlexaFluor 647 group of Tracer 178. Binding was assessed using a Perkin Elmer Envision instrument (Model 2101) equipped with filters and mirrors compatible with LANCE-type TR-FRET experiments. Data were represented graphically as the percentage of signal obtained in the absence of the competing compound. The background signal was obtained by omitting BTK from the reaction. If the compound is an irreversible covalent inhibitor, the tracer will be completely blocked from binding to the target throughout the course of the experiment. If the compound is a reversible covalent inhibitor, the tracer will bind to the target when the compound dissociates from the target. For durability measurements, the occupancy range for the compounds revealed at 1, 6, and 24 h of elimination is shown below.

Example 8 Bond Reversibility

[00331] The following approach was developed to determine whether a compound forms reversible covalent or irreversible covalent bonds with its targets. Reactions are prepared with the protein target at a higher concentration than the compounds of interest. Both irreversible and reversible covalent compounds bound to the target and were depleted in solution. The reactions are then treated with perturbations including both denaturation with 5 M guanidine hydrochloride and trypsin digestion, disrupting proper folding of the target. It will be found that the perturbation returned the reversible covalent compounds to solution due to dissociation from the target while the irreversible covalent compounds remained bound to the target. The concentration of the compound in solution is evaluated both before and after perturbation using high-resolution liquid chromatography (HPLC) coupled to tandem mass spectrometry. Using this technology, it can be demonstrated that the irreversible covalent compound of the disclosure in which Ra is hydrogen or fluorine is depleted in solution in both the native and perturbed state, whereas the compounds disclosed herein in which Ra is cyano are depleted in the folded state, but returned to solution after disturbing the target, showing that such compounds form reversible covalent bonds.

Formulation Examples

[00332] The following are representative pharmaceutical formulations containing a compound of Formula (I).

Tablet Formulation

[00333] The following ingredients are mixed intimately and compressed into single scored tablets.

Capsule Formulation

[00334] The following ingredients are mixed intimately and loaded into a hard-shelled gelatin capsule.

Injectable Formulation

[00335] The compound of disclosure (e.g., compound 1) in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. up to at least 20 mg/ml.

[00336] The previous description has been described in some detail by way of illustration and example, for purposes of clarity and understanding. Therefore, it should be understood that the above description is intended to be illustrative and not restrictive. The scope of the disclosure must therefore be determined not with reference to the above description, but must instead be determined with reference to the claims appended below, together with the full scope of equivalents to which such claims relate.

Claims (5)

1. Compound, characterized by the fact that it is selected from the group consisting of: and/or a pharmaceutically acceptable salt thereof. 2. Pharmaceutical composition, characterized by the fact that it comprises a compound and/or a pharmaceutically acceptable salt as defined in claim 1 and a pharmaceutically acceptable excipient. 3. Use of a compound and/or a pharmaceutically acceptable salt thereof as defined in claim 1, characterized by the fact that it is in the preparation of a composition/medicine for the treatment of a disease or cancer in a mammal in need thereof. 4. Use according to claim 4, characterized by the fact that: (i) the disease is necrotizing hemorrhagic leukoencephalitis, acute disseminated encephalomyelitis, autoimmune inner ear disease (AIED), autoimmune retinopathy, axonal and neuronal neuropathies, polyneuropathy chronic inflammatory demyelinating disease (CIDP), demyelinating neuropathies, Devic's disease (neuromyelitis optica), experimental allergic encephalomyelitis, giant cell arteritis (temporal arteritis), Guillain-Barre syndrome, Lambert-Eaton syndrome, chronic Meniere's disease, myasthenia gravis , neuromyotonia, opsoclonus-myoclonus syndrome, optic neuritis, paraneoplastic cerebellar degeneration, peripheral neuropathy, perivenous encephalomyelitis, restless legs syndrome, stiff person syndrome, sympathetic ophthalmia, Takayasu arteritis, temporal teritis/giant cell arteritis, transverse myelitis, multiple sclerosis, dysautonomia, age-related macular degeneration (wet and dry), cornea transplant, meningitis, vasculitis, or systemic lupus erythematosus (SLE); and/or (ii) the disease is rheumatoid arthritis, psoriatic arthritis, lupus, uveitis, myasthenia gravis, autoimmune hemolytic anemia, Wegener's granulomatosis, Sjogren's syndrome, Sjogren's dry eye, non-Sjogren's dry eye, psoriasis, pemphigus, urticaria , or asthma; and/or (iii) the cancer is diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma (CLL), chronic lymphocytic leukemia, prolymphocytic B-cell leukemia, small lymphocytic lymphoma (SLL), multiple myeloma, non-Hodgkin's lymphoma B-cell lymphoma, lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma , mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, or lymphomatoid granulomatosis. 5. Use according to claim 3 or 4, characterized in that the compound and/or a pharmaceutically acceptable salt thereof is used in combination with one or more anti-cancer or anti-inflammatory agents, wherein: (i ) the anticancer agent is a pro-apoptotic agent including, but not limited to, gossifol, genasenso, polyphenol E, chlorofusin, all-trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'- deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (GleevecTM), geldanamycin, 17-N- Allylamino-17- Demethoxygeldanamycin (17-AAG) , flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, or TaxolTM; and/or (ii) the anticancer agent is an inhibitor of mitogen-activated protein kinase signaling, including, but not limited to, U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituxan); (iii) the anticancer agent is Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, Acivicin; aclarubicin; acodazole hydrochloride; acronin; adozelesin; aldesleukin; altretamine; ambomycin; amethantron acetate; aminoglutethimide; ansacrine; anastrozole; anthramycin; asparaginase; asperline; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; sodium brequinar; bropyrimine; busulfan; cactinomycin; calusterone; characemid; carbetimer; carboplatin; carmustine; carubicin hydrochloride; - carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; chrysnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; empromate; epipropidine; epirubicin hydrochloride; erbulozole; esorrubicin hydrochloride; estramustine; estramustine sodium phosphate; ethanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabin; fenretinide; floxuridine; fludarabine phosphate; fluororouracil; flurocitabine; phosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide-; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; alpha-n1 interferon; alpha-n3 interferon; interferon beta-1a; Interferon gamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitochromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxysuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosphamide; pipobroman; poposulfan; pyroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porphyromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprin; rogletimide; safingol; safingol hydrochloride; semustina; syntrazene; sodium sparfosate; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; sodium tecogalan; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; thiazofurin; 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; vinepidine sulfate; vinglicinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride; and/or (iv) the anticancer agent is 20-epi-1, 25 dihydroxy vitamin D3; 5-ethynyluracil; abiraterone; aclarrubicin; acylfulvene; adecipenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; anrubicin; ansacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; G antagonist; antarelix; antidorsalization morphogenetic protein-1; antiandrogen prostate carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-aletin; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafida; bistratene A; bizelesin; breflate; bropyrimine; budotitan; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canaripox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; MEAT 700; cartilage-derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis- porphyrin; cladribine; clomiphene analogues; clotrimazole; colismycin A; colimycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; chrysnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentantraquinones; cycloplatam; cypemycin; cytarabine octophosphate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexiphosphamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselene; ecomustina; edelfosine; edrecolomab; eflomitin; element; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; ethanidazole; etoposide phosphate; exemestane; fadrozole; fazarabin; fenretinide; filgrastim; fmasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; gallocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfan; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifen; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulating peptides; insulin-like growth factor 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplatt; irsogladine; isobengazole; iso-homohalychondrin B; itasetron; jasplaquinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibitory factor; leukocyte interferon alpha; leuprolide+estrogen+progesterone; leuprorelin; Levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lysoclinamide 7; lobaplatin; lumbricin; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysophilin; lytic peptides; maytansine; mannostatin A; marimastate; masoprocol; maspine; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double-stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafida; mitotoxin-saporin fibroblast growth factor; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotropin; monophosphoryl lipid A+ left myobacterium cell wall; mopidamol; multidrug resistance gene inhibitor; multiple tumor suppressor-based therapy 1; mustard anticancer agent; micaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavine; nafterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric acid modulators; nitroxide antioxidant; nitrulin; 06- benzylguanine; octreotide; oquicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; Pazeliptin; pegaspargase; peldesine; sodium pentosan polysulfate; pentostatin; pentrozole; perflubrone; perfosphamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pyrarubicin; pyritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porphyromycin; prednisone; propyl bis-acridone; prostaglandin 12; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; glitter; pyrazoloacridine; pyridoxylated hemoglobin and polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; farnesyl ras protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; demethylated reteliptin; rhenium etidronate Re 186; rhizoxin; ribozymes; retinamide R.sub.11; rogletimide; roituchin; ruptured; roquinimex; rubiginone B1; ruboxyl; safingol; saintopine; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustina; senescence derivative 1; sense oligonucleotide; signal transduction inhibitors; transduction signal modulators; single-chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermine; sparphosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitors; stipiamide; stromelysin inhibitors; sulfosine; superactive vasoactive intestinal peptide antagonist; suradist; suramin; swainsonine; synthetic glycosaminoglycans; talimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; taliblastin; thiocoralin; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; timotrinan; thyroid-stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosterea; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; candlelight; veramine; greens; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin estimamer; and/or (v) the anticancer agent is selected from alkylating agents, antimetabolites, natural products or hormones, e.g., nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan ), nitrosoureas (e.g. carmustine, lomusitine, etc.), or triazenes (decarbazine, etc.); and/or (vi) the anti-inflammatory agent is selected from salicylates, arylalkanoic acids, 2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, or sulfonanilides.