MX2008005810A - Bi-aryl meta-pyrimidine inhibitors of kinases - Google Patents

Abstract

The invention provides biaryl meta-pyrimidine compounds having the general structure (A). The pyrimidine compounds of the invention are capable of inhibiting kinases, such as members of the Jak kinase family, and various other specific receptor and non receptor kinases.

Description

INHIBITORS OF BIARIL META-PYRIMIDINE OF KINASES FIELD OF THE INVENTION The present invention relates to the field of protein tyrosine kinase inhibitors, their pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders. In particular, the present invention relates to inhibitors of the JAK family of protein tyrosine kinases.

BACKGROUND OF THE INVENTION The protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified into tyrosine and serine / threonine kinases. Inappropriate kinase activity, which occurs from mutation, over-expression, or inappropriate regulation, dysregulation or de-regulation, as well as over- or under-production of growth factors or cytokines have been implicated in many diseases, including but not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer's disease. Inappropriate kinase activity triggers a variety of biological cellular responses related to cell growth, cell differentiation, survival, apoptosis, mitogenesis, cell cycle control, and cellular mobility involved in the aforementioned and related diseases. Protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention, in particular, the JAK family of cellular protein tyrosine kinases (Jak1, Jak2, Jak3, and Tyk2) plays a central role in cytokine signaling (Kisseleva et al. , Gene, 2002, 285, 1; Yamaoka et al., Genome Biology 2004, 5, 253)). By binding to its receptors, the cytokines activate JAK which then phosphorylates the cytokine receptor, thus creating starting sites for signaling molecules, notably members of the signal transducer and transcription activator (STAT) family that eventually lead to expression of genes. Numerous cytokines are known to activate the JAK family. These cytokines include, the IFN family (IFN-as / β /? / Limitin, IFN- ?, IL-10, IL-19, IL-20, IL-22), the gp130 family (IL-6, IL- 11, OSM, LIF, CNTF, NNT-1 / BSF-3, G-CSF, CT-1, Leptin, IL-12, IL-23), family yC (IL-2, IL-7, TSLP, IL- 9, IL-15, IL-21, IL-4, IL-13), IL-3 family (IL-3, IL-5, GM-CSF), single-chain family (EPO, GH, PRL TPO) , receptor tyrosine kinases (EGF PDGF, CSF-1, HGF), and G-protein coupled receptors (AT1). Until recently, the therapeutic potential of JAK inhibitors has been focused on diseases that affect several pathologies of the immune system. These include, but are not limited to atopy (allergic asthma, atopic dermatitis, allergic rhinitis), cell-mediated hypersensitivity (allergic contact dermatitis, hypersensitivity pneumonitis), rheumatic diseases (systemic lupus erythematosus (SLE), rheumatoid arthritis, juvenile arthritis) , Sjogren's syndrome, scleroderma, polymyositis, ankylosing spondylitis, psoriatic arthritis), transplantation (rejection of transplant, graft disease vs host), viral diseases (Epstein Barr virus, hepatitis B, hepatitis C, HIV, HTLV1, Varicella virus -Zoster, human papilloma virus), cancer (leukemia, lymphoma), cardiovascular disease (cardiac hypertrophy, atherosclerosis and arteriosclerosis), neurodegenerative diseases (motor neuron disease), food allergy, inflammatory bowel disease, Crohn's disease, inflammation cutaneous, and immune suppression induced by solid tumors. Most efforts to date have been directed to inhibition of JAK3 for immunosuppression, for example organ transplantation and allograft acceptance (for a review, see Borie et al., Current Opinion in Investigational Drugs, 2003, 4 (11) , 1297). Very recently, two significant findings of the role of the EPO-JAK2 signaling pathway in myeloproliferative disorders and proliferative diabetic retinopathy were found. First, a gain in function, somatic (acquired) mutation of JAK2 kinase (V617F) was reported to be a causative factor in a number of "typical" myeloproliferative disorders, including polycythemia vera, thrombocythemia essential and myelofibrosis with myeloid metaplasm, and the mutation has been found in patients with either "atypical" myeloproliferative disorders and myelodysplastic syndrome (for reviews, see Tefferi and Gilliland, Cell Cycle 2005, 4 (8), e61; Pesu et al. Molecular Interventions 2005, 5 (4), 211). In addition, it has been found that (a) the V617F JAK2 mutation was associated with constitutive phosphorylation of JAK2 and its effectors towards the 3 'end as well as induction of hypersensitivity to erythropoietin in cell-based experiments, (b) signals of cell proliferation induced by V617F JAK2-were inhibited by small molecule inhibitors of JAK2, and (c) murine bone marrow transduced with a retrovirus containing erythrocytosis induced by V617F JAK2 in mice that underwent transplantation. Furthermore, it has recently been found that mutations in EPO-R also maintain the JAK pathway constitutively activated leading to miloproliferative disorders. Second, EPO was found to be a potent angiogenic factor in proliferative diabetic retinopathy, an important cause of vision loss that affects diabetics of working age (see, eg, Aiello, New England Journal of Medicine, 2005, 353 (8). ), 839; Watanabe et al., New England Journal of Medicine 2005 353 (8), 782). In addition, findings from Watanabe's research showed that (a) intraocular EPO and VEGF levels (another well-known angiogenic factor in proliferative diabetic retinopathy) were significantly greater among those with proliferative diabetic retinopathy than those with Quiescent disease or non-diabetic control, (b) EPO and VEGF levels were not closely correlated, (c) EPO levels were more strongly correlated with the presence of proliferative diabetic retinopathy than VEGF, (d) EPO stimulated growth and intracellular signaling in retinal endothelial cells, and (e) inhibitors of either EPO or VEGF reduced retinal neovascularization induced by hypoxia in rodent models. It has recently been shown that mutations in the EPO receptor may also affect signaling related to the JAK pathway and this may have implications in terms of disease states where JAK signaling is important in the cell cycle. There is another feature regarding inhibitors of the pathway JAK It has been shown that the JAK pathway can be recruited into cell proliferation and survival. For example, in the case of cells that are positive on the Philadelphia chromosome that result in chronic myelogenous leukemia (CML), there is evidence that the Jak pathway is recruited into constitutive activation. Accordingly, the use of a JAK inhibitor may have use in CML in which the Philadelphia chromosome has been shown to produce the Bcr-Abl hybrid, thereby maintaining the constitutively active cells. In addition, in cases of resistance mutations that arise as an explanation of specific inhibitors to BCR-ABL, as in the case of the gate maintenance mutation T315I, or any other In the case of a mutation, it may be possible to use a JAK inhibitor to explain the pathway used by the BCR-ABL mutant (as in the case of the BCR-ABL mutation (T315Vff using the Jak pathway.) Therefore, Jak inhibitors can be use in the treatment of patients with resistance to known therapies where BCR-ABL is directly targeted and drug resistance has now shown to be the dominant (50-90%) of all resistance in patients where existing therapies fail. The use of JAK inhibitors may also find use in other conditions of myeloid disease, blood disorders and other disease states with myeloid implications, and other disease states in which the JAK pathway is directly or indirectly involved. , there is a need to develop compounds useful as inhibitors of kinases, particularly, JAK kinase, given the inadequate treatments available for diseases before where the JAK signaling path is deregulated, or recruited directly or indirectly.

BRIEF DESCRIPTION OF THE INVENTION In accordance with one modality, a compound having the structure (A) is provided: (A) According to another embodiment, a method for treating an angiogenic-associated disorder is provided, the method includes administering to a subject in need thereof a therapeutically effective amount of at least one compound having the structure (A), or salts, hydrates, solvates, polymorphs, crystal forms, pharmaceutically acceptable N-oxides, and individual enantiomers and diastereomers thereof, to a subject in need of such treatment. In accordance with other embodiments, pharmaceutical compositions and articles of manufacture are provided, including at least one compound having the structure (A), or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual pharmaceutically acceptable diastereomers thereof.

DETAILED DESCRIPTION OF THE INVENTION A. Terms and definitions The following terminology and definitions apply as used in the present application, generally in accordance with the terminology recommended by the International Union of Pure and Applied Chemistry (IUPAC): The term "heteroatom" refers to any atom other than carbon, for example, N, O, or S. The term "aromatic" refers to a molecular entity cyclically conjugated with a stability, due to derealization, significantly greater than that of a hypothetical localized structure, such as the structure of Kekulé. The term "heterocyclic," when used to describe an aromatic ring, refers to aromatic rings that contain at least one heteroatom, as defined above. The term "heterocyclic", when not used to describe an aromatic ring, refers to cyclic (i.e. ring-containing) groups other than aromatic groups, the cyclic group being formed from 3 to about 14 carbon atoms and at least one heteroatom described above. The term "substituted heterocyclic" refers, for both aromatic and non-aromatic structures, to heterocyclic groups also having one or more substituents described below. The term "alkyl" refers to a monovalent straight or branched chain hydrocarbon group having from one to about 12 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl , tert-butyl, n-pentyl (also known as n-amyl), n-hexyl, and Similar. The term "lower alkyl" refers to alkyl groups having from 1 to about 6 carbon atoms. The term "substituted alkyl" refers to alkyl groups further having one or more substituents such as hydroxy, alkoxy, mercapto, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, aryl, substituted heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy , halogen, cyano, nitro, amino, amido, aldehyde, acyl, oxyacyl, carboxyl, sulfonyl, sulfonamide, sulfuryl and the like. The term "alkenyl" refers to straight or branched chain hydrocarbyl groups having at least double carbon-carbon bond, and having between about 2 and about 12 carbon atoms, and the term "substituted alkenyl" refers to groups alkenyl which also have one or more substituents described above. The term "alkynyl" refers to straight or branched chain hydrocarbyl groups having at least triple carbon-carbon bond, and having between about 2 and about 12 carbon atoms, and the term "substituted alkynyl" refers to groups alkynyl which also have one or more substituents described above. The term "aryl" refers to aromatic groups having between about 5 and about 14 carbon atoms and the term "substituted aryl" refers to aryl groups further having one or more substituents described above. The term "heteroaryl" refers to aromatic rings, wherein the ring structure is formed by between 3 and about 14 carbon atoms and at least one heteroatom described above, and the term "substituted heteroaryl" refers to heteroaryl groups further containing one or more substituents described above. The term "alkoxy" refers to the -O-alkyl portion, wherein alkyl is as defined above, and the term "substituted alkoxy" refers to alkoxy groups further containing one or more substituents described above. The term "cycloalkyl" refers to alkyl groups having between 3 and about 8 carbon atoms arranged as a ring, and the term "substituted cycloalkyl" refers to cycloalkyl groups further containing one or more substituents described above. The term "alkylaryl" refers to alkyl-substituted aryl groups and the term "substituted alkylaryl" refers to alkylaryl groups further containing one or more substituents described above. The term "arylalkyl" refers to aryl-substituted alkyl groups and the term "substituted arylalkyl" refers to arylalkyl groups further containing one or more substituents described above. The term "arylalkenyl" refers to aryl-substituted alkenyl groups and the term "substituted arylalkenyl" refers to arylalkenyl groups further containing one or more substituents described above. The term "arylalkynyl" refers to aryl-alkyl groups substituted and the term "substituted arylalkyl" refers to arylalkynyl groups further containing one or more substituents described above. The term "arylene" refers to divalent aromatic groups having between 5 and about 14 carbon atoms and the term "substituted amylene" refers to arylene groups further containing one or more substituents described above. The term "chemically connected" is defined as forming a chemical entity in which two portions form a direct chemical bond between them. The term "kinase" refers to any enzyme that catalyzes the addition of phosphate groups to a protein residue; for example, serine and threonine kinases catalyze the addition of phosphate groups to serine and threonine residues. The term "JAK kinase" refers to an enzyme found in cells in the immune system that participate in the cell signaling process that results in the development of white blood cells. The term "therapeutically effective amount" refers to the amount of the compound or pharmaceutical composition that will induce the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, physician or other clinician, e.g., resumption or maintenance of vasculostasis or prevention of compromise or loss or vasculostasis; reduction of tumor burden; reduction of morbidity and / or mortality.

The term "pharmaceutically acceptable" refers to the fact that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The terms "administration of a compound" or "administering a compound" refers to the act of providing a compound of the invention or pharmaceutical composition to the subject in need of treatment. The term "antibody" refers to intact polyclonal or monoclonal antibody molecules, as well as fragments thereof, such as Fab and F (ab ') 2, Fv and SCA fragments that are capable of binding to an epitope determinant. The term "vasculostasis" refers to the maintenance of homeostatic vascular functioning that leads to normal physiological functioning. The term "vasculostatic agents" refers to agents that seek to face conditions in which the vasculostasis is compromised by preventing the loss of or resumption or maintenance of vasculostasis.

B. Modalities of the invention In accordance with one embodiment of the invention, compounds having the structure (A) are provided for the treatment of various diseases, disorders and pathologies: (A) In structure (A), X may be any one bond, O, C = O, SO2, or CH2, and Y may be a bond or NR9; or X and Y taken together can be a link. In addition, in structure (A) each of R1 and R2 can be any of H, substituted or unsubstituted C6 alkyl, unsubstituted or substituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, or substituted heteroaryl. or unsubstituted; or R1 and R2 taken together can be a bond; or R1 and R2 taken together can form a portion such as one of (CH2) m, (CH2) rS- (CH2) m, (CH2) rSO- (CH2) m, (CH2) -SO2- (CH2) m, (CH2) r-NR9- (CH2) ffi, or (CH2) rO- (CH2) m, wherein each of p, q, r, n, m is independently an integer having the value between 0 and 6. In addition, in the structure (A) R9 can be one of H, d-Cß alkyl, Ci-Ce cycloalkyl, branched C de-C6 alkyl, substituted d-C6 alkyl, CrC6 aminoalkyl, or C-hydroxy alkyl. -? - C6; G0 can be one of N, O, H, of CH, with the proviso that if G0 is N, then each of R3 and R4 can be one of H, Ci-Cß alkyl, substituted or unsubstituted hydroxyalkyl of Ci -Ce or aminoalkyl, substituted or unsubstituted branched alkyl of C Ce, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R3 and R4 taken together may form a portion such as a of (CH2) m, (CH2) rS- (CH2) m, (CH2) -SO- (CH2) m, (CH2) r-SO2- (CH2) m, (CH2) -NR9- (CH2) m, or (CH2) rO- (CH2) m. There are some additional conditions directed to G0 in the structure (A). More specifically, if G0 is N, then R1 and R9 taken together can form a portion such as one of (CHz) m, (CH2) rS- (CH2) m, (CH2) -SO- (CH2) m, CH2) -S02- (CH2) m, (CH2) -NR9- (CH2) m, or (CH2) r-0- (CH2) m; or R1 and R4 taken together can form a portion such as one of (CH2) m, (CH2) rS- (CH2) m, (CH2) r-SO- (CH2) m, (CH2) rS02- (CH2) m , (CH2) -NR9- (CH2) m, or (CH2) rO- (CH2) m; or R9 and R4 taken together can form a portion such as one of (CH2) m, (CH2) rS- (CH2) m, (CH2) r-SO- (CH2) m, (CH2) r-SO2- (CH2 ) m, (CH2) r-NR9- (CH2) m, or (CH2) rO- (CH2) m; or R3 and R4 taken together can form a portion such as one of (CH2) m, (CH2) rS- (CH2), (CH2) r-SO- (CH2) m, (CH2) r-S02- (CH2) m, (CH2) rNR6- (CH2) m, or (CH2) rO- (CH2) m. If in structure (A) G0 is O, then R3 may be one of H, CrC6 alkyl and hydroxyalkyl or substituted or unsubstituted C6 alkyl aminoalkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted cycloalkyl, substituted heterocyclic connected through carbon or nitrogen, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl connected through carbon or nitrogen, without R4 group; R1 and R9 taken together can form a portion such as one of (CH2) m, (CH2) -S- (CH2) m, (CH2) r-SO- (CH2) m, (CH2) r-SO2- (CH2 ) m, (CH2) r-NR9- (CH2) m, or (CH2) -0- (CH2) m; or R1 and R3 taken together can form a portion such as one of (CH2) m, (CH2) rS- (CH2) m, (CH2) rSO- (CH2) m, (CH2) r-SO2- (CH2) m , (CH2) r-NR9- (CH2) m, or (CH2) r-O- (CH2) m; or R9 and R3 taken together can form a portion such as one of (CH2) m, (CH2) rS- (CH2) m, (CH2) rSO- (CH2) m, (CH2), -SO2- (CH2) m , (CH2) r-NR9- (CH2) m, or (CH2) -O- (CH2) m. If in structure (A) Go = CH, then each of R3 and R4 may be one of H, CrC6 alkyl, hydroxyalkyl or substituted or unsubstituted aminoalkyl of CrC6, substituted or unsubstituted branched alkyl of CrC6, substituted aryl or unsubstituted aryl, substituted or unsubstituted heterocyclic of CrC6 connected through carbon or nitrogen, or substituted or unsubstituted heteroaryl connected through carbon or nitrogen, or R3 and R4 taken together may form a portion such as one of (CHR9) r, - (CHR9) m- (CHR9) p, (CHR9) rS- (CHR9) m, (CHR9) r-SO- (CHR9) m, (CHR9) r-SO2- (CHR9) m, (CHR9) r-NR9- (CHR9) m, or (CHR9) rO- (CHR9) m. Furthermore, in structure (A) G it can be N or CR6, and each G is independent of one another G, with the additional proviso that no more than two G groups can be N, with the proviso that for each CR, each R6 is independent of each other R6. In addition, in structure (A) R5 is methyl and portion Q is as shown below.

In the Q portion, each of R 6, n R7, n Rß can be one of H, unsubstituted or substituted C-Cß alkyl, substituted or unsubstituted C de-C6 alkenyl, substituted or unsubstituted alkynyl of CrC6, hydroxyalkyl or substituted or unsubstituted aminoalkyl of Ci-Cβ, substituted or unsubstituted branched alkyl of C C6, substituted cycloalkyl or unsubstituted of C -? - C6, substituted or unsubstituted aryl connected through carbon or a heteroatom, substituted or unsubstituted heteroaryl connected through carbon or a heteroatom, C6 alkoxy, a halogen, CF3, -OCF3 , CHR3R4, SR3, SOR3, SO2R3, SO2NR3R4, SO3R3, POR3, PO2R3, PO2NR3R4, P02CR3R4, P03R3, NR3R4, N02, CN, OH, CONR3R4, COR3, COOR3, NR3COR4, NR3CONR3R4, OCONR3R4, CSNR3R4, CSR3, NR3CSNR3R4, SCONR3R4, SCSNR3R4, or SCSNR3R4; or any of R6 and R7 taken together, or R7 and R8 taken together, or R6 and R8 taken together can form a portion independently selected from any of -HN-CH = CH-, -HN-N = CH-, -HN- N = N-, -O (CH2) nO- -S (CH2) nS-, -N = CH-S-, -CH = NO- -CH = NS-, -N = CH-O-, -C = NO-, -C = NO-, -CH = CH-CH = CH-, -N = CH-CH = CH-, -CH = N-CH = CH-, -O-CH = CH, and -S- CH = CH-; or R3 and R4 taken together can form a portion such as one of (CHR9) r (CHR9) ra- (CHR9) p > (CHR9) rS- (CHR9) m, (CHR9), - SO- (CHR9) m, (CHR9) -S02- (CHR9) m, (CHR9) rNR9- (CHR9) m, or (CHR9) -O- (CHR9) m. In addition, in structure (A), A may be one of O, NR3, CR3R4, S, SO, and S02; and in the Q portion, G-i can be any of CH, N, NH, S and O, and G2 can be any of CR7, N, NH, S and O, with each R7 group being independent of each other R7 group; and if G-i or G2 is NH, S, or O, then Q is a five-membered heteroaromatic ring, optionally fused to a aromatic or non-aromatic six-membered ring; and if G2 is N, then Q is a five or six membered aromatic ring, optionally fused to an aromatic or non-aromatic six membered ring, with the proviso that X or Go includes at least one hetero atom included with X and selected of O, S and N, or Go comprises at least four atoms that are not hydrogen, inclusive of the heteroatom, and R3 and R4, or R1 and R9, or R1 and R4, or R9 and R4 taken together can form a system of aromatic, heteroaromatic, cyclic or heterocyclic ring, or if a non-cyclic system is present, then more than one heteroatom is present, and if A is NR3, then either R6, R7 or R8, or any combination thereof independently includes at least two substituents that are not hydrogen, or if A is NR3, then Q forms a fused ring from Re to R7, r from R7 to Re- Some illustrative compounds described by structure (A) that can be used include, but are not are limited to, the following compounds I to C LXII shown below: eleven II] rv SAW Vile HIV IX XI XII Xlll XIV XV XVI XV 11 XV1IJ XIX XX XXI XXII XXIII XXJV XXV XXVI XXVII xxvni XXIX xxx XXX1 XXX1J xxxm XXXIV XXXV XXXVIII XL 20 XLV1 LT twenty LVll LX11I LXVI fifteen LXVIII LXXJGI LXXIH LXXVI1I LXXIX LXXXII LXXXIII LXXX? TÍ LXXX VII LXX XVIII LXXXIX XCII xvv XCV1I XCIX twenty cu CIV CX CXVl CXXl cxxip CXXV cxxvii cxxvpi fifteen CXXIX CXXXIV cxxxv CXXXVI cxxxvp CXXXVIll CXXXIX CXLI CXLIII CXLVJJ cxLvip CLIII fifteen CLVIIl CLXT CLXIl According to another embodiment of the invention, the compounds having the general structure (Z): B-C (Z) are provided for the treatment of various diseases, disorders and pathologies The general structure (Z) includes two chemically connected B and C portions. Portion B in the general structure (Z) includes any selected portion of the following group: Portion C in structure (Z), above, includes any selected portion of the following group: The compounds and methods of the present invention, or pharmaceutically acceptable individual diastereomers, hydrates, solvates, crystal forms and diastereomers thereof, either when administered alone or in combination with other agents (e.g., chemotherapeutic agents or agents) protein therapeutics described below) are useful in the treatment of a variety of disorders, including, but not limited to, for example, myeloproliferative disorders, proliferative diabetic retinopathy and other angiogenic-associated disorders including solid tumors and other cancers, disease of the eyes, inflammation, psoriasis, and a Viral infection. Types of cancer that can be treated include, but are not limited to, a cancer of the alimentary tract / gastrointestinal tract, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma , leukemia (including acute myelogenous leukemia and chronic myelogenous leukemia), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer or brain cancer. Some examples of diseases and disorders that can be treated also include ocular neovascularization, infantile hemangiomas; organ hypoxia, vascular hyperplasia, rejection of organ transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type 1 diabetes and complications of diabetes, inflammatory disease, acute pancreatitis, chronic pancreatitis, asthma, allergies, respiratory distress syndrome in adults, cardiovascular disease, liver disease, other blood disorders, asthma, rhinitis, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, conditions associated with cytokines, and other autoimmune diseases including glomerulonephritis, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopy (e.g., allergic asthma, atopic dermatitis, or allergic rhinitis), chronic active hepatitis, myasthenia gravis, multiple sclerosis, intestinal disease inflates matoria, graft-versus-host disease, neurodegenerative diseases including neuron disease motor, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, or neurodegenerative disease caused by traumatic injury, stroke, neurotoxicity due to gluatamate or hypoxia; ischemic / reperfusion injury in cerebral vascular accident, myocardial ischemia, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, hypoxia of organs, and aggregation of platelets. Examples of some additional diseases and disorders that can be treated also include cell-mediated hypersensitivity (allergic contact dermatitis, hypersensitivity pneumonitis), rheumatic diseases (e.g., systemic lupus erythematosus (SLE), juvenile arthritis, Sjogren's syndrome, scleroderma, polymyositis, alkylosing spondylitis, psoriatic arthritis), viral diseases (Epstein Barr virus, Hepatitis B, Hepatitis C, HIV, HTLV1, Varicella-Zoster virus, human papilloma virus), food allergy, skin inflammation and suppression Immune induced by solid tumors. The embodiments of the present invention also provide articles of manufacture which may include a packaging material and a pharmaceutical composition contained within the packaging material. The packaging material may comprise a label indicating that the pharmaceutical composition can be used for the treatment of one or more disorders identified above.

The pharmaceutical composition can include a compound according to the present invention. In addition to a compound of the present invention, the pharmaceutical composition may also contain other therapeutic agents, and may be formulated, for example, using conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the desired mode of administration ( for example, excipients, binders, preservatives, stabilizers, flavors, etc.) in accordance with techniques known in the pharmaceutical formulating art. Therefore, in one embodiment, the invention provides a pharmaceutical composition that includes a therapeutic agent and a compound of the invention. The compound is present in an effective concentration to treat, for example, cancer or to treat another disease or disorder described above. The compounds of the invention can be formulated into therapeutic compositions such as natural or salt forms. The non-toxic pharmaceutically acceptable salts include the basic addition salts (formed with free carboxyl or other anionic groups) which can be derived from inorganic bases such as, for example, sodium, potassium ammonium, calcium or ferric hydroxides, and bases organic compounds such as isopropylamine, trimethylamine, 2-ethylamino-ethanol, histidine, procaine, and the like. Said salts can also be formed as acid addition salts with any free cationic groups and will generally be formed with inorganic acids such as, for example, hydrochloric, sulfuric or phosphoric acids, or organic acids such as acetic, citric, p-toluenesulfonic, methanesulfonic, oxalic, tartaric, mandelic and the like. The salts of the invention can include amine salts formed by the protonation of an amino group with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric acid and the like. The salts of the invention may also include amine salts formed by the protonation of an amino group with suitable organic acids, such as p-toluenesulfonic acid, acetic acid, methanesulfonic acid and the like. Additional excipients that are contemplated for use in the practice of the present invention are those available to those skilled in the art, for example those found in the United States Pharmacopeia (Vol. XXII and National Formulary Vol. XVII). , US Pharmacopeia Convention, Inc., Rockville, MD (1989), whose relevant content is incorporated herein by reference. In addition, the polymorphs of the compounds of the invention are included in the present invention. The pharmaceutical compositions of the invention can be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingual; oral; parenteral, such as by subcutaneous, intravenous, intramuscular, intrathecal or intracystemic injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation, aspersion; topically, such as in the form of a cream ointment; or rectally such as in the form of suppositories; in unit dose formulations containing non-toxic pharmaceutically acceptable carriers or diluents. The compounds of the present, for example, can be administered in a form suitable for immediate release or prolonged release. Immediate release or prolonged release can be achieved by the use of suitable pharmaceutical compositions comprising the compounds of the present invention or, particularly in the case of prolonged release, by the use of devices such as subcutaneous implants or osmotic pumps. The compounds herein can also be administered liposomally. In addition to primates, such as humans, a variety of other mammals can be treated in accordance with the method of the present invention. For example, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other species of bovine, ovine, equine, canine, feline, rodent or murine can be treated. However, the method can also be implemented in other species, such as bird species (e.g., chickens). Pharmaceutical compositions for the administration of the compounds of this embodiment, either alone or in combination with other therapeutic agents, may conveniently be present in a dosage unit form and may be prepared by any of the methods well known in the art. pharmacy. All methods include bringing the active ingredient into association with the vehicle constituting one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately carrying the active ingredient in association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect on the disease process or condition. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. The compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and said compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives. in order to provide pharmaceutically elegant and palatable preparations. The tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; agents binders, for example, starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to retard disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated to form osmotic therapeutic tablets for control delivery. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the ingredient active is mixed with water or an oily medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Said excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; Dispersing or wetting agents can be a phosphatide occurring naturally, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with aliphatic alcohols of long chain, for example heptadecaethylene oxyketanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides , for example polyethylene sorbitan monooleate. Also useful as a solubilizer is, for example, polyethylene glycol. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. Suitable dispersible powders and granules for the preparation of an aqueous suspension by the addition of water provides the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Dispersing agents or Suitable humectants and dispersing agents are illustrated by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present. The syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Said formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated in accordance with the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a diluent or solvent or cosolvent or parenterally acceptable excipient or complexing agent or excipient or combination thereof, for example, 1,3-butanediol, polyethylene glycols, polypropylene glycols , ethanol or other alcohols, povidones, various brands of surfactant TWEEN, sodium dodecylsulfate, sodium deoxycholate, dimethylacetamide, polysorbates, poloxamers, cyclodextrins, lipids, and excipients such as inorganic salts (e.g., sodium chloride), pH regulating agents (e.g., sodium citrate, sodium phosphate), and sugars (e.g., sucrose and dextrose). Among the acceptable vehicles and solvents that can be used are water, dextrose solutions, Ringer's solutions and isotonic sodium chloride solution. Further, Sterile fixed oils are conventionally used as a solvent or suspension medium. For this purpose, any blended fixed oil can be used including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectable materials. Depending on the condition being treated, these pharmaceutical compositions can be formulated and administered systemically or locally. The techniques for formulation and administration can be found in the latest edition of "Remington's Pharmaceutical Sciences" (Mack Publishíng Co, Easton Pa.). Suitable routes may include, for example, oral or transmucosal administration; as well as parenteral administration, including intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal or intranasal administration. For injection, the pharmaceutical compositions of the invention can be formulated in aqueous solutions, preferably in physiologically compatible pH regulators such as Hanks' solution, Ringer's solution, or physiologically regulated saline at their pH. For tissue or cellular administration, the appropriate penetrants for the particular barrier to be penetrated are used in the formulation. Such penetrants are generally known in the art. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. In addition, suspensions of the active compounds can be prepared as suspensions of appropriate oily injection. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain stabilizers or suitable agents that increase the solubility of the compounds to allow the preparation of highly concentrated solutions. The compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-limiting excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. These materials are cocoa butter and polyethylene glycols. For topical use, the creams, ointments, jellies, solutions or suspensions, etc., which contain the compounds of the present invention are used. (For the purposes of this application, the topical application will include mouthwash and gargle). In one embodiment, the compounds of the invention are administered in combination with an anti-inflammatory agent, antihistamines, chemotherapeutic agent, immunomodulator, therapeutic antibody or a protein kinase inhibitor, e.g., a tyrosine kinase inhibitor, to a subject who needs such treatment. Although not wishing to be limiting, chemotherapeutic agents include antimetabolites, such as methotrexate, DNA crosslinking agents, such as cisplatin / carboplatin; alkylating agents, such as canbusil; Topoisomerase I inhibitors such as dactinomycin; microtubule inhibitors such as taxol (paclitaxel), and the like. Other chemotherapeutic agents include, for example, a vinca alkaloid, mitomycin-type antibiotic, bleomycin-type antibiotic, antifolate, colchicine, demecholine, etoposide, taxane, anthracycline antibiotic, doxorubicin, daunorubicin, carminomycin, epirubicin, darubicin, mitoxantrone, 4-dimethoxy-daunomycin, 11-deoxidaunorubicin, 13-deoxidaunorubicin, 14-adriamycin benzoate, adri-cyclin-14-octanoate, adriamycin-14-naphthalene acetate, amsacrine, carmustine, cyclophosphamide, cytarabine, etoposide, lovastatin, melphalan, topetecan, oxalaplatin, chlorambucil, methotrexate, lomustine, thioguanine, asparaginase, vinblastine, vindesine, tamoxifen, or mechlorethamine. Although not wishing to be limiting, therapeutic antibodies include antibodies directed against the HER2 protein, such as trastuzumab; antibodies directed against growth factors or growth factor receptors, such as bevacizumab, which directs vascular endothelial growth factor, and OSI-774, which directs epidermal growth factor; antibodies that direct integrin receptors, such as Vitaxin (also known as MEDI-522), and the like. Classes of anticancer agents suitable for use in compositions and methods of the present invention include, but are not limit to: 1) alkaloids, including microtubule inhibitors (eg, Vincristine, Vinblastine and Vindesine, etc.), microtubule stabilizers (eg, Paclitaxel [Taxol], and Docetaxel, Taxotere, etc.) , and inhibitors of chromatin function, including, topoisomerase inhibitors, such as, epipodophyllotoxins (e.g., Etoposide [VP-16], and Teniposide [VM-26], etc.), and topoisomerase I directing agents ( v.gr., Camptotecina and Isirinotecan [CPT-11], etc.); 2) covalent DNA binding agents [alkylating agents], including, nitrogen mustards (e.g., Mechlorethamine, Chlorambucil, Cyclophosphamide, Ifosfamide and Busulfan [Myleran], etc.), nitrosoureas (e.g., Carmustine, Lomustine and Semustine, etc.), and other alkylating agents (e.g., Dacarbazine, Hydroxymethylmelamine, Tiotepa and Mitocycline, etc.); 3) non-covalent DNA binding agents [antitumor antibiotics], including, nucleic acid inhibitors (e.g., Dactinomycin [Actinomycin D], etc.), anthracyclines (e.g., Daunorubicin [Daunomycin and Cerubidine], Doxorubicin [Adriamycin], and Idarubicin [Idamicin], etc.), anthracenediones (e.g., anthracycline analogs, such as, [Mitoxantrone], etc.), bleomycins (Blenoxane), etc., and plicamycin (Mithramycin), etc.; 4) antimetabolites, including, antifolates (e.g., Methotrexate, Folex and Mexato, etc.), purine antimetabolites (e.g., 6-Mercaptopurine [6-MP, Purinetol], 6-Thioguanine [6-TG ], Azathioprine, Acyclovir, Ganciclovir, Chlorodeoxyadenosine, 2-Chlorodeoxyadenosine [CdA], and 2'-Deoxicoformycin [Pentostatin], etc.), pyrimidine antagonists (e.g., fluoropyrimidines [e.g., 5-fluorouracil ( Adrucil), 5-fmorodeoxyuridine (FdUrd) (Floxuridine)] etc.), and cytosine arabinosides (e.g., Citosar [ara-C] and Fludarabine, etc.); 5) enzymes, including, L-asparaginase; 6) hormones, including, glucocorticoids, such as, antiestrogens (e.g., Tamoxifen, etc.), non-steroidal antiandrogens (e.g., Flutamide, etc.), and aromatase inhibitors (e.g., anastrozole [Arimidex], etc.); 7) platinum compounds (e.g., Cisplatin and Carboplatin, etc.); 8) conjugated monoclonal antibodies such as anticancer drugs, toxins, and / or radionuclides, etc .; 9) biological response modifiers (e.g., interferons [e.g., IFN-alpha, etc.] and interleukins [e.g., IL-2, etc.], etc.); 10) adoptive immunotherapy; 11) hematopoietic growth factors; 12) agents that induce differentiation of tumor cells (e.g., all-trans retinoic acid, etc.); 13) gene therapy techniques; 14) antisense therapy techniques; 15) tumor vaccines; 16) therapies directed against tumor metastasis (e.g., Batimistat, etc.); and 17) angiogenesis inhibitors. The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as indicated herein which are usually applied to the treatment of the aforementioned pathological conditions. Examples of other therapeutic agents include the following: cyclosporins (e.g., cyclosporin A), CTLA4-lg, antibodies such as ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti- CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, agents that block the interaction between CD40 and gp39, such as antibodies specific for CD40 and / or gp39 (ie, CD 154) , fusion proteins constructed of CD40 and gp39 (CD40lg and CD8gp39), inhibitors, such as inhibitors of nuclear translocation, of NF-kappa B function, such as deoxyspergualin (DSG), cholesterol biosynthesis inhibitors such as HMG CoA reductase inhibitors (lovastatin and simvastatin), nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and cyclooxygenase inhibitors such as rofecoxib, steroids such as prednisone or dexamethasone, gold compounds, antiproliferative agents such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate-mofetil, cytotoxic drugs such as azathioprine and cyclophosphamide, TNF-a inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof. Other agents that can be administered in combination with the compounds of the invention include protein therapeutic agents such as cytokines, immunomodulatory agents and antibodies. As used herein, the term "cytokine" encompasses chemokines, interleukins, lymphokines, monocins, colony stimulating factors, and receptor-associated proteins, and functional fragments thereof. As used herein, the term "functional fragment" refers to a polypeptide or peptide that possesses biological function or activity that is identified through a defined functional test. Cytokines include endothelial monocyte II activation polypeptide (EMAP-II), granulocyte-macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF), macrophage-CSF (M-CSF), IL-I, IL -2, IL-3, IL-4, IL-5, IL-6, IL-12 and IL-13, interferons, and the like and which are associated with a particular biological, morphological or phenotypic alteration in a cell or cellular mechanism. When other therapeutic agents are used in combination with the compounds of the present invention, they may be used for example in amounts as indicated in the Physician Desk Reference (PDR) or as otherwise determined by one skilled in the art. In the treatment or prevention of conditions involving cell proliferation, an appropriate dose novel may generally be between about 0.01 and about 1000 mg per 1 kg of patient body weight per day which may be administered in a single dose or in multiple doses. For example, the dose level may be between about 0.01 and about 250 mg / kg per day; very closely, between about 0.5 and about 100 mg / kg per day. A suitable dose level may be between about 0.01 and about 250 mg / kg per day, between about 0.05 and about 100 mg / kg per day, or between about 0.1 and about 50 mg / kg per day, or about 1.0 mg / kg per day. For example, within this range, the dose may be between about 0.05 and about 0.5 mg / kg per day, or between about 0.5 and about 5 mg / kg per day, or between about 5 and about 50 mg / kg per day. For oral administration, the compositions may be provided in the form of tablets containing between about 1.0 and about 1,000. mg of the active ingredient, for example, about 1.0, about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, and about 1,000.0 mg of the active ingredient for the symptomatic adjustment of the dose to the patient to be treated. The compounds can be administered in a regimen of 1 to 4 times per day, such as once or twice a day. There may be a period without administration followed by another administration regime. It will be understood, however, that the specific dose level and dose frequency for a particular patient can be varied and will depend on a variety of factors including the activity of the specific compound used., metabolic stability and duration of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, combination of drugs, the severity of the particular condition, and therapy to which the host is subjected. The compounds of the present invention can be used, alone or in combination with an effective amount of a therapeutic antibody (or therapeutic fragment thereof), a chemotherapeutic agent or an agent Nmunotoxic, for the treatment of tumors. Illustrative examples of chemotherapeutic agents that can be used for this purpose include doxorubicin, docetaxel or taxol. Furthermore, it is to be understood that the invention includes combination therapy which includes a compound of the invention, including but not limited to vasculostatic agents, such as tyrosine, serine or threonine kinase inhibitors, and any chemotherapeutic agent or therapeutic antibody.

C. EXAMPLES The following examples are provided to further illustrate the advantages and characteristics of the preferably, but are not intended to limit the scope of the invention.

EXAMPLE 1 General methods All experiments were performed under anhydrous conditions (ie, dry solvents) in an argon atmosphere, except where it was established, using oven drying apparatus and using standard techniques in handling of air sensitive materials. Aqueous solutions of sodium bicarbonate (NaHCO3) and sodium chloride (brine) were saturated. Chromatography of each analytical thin (TLC) was carried out on plates Merck Kieselgel 60 F254 with ultraviolet visualization and / or immersions in anisaldehyde, potassium permanganate or phosphomolybdic acid. Reverse phase HPLC chromatography was carried out on Gilson 215 liquid handler equipped with Waters SymmetryShield ™ RP 18 7μm (40 x 100mm) Prep-Pak cartridge. The mobile phase consisted of standard acetonitrile (ACN) and DI water, each with 0.1% added TFA. The purification was carried out at a flow rate of 40 ml / min. NMR spectra: 1 H nuclear magnetic resonance spectra were recorded at 500 MHz. The data are presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quadriplete, qn = quintuplete, dd -doublet doublet, m = multiplet, br s = broadband synglete), coupling constant (J / Hz) and integration. The coupling constants were taken directly from the spectra and not corrected. Low resolution mass spectrum: Electrospray ionization (EA +) was used. The protonated parent ion (M + H) or higher mass fragment is mentioned. The analytical gradient consisted of 10% ACN in water amounting to 100% ACN for 5 min unless otherwise stated.

EXAMPLE 2 ^ - (4-Methoxy-phenyl) -pyrimidine-2,4-diamine (Intermediary 1) A mixture of 4-chloro-pyrimidin-2-ylamine (0.30 g, 2.3 mmol) and 4-methoxy-phenylamine (0.30 g, 2.4 mmol) was suspended in acetic acid (10 rnl) and heated to 100 ° C. for 2 hr. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH ~ 7 with 7M NaOH solution. The resulting solution was extracted with EtOAc (30 ml) and the organic layer was separated. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel (hexane to EtOAc) to give the title 1 intermediate (0.23 g, 45%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): 3.69 (s, 3 H), 5.84 (d, J = 5.8 Hz, 1 H), 6.79 (d, J = 9.1 Hz, 2 H), 7.63 (d, J = 9.1 Hz , 2H), 7.78 (d, J = 5.8 Hz, 1H), 8.65 (s, 1 H); MS (ESI +): m / z 217 (M + H) +.

EXAMPLE 3 ^ - (4-Methoxy-phenyl) - ^ 2-. { 4- (2-pyrrolidin-1-yl-ethoxy) -phenyl > -pyr? midin-2,4-diamine (Compound I) To synthesize compound I, intermediary 1 described above and intermediate 2 were used. Intermediate 2, 1- [2- (4-bromo-phenoxy) -ethyl] -pyrrolidine, shown below is commercially available, and was used how it was received (2) A suspension of intermediate 1 (74 mg, 0.34 mmol), intermediate 2 (0.10 g, 0.37 mmol), Pd (OAc) 2 (5 mg, 0.022 mmol), Xantphos (26 mg, 0.05 mmol) and ferrous Potassium butoxide (80 mg, 0.71 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 15 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by HPLC to give the title compound I (20 mg TFA salt, 11%) as a brown solid. 1 H NMR (500 MHz, DMSO-d 6): 1.80-1.95 (m, 2H), 1.95-2.10 (m, 2H), 3.05-3.20 (m, 2H), 3.55-3.65 (m, 4H), 3.77 (s, 3H), 4.29 (t, J = 4.9 Hz, 2H), 6. 30 (d, J = 6.8 Hz, 1 H), 6.96 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 6.2 Hz, 1 H), 9.87 (br s, 1 H), 10.22 (br s, 1H), 10.44 (br s, 1H); MS (ESI +): m / z 406 (M + H) +.

EXAMPLE 4 4- [4- (4-Methoxy-phenylamino) -pyrimidin-2-ylamino] - - (2-pyrrolidin-1-yl-ethyl) -benzenesulfonamide (Compound II) ? I To synthesize compound II, intermediary 1 described above and intermediate 3 were used. The intermediate 3,4-bromo-N- (2-pyrrolidin-1-yl-ethyl) -benzenesulfonamide, whose formula is shown below, is synthesized from 4-bromophenylsulfonyl chloride and 2-ammoethylpyrrolidine, using commonly known synthesis techniques.

A suspension of intermediate 1 described above (70 mg, 0.32 mmol), intermediate 3 (0.12 g, 0.36 mmol), Pd (OAc) 2 (5 mg, 0.022 mmol), Xantphos (26 mg, 0.05 mmol) and tert-butoxide of potassium (80 mg, 0.71 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 15 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by HPLC to give the title compound II (0.16 g of TFA salt, 85%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): 1.80-1.95 (m, 2H), 1.95-2.05 (m, 2H), 2.95-3.05 (m, 4H), 3.23 (q, J = 5.8 Hz, 2H), 3.50-3.60 (m, 2H), 3.79 (s, 3H), 6.41 (d, J = 6.8 Hz, 1 H), 6.99 (d, J = 8.9 Hz, 2H), 7.43 (d, J = 8.9 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 7.85-7.95 (m, 2H), 7.96 (t, J = 6.1 Hz, 1 H), 8.02 (d, J = 6.2 Hz, 1 H), 9.64 (br s, 1 H), 10.21 (br s, 1 H), 10.71 (br s, 1 H); MS (ESI +): m / z 469 (M + H) +.

EXAMPLE 5 4- [4- (4-Hydroxy-phenylamino) -pyrimidin-2-ylamino-1 - V- (2-pyrrolidin-1-yl-ethyl) -benzenesulfonamide (Compound III) III To a solution of the compound II described above (50 mg, 0.09 mmol) in DCM (6 ml) at room temperature was added BBr3 (0.1 ml) and the mixture was stirred at room temperature for 2.5 hr. The reaction was quenched with saturated NaHCO3 solution until the pH was -7 and the mixture was extracted with EtOAc (30 mL). The organic layer was separated and washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated and the resulting solid was redissolved in a minimum of EtOAc. Hexane was added until the solid was triturated and the title compound III was filtered off as a white solid (25 mg, 64%) without further purification. 1 H NMR (500 MHz, DMSO-d 6): 1.55-1.65 (m, 4H), 2.30-2.40 (m, 4H), 2.43 (t, J = 7.0 Hz, 2H), 2.82 (t, J = 6.6 Hz, 2H), 6.20 (d, J = 5.8 Hz, 1 H), 6.70 (d, J = 8.8 Hz, 2H ), 7.40 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 5.5 Hz, 1 H), 8.93 (s, 1 H), 9.08 (br s, 1 H), 9.70 (s, 1 H); MS (ESI +): m / z 455 (M + H) +.

EXAMPLE 6 4- (4-Chloro-pyrimidin-2-ylamino) -N- (2-pyrrolidin-1-yl-ethyl) -benzenesulfonamide (Intermediate 4) A mixture of 4-chloro-pyrimidin-2-ylamine (1.0 g, 7.8 mmol), intermediary 3 described above (2.6 g, 7.8 mmol), Pd (OAc) 2 (90 mg, 0.40 mmol), Xantphos (0.50 g) , 0.86 mmol) and potassium tert-butoxide (2.2 g, 20 mmol) was suspended in dioxane (30 ml) and heated to reflux under an argon atmosphere for 16 hr. The mixture was poured into water (30 ml) and extracted with EtOAc (60 ml). The organic layer was separated and washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash chromatography on silica gel (DCM at 25% MeOH / DCM) to give the title 4 intermediate (0.15 g, 5%) as a brown solid. MS (ESI +): m / z 382 (M + H) +.

EXAMPLE 7 4-f4- (3-Methoxy-phenylamino) -pyrimidin-2-ylaminol-M- (2-pyrrolidin-1-yl-etl) -benzenesulfonamide (Compound IV) IV A mixture of intermediate 4 described above (0.10 g, 0.26 mmol) and 3-methoxy-phenylamine (0.05 ml, 0.45 mmol) was suspended in acetic acid (6 ml) and heated at 100 ° C for 1.5 hr. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH ~ 7. The resulting solution was extracted with EtOAc (30 ml) and the organic layer was separated. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo and the crude product was purified by HPLC to give the title IV compound (55 mg of TFA salt, 36%) as a white solid. H NMR (500 MHz, DMSO-d6): 1.80-1.90 (m, 2H), 1.95-2.05 (m, 2H), 2.95-3.05 (m, 4H), 3.24 (q, J = 6.0 Hz, 2H), 3.50-3.60 (m, 2H), 3.73 (s, 3H), 6.40 (d, J = 6.3 Hz, 1 H), 6.68 (d, J = 7.3 Hz, 1 H), 7.18 (d, J = 8.2 Hz , 1 H), 7.26 (t, J = 8.0 Hz, 1 H), 7.30 (s, 1 H), 7.72 (d, J = 8.9 Hz, 2H), 7.91 (t, J = 6.1 Hz, 1 H) , 7.95 (d, J = 8.7 Hz, 2H), 8.10 (d, = 6.2 Hz, 1 H), 9.59 (br s, 1 H), 9.87 (br s, 1 H), 10.38 (br s, 1 H ); MS (ESI +): m / z 469 (M + H) +.

EXAMPLE 8 4-f4- (3-Hydroxy-phenylamino) -pyrimidin-2-ylamino] -A / - (2-pyrrolidin-1-yl-ethyl) -benzenesulfonamide (Compound V) To a solution of the above-described compound IV (30 mg, 0.05 mmol) in DCM (6 ml) at room temperature was added BBr3 (0.1 ml) and the mixture was stirred at room temperature for 2.5 hr. The reaction was quenched with saturated NaHCO3 solution until the pH was ~7 and the mixture was extracted with EtOAc (30 mL). The organic layer was separated and washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated and the residue was purified by HPLC to give the title compound V (13 mg TFA salt, 46%) as an off-white solid. H NMR (500 MHz, DMSO-d6): 1.80-1.90 (m, 2H), 1.95-2.05 (m, 2H), 2.95-3.05 (m, 4H), 3.20-3.30 (m, 2H), 6.39 (d , J = 6.3 Hz, 1 H), 6.53 (d, J = 7.2 Hz, 1 H), 7.01 (d, J = 9.2 Hz, 1 H), 7.09 (s, 1 H), 7.14 (t, J = 8.1 Hz, 1 H), 7.73 (d, J = 8.8 Hz, 2H), 7.90 (t, J = 6.2 Hz, 1 H), 7.97 (d, J = 8.8 Hz, 2H), 8.08 (d, J = 6.4 Hz, 1 H), 9.48 (br s, 1 H), 9.57 (br s, 1 H), 9.86 (br s, 1 H), 10.41 (br s, 1 H); MS (ESI +): m / z 455 (M + H) +.

EXAMPLE 9 Benzo [1,3ldioxol-5-yl- (2-chloro-5-methyl-pyrimidin-4-yl) -amine (Intermediate 5) A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 5-bromo-benzo [1,3] dioxol (0.45 g, 2.2 mmol), Pd (OAc) 2 (30 mg, 0.13 mmol), Xantphos (0.15 g, 0.26 mmol) and potassium tert-butoxide (0.45 g, 4.0 mmol) was suspended in dioxane (15 mL) and heated to reflux under an argon atmosphere for 16 hr. The reaction mixture was cooled to room temperature and diluted with DCM (20 ml). The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (hexane at 50% EtOAc / Hexane) to give the title 5 intermediate (0.10 g, 18%) as a white solid. MS (ESI +): m / z 264 (M + H) +.

EXAMPLE 10 N4-Benzop, 31-dioxol-5-yl-5-methyl- / V2- [4- (2-pyrrolidin-1-yl-ethoxy) -fenin-pyrimidine-2,4-diamine (Compound VI) vi To synthesize compound VI, intermediary 5 described above and intermediate 6 were used. Intermediate 6, 4- (2-pyrrolidin-1-yl-ethoxy) -phenylamine, whose formula is shown below, was synthesized in two. Steps, first by alkylation of 4-nitrophenol using 2-chloroethylpyrrolidine, followed by reduction to give the aniline derivative. 6 Commonly known synthesis techniques were used to synthesize intermediate 6. A mixture of intermediary 5 described above (90 mg, 0.34 mmol), intermediate 6 (95 mg, 0.46 mmol), Pd2 (dba) 3 (20 mg, 0.02) mmoles), Xantphos (30 mg, 0.05 mmol) and cesium carbonate (0.30 g, 0.9 mmol) was suspended in dioxane (10 ml) and heated to reflux under argon atmosphere for 20 hr. The reaction mixture was cooled to room temperature and diluted with DCM (20 ml). The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to give the title compound VI (40 mg of TFA salt, 21%) as a brown solid. 1 H NMR (500 MHz, DMSO-d 6): 1.85-1.95 (m, 2H), 1.95-2.05 (m, 2H), 2.13 (s, 3H), 3.10-3.20 (m, 2H), 4.26 (t, J = 5.0 Hz, 2H), 6.07 (s, 2H), 6.90-7.00 (m, 4H), 7.19 (s, 1 H), 7.37 (d, J = 9.0 Hz, 2H), 7.84 (s, 1 H) , 9.60 (br s, 1 H), 9.89 (br s, 1 H), 10.32 (br s, 1 H); MS (ESI +): m / z 434 (M + H) +.

EXAMPLE 11 (4-Chloro-3-methoxy-phenyl) - (2-chloro-5-methyl-pyrimidin-4-yl) -amine (Intermediate 7) A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mmol), 4-bromo-1-chloro-2-methoxy-benzene (0.65 mL, 4.8 mmol), Pd2 (dba) 3 (0.17 g, 0.19 mmole), Xantphos (0.22 g, 0.38 mmole) and cesium carbonate (2.3 g, 7.1 mmole) was suspended in dioxane (20 ml) and heated to reflux under argon atmosphere for 5 hr. The reaction mixture was cooled to room temperature and diluted with DCM (30 ml). The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by chromatography Flash over silica gel (hexane at 40% EtOAc / Hexane) to give the title 7 intermediate (0.55 g, 55%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d 6): 2.18 (s, 3 H), 3.85 (s, 3 H), 7.35 (dd, J = 8.6 Hz, J = 2.3 Hz, 1 H), 7.39 (d, J = 8.7 Hz, 1 H), 7.56 (d, J = 2.3 Hz, 1 H), 8.09 (d, J = 0.9 Hz, 1 H), 8.91 (s, 1 H); MS (ESI +): m / z 284 (M + H) +.

EXAMPLE 12 (4-Chloro-3-methoxy-phenyl) - (2-chloro-5-methyl-pyrimidin-4-yl) -methyl-amine (Intermediate 8) A suspension of intermediate 7 (0.50 g, 1.8 mmol) and sodium hydride (60% in mineral oil, 0.15 g, 3.8 mmol) in THF (10 mL) was stirred under argon atmosphere at 0 ° C for 5 min. Methyl iodide (0.15 ml, 2.4 mmol) was applied with syringe at the same temperature as the previous mixture. The resulting solution was stirred at 0 ° C to room temperature for 15 min and further stirred at room temperature for an additional 17 hr. The reaction was quenched with water (10 mL) and then extracted with EtOAc (30 mL). The organic layer was separated and washed brine, dried over MgSO 4 and filtered. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (hexane at 20% EtOAc / Hexane) to give the title intermediate 8 (0.20 g, 38%) as a white solid. MS (ESI +): m / z 298 (M + H) +.

EXAMPLE 13? / 2- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -? F4- (4-chloro-3-methoxyphenyl) -V4,5-dimethylpyrimidine-2,4-diamine (Compound Vile) VII A mixture of intermediate 8 (0.15 g, 0.49 mmol) and intermediate 6 (0.15 g, 0.73 mmol), each of said intermediates was described above, suspended in acetic acid (8 ml) and heated at 100 ° C for 17 hr. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (15 ml) and neutralized to pH ~ 7 with 7M NaOH solution. The resulting solution was extracted with EtOAc (30 ml) and the organic layer was separated. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under vacuum and the crude product was purified by HPLC to give the title compound. title VII (0.14 g of TFA salt, 49%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): 1.85-1.95 (m, 2H), 2.00--2.10 (m, 2H), 3.08-3.18 (m, 2H), 3.46 (s, 3H), 3.55-3.65 (m, 4H), 3.85 (s, 3H), 4.27 (t, J = 5.0 Hz, 2H), 6.86 (d, J = 7.4 Hz, 1 H), 7.01 (d, J = 9.0 Hz, 2H), 7.15 (s, 1 H), 7.46 (d, J = 8.4 Hz, 1 H), 7.58 (d, J = 8.9 Hz, 2 H), 7.83 (s, 1 H), 9.85 (br s, 1 H), . 04 (br s, 1 H), 10.32 (br s, 1 H); MS (ESI +): m / z 468 (M + H) +.

EXAMPLE 14 (2-Chloro-5-methyl-pyrimidin-4-yl) - (4-chloro-phenyl) -amine (Intermediate 9) A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 1-bromo-4-chloro-benzene (0.60 g, 3.1 mmol), Pd2 (dba) 3 (95 mg, 0.10 mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) was suspended in dioxane (20 ml) and heated to reflux under argon atmosphere for 4 hr. The reaction mixture was cooled to room temperature and diluted with DCM (20 ml). The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by chromatography Flash over silica gel (hexane at 30% EtOAc / Hexane) to give the title intermediate 9 (0.15 g, 28%) as a pale yellow solid. MS (ESI +): m / z 254 (M + H) +.

EXAMPLE 15 ^ 4- (4-Chloro-phenyl) -5-methyl-V2-f4- (2-pyrrolidin-1-yl-ethoxy) -fenin-pyrimidine-2,4-diamine (Compound VIII) VIII A mixture of the intermediates described above 9 (0.15 g, 0.60 mmol) and 6 (0.20 g, 0.97 mmol) was suspended in acetic acid (8 ml) and heated at 100 ° C for 6 hr. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (15 ml) and neutralized to pH ~ 7 with 7M NaOH solution. The resulting brown solid was filtered and further purified by HPLC to give the title compound VIII (38 mg TFA salt, 12%) as a brown oil. 1 H NMR (500 MHz, DMSO-d 6): 1.80-1.95 (m, 2H), 2.00--2.10 (m, 2H), 2.15 (s, 3H), 3.10-3.20 (m, 2H), 3.55-3.65 (m, 4H), 3.77 (s, 3H), 4.28 (t, J = 5.0 Hz, 2H), 6.95 (d , J = 9.0 Hz, 2H), 7.38 (d, J = 8.9 Hz, 2H), 7.42 (d, J = 8.9 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.90 (s, 1 H), 9.48 (br s, 1 H), 9.84 (br s, 1 H), . 10 (br s, 1 H); MS (ESI +): m / z 424 (M + H) +.

EXAMPLE 16 2- (4-Amino-phenoxy) ethanol (Intermediate 10) , ^ "10 A solution of 2- (4-nitro-phenoxy) -ethanol (2.1 g, 12 mmol) in MeOH (30 ml) was flushed with argon and then loaded with Pd / C (10% by weight). The mixture was evacuated under vacuum and then filled with hydrogen from a hydrogen balloon.The cycle was repeated again and the mixture was stirred at room temperature for 2 hr.The heterogeneous reaction mixture was filtered through a pad of Celite was washed with MeOH and concentrated in vacuo to give the title 10 intermediate (1.8 g, 99%) as a brown solid, MS (ESI +): m / z 154 (M + H) +.

EXAMPLE 17 2-. { 4- [4- (4-Chloro-3-methoxy-phenylamino) -5-methyl-pyrimidin-2-ylaminol-phenoxy) -ethanol (Compound IX) IX A suspension of the intermediates described above 7 (50 mg, 0.17 mmol), 10 (40 mg, 0.26 mmol), Pd2 (dba) 2 (8 mg, 0.01 mmol), Xantphos (10 mg, 0.02 mmol) and cesium carbonate (0.13 g, 0.40 mmoles) in dioxane (3 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160X for 15 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (hexane to EtOAc) to give the title IX compound (14 mg, 21%) as a light brown solid. 1 H NMR (500 MHz, DMSO-d 6): 2.10 (s, 3 H), 3.69 (t, J = 5.3 Hz, 2H), 3.75 (s, 3H), 3.92 (t, J = 5.1 Hz, 2H), 4.83 (t, J = 5.6 Hz, 1 H), 6.78 (d, J = 9.0 Hz, 2H), 7.29 (d , J = 8.5 Hz, 1 H), 7.43 (dd, J = 8.6 Hz, J = 2.2 Hz, 1H), 7.48 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 9.0 Hz, 2H), 7.88 (s, 1 H), 8.31 (s, 1H), 8.80 (s, 1 HOUR); MS (ESI +): m / z 401 (M + H) +.

EXAMPLE 18 5-Methyl-V2- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl-pyrimidine-2,4-diamine (Intermediate 11) 1. 1 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.13 g, 0.87 mmol) and the intermediary 6 described above (0.30 g, 1.5 mmol) was suspended in acetic acid (8 ml) and heated to 100 g. ° C for 2 hr. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (15 ml) and neutralized to pH ~ 7 with 7M NaOH solution. The resulting solid was filtered (30 mg) and washed with ether.

The filtrate was extracted with EtOAc (30 ml) and the organic layer was separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated to give the additional solid (0.2 g), which was combined with the first batch and gave the title 11 intermediate (0.23 g, 85%) as a light brown solid. 1 H NMR (500 MHz, DMSO-d 6): 1.65-1.70 (m, 4H), 1.89 (s, 3H), 2. 74 (t, J = 6.0 Hz, 2H), 3.98 (t, J = 6.1 Hz, 2H), 6.30 (s, 2H), 6.78 (d, J = 9.1 Hz, 2H), 7.62 (d, J = 9.1 Hz, 2H), 7.64 (s, 1 H), 8.50 (s, 1 H); MS (ESI +): m / z 314 (M + H) +.

EXAMPLE 19 5-Methyl- ^ 4-phenyl- ^ 2-r 4 - (2-pyrrolidin-1-yl-ethoxy) -fenin-pyrimidine-2,4-diamine (Compound X) A suspension of intermediary 11 described above (25 mg, 0.08 mmol), bromobenzene (0.05 ml, 0.50 mmol), Pd2 (dba) 2 (5 mg, 0.006 mmol), Xantphos (10 mg, 0.02 mmol) and cesium carbonate ( 70 mg, 0.21 mmol) in dioxane (3 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 15 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (30% DCM MeOH / DCM) to give the title compound X (10 mg, 32%) as a light brown solid. 1 H NMR (500 MHz, DMSO-d 6): 1.65-1.72 (m, 4H), 2.10 (s, 3H), 2.48-2.58 (m, 4H), 2.75-2.82 (m, 2H), 4.00 (t, J = 5.9 Hz, 2H), 6.77 (d, J = 9.0 Hz, 2H), 7.04 (t, J = 7.3 Hz, 1 H), 7.32 (t, J = 7.9 Hz, 2H), 7.54 (d, J = 9.0 Hz, 2H), 7.71 (d, J = 7.8 Hz, 2H), 7.84 (s, 1 H), 8.20 (s, 1H), 8.76 (s, 1 H); MS (ESI +): m / z 390 (M + H) +.

EXAMPLE 20 (4-Chloro-3-fluoro-phenyl) - (2-chloro-5-methyl-pyrimidin-4-yl) -amine (Intermediate 12) 12 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mmol), 4-Bromo-1-chloro-2-fluoro-benzene (1.0 g, 4.8 mmol), Pd2 (dba) 3 (0.16 g, 0.17 mmole), Xantphos (0.20 g, 0.34 mmole) and cesium carbonate (2.3 g, 7.0 mmole) was suspended in dioxane (25 ml) and heated to reflux under argon atmosphere for 15 hr. The reaction mixture was cooled to room temperature and diluted with DCM (30 ml). The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (hexane at 40% EtOAc / Hexane) to give the title 12 intermediate (0.75 g, 80%) as an off-white solid. MS (ESI +): m / z 272 (M + H) +.

EXAMPLE 21 / V4- (4-Chloro-3-fluoro-phenyl) -5-methyl- / V2-r4- (2-pyrrolidin-1-yl-ethoxy) -phenn. pyrimidine-2,4-diamine (Compound XI) XI A mixture of the intermediates described above 12 (0.20 g, 0.74 mmol) and 6 (0.20 g, 0.97 mmol) was suspended in acetic acid (8 ml) and heated at 100 ° C for 6 hr. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (15 ml) and neutralized to pH ~ 7 with 7M NaOH solution. The resulting solution was extracted with EtOAc (30 ml) and the organic layer was separated. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash chromatography on silica gel (30% DCM MeOH / DCM) to give the title compound XI (90 mg, 28%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): 1.65-1.71 (m, 4H), 2.10 (s, 3H), 2.45-2.55 (m, 4H), 2.77 (t, J = 6.0 Hz, 2H), 4.01 ( t, J = 6.0 Hz, 2H), 6.82 (d, J = 9. 0 Hz, 2H), 7.44 (t, J = 8.8 Hz, 1 H), 7.50 (d, J = 9.0 Hz, 2H), 7.55 (dd, J = 8.9 Hz, J = 2.0 Hz, 1 H), 7.91 (s, 1 H), 8.07 (dd, J = 12.5 Hz, J = 2.0 Hz, 1 H), 8.43 (s, 1 H), 8.90 (s, 1 H); MS (ESI +): m / z 442 (M + H) +.

EXAMPLE 22 ^^ - Chloro-S-methoxy-phenyD-S-methyl-^^ -morpholin ^ -ylmethyl-phenyD-pyrimidine-2,4-diamine (Compound XII) XII A suspension of the intermediary 7 described above (50 mg, 0.17 mmol), 4-morpholin-4-ylmethyl-phenol amine (50 mg, 0.26 mmol), Pd2 (dba) 2 (8 mg, 0.009 mmol), Xantphos (10 mg). mg, 0.02 mmol) and cesium carbonate (0.13 g, 0.40 mmol) in dioxane (3 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 15 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by HPLC to give the title compound XII (40 mg of TFA salt, 43%) as a pale yellow solid. 1 H NMR (500 MHz, DMSO-d 6): 2.16 (s, 3 H), 3.05-3.15 (m, 2 H), 3. 10-3.20 (m, 2H), 3.60-3.70 (m, 2H), 3.90-4.00 (m, 2H), 4.28 (s, 2H), 4.01 (t, J = 6.0 Hz, 2H), 7.25-7.35 ( m, 3H), 7.35-7.41 (m, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.98 (s, 1 H), 9.10 (br s, 1 H), 9.86 (br s, 1 H ), 9.95 (br s, 1H); MS (ESI +): m / z 440 (M + H) +.

EXAMPLE 23 Benzo [b] thiophen-5-yl- (2-chloro-5-methyl-pyrimidin-4-yl) -amine (Intermediate 13) 13 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmole), 5-bromo-benzo [b] thiophene (0.6 g, 2.8 mmole), Pd2 (dba) 3 (95 mg , 0.10 mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) was suspended in dioxane (25 ml) and heated to reflux under argon atmosphere for 3 hr. The reaction mixture was cooled to room temperature and diluted with DCM (30 ml). The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (hexane at 30% EtOAc / Hexane) to give the title intermediate 13 (0.23 g, 40%) as a white solid. MS (ESI +): m / z 276 (M + H) +.

EXAMPLE 24 ^ 4-Benzofb1thiophen-5-yl-5-methyl- ^ 2-f4- (2-pyrrolidin-1-yl-ethoxy) -fenin-pyrimidine-2,4-diamine (Compound XIII) X1LI A mixture of the intermediates described above 13 (0.23 g, 0.83 mmoles) and 6 (0.35 g, 1.7 mmoles) was suspended in acetic acid (8 ml) and heated at 100 ° C for 1 day. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (15 ml) and neutralized to pH ~ 7 with 7M NaOH solution. The resulting solution was extracted with EtOAc (30 ml) and the organic layer was separated. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash chromatography on silica gel (DCM at 15% MeOH / DCM) to give the title compound XIII (0.13 g, 35%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): 1.65-1.75 (m, 4H), 2.12 (s, 3H), 2.50-2.62 (m, 4H), 2.75-2.85 (m, 2H), 3.99 (t, J = 5.9 Hz, 2H), 6.70 (d, J = 9.0 Hz, 2H), 7.36 (d, J = 5.4 Hz, 1 H), 7.51 (d, J = 9.1 Hz, 2H), 7.61 (dd, J = 8.7 Hz, J = 2.0 Hz, 1 H), 7.74 (d, J = 5.4 Hz, 1 H), 7.85 (d, J = 0.8 Hz, 1 H), 7.92 (d, J = 8.6 Hz, 1H), 8.29 (d, J = 1.7 Hz, 1H), 8.34 (s, 1H), 8.76 (s, 1H); MS (ESI +): m / z 446 (M + H) +.

EXAMPLE 25 Benzofbltiophen-3-yl- (2-chloro-5-methyl-pyrimidin-4-yl) -amine (Intermediate 14) 14 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 3-bromo-benzo [b] thiophene (0.6 g, 2.8 mmol), Pd2 (dba) 3 (95 mg , 0.10 mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) was suspended in dioxane (25 ml) and heated to reflux under argon atmosphere for 3 hr. The reaction mixture was cooled to room temperature and diluted with DCM (30 ml). The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (hexane to 30% EtOAc / Hexane) to give the title intermediate 14 (65 mg, 11%) as a yellow solid. MS (ESI +): m / z 276 (M + H) +.

EXAMPLE 26? ) -Benzorb1thiophen-3-yl-5-methyl-N2-f4- (2-pyrrolidin-1-yl-ethoxy) -phene-pyrimidine-2,4-diamine (Compound XIV) XIV A mixture of the intermediates described above 14 (50 mg, 0.18 mmol) and 6 (0.10 g, 0.48 mmol) was suspended in acetic acid (8 ml) and heated at 100 ° C for 15 hr. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (10 ml) and neutralized to pH ~ 7 with 7M NaOH solution. The resulting solution was extracted with EtOAc (20 ml) and the organic layer was separated. The organic layer was washed with brine, dried over MgSO and filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel (DCM at 15% MeOH / DCM) to give the title compound XIV (10 mg, 13%) as an off-white solid. 1 H NMR (500 MHz, DMSO-d 6): 1.70-1.80 (m, 4H), 2.19 (s, 3H), 2. 65-2.80 (m, 4H), 2.85-3.00 (m, 2H), 3.98-4.03 (m, 2H), 6.63 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.38-7.45 (m, 2H), 7.79-7.83 (m, 1H), 7.87 (s, 1 H), 7.90-8.03 (m, 1 H), 8.33 (s, 1 H), 8.78 (s, 1 H); MS (ESI +): m / z 446 (M + H) +.

EXAMPLE 27 (2-Chloro-5-methyl-pyrimidin-4-yl) - (3-chloro-phenyl) -amine (Intermediate 15) A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 1-bromo-3-chloro-benzene (0.60 g, 3.1 mmol), Pd2 (dba) 3 (95 mg , 0.10 mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) was suspended in dioxane (20 ml) and heated to reflux under argon atmosphere for 4 hr. The reaction mixture was cooled to room temperature and diluted with DCM (20 ml). The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (hexane at 40% EtOAc / Hexane) to give the title intermediate 15 (0.30 g, 56%) as a pale yellow solid. MS (ESI +): m / z 254 (M + H) +.

EXAMPLE 28 / '- (3-Chloro-phenyl) -5-methyl- / V2-r4- (2-pyrrolidin-1-yl-ethoxy) -phenyl-pyrimidine-2,4-diamine (Compound XV) XV A mixture of the intermediates described above (0.15 g, 0.59 mmoles) and 6 (0.25 g, 1.2 mmoles) was suspended in acetic acid (8 ml) and heated at 100 ° C for 21 hr. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (15 ml) and neutralized to pH ~ 7 with 7M NaOH solution. The resulting solution was extracted with EtOAc (30 ml) and the organic layer was separated. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel (DCM at 10% MeOH / DCM) to give the title compound XV (60 mg, 24%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): 1.65-1.72 (m, 4H), 2.10 (s, 3H), 2.50-2.60 (m, 4H), 2.78-2.83 (m, 2H), 4.01 (t, J = 5.9 Hz, 2H), 6.81 (d, J = 9.1 Hz, 2H), 7.05-7.08 (m, 1 H), 7.32 (t, J = 8.1 Hz, 1 H), 7.52 (d, J = 9.0 Hz, 2H), 7. 71 (d, J = 8.3 Hz, 1 H), 7.85 (t, J = 2.1 Hz, 1 H), 7.89 (d, J = 0.7 Hz, 1 H), 8.33 (s, 1 H), 8.86 (s, 1 H); MS (ESI +): m / z 424 (M + H) +.

EXAMPLE 29 3-Bromo-N-methyl-benzamide (Intermediary 16) 16 A solution of 3-bromo-benzoyl chloride (2.93 g, 13.3 mmol, 1 eq) in 30 mL of THF was stirred vigorously and treated with 2.0 M methylamine in THF (15 mL, 29.4 mmol, 2.2 eq). A white precipitate was observed and the reaction was allowed to stir for 20 minutes. The reaction was then poured into ethyl acetate (100 ml) and washed with water (2 x 150 ml) and brine (1 x 150 ml). The organic phase was separated from the aqueous phase and dried over sodium sulfate, filtered and evaporated to give the title 16 intermediate as a white powder. (2.29 g, 82% yield).

EXAMPLE 30 3- (2-Chloro-5-methyl-pyrimidin-4-ylamino) -? -methyl-benzamide (Intermediary 17) 17 In a rehydrated 50 ml dry bottom flask, 2-chloro-5-methyl-pyrimidin-4-ylamine (0.3 g, 2.09 mmol, 1 equiv), 3-bromo-N-methyl-benzamide (0.489 g, 2.29 mmoles, 1.1 equiv), cesium carbonate (2.04 g, 6.27 mmol, 3 equiv), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.242 g, 0.418 mmol, 0.2 equiv) and tris (dibenzylidenacetone) dipalladium (0.191 g, 0.209 mmoles, 0.1 equiv). The reagents were diluted with dioxane (20 ml), flushed with argon and passed through a reflux condenser. The reaction was heated to reflux for 16 hours. The reaction was then transferred into a centrifuge tube, rotated, decanted and evaporated. The resulting yellow solids were diluted with DCM and adsorbed on silica gel. Chromatography (gradient of 50% ethyl acetate in hexanes to 100% ethyl acetate) gave the title 17 intermediate as a pale yellow powder (0.25 g, 43% yield). MS (ESI +): 277.01 (M + H), t.a. = 1.92 min.

EXAMPLE 31 Salt of THF of M-methyl-3-. { 5-methyl-2- [4-f2-pyrrolidin-1-yl-ethoxy) -phenylaminol-pyrimidin-4-ylamino) -benzamide (Compound XVI) XVI The intermediary 17 described above (0.068 g, 0.246 mmol, 1 eq), 4- (2-pyrrolidin-1-yl-ethoxy) -phenylamine (0.061 g), 0.296 mmole, 1.2 eq), cesium carbonate (0.241 g, 0.74 mmole, 3 equiv), 4,5-bis (diphenylphosphino) -9,9-dimethyl xanthene (0.029 g, 0.05 mmole, 0.2 equiv) and tris ( dibenzylidene ketone) dipalladium (0.023 g, 0.025 mmol, 0.1 equiv) were combined in a 15 ml microwave vessel. The reagents were then diluted with 7 ml of dioxane and microwaved for 15 minutes at 160 ° C. The reaction vessel was then rotated, decanted and evaporated to dryness. Purification by HPLC gave the TFA salt of the title product XVI (0.084 g, 76%). MS (ESI +): 447.20 (M + H), t.a. = 1.53 min. 1 H NMR (DMSO-de): d 1.87-1.91 (m, 2H), 2.02-2.06 (m, 2H), 2.16 (s, 3H), 2.79 (d, J = 4.6 Hz, 3H), 3.11-3.15 (m, 2H), 3.57-3.61 (m, 5H), 4.23 (t, J = 5.0 Hz, 3H), 6.84 (d, J = 8.8 Hz, 2H), 7.34 (d, = 8.9 Hz, 2H), 7.47 (t, J = 7.9 Hz, 1 H), 7.68-7.70 (m, 2H), 7.93 (s, 1 H), 8.00 (s, 1 H), 8.46-8.47 (m, 1 H), 9.80 (bs, 1H), 9.93 (bs, 1 H) 10.41 (bs, 1 H).

EXAMPLE 32 TFA salt of N4- (4-Chloro-3-methoxy-phenyl) -5-methyl-N2-r4- (2-pyrrolidin-1-yl-ethoxy) -phenn-pyrimidin-2, 4-diamine (Compound XVII) XVII The intermediate 7 described above (0.083 g, 0.293 mmol, 1 eq), 4- (2-pyrrolidin-1-yl-ethoxy) -phenylamine (0.073 g, 0.352 mmol, 1.2 eq), cesium carbonate (0.287 g, 0.879 mmoles, 3 equiv), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.034 g, 0.059 mmol, 0.2 equiv) and tris (dibenzylideneacetone) dipalladium (0.027 g, 0.029 mmol, 0.1 equiv) were combined in a 15 ml microwave container. The reagents were then diluted with 7 ml dioxane and microwaved for 15 minutes at 160 ° C. The reaction vessel was then rotated, decanted and evaporated to dryness. Purification by HPLC gave the TFA salt of the title product XVII (0.1 g, 75%). MS (ESI +): 454.13 (M + H), t.a. = 1.82 min. 1 H NMR (DMSO-de): d 1.87-1.90 (m, 2H), 2.02-2.05 (m, 2H), 2.15 (s, 3H), 3.11-3.14 (m, 2H), 3.58-3.61 (m, 5H), 3.70 (s, 3H), 4.26 (t, = 5.0 Hz, 3H), 6.91 (d, = 8.9 Hz, 2H), 7.23 (m, 1 H), 7.34-7.4 (m, 4H), 7.93 (s, 1 H), 9.63 (bs, 1 H), 9.96 (bs, 1 H) 10.40 (bs, 1 H) .

EXAMPLE 33 N- (2-Chloro-5-methyl-pyrimidin-1-yl) -M \ M'-dimethyl-en-1,3-diamine (Intermediate 18) 18 2-Chloro-5-methyl-pyrimidin-4-ylamine (0.343 g, 2.38 mmol, 1 equiv), (3-bromo-phenyl) -dimethyl-amine (0.524 g, 2.62 mmol, 1.1 equiv), cesium carbonate (2.3 g, 7.15 mmol, 3 equiv), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.276 g, 0.476 mmol, 0.2 equiv) and tris (dibenzylidene ketone) dipalladium (0.218 g, 0.238 mmol, 0.1 equiv) ) were combined in a 30 ml microwave container. The reagents were then diluted with 12 ml of dioxane and microwaved for 25 minutes at 160 ° C. The reaction vessel was then rotated, decanted and evaporated to dryness. The resulting solids were diluted with DCM and adsorbed on silica gel. Chromatography (gradient of 0% methanol in DCM to 25% methanol in DCM) gave the title 18 intermediate as an orange solid (0.184 g, 29% yield). MS (ESI +): 263.02 (M + H), t.a. = 1.72 min.

EXAMPLE 34 TFA salt of α / 3-dimethylamino-phenyl) -5-methyl-β-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -pyrimidine-2,4-diamine (Compound XVIII) xvpi Intermediate 18 described above (0.092 g, 0.35 mmol, 1 eq), 4- (2-pyrroridin-1-yl-ethoxy) -phenylamine (0.087 g, 0.42 mmol, 1.2 eq), cesium carbonate (0.343 g, 1.05 g) mmoles, 3 equiv), 4,5-bis (diphenylphosphino) -9,9-dimethyl xanthene (0.041 g, 0.0702 mmol, 0.2 equiv) and tris (dibenzylideneacetone) dipalladium (0.032 g, 0.035 mmol, 0.1 equiv) were combined in a 15 ml microwave container. The reagents were then diluted with 7 ml of dioxane and microwaved for 15 minutes at 160 ° C. The reaction vessel was then rotated, decanted and evaporated to dryness. Purification by HPLC gave the TFA salt of the title compound XVIII (0.035 g, 23%). MS (ESI +): 433.21 (M + H), t.a. = 1.52 min. H NMR (DMSO-de): d 1.87-1.90 (m, 2H), 2.03-2.06 (m, 2H), 2.15 (s, 3H), 2.87 (s, 6H), 3.12-3.15 (m, 2H), 3.57-3.60 (m, 4H), 3.70 (s, 3H), 4.25 (t, J = 5.0 Hz, 3H), 6.34 (dd, J = 8.4 Hz, J = 2.3 Hz, 1 H), 6.82-6.90 (m, 4H), 7.20 (t, J = 8.0 Hz, 1 H), 7.39 (d, J = 9.1 Hz, 2 H), 7.85 (s, 1 H), 9.63 (bs, 1 H), 9.90 (bs, 1 H) 10.39 (bs, 1 H).

EXAMPLE 35 (2-Chloro-5-methyl-pyrimidin-4-yl) - (3,4-dichloro-phenyl) -amine (Intermediate 19) 19 2-Chloro-5-methyl-pyrimidin-4-ylamine (0.408 g, 2.83 mmol, 1 equiv), 4-bromo-1,2-dichloro-benzene (0.704 g, 3.12 mmol, 1.1 equiv), cesium carbonate (2.8 g, 8.49 mmoles, 3 equiv), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.328 g5 0.57 mmoles), 0.2 equiv) and tris (dibenzylidenacetone) dipalladium (0.26 g, 0.283 mmol, 0.1 equiv) were combined in a 30 ml microwave vessel. The reagents were then diluted with 12 ml of dioxane and microwaved for 25 minutes at 160 ° C. The reaction vessel was then rotated, decanted and evaporated to dryness. The resulting solids were diluted with DCM and adsorbed on silica gel. Chromatography (gradient from 15% ethyl acetate in hexanes to 80% ethyl acetate in hexanes) gave the title 19 intermediate as a pale yellow powder (0.366 g, 45% yield). MS (ESI +): 287.97 (M + H), t.a. = 3.12 min.

EXAMPLE 36 TFA salt of? ^ - Q ^ -dichloro-phenyD-S-methyl-A ^^ - fS-pyrrolidin-1-yl-ethoxy) -phene-pyrimidine-2,4-diamine (Compound XIX) XIX Intermediate 19 described above (0.09 g, 0.313 mmol, 1 eq), 4- (2-pyrrolidin-1-yl-ethoxy) -phenylamine (0.078 g, 0.376 mmol, 1.2 eq), cesium carbonate (0.307 g, 0.941 mmol, 3 equiv), 4,5-bis (diphenylphosphino) -9,9-dimethyl-xanthene (0.036 g, 0.063 mmol, 0.2 equiv) and tris (dibenzylidene ketone) dipalladium (0.029 g, 0.0314 mmol, 0.1 equiv) were combined in a 15 ml microwave container. The reagents were then diluted with 7 ml of dioxane and microwaved for 15 minutes at 160 ° C. The reaction vessel was then rotated, decanted and evaporated to dryness. Purification by HPLC gave the TFA salt of the title XIX compound (0.056 g, 39%). MS (ESI +): 458.1 (M + H), t.a. = 1.93 min. 1 H NMR (DMSO-de): d 1.87-1.91 (m, 2H), 2.03-2.06 (m, 2H), 2.14 (s, 3H), 3.12-3.15 (m, 3H), 3.57-3.60 (m, 4H), 4.26 (t, J = 5.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 1H), 7.40 ( d, J = 9 Hz, 2H), 7.60 (s, 2H), 7.97 (d, J = 15.35 Hz, 2H), 9.46 (bs, 1 H), 9.89 (bs, 1 H) 10.17 (bs, 1H) .

EXAMPLE 37 4- (3-f4- (4-Chloro-3-methoxy-phenylamino) -5-methyl-pyrimidin-2-ylaminol-benzyl) -piperazine-1-carboxylic acid tert-butyl ester (Intermediate 20) twenty (4-Chloro-3-methoxy-phenyl) - (2-chloro-5-methyl-pyrimidin-4-yl) -amine (0.092 g, 0.325 mmol, 1 eq), 4- (3-tert-butyl ester) -amino-benzyl) -piperazine-1-carboxylic acid (0.114 g, 0.39 mmol, 1.2 eq), cesium carbonate (0.318 g, 0.975 mmol, 3 equiv), 4,5-bis (diphenylphosphine) -9.9 Dimethylxanthene (0.038 g, 0.065 mmol, 0.2 equiv) and tris (dibenzylidene ketone) dipalladium (0.03 g, 0.0325 mmol, 0.1 equiv) were combined in a 15 ml microwave vessel. The reagents were then diluted with 7 ml of dioxane and microwaved for 15 minutes at 160 ° C. The reaction vessel was then rotated, decanted and evaporated to dryness. Purification by HPLC gave the TFA salt of the title 20 intermediate (0.075 g, 43%). MS (ESI +): 539.32 (M + H), t.a. = 2.09 min.

EXAMPLE 38 Salt of TFA from? 4- (4-Chloro-3-methoxy-phenyl) -5-methyl-β- / 2- (3-piperazin-1-ylmethyl-phenyl) -pyrimidine-2,4-diamine (Compound XX) XX A stirred solution of the intermediary described above (0.075 g, 0.14 mmol, 1 eq) in DCM (6 ml) was treated with TFA (2 ml). After 2 hr, the reaction solvents were evaporated and the resulting residue was triturated with ether to give the title compound XX, TFA salt as white hygroscopic solids. (0.05 g, 82%). MS (ESI +): 439.13 (M + H), t.a. = 1.67 min. 1 H NMR (DMSO-de): d 2.17 (s, 3H), 2.89 (bs, 4H), 3.2 (bs, 4H), 3. 68 (s, 3H), 3.82 (bs, 3H), 7.16-7.20 (m, 2H), 7.28 (t, J = 7.7 Hz, 1 H), 7.33 (d, = 2.3Hz, 1 H), 7.39 ( s, 1H), 7.42 (d, = 8.5 Hz, 1 H), 7.49-7.51 (m, 1H), 7.98 (s, 1H), 8.87 (bs, 1 H), 9.79 (bs, 1 H) 10.57 ( bs, 1 H).

EXAMPLE 39 2- (4- (2- (Pyrrolidin-1-yl) ethoxy) phenylamino) -4-aminopyrimidine-5-carbonitrile (Intermediate 21) twenty-one To a solution of 2,4-diaminopyrimidine-5-carbonitrile (135 mg, 1.00 mmol) in 1,4-dioxane (20 ml) was added 1- (2- (4-bromophenoxy) ethyl) -pyrrolidine (270 mg, 1.0 mmoles), Cs2CO3 (1.3 g, 4.0 mmol), Pd2 (dba) 3 (92 mg, 0.1 mmol), and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xant Phos, 174 mg, 0.3 mmol ). The mixture was heated under reflux for 4 hr under Ar. The solid was filtered and the filtrate was washed with brine (1 x 100 ml). The organic solution was separated and dried (Na2SO4). The solvent was removed to 5 ml and hexane (50 ml) was added, the solid was collected by filtration. The crude product was purified by HPLC and gave the title 21 intermediate (32 mg, 10%).

EXAMPLE 40 4- (2, 4-Dichloro-5-methoxyphenylamino) -2- (4- (2- (pyrrolidin-1-yl) ethoxy) phenylamino) pyrimidine-5-carbonitrile (Compound XXI) XXI To a solution of the intermediary described above (32 mg, 0.1 mmol) in 1,4-dioxane (10 ml) was added 1-bromo-2,4-dichloro-5-methoxybenzene (28 mg, 0.11 mmole), Cs2CO3 (97 mg, 0.3 mmole), Pd2 (dba) 3 (7 mg, 0.0074 mmole), and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xant Phos, 13 mg, 0.022 mmoles). The mixture was heated under reflux for 4 hr under Ar. The solid was filtered and the filtrate was washed with brine (1 x 50 ml). The organic solution was separated and dried (Na2SO4). The solvent was removed under vacuum. The crude product was purified by chromatography (SiO2 / CH2CI2, then CH2CI2: MeOH: NH3.H20 = 100: 10: 1) and gave the title compound XXI (35 mg, 67%). 1 H NMR (500 MHz, DMSO-d 6): 1.88-1.90 (m, 2H); 2.00-2.03 (m, 2H); 3.07-3.11 (m, 2H); 3.54-3.56 (m, 4H); 3.81 (s, 3H); 4.25 (br, 2H); 6.68 (br, 2H); 7.32 (br, 2H); 7.33 (s, 1 H); 7.75 (s, 1H); 8.50 (s, 1H); 9.73 (br, 1H); 9.94 (br, 1 H); 10.60 (br, 1 H). EM (El): 499.0.

EXAMPLE 41 2- (3- (2- (Pyrrolidin-1-yl) ethoxy) phenylamino) -4-aminopyrimidine-5-carbonitrile (Intermediary 22) 22 To a solution of 2,4-diaminopyrimidine-5-carbonitrile (145 mg, 1.07 mmol) in 1,4-dioxane (20 ml) was added 1- (2- (3-bromophenoxy) ethyl) -pyrrolidine (290 mg, 1.07 mmole), Cs2CO3 (1.43 g, 4.4 mmol), Pd2 (dba) 3 (92 mg, 0.1 mmol), and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xant Phos, 174 mg, 0.3 mmol ). The mixture was heated under reflux for 4 hr under Ar. The solid was filtered and the filtrate was washed with brine (1 x 100 ml). The organic solution was separated and dried (Na2SO). The solvent was removed to 5 ml and hexane (50 ml) was added, the solid was collected by filtration. The crude product was purified by HPLC and gave the title intermediate 22 (55 mg, 16%).

EXAMPLE 42 4- (2,4-Dichloro-5-methoxyphenylamino) -2- (3- (2- (pyrrolidin-1-yl) ethoxy) phenylamino) pyrimidine-5-carbonitrile (Compound XXII) XX11 To a solution of intermediate 22 described above (50 mg, 0.15 mmol) in 1,4-dioxane (10 ml) was added 1-bromo-2,4-dichloro-5-methoxybenzene (44 mg, 0.17 mmol), Cs2CO3 ( 200 mg, 0.62 mmole), Pd2 (dba) 3 (14 mg, 0.015 mmole), and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xant Phos, 27 mg, 0.05 mmole). The mixture was heated under reflux for 4 hr under Ar. The solid was filtered and the filtrate was washed with brine (1 x 50 ml). The organic solution was separated and dried (Na2SO4). The solvent was removed under vacuum. The crude product was purified by HPLC and gave the title compound XXII (6 mg, 8%). 1 H NMR (500 MHz, DMSO-d 6): 1.87-1.89 (m, 2H); 1.90-2.03 (m, 2H); 3.04-3.08 (m, 2H); 3.52-3.56 (m, 4H); 3.80 (s, 3H); 4.23 (br, 2H); 6.62 (d, J = 6.4 Hz, 2H); 6.97 (br, 1 H); 7.14 (br, 2H); 7.34 (s, 1H); 7.74 (s, 1 H); 8.54 (s, 1H); 9.70 (br, 1 H); 9.95 (br, 1 H); 10.83 (br, 1H). EM (El): 499.0.

EXAMPLE 43 2-Chloro-N- (2,4-diCloro-5-methoxyphenyl) -5-methylpyrimidin-4-amine (Intermediate 23) 2. 3 To a solution of 2-chloro-5-methylpyrimidin-4-amine (44.8 mg, 0.31 mmol) in 1,4-dioxane (20 ml) was added 1-bromo-2,4-dichloro-5-methoxybenzene (96 mg) , 0.37 mmole), Cs2CO3 (408 mg, 1.25 mmole), Pd2 (dba) 3 (37 mg, 0.04 mmole), and 4,5-bis (diphenylphosphine) -9,9-dimethylxantene (Xant Phos, 70 mg , 0.12 mmole). The mixture was heated under reflux for 4 hr under Ar. The solid was filtered and the filtrate was washed with brine (1 x 100 ml). The organic solution was separated and dried (Na2SO4). The solvent was removed under vacuum. The crude product was used for the next reaction without purification.

EXAMPLE 44 / V2- (3- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -N4- (2,4-dichloro-5-methoxyphenyl) -5-methylpyrimidine-2,4-diamine (Compound XXIII) xxm To a solution of intermediate 23 described above in 1,4-dioxane (10 ml) was added 3- (2- (pyrrolidin-1-yl) ethoxy) benzenamine (77.3 mg, 0.38 mmol), Cs2CO3 (488 mg, 1.25 mmol) ), Pd2 (dba) 3 (28 mg, 0.03 mmol), and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xant Phos, 53 mg, 0.09 mmol). The mixture was heated under reflux for 4 hr under Ar. The solid was filtered and the filtrate was washed with brine (1 x 50 ml). The organic solution was separated and dried (Na2SO4). The solvent was removed under vacuum. The crude product was purified by HPLC and gave the title compound XXIII (25 mg, 15%). 1 H NMR (500 MHz, DMSO-d 6): 1.87-1.89 (m, 2H); 1.90-2.03 (m, 2H); 2.18 (s, 3H); 3.04-3.08 (m, 2H); 3.52-3.56 (m, 4H); 3.80 (s, 3H); 4.24 (t, J = 5.0 Hz, 2H); 6.71 (d, J = 7.65 Hz, 1 H); 6.91 (s, 1 H); 6.96 (d, J = 8.5 Hz, 1 H); 7.02 (t, J = 8.2 Hz, 1 H); 7.37 (s, 1 H); 7.83 (s, 1 H); 8.02 (s, 1 H); 10.09 (br, 1 H); . 66 (br, 1 H); 10.82 (br, 1 H). MS (El): 488.2 EXAMPLE 45 2-Chloro-N- (3-methoxyphenyl) -5-methylpyrimidin-4-amine (Intermediate 24) 24 To a solution of 2-chloro-5-methylpyrimidin-4-amine (320 mg, 2.23 mmol) in 1,4-dioxane (40 ml) was added 1-bromo-3-methoxybenzene (458.5 mg, 2.45 mmol), Cs2CO3 (2.9 g, 8.9 mmoles), Pd2 (dba) 3 (201 mg, 0.22 mmoles), and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xant Phos, 382 nig, 0.66 mmoles). The mixture was heated under reflux for 4 hr under Ar. The solid was filtered and the filtrate was washed with brine (1 x 100 ml). The organic solution was separated and dried (Na2SO4). The solvent was removed to 5 ml and hexane (100 ml) was added, the solid was collected by filtration. The crude product, the title 24 intermediate (500 mg, 90%), was used for the next reaction without further purification.

EXAMPLE 46 ^ 2- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) - ^ 4- (3-methoxyphenyl) -5-methyl-pyrimidine-2,4-diamine (Compound XXIV) XX1V To a solution of the intermediary described above (240 mg, 0.96 mmol) in 1,4-dioxane (20 ml) was added 4- (2- (pyrrolidin-1-yl) ethoxy) benzenamine (200 mg, 0.96 mmol) , Cs2CO3 (1.3 mg, 4.0 mmol), Pd2 (dba) 3 (82 mg, 0.09 mmol), and 4,5-bis (diphenylfosphin) -9,9-dimethylxanthene (Xant Phos, 156 mg, 0.27 mmol). The mixture was heated under reflux for 4 hr under Ar. The solid was filtered and the filtrate was washed with brine (1 x 50 ml). The organic solution was separated and dried (Na2SO4). The solvent was removed under vacuum. The crude product was purified by HPLC and gave the title compound XXIV (85 mg, 20%). H NMR (500 MHz, DMSO-d 6): 1.89-1.91 (m, 2H); 1.98-2.05 (m, 2H); 2.16 (s, 3H); 3.07-3.12 (m, 2H); 3.52-3.56 (m, 4H); 3.73 (s, 3H); 4.33 (t, J = 4.5 Hz, 2H); 6.83-6.85 (m, 1H); 6.91 (d, J = 8.8 Hz, 2H); 7.17 (s, 1H); 7.34 (d, J = 8.8 Hz, 2H); 7.41 (t, J = 7.7 Hz, 1 H); 7.56 (d, J = 7.7 Hz, 1 H); 7.89 (s, 1 HOUR); 9.75 (s, 1 H); 10.51 (s, 1 H); 10.96 (br, 1 H). MS (El): 420.2 EXAMPLE 47 3- (2- (4- (2- (pyrrolidin-1-yl) ethoxy) phenylamino) -5-methyl-pyrimidin-4-ylamino) - phenol (Compound XXV) XX \ ' To a solution of compound XXIV described above (50 mg, 0.1 mmol) in anhydrous CH2Cl2 (10 ml) was added 1.0M BBr3 in CH2CI2 (0.3 ml, 0.3 mmol). The mixture was stirred for 3 hr at room temperature. Saturated NaHCO3 (20 ml) was added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (3 x 10 ml). The combined organic solution was dried (Na2SO4). The product was purified by HPLC and gave the title compound XXV (17 mg, 35%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d 6): 1.89 (br, 2H); 2.00 (br, 2H); 2.14 (s, 3H); 3.09 (br, 2H); 3.42 (br, 4H); 4.33 (br, 2H); 6.72 (d, J = 7.1 Hz, 1 H); 6.91 (d, J = 8.4 Hz, 2H); 6.96 (d, J = 7.6 Hz, 1 H); 7.00 (s, 1H); 7.18 (t, J = 8.0 Hz, 1 HOUR); 7.38 (d, J = 8.6 Hz, 2H); 7.88 (s, 1 H); 9.70 (s, 1 H); 9.74 (s, 1 H); 10.55 (s, 1 H); 11.09 (br, 1 H). MS (El): 406.2 EXAMPLE 48 2-Chloro-5-methyl-? - (3-nitrophenyl) pyrimidin-4-amine (Intermediary 25) To a solution of 2-chloro-5-methylpyrimidin-4-amine (232 mg, 1.61 mmol) in 1,4-dioxane (40 ml) was added 1-bromo-3-nitrobenzene (359 mg, 1.78 mmol), Cs2C03 (2.1 g, 6.4 mmol), Pd2 (dba) 3 (146 mg, 0.16 mmol), and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xant Phos, 278 mg, 0.48 mmol). The mixture was heated under reflux for 4 hr under Ar. The solid was filtered and the filtrate was washed with brine (1 x 100 ml). The organic solution was separated and dried (Na2SO4). The solvent was removed to 5 ml and hexane (100 ml) was added, the solid was collected by filtration. The crude product, the intermediate of title 25, was used for the next reaction without further purification.

EXAMPLE 49 N2- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -5-methyl-N4- (3-nitrophenyl) pyrimidine-2,4-diamine (Compound XXVI) XXVI To a solution of intermediary described above in 1,4-dioxane (40 ml) was added 4- (2- (pyrrolidin-1-yl) ethoxy) benzenamine (367 mg, 1.78 mmol), Cs2CO3 (2.1 g, 6.4 mmol) ), Pd2 (dba) 3 (146 mg, 0.16 mmol), and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xant Phos, 218 mg, 0.48 mmol). The mixture was heated under reflux for 4 hr under Ar. The solid was filtered and the filtrate was washed with brine (1 x 50 ml). The organic solution was separated and dried (Na2SO). The solvent was removed under vacuum. The crude product was purified by HPLC and gave the title compound XXVI (51 mg, 7%). 1 H NMR (500 MHz, DMSO-d 6): 1.89-1.92 (m, 2H); 1.98-2.05 (m, 2H); 2.21 (s, 3H); 3.10-3.12 (m, 2H); 3.52-3.57 (m, 4H); 4.33 (t, J = 4.8 Hz, 2H); 6.90 (d, J = 8.9 Hz, 2H); 7.32 (d, J = 8.9 Hz, 2H); 7.67 (t, J = 8.2 Hz, 1H); 7.99 (s, 1 H); 7.56 (dd, J = 8.4 Hz, J = 1.8 Hz, 1 H); 8.09 (d, J = 7.4 Hz, 1 H); 8. 45 (s, 1 H); 10.14 (s, 1 H); 10.60 (s, 1 H); 1 1.17 (br, 1 H). EM (El): 435.2 EXAMPLE 50 4- (2-Chloro-5-methylpyrimidin-4-ylamino) -2-chlorobenzonitrile (Intermediary 26) 26 To a solution of 2-chloro-5-methylpyrimidin-4-amine (144 mg, 1.0 mmol) in 1,4-dioxane (20 ml) was added 4-bromo-2-chlorobenzonitrile (217 mg, 1.0 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd2 (dba) 3 (91 mg, 0.1 mmol), and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xant Phos, 173 mg, 0.3 mmol). The mixture was heated under reflux for 4 hr under Ar. The solid was filtered and the filtrate was washed with brine (1 x 100 ml). The organic solution was separated and dried (Na2SO4). The solvent was removed to 5 ml and hexane (100 ml) was added, the solid was collected by filtration. The crude product, the intermediate of title 26, was used for the next reaction without further purification.

EXAMPLE 51 4- (2- (4- (2- (pyrrolidin-1-yl) ethoxy) phenylamino) -5-methylpyrimidin-4-ylamino) -2-chlorobenzonitrile (Compound XXVII) XXV11 To a solution of the intermediary described above (140 mg, 0.5 mmol) in 1,4-dioxane (20 ml) was added 4-. { 2- (pyrrolidin-1-yl) ethoxy) -benzenamine (113 mg, 0.55 mmole), Cs2CO3 (660 mg, 2.0 mmole), Pd2 (dba) 3 (46 mg, 0.05 mmole), and 4,5-bis ( diphenylphosphino) -9,9-dimethylxanthene (Xant Phos, 87 mg, 0.15 mmol). The mixture was heated under reflux for 4 hr under Ar. The solid was filtered and the filtrate was washed with brine (1 x 50 ml). The organic solution was separated and dried (Na2SO4). The solvent was removed under vacuum. The crude product was purified by HPLC and gave the title compound XXVII (11.5 mg, 5%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d 6): 1.89-1.92 (, 2H); 1.98-2.05 (m, 2H); 2.20 (s, 3H); 3.08-3.13 (m, 2H); 3.56-3.59 (m, 4H); 4.36 (t, J = 4.9 Hz, 2H); 7.03 (d, J = 9.0 Hz, 2H); 7.40 (d, J = 9.0 Hz, 2H); 7.87 (br, 1H); 7.92 (d, J = 8.6 Hz, 1 H); 8.03 (s, 1 H); 8.16 (s, 1 H); 9.82 (br, 1 H); 10.37 (br, 1 H); 10.90 (br, 1 H). MS (El): 449.1.

EXAMPLE 52 ^ 2- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl-5-methyl- ^ 4-p-tolylpyrimidine-2,4-diamine (Compound XXVIII) XVTJJ To a solution of intermediate 11 described above (50 mg, 0.16 mmol) in 1,4-dioxane (20 ml) was added 1-bromo-4-methylbenzene (28 mg, 0.16 mmol), Cs2CO3 (210 mg, 0.64 mmol) , Pd2 (dba) 3 (10 mg, 0.01 mmol), and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xant Phos, 18 mg, 0.03 mmol). The mixture was heated under reflux for 4 hr under Ar. The solid was filtered. The solvent was removed under vacuum. The crude product was purified by HPLC and gave the title compound XXVIII (15.7 mg, 6%) as a yellow solid. 1 H NMR (500 MHz, DMSO-de): 1.85-1.89 (m, 2H); 1.96-2.01 (m, 2H); 2.12 (s, 3H); 2.31 (s, 3H); 3.04-3.08 (m, 2H); 3.51-3.55 (m, 4H); 4.32 (br, 2H); 6.89 (br, 2H); 7.18 (br, 2H); 7.31 (br, 2H); 7.41 (br, 2H); 7.84 (s, 1H); 9.71 (s, 1 H); 10.46 (s, 1 H); 11.13 (br, 1 H). MS (El): 404.2 EXAMPLE 53 y2- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -A / - (4-chloro-3-methylphenyl) -5-methylpyrimidine-2,4-diamine (Compound XXIX) XXIX To a solution of the intermediary described above (80 mg, 0.25 mmol) in 1,4-dioxane (20 ml) was added 4-bromo-1-chloro-2-methylbenzene (63 mg, 0.30 mmol), Cs2CO3 (326 mg , 1.0 mmol), Pd2 (dba) 3 (18 mg, 0.02 mmol), and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xant Phos, 36 mg, 0.06 mmol). The mixture was heated under reflux for 4 hr under Ar. The solid was filtered. The solvent was removed under vacuum. The crude product was purified by HPLC and gave the title compound XXIX (17.5 mg, 15%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d 6): 1.85-1.89 (m, 2H); 1.96-2.01 (m, 2H); 2.12 (s, 3H); 2.25 (s, 3H); 3.04-3.08 (m, 2H); 3.51-3.55 (m, 4H); 4.32 (br, 2H); 6.91 (br, 2H); 7.04 (br, 1 H); 7.31 (br, 1H); 7.41 (br, 2H); 7.58 (s, 1 H); 7.89 (br, 1 H); 9.75 (s, 1 H); 10.54 (s, 1 H); 11.13 (br, 1 H). MS (El): 438.1 EXAMPLE 54? / - (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -4-benzyl-5-methylpyrimidin-2-amine (Compound XXX) XXX To a solution of 4-benzyl-2-chloropyrimidine (286 mg, 1.4 mmol) in 1,4-dioxane (20 ml) was added 4- (2- (pyrrolidin-1-yl) ethoxy) benzenamine (288 mg, 1.4 mmoles), Cs2CO3 (1.82 g, 5.6 mmoles), Pd2 (dba) 3 (92 mg, 0.1 mmoles), and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xant Phos, 173 mg, 0.3 mmoles). The mixture was heated under reflux for 4 hr under Ar. The solid was filtered. The solvent was removed under vacuum. The crude product was purified by HPLC and gave the title compound XXX (42 mg, 10%) as a yellow solid. H NMR (500 MHz, DMSO-d6): 1.89 (br, 2H); 2.00 (br, 2H); 3.09 (br, 2H); 3.54 (br, 4H); 4.31 (br, 2H); 6.71 (d, J = 5.0 Hz, 1 H); 6.93 (d, J = 8.8 Hz, 2H); 7.24 (m, 1 H); 7.32 (m, 4H); 7.62 (d, J = 8.8 Hz, 2H); 8.32 (d, J = 5.0 Hz, 1H); 9.66 (s, 1H); 10.92 (br, 1H). MS (El): 375.2 EXAMPLE 55 4 - ((1H-indol-4-yl) methyl) - ^ - (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -5-methylpyrimidin-2-amine (Compound XXXI) XXXI To a solution of intermediate 11 described above (460 mg, 1.46 mmol) in 1,4-dioxane (20 ml) was added 4-bromo-1H-indole (288 mg, 1.46 mmol), Cs2CO3 (1.95 g, 6.0 mmol) ), Pd2 (dba) 3 (128 mg, 0.14 mmol), and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xant Phos, 243 mg, 0.42 mmol).

The mixture was heated under reflux overnight under Ar. The solid was filtered.

The solvent was removed under vacuum. The crude product was purified by HPLC and gave the title compound XXXI (66 mg, 10%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d 6): 1.87 (br, 2H); 1.98-2.05 (m, 2H); 2. 21 (s, 3H); 3.15 (br, 2H); 3.52 (br, 2H); 3.69 (br, 2H); 4.24 (br, 2H); 6.33 (s, 1 HOUR); 6.60 (br, 2H); 6.82 (br, 1 H); 6.92 (br, 1 H); 7.02 (br, 2H); 7.16 (br, 1 H); 7. 26 (br, 1 H); 7.43 (m, 1 H); 7.88 (m, 1 H); 10.11 (s, 1 H); 11.40 (s, 1 H). MS (El): 429.1 EXAMPLE 56 2-Chloro-5-methyl -? / - (naphthalen-1-yl) pyrimidin-4-amine (Intermediary 27) 27 To a solution of 2-chloro-5-methylpyrimidin-4-amine (144 mg, 1.0 mmol) in 1,4-dioxane (40 ml) was added 1-bromonaphthalene (227 mg, 1.1 mmol), Cs2CO3 (1.3 g). , 4.0 mmol), Pd2 (dba) 3 (91 mg, 0.1 mmol), and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xant Phos, 183 mg, 0.3 mmol). The mixture was heated under reflux for 4 hr under Ar. The solid was filtered and the filtrate was washed with brine (1 x 100 ml). The organic solution was separated and dried (Na2SO). The solvent was removed to 5 ml and hexane (100 ml) was added, the solid was collected by filtration. The crude product, the intermediate of title 27, was used for the next reaction without further purification.

EXAMPLE 57 ^ - (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -5-methyl-4- (naphthalen-1-yl) pyrimidin-2-amine (Compound XXXII) XXXII To a solution of intermediate 27 described above (235 mg, 0.87 mmol) in 1,4-dioxane (20 ml) was added 4- (2- (pyrrolidin-1-yl) ethoxy) benzenamine (183 mg, 0.87 mmol) , Cs2CO3 (1.3 g, 4.0 mmol), Pd2 (dba) 3 (46 mg, 0.05 mmol), and 4,5-bis (diphenylphosphino-9,9-dimethylxanthene (Xant Phos, 87 mg, 0.15 mmol). it was heated under reflux for 4 hr under Ar. The solid was filtered and the filtrate was washed with brine (1 x 50 ml) The organic solution was separated and dried (Na2SO4) .The solvent was removed under vacuum. purified by HPLC and gave the title compound XXXII (89 mg, 21%) as a yellow solid.1H NMR (500 MHz, DMSO-d6): 1.88-1.90 (m, 2H); 1.97-2.03 (m, 2H ), 2.30 (s, 3H), 3.03-3.08 (m, 2H), 3.50-3.53 (m, 4H), 4.21 (t, J = 4.9 Hz, 2H), 6.50 (d, J = 7.2 Hz, 2H); 6.82 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H), 7.57-7.61 (m, 1 H), 7.63 (t, J = 7.4 Hz, 1 H), 7.89 ( d, J = 8.3 Hz, 2H), 7.95 (s, 1H), 8.02 (d, J = 8.3 Hz, 1 H), 8.08 (d, J = 7.7 Hz, 1 H); 10.37 (s, 1 H); 10.43 (s, 1 H); 10.93 (br, 1 H).

MS (El): 440.1 EXAMPLE 58 1- (2-Chloro-5-methylpyrimidin-4-yl) isoquinoline (Intermediary 28) 28 To a solution of 2-chloro-5-methylpyrimidin-4-amine (144 mg, 1.0 mmol) in 1,4-dioxane (40 mL) was added 1-chloroisoquinolin (164 mg, 1.0 mmol), Cs 2 CO 3 (1.3 g, 4.0 mmole), Pd2 (dba) 3 (91 mg, 0.1 mmol), and 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xant Phos, 183 mg, 0.3 mmol). The mixture was heated under reflux for 4 hr under Ar. The solid was filtered and the filtrate was washed with brine (1 x 100 ml). The organic solution was separated and dried (Na2SO4). The solvent was removed to 5 ml and hexane (100 ml) was added, the solid was collected by filtration. The crude product, the intermediate of title 28, was used for the next reaction without further purification.

EXAMPLE 59 / -f4- (2- (pyrrolidin-1-yl) ethoxy) phenyl-4- (isoquinolin-1-yl) -5-methylpyrimidin-2-amine (Compound XXXIII) H XXXIII To a solution of intermediate 28 described above (90 mg, 0.33 mmol) in 1,4-dioxane (20 ml) was added 4- (2- (pyrrolidin-1-yl) ethoxy) benzenamine (76 mg, 0.37 mmol), Cs2CO3 (391 mg, 1.2 mmol), Pd2 (dba) 3 (28 mg, 0.03 mmol), and 4,5-bis (diphenylfosphine) -9,9-dimethylxanthene (Xant Phos, 52 mg , 0.09 mmol). The mixture was heated under reflux for 4 hr under Ar. The solid was filtered and the filtrate was washed with brine (1 x 50 ml). The organic solution was separated and dried (Na2SO4). The solvent was removed under vacuum. The crude product was purified by HPLC and gave the title compound XXXIII (21 mg, 15%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d 6): 1.64-1.70 (m, 6H); 2.23 (s, 3H); 2. 78 (t, J = 5.9 Hz, 2H); 4.04 (t, J = 5.9 Hz, 2H); 6.38 (d, J = 7.2 Hz, 1 H); 6.93 (d, J = 9.0 Hz, 2H); 6.97 (d, J = 7.2 Hz, 1 H); 7.45 (br, 1H); 7.57 (d, J = 8.8 Hz, 1 HOUR); 7.58-7.62 (m, 1 H); 7.70-7.78 (m, 2H); 8.04 (s, 1 H); 8.75 (d, J = 8.1 Hz, 1 HOUR); 9.06 (s, 1 H); 9.19 (s, 1 H). MS (El): 441.2 EXAMPLE 60? / 2- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) - / V - (3- (trifluoromethyl) phenyl) -5-methylpyrimidin-2,4-diamine (Compound XXXIV) XXXIV A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (143 mg, 1.0 mmol), 1-bromo-3- (trifluoromethyl) benzene (225 mg, 1.0 mmol), Pd2 (dba) 3 (9.0 mg) , 0.01 mmol), Xantphos (12 mg, 0.02 mmol) and cesium carbonate (650 mg, 2.0 mmol) was suspended in dioxane (15 mL) and heated to reflux under an argon atmosphere for 15 hr. The reaction mixture was cooled to room temperature and diluted with DCM (30 ml). The mixture was filtered and the filtrate was concentrated under vacuum. The residue under purification using HPLC gave? / 4- (3- (trifluoromethyl) phenyl) -5-methylpyrimidine-2,4-diamine as an off-white solid (192 mg, 67%). MS (ESI +): m / z 288 (M + H) +. A mixture of? / 4- (trifluoromethyl) phenyl) -5-methylpyrimidine-2,4-diamine (28.7 mg, 0.1 mmol) and 4- (2- (pyrrolidin-1-yl) ethoxy) benzenamine (22 mg, 0.12 mmoles) was dissolved in acetic acid (5 ml) and heated under microwave at 150 ° C for 10 min. The mixture was cooled to room temperature and the acetic acid was removed under reduced pressure. The residue was purified by HPLC to give the compound of title XXXIV as a brown solid (16 mg, 35%). 1 H NMR (500 MHz, DMSO-d 6): 1.65-1.71 (m, 4H), 2.11 (s, 3H), 2.45-2.55 (m, 4H), 2.74 (t, J = 6.0 Hz, 2H), 3.98 ( t, J = 6.0 Hz, 2H), 6.76 (d, J = 9.0 Hz, 2H), 7.35 (d, J = 5.1 Hz, 1 H), 7.45-7.57 (m, 3H), 7.9-7.97 (m, 2H), 8.20 (d, J = 7.6 Hz, 1 H), 8.41 (s, 1 H), 8.85 (s, 1 H), m / z 458 (M + H) +.

EXAMPLE 61 2-Chloro-W- (4- (trifluoromethyl) phenyl) -5-methylpyrimidin-4-amine (Intermediate 29) 29 A suspension of 2-chloro-5-methylpyrimidin-4-amine (159 μl, 1.2 mmol), 1-bromo-4- (trifluoromethyl) benzene (150 mg, 1.0 mmol), potassium terbutoxide (224 mg, 2.0 mmol) , Xantphos (120 mg, 0.2 mmol), and palladium acetate (26 mg, 0.1 mmol) was sealed in a microwave reaction tube and irradiated at 160 ° C for 15 min. The mixture was allowed to cool to room temperature, the solids were filtered using DCM to rinse, and the solution was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane to EtOAc) to give the intermediate of title 29 (128.7 mg, 43%) as a white solid. MS (ESI +): m / z 288 (M + H) +.

EXAMPLE 62 A / 2- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -? / - (4- (trifluoromethyl) phenyl) -5-methylpyrimidine-2,4-diamine (Compound XXXV) XXXV A mixture of the intermediates described above 29 (128 mg, 0.5 mmol) and 6 (212 mg, 1.0 mmol) was suspended in acetic acid (5 ml) and heated at 75 ° C for 18 hr. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was basified with saturated aq NaHCO3 (50 ml) and extracted with DCM (2x50 ml). The organic layer was concentrated under vacuum and the crude product was purified by reverse phase flash chromatography on C18 (water to CH3CN, 0.1% TFA). The aqueous fractions were neutralized with saturated aq NaHCO3 and extracted with EtOAc. The organics were concentrated under vacuum and the residue was taken up in DCM. HCl in dioxane was added together with ether and the resulting solid was filtered to give the hydrochloride salt of the title compound XXXV (166 mg, 70%) as a gray solid. 1 H NMR (500 MHz, DMSO-d 6): 1.80-1.95 (m, 2H), 1.95-2.10 (m, 2H), 2.19 (s, 3H), 3.05-3.20 (m, 2H), 3.55-3.65 (m, 6H), 4.33 (t, J = 4.7 Hz, 2H), 6. 97 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.73 (d, J- 8.5 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.94 (s, 1 H), 9.92 (br s, 1 H), 10.44 (br s, 1 H), 10.85 (br s, 1 H); MS (ESI +): m / z 458.5 (M + H) +.

EXAMPLE 63 Benzo [1,3] dioxol-4-yl- (2-chloro-5-methyl-pyrimidin-4-y) -amine (Intermediate 30) A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.4 g, 9.7 mmol), 4-bromo-benzo [1, 3] dioxol (2.0 g, 10 mmol), Pd2 (dba) 3 (0.80) g, 0.87 mmol), Xantphos (1.0 g, 1.7 mmol) and cesium carbonate (6.3 g, 19 mmol) was suspended in dioxane (40 mL) and heated to reflux under argon atmosphere for 5 hr. The reaction mixture was cooled to room temperature and diluted with DCM (30 ml). The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (hexanes at 50% EtOAc / hexanes) to give the compound of the title (1.0 g, 39%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 2.13 (s, 3 H), 5.99 (s, 2 H), 6.80-6.90 (m, 3 H), 8.01 (s, 1 H), 8.92 (s, 1 H) . MS (ES +): m / z 264 (M + H) +.

EXAMPLE 64 / V4- Benzon.31-dioxol-4-yl-5-methyl-? / 2-r4- (2-pyrrolidin-1-yl-ethoxy) -phenimyrimidin-2,4-diamine (Compound XXXVI) xxxvi A mixture of intermediate 30 (0.25 g, 0.95 mmol) and 4- (2-pyrrolidin-1-yl-ethoxy) -phenylamine (0.40 g, 1.9 mmol) in acetic acid (15 ml) was heated at 100 ° C for 20 minutes. hr. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH ~ 7 with 10% NaOH solution. The resulting solution was extracted with EtOAc (2 x 30 ml) and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous Na2SO and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash chromatography on silica gel (DCM at 20% MeOH / DCM) to give the title compound (0.14 g, 34%) as a solid white. 1 H NMR (500 MHz, DMSO-d 6): d 1.65-1.75 (m, 4H), 2.06 (s, 3H), 2.55-2.65 (m, 4H), 2.78-2.88 (m, 2H), 3.98 (t, J = 5.8 Hz, 2H), 5.89 (s, 2H), 6.65 (d, J = 9.0 Hz, 2H), 6.79-6.84 (m, 2H), 6.89 (dd, J = 7.7, 1.7 Hz, 1 H) , 7.45 (d, J = 9.1 Hz, 2H), 7.81 (s, 1 H), 8.23 (s, 1 H), 8.73 (s, 1 H). MS (ES +): m / z 434 (M + H) +.

EXAMPLE 65 V-Benzo [1,3ldioxol-4-yl-5-methyl- ^ 2- [4- (4-methyl-piperazin-1-yl) -phenyl-1-pyrimidine-2,4-diamine (Compound XXXVII) xxxvp A mixture of intermediate 30 (0.10 g, 0.38 mmol) and 4- (4-methyl-piperazin-1-yl) -phenylamine (0.12 g, 0.51 mmol) in acetic acid (3 ml) was sealed in a tube of microwave reaction and irradiated with microwaves at 150 ° C for 15 min. After cooling to room temperature, the lid was removed and the mixture was concentrated. The residue was taken up in water (20 ml) and the mixture was neutralized with 10% NaOH solution until a solid precipitated. The solid was filtered and then purified by flash chromatography on silica gel (DCM at 15% MeOH / DCM) to give the title compound. title (22 mg, 14%) as a light red solid. 1 H NMR (500 MHz, DMSO-d 6): d 2.06 (s, 3 H), 2.21 (s, 3 H), 2.44 (t, J = 4.8 Hz, 4 H), 2.97 (t, J = 4.9 Hz, 4 H), 5.89 (s, 2H), 6.67 (d, J = 9.1 Hz, 2H), 6.80-6.86 (m, 2H), 6.91 (d, J = 7.6, 1.7 Hz, 1H), 7.41 (d, J = 9.0 Hz , 2H), 7.79 (s, 1 H), 8.17 (s, 1 H), 8.63 (s, 1 H). MS (ES +): m / z 419 (M + H) +.

EXAMPLE 66 (4-Chloro-3-methoxy-phenyl) - (2-chloro-5-methyl-pyrimidin-4-yl) -amine (Intermediate 31) 31 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mmol), 4-bromo-1-chloro-2-methoxy-benzene (0.65 mL, 4.8 mmol), Pd2 (dba) 3 (0.17 g, 0.19 mmole), Xantphos (0.22 g, 0.38 mmole) and cesium carbonate (2.3 g, 7.1 mmole) was suspended in dioxane (20 ml) and heated to reflux under argon atmosphere for 5 hr. The reaction mixture was cooled to room temperature and diluted with DCM (30 ml). The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (hexanes at 40% EtOAc / hexanes) to give the title compound (0.55 g, 55%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d 6): d 2.18 (s, 3 H), 3.85 (s, 3 H), 7.35 (d, J = 8.6, 2.3 Hz, 1 H), 7.39 (d, J = 8.7 Hz, 1 H), 7.56 (d, J = 2.3 Hz, 1 H), 8.09 (d, J = 0.9 Hz, 1 H), 8.91 (s, 1 H). MS (ES +): m / z 284 (M + H) +.

EXAMPLE 67 ^ 4- (4-Chloro-3-methoxy-phenyl) -5-methyl-β- 2- (4-pyrazol-1-ylmethyl-phenyl) -pyrimidine-2,4-diamine (Compound XXXVIII) xxxvip A suspension of intermediate 31 (0.20 g, 0.70 mmol), 4-pyrazol-1-ylmethyl-phenylamine (0.14 g, 0.81 mmol), Pd2 (dba) 3 (40 mg, 0.044 mmol), Xantphos (50 mg, 0.086 mmol) ) and cesium carbonate (0.50 g, 1.5 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by HPLC. The fractions were combined and drained in saturated NaHCO3 solution (40 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid was dissolved in a minimum amount of EtOAc and hexanes were added until a solid precipitated. After filtration, the title compound was obtained as an off-white solid (0.13 g, 44%). 1 H NMR (500 MHz, DMSO-d 6): d 2.11 (s, 3 H), 3.74 (s, 3 H), 5.22 (s, 2 H), 6.25 (t, J = 2.1 Hz, 1 H), 7.08 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 9.3 Hz, 1 H), 7.40-7.45 (m, 3H), 7.60 (d, J = 8.6 Hz, 2H), 7.75 (d, J = 1.8 Hz , 1 H), 7.91 (s, 1 H), 8.36 (s, 1 H), 9.04 (s, 1 H) MS (ES +): m / z 421 (M + H) +.

EXAMPLE 68 5-Methyl- / V2-r4- (4-methyl-piperazin-1-yl) -phenyl-2,4-diamine (Intermediary 32) 32 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.0 g, 6.9 mmol) and 4- (4-methyl-piperazin-1-yl) -phenylamine (1.5 mL, 7.8 mmol) in acetic acid ( 15 ml) was heated at 100 ° C for 2.5 hr. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (20 ml) and the mixture was neutralized with 10% NaOH solution until a solid precipitated. After filtering and washing With water, the title compound was obtained as a gray solid (1.3 g, 63%). 1 H NMR (500 MHz, DMSO-d 6): d 1.88 (s, 3 H), 2.21 (s, 3 H), 2.21 (s, 3 H), 2.44 (t, J = 4.8 Hz, 4 H), 3.00 (t, J = 4.8 Hz, 4H), 6.27 (s, 2H), 6.79 (d, J = 9.0 Hz, 2H), 7.57 (d, J = 9.0 Hz, 2H), 7.63 (s, 1 H), 8.42 (s, 1 HOUR). MS (ES +): m / z 299 (M + H) + EXAMPLE 69 ^ 4- (4-Chloro-3-methoxy-phenyl) -5-methyl- ^ 2-r4- (4-methyl-piperazin-1-yl) -pheno-pyrimidine-2,4-diamine (Compound XXXIX ) XXXIX A suspension of intermediate 32 (0.30 g, 1.0 mmol), 4-bromo-1-chloro-2-methoxy-benzene (0.20 ml, 1.5 mmol), Pd2 (dba) 3 (50 mg, 0.055 mmol), Xantphos ( 65 mg, 0.11 mmol) and cesium carbonate (0.70 g, 2.1 mmol) in dioxane / DMF (3/1, 8 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. . After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by HPLC. The fractions were combined and drained in saturated NaHCO3 solution (40 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na2SO and filtered. The filtrate was concentrated and the residue was triturated in a mixture of EtOAc / hexanes (1/5, 30 ml). After filtration, the title compound was obtained as an off-white solid (0.20 g, 46%). 1 H NMR (500 MHz, DMSO-d 6): d 2.09 (s, 3 H), 2.21 (s, 3 H), 2.45 (t, J = 4.9 Hz, 4 H), 3.02 (t, J = 4.9 Hz, 4 H), 3.73 (s, 3H), 6.79 (d, J = 9.1 Hz, 2H), 7.27 (d, J = 8.6 Hz, 1H), 7.42-7.47 (m, 3H), 7.49 (d, J = 2.3 Hz, 1H ), 7.86 (s, 1 H), 8.28 (s, 1 H), 8.72 (s, 1 H). MS (ES +): m / z 439 (M + H) +.

EXAMPLE 70 ^ 4- (4-Chloro-3-methoxy-phenyl) -5-methyl- ^ 2- (4-morpholin-4-l-phenyl) -pyrimidine-2,4-diamine (Compound XL) XL A mixture of intermediate 31 (0.10 g, 0.35 mmol) and 4-morpholin-4-yl-phenylamine (80 mg, 0.45 mmol) in acetic acid (3 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the mixture was concentrated. The residue was taken up in water (20 ml) and the The mixture was neutralized with 10% NaOH solution until a solid precipitated. The solid was filtered and then purified by flash chromatography on silica gel (DCM at 10% MeOH / DCM) to give the title compound (55 mg, 37%) as a light brown solid. 1 H NMR (500 MHz, DMSO-d 6): d 2.10 (s, 3 H), 3.00 (t, J = 4.8 Hz, 4H), 3.71-3.76 (m, 7H), 6.80 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 8.6 Hz, 1 H), 7.45 (dd, J = 8.7, 2.2 Hz, 1H) , 7.47-7.50 (m, 3H), 7.87 (s, 1H), 8.29 (s, 1 H), 8.75 (s, 1 H). MS (ES +): m / z 426 (M + H) +.

EXAMPLE 71? F4- (4-Chloro-3-methoxy-phenyl-5-methyl- ^ 2- (4-pyrazol-1-yl-Tenyl) -pyrimidine-2,4-diamine (Compound XLI) XLI A mixture of intermediate 31 (90 mg, 0.32 mmol) and 4-pyrazol-1-yl-phenylamine (70 mg, 0.44 mmol) in acetic acid (3 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the mixture was concentrated. The residue was taken up in water (20 ml) and the The mixture was neutralized with 10% NaOH solution until a solid precipitated. The solid was filtered and then purified by HPLC. The corrected fractions were combined and concentrated to give the title compound (40 mg of TFA salt, 24%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 2.17 (s, 3 H), 3.75 (s, 3 H), 6.54 (t, J = 1.9 Hz, 1 H), 7.30 (d, J = 6.6 Hz, 1 H ), 7.39 (d, J = 2.1 Hz, 1 H), 7.40 (d, J = 8.6 Hz, 1 H), 7.59 (d, J = 8.9 Hz, 2H), 7.71 (d, J = 8.9 Hz, 2H ), 7.73 (d, J = 1.6 Hz, 1 H), 7.93 (s, 1 H), 8.41 (d, J = 2.5 Hz, 1 H), 9.41 (s, 1 H), 10.05 (s, 1 H) ). MS (ES +): m / z 407 (M + H) +.

EXAMPLE 72 ^ 4- (4-Chloro-3-methoxy-phenyl) -5-methyl- ^ 2- (4-piperidin-1-yl-phenyl) -pyrimidine-2,4-diamine (XLII) XL1I A mixture of intermediate 31 (0.11 g, 0.39 mmol) and 4-piperidin-1-yl-phenylamine (90 mg, 0.51 mmol) in acetic acid (3 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the mixture was concentrated. The residue was taken up in water (20 ml) and the The mixture was neutralized with 10% NaOH solution until a solid precipitated. The solid was filtered and then purified by flash chromatography on silica gel (hexanes at 70% EtOAc / hexanes) to give the title compound (10 mg, 6%) as a light brown solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.48-1.53 (m, 2H), 1.59-1.65 (m, 4H), 2.09 (s, 3H), 3.00 (t, J = 5.4 Hz, 4H), 3.73 (s, 3H), 6.78 (d, J = 9.0 Hz, 2H), 7.27 (d, J = 8.7 Hz, 1 H), 7.40-7.47 (m, 3H), 7.50 (d, J = 2.2 Hz, 1 H), 7.86 (s, 1 H), 8.28 (s, 1 H), 8.71 (s, 1 H). MS (ES +): m / z 424 (M + H) +.

EXAMPLE 73 V4- (4-Chloro-3-methoxy-phenyl) -5-methyl-V2-f4- (4-methyl-piperazin-1-methylmethyl) -phenyl-pyrimidine-2,4-diamine (XLIII) XLIII A suspension of intermediate 31 (50 mg, 0.18 mmol), 4- (4-methyl-piperazin-1-ylmethyl) -phenylamine (50 mg, 0.24 mmol), Pd2 (dba) 3 (10 mg, 0. 011 mmole), Xantphos (13 mg, 0.022 mmol) and cesium carbonate (0.12 g, 0.37 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves. 160 ° C for 15 min. After After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (DCM at 10% MeOH / DCM) to give the title compound (35 mg, 44%) as an off-white solid. 1 H NMR (500 MHz, DMSO-d 6): d 2.11 (s, 3 H), 2.15 (s, 3 H), 2.20-2.45 (m, 8 H), 3.35 (s, 2 H), 3.75 (s, 3 H), 7.07 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz, 1 H), 7.44 (d, J = 8.7, 2.3 Hz, 1 H), 7.47 (d, J = 2.3 Hz, 1 H ), 7.57 (d, J = 8.5 Hz, 2 H), 7.91 (s, 1 H), 8.36 (s, 1 H), 8.98 (s, 1 H). MS (ES +): m / z 453 (M + H) +.

EXAMPLE 74 ^^ - Chloro-S-methoxy-phenyD-S-methyl-^^ -piperazin-l-yl-phenyD-pyrimidine-S-diamine (Compound XLIV) XLGV A mixture of intermediate 31 (0.20 g, 0.70 mmol) and 4- (4-amino-phenyl) -piperazine-1-carboxylic acid tert-butyl ester (0.22 g, 0.79 mmol) in acetic acid (4 ml) was added. sealed in a microwave reaction tube and irradiated with microwaves at 150 ° C for 15 min. After cooling to room temperature, the lid was removed and the mixture was concentrated. The residue was purified by HPLC and the corrected fractions were combined and drained in saturated NaHCO3 solution (40 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the resulting solid was dissolved in a minimum amount of EtOAc and hexanes were added until a solid precipitated. After filtration, the title compound was obtained as an off-white solid (0.10 g, 33%). 1 H NMR (500 MHz, DMSO-d 6): d 2.10 (s, 3H), 3.16 (s, 8H), 3.73 (s, 3H), 6.83 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 8.8 Hz, 1 H), 7.44 (dd, J = 8.7, 2.1 Hz, 1 H), 7.49-7.52 (m, 3H), 7.88 (s, 1 H), 8.32 (s, 1 H), 8.81 ( s, 1 H) MS (ES +): m / z 425 (M + H) +.

EXAMPLE 75 -fer -butyl-3- 5-methyl-2-f4- (4-methyl-piperazin-1-yl) -phenylammonol-pyrimidin-4-ylaminoj-benzenesulfonamide (Compound XLV) XLV A suspension of intermediate 32 (0.30 g, 1.0 mmol), 3-bromo-β-tert-butyl-benzenesulfonamide (0.35 g, 1.2 mmol), Pd2 (dba) 3 (60 mg, 0.066 mmol), Xantphos ( 70 nig, 0.12 mmole) and cesium carbonate (0.70 g, 2. 1 mmole) in dioxane / DMF (3/1, 8 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by HPLC. The fractions were combined and drained in saturated NaHCO3 solution (40 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the residue was triturated in a mixture of EtOAc / hexanes (1/7, 40 ml). After filtration, the title compound was obtained as an off-white solid (0.30 g, 59%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9 H), 2.1 1 (s, 3 H), 2.22 (s, 3 H), 2.45 (t, J = 4.7 Hz, 4 H), 3.02 (t, J = 4.8 Hz, 4H), 6.81 (d, J = 9.1 Hz, 2H), 7.45-7.52 (m, 4H), 7.56 (s, 1 H), 7.89 (s, 1 H), 8.10-8.16 (m , 2H), 8.51 (s, 1 H), 8.70 (s, 1 H) MS (ES +): m / z 510 (M + H) +.

EXAMPLE 76 N-Fer-Butyl-3- (2-chloro-5-methyl-pyrimidin-4-ylamino) -benzenesulfonamide (Intermediate 33) 33 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.4 g, 2.8 mmol), 3-bromo-? / - fe? -butyl-benzenesulfonamide (1.0 g, 3.4 mmol), Pd2 (dba) 3 (0.17 g, 0.19 mmole), Xantphos (0.2 g, 3.5 mmole) and cesium carbonate (2.0 g, 6.1 mmole) was suspended in dioxane (25 ml) and heated to reflux under argon atmosphere for 3 hr. The reaction mixture was cooled to room temperature and diluted with DCM (30 ml). The mixture was filtered and the filtrate was concentrated under vacuum. The residue was dissolved in EtOAc and hexanes added until a solid precipitated. After filtration, the title compound (1.2 g, 98%) was obtained as a light brown solid. This was used in the next step without purification. MS (ES +): m / z 355 (M + H) +.

EXAMPLE 77 / V-fer-Butyl-3- [5-methyl-2- (4-morpholin-4-ylmethyl-fenlamino) -pyrimidin-4-ylaminole-benzenesulfonamide (Compound XLVI) XLVI A mixture of intermediate 33 (0.50 g, 1.4 mmol), 4-morpholin-4-ylmethyl-phenylamine (0.35 g, 1.8 mmol), Pd2 (dba) 3 (0.10 g, 0.11 mmol), Xantphos (0.12 g, 0.21 mmoles) and cesium carbonate (1.0 g, 3.1 mmol) was suspended in dioxane (25 ml) and heated to reflux under argon atmosphere for 3 hr. The reaction mixture was cooled to room temperature and diluted with DCM (30 ml). The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC and the corrected fractions were combined and drained in saturated NaHCO3 solution (50 ml). The combined aqueous layers were extracted with EtOAc (2 x 50 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the resulting solid was dissolved in a minimum amount of EtOAc and hexanes were added until a solid precipitated. After filtration, the title compound was obtained as an off-white solid (0.23 g, 31%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9H), 2.13 (s, 3H), 2.28-2.34 (m, 4H), 3.35 (s, 2H), 3.55 (t, J = 4.8 Hz , 4H), 7.10 (d, J = 8.5 Hz, 2H), .45-7.52 (m, 2H), 7.57 (s, 1 H), 7.59 (d, J = 8.5 Hz, 2H), 7.94 (s, 1H), 8.10 (s, 1 H), 8.13-8.16 (m , 1 H), 8.58 (s, 1 H), 8.95 (s, 1 H). MS (ES +): m / z 511 (M + H) +.

EXAMPLE 78 ^ -fer-Butyl-3-. { 5-methyl-2-f4- (4-oxy-morpholin-4-ylmethyl) -phenylaminol-pyrimidin-4-ylamino) -benzenesulfonamide (Compound XLVII) XLVJU A solution of the XLVI compound described above (30 mg, 0.06 mmol) and 3-chloroperbenzoic acid (77%, 14 mg, 0.06 mmol) in chloroform (30 ml) was stirred at room temperature for 1 hour. The solvent was removed by rotary evaporation and the resulting mixture was purified by silica gel with 20% CH3OH / CHCl3 as an eluent to give the title compound as an off-white solid (15 mg, 48%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9 H), 2.14 (s, 3 H), 2.71. (d, J = 10.9 Hz, 2H), 3.63 (d, J = 9.9 Hz, 2H), 4.08 (t, J = 11.6 Hz, 2H), 4.28 (s, 2H), 7.38 (d, J = 8.5 Hz , 2H), 7.50 (d, J = 5.0 Hz, 2H), 7.61 (s, 1 H), 7.66 (d, J = 8.5 Hz, 2H), 7.96 (s, 1H), 8.13 (m, 2H), 8.63 (s, 1H), 9.13 (s, 1 H).

MS (ES +): m / z 527 (M + H) +.

EXAMPLE 79 ^ -ter-Butyl-3- [5-methyl-2- (4-pyrazol-1-yl-phenylamino) -pyrimidin-4-ylamino-1-benzenesulfonamide (Compound XLVIII) XLV? I1 A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-pyrazol-1-yl-phenylamine (50 mg, 0.31 mmol) in acetic acid (3 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 130 ° C for 15 min. After cooling to room temperature, the lid was removed and the mixture was concentrated. The residue was taken up in water (20 ml) and neutralized with 10% NaOH solution until a solid precipitated. The brown solid was filtered and then purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO 3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the resulting solid was dissolved in a minimum amount of EtOAc and hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (15 mg, 11%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9 H), 2.15 (s, 3 H), 6.49 (t, J = 2.2 Hz, 1 H), 7.50-7.55 (m, 2 H), 7.58 ( s, 1 H), 7.62 (d, J = 9.1 Hz, 2H), 7.68 (d, J = 1.3 Hz, 1 H), 7.77 (d, J- 9.1 Hz, 2H), 7.96 (s, 1H), 8.11 (s, 1H), 8.13-8.16 (m, 1 H), 8.33 (d, J = 2.5 Hz, 1 H), 8.64 (s, 1 H), 9.17 (s, 1H). MS (ES +): m / z 478 (M + H) +.

EXAMPLE 80? / - fer-Butyl-3- [5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -pyrimidin-4-ylaminole-benzenesulfonamide (Compound XLIX) XLIX A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4- (5-amino-pyridin-2-yl) -piperazine-1-carboxylic acid tert-butyl ester (90 mg, 0.32 mmol) in acetic acid ( 3 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 130 ° C for 15 min. After cooling to room temperature, the lid was removed and the mixture was concentrated. The residue was dissolved in DCM (5 ml) and 30% TFA / DCM (6 ml) was added. The mixture was stirred at room temperature for 1 hr, concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the organic layers The combined extracts were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid was dissolved in a minimum amount of EtOAc and hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (10 mg, 7%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9H), 2.11 (s, 3H), 2.83 (t, J = 5.0 Hz, 4H), 3.28-3.33 (m, 4H), 6.73 (d , J = 9.1 Hz, 1 H), 7.40-7.49 (m, 2H), 7.57 (s, 1 H), 7.86 (d, J = 9.1, 2.7 Hz, 1 H), 7.88 (s, 1 H), 8.10-8.16 (m, 2H), 8.28 (d, J = 2.5 Hz, 1 H), 8.53 (s, 1 H), 8.72 (s, 1 H). MS (ES +): m / z 497 (M + H) +.

EXAMPLE 81 / V-fer-Butyl-3- [5-methyl-2- (4-pyrazol-1-ylmethyl-phenylamino) -pyrimidin-4-ylamino) -benzenesulfonamide (compound L) A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-pyrazol-1-ylmethyl-phenylamine (50 mg, 0.29 mmol) in acetic acid (3 ml) was sealed in a microwave reaction tube and irradiated with microwaves to 130 ° C for 15 min. After cooling to room temperature, the lid was removed and the mixture was concentrated. The residue was purified by HPLC and the Corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the resulting solid was dissolved in a minimum amount of EtOAc and hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (12 mg, 9%). H NMR (500 MHz, DMSO-d6): d 1.12 (s, 9H), 2.13 (s, 3H), 5.21 (s, 2H), 6.24 (t, J = 1.9 Hz, 1 H), 7.08 (d, J = 8.5 Hz, 2H), 7.27-7.50 (m, 3H), 7.56 (s, 1 H), 7.60 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 2.1 Hz, 1 H), 7.94 (s, 1 H), 8.14 (d, J = 7.9 Hz, 1 H), 8.59 (s, 1H), 9.01 (s, 1H). MS (ES +): m / z 492 (M + H) +.

EXAMPLE 82 5-Methyl- ^ 2-f3- (piperidin-1-sulfonyl) -fenin-pyrimidine-2,4-diamine (Intermediary 34) 3. 4 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.25 g, 1.74 mmol) and 3- (piperidin-1-sulfonyl) -phenylamine (0.50 g, 2.1 mmol) in acetic acid (4 ml) were added. sealed in a microwave reaction tube and irradiated with microwave at 130 ° C for 15 min. After cooling to room temperature, the lid was removed and the mixture was concentrated. The residue was taken up in water (20 ml) and pH was adjusted to ~ 9 with 10% NaOH solution. The resulting solution was extracted with EtOAc (2 x 30 ml) and the organic layer was separated. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum and the crude product (-0.6 g) was used in the next step without purification. MS (ES +): m / z 348 (M + H) +.

EXAMPLE 83 M-fer-Butyl-3-. { 5-methyl-2- [3- (piperidin-1-sulfonyl) -phenylamino-1-pyrimidin-4-ylamino) -benzenesulfonamide (Compound Ll) Ll A suspension of intermediate 34 (0.10 g, 0.29 mmol), 3-bromo-? / - tert-butyl-benzenesulfonamide (84 mg, 0.29 mmol), Pd2 (dba) 3 (15 mg, 0.016 mmol), Xantphos (20 mg). mg, 0.035 mmol) and cesium carbonate (0.18 g, 0.55 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 15 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by HPLC. The fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the residue was dissolved in a minimum amount of EtOAc and hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (20 mg, 12%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9H), 1.30-1.40 (m, 2H), 1.50-1.56 (m, 4H), 2.16 (s, 3H), 2.88 (t, J = 5.3 Hz, 4H), 7.17 (d, J- 7.8 Hz, 1 H), 7.43 (t, J = 8.0 Hz, 1 H), 7.59-7.60 (m, 2H), 7.58 (s, 1 H), 8.13 (s, 1 H), 7.16 (dd, J = 7.9, 1.9 Hz, 1 H), 8.18-8.22 (m, 1 H), 8.67 (s, 1 H), 9.37 (s, 1 H). MS (ES +): m / z 559 (M + H) +.

EXAMPLE 84 A -fer-Butyl-3-methyl-2-f4- (4-methyl-piperazin-1-ylmethyl) -phenylamino] -pyrimidin-4-ylamino) -benzenesulfonamide (Compound Lll) LII A suspension of intermediate 33 (0.10 g, 0.28 mmol), 4- (4-methylpiperazin-1-ylmethyl) -phenylamine (65 mg, 0.32 mmol), Pd2 (dba) 3 (20 mg, 0. 022 mmol), Xantphos (25 mg, 0.043 mmole) and cesium carbonate (0.18 g, 0.55 mmole) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwave at 170 ° C for 15 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by HPLC. The fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the residue was dissolved in a minimum amount of EtOAc and hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (53 mg, 36%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9H), 2.13 (s, 3H), 2.15 (s, 3H), 2.20-2.45 (m, 4H), 3.25-3.40 (m, 6H) , 7.08 (d, J = 8.6 Hz, 2H), 7.45-7.52 (m, 2H), 7.56 (s, 1 H), 7.57 (s, J = 8.6 Hz, 2H), 7.94 (s, 1 H), 8.09 (s, 1 H), 8.13-8.16 (m, 1 H), 8.58 (s, 1 H), 8.94 (s, 1 H). MS (ES +): m / z 524 (M + H) +.

EXAMPLE 85 ^ -ter-Butyl-3- [5-methyl-2- (4-piperazin-1-yl-3-trifluoromethyl-phenylamino) -pyrimidin-4-ylaminol-benzenesulfonamide (Lili Compound) LIIJ A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4- (4-amino-2-trifluoromethyl-phenyl) -piperazine-1-carboxylic acid tert-butyl ester (0.1 g, 0.29 mmol), Pd2 (dba) ) 3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.18 g, 0.55 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and it was irradiated with microwaves at 170 ° C for 15 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM and the filtrate was concentrated. The residue was dissolved in DCM (5 ml) and 50% TFA / DCM (6 ml) was added. The mixture was stirred at room temperature for 2 hr, concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO 3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the resulting solid was dissolved in a minimum amount of EtOAc and hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (42 mg, 26%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9H), 2.14 (s, 3H), 2.70-2.75 (m, 4H), 2.80-2.85 (m, 4H), 7.36 (d, J = 8.5 Hz, 2H), 7.45-7.52 (m, 2H), 7.55 (s, 1 H), 7.90-8.00 (m, 3H), 8.07 (s, 1 H), 8.15 (d, J = 7.6 Hz, 1 H), 8.63 (s, 1 H), 9.22 (s, 1H) MS (ES +): m / z 564 (M + H) +.

EXAMPLE 86 3- (2-f4- (4-Acetyl-piperazin-1-yl) -3-trifluoromethyl-phenylamino-5-methyl-pyrimidin-4-ylamino) -N-tert-butyl-benzenesulfonamide (Compound LIV) LIV A mixture of intermediate 33 (0.10 g, 0.28 mmol), 1- [4- (4-amino-2-trifluoromethyl-phenyl) -piperazin-1-yl] -ethanone (0.1 g, 0.35 mmol), Pd2 (dba ) 3 (15 mg, 0.016 mmol), Xantphos (20 mg, 0.035 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 15 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM and the filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the resulting solid was dissolved in a minimum amount of EtOAc and hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (64 mg, 38%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9 H), 2.04 (3, H), 2.14 (s, 3 H), 2.73 (t, J = 4.9 Hz, 2 H), 2.79 (t, J = 4.7 Hz, 2H), 3.50-3.60 (m, 4H), 7.40 (d, J = 8.7 Hz, 2H), 7.45-7.52 (m, 2H), 7.56 (s, 1 H), 7.90-8.00 (m , 3H), 8.07 (s, 1 H), 8.14 (d, J = 7.2 Hz, 1 H), 8.64 (s, 1 H), 9.26 (s, 1 H). MS (ES +): m / z 606 (M + H) +.

EXAMPLE 87 5-Methyl-? F2-f3- (4-methyl-piperazin-1-sulfonyl) -phenyl-pyrimidine-2,4-diamine (Intermediate 35) A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.25 g, 1.74 mmole) and 3- (4-methyl-piperazin-1-sulfonyl) -phenylamine (0.50 g, 2.0 mmole) in acetic acid (4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 130X for 15 min. After cooling to room temperature, the lid was removed and the mixture was concentrated. The residue was collected in water (20 ml) and the pH was adjusted to ~ 9 with 10% NaOH solution. The resulting solution was extracted with EtOAc (2 x 30 ml) and the organic layer was separated. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under vacuum and the crude product (~ 0.42 g) was used in the next step without purification. MS (ES +): m / z 363 (M + H) +.

EXAMPLE 88 M-fer-Butyl-3-. { 5-methyl-2-r3- (4-methyl-piperazin-1-sulfonyl) -phenylaminol-pyrimidin-4-ylamino) -benzenesulfonamide (Compound LV) LV A suspension of intermediate 35 (0.10 g, 0.28 mmol), 3-bromo-β-tert-butyl-benzenesulfonamide (80 mg, 0.27 mmol), Pd2 (dba) 3 (15 mg, 0.016 mmol), Xantphos (20 mg , 0.035 mmole) and cesium carbonate (0.18 g, 0.55 mmole) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 15 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by HPLC. The fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO and filtered. The filtrate was concentrated and the residue was dissolved in a minimum amount of EtOAc and hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (10 mg, 6%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9 H), 2.13 (s, 3 H), 2.16 (s, 3H), 2.33-2.40 (m, 4H), 2.85-2.94 (m, 4H), 7.18 (d, J = 8.1 Hz, 1 H), 7.44 (t, J = 8.0 Hz, 1 H), 7.49-7.54 (m, 2H), 7.58 (s, 1 H), 8.00-8.03 (m, 2H), 8.13 (s, 1 H), 8.15 (dd, J = 8.6, 1.6 Hz, 1 H), 8.18-8.23 (m, 1 H), 8.66 (s, 1 H), 9.38 (s, 1 HOUR). MS (ES +): m / z 574 (M + H) +.

EXAMPLE 89 N-tert-Butyl-3- [5-methyl-2- (4-piperazin-1-ylmethyl-phenylamino) -pyrimidin-4-ylaminole-benzenesulfonamide (Compound LVI) LVl A mixture of intermediate 33 (0.10 g, 0.28 mmol), ter- butyl 4- (4-amino-benzyl) -piperazin-1-carboxylic acid (0.1 g, 0.34 mmol), Pd2 (dba) 3 (15 mg, 0.016 mmol), Xantphos (20 mg, 0.035 mmol) and carbonate cesium (0.20 g, 0.61 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwave at 170 ° C for 15 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM and the filtrate was concentrated. The residue was dissolved in DCM (6 ml) and TFA (3 ml) was added. The mixture was stirred at room temperature for 1 hr, concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the resulting solid was triturated in hexanes / EtOAc (10/1, 55 ml). After filtration, the title compound was obtained as a white solid (32 mg, 22%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9H), 2.13 (s, 3H), 2.30-2.40 (m, 4H), 2.85 (t, J = 4.7 Hz, 4H), 3.38 (s) , 2H), 7.09 (d, J = 8.5 Hz, 2H), 7.45-7.52 (m, 2H), 7.56 (s, 1 H), 7.59 (d, J = 8.5 Hz, 2H), 7.94 (s, 1 H), 8.10 (s, 1 H), 8.13-8.16 (m, 1 H), 8.59 (s, 1 H), 8.96 (s, 1 H). MS (ES +): m / z 510 (M + H) +.

EXAMPLE 90 ^ -fer-Butyl-3-. { 5-methyl-2- [4- (2-pyrrolidin-1-yl-ethoxy) -pheny'laminol-pyrimidin-4-ylamino) -benzenesulfonamide (Compound LVll) LV? A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4- (2-pyrrolidin-1-yl-ethoxy) -phenylamine (0.10 g, 0.49 mmol) in acetic acid (3 ml) was sealed in a reaction tube of microwave and irradiated with microwaves at 150 ° C for 20 min. After cooling to room temperature, the lid was removed and the mixture was concentrated. The residue was purified by HPLC and the corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the resulting solid was dissolved in a minimum amount of EtOAc and hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 27%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9 H), 1.65-1.70 (m, 4 H), 2. 12 (s, 3H), 2.45-2.55 (m, 4H), 2.76 (t, J = 5.8 Hz, 2H), 3.99 (t, J = 6.0 Hz, 2H), 6.79 (d, J = 9.0 Hz, 2H ), 7.46-7.53 (m, 4H), 7.56 (s, 1 H), 7.90 (s, 1 H), 8.10-8.15 (m, 2H), 8.53 (s, 1 H), 8.77 (s, 1 H) ).

MS (ES +): m / z 525 (M + H) +.

EXAMPLE 91 3-. { 5-Methyl-2-f4-r4-methy1-piperazin-1-yl) -phenylamino-1-pyrimidin-4-ylamino) -benzenesulfonamide (Compound LVIII) L? I A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-benzenesulfonamide (0.10 g, 0.42 mmol), Pd2 (dba) 3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) ) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane (3 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 15 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by HPLC. The fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated to give the title compound as a gray solid (10 mg, 7%). 1 H NMR (500 MHz, DMSO-d 6): d 2.10 (s, 3 H), 2.22 (s, 3 H), 2.44 (t, J = 4.9 Hz, 4 H), 3.03 (t, J = 4.9 Hz, 4 H), 6.81 (d, J = 9.0 Hz, 2H), 7.34 (s, 2H), .45-7.50 (m, 4H), 7.89 (s, 1 H), 8.06 (s, 1 H), 8.13-8.18 (m, 1H), 8.54 (s, 1H), 8.70 (s, 1H). MS (ES +): m / z 454 (M + H) +.

EXAMPLE 92 / V-Methyl-3-. { 5-methyl-2- [4- (4-methyl-piperazin-1-yl) -phenylamino-pyrimidin-4-ylamino) -benzenesulfonamide (Compound LIX) A suspension of intermediate 32 (0.10 g, 0.33 mmole), 3-bromo-N-methyl-benzenesulfonamide (0.11 g, 0.44 mmole), Pd2 (dba) 3 (20 mg, 0.022 mmole), Xantphos (25 mg, 0.043 mmole) ) and cesium carbonate (0.25 g, 0.77 mmole) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by HPLC. The fractions were combined and drained in saturated NaHCO 3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na2SO and filtered. The filtrate was concentrated and the residue was triturated in a mixture of DCM / Et20 (1/5, ml). After filtration, the title compound was obtained as a light brown solid (65 mg, 42%). 1 H NMR (500 MHz, DMSO-d 6): d 2.11 (s, 3 H), 2.23 (s, 3 H), 2.44 (d, J = 5.0 Hz, 3H), 2.45-2.50 (m, 4H), 3.03 (t, J = 4.9 Hz, 4H), 6.81 (d, J = 9.1 Hz, 2H), 7.40-7.43 (m, 2H), 7.46 (d, J = 9.1 Hz, 2H), 7.52 (t, J = 8.0 Hz, 1 H), 7. 89 (s, 1 H), 7.94 (t, J- 1.8 Hz, 1 H), 8.29 (br d, J = 8.3 Hz, 1 H), 8.56 (s, 1 H), 8. 72 (s, 1 H). MS (ES +): m / z 468 (M + H) +.

EXAMPLE 93, -Dimethyl-3- (5-methyl-2-r4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-ylamino) -benzenesulfonamide (Compound LX) LX A suspension of intermediate 32 (0.13 g, 0.43 mmol), 3-bromo-β /, β / - dimethyl-benzenesulfonamide (0.14 g, 0.53 mmol), Pd2 (dba) 3 (25 mg, 0.027 mmol), Xantphos ( 30 mg, 0.052 mmole) and cesium carbonate (0.33 g, 1.0 mmole) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. . After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by HPLC. The fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the residue was triturated in a mixture of EtOAc / hexanes (1/5, 30 ml). After filtration, the title compound was obtained as an off-white solid (60 mg, 29%). 1 H NMR (500 MHz, DMSO-d 6): d 2.17 (s, 3 H), 2.23 (s, 3 H), 2.44 (d, J = 5.0 Hz, 3H), 2.45-2.50 (m, 4H), 2.63 (s, 6H), 3.03 (t, J = 4.9 Hz, 4H), 6.81 (d, J- 9.1 Hz, 2H) , 7.36 (d, J = 8.0 Hz, 1 H), 7.45 (d, J = 9.1 Hz, 2H), 7.54 (t, J = 8. 0 Hz, 1 H), 7.84 (t, J = 1.9 Hz, 1 H), 7.90 (s, 1 H), 8.46 (br d, J = 7.8 Hz, 1 H), 8. 57 (s, 1 H), 8.74 (s, 1H). MS (ES +): m / z 482 (M + H) +.

EXAMPLE 94 / -lsopropyl-3- (5-ethyl-2- [4- (4-methyl-piperazin-1-yl) -phenylamino-1-pyrimidin-4-ylamino) -benzenesulfonamide (Compound LX1) LXI A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-? Msopropyl-benzenesulfonamide (0.11 g, 0.39 mmol), Pd2 (dba) 3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane / DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by HPLC. The fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the residue was triturated in a mixture of EtOAc / hexanes (1/10, 33 ml). After filtration, the title compound was obtained as an off-white solid (47 mg, 29%). 1 H NMR (500 MHz, DMSO-d 6): d 0.98 (d, J = 6.6 Hz, 6H), 2.11 (s, 3H), 2.24 (s, 3H), 2.45-2.50 (m, 4H), 3.03 (t , J = 4.8 Hz, 4H), 3.20-3.27 (m, 1 H), 6.80 (d, J = 9.0 Hz, 2H), 7.40-7.52 (m, 4H), 7.59 (d, J = 7.1 Hz, 1 H), 7.89 (s, 1 H), 8.21 (br d, J = 7.9 Hz, 1 H), 8.53 (s, 1 H), 8.71 (s, 1 H). MS (ES +): m / z 496 (M + H) +.

EXAMPLE 95 ^ 4- (3-Methanesulfonyl-4-methyl-phenyl) -5-methyl- ^ 2-f4- (4-methyl-piperazin-1-yl) -phenyl-1-pyrimidine-2,4-diamine (Compound LXII ) LXII A suspension of intermediate 32 (0.10 g, 0.33 mmole), 4-bromo-2-methanesulfonyl-1-methyl-benzene (0.10 g, 0.40 mmole), Pd2 (dba) 3 (20 mg, 0.022 mmole), Xantphos ( 25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 15 min. . After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by HPLC. The fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the residue was triturated in a mixture of EtOAc / hexanes (1/5, 30 ml). After filtration, the title compound was obtained as a light brown solid (41 mg, 27%). 1 H NMR (500 MHz, DMSO-d 6). d 2.09 (s, 3H), 2.22 (s, 3H), 2.45 (t, J = 4.7 Hz, 4H), 2.61 (s, 3H), 3.03 (t, J = 4.9 Hz, 4H), 3.20 (s, 3H), 6.80 (d, J = 9. 1 Hz, 2H), 7.35 (d, J = 8.5 Hz, 1 H), 7.44 (d, J = 9.0 Hz, 2H), 7.87 (s, 1H), 8.05 (d, J = 2.4 Hz, 1 H) , 8.21 (br d, J = 7.0 Hz, 1 H), 8.55 (s, 1 H), 8.71 (s, 1 H). MS (ES +): m / z 467 (M + H) +.

EXAMPLE 96 ^ -cyclohexyl-3- (5-methyl-2-f4- (4-methyl-p¡perazin-1-yl) -phenylamino-1-pyrimidin-4-ylamino) -benzenesulfonamide (Compound LXIII) LXIII A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-? / - cyclohexyl-benzenesulfonamide (0.13 g, 0.41 mmol), Pd2 (dba) 3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043) mmoles) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 15 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by HPLC. The fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the residue was triturated in a mixture of EtOAc / hexanes (1/10, 33 ml). After filtration, the title compound was obtained as an off-white solid (45 mg, 25%). 1 H NMR (500 MHz, DMSO-d 6): d 1.07-1.17 (m, 6H), 1.53-1.63 (m, 4H), 2.11 (s, 3H), 2.22 (s, 3H), 2.45 (t, J = 4.7 Hz, 4H), 2.90-3.00 (m, 1 H), 3.02 (t, J = 4.8 Hz , 4H), 6.80 (d, J = 9.1 Hz, 2H), 7.43-7.53 (m, 4H), 7.65 (d, J = 7. 3 Hz, 1 H), 7.89 (s, 1 H), 8.05 (s, 1 H), 8.18 (br d, J = 7.7 Hz, 1 H), 8.52 (s, 1 H), 8. 71 (s, 1 H). MS (ES +): m / z 536 (M + H) +.

EXAMPLE 97 ^ -Diethyl-3- (5-methyl-2-f4- (4-methyl-piperazin-1-yl) -phenylaminol-pyrimidin-4-ylamino) -benzenesulfonamide (Compound LXIV) LXGV A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-β /, β / - diethyl-benzenesulfonamide (0.12 g, 0.41 mmol), Pd2 (dba) 3 (20 mg, 0.022 mmol), Xantphos ( 25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 15 min. . After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the The residue was purified by HPLC. The fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the residue was triturated in a mixture of EtOAc / hexanes (1/10, 33 ml). After filtration, the title compound was obtained as an off-white solid (45 mg, 27%). 1 H NMR (500 MHz, DMSO-d 6): d 1.06 (t, J = 7.1 Hz, 6H), 2.11 (s, 3H), 2.22 (s, 3H), 2.44 (t, J = 4.7 Hz, 4H), 3.03 (t, J = 4.8 Hz, 4H), 3.16 (q, J = 7.1 Hz, 4H), 6.80 (d, J = 9.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 1 H), 7.45 (d, J = 9.0 Hz, 2H), 7.50 (t, J = 8.1 Hz, 1 H), 7.89 (t, J = 1.9 Hz, 1 H), 7.89 (s, 1 H), 8.39 (br d, J = 7.9 Hz, 1 H), 8.53 (s, 1 H), 8.74 (s, 1 H). MS (ES +): m / z 510 (M + H) +.

EXAMPLE 98 5-Methyl-JV -r4- (4-methyl-piperazin-1-yl) -phenin-? F4-r3- (morpholin-4-sulfonyl) -phenin-pyrimidine-2,4-diamine (Compound LXV) LXV A suspension of intermediate 32 (0.10 g, 0.33 mmol), 4- (3- bromo-benzenesulfonyl) -morpholine (0.12 g, 0.39 mmol), Pd2 (dba) 3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160X for 15 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by HPLC. The fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the residue was triturated in a mixture of EtOAc / hexanes (1/10, 33 ml). After filtration, the title compound was obtained as a light red solid (90 mg, 52%). 1 H NMR (500 MHz, DMSO-d 6): d 2.12 (s, 3 H), 2.22 (s, 3 H), 2.45 (t, J = 4.8 Hz, 4 H), 2.89 (t, J = 4.6 Hz, 4 H), 3.03 (t, J = 4.8 Hz, 4H), 3.64 (t, J = 4.7 Hz, 4H), 6.81 (d, J = 9.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 1 H), 7.45 (d, J = 9.0 Hz, 2H), 7.56 (t, J = 8.1 Hz, 1 H), 7.84 (t, J = 1.9 Hz, 1 H), 7.91 (s, 1H), 8.47 (br d, J = 8.4 Hz, 1 H), 8.59 (s, 1 H), 8.75 (s, 1 H). MS (ES +): m / z 524 (M + H) +.

EXAMPLE 99 Ethyl ester of 3- acid. { 5-methyl-2-f4- (4-methyl-piperazin-1-yl) -phenylamine-1-pyrimidin-4-ylamino) -benzoic acid (Intermediate 36) 36 A suspension of intermediate 32 (0.10 g, 0.33 mmol), ethyl ester of 3-bromo-benzoic acid (0.07 ml, 0.44 mmol), Pd2 (dba) 3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043) mmoles) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane (3 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 15 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (DCM at 10% MeOH / DCM) to give the title compound (0.10 g, 68%). MS (ES +): m / z 447 (M + H) +.

EXAMPLE 100 3- 5-Methyl-2-f4- (4-methyl-piperazin-1-yl) -phenylamino-1-pyrimidin-4-ylamino > - benzamide (Compound LXVI) A mixture of intermediate 36 (0.10 g, 0.22 mmol) in concentrated NH 4 OH was sealed in a reaction tube and heated at 50 ° C for 3 days. The mixture was poured into water (15 ml) and extracted with EtOAc (2 x 30 ml). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The aqueous layer was extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the residue was triturated in a mixture of EtOAc / hexanes (1/10, 33 ml). After filtration, the title compound was obtained as a white solid (10 mg, 11%). 1 H NMR (500 MHz, DMSO-d 6): d 2.10 (s, 3H), 2.22 (s, 3H), 2.40- 2.50 (m, 4H), 2.95-3.05 (m, 4H), 6.75 (d, J = 9.1 Hz, 2H), 7.30-7.40 (m, 2H), 7.45 (d, J = 9.1 Hz, 2H), 7.53-7.58 (m, 1 H), 7.85 (s, 1H), 7.90 (br s, 2H) ), 8.03 (s, 1 H), 8.37 (s, 1 H), 8.71 (s, 1 H).

MS (ES +): m / z 418 (M + H) +.

EXAMPLE 101 Ethyl ester of 2-methyl-3- acid. { 5-methyl-2- [4- (4-methyl-piperazin-1-yl) -phen-1-amino-1-pyrimidin-4-ylamino) -benzoic acid (Compound LXVII) ] or LXVII A suspension of intermediate 32 (0.10 g, 0.33 mmole), ethyl ester of 3-bromo-2-methyl-benzoic acid (0.10 ml, 0.41 mmole), Pd2 (dba) 3 (20 mg, 0.022 mmole), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane (3 ml) was sealed in a reaction tube microwave and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (DCM at 30% MeOH and 1% TEA in DCM) to give the title compound (0.14 g, 92%) as a light brown oil. 1 H NMR (500 MHz, DMSO-d 6): d 1.32 (t, J = 7.1 Hz, 3 H), 2.10 (s, 3 H), 2.21 (s, 3 H), 2.32 (s, 3 H), 2.40-2.45 (m , 4H), 2.94 (t, J = 4.8 Hz, 4H), 4.30 (q, J = 7.1 Hz, 2H), 6.57 (d, J = 9.1 Hz, 2H), 7.25 (d, J = 8.9 Hz, 2H ), 7.35 (t, J = .8 Hz, 1 H), 7.48 (dd, J = 7.9, 1.0 Hz, 1 H), 7.70 (dd, J = 7.8, 1.1 Hz, 1 H), 7.78 s, 1 H), 8.23 (s, 1 H), 8.58 (s, 1 H). MS (ES +): m / z 461 (M + H) +.

EXAMPLE 102 2-Methyl-3-. { 5-methyl-2-f4- (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-ylamino) -benzamide (Compound LXVlll) LXVIII To a mixture of the compound LXVII described above (0.10 g, 0.22 mmol) and formamide (0.05 ml, 1.3 mmol) in DMF (5 ml) at 100 ° C was added NaOMe (0.10 g, 0.46 mmol) under an argon atmosphere. The mixture was stirred at the same temperature for 2 hr and then at room temperature for an additional 15 hr. The mixture was poured into water (15 ml) and extracted with EtOAc (2 x 15 ml). The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The aqueous layer was extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate is The mixture was concentrated and the residue triturated in a mixture of EtOAc / hexanes (1/5, 30 ml). After filtration, the title compound was obtained as a white solid (20 mg, 21%). 1 H NMR (500 MHz, DMSO-d 6): d 2.09 (s, 3 H), 2.21 (s, 3 H), 2.23 (s, 3 H), 2.40-2.45 (m, 4 H), 2.97 (t, J = 4.8 Hz , 4H), 6.69 (d, J = 9.1 Hz, 2H), 7.24-7.28 (m, 2H), 7.35 (d, J = 9.0 Hz, 2H), 7.39-7.43 (m, 2H), 7.69 (s, 1 H), 7.78 (s, 1 H), 8.01 (s, 1 H), 8.53 (s, 1 H). MS (ES +): m / z 432 (M + H) +.

EXAMPLE 103 (2-Chloro-5-methyl-pyrimidin-4-yl) -4-chloro-3-trifluoromethyl-phenyl) -amine (Intermediate 37) 37 A mixture of 2-chloro-5-memyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmole), 4-bromo-1-chloro-2-trifluoromethyl-benzene (0.40 ml, 2.7 mmole), Pd2 (dba) 3 (0.10 g, 0.11 mmole), Xantphos (0.13 g, 0.22 mmole) and cesium carbonate (1.5 g, 4.6 mmole) in dioxane / DMF (6/1, 7 ml) was sealed in a reaction tube of microwaves and it was irradiated with microwaves at 160 ° C for 15 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate is concentrated and the residue was purified by flash chromatography on silica gel (hexanes to 50% EtOAc / hexanes) to give the title compound (0.65 g, 96%) as a white solid. MS (ES +): m / z 322 (MH-H) +.

EXAMPLE 104 ^ 4- (4-Chloro-3-trifluoromethyl-phenyl) -5-methyl- ^ 2-r4- (piperidin-4-yloxy) -phene-pyrimidine-2,4-diamine (Compound LXIX) LXIX A mixture of intermediate 37 (0.10 g, 0.31 mmol) and 4- (4-amino-phenoxy) -piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.41 mmol) in acetic acid (3 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 150 ° C for 15 min. After cooling to room temperature, the lid was removed and the mixture was concentrated. The residue was taken up in water (20 ml) and neutralized with 10% NaOH solution until a solid precipitated. The resulting solid was filtered and purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The aqueous layer was extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the title compound as a white solid (30 mg, 20%). H NMR (500 MHz, DMSO-d6): d 1.69-1.77 (m, 2H), 2.00--2.04 (m, 2H), 2.11 (s, 3H), 2.90-3.00 (m, 2H), 3.10-3.20 ( m, 2H), 4.40-4.48 (m, 1 H), 6.84 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.8 Hz, 1 H ), 7.94 (s, 1 H), 8.12 (d, J = 2.6 Hz, 1 H), 8.21 (br d, J = 8.2 Hz, 1 H), 8.64 (s, 1 H), 8.93 (s, 1 H). MS (ES +): m / z 478 (M + H) +.

EXAMPLE 105 5-Methyl-2- [4- (2-pyrrolidin-1-yl-ethoxy) -phenyl-pyrimidine-2,4-diamine (Intermediary 38) 38 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mmol) and 4- (2-pyrrolidin-1-yl-ethoxy) -phenylamine (1.1 g, 5.3 mmol) in acetic acid (8 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 150 ° C for 15 min. After cooling to room temperature, the lid was removed and the mixture was concentrated. The residue was taken up in water (30 ml) and neutralized with 10% NaOH solution until pH ~ 10.

The resulting aqueous layer was extracted with EtOAc (2 x 30 ml) and the layers The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the title compound as a gray solid (0.80 g, 73%). This was used in the next step without purification. MS (ES +): m / z 314 (M + H) +.

EXAMPLE 106 3- 5-Methyl-2- [4- (2-pyrrolidin-1-yl-ethoxy) -phenylaminol-pyrimidin-4-ylamino) -benzenesulfonamide (Compound LXX) H LXX A mixture of intermediate 38 (0.10 g, 0.32 mmole), 3-bromo-benzenesulfonamide (0.10 g, 0.42 mmole), Pd2 (dba) 3 (20 mg, 0.022 mmole), Xantphos (25 mg, 0.043 mmole) and Cesium carbonate (0.20 g, 0.61 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwave at 170X for 25 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered and the filtered solid was washed with DCM. The filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO 3 solution (30 ml). The aqueous layer was extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried on anhydrous Na2SO4 and filtered. The filtrate was concentrated and the solid was triturated in a mixture of EtOAc / hexanes (1/10, 33 ml). After filtration, the title compound was obtained as a white solid (11 mg, 7%). 1 H NMR (500 MHz, DMSO-d 6): d 1.65-1.72 (m, 4H), 2.11 (s, 3H), 2.49-2.52 (m, 4H), 2.75-2.80 (m, 2H), 4.00 (t, J = 5.9 Hz, 2H), 6.80 (d, J = 9.0 Hz, 2H), 7.34 (s, 2H), 7.45-7.50 (m, 2H), 7.52 (d, J = 9.0 Hz, 2H), 7.90 ( s, 1 H), 8.05 (s, 1 H), 8.10-8.15 (m, 1 H), 8.57 (s, 1 H), 8.77 (s, 1 H). MS (ES +): m / z 469 (M + H) +.

EXAMPLE 107 5-Methyl-? 2- (4-morpholin-4-ylmethyl-phenyl) -pyrimidin-2,4-diamine (Intermediary 39) 39 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.40 g, 2.8 mmol) and 4-morpholin-4-ylmethyl-phenylamine (0.60 g, 3.1 mmol) in acetic acid (15 ml) was heated to 70 ° C for 17 hr. After cooling to room temperature, the mixture was concentrated. The residue was taken up in water (30 ml) and neutralized with 10% NaOH solution to pH -10. The resulting aqueous layer was extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and they filtered. The filtrate was concentrated to give the title compound as a brown syrup (0.70 g, 83%). This was used in the next step without purification. MS (ES +): m / z 300 (M + H) + EXAMPLE 108 ^ - (1H-lndol-4-yl) -5-methyl- ^ 2- (4-morpholin-4-ylmethyl-phenyl) -pyrimidine-2,4-diamine (Compound LXXI) LXXI A mixture of intermediate 39 (0.40 g, 1.3 mmol), 4-bromo-1-triisopropylsilanyl-1 H-indole (0.50 g, 1.4 mmol), Pd2 (dba) 3 (0.10 g, 0.11 mmol), Xantphos (0.12 g) g, 0.21 mmol) and cesium carbonate (0.90 g, 2.8 mmol) was suspended in dioxane (20 ml) and heated to reflux under argon atmosphere for 4 hr. The reaction mixture was cooled to room temperature and diluted with DCM (30 ml). The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel (hexanes to EtOAc) to give the TIPS-protected precursor as a yellow oil. To the above TIPS-protected precursor (50 mg, 0.088 mmol) in THF (5 mL) was added TBAF (0.5 mL, 1M in THF). The mixture was stirred room temperature for 1 hr and then it was poured into water (20 ml). The aqueous layer was extracted with EtOAc (2 x 20 ml) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO 3 solution (30 ml). The aqueous layer was extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the solid was dissolved in a minimum amount of EtOAc and then hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a light brown solid (6 mg, 1% total yield). 1 H NMR (500 MHz, DMSO-d 6): d 2.17 (s, 3 H), 2.25-2.30 (m, 4 H), 3.29 (s, 2 H), 3.54 (t, J = 4.5 Hz, 4 H), 6.40 (t , J = 2.2 Hz, 1H), 6.89 (d, J = 8.5 Hz, 2H), 7.09 (t, J = 7.8 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 2.8 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1 H), 7.43 (d, J = 8.5 Hz5 2H), 7.85 (s, 1 H), 8.14 (s, 1 H), 8.77 ( s, 1 H), 11.10 (s, 1 H). MS (ES +): m / z 415 (M + H) +.

EXAMPLE 109 4-f4- (4-Amino-5-methyl-pyrimidin-2-ylamino) -benzyl-piperazine-1-carboxylic acid tert-butyl ester (Intermediate 40) 40 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.35 g, 2.4 mmol) and 4- (4-amino-benzyl) -piperazine-1-carboxylic acid tert-butyl ester (0.80 g, 2.8 mmoles) in acetic acid (20 ml) was heated at 70 ° C for 1 day. After cooling to room temperature, the mixture was concentrated. The residue was taken up in water (30 ml) and neutralized with 10% NaOH solution until pH ~ 10. The resulting aqueous layer was extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and the title compound was used in the next step without purification. MS (ES +): m / z 399 (M + H) +.

EXAMPLE 110 ^ - (1H-lndol-4-yl) -5-methyl- ^ 2- (4-piperazin-1-ylmethyl-phenyl) -pyrimidine-2,4-diamine (Compound LXXII) LXXII A mixture of intermediate 40 (0.78 g, 2.0 mmol), 4-bromo-1 -triisopropylsilanyl-1 H-indole (0.70 g, 2.0 mmol), Pd2 (dba) 3 (0.15 g, 0.16 mmol), Xantphos (0.19 g, 0.32 mmole) and cesium carbonate (1.3 g4.0 mmol) was suspended in dioxane (20 ml) and heated to reflux under argon atmosphere for 4.5 hr. The reaction mixture was cooled to room temperature, filtered and the filtered solid was washed with DCM (30 ml). The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (hexanes at 30% EtOAc / hexanes) to give the TIPS-protected precursor. To the previous TIPS-protected precursor (0.10 g, 0.15 mmol) in DCM (8 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 hr and then concentrated. The residue was purified by HPLC and the corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The aqueous layer was extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over Na2SO anhydrous and filtered. The filtrate was concentrated and the solid was triturated in a mixture of EtOAc / hexanes (1/5, 30 ml). After filtration, the title compound was obtained as a white solid (25 mg, 3% total yield). 1 H NMR (500 MHz, DMSO-d 6): d 2.17 (s, 3 H), 2.20-2.30 (m, 4 H), 2.73 (t, J = 4.6 Hz, 4 H), 3.28 (s, 2 H), 6.41 (t , J = 2.2 Hz, 1H), 6.89 (d, J = 8.5 Hz, 2H), 7.09 (t, J = 7.8 Hz, 1 H), 7.24 (d, J = 8.3 Hz, 1 H), 7.27 (t , J = 2.8 Hz, 1 H), 7.31 (d, J = 7.5 Hz, 1 H), 7.44 (d, J = 8.5 Hz, 2 H), 7.85 (s, 1 H), 8.13 (s, 1 H) , 8.77 (s, 1 H), 11.10 (s, 1 H) MS (ES +): m / z 414 (M + H) +.

EXAMPLE 111 5-Methyl- ^ 4- (7-methyl-1H-indol-4-yl) - ^ 2- (4- (4-methyl-piperazin-1-ylphenyl) -pyrimidine-2,4-diamine (Compound LXXIII) A mixture of intermediate 32 (674 mg, 2.25 mmol), 4-bromo-7-methyl-1 H-indole (522 mg, 2.48 mmol), Pd2 (dba) 3 (182 mg, 0.2 mmol), Xantphos (360 mg , 0.6 mmol) and cesium carbonate (2.6 g, 8 mmol) was suspended in dioxane (50 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under empty. The residue was purified by HPLC to give the title compound (136 mg of HCl salt, 13%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 2.21 (s, 3 H), 2.55 (s, 3 H), 2.80 (d, J = 4.6 Hz, 3H), 3.00-3.05 (m, 2H), 3.10-3.16 (m, 2H), 3.45-3.48 (m, 2H), 3.64-3.66 (m, 2H), 6.33-6.34 (m, 1H), 6.63 (br, 2H), 6.92-6.97 (m, 4H), 7.35 (t, J = 2.7 Hz, 1 H), 7.83 (s, 1 H), 10.04 (s, 1 H), 10.24 (s, 1 H), 11.08 (br s, 1 H), 11. 34 (s, 1 H), 12.12 (br s, 1 H). MS (ES +): m / z 428 (M + H) +.

EXAMPLE 112 / V4- (7-Chloro-1H-indol-4-yl) -5-methyl-α- 2- (4- (4-methyl-piperazin-1-phenyl) -pyrimidine-2,4-diamine (Compound LXXIV ) LXXIV A mixture of intermediate 32 (298 mg, 1.0 mmol), 4-bromo-7-chloro-1H-indole (231 mg, 1.04 mmol), Pd2 (dba) 3 (92 mg, 0.1 mmol), Xantphos (180 mg , 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (50 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to give the title compound (251 mg of salt HCl, 51%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 2.21 (s, 3 H), 2.80 (d, J = 4.6 Hz, 3H), 3.01-3.05 (m, 2H), 3.08-3.13 (m, 2H), 3.46-3.48 (m, 2H), 3.65-3.67 (m, 2H), 6.46-6.47 (m, 1 H), 6.64 (br s, 1 H), 6.93 (d, J = 8.9 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.43-7.44 (m, 1 H), 7.87 (s, 1 H), 10.13 (s, 1 H), . 27 (s, 1 H), 11.00 (br s, 1 H), 11.70 (s, 1 H), 12.23 (br s, H). MS (ES +): m / z 448 (M + H) +.

EXAMPLE 113 / ^ 2- (4- (2- (Pyrrolidin-1-yl) ethoxy) phenyl) -5-methyl-V4- (7-methyl-1H-indo-yl) pyrimidine-2,4-diamine (Compound LXXV) LXXV A mixture of intermediate 38 (410 mg, 1.3 mmol), 4-bromo-7-methyl-1 H-indole (275 mg, 1.3 mmol), Pd2 (dba) 3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (50 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to give the title compound (92 mg of HCl salt, 15%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.88-1.90 (m, 2H), 1.93-2.02 (m, 2H), 2.21 (s, 3H), 2.55 (s, 3H), 3.06-3.10 (m, 2H), 3.51-3.54 (m, 4H), 4.26 (t, J = 4.9 Hz, 2H), 6.33-6.34 (m, 1 H), 6.61 (br d, 2H), 6.93-6.95 (m, 2H), 7.03 (d, J = 8.9 Hz, 2H), 7.34 (t, J = 2.8 Hz, 1H), 7.85 (s, 1 H), 10.07 (s, 1 H), 10.33 (s, 1 H), 10.91 (br s, 1 H), 11.34 (s, 1 H), 12.15 (br s, H). MS (ES +): m / z 443 (M + H) +.

EXAMPLE 114? Y2- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -5-methyl- / V4- (7-chloro-1H-indol-4-yl) pyrimidine-2,4-diamine (Compound LXXVI) LLXVI A mixture of intermediate 38 (270 mg, 0.86 mmol), 4-bromo-7-chloro-1 H-indole (198 mg, 0.86 mmol), Pd2 (dba) 3 (72 mg, 0.08 mmol), Xantphos (140 mg, 0.24 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (50 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to give the title compound (33 mg of HCl salt, 8%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.88-1.90 (m, 2H), 1.93-2.02 (m, 2H), 2.22 (s, 3H), 3.06-3.10 (m, 2H), 3.51-3.54 (m, 4H), 4.27 (t, J = 4.9 Hz, 2H), 6.46-6.47 (m, 1 H), 6.63 (br d, 2H), 6.95 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.0 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 1 H), 7.43 (t, J = 2.8 Hz, 1 H), 7.90 (s, 1 H), 10.13 (s, 1 H), 10.40 (s, 1 H), 10.94 (br s, 1 H), 11.70 (s, 1 H) ), 12.33 (br s, H). MS (ES +): m / z 463 (M + H) +.

EXAMPLE 115? / 2 - (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -5-methyl- / V4- (7-fluoro-1 H -indol-4-yl) pyrimid lin-2, 4-diamine (Compound LXXVII) LXXVII A mixture of intermediate 38 (413 mg, 1.3 mmol), 4-bromo-7-fluoro-1 H-indole (310 mg, 1.45 mmol), Pd2 (dba) 3 (92 mg, 0.1 mmol), Xantphos (180 mg) mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (50 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to give the title compound (10 mg of HCl salt, 1.5%) as a brown solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.88-1.90 (m, 2H), 1.93-2.02 (m, 2H), 2.21 (s, 3H), 3.06-3.10 (m, 2H), 3.51-3.56 ( m, 4H), 4.26 (t, J = 4.9 Hz, 2H), 6.42-6.43 (m, 1 H), 6.63 (br d, 2H), 6.95-7.04 (m, 3H), 7.35 (d, J = 8.9 Hz, 1 H), 7.42 (t, J = 2.8 Hz, 1 H), 7.89 (s, 1 H), 10.08 (s, 1 H), 10.41 (s, 1 H), 10.90 (br s, 1 H), 11.85 (s, 1 H), 12.33 (br s, H). MS (ES +): m / z 447 (M + H) +.

EXAMPLE 116 ^ -Q-fer-butylphenyl-S-methyl-^^^ -methylpiperazin-1-iDfeniDpyrimidin-S ^ -diamine (Compound LXXVIII) LXXVIII A mixture of intermediate 32 (298 mg, 1.0 mmol), 1-ér-butyl-3-bromobenzene (256 mg, 1.2 mmol), Pd2 (dba) 3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmoles) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (50 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to give the title compound (27 mg of HCl salt, 6%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.25 (s, 9H), 2.16 (s, 3H), 2.80 (d, J = 4.6 Hz, 3H), 3.04-3.16 (m, 4H), 3.47-3.49 (m, 2H), 3.65-3.67 (m, 2H), 6.90 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 9.0 Hz, 2H), 7.28-7.35 (m, 2H), 7.45 ( t, J = 1. 8 Hz, 1 H), 7.50 (d, J = 7.8 Hz, 1 H), 7.86 (s, 1 H), 9.70 (s, 1 H), 10.37 (s, 1 H), 11.01 (br s, 1 H), 12.34 (br s, H). MS (ES +): m / z 431 (M + H) +.

EXAMPLE 117 / V- (3-tert-butyl-phenyl) -2-chloro-5-methylpyrimid-4-amine (Intermediate 41) A mixture of 2-chloro-5-methylpyrimidin-4-amine (670 mg, 4.7 mmol), 1-tert-butyl-3-bromobenzene (1.5 g, 7 mmol), Pd2 (dba) 3 (366 mg, 0.4 mmole), Xantphos (695 mg, 1.2 mmol) and cesium carbonate (6.2 g, 19 mmol) was suspended in dioxane (150 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was dissolved in EtOAc (10 mL) and hexanes (100 mL) was added. The solid was collected by filtration and washed with hexanes to give the crude title compound (1.2 g, 99%) as a yellow solid.

EXAMPLE 118 ^ 4- (3-fer-butylphenyl) -5-methyl- / V2- (4- (piperidin-4-yloxy) phenyl) pyrimidin-2,4-diamine (Compound LXXIX) LXXLX A mixture of intermediate 41 (740 mg, 2.68 mmol) and 4- (4-aminophenoxy) piperidin-1-tert-butyl carboxylate (500 mg, 1.71 mmol) was suspended in acetic acid (10 ml) and heated to 100 ° C for 4 hr. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH ~ 7. The resulting solution was extracted with EtOAc (30 ml) and the organic layer was separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under vacuum and the crude product was purified by HPLC to give the title compound (276 mg of HCl salt, 35%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.22 (s, 9H), 1.77-1.81 (m, 2H), 2.03-2.07 (m, 2H), 2.14 (s, 3H), 3.00-3.04 (m, 2H), 3.18 (brs, 2H), 4.56-4.57 (m, 1 H), 6.86 (d, J = 8.9 Hz, 2H), 7.26-7.31 (m, 4H), 7.40 (s, 1 H), 7.44 (d, J = 7. 5 Hz, 1 H), 7.84 (s, 1 H), 8.93 (br s, 1 H), 8.99 (br s, 1 H), 9.67 (s, 1 H), 10.31 (s, 1 H).

MS (ES +): m / z 432 (M + H) +.

EXAMPLE 119 4- (4- (4-Amino-5-methylpyrimidin-2-ylamino) phenoxy) piperidin-1-tert-butylcarboxylate (Intermediate 42) 42 A mixture of 2-chloro-5-methylpyrimidin-4-amine (540 mg, 3.7 mmol), 4- (4-aminophenoxy) piperidin-1-tert-butyl carboxylate (1.1 g, 3.7 mmol) was suspended in acetic acid (20 ml) and heated at 70 ° C for 1 hr. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH ~ 7. The resulting solution was extracted with EtOAc (30 ml) and the organic layer was separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under vacuum to give the title compound (1.4 g, 95%) as a yellow solid.

EXAMPLE 120 / V - (1 H-lndazol-4-yl) -5-methyl- / V 2 - (4- (piperidin-4-yloxy) phenyl) pyrimidine-2,4-diamine (Compound LXXX) LXXX A mixture of intermediate 42 (480 mg, 1.2 mmol), 4-bromo-1H-imidazole (236 mg, 1.2 mmol), Pd2 (dba) 3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol). it was suspended in dioxane (50 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to give the title compound (4 mg of HCl salt, 1.2%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.75-1.80 (m, 2H), 2.02-2.07 (m, 2H), 2.24 (s, 3H), 3.05-3.09 (m, 2H), 3.17-3.21 (m, 2H), 4.52 (br s, 1 H), 6. 63 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 7.3 Hz, 2H), 7.38-7.44 (m, 2H), 7.62 (d, J) = 8.9 Hz, 2H), 7.92 (s, 1 H), 8.02 (s, 1 H), 9.00 (br s, 1 H), 9.04 (br s, 1 H), 10.20 (s, 1 H), 10.33 (s, 1H). MS (ES +): m / z 416 (M + H) +.

EXAMPLE 121 4-f3-f4- (4-Chloro-3-methoxy-phenylamino) -5-methyl-pyrimidin-2-ylamino-1-benzyl) -piperazine-1-carboxylic acid tert-butyl ester (Intermediate 43) 43 A mixture of intermediate 31 (0.092 g, 0.33 mmol), 4- (3-amino-benzyl) -piperazine-1-carboxylic acid tert-butyl ester (0.11 g, 0.39 mmol), Pd2 (dba) 3 (0.03 g) , 0.033 mmole), Xantphos (0.038 g, 0.065 mmole) and cesium carbonate (0.32 g, 0.98 mmole) was suspended in dioxane (5 ml) and microwaved at 160 ° C for 15 min. The reaction mixture was cooled to room temperature and centrifuged. The reaction was decanted and the organic phase was concentrated under vacuum. The residue was purified by HPLC to give the title compound (0.075 g, 43%) as a brown solid.

EXAMPLE 122 / ^ - Chloro-3-methoxy-phenyl] -5-methyl- ^ 2- (3-piperazin-1-ylmethyl-phenyl) -pyrimidine-2,4-diamine (Compound LXXXI) LXXX1 A solution of intermediate 43 (0.075 g, 0.14 mmol) in DCM (8 ml) was treated with TFA (2 ml). After 2 hr of stirring, the solvents were removed and the resulting residue was triturated with diethyl ether resulting in white hygroscopic powder (0.05 g, 82%). 1 H NMR (500 MHz, DMSO-d 6): d 2.17 (s, 3 H), 2.89 (br s, 4 H), 3.2 (br s, 4 H), 3.68 (s, 4 H), 3.82 (br s, 3 H), 7.16-7.19 (m, 2H), 7.28 (t, J = 7.9 Hz, 1 H), 7.33 (d, J- 2.3 Hz, 1 H), 7.39 (s, 1 H), 7.43 (d, J = 8.5 Hz, 1 H), 7.49 (d, 8.6 Hz, 1 H), 7.98 (s, 1 H), 8.8 (br s, 2 H), 9.78 (br s, 1 H), 10.57 (br s, 1 H) . MS (ES +): m / z 439 (M + H) +.

EXAMPLE 123 A 4-f4-Chloro-3-methoxy-phenyl) -5-methyl-2-f4- (piperidin-4-yloxy) -phenyl] -pyrimidine-2,4-diamine (Compound LXXXII) LXXXJI A mixture of intermediate 31 (0.66 g, 2.3 mmol) and 4- (4-amino-phenoxy) -piperidine-1-carboxylic acid tert-butyl ester (0.88 mg, 3.0 mmol) in acetic acid (15 ml) was subjected to Microwave at 160 ° C for 15 min. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (20 ml) and the mixture was neutralized with 10% NaOH solution until a solid precipitated. Filtration followed by column chromatography gave the title compound as beige solids (0.51 g, 50%). 1 H NMR (500 MHz, DMSO-d 6): d 1.37-1.44 (m, 2H), 1.86-1.89 (m, 2H), 2.09 (s, 3H), 2.50-2.56 (m, 2H), 2.91-2.95 (m, 2H), 3.16 (s, 3H), 3.32 (br s, 3H), 3.72 (s, 3H), 4.09 (br s, 1 H), 4.21-4.26 (m, 1H), 6.77 (d, J = 9 Hz, 2H), 7.27 (d, J = 8.5 Hz, 1 H), 7.40-7.42 (m, 1 H), 7.46-7.49 (m, 3H), 7.87 (s, 1 H), 8.31 (s, 1 H), 8.78 (s, 1 H). MS (ES +): m / z 440 (M + H) +.

EXAMPLE 124 4- Tertiary butyl ester. { 3-f4- (4-chloro-3-methoxy-phenylamino) -5-methyl-pyrimidin-2-ylamino] -phenyl) -piperazine-1-carboxylic acid (Intermediate 44) 44 A mixture of intermediate 31 (0.13 g, 0.46 mmol) and 4- (3-amino-phenyl) -piperazine-1-carboxylic acid fer-butyl ester (0.19 mg, 0.68 mmol) in acetic acid (8 ml) was heated at 80 ° C for 15 hr. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (20 ml) and the mixture was neutralized with 10% NaOH solution. This was then extracted with ethyl acetate, washed with brine and evaporated to oily residue. Column chromatography gave the title compound as white solids (0.12 g, 48%).

EXAMPLE 125 ^ -f-Chloro-S-methoxy-phenyD-S-methyl-^ -Q-piperazin-l-yl-phenyD-pyrimidine-S-diamine (Compound LXXXIII) LXXXIII A solution of intermediate 44 (0.11 g, 0.21 mmol) in DCM (8 ml) was treated with TFA (1 ml). After 3 hr of stirring, the solvents were removed and the resulting residue was taken up in ethyl acetate and washed with 10% sodium bicarbonate solution. The organic phase was then dried over sodium sulfate, filtered and evaporated to white powder. This was diluted with DCM (5 ml) and treated with 4M HCl in dioxane (0.5 ml). The solvents were removed immediately giving HCl salt of the title compound as white solids (0.06 g, 67%). 1 H NMR (500 MHz, DMSO-d 6): d 2.18 (s, 3 H), 3.12 (br s, 4 H), 3.22 (br s, 4 H), 3.65 (s, 3 H), 6.80 (d, J = 8.1 Hz , 1 H), 6.95 (s, 2H), 7.14 (t, J = 8.2 Hz, 1 H), 7.23 (d, J = 7.0 Hz, 1 H), 7.37-7.40 (m, 2H), 7.95 (s) , 1 H), 9.33 (br s, 2 H), 9.88 (s; 1 H), 10.62 (s, 1 H). MS (ES +): m / z 425 (M + H) +.

EXAMPLE 126 2-f4- (3-Bromo-phenyl) -piperidin-1-yl-ethanol (Intermediate 45) 4- (3-Bromo-phenyl) -piperidine (1.2 g, 4.8 mmol) and 2-bromoethanol (0.72 ml, 10 mmol) were diluted with DMF (20 ml) and treated with potassium carbonate (2.7 g, 20 mmol). ). These were stirred at room temperature for 18, then were poured into water and extracted with ethyl acetate. Then, the organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to clear oil (0.6 g, 44%).

EXAMPLE 127 2- [4- (3- { 5-Methyl-2- [4- (4-methyl-piperazin-1-yl) -phenylaminol-pyrimidin-4-ylamino) -phenyl) -piperidin-1- ip-ethanol (Compound LXXXIV) XXX? V A mixture of intermediate 32 (0.11 g, 0.38 mmole), intermediate 45 (0.21 g, 0.75 mmole), Pd2 (dba) 3 (0.034 g, 0.037 mmole), Xantphos (0.043 g, 0.075 mmole) and cesium carbonate (0.37 g, 1.1 mmole) was suspended in dioxane (10 ml) and microwaved at 160 ° C for 15 min. The reaction mixture was cooled to room temperature and centrifuged. The reaction was decanted and the organic phase was concentrated under vacuum. The residue was purified by HPLC to give the title compound (0.075 g, 43%) as a purple solid (0.02 g, 11%). 1 H NMR (500 MHz, DMSO-d 6): d 1.60-1.67 (m, 2H), 1.73 (d, J = 11. 3 Hz, 2H), 2.02-2.07 (m, 2H), 2.08 (s, 3H), 2.21 (s, 3H), 2.39-2.45 (m, 7H), 2. 95 (d, J = 11.4 Hz, 2H), 3.00 (t, J = 4.66 Hz, 4H), 3.50 (t, J = 6.44 Hz, 2H), 6.76 (d, J = 9 Hz, 2H), 6.92 ( d, J = 8.5 Hz, 1 H), 7.22 (t, J = 7.8 Hz, 1 H), 7.45- 7.49 (m, 3H), 7.66 (d, J = 7.7 Hz, 1 H), 7.82 (s, 1 H), 8.09 (s, 1 H), 8.67 (s, 1 H). MS (ES +): m / z 502 (M + H) +.

EXAMPLE 128 4- (3-Bromo-benzenesulfonylamino) -piperidine-1-carboxylic acid tert-butyl ester (Intermediate 46) 46 3-Bromo-benzenesulfonyl chloride (2.2 g, 8.7 mmol) and 4-amino-piperidin-1-carboxylic acid tert-butyl ester (2 g, 10 mmol) were combined and diluted with DCM (50 mL) and TEA (3.6 ml, 26 mmol).

After 16 hr, the reaction was evacuated in a separatory funnel and washed with water. The organic phase was then washed with brine, dried over sodium sulfate, filtered and evaporated to clear oil which solidified on standing (3.6 g, 98%).

EXAMPLE 129 4- (3. {5-Methyl-2-f4- (4-methyl-piperazin-1-yl) -phenylaminol-pyrimidin-4-ylamino) -benzenesulfonylamino) -piperidin-tert-butyl ester -1- carboxylic (Intermediary 47) 47 A mixture of intermediate 32 (0.15 g, 0.518 mmol), intermediate 46 (0.28 g, 0.67 mmol), Pd2 (dba) 3 (0.024 g, 0.026 mmol), Xantphos (0.03 g, 0.052 mmol) and cesium carbonate ( 0.34 g, 1 mmol) was suspended in dioxane (10 ml) and microwaved at 160 ° C for 15 min. The reaction mixture was cooled to room temperature and centrifuged. The reaction was decanted on ice. The resulting precipitate was dried and brought directly to the deprotection step (0.2 g).

EXAMPLE 130 3- (5-Methyl-2-f4- (4-methyl-piperazin-1-yl) -phenylamino-piñmidin-4-ylamino > - ^ - piperidin-4-yl-benzenesulfonamide (Compound LXXXV) LXXXV Intermediate 47 (0.2 g, 0.32 mmol) was diluted with DCM (10 ml) and treated with TFA (0.3 ml). After 3 hr, the reaction solvents were removed and the resulting residue was purified by HPLC (0.01 g, 6%). 1 H NMR (500 MHz, DMSO-d 6): d 1.30-1.35 (m, 2H), 1.56-1.58 (m, 2H), 1.98 (s, 2H), 2.11 (s, 3H), 2.21 (s, 3H), 2.43-2.45 (m, 4H), 2.84-2.87 (m, 2H), 3.02 (t, J = 4.6 Hz, 2H), 6.80 (d, J = 9 Hz, 2H), 7.45-7.51 (m, 4H), 7.78 (br s, 1 H), 7.88 (s, 1 H), 8.05 (s, 1 H), 8.20 (d, J = 7.6 Hz, 1 H), 8.53 (s, 1 H), 8.71 (s, 1 H) ). MS (ES +): m / z 537 (M + H) +.

EXAMPLE 131? T- (4- (trifluoromethyl) -3-methylphenyl) -5-methyl- / V2- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidine-2,4-diamine hydrochloride ( Compound LXXXVI) LXXXVI A suspension of intermediate 32 (0.12 g, 0.40 mmole), 1-bromo-3- (trifluoromethyl) -2-methylbenzene (0.14 g, 0.59 mmole), Pd2 (dba) 3 (37 mg, 0.04 mmole), Xantphos (47 mg, 0.08 mmol) and cesium carbonate (0.39 g, 1.20 mmol) in dioxane (20 ml) was degassed with argon for 2 min then refluxed in a sealed tube overnight. After cooling to room temperature, the solvent was removed by rotary evaporation and the resulting mixture was purified by silica gel with 10% CH3OH / CHCl3 as an eluent to give the title compound as a white solid. The white solid was dissolved in CHCl3 (30 ml) and titrated with HCl 2 M in dioxane at pH 1. The solvent was removed by rotary evaporation and the solid was recrystallized from acetone (25 mg, 13%). 1 H NMR (500 MHz, DMSO-d 6): d 2.20 (s, 3 H), 2.26 (s, 3 H), 2.77 (d, J = 4.5 Hz, 3H), 3.00-3.20 (m, 4H), 3.45 (d, J = 11.6 Hz, 2H), 3.63 (d, J = 12. 2 Hz, 2H), 6.71 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 9.0 Hz, 2H), 7.55 (t, J = 1.9 Hz, 1 H), 7.63 (d, J = 7.8 Hz, 1 H), 7.77 (d, J = 7.77 Hz, 1 H), 7.94 (s, 1 H), 10.13 (s, 1 H), 10.60 (s, 1 H), 1 1.28 (s, 1 H). MS (ES +): m / z 457 (M + H) +.

EXAMPLE 132 S-Methyl- ^^^ - methylpiperazin-l-iDfeniD -? ^ - O -dnethylsulfoniDphenyl) -pyrimidine-2,4-diamine (Compound LXXXVII) LXXXV1I A suspension of intermediate 32 (0.13 g, 0.44 mmol), 1-bromo-3- (methylsulfonyl) benzene (0.24 g, 1.0 mmol), Pd2 (dba) 3 (40 mg, 0.04 mmol), Xantphos (50 nig, 0.08 mmole) and cesium carbonate (0.43 g, 1.32 mmole) in dioxane (50 ml) was degassed with argon for 2 min, then refluxed overnight. After cooling to room temperature, the solvent was removed by rotary evaporation and the resulting mixture was purified by silica gel with 30% CH3OH / CHCl3 as an eluent to give the title compound as pale yellow solid (35 mg, 15% ). 1 H NMR (500 MHz, DMSO-d 6): d 2.11 (s, 3 H), 2.23 (s, 3 H), 2.46 (br s, 4H), 3.03 (t, J = 4.4 Hz, 4H), 3.19 (s, 3H), 6.81 (d, J = 9.0 Hz, 2H), 7.45 (d, J = 8.9 Hz, 2H), 7.5-7.6 (m, 2H), 7.91 (s, 1 H), 8.05 (s, 1H), 8.36 (d, J = 6.7 Hz, 1 H), 8.60 (s, 1 H), 8.77 (s, 1H) ).H.

MS (ES +): m / z 453 (M + H) +.

EXAMPLE 133 1-Bromo-3- (propylsulfonyl) benzene (Intermediate 48) To a solution of 3-bromobenzenethiol (0.50 g, 2.6 mmol) in dioxane (50 ml) was added 1-iodopropane (1.1 g, 6.5 mmol) and cesium carbonate (2.2 g, 6.8 mmol) was stirred at reflux until all 3-bromobenzenethiol reacted. The reaction was quenched with saturated NaHCO3 solution (25 ml) and the mixture was extracted with CHCl3 (60 ml). The product in CHCl3 was refluxed with mCPBA (2.9 g, 13 mmol) until all of the starting material reacted. The organic layer was washed with 2M NaOH to remove excess mCPBA, dried over Na SO4 and filtered. The filtrate was concentrated and the crude product was purified by column on silica gel with 1: 1 hexanes / CHCl3 as an eluent to give colorless oil (0.30 g, 43% in 2-steps). 1 H NMR (500 MHz, DMSO-d 6): 0.92 (t, J = 7.4 Hz, 3 H), 1.52-1.60 (m, 2 H), 3.35-3.38 (m, 2 H), 7.63 (t, J = 8.0 Hz, 1 H), 7.88-7.91 (m, 1 H), 7.95-7.98 (m, 1 H), 8.04 (t, J = 1.8 Hz, 1 H).

EXAMPLE 134 5-Methyl- ^ 2- (4-r4-methylpiperazin-1-yl) phenyl) - ^ - (3- (propylsulfonyl) phenyl) -pyrimidine-2,4-diamine hydrochloride (Compound LXXXVIII) LXXXVIII A suspension of intermediate 32 (0.25 g, 0.84 mmol), intermediate 48 (0.26 g, 1 mmol), Pd2 (dba) 3 (8 mg, 0.01 mmol), Xantphos (16 mg, 0.03 mmol) and cesium carbonate ( 0.82 g, 2.52 mmole) in dioxane (50 ml) was degassed with argon for 2 min, then refluxed overnight. After cooling to room temperature, the solvent was removed by rotary evaporation and the resulting mixture was purified by silica gel with 10% CH3OH / CHCl3 as an eluent to give the title compound as a white solid. The white solid was dissolved in CHCl 3 (30 ml) and titrated with 2 M HCl in dioxane to pH 1. The solvent was removed by rotary evaporation and the solid was recrystallized from methanol (65 mg, 15%). 1 H NMR (500 MHz, DMSO-d 6): 0.90 (t, J = 7.4 Hz, 3H), 1.50-1.60 (m, 2H), 2.18 (s, 3H), 2.81 (s, 3H), 3.00-3.13 ( m, 4H), 3.27 (t, J = 7.7 Hz, 2H), 3.48 (d, J = 10.9 Hz, 2H), 3.75 (d, J = 11.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.9 Hz, 2H), 7.64 (t, J = 8.0 Hz, 1 H), 7.73 (d, J = 7.8 Hz, 1 H), 7.93 (s, 1 H), 8.00 (s, 1 H), 8.07 (s, 1 H), 9.92 (s, 1 H), 10.36 (s, 1 H), 10.99 (s, 1 H).

MS (ES +): m / z 481 (M + H) +.

EXAMPLE 135 3- (Morpholinomethyl) benzenamine (Intermediate 49) 49 Zinc chloride (0.1 g, 0.73 mmol) was added to the solution of 3-nitrobenzaldehyde (5.9 g, 39.02 mmol), morpholine (3.4 g, 39.02 mmol), sodium cyanoborohydride (2.7 g, 43 mmol) in methanol (50 g). ml) at room temperature. The solution was heated to reflux for 1 hour. After cooling, the reaction was quenched with water (2 ml) and the methanol was removed by rotary evaporation. The crude product was dissolved in 2M NaOH (50 ml) and extracted with CHCl3, dried over Na2SO and filtered. The filtrate was concentrated under vacuum. The above crude product in methanol (200 ml) was reduced by Raney's Ni and hydrazine at room temperature. The reaction was monitored by CCD in ethyl acetate. After all the starting material was reacted, the methanol was removed by rotary evaporation. The crude was purified by silica gel with ethyl acetate as an eluent to give a white solid (1.5 g, 50% in 2-steps). 1 H NMR (500 MHz, DMSO-d 6): 2.31 (s, 4 H), 3.28 (s, 2 H), 3.56 (t, J = 4.6 Hz, 4 H), 4.97 (s, 2 H), 6.40-6.45 (m, 2H), 6.53 (t, J = 1.8 Hz, 1 H), 6.93 (t, = 7.7 Hz, 1 H).

EXAMPLE 136 5-Methyl-M2- (3- (morpholinomethyl) phenyl) pyrimidine-2,4-diamine (Intermediate 50) fifty A mixture of 2-chloro-5-methylpyrimidin-4-amine (0.17 g, 1.17 mmol) and intermediate 49 (0.25 g, 1.30 mmol) was suspended in acetic acid (10 ml) and heated at 100 ° C for 2 hr. . The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH ~ 8. The resulting solution was extracted with CHCl3 (100 mL) and the organic layer was separated. The organic layer was washed with brine, dried over Na2SO and filtered. The filtrate was concentrated under vacuum and the crude product was purified by silica gel column with 10% CH3OH / EtOAc as an eluent to give the title compound as oil (0.15 g, 43%). 1 H NMR (500 MHz, DMSO-d 6): 1.91 (s, 3 H), 2.35 (s, 4 H); 3.17 (s, 2H), 3.57 (t, J = 4.4 Hz, 4H), 6.37 (s, 2H), 6.78 (d, J = 7.5 Hz, 1 H), 7.13 (t, J = 7.8 Hz, 1 H), 7.59 ( s, 1 H), 7.69 (s, 1 H), 7.74 (d, J = 9.3 Hz, 1 H), 8.68 (s, 1 H).

EXAMPLE 137 N-tert-Butyl-3- [5-methyl-2- (3-morpholin-4-ylmethyl-phenylamino) -pyrimidin-4-ylaminol-benzenesulfonamide hydrochloride (Compound LXXXIX) LXXXIX A suspension of intermediate 50 (1.0 g, 3.42 mmol), 3-bromo-β / - / e? -butyl-benzenesulfonamide (1.28 g, 4.28 mmol), Pd2 (dba) 3 (30 nag, 0.03 mmol), Xantphos (40 mg, 0.07 mmol) and cesium carbonate (3.34 g, 10.24 mmol) in dioxane (50 ml) was degassed with argon for 2 min, then refluxed overnight. After cooling to room temperature, the solvent was removed by rotary evaporation and the resulting mixture was purified by silica gel with 10% CH3OH / CHCl3 as an eluent to give the title compound as a white solid. The white solid was dissolved in hot dioxane (150 ml) and titrated with 2 M HCl in dioxane to pH 1. The solvent was removed by rotary evaporation and the solid was recrystallized from methanol (0.15 g, 8%). 1 H NMR (500 MHz, DMSO-d 6): 1.08 (s, 9H), 2.20 (s, 3H), 3.0-3.2 (m, 4H), 3.7-4.0 (m, 4H), 4.23 (s, 2H), 7.33 (t, J = 7.9 Hz, 1 H), 7.38 (d, J = 7.7 Hz, 1 H), 7.48 (s, 1 H), 7.55-7.65 (m, 3H), 7.71 (d, J = 7.9 Hz, 1 H), 7.90 (d, J = 7.4 Hz, 1 H), 8.01 (s, 1 H), 9.96 (br s, 1 H), 10.61 (br s, 1 H), 11.31 (br s, 1 H). MS (ES +): m / z 511 (M + H) +.

EXAMPLE 138 2-Chloro-5-methyl-M- (3,5-dimethylphenyl) pyrimidin-4-amine (Intermediate 51) 51 A mixture of 1-bromo-3,5-dimethylbenzene (104 μl, 0.77 mmol), 2-chloro-5-methyl-pyrimidin-4-ylamine (104 mg, 0.72 mmol), Pd (OAC) 2 (15 mg , 0.07 mmol), Xantphos (83 mg, 0.14 mmol) and potassium tert-butoxide (159 mg, 1.42 mmol) in dioxane (8 ml) was microwaved at 160 ° C for 20 min. The reaction mixture was cooled to room temperature and filtered by rinsing with DCM and methanol. The filtrate was concentrated and purified using flash gradient chromatography (0-100% ethyl acetate in hexanes) to give the title compound as a yellow oil (89 mg, 50%). MS (ES +): m / z 248 (M + H) +.

EXAMPLE 139 S-Methyl -? ^ - O.S-dimethylpheniD - ^^ - tpiperidin ^ -iloxDfeniQpyrimidine-S ^ -diamine (Compound XC) XC A mixture of intermediate 51 (89 mg, 0.36 mmol), and 4- (4-aminophenoxy) -piperidine-1-carboxylic acid tert-butyl ester (139 mg, 0.47 mmol) in acetic acid was stirred at room temperature for 16 hr, then heated at 95 ° C for 2 hr. The reaction mixture was concentrated under vacuum, and purified by preparative HPLC. The product was basified with NaHCO3 (aq) (10 ml) and extracted with ethyl acetate (3x30 ml). The combined organic layers were washed with brine (5 ml), dried (Na2SO4), and concentrated. The free base was taken up in MeOH (5 ml) and conc. HCl. (5 drops) and after 2 min was concentrated under vacuum in the presence of DCM and hexanes to give the HCl salt of the title compound as an off-white solid (63 mg, 40%). 1 H NMR (500 MHz, DMSO-d 6): d 1.72-1.83 (m, 2H), 2.02-2.08 (m, 2H), 2.14 (d, J = 0.6 Hz, 3H), 2.24 (s, 6H), 3.04-3.15 (m, 2H), 3.21-3.31 (m, 2H), 4.57-4.60 (m, 1 H), 6.85 (s, 1 H), 6.91 (d, J = 8.9 Hz, 2H), 7.20 (s, 2H), 7.37 (d, = 8.9 Hz, 2H), 7.85 (s, 1 H), 8.50 (br s, 1 H), 8.56 (br s, 1 H), 9.36 (br s, 1 H), . 10 (br s, 1 H). MS (ES +): m / z 404 (M + H) +.

EXAMPLE 140 2-Chloro -? / - (3,5-dimethoxy-phenyl-5-methylpyrimidin-4-amine (Intermediate 52) 52 A mixture of 1-bromo-3,5-dimethoxybenzene (436 mg, 2.01 mmol), 2-chloro-5-methyl-pyrimidin-4-ylamine (287 mg, 2.00 mmol), Pd (OAc) 2 (44 mg, 0.20 mmoles), Xantphos (237 mg, 0.41 mmol) and potassium tert-butoxide (448 mg, 3.99 mmol) in dioxane (15 ml) and DMF (5 ml) was microwaved at 160 ° C for 20 min. The reaction mixture was cooled to room temperature and filtered by rinsing with DCM and methanol. The filtrate was concentrated and purified using flash gradient chromatography (0-100% ethyl acetate in hexanes) to give the title compound as a yellow solid (182 mg, 33%). 1 H NMR (500 MHz, DMSO-d 6): d 2.17 (s, 3 H), 3.74 (s, 6 H), 6.27 (t, J-2.2 Hz, 1 H), 6.99 (d, J = 2.2 Hz, 2 H) , 8.06 (s, 1 H), 8.71 (s, 1 H). MS (ES +): m / z 280 (M + H) +.

EXAMPLE 141 f > - (3,5-Dimethoxyphenyl) -5-methyl- / V2- (4- (piperidin-4-yloxy) phenyl) pyrimidine-2,4-diamine (Compound XCI) CI A mixture of intermediate 52 (100 mg, 0.36 mmole), and 4- (4-amino-phenoxy) -piperidine-1-carboxylic acid tert-butyl ester (106 mg, 0.36 mmole) in acetic acid was heated to 95 ° C for 2 hr. The reaction mixture was concentrated under vacuum, and purified by preparative HPLC to give the TFA salt of the title compound as a tan solid (75 mg, 39%). 1 H NMR (500 MHz, DMSO-d 6): d 1.74-1.83 (m, 2H), 2.03-2.11 (m, 2H), 2.15 (s, 3H), 3.06-3.15 (m, 2H), 3.21-3.30 (m, 2H), 3.69 (s, 6H), 4.57-4.60 (m, 1 H), 6.39 ( t, J = 2.2 Hz, 1 H), 6.80 (d, J = 2.2 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 7.37 (d, J = 9.0 Hz, 2H), 7.86 (s) , 1 H), 8.53 (br s, 1 H), 8.58 (br s, 1 H), 9.49 (br s, 1 H), 10.24 (br s, 1 H). MS (ES +): m / z 436 (M + H) +.

EXAMPLE 142 5-Methyl-V2- (4- (4-methylpiperazin-1-yl) phenyl) - / - (3- (piperidin-1-yl) phenyl) pyrimidine-2,4-diamine (Compound XCII) XC1I A mixture of 1- (3-bromophenyl) piperidine (91 mg, 0.38 mmole), intermediate 32 (99 mg, 0.33 mmole), Pd2 (dba) 3 (15 mg, 0.02 mmol), Xantphos (24 mg, 0.04 mmole) ) and cesium carbonate (219 mg, 0.67 mmol) in dioxane (4 ml) was microwaved at 160 ° C for 15 min. The reaction mixture was cooled to room temperature, concentrated in vacuo, taken up in methanol, and filtered by rinsing with DCM and methanol. The filtrate was concentrated and purified by preparative HPLC to give the TFA salt of the title compound as an off white solid (14 mg, 8%). 1 H NMR (500 MHz, DMSO-d 6): d 1.47-1.53 (m, 2H), 1.56-1.61 (m, 4H), 2.07 (s, 3H), 2.21 (s, 3H), 2.44 (t, J = 4.9 Hz, 4H), 3.01 (t, J = 4.9 Hz, 4H), 3.08 (t, J = 5.4 Hz, 4H), 6.63 (dd, J = 8.2, 2.3 Hz, 1 H), 6.76 (d, J = 9.0 Hz, 2H), 7.12 (t, J = 8.3 Hz, 1 H), 7.14 (s, 1 H), 7.27 (d, J = 7.6 Hz, 1 H), 7.50 (d, J = 9.0 Hz, 2H), 7.81 (s, 1 H), 8.00 (s, 1 H), 8.67 (s, 1 H). MS (ES +): m / z 458 (M + H) +.

EXAMPLE 143 N4- (3- (1H-Pyrrol-1-yl) phenyl) -5-methyl- / V2- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidine-2,4-diamine (Compound XCIII ) xcip A mixture of 1- (3-bromophenyl) -1H-pyrrole (86 mg, 0.39 mmole), intermediate 32 (99 mg, 0.33 mmole), Pd2 (dba) 3 (16 mg, 0.02 mmole), Xantphos (26 mg , 0.05 mmole) and cesium carbonate (215 mg, 0.66 mmole) in dioxane (4 ml) was microwaved at 160 ° C for 15 min. The reaction mixture was cooled to room temperature, concentrated in vacuo, taken up in methanol, and filtered by rinsing with DCM and methanol. The filtrate was concentrated and purified by preparative HPLC to give the TFA salt of the title compound as an off white solid (32 mg, 18%). 1 H NMR (500 MHz, DMSO-d 6): d 2.11 (s, 3 H), 2.21 (s, 3 H), 2.42. (t, J = 4.9 Hz, 4H), 2.95 (t, J = 4.9 Hz, 4H), 6.24 (t, 7 = 2.2 Hz, 2H), 6.58 (d, J = 8.9 Hz, 2H), 7.23 (dd, J = 7.8, 1.8 Hz, 1 H), 7.31 (t, J = 2.2 Hz, 2H), 7.37 (t, 7 = 8.1 Hz, 1 H), 7.43 (d, J = 9.0 Hz, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.86 (t, J = 2.2 Hz, 1 H), 7.87 (s, 1 H) , 8.30 (s, 1 H), 8.74 (s, 1 H). MS (ES +): m / z 440 (M + H) +.

EXAMPLE 144 5- Tertiary butyl ester. { 2- [4- (1-Tef-butoxycarbonyl-piperidin-4-yloxy) -phenylamino-5-methyl-pyrimidin-4-ylammon) -indol-1-carboxylic acid (Intermediate 53) 53 A mixture of 5-bromo-1 / - / - indole-1-tert-butylcarboxylate (161 mg, 0.54 mmol), intermediate 42 (202 mg, 0.50 mmol), Pd2 (dba) 3 (29 mg, 0.03) mmoles), Xantphos (36 mg, 0.07 mmol) and cesium carbonate (321 mg, 0.98 mmol) in dioxane (5 ml) was microwaved at 160 ° C for 20 min. The reaction mixture was cooled to room temperature and filtered by rinsing with DCM. The filtrate was concentrated and purified by flash gradient chromatography (0-20% MeOH in DCM) to give the title compound as a light brown solid (290 mg, 94%). MS (ES +): m / z 615 (M + H) +.

EXAMPLE 145 / V4- (1H-lndol-5-yl) -5-methyl- ^ 2- (4- (piperidin-4-yloxy) phenyl) pyrimidin-2,4-diamine (Compound XCIV) xciv To a solution of acetyl chloride (670 μl, 9.42 mmol) in methanol (22 ml) was added intermediate 53 (290 mg, 0.47 mmol), and the reaction mixture was heated at 60 ° C for 4 h. The mixture was concentrated under vacuum and purified by preparative HPLC to give the TFA salt of the title compound as a brown solid (6 mg, 2%). 1 H NMR (500 MHz, DMSO-d 6): d 1.70-1.78 (m, 2H), 1.98-2.07 (m, 2H), 2.16 (s, 3H), 3.02-3.11 (m, 2H), 3.21-3.30 ( m, 2H), 4.44-4.53 (m, 1 H), 6. 43 (s, 1 H), 6.75 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 8.4 Hz, 1 H), 7.31 (d, J = 8.7 Hz, 2H), 7.40-7.42 (m, 2H), 7.71 (s, 1H), 7.78 (s, 1H), 8.48 (br s, 1H), 8.54 (br s, 1 H), 9.65 (br s, 1 H), 9.99 (br s, 1 H), 11.18 (s, 1 H). MS (ES +): T7 / z 415 (M + H) +.

EXAMPLE 146 ^^ - Chloro-S-methoxy-phenyD-S-methyl-^ -fS-piperazin-l-yl-pyridin-S-yl) -pyrimidine-2,4-diamine (Compound XCV) XCV A mixture of intermediate 31 (0.10 g, 0.35 mmole), 4- (5-amino-pyridin-2-yl) -piperazin-1-carboxylic acid tert-butyl ester (0.10 g, 0.36 mmole) , Pd2 (dba) 3 (30 mg, 0.033 mmole), Xantphos (35 mg, 0.06 mmole) and cesium carbonate (0.23 g, 0.71 mmole) in dioxane / DMF (3/1, 4 ml) was sealed in a tube of microwave reaction and irradiated with microwaves at 170 ° C for 30 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (hexanes to EtOAc) to give the protected Boc precursor. To a solution of the precursor in DCM (5 ml) was added TFA (3 ml). The mixture was stirred at room temperature for 30 min, concentrated and the residue purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO 3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na2SO and filtered. The filtrate was concentrated and the resulting solid was triturated in a mixture of hexanes / EtOAc (10/1, 55 ml). After filtration, the title compound was obtained as a white solid (20 mg, 13%). 1 H NMR (500 MHz, DMSO-d 6): d 2.09 (s, 3 H), 2.81 (t, J = 5.0 Hz, 4 H), 3.29-3.31 (m, 4 H), 3.73 (s, 3 H), 6.70 (d , J = 9.1 Hz, 1 H), 7.26 (d, J = 8.6 Hz, 1 H), 7.42 (d, J = 9.1 Hz, 1 H), 7.49 (d, J = 2.2 Hz, 1 H), 7.76 (dd, J = 9.1, 2.6 Hz, 1 H), 7.86 (s, 1 H), 8.29 (s, 1 H), 8.31 (d, J = 2.6 Hz, 1 H), 8.71 (s, 1 H) . MS (ES +): m / z 426 (M + H) +.

EXAMPLE 147 4- (4-Amino-2-methoxycarbonyl-phenyl) -piperazine-1-carboxylic acid tert-butyl ester (Intermediate 54) 54 To a solution of 4- (2-methoxycarbonyl-4-nitro-phenyl) -piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 2.7 mmol) in MeOH (30 mL) was added 10% by weight of Pd / C (0.1 equiv in weight) under argon atmosphere. The mixture was evacuated and then filled with hydrogen (3 cycles) and stirred at room temperature for 2 hr. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with MeOH and concentrated in vacuo. The crude amino compound was used in the next step without purification.

MS (ES +): m / z 336 (M + H) +.

EXAMPLE 148 5-f4- (4-Chloro-3-methoxy-phenylamino) -5-methyl-pyrimidin-2-ylamino-1-piperazin-1-yl-benzoic acid methyl ester (Compound XCVI) XCVI A mixture of intermediate 31 (0.10 g, 0.35 mmol), intermediate 54 (0.14 g, 0.42 mmol), Pd2 (dba) 3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06 mmol) and cesium carbonate (0.23) g, 0.71 mmol) was suspended in dioxane (15 ml) and heated to reflux under an argon atmosphere for 2.5 hr. The reaction mixture was cooled to room temperature and diluted with DCM (30 ml). The mixture was filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (hexanes to 60% EtOAc / hexanes) to give the protected Boc precursor. To a solution of the precursor in DCM (5 ml) was added TFA (2 ml). The mixture was stirred at room temperature for 1 hr, concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 24%). 1 H NMR (500 MHz, DMSO-d 6): d 2.11 (s, 3 H), 2.80-2.90 (m, 8 H), 3.73 (s, 3 H), 3.74 (s, 3 H), 6.98 (d, J = 8.9 Hz , 1 H), 7.25 (d, J = 8.5 Hz, 1 H), 7.40-7.48 (m, 2H), 7.69 (d, J = 8.9, 2.6 Hz, 1 H), 7.90 (d, J = 2.6 Hz , 1 H), 7.91 (s, 1 H), 8.36 (s, 1 H), 9.04 (s, 1 H). MS (ES +): m / z 483 (M + H) +.

EXAMPLE 149 5-Amino-2- (2-pyrrolidin-1-yl-ethoxy) -benzoic acid methyl ester (Intermediate 55) 55 A suspension of 5-amino-2-hydroxy-benzoic acid methyl ester (1.0 g, 6.0 mmol), 1- (2-chloro-ethyl) -pyrrolidine hydrochloride (1.2 g, 7.1 mmol) and cesium carbonate (5.0 g, 15 mmol) in DMF (40 mL) was heated at 60 ° C for 17 hr. The mixture was allowed to cool to room temperature, was poured into water (60 ml) and extracted with EtOAc (2 x 50 ml). The combined extracts were washed with brine, dried over Na2SO anhydrous and filtered. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (30% DCM MeOH / DCM) to give the title compound (0.2 g, 13%) as a light brown solid. MS (ES +): m / z 265 (M + H) +.

EXAMPLE 150 5-F4- (Benzori, 31-dioxol-4-ylamino) -5-methyl-pyrimidin-2-ylaminol-2- (2-pyrrolidin-1-yl-ethoxy) -benzoic acid methyl ester (Compound XCVII ) XCVll A mixture of intermediate 30 (0.15 g, 0.57 mmole), intermediate 55 (0.20 g, 0.75 mmole), Pd2 (dba) 3 (50 mg, 0.055 mmole), Xantphos (60 mg, 0.10 mmole) and cesium carbonate ( 0.30 g, 0.92 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM, the filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as an off-white solid (30 mg, 11%). 1 H NMR (500 MHz, DMSO-d 6): d 1.65-1.72 (m, 4H), 2.07 (s, 3H), 2.50-2.62 (m, 4H), 2.75-2.85 (m, 2H), 3.73 (s, 3H), 4.02 (t, J = 5.8 Hz, 2H), 5.88 (s, 2H), 6.78-6.88 (m, 3H), 6.92 (dd, J = 8.0, 2.1 Hz, 1H), 7.75-7.80 (m , 2H), 7.83 (s, 1 H), 8.22 (s, 1 H), 8.89 (s, 1 H). MS (ES +): m / z 492 (M + H) +.

EXAMPLE 151 -ter-butyl-3-. { 5-methyl-2-r4- (piperdin-4-yloxy) -phenylamino '- pyrimidin-4-ylamino} -benzenesulfonamide (Compound XCVIII) XCVIII A mixture of intermediate 33 (0.15 g, 0.42 mmol) and 4- (4-amino-phenoxy) -piperidin-1-carboxylic acid tert-butyl ester (0.15 g, 0.51 mmol) in acetic acid (3 ml) is sealed in a microwave reaction tube and irradiated with microwaves at 150 ° C for 20 min. After cooling to room temperature, the lid was removed and the mixture was concentrated. The residue was taken up in water (20 ml) and the pH adjusted with solution of 10% NaOH until a solid precipitated. The solid was filtered and then purified by HPLC. The corrected fractions were combined, emptied into saturated NaHCO3 solution (30 ml) and extracted with EtOAc (2 x 30 ml). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (20 mg, 9%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9H), 1.65-1.73 (m, 2H), 1.95-2.05 (m, 2H), 2.12 (s, 3H), 2.89-2.95 (m, 2H), 3.10-3.20 (m, 2H), 4.40-4.45 (m, 1 H), 6.84 (d, J = 9.1 Hz, 2H), 7.45-7.60 (m, 6H), 7.90 (s, 1 H) , 8.10-8.15 (m, 2H), 8.55 (s, 1 H), 8.81 (s, 1 H). MS (ES +): m / z 511 (M + H) +.

EXAMPLE 152 2- (5-Amino-pyridin-2-yloxy) -ethanol (Intermediate 56) 56 To a solution of 2- (5-nitro-pyridin-2-yloxy) -ethanol (1.0 g, 5.4 mmol) in MeOH (30 mL) was added 10% by weight of Pd / C (0.1 equiv. By weight) under an atmosphere of argon. The mixture was evacuated and then refilled with hydrogen (3 cycles) and stirred at room temperature for 1 hr. The Heterogeneous reaction mixture was filtered through a pad of Celite, washed with MeOH and concentrated in vacuo. The crude amino compound was used in the next step without purification. MS (ES +): m / z 155 (M + H) +.

EXAMPLE 153 2- 5- [4- (Benzo [1,3] dioxol-4-ylamino) -5-methyl-pyrimidin-2-ylamino '| -pyridin-2-yloxy-ethanol (Compound XCIX) XCLX A mixture of intermediate 30 (0.10 g, 0.38 mmol), intermediate 56 (0.10 g, 0.65 mmol), Pd2 (dba) 3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06 mmol) and cesium carbonate ( 0.26 g, 0.80 mmoles) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM, the filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as an off-white solid (50 mg, 35%). 1 H NMR (500 MHz, DMSO-d 6): d 2.06 (s, 3 H), 3.66 (q, J = 5.4 Hz, 2H), 4.15 (t, J = 5.2 Hz, 2H), 4.77 (t, J = 5.5 Hz, 2H), 5.91 (s, 2H), 6.52 (d, J = 9.0 Hz, 1 H), 6.78-6.90 (m, 3H), 7.82 (s, 1 H), 7.96 (dd, J = 8.9, 2.7 Hz, 1 H), 8.22 (d, J = 2.6 Hz, 1 H), 8.27 (s, 1 H), 8.84 (s, 1 H). MS (ES +): m / z 382 (M + H) +.

EXAMPLE 154 1-r2- (2-Methoxy-4-nitro-phenoxy) -etin-pyrrolidine (Intermediate 57) 57 A suspension of potassium 2-methoxy-4-nitro-phenolate (2.0 g, 9.7 mmol), 1- (2-chloro-ethyl) -pyrrolidine hydrochloride (2.0 g, 12 mmol) and cesium carbonate (7.0, 22 mmoles) in DMF (35 ml) was heated at 80 ° C for 16 hr. The mixture was allowed to cool to room temperature, was poured into water (60 ml) and extracted with EtOAc (2 x 50 ml). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and used in the next step without purification.

MS (ES +): m / z 267 (M + H) +.

EXAMPLE 155 3-Methoxy-4- (2-pyrrolidin-1-yl-ethoxy) -phenylamine (Intermediary 58) 58 To a solution of intermediate 57 (1.7 g, 6.4 mmol) in MeOH (30 ml) was added 10% by weight of Pd / C (0.1 equiv by weight) under argon atmosphere. The mixture was evacuated and then refilled with hydrogen (3 cycles) and stirred at room temperature for 1 hr. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with MeOH and concentrated in vacuo. The crude amino compound was used in the next step without purification. MS (ES +): m / z 237 (M + H) +.

EXAMPLE 156? ^ - Benzori, 31-dioxol-4-yl -? / 2-r3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) -fenin-5-methyl-pyrimidine-2,4-diamine ( Compound C) C A mixture of intermediate 30 (0.10 g, 0.38 mmole), intermediate 58 (0.11 g, 0.46 mmole), Pd2 (dba) 3 (30 mg, 0.033 mmole), Xantphos (35 mg, 0.06 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM, the filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO 3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine.were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (50 mg, 28%). 1 H NMR (500 MHz, DMSO-d 6): d 1.65-1.72 (m, 4H), 2.06 (s, 3H), 2. 50-2.62 (m, 4H), 2.75-2.85 (m, 2H), 3.50 (s, 3H), 3.94 (t, J = 6.1 Hz, 2H), 5.84 (s, 2H), 6.67 (d, J = 8.8 Hz, 1 H), 6.78 (dd, J = 7.8, 1.1 Hz, 1 H), 6.83 (t, J = 7.9 Hz, 1 H), 6.92 (dd, J = 8.1, 1.1 Hz, 1 H), 7.14 (dd, J = 8.7, 2.4 Hz, 1 H), 7.23 (d, J = 2.4 Hz, 1 H), 7.83 (s, 1 H), 8.21 (s, 1 H), 8.69 (s, 1 H) ). MS (ES +): m / z 464 (M + H) +.

EXAMPLE 157 / V-tert-butyl-3-r2- (4-ylazol-1-yl-phenylamino) -5-methyl-pyrimidin-4-ylamino-1-benzenesulfonamide (Compound Cl) Cl A mixture of intermediate 33 (0.40 g, 1.1 mmol), 4-imidazol-1-yl-phenylamine (0.20 g, 1.3 mmol), Pd2 (dba) 3 (0.10 g, 0.11 mmol), Xantphos (0.12 g, 0.21 mmol) and cesium carbonate (0.80 g, 2.5 mmol) in dioxane / DMF (3/1, 8 mL) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 30 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM, the filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO3 solution (40 ml). The combined aqueous layers were extracted with EtOAc (2 x 40 ml) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as an off-white solid (0.15 g, 28%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9H), 2.15 (s, 3H), 7.07 (s, 1 H), 7.43 (d, J = 9.0 Hz, 2H), 7.50-7.60 ( m, 3H), 7.61 (s, 1 H), 7.79 (d, J = 9.0 Hz, 2H), 7.98 (s, 1 H), 8.08-8.13 (m, 3H), 8.64 (s, 1 H), 9.19 (s, 1 H). MS (ES +): m / z 478 (M + H) +.

EXAMPLE 158 W-fer-Butyl-3- [2- (4-imidazol-1-ylmethyl-phenylamino) -5-methyl-pyrimidin-4-ylaminole-benzenesulfonamide (Compound CU) CU A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-imidazol-1-ylmethyl-phenylamine (60 mg, 0.35 mmol), Pd2 (dba) 3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052) mmoles) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM, the filtrate was concentrated and the residue was purified by CLAR. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and then taken up in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 29%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9 H), 2.13 (s, 3 H), 5.07 (s, 2 H), 6.89 (s, 1 H), 7.12 (d, J = 8.6 Hz, 2H), 7.15 (s, 1H), 7.46 (t, = 7.9 Hz, 1H), 7.49-7.52 (m, 1H), 7.56 (s, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.72 (s, 1 H), 7.94 (s, 1 H), 8.09 (s, 1 H), 8.14 (d, J = 8.1 Hz, 1 H), 8.60 (s, 1 H), 9.02 (s, 1 H) ). MS (ES +): m / z 492 (M + H) +.

EXAMPLE 159 2- (4-Amino-phenoxy) -ethanol (Intermediate 59) 59 A solution of 2- (4-nitro-phenoxy) -ethanol (2.1 g, 12 mmol) in MeOH (30 ml) was flushed with argon and then loaded with 10% by weight of Pd / C (0.1 equiv in weight). The mixture was evacuated under vacuum and then filled with hydrogen from a hydrogen balloon. The cycle was repeated again and the mixture was stirred at room temperature for 2 hr. The Heterogeneous reaction mixture was filtered through a pad of Celite, washed with MeOH and concentrated under vacuum to provide the title compound (1.8 g, 99%) as a brown solid. MS (ES +): m / z 154 (M + H) +.

EXAMPLE 160 W-ter-Butyl-3-. { 2- [4- (2-hydroxy-ethoxy) -phenylamino-5-methyl-pyrimidin-4-ylaminoj-benzenesulfonamide (Compound Clll) cpi A mixture of intermediate 33 (0.10 g, 0.28 mmole), intermediate 59 (55 mg, 0.36 mmole), Pd2 (dba) 3 (25 mg, 0.027 mmole), Xantphos (30 mg, 0.052 mmole) and cesium carbonate ( 0.20 g, 0.61 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM, the filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na2SO and filtered. The filtrate is concentrated and then collected in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (15 mg, 11%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9 H), 2.12 (s, 3 H), 3.69 (q, J = 5.2 Hz, 2 H), 3.91 (t, J = 5.1 Hz, 2 H), 4.82 (t, J = 5.5 Hz, 2H), 6.80 (d, J = 9.1 Hz, 2H), 7.45-7.50 (m, 2H), 7.52 (d, J = 9.0 Hz, 2H), 7.55 (s, 1H) ), 7.90 (s, 1 H), 8.08-8.15 (m, 2H), 8.53 (s, 1 H), 8.77 (s, 1 H). MS (ES +): m / z 472 (M + H) +.

EXAMPLE 161 ^ - (4-Chloro-3-methoxy-phenyl) -5-methyl-W2- (4-piperazin-1-ylmethyl-phenyl) -pyrimidine-2,4-diamine (Compound CIV) C1V A mixture of intermediate 31 (0.10 g, 0.35 mmol), 4- (4-amino-benzyl) -piperazin-1-carboxylic acid tert-butyl ester (0.12 g, 0.41 mmol), Pd2 (dba) 3 (30 mg , 0.033 mmole), Xantphos (35 mg, 0.06 mmole) and cesium carbonate (0.23 g, 0.71 mmole) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid stirred and the resulting mixture was filtered. The filtered solid was washed with DCM and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (hexanes to 60% EtOAc / hexanes) to give the protected Boc precursor. To a solution of the precursor in DCM (5 ml) was added TFA (3 ml). The mixture was stirred at room temperature for 1 hr, concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO 3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO and filtered. The filtrate was concentrated and then taken up in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (13 mg, 9%). 1 H NMR (500 MHz, DMSO-d 6): d 2.11 (s, 3 H), 2.30-2.40 (m, 4 H), 2.83 (t, J = 4.8 Hz, 4 H), 3.37 (s, 2 H), 3.75 (s) , 3H), 7.08 (d, J = 8.6 Hz, 2H), 7.29 (d, J = 8.6 Hz, 1H), 7.43 (d, J = 8.6, 2.2 Hz, 1H), 7.47 (d, J = 2.2 Hz , 1H), 7.59 (d, J = 8.6 Hz, 2H), 7.91 (s, 1 H), 8.37 (s, 1 H), 8.99 (s, 1 H). MS (ES +): m / z 439 (M + H) +.

EXAMPLE 162 ^ -ter-Butyl-3-. { 5-methyl-2- [4- (2-methyl-imidazol-1-yl) -phenylamino-pyrimidin-4-ylaminoj-benzenesulfonamide (Compound CV) A mixture of intermediate 33 (0.10 g, 0.28 mmole), 4- (2-methyl-imidazol-1-yl) -phenylamine (60 mg, 0.35 mmole), Pd2 (dba) 3 (25 mg, 0.027 mmole), Xantphos (30 mg, 0.052 mmole) and cesium carbonate (0.20 g, 0.61 mmole) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 minutes. min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM, the filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO 3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and then taken up in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (30 mg, 22%). 1 H NMR (500 MHz, DMSO-d 6): d 1.11 (s, 9 H), 2.15 (s, 3 H), 2.24 (s, 3 H), 6.87 (d, J = 1.2 Hz, 1 H), 7.18 (d, J = 1.3 Hz, 1 H), 7.22 (d, J = 8.9 Hz, H), 7.50-7.55 (m, 2H), 7.56 (s, 1 H), 7.79 (d, J = 8.9 Hz, 2H), 7.98 (s, 1 H), 8.07-8.10 (m, 2H), 8.65 (s, 1 H), 9.26 (s, 1 H). MS (ES +): m / z 492 (M + H) +.

EXAMPLE 163 M-ter-Butyl-3-. { 5-methyl-2-r4- (2-methyl-imidazol-1-ylmethyl) -phenylaminol-pyrimidin-4-ylamino) -benzenesulfonamide (Compound CVI) CVI A mixture of intermediate 33 (0.10 g, 0.28 mmole), 4- (2-methyl-imidazol-1-ylmethyl) -phenylamine (65 mg, 0.35 mmole), Pd2 (dba) 3 (25 mg, 0.027 mmole), Xantphos (30 mg, 0.052 mmole) and cesium carbonate (0.20 g, 0.61 mmole) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 minutes. min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM, the filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. He The filtrate was concentrated and then taken up in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (30 mg, 21%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9H), 2.13 (s, 3H), 2.24 (s, 3H), 5.01 (s, 2H), 6.73 (d, J = 1.2 Hz, 1 H), 7.01 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 1.1 Hz, 1 H), 7.44 (t, J = 7.9 Hz, 1 H), 7.48-7.51 (m, 1 H) , 7.56 (s, 1H), 7.62 (d, J = 8.6 Hz, 2H), 7.94 (s, 1 H), 8.08 (s, 1 H), 8.12 (d, J = 8.1 Hz, 1 H), 8.60 (s, 1 H), 9.02 (s, 1 H). MS (ES +): m / z 506 (M + H) +.

EXAMPLE 164 Af-tert-Butyl-3-F5-methyl-2- (4-pyridin-4-ylmethyl-phenylamino) -pyrimidin-4-ylamino] -benzenesulfonamide (Compound CVII) CVTI A mixture of intermediate 33 (0.10 g, 0.28 mmole), 4-pyridin-4-ylmethyl-phenylamine (65 mg, 0.35 mmole), Pd2 (dba) 3 (25 mg, 0.027 mmole), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to At room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM, the filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and then taken up in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (45 mg, 32%). 1 H NMR (500 MHz, DMSO-d 6): d 1.11 (s, 9 H), 2.13 (s, 3 H), 3.87 (s, 2H), 7.07 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 6.0 Hz, 2H), 7.43 (t, J = 7.9 Hz, 1H), 7. 47-7.50 (m, 1 H), 7.56 (d, J = 6.3 Hz, 2H), 7.58 (s, 1 H), 7.93 (s, 1 H), 8.09 (s, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 8.44 (d, J = 5.8 Hz, 2 H), 8.58 (s, 1 H), 8.94 (s, 1 H). MS (ES +): m / z 503 (M + H) +.

EXAMPLE 165? -tert-butyl-3-r5-methyl-2- (4-morform-4-yl-phenylamino) -pyrimidin-4-ylamino-1-benzenesulfonamide (Compound CVIII) CVIII A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4- morpholin-4-yl-phenylamine (60 mg, 0.34 mmole), Pd2 (dba) 3 (25 mg, 0.027 mmole), Xantphos (30 mg, 0.052 mmole) and cesium carbonate (0.20 g, 0.61 mmole) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM, the filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine.were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a gray solid (45 mg, 32%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9 H), 2.12 (s, 3 H), 3.00 (t, J = 4.8 Hz, 4 H), 3.73 (t, J = 4.8 Hz, 4 H), 6.82 (d, J = 9.1 Hz, 2H), 7.45-7.52 (m, 4H), 7.56 (s, 1 H), 7.89 (s, 1 H), 8.10-8.17 (m, 2H), 8.52 (s, 1 H), 8.73 (s, 1 H). MS (ES +): m / z 497 (M + H) +.

EXAMPLE 166 ^ -ter-Butyl-3-f5-methyl-2-r4- [1,2,4] triazol-1-ylmethyl-phenylamino) -pyrimidin-4-ylaminole-benzenesulfonamide (Compound CIX) CIX A mixture of intermediate 33 (0.10 g, 0.28 mmole), 4- [1, 2,4] triazol-1-ylmethyl-phenylamine (60 mg, 0.34 mmole), Pd2 (dba) 3 (25 mg, 0.027 mmole) , Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane (4 ml) were sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM, the filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and then taken up in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (37 mg, 27%). 1 H NMR (500 MHz, DMSO-d 6): d 1.17 (s, 9 H), 2.13 (s, 3 H), 5.29 (s, 2 H), 7.14 (d, J = 8.6 Hz, 2 H), 7.46 (t, J = 7.8 Hz, 1 H), 7.48-7.51 (m, 1 H), 7.56 (s, 1 H), 7.63 (d, J = 8.6 Hz, 2H), 7.94 (s, 1 H), 7.95 (s, 1 H), 8.08 (s, 1H), 8.13 (d, J = 8.0 Hz , 1 H), 8.59 (s, 1 H), 8.60 (s, 1 H), 9.04 (s, 1 H). MS (ES +): m / z 493 (M + H) +.

EXAMPLE 167 ^ -ter-butyl-3-. { 5-methyl-2-r4- (4-methyl-imidazol-1-yl) -phenylamino-1-pyrimidin-4-ylaminoj-benzenesulfonamide (Compound CX) CX A mixture of intermediate 33 (0.10 g, 0.28 mmole), 4- (4-methyl-imidazol-1-yl) -phenylamine (60 mg, 0.35 mmole), Pd2 (dba) 3 (25 mg, 0.027 mmole), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane (3 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM, the filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na2SO and filtered. The filtrate is concentrated and then collected in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as an off-white solid (20 mg, 15%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9 H), 2.15 (s, 3 H), 2.16 (s, 3 H), 7.30 (s, 1 H), 7.38 (d, J = 9.0 Hz, 2H), 7.50-7.56 (m, 2H), 7.57 (s, 1 H), 7.76 (d, J = 9.0 Hz, 2H), 7.96 (s, 1 H), 7.97 (s, 1 H), 8.09- 8.13 (m, 2H), 8.63 (s, 1 H), 9.16 (s, 1 H). MS (ES +): m / z 492 (M + H) +.

EXAMPLE 168 ^ -ter-Butyl-3- [5-methyl-2- (4-ri, 2,41-triazol-1-yl-phenylamino) -pyrimidin-4-ylaminole-benzenesulfonamide (Compound CXI) CXI A mixture of intermediate 33 (0.10 g, 0.28 mmole), 4- [1,2,4] triazol-1-yl-phenylamine (55 mg, 0.34 mmole), Pd2 (dba) 3 (25 mg, 0.027 mmole) , Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane (3 ml) were sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM, the filtrate was concentrated and the residue was purified by CLAR. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and then taken up in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 29%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9 H), 2.15 (s, 3 H), 7.50-7.58 (m, 3 H), 7.63 (d, J = 9.1 Hz, 2 H), 7.83 (d , J = 9.0 Hz, 2H), 7.99 (s, 1 H), 8.09 (s, 1 H), 8.10-8.15 (m, 1 H), 8.17 (s, 1 H), 8.66 (s, 1H), 9.12 (s, 1 H), 9.27 (s, 1 H). MS (ES +): m / z 479 (M + H) +.

EXAMPLE 169? / - fer-Butyl-3- (5-methyl-2-r3- (1H-tetrazol-5-in-phenylaminol-pyrimidin-4-ylamino) -benzenesulfonamide (Compound CXII) CXII A mixture of intermediate 33 (0.10 g, 0.28 mmol), 3- (1 H -tetrazol-5-yl) -phenylamine (55 mg, 0.34 mmol), Pd2 (dba) 3 (25 mg, 0.027) mmoles), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane (3 ml) were sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM, the filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and then taken up in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (15 mg, 11%). 1 H NMR (500 MHz, DMSO-d 6): d 1.13 (s, 9 H), 2.15 (s, 3 H), 7.26 (t, J = 7.9 Hz, 1 H), 7.38 (t, J = 8.0 Hz, 1 H ), 7.44 (dd, J = 7.9, 1.1 Hz, 1 H), 7.50 (d, J = 7.6 Hz, 1 H), 7.58 (s, 1 H), 7.79 (dd, J = 8.1, 1.4 Hz, 1 H), 7.98 (s, 1 H), 8.16 (s, 1 H), 8.22 (s, 1 H), 8.27 (d, J = 7.8 Hz, 1 H), 8.57 (s, 1 H), 9.08 ( s, 1 H). MS (ES +): m / z 480 (M + H) +.

EXAMPLE 170 4- (1H-Tetrazol-5-yl) -phenylamine (Intermediary 60) 60 To a solution of 5- (4-nitro-phenyl) -1 / - / - tetrazole (1.0 g, 5.2 mmol) in MeOH (30 mL) was added 10% by weight of Pd / C (0.1 equiv. By weight) under argon atmosphere. The mixture was evacuated, refilled with hydrogen (3 cycles) and stirred at room temperature for 1.5 hr. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with MeOH and concentrated in vacuo. The crude amino compound was used in the next step without purification. MS (ES +): m / z 162 (M + H) +.

EXAMPLE 171 ^ -ter-Butyl-3-. { 5-methyl-2-f4- (1H-tetrazol-5-yl) -phenylamino-1-pyrimidin-4-ylamino) -benzenesulfonamide (Compound CXIII) CXIII A mixture of intermediate 33 (0.10 g, 0.28 mmol), intermediate 60 (60 mg, 0.37 mmol), Pd2 (dba) 3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate ( 0.20 g, 0.61 mmol) in dioxane / DMF (3/1, 4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM, the filtrate was concentrated and the residue was purified by CLAR. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and then taken up in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (15 mg, 11%). 1 H NMR (500 MHz, DMSO-d 6): d 1.13 (s, 9 H), 2.16 (s, 3 H), 7.52-7.56 (m, 2 H), 7.57 (s, 1 H), 7.83 (s, 4 H), 8.01 (s, 1 H), 8.08 (s, 1 H), 8.13-8.19 (m, 1 H), 8.69 (s, 1 H), 9.34 (s, 1 H). MS (ES +): m / z 480 (M + H) +.

EXAMPLE 172 3- (2-f4- (4-Acetyl-piperazin-1-yl) -phenylamino-1-5-methyl-pyrimidin-4-ylamino) - ^ - tert -butyl-benzenesulfonamide (Compound CXIV) CXÍV A mixture of intermediate 33 (0.10 g, 0.28 mmol), 1 - [4- (4-amino-phenyl) -piperazin-1-yl] -ethanone (80 mg, 0.36 mmol), Pd2 (dba) 3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane (3 mL) was sealed in a reaction tube of microwave and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM, the filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated and then taken up in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as an off-white solid (55 mg, 37%). H NMR (500 MHz, DMSO-d6): d 1.12 (s, 9H), 2.04 (s, 3H), 2.12 (s, 3H), 2.97 (t, J = 5.2 Hz, 2H), 3.03 (t, J = 5.1 Hz, 2H), 3.57 (q, J = 5.4 Hz, 4H), 6.85 (d, J = 9.0 Hz, 2H), 7.46-7.52 (m, 4H), 7.56 (s, 1 H), 7.90 ( s, 1 H), 8.10-8.17 (m, 2H), 8.52 (s, 1 H), 8.75 (s, 1 H). MS (ES +): m / z 538 (M + H) +.

EXAMPLE 173 ^ -ter-Butil-3-. { 5-methyl-2-f4- (1-morpholin-4-yl-ethyl) -phenylamino-1-pyrimidin-4-ylamino) -benzenesulfonamide (Compound CXV) CXV A mixture of intermediate 33 (0.10 g, 0.28 mmole), 4- (1-morpholin-4-yl-ethyl) -phenylamine (80 mg, 0.39 mmole), Pd2 (dba) 3 (30 mg, 0.033 mmole), Xantphos (35 mg, 0.061 mmol) and cesium carbonate (0.26 g, 0.80 mmol) in dioxane (4 ml) was sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 20 min. After cooling to room temperature, the lid was removed and the resulting mixture was filtered. The filtered solid was washed with DCM, the filtrate was concentrated and the residue was purified by HPLC. The corrected fractions were combined and drained in saturated NaHCO 3 solution (30 ml). The combined aqueous layers were extracted with EtOAc (2 x 30 ml) and the combined organic layers were washed with brine, dried over anhydrous Na2SO and filtered. The filtrate was concentrated and then taken up in a minimum amount of EtOAc. Hexanes were added until a solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 27%). 1 H NMR (500 MHz, DMSO-d 6): d 1.12 (s, 9 H), 1.25 (d, J = 6.6 Hz, 3H), 2.13 (s, 3H), 2.20-2.30 (m, 2H), 2.30-2.40 (m, 2H), 3.24 (q, J = 6.6 Hz, 1 H), 3.54 (t, J = 4.4 Hz, 4H), 7.10 (d, J = 8.5 Hz, 2H), 7.45-7.52 (m, 2H), 7.55 (s, 1 H), 7.57 (d, J = 8.5 Hz, 2H), 7.93 (s, 1 H) ), 8.09 (s, 1 H), 8.15 (d, J = 7.7 Hz, 1 H), 8.57 (s, 1 H), 8.92 (s, 1 H). MS (ES +): m / z 525 (M + H) +.

EXAMPLE 174 ^ - (1 H-lndol-4-yl) -5-methyl- ^ 2- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidine-2,4-diamine (Compound CXVl) CXVl A mixture of intermediate 32 (270 mg, 0.9 mmol), 4-bromo-1H-indole (196 mg, 0.9 mmol), Pd2 (dba) 3 (91 mg, 0.09 mmol), Xantphos (157 mg, 0.27 mmol) and Cesium carbonate (1.2 g, 3.6 mmol) was suspended in dioxane (100 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to give the title compound (55 mg of HCl salt, 14%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 2.22 (s, 3 H), 2.79 (d, J = 4.3 Hz, 3 H), 2.98-3.03 (m, 2 H), 3.08-3.14 (m, 2 H), 3.46. -3.48 (m, 2H), 3.64-3.66 (m, 2H), 6.35-6.36 (m, 1 H), 6.63 (br d, = 8.0 Hz, 1 H), 6.98 (d, J = 9.1 Hz, 2H ), 7.05 (d, J = 7.4 Hz, 1 H), 7.16 (t, J = 7.6 Hz, 1 H), 7.36 (t, J = 2.8 Hz, 2H), 7.43 (d, J = 8.0 Hz, 1 H), 7.86 (s, 1 H), 10.07 (s, 1 H), 10.27 (s, 1 H), 11.00 (br s, 1 H), 11.38 (s, 1 H), 12.16 (br s, H ). MS (ES +): m / z 414 (M + H) +.

EXAMPLE 175 2-Chloro-5-methyl-M- (2,3-dimethylphenyl) pyrimidin-4-amine (Intermediate 61) 61 A mixture of 2-chloro-5-methylpyrimidin-4-amine (143.6 mg, 1 mmol), 1-bromo-2,3-dimethylbenzene (222 mg, 1.2 mmol), Pd2 (dba) 3 (92 mg, 0.1 mmoles), Xantphos (174 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (150 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was dissolved in EtOAc (10 mL) and hexanes (100 mL) was added. The solid was collected by filtration and washed with hexanes to give the crude title compound as a yellow solid.

EXAMPLE 176 5-Methyl-? F4- (2,3-dimethylphenyl) -2- (4-piperidin-4-yloxy) phenyl) pyrimidine-2,4-diamine (Compound CXVII) CXVII A mixture of intermediate 61 (1.0 mmol) and fer-butyl 4- (4-aminophenoxy) piperidin-1-carboxylate (292.4 mg, 1.0 mmol) was suspended in acetic acid (10 mL) and heated at 100 ° C for 4 hr. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH ~ 7. The resulting solution was extracted with EtOAc (30 ml) and the organic layer was separated. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under vacuum and the crude product was purified by HPLC to give the title compound (105 mg of HCl salt, 24%) as a yellow solid. H NMR (500 MHz, DMSO-d6): d 1.76-1.83 (m, 2H), 2.03 (s, 3H), 2.05-2.09 (m, 2H), 2.17 (s, 3H), 2.30 (s, 3H) , 3.02-3.05 (m, 2H), 3.18 (br s, 2H), 4.53-4.56 (m, 1 H), 6.72 (d, J = 8.5 Hz, 2H), 7.11-7.14 (m, 3H), 7.19 -7.24 (m, 2H), 7.87 (s, 1 H), 9.06 (br s, 1 H), 9.13 (br s, 1 H), 9.92 (s, 1 H), 10.43 (s, 1 H). MS (ES +): m / z 404 (M + H) +.

EXAMPLE 177 ^ 4- (4-Chloro-3,15-dimethylphenyl) -5-methyl- ^ 2- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidine-2,4-diamine (Compound C XVIII) A mixture of intermediate 32 (240 mg, 0.8 mmol), 5-bromo-2-chloro-1,3-dimethylbenzene (212 mg, 0.96 mmol), Pd2 (dba) 3 (92 mg, 0.1 mmol), Xantphos (170 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (100 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to give the title compound (63 mg of HCl salt, 17%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 2.15 (s, 3 H), 2.17 (s, 3 H), 2.80 (d, J = 4.5 Hz, 3 H), 3.06-3.14 (m, 4 H), 3.48-3.52. (m, 2H), 3.75-3.77 (m, 2H), 6.93 (d, J = 8.9 Hz, 2H), 7.29 (d, J = 8.9 Hz, 2H), 7.46 (s, 2H), 7.90 (s, 1 H), 9.65 (s, 1 H), 10.49 (s, 1 H), 11.13 (br s, 2H). MS (ES +): m / z 437 (M + H) +.

EXAMPLE 178 JV2- (4- (2- (Pyrrolidin-1-yl) ethoxy) phenyl) -V4- (3-tert-butylphenyl) -5-methyl-pyrimidine-2,4-diamine (Compound CXIX) CXIX A mixture of intermediate 41 (365 mg, 1.32 mmol) and 4- (2- (pyrrolidin-1-yl) ethoxy) benzenamine (410 mg, 1.98 mmol) was suspended in acetic acid (20 ml) and heated to 100 ° C for 4 hr. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH ~ 7. The resulting solution was extracted with EtOAc (30 ml) and the organic layer was separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product was purified by HPLC to give the title compound (127 mg of HCl salt, 20%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.89-1.91 (m, 2H), 1.98-2.02 (m, 2H), 2.17 (s, 3H), 3.07-3.12 (m, 2H), 3.52-3.57 ( m, 4H), 4.32 (t, J = 4.8 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 7.29-7.38 (m, 4H), 7.43-7.44 (m, 1 H), 7.48 ( d, J = 1.9 Hz, 1H), 7.89 (s, 1 H), 9.75 (s, 1 H), 10.51 (s, 1 H), 11.07 (br, 1 H). MS (ESI +): m / z 446 (M + H) +.

EXAMPLE 179 / V2- (4- (2- (Pyrrolidin-1-yl) ethoxy) phenyl) -? R - (4- (3-tert-butylphenylamino) -5-methylpyrimidin-2-yl) -5-methylpyrimidine- 2,4-diamine (Compound CXX) CXX A mixture of intermediate 41 (210 mg, 0.67 mmol), intermediate 38 (185 mg, 0.67 mmol), Pd2 (dba) 3 (55 mg, 0.06 mmol), Xantphos (104 mg, 0.18 mmol) and cesium carbonate ( 782 g, 2.4 mmol) was suspended in dioxane (50 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to give the title compound (94 mg of HCl salt, 24%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.29 (s, 9 H), 1.84-1.88 (m, 2 H), 1.94-2.01 (m, 2 H), 2.14 (s, 3 H), 2.27 (s, 3 H) , 3.06-3.10 (m, 2H), 3.51-3.56 (m, 4H), 4.29 (t, J = 4.9 Hz, 2H), 6.97 (d, J = 9.1 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H), 7.34 (t, J = 7.9 Hz, 2H), 7.57 (t, J = 1.9 Hz, 2H), 7.65 (d, J = 9.1 Hz, 1H), 7.72 (d, J = 8.6 Hz, 2H), 8.15 (s, 1 H), 8.39 (s, 1 H), 9.82 (s, 1 H), 10.21 (br s, 1 H), 10.68 (br s, 1 H), 10.93 (br s, 1 HOUR). MS (ES +): m / z 553 (M + H) +.

EXAMPLE 180 5-Methyl-? / 2-f4- (4-methyl-piperazin-1-yl) -phenyl- ^ -r3- (piper? Din-1-sulfonyl) -phenn-pyrimidine-2,4- diamine (Compound CXXl) CXXl A mixture of intermediate 32 (150 mg, 0.5 mmol), 1- (3-bromo-benzenesulfonyl) -piperidine (152 mg, 0.5 mmol), Pd2 (dba) 3 (46 mg, 0.05 mmol), Xantphos (87 mg , 0.15 mmol) and cesium carbonate (652 mg, 2 mmol) was suspended in dioxane (20 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to give the title compound (84 mg of HCl salt, 37%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.30-1.34 (m, 2H), 1.50-1.55 (m, 4H), 2.17 (s, 3H), 2.81 (d, J = 4.5 Hz, 3H), 2.88 (t, J = 5.3 Hz, 4H), 3.04-3.16 (m, 4H), 3.47-3.51 (m, 2H), 3.75-3.77 (m, 2H), 6.33-6.34 (m, 1 H), 6.95 ( d, J = 9.0 Hz, 2H), 7.25 (d, J = 9.0 Hz, 2H), 7.56-7.63 (m, 2H), 7.83 (t, J = 1.7 Hz, 1 H), 7.92 (s, 1H) , 8.05 (d, J = 9.3 Hz, 1 H), 9.94 (s, 1 H), 10.38 (s, 1H), 10.88 (br s, 1H). MS (ES +): m / z 522 (M + H) +.

EXAMPLE 181 S-Methyl-^^^ -methyl-piperazin-1-iD-phenin-^ -fS-t? -methyl-piperidin-1-sulfonyl) -fenin-pyrimidine-2,4-diamine (Compound CXXll) CXXll A mixture of intermediate 32 (161 mg, 0.54 mmole), 1- (3-bromo-benzenesulfonyl) -2-methyl-piperidine (172 mg, 0.54 mmole), Pd2 (dba) 3 (46 mg, 0.05 mmole), Xantphos (87 mg, 0.15 mmol) and cesium carbonate (652 mg, 2 mmol) was suspended in dioxane (20 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to give the title compound (10 mg of HCl salt, 3%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 0.98 (d, J = 6.9 Hz, 3H), 1.15-1.21 (m, 1 H), 1.36-1.40 (m, 3H), 1.47-1.53 (m, 2H ), 2.18 (s, 3H), 2.80 (d, J = 4.5 Hz, 3H), 2.94-2.99 (m, 1 H), 3.05-3.16 (m, 4H), 3.47-3.49 (m, 2H), 3.59 -3.61 (m, 2H), 3.73-3.76 (m, 2H), 4.08-4.10 (m, 1 H), 6.93 (d, J = 8.9 Hz, 2H), 7.25 (d, J = 8.9 Hz, 2H) , 7.58 (t, J = 8.0 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.92 (d, J = 7.1 Hz, 2H), 7.96 (br, 1 H), 9.95 (s) , 1 H), 10.45 (s, 1H), 11.00 (br s, 1 H). MS (ES +): m / z 536 (M + H) +.

EXAMPLE 182 V-Cyclopentyl-3- (5-methyl-2-f4- (4-methyl-piperazin-1-yl) -phenylaminol-pyrimidin-4-ylamino) -benzenesulfonamide (Compound CXXIH) C A mixture of intermediate 32 (229 mg, 0.78 mmol), 3-bromo-β-cyclopentyl-benzenesulfonamide (280 mg, 0.92 mmol), Pd 2 (dba) 3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmoles) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (100 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to give the title compound (130 mg of HCl salt, 25%) as a white solid. H NMR (500 MHz, DMSO-d6): d 1.27-1.36 (m, 4H), 1.36-1.58 (m, 4H), 2.18 (s, 3H), 2.80 (d, J = 4.6 Hz, 3H), 3.05 -3.15 (m, 4H), 3.36-3.42 (m, 1 H), 3.47-3.49 (m, 2H), 3.74-3.76 (m, 2H), 6.94 (d, J = 8.7 Hz, 2H), 7.26 ( d, J = 8.9 Hz, 2H), 7.59 (t, J = 8.0 Hz, 1 H), 7.68 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 7.1 Hz, 2H), 7.92 (br, 2H), 7.93 (br, 1 H), 9.96 (s, 1 H), 10.45 (s, 1H), 11.98 (br s, 1 H). MS (ES +): m / z 522 (M + H) +.

EXAMPLE 183 5-Methyl-V2-r4- (4-methyl-piperazin-1-yl) -phenyl] - / V4- [3- (pyrrolidin-1-sulfonyl) phenyl] -pyrimidine-2,4-diamine (Compound CXXIV) CXXIV A mixture of intermediate 32 (298 mg, 1.0 mmol), 1- (3-bromo-benzenesulfonyl) -pyrrolidine (360 mg, 1.24 mmol), Pd2 (dba) 3 (92 mg, 0.1 mmol), Xantphos (180 mg , 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (100 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to give the title compound (200 mg of HCl salt, 37%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.61-1.65 (m, 4H), 2.19 (s, 3H), 2. 80 (br, 3H), 3.06-3.16 (m, 10H), 3.74-3.77 (br, 2H), 6.94 (d, J = 9.0 Hz, 2H), 7. 26 (d, = 9.0 Hz, 2H), 7.60 (t, J = 8.0 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.91 (t, J = 1.7 Hz, 1H), 7.93 (s, 1H), 8.05 (d, J = 7.5 Hz, 1 H), 9.95 (s, 1 H), 10.43 (s, 1 H), 11.07 (br s, 1 H). MS (ES +): m / z 508 (M + H) +.

EXAMPLE 184? / 4-r3- (2,5-Dimethyl-pyrrolidin-1-sulfonyl) -phenyl-5-methyl-? / 2-yl- (4-methyl-piperazin-1-yl) -fenin-pyrimidin-2, 4-diamine (Compound CXXV) CXXV A mixture of intermediate 32 (298 mg, 1.0 mmol), 1- (3-bromo-benzenesulfonyl) -2,5-dimethyl-pyrrolidine (318 mg, 1.0 mmol), Pd2 (dba) 3 (92 mg, 0.1 mmol) , Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (100 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to give the title compound (100 mg of HCl salt, 17%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.26 (s, 3 H), 1.27 (s, 3 H), 1.45-1.48 (m, 4 H), 2.19 (s, 3 H), 2.80 (d, J = 4.6 Hz , 3H), 3.06-3.15 (m, 4H), 3.47-3.50 (m, 2H), 3.60-3.64 (m, 2H), 3.74-3.76 (m, 2H), 6.94 (d, J = 9.0 Hz, 2H ), 7.25 (d, J = 9.0 Hz, 2H), 7.59 (t, J = 8.0 Hz, 1 H), 7.68 (d, J = 7.6 Hz, 1 H), 7.93 (br, 2H), 8.02 (br , 1 H), 9.97 (s, 1 H), 10.47 (s, 1 H), 11.07 (br s, 1 H). MS (ES +): m / z 536 (M + H) +.

EXAMPLE 185 A / -ter-Butyl-3-f5-methyl-2- (4-piperazin-1-yl-phenylamino) -pyrimidin-4-ylamino-1-benzenesulfonamide (Compound CXXVI) CXX T A mixture of intermediate 33 (355 mg, 1.0 mmol), 4- (4-aminophenyl) piperazine-1-tert-butylcarboxylate (278 mg, 1.0 mmol), Pd (dba) 3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (100 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was dissolved in CH2Cl2 (10 ml) and trifuloroacetic acid (2 ml) was added. The mixture was stirred for 4 hr at room temperature before 10% NaOH was added. The organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2 (10 ml x 2). The combined organic layers were dried (Na2SO4). The solvent was removed under vacuum. The residue was purified by HPLC to give the title compound (62 mg, 12%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.10 (s, 9H), 2.18 (s, 3H), 3.20 (br, 4H), 3.33 (br, 4H), 6.94 (d, J = 9.0 Hz, 2H ), 7.25 (d, J = 9.0 Hz, 2H), 7.57 (t, J = 8.0 Hz, 1 H), 7.63 (s, 1 H), 7.71 (d, J = 8.1 Hz, 1 H), 7.87 ( br, 1 H), 7.92 (br, 1 H), 7.96 (br, 1 H), 9.30 (br, 1 H), 9.96 (s, 1 H), 10.46 (s, 1H). MS (ES +): m / z 496 (M + H) +.

EXAMPLE 186 ^ -ter-Butyl-3- (2-4- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -phenylamino) - [5-methyl-pyrimidin-4-ylamino-benzenesulfonamide (Compound CXXVII) cxxvp The compound CXXVI described above (31 mg, 0.06 mmol) was dissolved in DMF (10 ml) followed by the addition of 2-bromoethanol (16 mg, 0.13 mmol) and diisopropyllethallylamine (33 mg, 0.25 mmol). The mixture was stirred for 48 hr at room temperature. The solvent was removed under vacuum and the residue was dissolved in EtOAc (20 ml). The solution was washed with saturated NaHCO3 and brine. The combined organic layers were dried and concentrated to 2 ml of solution followed by the addition of Et20 (20 ml). The solid was collected by centrifugation and transferred to its HCl salt (10.7 mg, 30%). 1 H NMR (500 MHz, DMSO-d 6): d 1.09 (s, 9 H), 2.17 (s, 3 H), 3.12-3.23 (m, 4 H), 3.56-3.60 (m, 2 H), 3.69-3.74 (m, 2H), 3.83 (br, 2H), 4.13 (br, 2H), 6.94 (d, J = 9.0 Hz, 2H), 7.25 (d, J = 9.0 Hz, 2H), 7.57 (t, J = 8.0 Hz, 1 HOUR), .63 (s, 1 H), 7.71 (d, J = 8.1 Hz, 1 H), 7.87 (br, 1 H), 7.93 (br, 1 H), 7.95 (br, 1H), .98 (s, 1 H), 10.53 (s, 1 H), 10.75 (br, 1 H). MS (ES +): m / z 540 (M + H) +.

EXAMPLE 187 ^ -ter-Butyl-3- [5-methyl-2- (3-piperazin-1-yl-phenylamino) -pyrimidin-4-ylamino-1-benzenesulfonamide (Compound CXXVIII) cxxvm A mixture of intermediate 33 (240 mg, 0.67 mmol), 4- (3-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (166 mg, 0.6 mmol), Pd2 (dba) 3 (55 mg, 0.06 mmol) , Xantphos (104 mg, 0.18 mmol) and cesium carbonate (782 mg, 2.4 mmol) was suspended in dioxane (100 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was dissolved in CH2Cl2 (10 ml) and trifuloroacetic acid (2 ml) was added. The mixture was stirred for 4 hr at room temperature before 10% NaOH was added. The organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2 (10 ml x 2). The combined organic layers were dried (Na2SO4). The solvent was removed under vacuum. The residue was purified by HPLC to give the title compound (18 mg, 6%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.10 (s, 9H), 2.19 (s, 3H), 3.17 (br, 4H), 3.27-3.29 (m, 4H), 6.80 (d, J = 8.1 Hz , 1 H), 6.87 (br, 1 H), 6.96 (d, J = 8.1 Hz, 1 H), 7.16 (t, J = 8.1 Hz, 1 H), 7.53 (t, J = 8.3 Hz, 1 H) , 7.61 (s, 1 H), 7.70 (d, J = 7.8 Hz, 1 H), 7.94 (br, 3H), 9.19 (br, 2H), 9.93 (s, 1H), 10.48 (s, 1 H) . MS (ES +): m / z 496 (M + H) +.

EXAMPLE 188? / - tert-Butyl-3- (2-r4- (2-hydroxy-ethyl) -piperazin-1-in-phenylamino-5-methyl-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXXIX) CXX IX The compound CXXVI described above (12 mg, 0.024 mmol) was dissolved in DMF (10 ml) followed by the addition of 2-bromoethanol (6.1 mg, 0.048 mmol) and diisopropylethylamine (12 mg, 0.092 mmol). The mixture was stirred for 48 hr at room temperature. The solvent was removed under vacuum and the residue was dissolved in EtOAc (20 ml). The solution was washed with saturated NaHCO3 and brine. The combined organic layers were dried and concentrated to 2 ml of solution followed by the addition of Et2O (20 ml). He solid was collected by centrifugation and transferred to its HCl salt (7 mg, 51%). 1 H NMR (500 MHz, DMSO-d 6): d 1.09 (s, 9H), 2.19 (s, 3H), 3.12-3.22 (m, 4H), 3.56-3.60 (m, 2H), 3.69-3.74 (m, 2H), 3.81 (br, 2H), 4.12 (br, 2H), 6.80 (br, 1 H), 6.88 (br, 1 H), 6.96 (br, 1 H), 7.16 (br, 1 H), 7.57 (br, 1 H), 7.60 (s, 1 H), 7.69 (d, J = 7.8 Hz, 1 H), 7.94 (br, 3 H), 9.94 (s, 1 H), 10.49 (s, 1 H) . MS (ES +): m / z 540 (M + H) +.

EXAMPLE 189? / 2- (4- (1H-pyrazol-1-yl) phenin-? Rl- (3-fer-butylphenyl) -5-methylpyrimidine-2,4-diamine (Compound CXXX) CXXX A mixture of intermediate 41 (580 mg, 2.1 mmol) and 4- (1H-pyrazol-1-yl) benzenamine (335 mg, 2.1 mmol) was suspended in acetic acid (10 ml) and heated at 100 ° C for 4 hr. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH ~ 7. The resulting solution was extracted with EtOAc (30 ml) and the organic layer was separated. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under vacuum and the crude product was purified by HPLC to give the title compound (31 mg, 4%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.24 (s, 9 H), 2.18 (s, 3 H), 6.53 (t, J = 2.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H ), 7.38 (t, J = 7.9 Hz, 1 H), 7.44 (s, 1 H), 7.47 (d, J = 8.2 Hz, 1 H), 7.50 (d, J = 8.9 Hz, 2H), 7.67 ( d, J = 8.9 Hz, 2H), 7.73 (s, 1 H), 7.95 (s, 1 H), 8.43 (d, J = 2.4 Hz, 1 H), 9.81 (br s, 1 H), 10.67 (s) , 1 HOUR). MS (ES +): m / z 399 (M + H) +.

EXAMPLE 190 / V - (7-Chloro-1H-indol-4-yl) -5-methyl-γ / 2-r4 - ((piperazin-1-yl) methyl) phenyl) -pyrimidine-2,4- diamine (Compound CXXXI) CXXXI A mixture of intermediate 40 (150 mg, 0.37 mmol), 4-bromo-7-chloro-1H-indole (87 mg, 0.37 mmol), Pd2 (dba) 3 (38 mg, 0.04 mmol), Xantphos (76 mg, 0.12 mmol) and cesium carbonate (521 mg, 1.6 mmol) was suspended in dioxane (50 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was dissolved in CH2Cl2 (10 ml) and trifuloroacetic acid (2 ml) was added. The mixture was stirred for 4 hr at room temperature before 10% NaOH was added. The organic layer was separated and the layer aqueous was extracted with CH2Cl2 (10 ml x 2). The combined organic layers were dried (Na2SO4). The solvent was removed under vacuum. The residue was purified by HPLC to give the title compound (26 mg, 15%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 2.21 (s, 3 H), 3.30 (br, 4 H), 3.50 (br, 4 H), 4.42 (br, 2 H), 6.91 (s, 1 H), 7.11 ( d, J = 8.3 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1 H), 7.42 (t, J = 2.7 Hz, 1 H), 7.70 (br, 4H), 8.03 (s, 1 H) , 9.87 (br, 1 H), 9.95 (s, 1 H), 10.64 (s, 1 H), 11.64 (s, 1 H). MS (ES +): m / z 448 (M + H) +.

EXAMPLE 191? / - (3-tert-Butylphenyl) -5-methyl-V2- (4- (2-methyl-1H-imidazol-1-yl) phenyl) -pyrimidine-2,4-diamine (Compound CXXXII) CXXXII A mixture of intermediate 41 (180 mg, 0.65 mmole) and 4- (2-methyl-1 H-imidazol-1-yl) benzenamine (113 mg, 0.65 mmole), Pd2 (dba) 3 (55 mg, 0.06 mmole ), Xantphos (104 mg, 0.18 mmol) and cesium carbonate (782 mg, 2.4 mmol) was suspended in dioxane (100 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to give the title compound (78 mg of HCl salt, 27%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.26 (s, 9 H), 2.21 (s, 3 H), 2.50 (s, 3H), 7.31-7.36 (m, 1 H), 7.40 (t, J = 7.8 Hz, 1 H), 7.44 (d, J = 8.9 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.9 Hz, 2H), 7.75 (d, J = 2.1 Hz, 1 H), 7.79 (d, J = 2. 1 Hz, 2H), 8.03 (s, 1H), 10.02 (s, 1H), 11.26 (s, 1H).

MS (ES +): m / z 413 (M + H) +.

EXAMPLE 192 4- (4-Methyl-1H-imidazol-1-yl) benzenamine (Intermediary 62) 62 To a solution of 1-fluoro-4-nitrobenzene (1.7 g, 12 mmol) in DMF (100 ml) was added 4-methyl-1H-imidazole (0.82 g, 10 mmol) and K2C03 (11 g, 80 mmol). The mixture was heated to reflux under argon atmosphere for hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue is Dissolve in EtOAc (100 ml) and wash with brine (100 ml x 2). The layer Organic dried and concentrated. The solid was dissolved in MeOH and made Bubble with Ar for 2 min, before adding 10% Pd-C. The hydrogenation was finished in 4 hr. The catalyst was removed by filtration and the The solvent was removed under vacuum to give the title compound (1.5 g, 87%) as a brown solid.

EXAMPLE 193 ^ - (3-Fer-Butylphenyl) -5-methyl-2- (4- (4-methyl-1H-N-idiozol-1-yl) phenyl) pyrimidine-2,4-diamine (Compound CXXXIll) CXXXIII A mixture of intermediate 41 (318 mg, 1.15 mmoles) and intermediate 62 (200 mg, 1.15 mmoles), Pd2 (dba) 3 (92 mg, 0.1 mmoles), Xantphos (180 mg, 0.3 mmoles) and cesium carbonate ( 1.3 g, 4 mmol) was suspended in dioxane (100 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to give the title compound (66 mg of HCl salt, 20%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.26 (s, 9 H), 2.19 (s, 3 H), 2.36 (s, 3H), 7.30 (d, J = 7.9 Hz, 1 H), 7.41 (d, J = 7.9 Hz, 1 H), 7.44 (t, J = 1.8 Hz, 1 H), 7.54 (d, J = 7.9 Hz, 1 H), 7.59 (d, J = 9.0 Hz, 2H), 7.68 (d, J = 9.0 Hz, 2H), 7.94 (s, 1 H), 7.99 (s, 1H), 9.53 (d , J = 1.3 Hz, 1H), 9.72 (br s, 1H), 10.81 (br s, 1 H). MS (ES +): m / z 413 (M + H) +.

EXAMPLE 194 4- [4-Aminophenyl) piperidin-1-tert-butylcarboxylate (Intermediate 63) 63 To a solution of 4- (4-nitrophenyl) piperidine (412 mg, 2 mmol) in CH 2 Cl 2 (100 mL) was added di-butyl carbonate (480 mg, 2.2 mmol) and N, N-dimethylpyridin-4. amine (50 mg, 0.4 mmol). The mixture was stirred for 20 h at room temperature. Saturated NaHCO3 (100 mL) was added to the mixture. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (50 ml x 2). The combined organic solution was dried and concentrated in vacuo. The residue was dissolved in MeOH and bubbled with Ar for 2 min, before adding 10% Pd-C. The hydrogenation was finished in 4 hr. The catalyst was removed by filtration and the solvent was removed under vacuum to give the title compound (460 mg, 83%) as a white solid.

EXAMPLE 195 ^ 4- (3-tert-butylphenyl) -5-methyl-? 2- (4- (piperidin-4-yl) phenyl) -pyrimidine-2,4-diamine (Compound CXXXIV) CXXX3V A mixture of intermediate 41 (170 mg, 0.6 mmol) and intermediate 63 (170 mg, 0.6 mmol) was suspended in acetic acid (10 ml) and heated at 100 ° C for 4 hr. The mixture was allowed to cool to room temperature and the acetic acid was removed under reduced pressure. The residue was taken up in water (20 ml) and neutralized to pH -1. The resulting solution was extracted with EtOAc (30 ml) and the organic layer was separated. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated under vacuum and the crude product was purified by HPLC to give the title compound (8 mg, 3%) as a white solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.26 (s, 9 H), 1.76-1.88 (m, 4 H), 2.17 (s, 3 H), 2.76-2.81 (m, 1 H), 2.93-3.00 (m , 2H), 3.36-3.40 (m, 2H), 7.07 (d, J = 8.5 Hz, 1 H), 7.30-7.36 (m, 4H), 7.44 (s, 1 H), 7.46 (d, J = 8.7 Hz, 1 H), 7.91 (s, 1 H), 8.84 (br s, 1 H), 8.92 (br s, 1 H), 9.73 (s, 1 H), 10.45 (s, 1 H). MS (ES +): m / z 416 (M + H) +.

EXAMPLE 196 V- (3-tert-Butylphenyl) -5-methyl- ^ 2- (4- (1-morpholinyl) phenyl) pyrimidine-2,4-diamine (Compound CXXXV) CXXXV A mixture of intermediate 41 (276 mg, 1.0 mmol) and 4- (1-morpholinyl) benzenamine (210 mg, 1.0 mmol), Pd2 (dba) 3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) ) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (100 ml) and heated to reflux under argon atmosphere for 20 hr. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by HPLC to give the title compound (17 mg of HCl salt, 4%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d 6): d 1.26 (s, 9H), 1.66 (d, J = 6.8 Hz, 3H), 2.19 (s, 3H), 2.79 (br, 2H), 2.92 (br, 1 H), 3.61-3.64 (m, 2H), 3.77-3.82 (m, 2H), 3.94-3.99 (m, 2H) ), 7.32 (d, J = 7.8 Hz, 1H), 7.42 (t, J = 1.9 Hz, 1 H), 7.43 (d, J = 7.8 Hz, 1 H), 7.46-7.52 (m, 5H), 7.97 (s, 1 H), 9.86 (s, 1 H), 10.78 (s, 1 H), 11.72 (br s, 1 H). MS (ES +): m / z 446 (M + H) +.

EXAMPLE 197 5-Bromo-2-methyl-benzenesulfonyl chloride (Intermediary 64) 64 Bromide (1.99 g, 1.61 mmol) was vigorously stirred and treated with chlorosulfonic acid (1.55 mL, 23.22 mmol). Once the addition was complete, the resulting red syrup was heated to 60 ° C. The reaction by CCD after 10 min, showed no starting material and the reaction was extinguished by emptying it on ice. The product was extracted by washing with EtOAc (2 x 150 ml). The organic phase was dried over Na2SO4, filtered and evaporated to yellow oil (2.2 g, 70%).

EXAMPLE 198 5-Bromo-2,? / - dimethyl-benzenesulfonamide (Intermediary 65) 65 A stirred suspension of intermediate 64 (0.43 g, 1.58 mmol) in DCM (5 ml) was treated with 2.0 M methylamine solution in THF (2.4 ml, 4.8 mmol). After 16 hr the reaction solvents were removed and the resulting residue was diluted with EtOAc (150 ml) and washed with water. The organic phase was dried over Na2SO4, filtered and evaporated to white solids (0.37. g, 89%).

EXAMPLE 199 2, ^ - Dimethyl-5-. { 5-methyl-2-f4- (2-pyrrolidin-1-yl-ethoxy) -phenylamino-pyrimidin-4-ylamino) -benzenesulfonamide (Compound CXXXVI) CXXXVI A mixture of intermediate 65 (0.14 g, 0.52 mmole), intermediate 38 (0.14 g, 0.43 mmole), Pd2 (dba) 3 (0.040 g, 0.043 mmole), Xantphos (0.050 g, 0.087 mmole) and cesium carbonate (0.43) g, 1.3 mmol) was suspended in dioxane (10 ml), sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 15 min. The reaction mixture was cooled to room temperature and centrifuged. The reaction was decanted and the organic phase was concentrated under vacuum. The residue was purified by HPLC to give the title compound as a white solid (0.052 g, 24%). 1 H NMR (500 MHz, DMSO-d 6): d 1.66-1.70 (m, 4 H), 2.08 (s, 3 H), 2.43 (d, J = 4.9 Hz, 3 H), 2.5 (br s, 4 H), 2.78, (t, J = 5.7 Hz), 4.00 (t, J = 5.9 Hz), 6.79 (d, J = 9.0 Hz, 2H), 7.31 (d, J = 9.7 Hz, 1 H), 7.42 (q, J = 9.8 Hz, 1 H), 7.49 (d, J = 9.0 Hz, 1 H), 7.87 (s, 1 H), 7.97 (d, J = 2.3 Hz, 1 H), 8.07-8.09 (m, 1 H) , 8.49 (s, 1 H), 8.75 (s, 1 H). MS (ES +): m / z 497 (M + H) +.

EXAMPLE 200 5-Bromo-W-tert-butyl-2-methyl-benzenesurfonamide (Intermediate 66) A stirred suspension of intermediate 64 (1.22 g, 4.5 mmol) in DCM (25 ml) was treated with tert-butylamine (1.4 ml, 13.6 mmol).

After 16 hr, the reaction solvents were removed and the resulting solids were triturated with water. The solids were dried under vacuum overnight (1.3 g, 94%).

EXAMPLE 201? / - fer-Butyl-5- (2-chloro-5-methyl-pyrimidin-4-ylamino) -2-methyl-benzenesulfonamide (Intermediate 67) 67 A mixture of intermediate 66 (0.90 g, 2.96 mmole), 2-chloro-5-methyl-pyrimidin-4-ylamine (0.33 g, 2.28 mmole), Pd2 (dba) 3 (0.21 g, 0.23 mmole), Xantphos ( 0.264 g, 0.46 mmol) and cesium carbonate (2.2 g, 6.8 mmol) was suspended in dioxane (15 ml), sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 15 min. Mix of reaction was cooled to room temperature and centrifuged. The reaction was decanted and the organic phase was concentrated under vacuum. The residue was purified on a column of silica gel to give the title compound as a white solid (0.12 g, 14%).

EXAMPLE 202 ^ -ter-Butyl-5-f2- (4-imidazol-1-yl-phenylamino) -5-methyl-pyrimidin-4-ylamino-1-2-methyl-benzenesulfonamide (Compound CXXXVII) CXXXVII A mixture of intermediate 67 (0.113 g, 0.31 mmol), 4-imidazol-1-yl-phenylamine (0.059 g, 0.37 mmol), Pd2 (dba) 3 (0.028 g, 0.03 mmol), Xantphos (0.036 g, 0.06 mmoles) and cesium carbonate (0.3 g, 0.92 mmol) was suspended in dioxane (6 ml), sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 15 min. The reaction was decanted and the organic phase was concentrated under vacuum. The residue was purified by HPLC to give the title compound as a white solid (0.052 g, 24%). 1 H NMR (500 MHz, DMSO-d 6): d 1.11 (s, 9 H), 2.13 (s, 3 H), 2.58 (s, 3 H), 7.07 (s, 1 H), 7.34 (d, J = 8.5 Hz, 1 H), 7.42 (d, J = 8.9 Hz, 2H), 7.48 (s, 1 H), 7.60 (s, 1 H), 7.78 (d, J = 8.9 Hz, 2H), 7.94 (s, 1 H) ), 7.98-8.00 (m, 1 H), 8.09 (s, 1 H), 8.12 (d, J = 2.3 Hz, 1 H), 8.56 (s, 1H), 9.16 (s, 1 H). MS (ES +): m / z 492 (M + H) +.

EXAMPLE 203 f -tert-Butyl-3- (5-methyl-2-f4- (pyrrolidin-1-carbonyl) -phenylamino-1-pyrimidin-4-ylamino) -benzenesulfonamide (Compound CXXXVIll) io cxxxvm A mixture of intermediate 33 (0.11 g, 0.32 mmole), (4-amino-phenyl) -pyrrolidin-1-yl-methanone (0.072 g, 0.38 mmole), Pd2 (dba) 3 (0.029 g, 0.032 mmole) , Xantphos (0.037 g, 0.063 mmol) and cesium carbonate (0.3 g, 0.95 mmol) was suspended in dioxane (6 ml), sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 15 minutes. min. The reaction was decanted and the organic phase was concentrated under vacuum. The residue was purified by HPLC to give the title compound as a white solid (0.040 g, 25%). 1 H NMR (500 MHz, DMSO-d 6): d 1.11 (s, 9 H), 1.8 (br s, 4 H), 2.14 20 (s, 3 H), 3.44 (t, J = 6.6 Hz, 4 H), 7.38 (d , J = 9.0 Hz, 2H), 7.52-7.54 (m, 2H), 7.56 (s, 1 H), 7.70 (d, J = 9.8 Hz, 2H), 7.98 (s, 1 H), 8.08-8.10 ( m, 2H), 8.60 (br s, 1 H), 9.24 (s, 1 H). MS (ES +): m / z 509 (M + H) +.

EXAMPLE 204 ^ -ter-Butyl-3- (5-methylene-2-f4- (morpholine-4-carbonyl) -phenylaminol-pyrimidin-4-ylamino) -benzenesulfonamide (Compound CXXXIX) A mixture of intermediate 33 (0.13 g, 0.37 mmole), (4-amino-phenyl) -morpholin-4-yl-methanone (0.092 g, 0.45 mmole), Pd2 (dba) 3 (0.034 g, 0.037 mmole), Xantphos (0.043 g, 0.075 mmol) and cesium carbonate (0.37 g, 1.1 mmol) was suspended in dioxane (6 ml), sealed in a microwave reaction tube and irradiated with microwave at 160 ° C for 15 min. The reaction was decanted and the organic phase was concentrated under vacuum. The residue was purified by HPLC to give the title compound as a white solid (0.065 g, 33%). 1 H NMR (500 MHz, DMSO-d 6): d 1.11 (s, 9H), 2.14 (s, 3H), 3.49 (br s, 4H), 3.59 (br s, 4H), 5.75 (s, 1 H), 7.25 (d, J = 9.0 Hz, 2H), 7.52-7.54 (m, 2H), 7.56 (s, 1 H), 7.71 (s, J = 9.0 Hz, 2H), 7.98 (s, 1 H), 8.06 -8.08 (m, 2H), 8.65 (br s, 1 H), 9.26 (s, 1 H). MS (ES +): m / z 525 (M + H) +.

EXAMPLE 205 W-tert-Butyl-3-45-methyl-2- [4- (piperazin-1-carbonin-phenylamino] -pyrimidin-4-ylamino) -benzenesulfonamide (Compound CXL) CXL A mixture of intermediate 33 (0.12 g, 0.33 mmol), 4- (4-amino-benzoyl) -piperazine-1-carboxylic acid tert-butyl ester (0.12 g, 0.45 mmol), Pd2 (dba) 3 (0.030) g, 0.037 mmol), Xantphos (0.038 g, 0.075 mmol) and cesium carbonate (0.33 g, 1.1 mmol) was suspended in dioxane (6 ml), sealed in a microwave reaction tube and irradiated with microwaves at 160 ° C for 15 min. The reaction was decanted and the organic phase was concentrated under vacuum. The residue was purified by silica gel chromatography (25% -100% EtOAc in hexanes). The product was then treated with 20 ml of 20% TFA solution in DCM. Then, the solvents were removed by rotary evaporation. The resulting material was purified by HPLC to give the title compound as a white solid (0.045 g, 26%). 1 H NMR (500 MHz, DMSO-d 6): d 1.11 (s, 9 H), 2.14 (s, 3 H), 2.82 (br S, 4 H), 3.48 (br S, 4 H), 7.24 (d, J = 9.0 Hz , 2H), 7.51-7.53 (m, 2H), 7.55 (s, 1 H), 7.71 (d, J = 9.0 Hz, 2H), 7.94 (s, 1 H), 8.06-8.08 (m, 2H), 8.65 (br s, 1 H), 9.25 (s, 1 H). MS (ES +): m / z 524 (M + H) +.

EXAMPLE 206 4- (4- (4- (3-methoxyphenylamino) -5-methylpyrimidin-2-ylamino) phenoxy) piperidine-1-tert-butyl carboxylate (Intermediate 68) 68 A mixture of 1-bromo-3-methoxybenzene (69.5 μl, 0.56 mmole), intermediate 42 (205 mg, 0.51 mmole), Pd2 (dba) 3 (23 mg, 0.03 mmole), Xantphos (33 mg, 0.06 mmoles) and cesium carbonate (359 mg, 1.10 mmol) in dioxane (3 ml) was irradiated in the microwave at 160 ° C for 20 min. The reaction mixture was cooled to room temperature, filtered and the filtrate was rinsed with DCM and MeOH. The combined liquids were concentrated under vacuum, and purified using flash gradient chromatography (0-100% ethyl acetate in hexanes) to give the title compound as a beige solid (215 mg, 83%).

EXAMPLE 207 3- (2- (4- (Piperidin-4-yloxy) phenylamino) -5-methylpyrimidin-4-ylamino) phenol (Compound CXLI) CXLI To a mixture of intermediate 68 (215 mg, 0.42 mmol) in DCM (4 mL) was added BBr3 (120 μL, 1.27 mmol) and stirred at room temperature for 64 hr. The reaction was quenched with MeOH and concentrated in vacuo. The residue was purified by preparative HPLC and the fractions were concentrated under vacuum to give the TFA salt of the title compound (116 mg, 56%). The TFA salt was taken up in MeOH and passed through SPE PL-HCO3 MP-Resin cartridges, concentrated in vacuo, triturated with ether, and filtered to provide the title compound as a white solid (31 mg , 69% recovery). 1 H NMR (500 MHz, DMSO-d 6): d 1.51-1.60 (m, 2H), 1.90-1.98 (m, 2H), 2.07 (s, 3H), 2.70-2.78 (m, 2H), 3.02-3.09 (m, 2H), 4.28-4.36 (m, 1 H), 6.48 (dd, J = 8.1, 2.2 Hz, 1 H), 6.79 (d, J = 9.1 Hz, 2H), 7.06-7.11 (m, 2H), 7.16 (d, J = 8.5 Hz, 1 H), 7.57 (d, J = 9.1 Hz, 2 H), 7.82 (s, 1 H), 8.08 (s, 1 H), 8.73 (s, 1 H), 9.27 (br s, 1 H). MS (ES +): m / z 392 (M + H) +.

EXAMPLE 208 (2-Chloro-5-methyl-pyrimidin-4-yl) - (4-fluoro-3-methoxy-phenyl) -amine (Intermediate 69) 69 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.2 g, 8.1 mmol), 4-bromo-1-fluoro-2-methoxy-benzene (1.8 g, 8.9 mmol), Pd2 (dba) 3 (0.74 g, 0.81 mmol), Xantphos (0.93 g, 1.6 mmol) and cesium carbonate (7.88 g, 24.2 mmol) was suspended in dioxane (60 ml) and heated to reflux under argon atmosphere for 5 hr. The reaction mixture was cooled to room temperature and diluted with DCM (30 ml). The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give the title compound (0.3 g, 14%) as a beige solid.

EXAMPLE 209 ^ - (4-Fluoro-3-methoxy-phenyl) -5-methyl-? / 2- f4- (2-pyrrolidin-1-yl-ethoxy) -pheno-pyrimidine-2,4-diamine ( Compound CXLII) CXLII A mixture of intermediate 69 (0.1 g, 0.37 mmol) and 4- (2-pyrrolidin-1-yl-ethoxy) -phenylamine (0.16 g, 0.75 mmol) was suspended in acetic acid (10 ml) and heated to 110 °. C for 16 hr. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by HPLC to give the title compound (0.03 g, 17%) as green solids. 1 H NMR (500 MHz, DMSO-d 6): d 1.88 (br s, 2 H), 2.0 (br s, 2 H), 2. 15 (s, 3H), 3.08 (br s, 2H), 3.55 (br s, 4H), 3.7 (s, 3H), 4.32 (br s, 2H), 6.9 (d, J = 7.9 Hz, 2H), 7.13 (br s, 1 H), 7.21-7.25 (m, 1 H), 7.32-7.34 (m, 3H), 7.89 (s, 1 H), 9.78 (br s, 1 H), 10.48 (br s, 1 H), 10.92 (br s, 1 H). MS (ES +): m / z 438 (M + H) +.

EXAMPLE 210 (2-Chloro-pyrimidin-4-yl) - (3-methoxy-2-methyl-phenyl) -amine (Intermediate 70) 70 A mixture of 3-methoxy-2-methyl-phenylamine (0.68 g, 5 mmol) and 2,4-dichloro-pyrimidine (0.74 g, 5 mmol) was suspended in ethyl alcohol (10 ml) and stirred at room temperature for 20 hr. The reaction mixture was diluted with DCM (50 ml), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (0.085 g, 7%) as yellow solids.

EXAMPLE 211 ^ -Q-Methoxy-S-methyl-phenyD-^^ -t? -pyrrolidin-l-yl-ethoxD-phenyl-pyrimidine-S-diamine (Compound CXLIII) CXLlll A mixture of intermediate 70 (0.08 g, 0.32 mmol) and 4- (2- pyrrolidin-1-yl-ethoxy) -phenylamin (0.13 g, 0.64 mmol) was suspended in acetic acid (10 ml) and heated at 80 ° C for 16 hr. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by HPLC to give the title compound (0.03 g, 17%) as gray-colored solids. 1 H NMR (500 MHz, DMSO-d 6): d 1.89 (br s, 2 H), 2.0 (br s, 4 H), 3.08 (br s, 2 H), 3.4 (br s, 4 H), 3.54 (br s, 4 H ), 3.83 (s, 3H), 4.31 (br s, 2H), 6.86 (br s, 2H), 6.97 (d, J = 8.1 Hz, 2H), 7.26 (t, J = 8.1 Hz 1 H), 7.34 (br s, 2H), 7.89 (s, 1 H), 9.73 (br s, 1 H), 10.62 (br s, 2H), 11.01 (br s, 1 H). MS (ES +): m / z 420 (M + H) +.

EXAMPLE 212 4- (4-Acetylamino-benzenesulfonyl) -piperidine-1-carboxylic acid tert-butyl ester (Intermediate 71) 71 A mixture of 4- (4-bromo-benzenesulfonyl) -piperidin-1-carboxylic acid tert-butyl ester (4 g, 9.92 mmol), acetamide (0.88 g, 14. 9 mmole), Pd2 (dba) 3 (0.46 g, 0.49 mmole), Xantphos (0.56 g, 0.99 mmole) and cesium carbonate (9.7 g, 29.8 mmole) was suspended in dioxane. (60 ml) and heated to reflux under argon atmosphere for 4 hr. Mix The reaction mixture was cooled to room temperature and emptied on ice. The resulting yellow solids were collected by filtration and dried. The crude product was purified by flash chromatography on silica gel to give the title compound as a beige solid (3.12 g, 82%).

EXAMPLE 213 4- (4-Amino-benzenesulfonyl) -piperidine-1-carboxylic acid tert-butyl ester (Intermediate 72) 72 A suspension of intermediate 71 (2.6 g, 6.7 mmol) was diluted with 60 ml of Claisen's alkali (88 g of KOH dissolved in 63 ml of H 2 O diluted to 250 ml with MeOH) and heated to 90 ° C. After 2 hr, the reaction was removed from heating, cooled to room temperature and diluted with water (50 ml). Gray colored solids were collected by suction filtration, washed with water and dried overnight (2.2 g, 97%).

EXAMPLE 214 ^ 4- (4-Chloro-3-methoxy-phenyl) -5-methyl-2-f4- (piperidin-4-sulfonyl) -fenin-pyrimidine-2,4-diamine (Compound CXLIV) CXLGV A mixture of intermediate 31 (0.14 g, 0.51 mmole), intermediate 72 (0.19 g, 0.56 mmole), Pd2 (dba) 3 (0.046 g, 0.051 mmole), Xantphos (0.59 g, 0.1 mmol) and cesium carbonate (0.5 g, 1.52 mmol) was suspended in dioxane (8 ml) and microwaved at 160 ° C for 15 min. The reaction mixture was cooled to room temperature and centrifuged.

The solvents were then decanted and evaporated. The resulting residue was purified by flash chromatography on silica gel to give the protected? / - precursor of the title compound. These solids were treated with % TFA in DCM solution and evaporated immediately. The residue was dissolved in a minimum amount of EtOAc and added dropwise to a large excess of diethyl ether. The resulting light yellow powder was collected by filtration and dried (0.16 g, 55%). 1 H NMR (500 MHz, DMSO-d 6): d 1.61-1.69 (m, 2H), 1.98-2.01 (m, 2H), 2.16 (s, 3H), 2.86 (q, J = 12 Hz, 2H), 3.35 (d, J = 12.6 Hz, 2H), 3.64 (tt, J = 11.7 Hz, J = 3.8 Hz, 1 H), 3.79 (s, 3H), 7.34 (dd, J = 8.7 Hz, J = 2.0 Hz, 1 HOUR), .39-7.41 (m, 2H), 7.6 (d, J = 8.9 Hz, 2H), 7.91 (d, J = 8.9 Hz, 2H), 8.02 (s, 1H), .19-8.21 (m, 1 H) ), 8.6-8.63 (m, 1 H), 8.89 (br s, 1 H). MS (ES +): m / z 488 (M + H) +.

EXAMPLE 215 (4-Chloro-3-methyl-phenyl) - (2-chloro-5-methyl-pyrimidin-4-yl) -amine (Intermediary 73) 73 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.34 g, 2.34 mmole), 4-bromo-1-chloro-2-methyl-benzene (0.58 g, 2.8 mmole), Pd2 (dba) 3 (0.21 g, 0.23 mmole), Xantphos (0.47 g, 0.47 mmole) and cesium carbonate (2.3 g, 7 mmole) was suspended in dioxane (9 ml), microwaved at 160 ° C for 20 min. The reaction mixture was cooled to room temperature and centrifuged. The solvents were then decanted and evaporated. The resulting residue was purified by flash chromatography on silica gel to give the title compound as yellow solids (0.24 g, 38%).

EXAMPLE 216 ^ > - (4-Chloro-3-methyl-phenyl) -5-methyl- ^ 2- [4- (piperidin-4-yloxy) -fenin-pyrimidine-2,4-diamine (Compound CXLV) CXLV A mixture of intermediate 73 (0.071 g, 0.27 mmol) and 4- (4-amino-phenoxy) -piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.35 mmol) was diluted with HOAc (5 mL) and it was microwaved at 150 ° C for 15 min. Then, the solvents were removed and the resulting residue was purified by HPLC. The title compound was isolated as white solids (0.025 g, 22%). H NMR (500 MHz, DMSO-d6): d 1.76-1.83 (m, 2H), 2.05-2.09 (m, 2H), 2.13 (s, 3H), 2.27 (s, 3H), 3.10 (br s, 2H), 3.16 (br s, 2H), 4.58-4.61 (m, 1 H), 6.93 (d, J = 9 Hz, 2H), 7.34-7.39 (m, 3H), 7.43-7.45 (m, 1 H), 7.59 (s, 1 H), 7.87 (s, 1 H), 8.51 (br s, 1 H ), 8.55 (br s, 1 H), 9.38 (br s, 1 H), 10.0 (br s, 1 H). MS (ES +): m / z 424 (M + H) +.

EXAMPLE 217 W- (3-Bromo-phenyl) -acetamide (Intermediary 74) 74 A solution of 3-bromo-phenylamine (1.04 g, 6 mmol) was treated with DIEA (2.3 ml, 13.3 mmol) and cooled to zero degrees. Acetyl chloride (0.47 ml, 6.7 mmol) was added dropwise by syringe. The reaction was allowed to return to room temperature and stirred for 1 hour. The reaction was then poured into water and washed once. The organic phase was evaporated to beige solids (1.25 g, 98%).

EXAMPLE 218? / - r3- (2-Chloro-5-methyl-pyrimidin-4-ylamino) -phenyl-acetamide (Intermediate 75) 75 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.71 g, 4.9 nimol), intermediate 74 (1.25 g, 5.9 mmol), Pd2 (dba) 3 (0.45 g, 0.49 mmol), Xantphos ( 0.57 g, 0.98 mmol) and cesium carbonate (4.8 g, 14.7 mmol) was suspended in dioxane (40 mL), refluxed for 18 h. The The reaction mixture was then cooled to room temperature, filtered and the solvents evaporated. The resulting residue was purified by flash chromatography on silica gel to give the title compound as white solids (0.44, 32%).

EXAMPLE 219 ^ - (3-. {5-Methyl-2-r4- (piperidin-4-yloxy) -phenylamino-1-pyrimidin-4-ylamino) -phenyl) -acetamide (Compound CXLVI) CXL VI A mixture of intermediate 75 (0.074 g, 0.27 mmol) and 4- (4-amino-phenoxy) -piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.35 mmol) was diluted with HOAc (5 ml ) and subjected to microwave at 150 ° C for 15 min. The solvents were then removed and the resulting residue was purified by HPLC. The title compound was isolated as white solids (0.072 g, 62%). 1 H NMR (500 MHz, DMSO-d 6): d 1.74-1.81 (m, 2H), 2.03-2.07 (m, 5H), 2.15 (s, 3H), 3.09 (br s, 2H), 3.24 (br s, 2H), 4.54-4.57 (m, 1 H), 6.85 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 7.7 Hz, 2H), 7.29-7.39 (m, 4H), 7.77 (s, 1 H), 7.87 (s, 1 H), 8.55 (br s, 1 H), 8.60 (br s, 1 H), 9.67 (s, 1 H), 10.0 (br s, 1 H), 10.2 (br s, 1 H).

MS (ES +): m / z 433 (M + H) +.

EXAMPLE 220 M- (3-Bromo-2-methyl-phenyl) -acetamide (Intermediate 76) 76 A solution of 3-bromo-2-methyl-phenylamine (4.1 g, 21.9 mmol) was treated with DIEA (8.4 mL, 48 mmol) and cooled to zero degrees. Acetyl chloride (1.7 ml, 24.1 mmol) was added dropwise by syringe. The reaction was allowed to return to room temperature and stirred for 1 hour. The reaction was then poured into water and washed once. The organic phase was evaporated to off-white solids. Trituration with hexanes gave the title compound as white solids (4.4 g, 89%).

EXAMPLE 221 ^ -F3- (2-Chloro-5-methyl-pyrimidin-4-ylamino) -2-methyl-phenyl-acetamide (Intermediate 77) 77 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.86 g, 5.9 mmoles), intermediate 76 (1.6 g, 7.1 mmol), Pd2 (dba) 3 (0.55 g, 0.59 mmol), Xantphos (0.69 g, 1.2 mmol) and cesium carbonate (5.8 g, 17.8 mmol) were suspended in dioxane ( 40 ml), was refluxed for 16 hr. The reaction mixture was then cooled to room temperature, filtered and the solvents evaporated. The resulting residue was purified by flash chromatography on silica gel to give the title compound as white solids (0.56 g, 32%).

EXAMPLE 222 ^ - (2-Methyl-3. {5-methyl-2-f4- (piperidin-4-yloxy) -phenylamino-pyrimidin-4-ylamino) -phenyl) -acetamide (Compound CXLVII) CXL VII A mixture of intermediate 77 (0.15 g, 0.5 mmol) and 4- (4-amino-phenoxy) -piperidine-1-carboxylic acid tert-butyl ester (0.19 g, 0.65 mmol) was diluted with HOAc (5 ml ) and subjected to microwave at 150 ° C for 15 min. The solvents were then removed and the resulting residue was purified by HPLC. The title compound was isolated as white solids (0.091 g, 41%). 1 H NMR (500 MHz, DMSO-d 6): d 1.71-1.78 (m, 2H), 2.02-2.08 (m, 8H), 2.16 (s, 3H), 3.09 (br s, 2H), 3.24 (br s, 2H), 4.50-4.52 (m, 1 H), 6.77 (d, J = 8.4 Hz, 2H), 7.09-7.15 (m, 3H), 7.27 (t, J = 7.9 Hz, 1 H), 7.49 (d, J = 8.1 Hz, 1H), 7.86 (s, 1 H), 8.54 (br s, 1 H), 8.59 (br s, 1 H), 9.45 (s, 1 H), 9.84 (br s, 1 H), 10.34 (br s, 1 H). MS (ES +): m / z 447 (M + H) +.

EXAMPLE 223 S-Methyl - ^ - ^^ - methyl-piperazin-l-iD-phenyl-^ -Q-nitro-phenyl-pyrimidine-S-diamine (Intermediary 78) 78 A mixture of 1-bromo-3-nitro-benzene (0.77 g, 3.8 mmole), intermediate 32 (0.95 g, 3.2 mmole), Pd2 (dba) 3 (0.29 g, 0.32 mmole), Xantphos (0.37 g, 0.64 mmoles) and cesium carbonate (3.1 g, 9.6 mmol) was suspended in dioxane (40 ml) and refluxed for 16 hr. The reaction mixture was then cooled to room temperature, filtered and the solvents evaporated. The resulting residue was purified by flash chromatography on silica gel to give the title compound as white solids (0.53 g, 40%).

EXAMPLE 224? F - (3-Amino-phenyl) -5-methyl- ^ 2-f4- (4-methyl-piperazin-1-yl) -phenyl] -pyrimidine-2,4-diamine (Intermediate 79) Suspension of intermediate 78 (0.23 g, 0.54 mmol) in MeOH (25 ml) was purged with argon and treated with 10% by weight of Pd / C. (0.18 g). The reaction atmosphere was replaced with hydrogen and stirred for 4 h. The hydrogen balloon was then removed and argon was passed through the reaction before filtering through Celite. The solvents were then evaporated to pale brown solids (0.17 g, 83%).

EXAMPLE 225 1- (3. {5-Methyl-2- [4- (4-methyl-piperazin-1-yl) -phenylamino-1-pyrimidin-4-ylamino) -phenyl) -3-phenyl -urea (Compound CXLVIII) CX VUT A suspension of intermediate 79 (0.17 g, 0.45 mmol) in DCM (10 ml) was treated with phenyl isocyanate (0.058 ml, 0.54 mmol) and stirred for 1 hour, then, the reaction solvents were removed and the resulting residue was purified by HPLC to provide the title compound as white solids. (0.075 g, 33%). 1 H NMR (500 MHz, DMSO-d 6): d 2.09 (s, 3H), 2.15 (s, 3H), 2.30-2.32 (m, 4H), 2.92-2.94 (m, 4H), 6.74 (d, J = 8.4 Hz, 2H), 6.94-6.97 (m, 1 H), 7.19-7.28 (m, 5H), 7.45 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 9.0 Hz, 2H), 7.73 (br s, 1 H), 7.83 (s, 1 H), 8.23 (s, 1 H), 8.68 (s, 1 H), 8.74 (s, 1 H), 8.78 (s, 1 H). MS (ES +): m / z 509 (M + H) +.

EXAMPLE 226 1- (3-5-Methyl-2-f4- (4-methyl-piperazin-1-yl) -phenylamino-1-pyrimidin-4-ylamino > -phenyl) -3- (3-trifluoromethyl-phenyl) - urea (Compound CXLIX) CXLIX A suspension of intermediate 79 (0.1 g, 0.26 mmol) in DCM (8 ml) was treated with 1-isocyanato-3-trifluoromethyl-benzene (0.043 ml, 0.31 mmol) and stirred for 1 hour. The reaction solvents were then removed and the resulting residue was purified by HPLC to provide the title compound as white solids (0.039 g, 26%). H NMR (500 MHz, DMSO-d 6): d 2.16 (s, 3 H), 2.82 (s, 3 H), 2.86. (br s, 2H), 3.08 (br s, 2H), 3.42 (br s, 2H), 3.69 (br s, 2H), 6.88 (br, J = 8.4 Hz, 2H), 7.20 (br s, 1 H ), 7.29-7.33 (m, 5H), 7.52 (t, J = 7.9 Hz, 1 H), 7.57 (d, J = 8.5 Hz, 1 H), 7.77 (s, 1 H), 7.84 (s, 1 H), 8.09 (s, 1H), 9.42 (s, 1 H), 9.66 (s, 1 H), 9.71 (br s, 1 H), 10.1 (br s, 1 H). MS (ES +): m / z 577 (M + H) +.

EXAMPLE 227 (2-Chloro-5-methyl-pyrimidin-4-yl) - (2-methyl-3-trifluoromethyl-phenyl) -amine (Intermediary 80) 80 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.18 g, 5.9 mmol), 1-bromo-2-methyl-3-trifluoromethyl-benzene (0.33 g, 1.4 mmol), Pd2 (dba) 3 (0.12 g, 0.13 mmol), Xantphos (0.15 g, 0.25 mmol) and cesium carbonate (1.23 g, 3.8 mmol) was suspended in dioxane (8 ml), microwaved at 160 ° C for 18 min. The reaction vessel was then centrifuged and decanted. The solvents were then evaporated and the resulting residue was purified by flash chromatography on silica gel to give the title compound as white solids (0.095 g, 25%).

EXAMPLE 228 5-Methyl- ^ 4- (2-methyl-3-trifluoromethyl-phenyl) - ^ 2- [4- (piperidin-4-yloxy) -pheno-pyrimidine-2,4-diamine (Compound CL) CL A mixture of intermediate 80 (0.058 g, 0.2 mmol) and 4- (4-amino-phenoxy) -piperidin-1-carboxylic acid te? -butyl ester (0.073 g, 0.25 mmol) was diluted with HOAc (5 ml ) and subjected to microwave at 150 ° C for 15 min. The solvents were then removed and the resulting residue was purified by HPLC. The title compound was isolated as white solids (0.025 g, 30%). 1 H NMR (500 MHz, DMSO-d 6): d 1.71-1.78 (m, 2H), 2.00-2.04 (m, 2H), 2.18 (s, 3H), 2.25 (s, 3H), 3.08 (br s, 2H ), 3.22 (br s, 2H), 4.50-4.52 (m, 1 H), 6.70 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 8.9 Hz, 2H), 7.54 (t, J = 7.8, 1 H), 7. 62 (d, J = 7.7 Hz, 1 H), 7.75 (d, J = 7.8 Hz, 1 H), 7.91 (s, 1 H), 8.54 (br s, 1 H), 8. 61 (br s, 1 H), 9.88 (s, 1 H), 10.34 (br s, 1 H). MS (ES +): m / z 458 (M + H) +.

EXAMPLE 229 (3-Bromo-phenyl) -pyrrol? Din-1-yl-methanone (Intermediate 81) A solution of 3-bromo-benzoyl chloride (2.7 g, 12 mmol) in DCM (40 ml) was cooled to zero degrees and treated with pyrrolidine (3 ml, 36.8 mmol). The reaction was allowed to come to room temperature and was stirred for 4 hr. The mixture was then poured into water and washed once. The organic phase was then washed with brine, dried over sodium sulfate, filtered and evaporated to amber oil (3.1 g, 100%).

EXAMPLE 230 r3- (2-Chloro-5-methyl-pyrimidin-4-ylamino) -fenin-pyrrolidin-1-yl-methanone (Intermediate 82) 82 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.22 g, 1.5 mmol), intermediate 81 (0.46 g, 1.8 mmol), Pd2 (dba) 3 (0.14 g, 0.15 mmol), Xantphos ( 0.17 g, 0.3 mmol) and cesium carbonate (1.5 g, 4.5 mmol) was suspended in dioxane (8 ml), microwaved at 160 ° C. for 18 min. The reaction vessel was then centrifuged and decanted. The solvents were then evaporated and the resulting residue was purified by flash chromatography on silica gel to give the title compound as white solids (0.25 g, 53%).

EXAMPLE 231 (3-. {5-Methyl-2-r4- (piperidin-4-yloxy) -phenylamino-1-pyrimidin-4-ylamino) -phenyl) -pyrrolidin-1-yl-methanone (Compound CLl) CLl A mixture of intermediate 82 (0.1 g, 0.32 mmol) and 4- (4-amino-phenoxy) -piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.41 mmol) was diluted with HOAc (6 mL). ml) and subjected to microwave at 150 ° C for 15 min. The solvents were then removed and the resulting residue was purified by HPLC. The title compound was isolated as white solids (0.005 g, 3%). 1 H NMR (500 MHz, DMSO-d 6): d 1.74-1.81 (m, 4H), 1.83-1.88 (m, 2H), 2.05-2.09 (m, 2H), 2.16 (s, 3H), 2.25 (s, 3H), 3.25 (br s, 2H), 3.34 (t, J = 6.5 Hz, 2H), 3.46 (t, J = 6.9 Hz, 2H), 4.45-4.59 (m, 1H), 6.91 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.9 Hz, 2H), 7.36 (d, J = 7.7 Hz, 1 H), 7.43 (t, J = 7.8, 1 H), 7.67 (d, J = 7.9 Hz, 1 H), 7.70 (s, 1 H), 7.89 (s, 1 H), 8.50 (br s, 1 H), 8.56 (br s, 1 H), 9. 64 (br s, 1 H), 10.21 (br s, 1 H). MS (ES +): m / z 473 (M + H) +.

EXAMPLE 232 3-Bromo-M-isopropyl-benzamide (Intermediary 83) A solution of 3-bromo-benzoyl chloride (0.83 g, 3.8 mmol) in DCM (40 ml) was cooled to zero degrees and treated with isopropylamine (0.96 ml, 11.32 mmol). The reaction was allowed to come to room temperature and was stirred for 24 hr. Then, the mixture was poured into water and washed once. The organic phase was then washed with brine, dried over sodium sulfate, filtered and evaporated to white solids (0.6 g, 66%).

EXAMPLE 233? / - lsopropyl-3-. { 5-methyl-2-f4- (4-methyl-piperazin-1-yl) -phenylamino-1-pyrimidin-4-ylamino) -benzamide (Compound CLII) CLII A mixture of intermediate 32 (0.1 g, 0.34 mmol), intermediate 83 (0.13 g, 0.54 mmole), Pd2 (dba) 3 (0.031 g, 0.034 mmole), Xantphos (0.039 g, 0.067 mmole) and cesium carbonate (0.33 g, 1 mmole) was suspended in dioxane (8 ml) , it was microwaved at 160 ° C for 15 min. The reaction vessel was then centrifuged and decanted. The solvents were then evaporated and the resulting residue was purified by HPLC to give the title compound as white solids (0.011 g, 7%). 1 H NMR (500 MHz, DMSO-d 6): d 1.14 (d, J = 6.7 Hz, 6H), 2.16 (s, 4H), 2.87 (s, 4H), 3.10 (br s, 2H), 3.51 (s, 2H), 4.22 (m, 1 H), 6.85 (d, = 8.8 Hz, 2H), 7.30-7.32 (m, 2H), 7.45 (t, J = 7.8 Hz, 1 H), 7.69-7.70 (m, 2H), 7.90 (s, 1 H), 7.99 (s, 1 H ), 8.24 (d, J = 7.7 Hz, 1H), 9.70 (br s, 1 H), 9.94 (br s, 1 H), 10.2 (br s, 1H). MS (ES +): m / z 460 (M + H) +.

EXAMPLE 234 3-Bromo- / V-tert-butyl-benzamide (Intermediary 84) 84 A solution of 3-bromo-benzoyl chloride (0.83 g, 3.8 mmol) in DCM (10 ml) was cooled to zero degrees and treated with tert-butylamine (1.2 ml, 11.3 mmol). The reaction was allowed to come to room temperature and was stirred for 4 hr. The mixture was then poured into water and washed once. The organic phase was then washed with brine, dried over Sodium sulfate, filtered and evaporated to amber oil (0.9 g, 94%).

EXAMPLE 235 ^ -ter-Butyl-3- 5-methyl-2-f4- (4-methyl-piperazin-1-yl) -phenylamino-pyrimidin-4-ylamino) -benzamide (Compound CLIII) CLUI A mixture of intermediate 32 (0.1 g, 0.34 mmol), intermediate 84 (0.1 g, 0.4 mmol), Pd2 (dba) 3 (0.031 g, 0.034 mmol), Xantphos (0.039 g, 0.067 mmol) and cesium carbonate ( 0.33 g, 1 mmol) was suspended in dioxane (8 ml), microwaved at 160 ° C for 15 min. The reaction vessel was then centrifuged and decanted. The solvents were then evaporated and the resulting residue was purified by HPLC to give the title compound as white solids (0.055 g, 35%). 1 H NMR (500 MHz, DMSO-d 6): d 1.36 (s, 9 H), 2.09 (s, 3 H), 2.21 (s, 3 H), 2.43 (t, J = 2.8 Hz, 4 H), 3.00 (t, J = 2.8 Hz, 4H), 6.74 (d, J = 9.1 Hz, 2H), 7.35 (t, J- 7.9 Hz, 1 H), 7.44-7.48 (m, 3H), 7.67 (s, 1 H), 7.85 (s, 1 H), 7.88-7.92 (m, 2H), 8.36 (s, 1 H), 8.74 (s, 1 H). MS (ES +): m / z 47 '4 (M + H) +.

EXAMPLE 236 5-Methyl- / V2-f4- (4-methyl-piperazin-1-yl) -phenn-4- (3-piperidin-4-yl-phenyl) -pyrimidine-S-diamine ( CLIV compound) CLIV A mixture of intermediate 32 (0.08 g, 0.27 mmole), 4- (3-bromo-phenyl) -piperidine (0.084 g, 0.35 mmole), Pd2 (dba) 3 (0.025 g, 0.027 mmole), Xantphos (0.031 g) , 0.054 mmole) and cesium carbonate (0.26 g, 0.81 mmole) was suspended in dioxane (8 ml), subjected to mcroondas at 160 ° C for 15 min. The reaction vessel was then centrifuged and decanted. The solvents were then evaporated and the resulting residue was purified by HPLC to give the title compound as white solids (0.007 g, 6%). 1 H NMR (500 MHz, DMSO-d 6): d 1.74-1.79 (m, 3H), 2.09 (s, 3H), 2.21 (s, 3H), 2.43 (t, J = 2.8 Hz, 4H), 3.00 (t , J = 2.8 Hz, 4H), 6.76 (d, J = 9.1 Hz, 2H), 6.90 (d, J = 7.7 Hz, 1H), 7.24 (t, J = 1.9 Hz, 1H), 7.47-7.53 (m , 3H), 7.68 (d, J = 8.2 Hz, 1 H), 7.82 (s, 1 H), 8.18 (s, 1H), 8.67 (s, 1H). MS (ES +): m / z 458 (M + H) +.

EXAMPLE 237 4- (3. {5-Methyl-2- [4- (4-methyl-piperazin-1-yl) -phenylamino-1-pyrimidin-4-ylamino) -benzenesulfonyl) -piperidin-1-benzyl ester -carboxylic (Intermediary 85) 85 A mixture of intermediate 32 (0.17 g, 0.58 mmole), 4- (3-bromo-benzenesulfonyl) -piperidine-1-carboxylic acid benzyl ester (0.28 g, 0.64 mmole), Pda (dba) 3 (0.053 g, 0.058 mmoles), Xantphos (0.067 g, 0.12 mmol) and cesium carbonate (0.57 g, 1.74 mmol) was suspended in dioxane (8 ml), microwaved at 160 ° C for 15 min. The reaction vessel was then centrifuged and decanted on ice. Yellow solids were collected, dried and used without further purification (0.4 g, 100%).

EXAMPLE 238 S-Methyl-^ - ^ -methyl-piperazin-l-iD-phenyl-^-rS-tpiperidin ^ -sulfonyl) -phenyl] -pyrimidine-2,4-diamine (CLV Compound) CLV A stirred solution of intermediate 85 (0.17 g, 0.26 mmol) in DCM (15 ml) was treated with 1 M BBr 3 in DCM (2 ml, 2 mmol). After 4 hr, the reaction was quenched by slow addition of MeOH (4 ml) followed by solvent removal. The residue was purified by HPLC to provide the title compound as a purple powder (0.008 g, 6%). 1 H NMR (500 MHz, DMSO-d 6): d 1.31-1.40 (m, 2H), 1.75 (d, J = . 8 Hz, 2H), 2.12 (s, 3H), 2.21 (s, 3H), 2.36-2.41 (m, 2H), 2.44 (t, J = 4.9 Hz, 4H), 2.95 (d, J = 12.5 Hz, 2H), 3.02 (t, J = 4.9 Hz, 4H), 3.24 (tt, = 11.7 Hz, J = 3. 8 Hz, 1 H), 6.81 (d, J = 9.0 Hz, 2H), 7.44 (m, 3H), 7.56 (t, J = 8.0 Hz, 1 H), 7. 90-7.91 (m, 2H), 8.49 (d, J = 7.6 Hz, 1 H), 8.60 (s, 1 H), 8.74 (s, 1 H). MS (ES +): m / z 522 (M + H) +.

EXAMPLE 239 4- (4- (4- (1H-indol-4-ylamino) -5-methylpyrimidin-2-ylamino) phenoxy) piperidin-1-tert-butyl carboxylate (Intermediate 86) 86 A mixture of 4-bromo-1 H-indole (41 μl, 0.33 mmole), intermediate 42 (131 mg, 0.33 mmole), Pd2 (dba) 3 (30 mg, 0.03 mmole), Xantphos (60 mg, 0.10 mmole) ) and cesium carbonate (428 mg, 1.31 mmol) in dioxane (3 ml) was irradiated in the microwave at 160 ° C for 20 min. The reaction mixture was cooled to room temperature and filtered by rinsing with DCM. The filtrate was concentrated and purified by flash gradient chromatography (0-15% MeOH in DCM) to give the title compound as a white solid (30 mg, 17%).

EXAMPLE 240 t- (1H-indol-4-yl) -5-methy1- V2- (4- (piperidin-4-yloxy) phenyl) pyrimidine-2,4-diamine (Compound CLVI) CLV1 A mixture of intermediate 86 (27 mg, 0.05 mmol) in 30% TFA / DCM (1 ml) was stirred for 3 hr. The reaction mixture was concentrated under vacuum and purified by preparative HPLC. The resulting fractions were concentrated under vacuum to obtain the TFA salt of the title compound as a tan solid (11 mg, 43%). H NMR (500 MHz, DMSO-d6): d 1.71-1.77 (m, 2H), 1.98-2.06 (m, 2H), 2.22 (s, 3H), 3.03-3.12 (m, 2H), 3.19-3.27 ( m, 2H), 4.44-4.53 (m, 1 H), 6. 34-6.37 (m, 1 H), 6.64 (br d, J = 8.3 Hz, 2H), 7.08 (t, J = 7.2 Hz, 3H), 7.14 (t, J = 7.8 Hz, 1 H), 7.36 (t, J = 2.7 Hz, 1 H), 7.39 (d, J = 8.1 Hz, 1 H), 7.84 (s, 1 H), 8. 48 (br s, 1 H), 8.55 (br s, 1 H), 9.85 (br s, 1 H), 9.98 (br s, 1 H), 11.27 (s, 1 H).

EXAMPLE 241 2-Chloro-^ - (2-f4- (2-pyrrolidin-1-yl-ethoxy) -phenylamino-pyrimidin-5-yl) -5- (3-trifluoromethyl-benzoylamino) -benzamide (Compound CLVII) C VI1 A mixture of 3-bromopyridine (379 mg, 2.4 mmol), 4-amino-2-chloro-5-methylpyrimidine (287 mg, 2.0 mmol), Pd2 (dba) 3 (18 mg, 0.02 mmol), xantphos ( 23 mg, 0.04 mmol) and cesium carbonate (975 mg, 3.0 mmol) in dioxane (15 ml) was heated under reflux for 1 hr under argon. The solvent was removed and the residue purified by HPLC gave an intermediate, 2-chloro-5-methyl-? / - (pyridin-3-yl) pyrimidin-4-amine as a yellow solid (252 mg, 57%) . Then, a mixture of 2-chloro-5-methyl-? / - (pyridin-3-yl) pyrimidin-4-amine (80 mg, 0.36 mmol), 4- (2- (pyrrolidin-1-yl) ethoxy) Benzenamine (74 mg, 0.34 mmol), Pd2 (dba) 3 (3.2 mg, 0.003 mmol), xantphos (4.2 mg, 0.007 mmol) and cesium carbonate (234 mg, 0.72 mmol) in dioxane (5 mL) were heated under reflux for 1 hr under argon. The crude reaction mixture upon purification using HPLC gave the title compound as a light brown solid (28 mg, 20%). 1 H NMR (500 MHz, DMSO-d 6): d 1.85-1.95 (m, 2H), 2.0-2.09 (m, 2H), 2.18 (s, 3H), 3.09-3.18 (m, 2H), 3.55-3.65 ( m, 4H), 4.27 (dd, J = 5.2, 4.7 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 7.35 (d, J = 8.9 Hz, 2H), 7.50 (dd, J = 8.2 , 4.8 Hz, 1 H), 7.92-7.96 (m, 1 H), 8.08-8.15 (m, 1 H), 8.45 (dd, J = 4.8, 1.4, 1H), 8.84, 9.75, 9.85, 10.24 (4 br s , 1 H each). MS (ES +): m / z 329 (M + H) +.

EXAMPLE 242? / 2- (4- (2- (pyrrolidin-1-yl) ethoxy) phenyl) -5-methyl-? R1- (3- (trifluoromethoxy) phenyl) pyrimidine-2,4-diamine (Compound CLVIII) CLV? I A mixture of 1-bromo-3- (trifluoromethoxy) benzene (241 mg, 1.0 mmol), 4-amino-2-chloro-5-methylpyrimidine (143 mg, 1.0 mmol), Pd2 (dba) 3 (9) mg, 0.01 mmol), xantphos (14 mg, 0.02 mmol) and cesium carbonate (650 mg, 2.0 mmol) in dioxane (15 mL) was heated under reflux for 10 hr under argon. The solvent was removed and the residue, on purification by HPLC, gave an intermediate, 2-chloro-5-methyl-N- (pyridin-3-yl) pyrimidin-4-amine as a brown solid (260 mg, 85%). . A mixture of this intermediate (100 mg, 0.33 mmol) and 4- (2- (pyrrolidin-1-yl) ethoxy) benzenamine (67 mg, 0.33 mmol) in glacial acetic acid (5 ml) was heated under reflux for 3 hr. under argon. The crude reaction mixture on purification using HPLC gave the title compound as a white solid (11 mg, 7%). 1 H NMR (500 MHz, DMSO-d 6): d 1.65-1.72 (m, 4H), 2.11 (s, 3H), 2. 51-2.55 (m, 2H, superimposed with solvent peak), 2.75 (t, J = 5.9 Hz, 2H), 3.25-3.34 (m, 2H, superimposed with water peak), 3.99 (t, J = 5.9 Hz , 2H), 6.79 (d, J = 8.9 Hz, 2H), 6.98 (d, J = 8.0 Hz, 1 H), 7.40 (dd, J = 7.6, 7.4 Hz, 1 H), 7.50 (d, J = 8.9 Hz, 2H), 7.76 (br s, 1 H), 7.87 (d, J = 8.4 1 H), 7.90, 8.31, 8.41, 8.84 (4 s, 1 H each). MS (ES +): m / z 474 (M + H) +.

EXAMPLE 243 ^^ - (S-fpyrrolidin-l-i DetoxDfeniD -? ^^ - Chloro-S -trifluoromethylDfeniD-S-methylpyrimidine-2,4-diamine (Compound CLIX) CLIX A mixture of 4-bromo-1-chloro-2- (trifluoromethyl) benzene (259 mg, 1.0 mmol), 4-amino-2-chloro-5-methylpyrimidine (143 mg, 1.0 mmol), Pd2 (dba) 3 (9 mg, 0.01 mmol), xantphos (14 mg, 0.02 mmol) and cesium carbonate (650 mg, 2.0 mmol) in dioxane (15 mL) was heated under reflux for 10 hr under argon. The solvent was removed and the residue was purified by HPLC to give an intermediate, 2-chloro -? / - (4-chloro-3- (trifluoromethyl) phenyl) -5-methylpyrimidin-4-amine as a brown solid (200 mg, 62%). A mixture of this intermediate (161 mg, 0.5 mmol) and 4- (2- (pyrrolidin-1-yl) ethoxy) benzenamine (103 mg, 0.5 mmol) in glacial acetic acid (5 ml) was heated under reflux for 3 hr under argon. The crude reaction mixture upon purification using HPLC gave the title compound as a brown solid (75 mg, 31%). 1 H NMR (500 MHz, DMSO-d 6): d 1.65-1.72 (m, 4H), 2.10 (s, 3H), 2. 51-2.55 (m, 4H, superimposed with solvent peak), 2.75 (t, J = 6.0 Hz, 2H), 4.0 (t, J = 5.9 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H) , 7.47 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 9.0 Hz, 2H), 7.93 (s, 1 H), 8.01 (d, J = 2.5 Hz, 1 H), 8.22 (d, J = 8.5 Hz, 2H), 8. 60, 8.88 (2 s, 1H each). MS (ES +): m / z 492 (M + H) +.

EXAMPLE 244 Determination of IC50 values for Jak2 kinase The Cl 0 values for the compounds were determined using a luminescence-based kinase test with recombinant JAK2 obtained from Upstate Cell Signaling Solutions. In 96-well, flat-bottomed plates (Nunc), parallel tests were performed at room temperature to a final volume of 50 μl. Each well contained 40 μl of pH buffer consisting of 40 mM Tris pH regulator, pH 7.4, containing 50 mM MgCl 2, 800 μM EGTA, 350 μM Triton X-100, 2 mM β-mercaptoethanol, 100 μM peptide substrate (PDKtide; Upstate Cell Signaling Solutions) and an appropriate amount of JAK2 (75 - 25 ng / well) such that the test was linear for 60 min. The final concentrations of TargeGen compounds for IC50 value determinations they varied from 1000 to 0.01 μM by adding the appropriate amount of compound in 2.5 μl of DMSO; the DMSO present in each test was constant at 5%. The reaction was initiated by the addition of 10 μl of ATP to a final test concentration of 3 μM. After the reaction had proceeded for 60 min, 50 μl of Kinase-Glo reagent (Promega) was added to terminate the reaction. This solution was then allowed to proceed for an additional 10 min to maximize the luminescence reaction. The values were then measured using an Ultra 384 (Tecan) instrument prepared for luminosity measurements. Two control reactions were also carried out: one reaction that did not contain a compound and the second one that did not contain an inhibitor or a peptide substrate. The Cl50 values were derived from experimental data using the non-linear curve fitting capabilities of Prism (Version 4, GraphPad software). The results are shown in the quad.

TABLE 1 Compounds of the invention and their Cl values for Jak2 kinase 3- (5-Methyl-2- [4- (2-72.2 pyrrolidin-1-yl-ethoxy) -phenylamino] -pyrimidin-4-ylamino) -benzenesulfonamide N-lsopropyl-3-. { 5-methyl-2- 11.8 [4- (4-methyl-piperazin-1-yl) -phenylaminoj-pyrimidin-4-ylamino) -benzenesulfonamide N-tert-Butyl-3- (5-methyl-2-6.6 [4 - (4-methyl-piperazin-1-yl) -phenylaminoj-pyrimidin-4-ylamino.} - benzenesulfonamide 5-methyl-N2- 24.8 hydrochloride [4- (4-methyl-piperazin-1-yl) -phenyl] -N 4 - [3- (piperidin-1-sulfoni) -phenyl] -pyrimidin-2,4-diamine -Methyl-N2-33.5 [4- (4-methyl-piperazin-1-yl) -phenyl] -N4- [3- (2-methyl-piperidin-1-sulfonyl) -phenyl] -15-pyramidine hydrochloride 2,4-diamine N4- (3-Methanesulfonyl-4-methyl-160 phenyl) -5-methyl-N2- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrimidine-2,4-diamine N-Cyclohexyl-3- (5-methyl-2-39.4 [4- (4-methyl-piperazin-1-yl) -phenylaminoj-pyrimidin-4-ylamino} - benzenesulfonamide N4- [3- (2,5- 18.8-dimethyl-pyrrolidin-1-sulfonyl) -phenyl] -5-methyl-N2- [4- (4-methyl-piperazin-1-yl) -phenyl-pyrimidine- hydrochloride] 2,4-diamine N-tert-butyl-3-7.90 (2- {4- [4- (2-hydroxy-ethyl) -piperazin-1-yl-phenylamino} - [5-methyl-pyrimidin-4-] hydrochloride ilaminoj-benzenesulfonamide N-tert-Butyl-3- [5-methyl-2- (4-pyrazol-1-yl-phenylamino) -pyrimidin-4-ylaminoj-benzenesulfonamide N-tert-Butyl-3- [5-methyl-2- (6-piperazin-1-yl-pyridin-3-ylamino) -pyrimidin-4-ylaminoj-benzenesulfonamide 2- [4- (3. {5-Methyl-2- [4- 8.46 (4-methyl-piperazin-1-yl) -phenylamino] -pyrimidin-4-lactam} -phenol) -piperidin-1-yl] - ethanol N-tert-Butyl-3- [5-methyl-2-7,06 (3-morpholin-4-ylmethyl-phenylamino) -pyrimidin-4-ylamino] -benzenesulfonamide N2- (4- (2-9.28 (pyrrolidin-1-yl) ethoxy) phenyl) -N4- (7-fluoro-1 H -indol-4-yl) -5-methylpyrimidine-2,4-diamine hydrochloride N4- (4-Chloro-3-methoxy-phenyl) -12.1 5-methyl-N2- (6-piperazin-1-yl-pyridin-3-yl) -pyrimidine-2,4-diamine - [4- 5.12 (4-Chloro-3-methoxy-phenylamino) -5-methyl-pyrimidin-2-ylamino] -2-piperazin-1-yl-benzoic acid methyl ester 5- [4 - 16.4 (benzo [1,3-dioxol-4-ylamino) -5-methyl-pyrimidin-2-ylamino] -2- (2-pyrrolidin-1-yl-ethoxy) -benzoic acid N-ter-Butyl-3-. { 5-methyl-2- 7.3 [4- (piperidin-4-yloxy) -phenylaminoj-pyrimidin-4-ylamino] -benzenesulfonamide N 4 - (1 H -indol-5-yl) -5-methyl-N 2 - [4- ( piperidin-4-yloxy) -phenyl] -pyrimidine-2,4-diamine 2-. { 5- [4- (Benzo [1,3] dioxol-1,16-ylamino) -5-methyl-pyrimidin-2-ylamino] -pyridin-2-yloxy} - ethanol N4-Benzo [1, 3] dioxol-4-yl-N2- 9.34 [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5-methyl-pyrimidin-2,4-diamine N-tert-Butyl-3- [2- (4-imidazol-12.3 1 -yl-phenylamino) -5-methyl-pyrimidin-4-ylaminoj-benzenesulfonamide N-tert-Butyl-3- [2- (4-imidazol-8.42 1-methylmethyl-phenylamino) -5-methyl-pyrimidin-4-ylamino-benzenesulfonamide N-ter-Butyl-3-. { 2- [4- (2- 20.3 hydroxy-ethoxy) -phenylamino] -5-methyl-pyrimidin-4-ylaminoj-benzenesulfonamide N-ter-Butyl-3-. { 5-methyl-2-48.6 [4- (4-oxy-morpholin-4-ylmethyl) -phenylaminoj-pyrimidin-4-ylamino} - 15 benzenesulfonamide N4- (4-Chloro-3-methoxy-phenyl) - 15.2 5-methyl-N2- (4-piperazin-1-methyl-phenyl) -pyrimidine-2,4-diamine N-ter-Butyl-3-. { 5-methyl-2- 34.3 [4- (2-methyl-imidazol-1-yl) -phenylaminoj-pyrimidin-4-ylamino} - benzenesulfonamide N-tert-Butyl-3- (5-methyl-2- 21 .9 [4- (2-methyl-imidazol-1-ylmethyl) -phenylamino] -pyrimidin-4-ylamine.} - benzenesulfonamide N-ter- Butyl-3- [5-methyl-2- (4-80.7-pyridin-4-ylmethyl-phenylamino) -pyrimidin-4-ylamino] -benzenesulfonamide N-tert-Butyl-3- [5-methyl-2-12.1 (4-morpholin-4-yl-phenylamino) -pyrimidin-4-laminoj-benzenesulfonamide N 2 - (4- (1 H -pyrazol-1-yl) phenyl) -N 4 - (3-tert-butylphenyl) -5-methylpyrimidine-2,4-diamine N4- (7-chloro-694 1 H -indol-4-yl) -5-methyl-N2- (4- ((piperazin-1-yl) methyl) phenyl) pyrimidine-2,4-diamine hydrochloride N4- (3-tert-38.4-butylphenyl) -5-methyl-N2- (4- (2-methyl-1H-imidazol-1-yl) phenyl) pyrimidine-2,4-diamine hydrochloride N4- (3-tert-94.1 butylphenyl) -5-methyl-N2- (4- (2-methyl-1 H -imidazol-1-yl) -phenyl) pyrimidine-2,4-diamine hydrochloride N4- (4-chloro-15.9 2-methylphenyl) -5-methyl-N2- (4- (4-methyl-piperazin-1-yl) phenyl) pyrimidine-2,4-diamine hydrochloride -Methyl-N4-16.6 (3,4-dimethylphenyl) -N2- (4- (4-methyl-piperazin-1-yl) phenyl) pyrimidine-2,4-diamine hydrochloride EXAMPLE 245 Determination of the effectiveness of selected compounds HEL, CTLL-2 and normal human dermal fibroblasts (NHDF) They were from American Tissue Culture Collection Rockville, MD. BaF / 3 cells are obtained from DKFZ Cancer Research Center (Heidelberg, Germany).

BaF / 3 cells, HEL and NHDF were grown in a medium RPMI 1640 (Gibco BRL, Gaithersburg, MD) supplemented with penicillin, streptomycin, L-glutamine, and 10% fetal bovine serum (FBS). The CTLL-2 cells were grown in the same medium supplemented in addition with 20 U / ml of recombinant IL-2 (Hoffmann-LaRoche, Nutley, NJ). Plasmid containing the human JAK2 coding sequence was purchased from Invitrogen (Madison, Wl). JAK2V617F cDNA was generated using mutagenesis self-directed to introduce the V617F mutation into the human JAK2 coding sequence followed by verification using bidirectional sequencing.

This cDNA was subsequently subcloned into a retroviral vector and transduced into BaF / 3 cells. Permanently transduced BaF / 3 c cells expressing JAK2V617F were selected and maintained with 1 mg / ml G418. GFP was introduced into these cells by lentiviral transduction using pLenti6-GFP (Invitrogen) followed by blasticidin selection and confirmation of GFP expression using FACs analysis. The cell proliferation test was performed using the XTT cell proliferation kit in accordance with the manufacturer's instructions (Roche, Alameda, CA). In brief, approximately 2.5 x 10 3 cells were placed in triplicate in wells of microtiter plates in 100 μl of RPMI growth medium plus several doses of XLV. After 72 hours of incubation, twenty microliters of XTT was added to the wells and allowed to incubate for 4-6 hours. The color formazan product that formed was measured spectrophotometrically using the Vmax spectrophotometer (Molecular Devices, Sunnyvale, CA) at 450 nm with correction at 650 nm. The Cl50 values were determined using the GraphPad Prism 4.0 software (San Diego, CA), where the OD values were plotted on the y-axis (linear scale) and the concentration (mM) on the x-axis (logarithmic scale). ). The data were subjected to a non-linear regression adjustment analysis and the Cl50 values were determined as the concentration that inhibited 50% proliferation.

Proliferation CE50: HEL-270 nM Baf3: JAK2V617F - 297 nM Control data: JAK3-dependent proliferation induced by IL-2 - 3395 nM Control data: Control of normal human dermal fibroblasts - 6487 nM Apoptosis test BaF / 3-JAKV6 7F cells cultured in a growth medium (RPMI, 10% FBS, 1 mg / ml G418 and 10 μg / ml blasticidin) were treated with XLV at 1, 3 and 10 μM for 24 hr. After harvesting the cells by centrifugation at 890 RCF (relative centrifugation force) for 5 min, the genomic DNA was isolated from cell pellets using a DNA isolation kit (Puregen, Chino, CA). 5 μg of genomic DNA from each sample was subjected to electrophoresis of 1.2% agarose gel to detect fragmentation of genomic DNA (DNA ladder test). As a control, normal adherent human dermal fibroblasts (NHDF) grown in a growth medium (Cambrex, Walkersville, MD) at 60% confluence were treated with XLV as described above. After 2 washes with ice cold PBS, the genomic DNA was isolated from the NHDF cells for agarose gel electrophoresis.

Immunoblotting BaF / 3-JAKV617F cells treated with XLV or vehicle control were centrifuged, washed 2X with ice-cold PBS and used using pH regulator RIPA. The protein concentration was determined using the BCA method (Pierce, Rockford, IL) and 100 μg of total cell protein from each sample in 1X pH regulator Laemmli were subjected to Western blot analysis. Protein transfer was probed with an anti-phospho-STAT5 (Tyr694 / 699) (Upstate Biotechnology, Charlottesville, VA), subsequently separated and re-probed with an anti-STAT5 antibody (Cell Signaling Technology, Danvers, MA). The protein phospho-STAT5 or STAT5 was visualized by the improved chemiluminescent method (Pierce). In vivo signaling studies were done in a similar way. In brief, on day 11 after cell injection, the animals were dosed orally either with vehicle or 100 mg / kg of XLV. Spleens were harvested 7 hr after dosing and rapidly homogenized on a FastPrep machine (Qbiogen, Irvine, CA). 100 μg of each spleen homogenate was subjected to Western blot analysis. The protein transfer was probed with an anti-phospho-STAT5 (Tyr694 / 699) and subsequently with an anti-STAT5 antibody and visualized by the improved chemiluminescent method.

FACs analysis of circulating tumor load On day 11 after the injection of BaF / 3-JAK2V617F cell suspension, 1 ml of blood was collected by a bleeding method Cardiac terminal of a mouse that received vehicle, in addition, 0.1 ml of blood was collected by a non-lethal retro-orbital collection method of 10 mice from each of the three groups dosed with 10, 30 or 100 mg / kg of XLV and they were put together in the dose groups. The mononuclear blood cells were isolated by a Ficoll pad centrifugation method (Sigma-Aldrich, St. Louis, MO) (600 RCF and 30 min). The isolated cells were subjected to FACS analysis to determine the percentage of BaF / 3: JAK2v617F GFP positive cells. The results are shown in figure 1.

Circulating tumor model Mice with SCID were injected intravenously with BaF / 3 cells expressing JAK2V617F and GFP. XLV was dosed orally at the indicated doses starting 3 days after the infusion and ending 20 days after the infusion. On day 1 1, blood was obtained from the animals in each group and subjected to FAC analysis to determine the percentage of circulating cells that were GFP positive. In a parallel study, the animals were treated as described above except that they were given a single dose of 100 mg / kg of drug on day 1 1 followed 4 hours later by sacrifice and phosphorylation analysis of STAT5 in the spleen enlarged that has a tumor. The results are shown in figure 2.

Eye exposure data and efficacy Exposure data of compounds at 0.1% by administration of eye drops: With topical dosing of compounds formulated as 0.1% doses in 0.2% tyloxapol / 1% HPMC / 4% Mannitol, the exposure levels found in the black of mouse eye tissues are shown at two different time points, namely at 2 hr and at 7 hr. The efficacy data for selected compounds are shown in table 2.

TABLE 2 Concentration (nM) in mouse ocular tissues after bilateral topical instillation of 0.1% formulation QDX1 EXAMPLE 246 Compound XVII in an ocular efficacy study in a model of oxygen-induced retinopathy (OIR) Compound XVII was tested using the model of mouse-induced oxygen retinopathy (OIR), in which retinal neurovascularization is triggered by cycling mouse pups from normoxia to hyperoxia and then returning to normoxia. The C57BL / 6 mouse pups were transferred to a hyperoxic environment (70% O2) starting on day 7 after birth (P7). After 5 days, the pups were returned to a normoxic environment (21% of O2), where they were kept for an additional 5 days, during which time they received topical applications of either compound XVII or an appropriate vehicle. At the end of this period, whole retinal quantities were prepared and stained with a fluorescently labeled lectin (BSL 1) that recognizes murine endothelium. Finally, digital images were obtained by fluorescence microscopy and analyzed with an image software program to quantify the vascular area. In one study, animals dosed with a 0.1% formulation of compound XVII twice daily (bid) showed a 29% reduction in vascular area compared to vehicle treated animals (P <0.05, n = 11-15 ); in a second study, a reduction of 22% was observed (P <0.02, n = 6). The results are summarized in table 3.

TABLE 3 Although the invention has been described with reference to the previous examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

Claims (15)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has structure (A):

(TO) wherein: X is selected from a group consisting of a bond, O, C = O, SO2, and CH2; And it is selected from a group consisting of a link or NR9; or X and Y taken together are a link; each of R1 and R2 is independently selected from a group consisting of H, substituted or unsubstituted C6 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, and substituted or unsubstituted aryl; or R1 and R2 taken together are a bond; or R1 and R2 taken together form a portion selected from a group consisting of (CH2) m, (CH2) rS- (CH2) m, (CH2) r-SO- (CH2) m, (CH2) rS? 2- (CH2) m, (CH2) NR9- (CH2) m, and (CH2) rO- (CH2) m; each of p, q, r, n, m is independently an integer having the value between 0 and 6, R9 is selected from a group consisting of H, C? -C6 alkyl, CrC6 cycloalkyl, branched alkyl of CrC6, substituted alkyl of CrC6, aminoalkyl of C Cß, and hydroxyalkyl of Ci-Cβ; Go is selected from a group consisting of N, O, H, and CH, G is CH, N, CR6, or C when linked to X, and each G is independent of one another G, with the additional proviso that no more than two groups G may be N, with the additional proviso that for each CR6, each R6 is independent of one another group R6; R5 is methyl; wherein each of R6 and R7 is independently selected from a group consisting of H, substituted or unsubstituted alkyl of C-1-C6, unsubstituted or substituted alkenyl of C Ce, unsubstituted or substituted alkynyl of Cr C6, hydroxyalkyl or aminoalkyl of C-pCβ, substituted or unsubstituted cycloalkyl of Ci-Cβ, substituted or unsubstituted aryl connected through a carbon or a heteroatom, substituted or unsubstituted heteroaryl connected through a carbon or a heteroatom, C-alkoxy ? -C6, a halogen, CF3, -OCF3, S02H, S02 (C? -C6 alkyl), S02-heterocycle, SO2-cycloalkyl, SO2NH2, S02N (C6 alkyl) H, SO2N (C? C6) (C? -C6 alkyl), SO2NH (C6 cycloalkyl), S02NH-heterocycle, S02N (branched alkyl of CrC6) H, NH2, NO2, CN, OH, CONH2, CO- (C6 alkyl) , COOH, COO- (C6 alkyl), NHCO- (d6C6 alkyl), and NHCONH-aryl; R8 is independently selected from the group consisting of H, alkenyl substituted or unsubstituted substituted or unsubstituted alkynyl of d-CQ, hydroxyalkyl or aminoalkyl of C1-C6, unsubstituted or substituted branched alkyl of CrC6, substituted or unsubstituted cycloalkyl of CrC6, substituted or unsubstituted aryl connected through a carbon or a heteroatom, substituted or unsubstituted heteroaryl connected through a carbon or a hetero atom, halogen, CF3, -OCF3, SO2H, SO2 (C6 alkyl), SO2-heterocyclic, SO2-cycloalkyl, SO2NH2, SO2N (alkyl) of C C6) H, SO2N (CrC6 alkyl) (C6 alkyl), SO2NH (cycloalkyl of C ^ Ce), SO2NH-heterocycle, SO2N (branched alkyl of C CeJH, -NO2, CN, OH, CONH2, CO - (C Ce alkyl), COOH, COO- (C Ce alkyl), NHCO- (C6 alkyl), and NHCONH-aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or substituted heterocycle , for each occurrence, if any, has one or more substituents selected from the group consisting of hydroxy, alkoxy, mercapto, cycloalkyl heterocyclic, aryl, halogen, cyano, nitro, amino, amido, aldehyde, acyl, oxyacyl, carboxyl, sulfonyl, sulfonamide or sulfuryl; A is selected from a group consisting of O, NH, N- (C-C alkyl), CH2, S, SO, and SO2; d is selected from a group consisting of CH, N, NH, S, and O; G2 is selected from a group consisting of CR7, N, NH, S, and O, with each group R7 being independent of one another group R7; and R3 and R4, taken together form a heterocyclic ring system; or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides and individual diastereomers of the compound (A). 2. A compound represented by: a first portion chemically connected to a second portion, or pharmaceutically acceptable individual salts, hydrates, solvates, crystal forms, N-oxides and diastereomers thereof, wherein the first portion is selected from the group consisting of: and wherein the second portion is selected from the group consisting of:

3. - The compound according to claim 1, further characterized in that the compound is selected from the group it consists of: Vile vui IX X O XI XII 10 XV XVI XVI 1 XVI II XIX XX XXHI XXIV XXV XXVI 10 XXVII fifteen XX Vil I CIADL NH XXIX 10 XXXII 15 XXXIV 20 XXXV XXXVU I XXXIX XL XLI XLI1 XLlll XL1V XLV XLVl XLV 11 Ll Lll LV LVI .Vile LVlll 10 LIX LX LXI LXII LXIII 10 LX1V LXV LXVl LXVl i J.XVIII .XIX LXX LXXV II l LXX1X LXXXl LXXX II LXXXlll Í.XXX1V 10 LXXXV LXX XVI ' LXXXVII LXXXV1II LXXX1X fifteen XCI twenty XCIT XCIII CVIII Cl CU CIV CV CVT CV1I CV1JI CIX X 10 CXI C 11 CXIII CX IV exv CXV 11 CXVl 11 CXIX CXXl CXX II CXXl 11 CXX IV CXXV CXXVI CXXVII CXXVIll CXX IX 10 CXXX 15 CXXXII 20 CXXXIÍI CXXX IV CXXXV CXXXVI CXXXV CXXXVIll CXXX IX CXL 15 CXLI 20 CXLll CXLll I CXLIV 10 CXLV CXLV! CXLVII CXLVlll 10 CXLIX CL 15 CLl CLI1 C Ill CLIV CLV CLVII CLIX C X CLXl CLXI I

4. The use of at least one compound of any of claims 1-3, or pharmaceutically acceptable individual salts, hydrates, solvates, crystal forms, N-oxides and diastereomers thereof, for the preparation of a medicament. useful for treating an angiogenic-associated disorder in a subject who needs it.

5. The use as claimed in claim 4, wherein the disorder is a myeloproliferative disorder, polycythemia vera, essential thrombocythemia, myeloid fibrosis with myeloid metaplasm, retinopathy proliferative diabetic, a cancer, eye disease, inflammation, psoriasis, or viral infection.

6. The use as claimed in claim 4, wherein the disorder is polycythemia vera.

7. The use as claimed in claim 4, wherein the disorder is essential thrombocythemia.

8. The use as claimed in claim 4, wherein the disorder is myeloid fibrosis with myeloid metaplasm.

9. The use as claimed in claim 4, wherein the disorder is any myeloid-linked disorder.

10. The use as claimed in claim 5, wherein the cancer is selected from the group consisting of a cancer of the alimentary tract / gastrointestinal, colon cancer, liver cancer, skin cancer, breast cancer , ovarian cancer, prostate cancer, lymphoma, leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer or brain cancer.

11. The use as claimed in claim 4, wherein the disorder is chronic myelogenous leukemia (CML).

12. The use as claimed in claim 11, wherein chronic myelogenous leukemia is resistant to current treatments.

13. The use as claimed in claim 4, wherein the disorder is a myeloproliferative disorder.

14. The use as claimed in claim 13, in where the myeloproliferative disorder arises due to mutations in a kinase.

15. The use as claimed in claim 13, wherein the myeloproliferative disorder arises due to gain of function of a kinase pathway of the JAK family. 16 - The use as claimed in claim 13, wherein the myeloproliferative disorder arises as a result of gene or protein fusions due to gain of function of a kinase pathway of the JAK family. 17. Use as claimed in claim 4, wherein the disorder is associated with a kinase. 18. The use as claimed in claim 4, wherein the kinase is a kinase of the JAK family. 19. A pharmaceutical composition comprising at least one compound of any of claims 1-3, or its N-oxides, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, and a carrier pharmaceutically acceptable therefor. 20. The compound according to claim 1, further characterized in that X is O. 21. The compound according to claim 1, further characterized in that Go is N. 22. The compound according to claim 20, further characterized in that Go is N. 23. The compound according to claim 22, further characterized in that Y is a bond, and R1 and R2 are each H. 24 - The compound according to claim 23, further characterized in that R7 is SO2NH- (branched alkyl of C -? - C6). 25 - The compound according to claim 22, further characterized in that R3 and R4 taken together form a heterocyclic ring. 26.- A compound represented by: or its pharmaceutically acceptable salts thereof. 27. A pharmaceutical composition comprising a compound of claim 26 and a pharmaceutically acceptable carrier. 28. The use of a compound of claim 26 for the preparation of a drug useful for treating a myeloproliferative disorder in a patient in need thereof. 29. The use as claimed in claim 28, wherein the disorder is essential thrombocythemia or polymetaemia vera.