Compounds and compositions for modulating EGFR mutant kinase activities

Description

FIELD OF THE INVENTION

[0001] The present invention relates to novel chemical compounds and pharmaceutically acceptable compositions thereof which display inhibition activity against certain mutated forms of EGFR.BACKGROUND OF THE INVENTION

[0002] Protein kinases catalyze the transfer of the terminal phosphate from ATP or GTP to the hydroxyl group of tyrosine, serine and / or threonine residues of proteins. Protein kinases are categorized into families by the substrates they phosphorylate, for example, protein tyrosine kinases (PTK), and protein serine / threonine kinases. Phosphorylation via protein kinase(s) results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location or association with other proteins. Protein kinases play vital role in variety of cellular processes; cell proliferation, cell survival, metabolism, carbohydrate utilization, protein synthesis, angiogenesis, cell growth and immune response.

[0003] Misregulation of the protein kinases has been implicated in numerous diseases and disorders such as central nervous system disorders (e.g., Alzheimer's disease), inflammatory and autoimmune disorders (e.g., asthma, rheumatoid arthritis, Crohn's disease, and inflammatory bowel syndrome, and psoriasis), bone diseases (e.g., osteoporosis), metabolic disorders (e.g., diabetes), blood vessel proliferative disorders, ocular diseases, cardiovascular disease, cancer, restenosis, pain sensation, transplant rejection and infectious diseases.

[0004] Among them, overexpression and misregulation of EGFR is commonly found in breast, lung, pancreas, head and neck, as well as bladder tumors. EGFR is a transmembrane protein tyrosine kinase member of the erbB receptor family. Upon binding of a growth factor ligand such as epidermal growth factor (EGF), the receptor can dimerize with EGFR or with another family member such as erbB2 (HER2), erbB3 (HER3) and erbB4 (HER4). The dimerization of erbB receptors leads to the phosphorylation of key tyrosine residues in the intracellular domain and sequentially to stimulation of numerous intracellular signal transduction pathways involved in cell proliferation and survival. Misregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor survival and has been described in many human cancers such as lung and breast.

[0005] Therefore, the erbB family is a rational target for anticancer drug development and a number of compounds targeting EGFR or erbB2 are now clinically available, including gefitinib (IRESSA ™< ) and erlotinib (TARCEVA ™< ), the first generation inhibitor. It was reported that the most common EGFR activating mutations, L858R and del E746-A750 were sensitive to treatment of gefitinib or erlotinib but ultimately acquired resistance to therapy with gefitinib or erlotinib arises predominantly by mutation of the gatekeeper residue T790M, which is detected in approximately half of clinically resistant patients, resulting in double mutants, L858R / T790M and del E746-A750 / T790M.

[0006] Biological and clinical importance of EGFR mutants has been recognized in the field and several second generation drugs such as BIBW2992 (Afatinib), HKI-272 and PF0299804 are in development and effective against the T790M resistance mutation but show concurrent strong inhibition of wildtype (WT) EGFR, which causes severe adverse effect. Therefore, a strong need still exists for compounds which potently inhibit EGFR single and double mutants as well as are selective over WT EGFR to provide an effective and safe clinical therapy for the diseases associated with or mediated by EGFR mutants.

[0007] The US patent US2010029610 discloses EGFR kinase inhibitors based on substituted pyrimidines.

[0008] Another example of misregulation of the protein kinases that has been implicated in numerous diseases and disorders is Janus kinase (JAK) 3. In contrast to the relatively ubiquitous expression of Janus family member, JAK1, JAK2 and Tyk2, JAK3 is predominantly expressed in hematopoietic lineage such as NK cells, T cells and B cells and intestinal epithelial cells. Targeting JAK3 could be a useful strategy to generate a novel class of immunosuppressant drugs. Due to primary expression in hematopoietic cells, so a highly selective JAK3 inhibitor should have precise effects on immune cells and minimal pleiotropic defects. The selectivity of a JAK3 inhibitor would also have advantages over the current widely used immunosuppressant drugs, which have abundant targets and diverse side effects. A JAK3 inhibitor could be useful for treating autoimmune diseases, and JAK3 mediated leukemia and lymphoma.

[0009] For example, somatic mutations of JAK3 were also identified in a minority of acute megakaryoblastic leukaemia (AMKL) patients both in Down syndrome children and non-Down syndrome adults, and in a patient with acute lymphoblastic leukaemia. In addition, JAK3 activation was identified in several lymphoproliferative disorders, including mantle cell lymphoma, Burkitt's lymphoma, human T-cell leukemia / lymphoma, virus-1-induced adult T-cell lymphoma / leukemia and anaplastic large cell lymphoma. It was shown that constitutive activation of the JAK3 / STAT pathway has a major role in leukemia and lymphoma cell growth and survival and in the invasive phenotype. Therefore, the constitutive activation of JAK3, which can result from JAK3-activating mutations, is a frequent feature of several leukemia and lymphoma so that selective inhibition of JAK3 could be therapeutic target.

[0010] Therefore, a strong need exists for compounds which selectively and potently inhibit JAK3 wildtype and mutants as well as are selective over other JAK family members to provide an effective and safe clinical therapy for the diseases associated with or mediated by JAK3.

[0011] A need also exists for methods of administering such compounds, pharmaceutical formulations and medicaments to patients or subjects in need thereof.SUMMARY OF THE INVENTION

[0012] The present invention relates to novel hydrates and salts of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide and pharmaceutically acceptable compositions thereof which display inhibition activity against certain mutated forms of EGFR.

[0013] The invention provides hydrates, pharmaceutically acceptable salts, and hydrates of pharmaceutically acceptable salts of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide which are useful for the treatment of a disease or condition selected from the group consisting of cancer, allograft rejection, graft vs. host disease, diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, osteoarthritis, rheumatoid arthritis, synovial pannus invasion in arthritis, multiple sclerosis, myasthenia gravis, diabetes mellitus, diabetic angiopathy, retinopathy of prematurity, fibrosis, atherosclerosis, restenosis, autoimmune disease, allergy, respiratory diseases, asthma, transplantation rejection, inflammation, thrombosis, retinal vessel proliferation, inflammatory bowel disease, Crohn's disease, ulcerative colitis, bone diseases, transplant or bone marrow transplant rejection, lupus, chronic pancreatitis, cachexia, septic shock, fibroproliferative and differentiative skin diseases or disorders, central nervous system diseases, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, disorders or conditions related to nerve damage and axon degeneration subsequent to a brain or spinal cord injury, ocular diseases, viral infections, heart disease, lung or pulmonary diseases, kidney or renal diseases and bronchitis.

[0014] The present invention also relates to compositions comprising these compounds. Methods of making these compounds are described herein. Compounds of the present invention may be used in methods of inhibiting enzyme activity, particularly one or more EGFR mutant and JAK3 kinase activity, and may be used in a method of treating disease or disease symptoms in a mammal, particularly where inhibition of the kinase activity can affect disease outcome.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 shows visualization of Western blots showing the results of inhibition of phosphorylation level of mutant EGFR as compared to wildtype EGFR.DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention provides a group of hydrates, pharmaceutically acceptable salts, and hydrates of pharmaceutically acceptable salts of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide that are useful for inhibiting one or more protein kinases and for treating diseases and disorders that are mediated by the protein kinase, for example, cell proliferative disease and disorder such as cancer, autoimmune diseases, infection, cardiovascular disease, and neurodegenerative disease and disorder. Methods for synthesizing and administering the hydrates, pharmaceutically acceptable salts, and hydrates of pharmaceutically acceptable salts of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide are described herein. The present invention also provides pharmaceutical formulations comprising at least one of the hydrates, pharmaceutically acceptable salts, and hydrates of pharmaceutically acceptable salts of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide together with a pharmaceutically acceptable carrier, diluent or excipient therefor. The invention also provides useful intermediates generated during syntheses of the aminopyrimidine derivative compounds.

[0017] The present invention provides compositions which may be used in methods for modulating the activity of the epidermal growth factor receptor (EGFR) mutants and / or Janus kinase 3 (JAK3). Compounds of the present invention may act as inhibitors of EGFR mutants or JAK3.

[0018] In a first embodiment, provided herein is a compound which is a hydrate form of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide.

[0019] In a second embodiment, provided herein is a compound which is a hydrate form of a pharmaceutically acceptable salt of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide.

[0020] In a third embodiment, provided herein is a compound which is a pharmaceutically acceptable salt of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide and an acid selected from hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic, or hexanoic acid.

[0021] In certain embodiments of the compounds which are hydrate forms of a pharmaceutically acceptable salt of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide, the pharmaceutically acceptable salt is a salt of an acid selected from hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic, or hexanoic acid.

[0022] In a certain further embodiment, the compound is a hydrate form of a methanesulfonic acid salt of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide.

[0023] In a certain further embodiment, the compound is a methanesulfonic acid salt of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide.

[0024] Compounds of the present invention may be used in a method of treating protein kinase-mediated disease in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound of the invention , that is effective in treating abnormal cell growth and immune disease.

[0025] Compounds of the present invention may be used in a method of inhibiting at least one mutant of EGFR selectively as compared to wild type EGFR, in biological sample or in a patient, comprising contacting the biological sample with or administering to the patient a compound according of the invention, or a composition thereof (e.g., a pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable carrier). In certain embodiments, the at least one mutant is Del E746-A750, L858R or T790M. In certain embodiments, the at least one mutant is at least one double mutant selected from Del E746-A750 / T790M or L858R / T790M.

[0026] Compounds of the present invention may be used in a method of inhibiting Janus kinase 3 (JAK3) selectively as compared to other kinases, in biological sample or in a patient, comprising contacting the biological sample with or administering to the patient a compound of the invention, or a composition thereof, that is effective in treating abnormal cell growth including leukemia and lymphoma (B-cell & T-cell) and immune diseases including arthritis, rheumatoid arthritis and autoimmune diseases.

[0027] Compounds of the present invention may be used in the manufacture of a medicament for treating protein kinase-mediated disease. Further, compounds of the invention may be used in the manufacture of a medicament for inhibiting at least one mutant of EGFR selectively as compared to wild type EGFR.

[0028] Pharmaceutical compositions comprising a compound of the invention may be used in treating protein kinase-mediated disease. Further, a pharmaceutical composition comprising a compound of the invention may be used in inhibiting at least one mutant of EGFR selectively as compared to wild type EGFR.

[0029] The term "hetero" refers to the replacement of at least one carbon atom member in a ring system with at least one heteroatom such as nitrogen, sulfur, and oxygen.

[0030] As used herein, the term "aryl" refers to unsubstituted or substituted aromatic monocyclic or polycyclic groups and includes, for example, phenyl and naphthyl. The term "aryl" also includes a phenyl ring fused to a non-aromatic carbocyclic or heterocyclic ring. The term "aryl" may be interchangeably used with "aryl ring," aromatic group," and "aromatic ring. " Heteroaryl groups have 4 to 14 atoms, 1 to 9 of which are independently selected from the group consisting of oxygen, sulfur and nitrogen. Heteroaryl groups have 1-3 heteroatoms in a 5-8 membered aromatic group. An aryl or heteroaryl can be a mono- or bicyclic aromatic group. Typical aryl and heteroaryl groups include, for example, phenyl, quinolinyl, indazoyl, indolyl, dihydrobenzodioxynyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl, pyrimidinyl, 3- methylpyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4- diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, pyrrole, pyrazole, imidazole, thiazole, and the like. An aryl or heteroaryl can be unsubstituted or substituted with one or more suitable substituents.

[0031] As used herein, the term "hydroxyl" or "hydroxy" refers to -OH.

[0032] As used herein, the term "amino" refers to -NH 2 .

[0033] A "substituent" as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a ring substituent may be a moiety such as a halogen, alkyl group, haloalkyl group or other group that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member. Substituents of aromatic groups are generally covalently bonded to a ring carbon atom.

[0034] As described above, certain groups can be unsubstituted or substituted with one or more suitable substituents other than hydrogen at one or more available positions, typically 1, 2, 3, 4 or 5 positions, by one or more suitable groups (which may be the same or different). Certain groups, when substituted, are substituted with 1, 2, 3 or 4 independently selected substituents..

[0035] Compounds of the present invention and intermediates can be provided by (i) a method of preparing a compound of formula (c) by reacting a compound of formula (a) with a compound of formula (b) in the presence of the first base in the first organic solvent (see Scheme 1); (ii) a method of preparing a compound of formula (e) by reacting the compound of formula (c) with heteroaryl intermediates (d) in the presence of the second base, in the second organic solvent (see Scheme 1); (iii) a method of preparing a compound of formula (f) by reductive amination of the compound of formula (e) and an amine derivatives by using a reducing agent in the third solvent (see Scheme 1); (iv) a method of preparing a compound of Formula (I) by reduction of the compound of formula (f) by using a reducing agent in the fourth solvent and followed by amide formation in the presence of acryloyl chloride, the third base in the fifth solvent (see Scheme 1). A compound of Formula (I) can be prepared according to Scheme 1.

[0036] A compound of formula (e) can be prepared by reaction of the compound of formula (h) with aniline intermediates (g) in the presence of the fourth base in the first solvent, a ligand, a palladium catalyst in the first organic solvent (see Scheme 2). A compound of Formula (I) can be prepared according to Scheme 2.

[0037] Compounds of the present invention and intermediates can be provided by (i) a method of preparing a compound of formula (j) from the compound of formula (i) with aniline intermediates (g) with the procedure as described in WO2013 / 109882 A1; (ii) a method of preparing a compound of formula (j) from the compound of formula (j) by oxidation with mCPBA or Oxone ®< as described in WO2013 / 109882 A1; (iii) a method of preparing the compound of formula (e) from a compound of formula (k) by reaction with the compound of formula (d) in the presence of the second base in the second organic solvent (see Scheme 3). A compound of Formula (I) can be prepared according to Scheme 3.

[0038] With reference to Schemes 1-3, while appropriate reaction solvents can be selected by one of ordinary skill in the art, the first organic solvent is generally selected from relatively polar, aprotic solvents such as acetone, tetrahydrofuran, N,N- dimethylformamide, N,N-dimethylacetamide, dichloromethane, dichloroethane, or acetonitrile; the second organic solvent is generally selected from aprotic solvents such as toluene, dioxane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide or N- methylmorpholine; the third organic solvent is generally selected from relatively polar, solvents such as tetrahydrofuran, methanol, ethanol, dichloromethane, dichloroethane, N,N-dimethylacetamide or N,N-dimethylformamide; the fourth solvent is generally selected from relatively polar, protic solvents such as methanol, ethanol, tert-butanol or water, and the fifth solvent is generally selected from solvents such as dichloromethane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, or water.

[0039] With reference to Schemes 1-3, while bases and other reactants can be selected by one of ordinary skill in the art, the first and the second bases are generally selected from bases such as K 2 CO 3 , Cs 2 CO 3 , NaOH, KOH, NaH, tert-BuOK, ter-BuONa, triethylamine, or diisopropylethylamine; the third base is generally selected from bases such as triethylamine, diisopropylethylamine, NaH, NaHCO 3 , tert- BuOK, tert-BuONa, Cs 2 CO 3 , or K 2 CO 3 ; the fourth base is selected generally from bases such as NaH, n-BuLi, Cs 2 CO 3 , triethylamine, or diisopropylethylamine; a palladium catalyst is generally selected from Pd(OAc) 2 , Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , or Pd(dppf)Cl 2 ; a ligand is generally selected from BINAP, Xantphos, or S-Phos; the oxidizing agent is selected from oxidizing agents such as m-chloroperbenzoic acid (mCPBA) or Oxone ®< ; and the reducing agent is generally selected from NaBH(OAc) 3 , NaBH 4 , or NaBH(CN) 3 .

[0040] Representative compounds of Formula (I) are listed below: N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide, or a pharmaceutically acceptable salt thereof.

[0041] As used herein, the term "cancer" refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize. The types of cancer include, but is not limited to, solid tumors, such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid), prostate, skin (melanoma) or hematological tumors (such as the leukemias).

[0042] As used herein, the term "EGFR mutation" refers to mutation of T790M (resistant or oncogenic), L858R (activating), del E746-A750 (activating) or a combination thereof.

[0043] Compounds of the present invention may selectively inhibit at one activating mutation and at one point mutation. An at least one activating mutation may be a deletion mutation, del E746-A750. An at least one activating mutation may be a point mutation L858R. The at least one resistant mutation may be a point mutation, T790M. The at least one mutation of EGFR may be L858R and / or T790M.

[0044] As used herein, the term "mutant selective inhibition", as used in comparison to inhibition of wildtype (WT) EGFR, refers to the state that invention inhibits at least one mutation of EGFR (i.e. at least one deletion mutation, at least one activating mutation, at least one resistant mutation, or a combination of at least one deletion mutation and at least one point mutation) in at least one assay described herein (e.g., biochemical or cellular).

[0045] As used herein, the term "selectively inhibits", as used in comparison to inhibition of other kinases, refers to that invention poorly inhibits at least one of kinase panel.

[0046] As used herein, the term "EGFR wildtype selectivity" refers to that a selective inhibitor of at least one mutation of EGFR, as defined and described above and herein, inhibits EGFR at the upper limit of detection of at least one assay as described herein (e.g. cellular as described in detail in Table 1 and Table 2). The term "EGFR wildtype selectivity" may mean that the invention inhibits WT EGFR with an IC 50 of at least 200-1000nM or > 1000nM.

[0047] As used herein, the term "inhibitor" refers to a compound which inhibits one or more kinase described herein. For example, the term "EGFR mutant inhibitor" refers to a compound which inhibits the EGFR mutant receptor or reduces the signaling effect.

[0048] As used herein, the term "pharmaceutically acceptable" refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein. Such materials are administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0049] As used herein, the term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compounds described herein.

[0050] As used herein, the term "pharmaceutical combination" means a product that results from the mixing or combining of more than one active ingredient.

[0051] As used herein, the term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and / or excipients.

[0052] As used herein, the term "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. Prodrugs are bio-available by oral administration whereas the parent is not. Prodrugs improve solubility in pharmaceutical compositions over the parent drug. A non-limiting example of a prodrug of the compounds described herein is a compound described herein administered as an ester which is then metabolically hydrolyzed to a carboxylic acid, the active entity, once inside the cell. A further example of a prodrug is a short peptide bonded to an acid group where the peptide is metabolized to reveal the active moiety.

[0053] As used herein, the term "protein kinase-mediated disease" or a "disorder or disease or condition mediated by inappropriate protein kinase activity" refers to any disease state mediated or modulated by protein kinases described herein. Such disease states include, but are not limited to non-small cell lung cancer (NSCLC).

[0054] As used herein, the term "EGFR mutant-mediated disease" or a "disorder or disease or condition mediated by inappropriate EGFR activity" refers to any disease state mediated or modulated by EGFR mutant kinase mechanisms. Such disease states include, but are not limited to NSCLC, metastatic brain cancer and other solid cancers.

[0055] As used herein, the term "JAK3-mediated disease" or a "disorder or disease or condition mediated by inappropriate JAK3 activity" refers to any disease state mediated or modulated by JAK3 kinase mechanisms. Such disease states include, but are not limited to rheumatoid arthritis, psoriasis and organ transplant rejection and some solid cancers.

[0056] As used herein, the term "treat," "treating" or "treatment" refers to methods of alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.

[0057] As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of Formula (I) or a pharmaceutically acceptable salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Non-limiting examples of suitable solvents include water, acetone, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Non-limiting examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid.

[0058] As used herein, the term "subject" or "patient" encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes monkeys, cattle, horses, sheep, goats, swine; rabbits, dogs, cats, rats, mice, guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like.

[0059] As used herein, the term "administration" or "administering" of the subject compound refers to providing a compound of the invention and / or prodrugs thereof to a subject in need of treatment.

[0060] As used herein, the term "carrier" refers to chemical compounds or agents that facilitate the incorporation of a compound described herein into cells or tissues.

[0061] As used herein, the term "co-administration" or "combined administration" or the like as used herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

[0062] As used herein, the term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0063] As used herein, the term "diluent" refers to chemical compounds that are used to dilute a compound described herein prior to delivery. Diluents can also be used to stabilize compounds described herein.

[0064] As used herein, the term "effective amount" or "therapeutically effective amount" refer to a sufficient amount of a compound described herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study. By way of example only, a therapeutically effective amount of a compound of the invention may be in the range of e.g., about 0.01 mg / kg / day to about 100 mg / kg / day, or from about 0.1 mg / kg / day to about 10 mg / kg / day.Human Protein Kinase

[0065] Compounds of the present invention are screened against the kinase panel (wild type and / or mutation thereof) and inhibit the activity of at least one kinase on the kinase panel. Examples of kinases include, but are not limited to EGFR and JAK3 (JH1domain-catalytic) kinases, and mutant forms thereof. As such, the compounds and compositions of the invention are useful for treating diseases or disorders in which such kinases contribute to the pathology and / or symptomology of a disease or disorder associated with or mediated by such kinase.

[0066] Many diseases are associated with abnormal cellular responses triggered by protein kinase mediated events. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, respiratory diseases, allergies and asthma, Alzheimer's disease, and hormone related diseases.

[0067] Phosphorylation regulates a variety of cellular processes such as proliferation, growth, differentiation, metabolism, apoptosis, motility, transcription, translation and other signaling processes. Aberrant or excessive PTK activity has been observed in many disease states such as benign and malignant proliferative disorders, diseases resulting from inappropriate activation of the immune system and diseases resulting from inappropriate activation of the nervous systems. Specific diseases or conditions include, but are not limited to, allograft rejection, graft vs. host disease, diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, osteoarthritis, rheumatoid arthritis, synovial pannus invasion in arthritis, multiple sclerosis, myasthenia gravis, diabetes mellitus, diabetic angiopathy, retinopathy of prematurity, infantile hemangiomas, non-small cell lung, bladder and head and neck cancers, prostate cancer, breast cancer, ovarian cancer, gastric and pancreatic cancer, psoriasis, fibrosis, atherosclerosis, restenosis, autoimmune disease, allergy, respiratory diseases, asthma, transplantation rejection, inflammation, thrombosis, retinal vessel proliferation, inflammatory bowel disease, Crohn's disease, ulcerative colitis, bone diseases, transplant or bone marrow transplant rejection, lupus, chronic pancreatitis, cachexia, septic shock, fibroproliferative and differentiative skin diseases or disorders, central nervous system diseases, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, disorders or conditions related to nerve damage and axon degeneration subsequent to a brain or spinal cord injury, acute or chronic cancer, ocular diseases, viral infections, heart disease, lung or pulmonary diseases or kidney or renal diseases and bronchitis.Epidermal growth factor receptor (EGFR)

[0068] The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in human) is the cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands. The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four related receptor tyrosine kinases: EGFR (ErbB-1), HER2 / c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). Mutations affecting EGFR expression or activity could result in cancer.

[0069] EGFR exists on the cell surface and is activated by binding of its specific ligands, including epidermal growth factor and transforming growth factor α (TGFα). Upon activation by its growth factor ligands, EGFR undergoes a transition from an inactive monomeric form to an active homodimer. In addition to forming homodimers after ligand binding, EGFR may pair with another member of the ErbB receptor family, such as ErbB2 / Her2 / neu, to create an activated heterodimer. ErbB2 has no known direct activating ligand, and may be in an activated state constitutively or become active upon hetero-dimerization with other family members such as EGFR.

[0070] The dimerization of EGFR stimulates its intrinsic intracellular protein-tyrosine kinase activity. As a result, autophosphorylation of several tyrosine (Y) residues in the C-terminal domain of EGFR takes place. These include Y992, Y1045, Y1068, Y1148 and Y1173 at cytoplasmic domain. This autophosphorylation elicits downstream activation and signaling by several other proteins that associate with the phosphorylated tyrosines through their own phosphotyrosine-binding SH2 domains. These downstream signaling proteins initiate several signal transduction cascades, principally the MAPK, Akt and JNK pathways, leading to DNA synthesis and cell proliferation. Such proteins modulate phenotypes such as cell migration, adhesion, and proliferation. Activation of the receptor is important for the innate immune response in human skin. The kinase domain of EGFR can also cross-phosphorylate tyrosine residues of other receptors it is aggregated with, and can itself be activated in that manner.

[0071] Mutations that lead to EGFR overexpression (known as upregulation) or overactivity have been associated with a number of cancers, including lung cancer, anal cancers and glioblastoma multiforms. These somatic mutations involving EGFR lead to its constant activation, which produces uncontrolled cell division. In glioblastoma a more or less specific mutation of EGFR, called EGFRvVIII is often observed. Mutations, amplifications or misregulations of EGFR or family members are implicated in about 30% of all epithelial cancers.

[0072] The most common form of lung cancer is non-small cell lung carcinoma (NSCLC) and in a subset of these patients lung tumor growth is caused by activating mutations in the epidermal growth factor receptor (EGFR). The most common activating mutations, accounting for 85-90% of all EGFR mutations, are the in-frame deletion in exon 19 (DelE746-A750) and the L858R point mutation in exon 21. EGFR mutations occur in 10-15% of NSCLC patients of Caucasian descent and 30-35% of NSCLC patients of East Asian descent. Clinical features likely to be associated with EGFR mutations are non-smoker and of East Asian ethnicity.

[0073] It was well known that the most common EGFR activating mutations, L858R and del E746-A750 were sensitive to treatment of gefitinib or erlotinib, which are associated with dose-limiting toxicities such as diarrhea and rash / acne in response to inhibition of wildtype EGFR in intestine and skin, respectively. Ultimately acquired resistance to therapy with gefitinib or erlotinib occurs predominantly by mutation of the gatekeeper residue T790M, which is detected in nearly half of clinically resistant patients, resulting in double mutants, L858R / T790M or del E746-A750 / T790M.

[0074] Brain metastases are the most common intracranial neoplasm, occurring in 8-10% of cancer patients, and are a significant cause of cancer-related morbidity and mortality worldwide Brain metastases develop in approximately 30% of patients with non-small cell lung cancer (NSCLC). Among the various histologies of NSCLC, the relative frequency of brain metastases in patients with adenocarcinoma and large cell carcinoma was much higher than that in patients with squamous cell carcinoma.

[0075] The compounds described herein are inhibitors of EGFR mutant kinase activity and have therapeutic benefit in the treatment of disorders associated with inappropriate EGFR mutant activity, in particular in the treatment and prevention of disease states mediated by EGFR mutant. Such disease states include NSCLC, breast cancer, metastatic brain cancer and other solid cancers. Furthermore, the compounds and compositions of the present invention can be used in methods of regulating, and in particular inhibiting, signal transduction cascades in which EGFR mutant(s) plays a role. The method generally involves contacting a EGFR mutant-dependent receptor or a cell expressing a EGFR mutant -dependent receptor with an amount of a compound described herein, or prodrug a compound described herein, or an acceptable salt, hydrate, solvate, N-oxide and / or composition thereof, effective to regulate or inhibit the signal transduction cascade. The methods are used to regulate, and in particular inhibit, downstream processes or cellular responses elicited by activation of the particular EGFR mutant-dependent signal transduction cascade. The methods are practiced to regulate any signal transduction cascade where EGFR mutant is not known or later discovered to play a role. The methods are practiced in in vitro contexts or in in vivo contexts as a therapeutic approach towards the treatment or prevention of diseases characterized by, caused by or associated with activation of the EGFR mutant-dependent signal transduction cascade.Janus kinase 3 (JAK3)

[0076] Janus kinase 3 (JAK3) is a tyrosine kinase that belongs to the Janus family of kinases. Other members of the Janus family include JAK1, JAK2 and TYK2. They are cytosolic tyrosine kinases that are specifically associated with cytokine receptors. Since cytokine receptor proteins lack enzymatic activity, they are dependent upon JAKs to initiate signaling upon binding of their ligands (e.g. cytokines). The cytokine receptors can be divided into five major subgroups based on their different domains and activation motifs. JAK3 is required for signaling of the type I receptors that use the common gamma chain (γc).

[0077] In contrast to the relatively ubiquitous expression of JAK1, JAK2 and Tyk2, JAK3 is predominantly expressed in hematopoietic lineage such as NK cells, T cells and B cells and intestinal epithelial cells. JAK3 functions in signal transduction and interacts with members of the STAT (signal transduction and activators of transcription) family. JAK3 is involved in signal transduction by receptors that employ the common gamma chain (γc) of the type I cytokine receptor family (e.g. IL-2R, IL-4R, IL-7R, IL-9R, IL-15R, and IL-21R). Mutations of JAK3 result in severe combined immunodeficiency (SCID). Mice that do not express JAK3 have T-cells and B-cells that fail to respond to many cytokines.

[0078] Since JAK3 is required for immune cell development, targeting JAK3 could be a useful strategy to generate a novel class of immunosuppressant drugs. Moreover, unlike other JAKs, JAK3 is primarily expressed in hematopoietic cells, so a highly specific JAK3 inhibitor should have precise effects on immune cells and minimal pleiotropic defects. The selectivity of a JAK3 inhibitor would also have advantages over the current widely used immunosuppressant drugs, which have abundant targets and diverse side effects. A JAK3 inhibitor could be useful for treating autoimmune diseases, especially those in which a particular cytokine receptor has a direct role on disease pathogenesis. For example, signaling through the IL-15 receptor is known to be important in the development rheumatoid arthritis, and the receptors for IL-4 and IL-9 play roles in the development of allergic responses.

[0079] Extranodal, nasal-type natural killer (NK) / T-cell lymphoma (NKCL) is an aggressive malignancy with poor prognosis in which, usually, signal transducer and activator of transcription 3 (STAT3) is constitutively activated and oncogenic. It was demonstrated that STAT3 activation mostly results from constitutive Janus kinase 3(JAK3) phosphorylation on tyrosine 980, as observed in three of the four tested NKCL cell lines and in 20 of the 23 NKCL tumor samples. In one of the cell lines and in 4 of 19 NKCL primary tumor samples, constitutive JAK3 activation was related to an acquired mutation (A573V or V722I) in the JAK3 pseudokinase domain. In addition, it was shown that constitutive activation of the JAK3 / STAT3 pathway has a major role in NKCL cell growth and survival and in the invasive phenotype. Indeed, NKCL cell growth was slowed down in vitro by targeting JAK3 with chemical inhibitors or small-interfering RNAs. In a human NKCL xenograft mouse model, tumor growth was significantly delayed by the JAK3 inhibitor. Therefore, the constitutive activation of JAK3, which can result from JAK3-activating mutations, is a frequent feature of NKCL so that it could be therapeutic target.

[0080] The compounds described herein are inhibitors of JAK3 kinase activity and have therapeutic benefit in the treatment of disorders associated with inappropriate JAK3 activity, in particular in the treatment and prevention of disease states mediated by JAK3. Such disease states include rheumatoid arthritis, psoriasis and organ transplant rejection, lymphoma and some solid cancers.Pharmaceutical Compositions, Formulation and Administration

[0081] For the therapeutic uses of compounds of the invention, , such compounds are administered in therapeutically effective amounts either alone or as part of a pharmaceutical composition. Accordingly, provided herein are pharmaceutical compositions, which comprise at least one compound of the invention, , and one or more pharmaceutically acceptable carriers, diluents, adjuvant or excipients. In addition, such compounds and compositions are administered singly or in combination with one or more additional therapeutic agents. The methods of administration of such compounds and compositions include, but are not limited to, intravenous administration, inhalation, oral administration, rectal administration, parenteral, intravitreal administration, subcutaneous administration, intramuscular administration, intranasal administration, dermal administration, topical administration, ophthalmic administration, buccal administration, tracheal administration, bronchial administration, sublingual administration or optic administration. Compounds provided herein are administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, lotions, gels, ointments or creams for topical administration, and the like.

[0082] The therapeutically effective amount will vary depending on, among others, the disease indicated, the severity of the disease, the age and relative health of the subject, the potency of the compound administered, the mode of administration and the treatment desired. The required dosage will also vary depending on the mode of administration, the particular condition to be treated and the effect desired.

[0083] Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidicanionic or basic / cationic salts. Pharmaceutically acceptable acidic / anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, hydrogensulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts. Pharmaceutically acceptable basic / cationic salts include, the sodium, potassium, calcium, magnesium, diethanolamine, N-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine salts.

[0084] A pharmaceutically acceptable acid salt is formed by reaction of the free base form of a compound with a suitable inorganic or organic acid including, but not limited to, hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2-naphthalenesulfonic, or hexanoic acid. A pharmaceutically acceptable acid addition salt of a compound of Formula (I) can comprise or be, for example, a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formarate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g., 2- naphthalenesulfonate) or hexanoate salt.

[0085] The free acid or free base forms of the compounds of the invention may be prepared from the corresponding base addition salt or acid addition salt form, respectively. For example a compound of the invention in an acid addition salt form may be converted to the corresponding free base form by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of the invention in a base addition salt form may be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

[0086] Prodrug derivatives of the compounds of the invention may be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al, Bioorg. Med. Chem. Letters, 1994, 4, 1985).

[0087] Protected derivatives of the compounds of the invention may be prepared by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, "Protecting Groups in Organic Chemistry," 3rd edition, John Wiley and Sons, Inc., 1999. Compounds of the invention may be prepared as their individual stereoisomers by reaction of a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. Resolution of enantiomers may be carried out using covalent diastereomeric derivatives of the compounds of the invention, or by using dissociable complexes (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and may be readily separated by taking advantage of these dissimilarities. The diastereomers may be separated by chromatography, or by separation / resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet and Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley And Sons, Inc., 1981.

[0088] Suitable pharmaceutically acceptable carriers, diluents, adjuvants, or excipients for use in the pharmaceutical compositions of the invention include tablets (coated tablets) made of for example collidone or shellac, gum Arabic, talc, titanium dioxide or sugar, capsules (gelatin), solutions (aqueous or aqueous ethanolic solution), syrups containing the active substances, emulsions or inhalable powders (of various saccharides such as lactose or glucose, salts and mixture of these excipients with one another) and aerosols (propellant-containing or -free inhale solutions).

[0089] Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g., petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g., ethanol or glycerol), carriers such as natural mineral powders (e.g., kaoline, clays, talc, chalk), synthetic mineral powders (e.g., highly dispersed silicic acid and silicates), sugars (e.g., cane sugar, lactose and glucose), emulsifiers (e.g., lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

[0090] Compounds of Formula (I) can be made according to a variety of methods, some of which are known in the art. For example, the methods disclosed in PCT Publication WO2011 / 060295 can be used, with suitable modifications, to prepare compounds according to the present invention. Exemplary methods for preparing the compounds of the invention are described herein, including in the Examples.EXAMPLES

[0091] The present invention is further exemplified by the following examples that illustrate the preparation of compounds of Formula (I) according to the invention. The examples are for illustrative purpose only and are not intended, nor should they be construed as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications can be made without changing the scope of the invention.

[0092] Nuclear magnetic resonance (NMR) and mass spectrometry (MS) spectra obtained for compounds described in the examples below and those described herein were consistent with that of the compounds of formulae herein.Liquid chromatography- mass spectrometry (LC-MS) Method:

[0093] 1. Samples are run on Agilent Technologies 6120 MSD system with a Zorbax Eclipse XDB-C18 (3.5 µm) reverse phase column (4.6 x 50 mm) run at room temperature with flow rate of 1.5 mL / minute. 2. The mobile phase uses solvent A (water / 0.1 % formic acid) and solvent B (acetonitrile / 0.1 % formic acid): 95 % / 5 % to 0 % / 100 % (A / B) for 5 minute. 3. The mass spectra (m / z) were recorded using electrospray ionization (ESI). 4. Ionization data was rounded to the nearest integer. Proton NMR Spectra:

[0094] Unless otherwise indicated, all 1< H NMR spectra are run on a Varian series Mercury 300 MHz or a Bruker 500MHz. All observed protons are reported as parts-per-million (ppm) downfield from tetramethylsilane using conventional abbreviations for designation of major peaks: e.g., s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad).Intermediate 1: 1-(2-(2-Methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-pyrazole-4-carbaldehyde Method B

[0095]

[0096] 1-(2-Chloropyrimidin-4-yl)-3-methyl-1H-pyrazole-4-carbaldehyde (130 mg, 0.59 mmol) was added to a mixture of 2-methoxy-5-nitroaniline (88.6 mg, 0.53 mmol), Pd(OAc) 2 (6.5 mmol, 0.029 mmol), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP, 36.5 mg, 0.059 mmol), K 2 CO 3 (161.8 mg, 1.17 mmol) in 10 mL of 1,4-dioxane (degassed for 20 min prior to use). 1-(2-Chloropyrimidin-4-yl)-3-methyl-1H-pyrazole-4-carbaldehyde was prepared by the known procedure as described in WO 2013 / 109882 A1.

[0097] The resulting mixture was stirred at 100 °C for 5 h and then concentrated in vacuo. Cold water was added and the precipitated solid was collected by filtration, washed with DCM (5 mL) and dried to give the desired Intermediate 1 as a yellow solid (0.13 g, 65%); MS (ESI) m / z 355.4 [M+H] +< .Intermediate 9: 1-(2-(4-fluoro-3-nitrophenylamino)pyrimidin-4-yl)-3-methyl-1H-pyrazole-4-carbaldehyde

[0098] Using 4-fluoro-3-nitroaniline and 1-(2-chloropyrimidin-4-yl)-3-methyl-1H-pyrazole-4-carbaldehyde, Intermediate 9 was prepared as described in Method B; MS (ESI) m / z 343.1 [M+H] +< .Intermediate 10: 3-methyl-1-(2-(4-morpholino-3-nitrophenylamino)pyrimidin-4-yl)-1H-pyrazole-4-carbaldehyde

[0099] To a solution of Intermediate 9 (200 mg, 0.59 mmol), DIPEA (0.20 mL, 1.17 mmol) in DMAA (10 mL) was added morpholine (0.076 mL, 0.88 mmol). The reaction mixture was heated to 80 °C for 2h. Solvent was removed in vacuo and the mixture was extracted with DCM. The crude mixture was purified by column chromatography (0 to 5% MeOH in DCM) to give the desired intermediate as a red solid (220.2 mg, 92%); MS (ESI) m / z 410.2 [M+H] +< .Intermediate 63: 1-(2-(4-fluoro-2-methoxy-5-nitrophenylamino)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde

[0100] Using 4-fluoro-2-methoxy-5-nitroaniline and 1-(2-chloropyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde, Intermediate 63 was prepared as described in Method B; MS (ESI) m / z 435.1 [M+H] +< .Intermediate 64: 1-(2-(2-methoxy-4-morpholino-5-nitrophenylamino)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde

[0101] Using Intermediate 63, Intermediate 64 was prepared as described in the preparation of Intermediate 10; MS (ESI) m / z 502.2 [M+H] +< .Example 1 (This example no longer forms part of the present invention) Compound 1: N-(3-(4-(4-(azetidin-1-ylmethyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxyphenyl)acrylamide

[0102] Step 1:

[0103] To a solution of Intermediate 1 (35.0 mg, 0.10 mmol), diisopropylethylamine (DIPEA, 50 µL, 0.30 mmol) in dimethylacetamide (DMAA, 2 mL) was added 18.5 mg of azetidine hydrochloride (0.20 mmol) at rt. After being stirred for 20 min, 62.8 mg of sodium triacetoxyborohydride (NaBH(OAc) 3 , 0.30 mmol) was added into the mixture and the resulting mixture was stirred at rt for 16 h. Solvent was evaporated in vacuo and the mixture was purified by column chromatography (0 to 10% MeOH in DCM) to give 4-(4-(azetidin-1-ylmethyl)-3-methyl-1H-pyrazol-1-yl)-N-(2-methoxy-5-nitrophenyl)pyrimidin-2-amine as a red solid (32.0 mg, 82%); MS (ESI) m / z 396.2 [M+H] +< .Step 2:

[0104] To a solution of the nitro compound above (56.0 mg, 0.14 mmol) in 3 mL mixture of ethanol and water (5:1) were added 78.2 mg of iron (1.42 mmol) and ammonium chloride (38.0 mg, 0.71 mmol). The mixture was heated to 80 °C for 2h. 2M solution of ammonia in MeOH (2mL) was added and the resulting mixture was filtered through Celite. The filtrate was concentrated. The resulting residue was extracted with DCM, washed with sat.NaHCO 3 solution, brine, dried over anhydrous Na 2 SO 4 . The crude oil was purified by column chromatography (0 to 20% MeOH in DCM with 0.1% NH 3 ) to give N-(4-(4-(azetidin-1-ylmethyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxybenzene-1,3-diamine as an off-white solid (38.0 mg, 69%); MS (ESI) m / z 366.2 [M+H] +< .Step 3:

[0105] To a solution of above aniline (36.0 mg, 0.10 mmol) and DIPEA (18.8 µL, 0.11 mmol) in DCM (2 mL) was added a solution of acryloyl chloride (8.01 µL, 0.10 mmol) in DCM (0.2 mL) at -20 °C. The mixture was stirred for 1 h and quenched by addition of sat NaHCO 3 solution. The mixture was extracted with DCM and dried over anhydrous Na 2 SO 4 . The crude mixture was purified by column chromatography (0 to 10% MeOH in DCM with 0.1% NH 3 ) to give the title compound as an off-white solid. (26.9 mg, 65%); MS (ESI) m / z 420.2 [M+H] +< .Example 73 Compound 73: N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide

[0106] Using Intermediate 64 and dimethylamine, the title compound was prepared as described in Example 1; MS (ESI) m / z 555.3 [M+H] +< .

[0107] 1< H NMR: δ (DMSO-d 6 ), 2.21 ppm (6H, s), 2.85~2.86 ppm (4H, t), 3.46 ppm (2H, s), 3.81~3.83 ppm (4H, t), 3.91 ppm (3H, s), 5.82~6.43 ppm (2H, dd), 6.72~6.76 ppm (1H, dd), 6.96 ppm (1H, s), 7.34~7.35 (1H, d), 7.41~7.43 ppm (1H, t), 7.47~7.50 ppm (2H, t), 8.04~8.05 ppm (2H, d), 8.18 ppm (1H, s), 8.53~8.54 ppm (1H, d), 9.07 ppm (1H, s), 9.15 ppm (2H, s)Comparative Example 1 Compound 146: 4-(3-((dimethylamino)methyl)-4-methyl-1H-pyrrol-1-yl)-N-(3,5-dimethylphenyl)pyrimidin-2-amine

[0108] Compound 146 was prepared as described in US 8626132 B2; MS (ESI) m / z 356.4 [M+H] +< .Comparative Example 2 Compound 147: 1-((1-(2-(3,5-dimethylphenylamino)pyrimidin-4-yl)-3-methyl-1H-pyrazol-4-yl)methyl)azetidin-3-ol

[0109] Compound 147 was prepared as described in US 8626132 B2; MS (ESI) m / z 365.3 [M+H] +< .Comparative Example 3 Compound 148: (R)-1-((1-(2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-yl)-3-methyl-1H-pyrazol-4-yl)methyl)pyrrolidin-3-ol

[0110] Compound 148 was prepared as described in US 8626132 B2; MS (ESI) m / z 492.5 [M+H] +< .Comparative Example 4 Compound 149: 1-((1-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenylamino)pyrimidin-4-yl)-3-methyl-1H-pyrazol-4-yl)methyl)azetidin-3-ol

[0111] Compound 149 was prepared as described in US 8626132 B2; MS (ESI) m / z 425.4 [M+H] +< .Comparative Example 5 Compound 150: 1-((4-methyl-1-(2-(2-methylbiphenyl-4-ylamino)pyrimidin-4-yl)-1H-pyrrol-3-yl)methyl)azetidin-3-ol

[0112] Compound 150 was prepared as described in US 8626132 B2; MS (ESI) m / z 426.3 [M+H] +< .Comparative Example 6 Compound 151: 1-((3-cyclopropyl-1-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenylamino)pyrimidin-4-yl)-1H-pyrazol-4-yl)methyl)azetidin-3-ol

[0113] Compound 151 was prepared as described in US 8626132 B2; MS (ESI) m / z 451.5 [M+H] +< .Comparative Example 7Compound 152: 4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine

[0114] Using Intermediate 64, compound 152 was prepared as described in the preparation of example 1; MS (ESI) m / z 531.2 [M+H] +< .Comparative Example 8 Compound 153: N1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine

[0115] Using compound 152, compound 153 was prepared as described in the preparation of example 1; MS (ESI) m / z 501.4 [M+H] +< .Comparative Example 9 Compound 154: N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)but-3-enamide

[0116] Using compound 153, compound 154 was prepared as described in the preparation of example 1; MS (ESI) m / z 569.3 [M+H] +< .Comparative Example 10 Compound 155: (E)-N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)pent-2-enamide

[0117] Using compound 153, compound 155 was prepared as described in the preparation of example 1; MS (ESI) m / z 583.3 [M+H] +< .Comparative Example 11 Compound 156: (Z)-N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)hex-3-enamide

[0118] Using compound 153, compound 157 was prepared as described in the preparation of example 1; MS (ESI) m / z 597.3 [M+H] +< .Comparative Example 12 Compound 157: N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)propionamide

[0119] Using compound 153, compound 157 was prepared as described in the preparation of example 1; MS (ESI) m / z 557.7 [M+H] +< .Comparative Example 13 Compound 158: N-(5-(4-(4-(azetidin-1-ylmethyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)propionamide

[0120] Using compound 153, compound 158 was prepared as described in the preparation of example 1; MS (ESI) m / z 569.7 [M+H] +< .Comparative Example 14 Compound 159: N-(5-(4-(4-(azetidin-1-ylmethyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)-2-fluoroacrylamide

[0121] Using compound 153, compound 159 was prepared as described in the preparation of example 1; MS (ESI) m / z 585.6 [M+H] +< .BIOLOGICAL ASSAYS 1. Kinase Inhibition Assays

[0122] Compounds of the present invention were assayed to measure their capacity to inhibit a kinase panel which includes SYK, KDR, JAK3, and EGFR mutants.Method: Inhibition of enzymatic activity of SYK, KDR, JAK3, and EGFR mutant kinase

[0123] Compounds of the invention were initially diluted to 10mM in 100 % DMSO for storage and made into kinase buffer solution to create a compound concentration ranging from 1uM and 10uM. Serial dilutions of compounds of the invention were dispensed into the 96-well plate (Greiner Biosciences ™< ) at 6 µL each. The first generation reversible inhibitor Erlotinb and the irreversible inhibitor Afatinib were used as reference compound. Purified human, full-length SYK, KDR, and truncated human JAK3, EGFR mutants such as del E746-A750, L858R, L858R / T790M and del E746-A750 / T790M (Carna Biosciences ™< ), were diluted in kinase buffer and added to the compound solutions and pre-incubated for 30 minutes (EGFR mutants for 2 hours) at room temperature. Next, ATP (Teknova ™< ) of approximate ATP concentration (1mM for EGFR mutants) and substrate solution (Ulight ™< -TK peptide for SYK, Ulight ™< -Jak1 for KDR and JAK3, and Ulight ™< -PolyGT for EGFR mutants (PerkinElmer ™< )) was added (12 µL each) to the wells containing the compound solution and enzyme and incubated for 1 hour. Following the incubation, the stop solution made with EDTA, water, and Lance detection buffer (PerkinElmer ™< ) was added (12 µL each) to the reaction mixture to stop the phosphorylation. Following the addition of the stop solution and 5 minutes of shaking, the detection solution containing the Europium-labeled antibody, water, and Lance detection buffer was added (12 µL each) to the reaction mixture and incubated again for 50 minutes. Substrate phosphorylation was a function of the 665 nm emission measured following the addition of the detection solution and 50 minutes of incubation.

[0124] The potency of compound was assigned as < 20 nM in IC 50 , 21 to 200 nM in IC 50 , 201 to 1000nM in IC 50 and >1000nM in IC 50 . The IC 50 value was determined by GraphPad Prism 5.Result

[0125] Compounds of Formula (I) exhibited useful pharmacological properties. As used herein, the half maximal inhibitory concentration (IC 50 ) indicates 50% inhibition on the given kinase activity (e.g., 0 % inhibition in control treated with no inhibitor) by the compounds of Formula (I). Compounds of Formula (I) exhibited various levels of inhibition of the given protein kinase on the panel. Certain compounds exhibited a potent inhibition of all test EGFR mutants and good selectivity over other kinases, KDR and SYK as shown in Tables 1 to 5.

[0126] Compound 73 of Formula (I), namely, N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide, was shown to potently inhibit the kinase activity of JAK3 and all four EGFR mutants at the 1mM ATP concentration (< 20nM in IC 50 ) but to poorly inhibit that of SYK and KDR at approximate ATP Km concentration (see Tables 1 to 5).

[0127] Reference compound Erlotinib shows moderate inhibition against EGFR Del E746-A750 mutant and EGFR L858R mutant (20-200nM in IC 50 ) but no or little inhibition against other EGFR mutants, SYK, KDR and JAK3(>1000nM in IC 50 ). The irreversible inhibitors Afatinib displayed potent inhibition against all EGFR mutants and JAK3 (< 20nM in IC 50 ) but no or little inhibition against SYK and KDR (>1000nM in IC 50 ). Compound 73 is similar to the irreversible inhibitor Afatinib in terms of potency against all test EGFR mutants. However, unlike Afatinib inhibiting both EGFR mutants and wildtype, compound 73 shows no or little inhibition against EGFR wildtype (see Table 1, Table 2 and Figure 1), suggesting that it is selective to EGFR wildtype. In addition, potent and selective inhibition (<20nM) of JAK3 by indicates that it could be therapeutically valuable to treat JAK3 mediated diseases such as rheumatoid arthritis, immune diseases, leukemia, lymphoma and metastatic cancer. Table 1. The kinase potency EGFR mutant(T790M) by the representative compounds of Formula (I).Biochemical potency: < 20 nM, 20-200 nM, 201-1000nM and >1000nMCompound No EGFR mutant T790M Afatinib<20Erlotinib20-20073 <20146 >1000147 >1000148 >1000149 >1000150 >1000151 >1000152 >1000153 >1000157 >1000158 >1000159 >1000 Table 2. The kinase potency EGFR mutants by the representative compounds of Formula (I). Biochemical potency: < 20 nM, 20-200 nM, 201-1000nM and >1000nMCompound No EGFR mutants Del19 (E746-A750) L858R L858R / T790M Del19 / T790M Afatinib<20<20<20<20Erlotinib20-20020-200>1000>100073 <20<20<20<20146 >1000>1000201-1000201-1000147 >1000>1000201-1000>1000148 >1000>1000201-1000201-1000149 >1000>1000201-1000>1000150 >1000>1000201-1000>1000151 >100020-20020-200201-1000152 >1000>1000>1000>1000153 >1000>1000>1000>1000156 >1000>1000201-100020-200157 >1000>1000>1000>1000158 >1000>1000>1000>1000159 >1000>100020-20020-200 Table 3. The kinase potency of JAK3 by the representative compounds of Formula (I). Biochemical potency: < 20 nM, 20-200 nM, 201-1000nM and >1000nMCompound No JAK3 Afatinib>1000Erlotinib201-100073 <20 Table 4. The kinase potency of SYK by the representative compounds of Formula (I). Biochemical potency: < 20 nM, 20-200 nM, 201-1000nM and >1000nMCompound No Syk Afatinib>1000Erlotinib>100073 201-1000146 20-200147 20-200148 201-1000149 >1000150 >1000151 201-1000152 >1000153 >1000156 >1000157 >1000158 >1000159 >1000 Table 5. The kinase potency of KDR by the representative compounds of Formula (I). Biochemical potency: < 20 nM, 20-200 nM, 201-1000nM and >1000nMCompound No KDR Afatinib>1000Erlotinib201-100073 >1000 2. Cell viability assay

[0128] Compounds of the invention are tested for their effects on NSCLC cell lines to illustrate efficacy of the invention at the cellular level. Mis-regulation and, in particular, over-activation of EGFR mutants have been implicated in increased proliferation of NSCLC lines. Among those cell lines, the cell viability of NSCLC PC9 depends on activation of EGFR del E746-A750 mutant as that of H1975 cell does on activation of EGFR L858R / T790M mutant. And cell viability of H2073 depends on EGFR wildtype.

[0129] Therefore, the viability of PC9 by compound of Formula (I) represents cellular potency of test compound against EGFR del E746-A750 mutant and that of H1975 does that against EGFR L858R / T790M mutant. And that of H2073 represents EGFR wildtype potency in NSCLC line.Method

[0130] Compounds of the invention and references were tested against H2073, PC9 and H1975 obtained from the American Type Culture Collection (ATCC, Manassas, VA). This cell line was maintained with an Roswell Park Memorial Institute (RPMI) medium (GIBCO ™< ) containing 10 % fetal bovine serum (FBS; GIBCO ™< ) and 0.05 mM 2-mercaptoethanol. The cells were seeded at 3x10 3< cells / 100 µL / well into 96 well culture plate, and serially diluted compound was then added. The first generation reversible inhibitor Erlotinb and the irreversible inhibitor Afatinib were used for reference inhibitor. After 72-hour incubation period at 37 °C, the cells were subjected to an ATPLite (Promega) assay to determine the cytotoxic effects of compound.

[0131] The potency of compound was assigned as < 20 nM in IC 50 , 21 to 200 nM in IC 50 , 201 to 1000nM in IC 50 and >1000nM in IC 50 . The IC 50 value was determined by GraphPad Prism 5.Result

[0132] As used herein, the half maximal inhibitory concentration (IC 50 ) indicates 50% inhibition on the given cell's viability by the compounds of Formula (I).

[0133] Table 6 shows cellular viability of mutant EGFR expressing cells as compared to wildtype EGFR expressing cell and provides the selectivity ratio of wildtype EGFR expressing cell to mutant expressing cell for each test compound. Compounds of Formula (I) exhibited an potent inhibition range (<20nM in IC 50 ) in PC9 cell and furthermore in H1975 cell where Erlotinib did not show any potent inhibition. For example, Compound 73 of Formula (I), namely, N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide, showed potent inhibition in both PC9 and H1975 cell but not in H2073, whereas Afatinib showed potent inhibition in H2073, PC9 and H1975. Unlike Afatinib, some of this invention showed great EGFR wildtype selectivity in cellular level (for example, compound 73 with > 200 fold selective in cellular potency shown in Table 6). Table 6. The anti-proliferation activity against H2073, PC9 and H1975 by the selected compounds of Formula (I).Cellular potency: < 20 nM, 20-200 nM, 201-1000nM and >1000nMFold comparison (selectivity): < 20 fold, 20-100 fold, 101-200 fold and >200 foldCompound No EGFR wildtype EGFR Mutants Selectivity over wildtype Wildtype vs mutant H2073 (nM) PC9 (nM) H1975 (nM) H2073 / PC9 (fold) H2073 / H1975 (fold) Afatinib20-200<2020-200<20<20Erlotinib>100020-200>100020-100<2073 >1000<20<20>200>200146 >1000>1000>1000<20<20147 >1000>1000>1000<20<20148 >1000>1000>1000<20<20149 >1000>1000>1000<20<20151 >1000>1000>1000<20<20154 >100020-200201-1000<20<20155 >1000201-1000201-1000<20<20156 >1000>1000>1000<20<20157 >1000>1000>1000<20<20158 >100020-200201-1000<20<20159 >1000>1000>1000<20<20 3. Western Analysis

[0134] Compounds of the invention and references are tested for their effects on NSCLC cell lines to measure molecular potency against phosphorylation level of wildtype and mutant EGFR and illustrate selectivity over p-wildtype EGFR. The inhibition level of phosphorylation of mutant EGFR in NSCLC lines PC9 and H1975 should be illustrated to understand whether it is correlated with kinase enzyme potency and cellular potency of the compound. Based on these results, the selectivity of the compound against EGFR mutants over EGFR wildtype can be addressed in physiologically relevant molecular level.Method

[0135] NSCLC lines H1299, PC9, and H1975 were treated with the indicated concentration of compounds for 4 hours. The first generation reversible inhibitor Erlotinib and the irreversible inhibitor Afatinib were used for reference inhibitor. For wild EGFR activation experiment, H1299 cell line was simultaneously treated with addition of 3 nM EGF ligand. Cells were lysed in RIPA buffer (25mM Tris•HCl pH 7.6, 150mM NaCl, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS) containing protease and phosphatase inhibitor cocktail (Thermo scientific). Equivalent amounts of protein were separated by NuPAGE 4-12% Bis-Tris Gel system (Invitrogen ™< ), and then transferred to polyvinylidene difluoride membranes. Membranes were probed with an anti-phospho-Y1067 EGFR antibody (Cell Signaling Technology ™< ) and then stripped with Restore Western Blot Stripping Buffer (Thermo Scientific ™< ). Membranes were probed again with an anti-EGFR or anti-actin antibody (Cell Signaling Technology ™< ) for assessing loading control. The membranes were visualized by enhanced chemiluminescence.

[0136] To calculate inhibition of phosphorylation level of p-EGFR wildtype, p-EGFR del E746-A750 and p-EGFR L858R / T790M, the intensity of each band treated by indicated concentration of inhibitor was measured by densitometer to translate to numeric value and numeric value of each intensity was compared over that of each actin control at indicated concentration. The IC 50 value was determined by GraphPad Prism 5.Result

[0137] As used herein, the half maximal inhibitory concentration (IC 50 ) indicates 50% inhibition on the given phosphorylation level at Y1068 of each EGFR protein (e.g., p-EGFR wildtype, p-EGFR del E746-A750 and p-EGFR L858R / T790M) by the compounds of Formula (I).

[0138] Table 7 shows inhibition of phosphorylation level of mutant EGFR as compared to wildtype EGFR and provides the selectivity ratio of wildtype to mutant for each test compound. Selected compounds of Formula (I) such as compound 73 exhibited a potent inhibition against p-EGFR del E746-A750 and p-EGFR L858R / T790M but not p-EGFR wildtype (shown in Figure 1 and Table 7), while Afatinib showed potent inhibition against both p-EGFR wildtype, p-EGFR del E746-A750 and p-EGFR L858R / T790M. Table 7. The potency in phosphorylation level of EGFR wildtype and mutants by representative compounds of Formula (I)Molecular potency: < 20 nM, 20-200 nM, 201-1000nM and >1000nMFold comparison (selectivity): < 20 fold, 20-100 fold, 101-200 fold and >200 foldCompound No H1299 PC9 H1975 Selectivity over wildtype p-EGFR wildtypep-EGFR del 19 (E746-A750p-EGFR L858R, T790Mp-wildtype over p-EGFR del19p-wildtype over p-EGFR L858R, T790MErlotinib>1000<20>100020-100n.d.Afatinib20-200<20<2020-100<2073 201-1000<20<2020-10020-100

Claims

1. A compound which is a hydrate form of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide.

2. A compound which is a hydrate form of a pharmaceutically acceptable salt of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide.

3. A compound which is a pharmaceutically acceptable salt of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide and an acid selected from hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic, or hexanoic acid.

4. The compound of claim 2, wherein the pharmaceutically acceptable salt is a salt of an acid selected from hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic, or hexanoic acid.

5. The compound of claim 2, which is a hydrate form of a methanesulfonic acid salt of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide.

6. The compound of claim 3 which is a methanesulfonic acid salt of N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide.

7. A pharmaceutical composition comprising a compound according to any of claims 1 to 6 as an active ingredient.

8. A compound according to any of claims 1 to 6 or a pharmaceutical composition according to claim 7, for use in therapy.

9. A compound according to any of claims 1 to 6 or a pharmaceutical composition according to claim 7, for use in treating a disease or condition selected from allograft rejection, graft vs. host disease, diabetic retinopathy, choroidal neovascularization due to agerelated macular degeneration, psoriasis, arthritis, osteoarthritis, rheumatoid arthritis, synovial pannus invasion in arthritis, multiple sclerosis, myasthenia gravis, diabetes mellitus, diabetic angiopathy, retinopathy of prematurity, fibrosis, atherosclerosis, restenosis, autoimmune disease, allergy, respiratory diseases, asthma, transplantation rejection, inflammation, thrombosis, retinal vessel proliferation, inflammatory bowel disease, Crohn's disease, ulcerative colitis, bone diseases, transplant or bone marrow transplant rejection, lupus, chronic pancreatitis, cachexia, septic shock, fibroproliferative and differentiative skin diseases or disorders, central nervous system diseases, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, disorders or conditions related to nerve damage and axon degeneration subsequent to a brain or spinal cord injury, ocular diseases, viral infections, heart disease, lung or pulmonary diseases, kidney or renal diseases and bronchitis.

10. A compound according to any of claims 1 to 6 or a pharmaceutical composition according to claim 7, for use in treating a disease or condition selected from cancer, allograft rejection, graft vs. host disease, diabetic retinopathy, choroidal neovascularization due to age related macular degeneration, psoriasis, arthritis, osteoarthritis, rheumatoid arthritis, synovial pannus invasion in arthritis, multiple sclerosis, myasthenia gravis, diabetes mellitus, diabetic angiopathy, retinopathy of prematurity, atherosclerosis, restenosis, asthma, transplant rejection, inflammation, thrombosis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, lupus, chronic pancreatitis, Alzheimer's disease and Parkinson's disease.

11. A compound according to any of claims 1 to 6 or a pharmaceutical composition according to claim 7, for use in treating cancer.

12. The compound or the pharmaceutical composition for use according to claim 11, wherein the cancer is infantile hemangiomas, non-small cell lung, bladder cancer, head and neck cancer, prostate cancer, breast cancer, ovarian cancer, gastric or pancreatic cancer.

13. The compound or the pharmaceutical composition for use according to claim 12, wherein the cancer is non-small cell lung cancer.

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