AU2012230091B2 - 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. Sq R4 H H R' R2 (A)

Description

P/101I Regulation 3.2 AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Bi-aryl meta-pyrimidine inhibitors of kinases The following statement is a full description of this invention, including the best method of performing it known to us: IA BI-ARYL META-PYRIMIDINE WIHBITORS OF KINASES FIELD OF INVENTION [00011 The present invention relates to the field of inhibitors of protein tyrosine kinases, their pharmaceutically acceptable compositions comprising the compounds of the invention and the 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 INVENTION [00021 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, arising from mutation, over-expression, or inappropriate regulation, dys-regulation or de-regulation, as well as over- or under-production of growth factors or cytokines has been implicated in many diseases, including but not limited too 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 relating to cell growth, cell differentiation, survival, apoptosis, mitogenesis, cell cycle control, and cell mobility implicated in the aforementioned and related diseases. [00031 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 (Jakl, Jak2, Jak3, and Tyk2) play a central role in cytokine signaling (Kisseleva et al, Gene, 2002, 285, 1; Yanaoka et al. Genome Biology 2004, 5, 253)). Upon binding to their receptors, cytokines activate JAK which then phosphorylate the cytokine receptor, thereby creating docking sites for signaling molecules, notably, members of the signal transducer and activator of transcription (STAT) family that ultimately lead to gene expression. Numerous cytokines are known to activate the JAK family. These cytokines include, the IFN family (IFN-cs/p/o/Limitin, IFN-y, IL-1 0, IL-19, IL-20, IL-22), the gp130 family (IL-6, IL-11, 2 OSM, LIF, CNTF, NNT-1/BSF-3, G-CSF, CT-1, Leptin, IL-12, IL-23), yC family (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). [00041 Until recently, the therapeutic potential of JAK inhibitors has focused on diseases affecting various 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 (transplant rejection, graft vs host disease), viral diseases (Epstein Barr Virus, Hepatitis B, Hepatitis C, HIV, HTLV1, Vaicella-Zoster Virus, 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, cutaneous inflammation, and immune suppression induced by solid tumors. Most efforts to date have targeted JAK3 inhibition 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). [0005] Most recently, two significant-findings- of the role of the EPO-JAK2 signaling pathway in myeloproliferative disorders and prolfierative diabetic retinopathy were found. First, a gain-of-function, somatic (acquired) mutation of the JAK2 kinase (V617F) was reported to be a causative factor in a number of "typical" myeloproliferative disorders, including polycethemia vera, essential thrombocythemia and melofibrosis with myeloid metaplasia, 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). Additionally it was found that (a) the V617F JAK2 mutation was associated with constitutive phosphorylation of JAK2 and its downstream effectors as well as induction of erythropoietin hypersensitivity in cell based experiments, (b) V617F JAK2-indcued cell proliferation signals were inhibited by small molecule inhibitors of JAK2, and (c) murine bone marrow transduced with a retrovirus containing V617F JAK2 incuded erythrocytosis in the transplanted mice.

3 [0006] Furthermore, recently it has been found that mutations in EPO-R also keep the JAK pathway constitutively activated leading to myleoproliferative disorders. [0007] Second, EPO was found to be a potent angiogenic factor in proliferative diabetic retinopathy, a major cause of vision loss affecting diabetic, working-age persons (see for example Aiello, New England Journal of Medicine, 2005, 353 (8), 839; Watanabe et al. New England Journal of Medicine 2005 353 (8), 782). [00081 Further, findings from the Watanabe research showed (a) intraocular EPO levels and VEGF (another well-known angiogenic factor in proliferative diabetic retinopathy) were significantly higher 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 hypoxia-induced retinal neovascularization in rodent models. [0009] Recently it has been shown that mutations in the EPO receptor may also affect the. 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. [00101 There is another feature regarding inhibitors of the JAK pathway. It has been demonstrated that the JAK pathway may be recruited in cell survival and proliferation. For example, in the case of the cells that are Philadelphia chromosome positive that result in chronic myelogenous leukemia (CML), there is evidence that the Jak pathway is recruited in constitutive activation. Accordingly, using a JAK inhibitor may have use in CML in which the Philadephia chromosome has been shown to produce the hybrid Bcr-Abl, thus keeping cells constitutively active. [0011] More telling is that in cases of resistance mutations that arise on account of specific inhibitors to BCR-ABL, as in the case of the T3151 gatekeeper mutation, or any other mutation, it may be possible to use a JAK inhibitor on account of the pathway used by the BCR-ABL mutant (as in the case of BCR-ABL(T3151) mutation) utilizing the Jak pathway. Thus Jak inhibitors may be used in the treatment of patients with resistance to known 4 therapies where BCR-ABL is directly targeted and drug resistance has now been shown as the dominant (50-90%) of all resistance in patients where existing therapies fail. [00121 The use of JAK inhibitors may also find utility in other myeloid disease states, both blood disorders and other disease states with myeloid implications, and other disease states in which the JAK pathway is implicated directly or indirectly. [0013] Accordingly, there is a need to develop compounds useful as inhibitors of kinases, particularly, JAK kinase, given the inadequate treatments available for the aforementioned diseases where the JAK signaling pathway is dysregulated, or recruited directly or indirectly. [0013a] Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment, or any form of suggestion, that this prior art forms part of the common general knowledge in Australia or any other jurisdiction or that this prior art could reasonably be expected to be ascertained, understood and regarded as relevant by a person skilled in the art. [0013b] As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude other additives, components, integers or steps. SUMMARY [00141 According to one embodiment, a compound having the structure (A) is provided: A R' R H H N N H H (A) [0015] According to another embodiment, a method is provided for treating an angiogenic-associated disorder, the method including administering to a subject in need thereof a therapeutically effective amount of at least one compound having the structure (A), or 4al pharmaceutically acceptable salts, hydrates, solvates, polymorphs, crystal forms, N-oxides, and individual enatiomers and diastereomers thereof, to a subject in need of such treatment. [0015a] Embodiments of the invention are defined by each of the accompanying claims. For example, in one embodiment, the invention relates to a compound, or a salt thereof as defined by claim 1. [0016] According to 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 diastereomers thereof.

12923136_6.DOC [0016a] In one embodiment, the invention provides a compound having the structure (A): A

R

3

R

5 H G, X q nR H N N R1 R2 H H (A) wherein: X is selected from a group consisting of a bond, 0, and CH 2 ; Y is selected from a group consisting of a bond or NR?; or X and Y taken together is a bond; each of R1 and R2 is independently selected from a group consisting of H, Ci-C 6 unsubstituted alkyl, substituted or unsubstituted C 3

-C

8 cycloalkyl, substituted or unsubstituted

(C

3

-C

14 heterocycle, substituted or unsubstituted C 5

-C

1 4 aryl, and substituted or unsubstituted C 5 o C 1 4 heteroaryl; or R' and R2 taken together is a bond; or R' and R2 taken together form a moiety selected from a group consisting of (CH 2 )m, (CH 2

)-S-(CH

2 )m, (CH 2 )rS0-(CH 2 )m, (CH 2 )r-SO 2 (CH 2 )m, (CH 2 )c-NR 9

-(CH

2 )m, and (CH 2

)C-O-(CH

2 )m; each of p, q, r, n, m is independently an integer having the value between 0 and 6,

R

9 is selected from a group consisting of H, CI-C 6 alkyl, C 3

-C

6 cycloalkyl, C 3

-C

6 5 branched alkyl, CI-C 6 substituted alkyl, C 1

-C

6 aminoalkyl, and C 1

-C

6 hydroxyalkyl; Go is selected from a group consisting of N, 0, H, and CH, with the proviso that if Go is N, then: each of R 3 and R 4 is independently selected from a group consisting of H, CI-C 6 alkyl, Ci-C 6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C 3

-C

6 20 substituted or unsubstituted branched alkyl, substituted or unsubstituted C 5

-C

1 4 aryl, and substituted or unsubstituted C5-C4 lheteroaryl, or RW and R 4 taken together form a moiety selected from a group consisting of (CH 2 )m, (CH 2 )rS

(CH

2 )m, (CH 2 )cSO-(CH 2 )m, (CH 2 )cSO2-(CH 2 )m, (CH 2 )rNR 9

-(CH

2 )m, and 4a 12928136_6DOC

(CH

2 )--(CH2)m, or R 3 and R 4 are taken together with Go to form a heteroaromatic or heterocyclic ring system; with the further proviso that if Go is 0, then: R3 is selected from a group consisting of H, CI-C 6 alkyl and Ci-C 6 substituted or 5 unsubstituted hydroxyalkyl or aminoalkyl, substituted or unsubstituted branched

C

3

-C

6 alkyl, substituted or unsubstituted G 3

-C

8 cycloalkyl, substituted C 3

-C

14 heterocyclic connected through carbon or nitrogen, substituted or unsubstituted

C

5

-C

14 aryl, substituted or unsubstituted Cs-CI 4 heteroaryl connected through carbon or nitrogen, with no group R 4 ; or R' and R3 taken together form a moiety selected from a group consisting of (CH 2 )m, (CH 2 )r-S-(CH 2 )m, (CH 2 )r-SO

(CH

2 )m, (CH 2 )cSO2-(CH 2 )m, (CH 2 )r-NR 9

-(CH

2 )m, and (CH 2 )r-0-(CH 2 )m; with the further proviso that if Go=CH, then: each of R 3 and R 4 is independently selected from a group consisting of H, Ci-C 6 alkyl, Ci-C 6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C 3

-C

6 15 substituted or unsubstituted branched alkyl, substituted or unsubstituted C 5

-C

14 aryl, substituted or unsubstituted C 3

-C

1 4 heterocycle connected through carbon or nitrogen, and substituted or unsubstituted C 5

-C

1 4 heteroaryl connected through carbon or nitrogen, or R 3 and R 4 taken together form a moiety selected from a group consisting of (CHR 9 )r-(CHR 9 )m-(CHR 9 )p, (CHR 9

),S(CHR

9 )m, (CHR 9 )r 20 SO-(CHR 9 )m, (CHR 9 )r-S02-(CHR 9 )m, (CHR 9 )r-NR 9

-(CHR

9 )m, and (CHR 9 )rO

(CHR

9 )m; with the further proviso that if Go is H, then there is no group R3 and no group R; each G is independently N or CR 6 , or C when bonded to X, provided that not more than two groups G can be N, and each R is independent of each other group R6; 25 R' is methyl; 4b 1292:m166.DOC

R

7

R

8 R6 G2 ' each of R 6 , R 7 , R 8 is independently selected from a group consisting of H, C 2

-C

6 substituted or unsubstituted alkenyl, C 2

-C

6 substituted or unsubstituted alkynyl, CI-C 6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C 3

-C

6 substituted or unsubstituted cycloalkyl, 5 substituted or unsubstituted C 5

-C

1 4 aryl, substituted or unsubstituted C5-C 1 4 heteroaryl connected through carbon or a heteroatom, a halogen, CF 3 , -OCF 3 , SO 2 H, SO 2 (C i-C 6 alkyl), S02 heterocycle, S0 2 -cycloalkyl, SO 2 NH(Ci-C 6 alkyl), SO 2

N(CI-C

6 alkyl)(CI-C 6 alkyl), SO 2

NH(C

3 C 6 cycloalkyl), SO 2 NH-heterocycle, SO 2

NH(C

3

-C

6 branched alkyl), NH 2 , NH(Ci-C 6 alkyl),

N(CI-C

6 alkyl)(Ci-C 6 alkyl), NO 2 , CN, CONH 2 , CONH(CI-C 6 alkyl), CON(CI-C 6 alkyl)(CI-C 6 0 alkyl), CO(Ci-C 6 alkyl), CO-heterocycle, COOH, COO(Ci-C 6 alkyl), -NHCO-(Ci-C 6 alkyl), and NHCONH-aryl, or any of R 6 and R 7 taken together, or R 7 and R 8 taken together, or R 6 and R 8 taken together form a moiety independently selected from a group consisting of -HN-CH=CH-, --HN-N=CH-, -HN-N=N-, -O(CH 2 )nO-, -S(CH 2 )nS-, -N=CH-S-, -CH=N-O-, -CH=N-S-, N=CH-0--, -C=N-O-, CH=CH-CH=CH-, -N=CH-CH=CH-, -CH=N-CH=CH-, -O-CH=CH, 5 and -S-CH=CH-; A is selected from a group consisting of 0, NH, N-(CI-C 6 alkyl), CH 2 , S, SO, and SO 2 ; Gi is selected from a group consisting of CH and N;

G

2 is selected from a group consisting of CR 7 and N, with each group R 7 being independent of every other group R7; 20 wherein the substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycle, for each occurence if any, have 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; or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual 25 diastereomers of the compound (A). 4c 129231366.DOC [0016b] In another embodiment, the invention provides a compound comprising a first moiety chemically connected to a second moiety, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, wherein the first moiety is selected from the group consisting of: NN NH 0 NH NH N NH N N N N NN O NN 5 H H H H NC CI N NH CI NH NH CI NH N N NN H , H H , H HN CI S NH NH N NH NH N NN N N H , H H , H 0 F aNH CI aNHNHH NN N N H , H , H , H ,

F

3 C 5

F

3 C NH NH F 3 CO NH NNN N!NN "CN'111N V -'NN>$ H , H , H 4d 12921:1366DOC CI 0 F NH H 2 N naNH N NH N NNH NH H , H , H HN CI N H HN NH HL N. N6 N H0 H , NH N N NH NH N HC H N O N H , H H NH H NNH N N N H H H H N H NH 0 0 9 ' N H NH ', NH H s NH 13CN N N H , H H NH NHNH NN\ O N N NANY HH H, H S NH SH S 0 0 0 NNY -'N NY NNY H , H ,H H NH I NH NH 0 XN NA NYk N'Y N H H H ON'O0"e 1292E.1366 DOC NH NH S NH o HN N N H , H , H O NNHSNH NNH N HN O N H H H HN-N HI NH N, NH H N H0 N H ,H H I - H N \ H N RN I NH N H ,and H 5 and wherein the second moiety is selected from the group consisting of: I rNH O N N N0 NH\ N N O N N N N N 4f 29231366i DOC NH N N " N ,, 0 - N rN rNH N N,)r ' 0

CF

3 rNH

CF

3 'k NN N N "N' 11 N N '- NH 5N" OH, 0 00 U NH 00U N.-, N. N.N N' NN 0 'N-k NH N" N, N. ,and 4g 129::136_6.DOC [0016c] In a further embodiment, the invention provides a compound, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, wherein the compound is of the formula selected from the group consisting of: O NH N O N H 5 1 NH 0 N N NH I I I HO NH O N N H III O NH 0 N S N--'N 10 H IV HO N O N N NN H 4h 129:%gL36 6DOC c I N N H ViI CI ' NH o--O N'N H ix CI O NH 0 NIN H x~i NH NIN H xIv 4i 1292,Il36_6DOC c I '-0'I~NH 0 N N Na H N NHH "-l IN C:-' N H H 5 xx o ) NH NC, - 0, N N,, H 0'XXNH o NH 10 H1 XXIII CI 4j 129281366.DOC MeO aNH ~-0 N N N Na H xxiv HO a NH N -Nl N o 7 H 5 xxv NH N No H ,DNH NH N Njao'N 10 H xxx 4k 12928136 6.DOC CI MeO NH NA N N H XXXVIII CI DNH MeO NH NNI N N H 5 XXXIX CI DNH MeO NH O N N H XL C1 MeO NH N ' N "(N-N NI H XLI C1 MeO N NH N 10 H XLII 41 129281366.DOC C1 MeO NH N N N N H XLIII Cl MeO NH NH

SNI

N N H XLIV H NH NN N,, 5 NH 1LI >rNH O NN N HH 0 ~"0 LV HN NH N1< N NN 11' H 50 LVI 04 m N NS H 10 ~LVI o4 1292-51366 DOC o s NH N 1N N 0 NH N N H LXII o OEt NH N N N H LXVII o

NH

2 NH N N) N N 5 H LXVIII s NH NNo N N H LXX 4n 1292836_6 DOC NH HN N N N H LXXIII N NH HN O N H LXXV HN N N N N 5 H LXXVIII HN N O CNH N Nj H LXXIX 4o 12923136_6DOC O NHH N N N N H LXXXI C NH "ON.' NH N N H LXXXII C0 NH N N N H NH LXXXIII NH N HO N N N H LXXXIV

F

3 C 'N NH N N N H 10 LXXXVI 4 p 1292:1366.DOC NH 12j N Oi NH H xc 04 "O Oj INH rN aO NH H XcI N NH N N N 5 H XCII CI 'NO NH NH N N H xcv C1 'NO N NH ONH N N H 10 XCVI 4q 12923136_6DOC Cl NHH N N H civ NH i o'-S NH N NN, H , H >r ; 5 NH HN- , N N 5 H CXIII &'-NH H CXVII C &NH r" N'IN H 10 CXVIII 4r 12928136_6DOC SNH N N H cxix N NH N Nr N N H H CXX SNH N N!NjaN 5 H CXXX ~ NH NH ~ NH N N IN IaN 4s 129281366.DOC HH CXXXIV NH NIN H CXXXV 5 S NH NH NNN H CXXXVI HI N, / NHN N NN H cxxxv'i 10 H CXXXVIII 4t 12928136 &DOC H N, S NH 0 00 N NH N H CXXXIX H NN O N N No N O N% H CXL HO aNH ON N'I N a 5 H CXLI F4 " O:)NH NIN H CXLII 0 NH NNI H 10 CXLIII 4u 12928136_6.DOC NH 00 SN NH H CXLIV Cl N H H CXLV N NH HI0 e"JN , 0- N SN 5 H CXLVII

F

3 C NH N o NH H CL NH N HNN H 10 CLIV 4v 12981366.DOC &NH N N N H CLX CI C NH N 7 N N H ,and CLXI '- NH N 7 N N N 5 H CLXII [0016d] In another embodiment, the invention provides a pharmaceutical composition comprising: Ho N NH N 0 N I-N HN, NN H 10 or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, and a pharmaceutically acceptable carrier. [0016e] In a further embodiment, the invention provides a pharmaceutical composition comprising: 4w 129281366.DOC H S, NH H or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, and a pharmaceutically acceptable'carrier. [0016f] As used herein, except where the context requires otherwise, the term "comprise" and s variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude other additives, components, integers or steps. 10016g] Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment, or any form of suggestion, that this prior art forms part of the common general knowledge in Australia or any other jurisdiction or that this prior art could reasonably be o expected to be ascertained, understood and regarded as relevant by a person skilled in the art. 4x 5 DETAILED DESCRIPTION A. Terms and Definitions. [0017] The following terminology and definitions apply as used in the present application, generally in conformity with the terminology recommended by the International Union of Pure and Applied Chemistry (IUPAC): [00181 The term "heteroatom" refers to any atom other than carbon, for example, N, 0, or S. [0019] The term "aromatic" refers to a cyclically conjugated molecular entity with a stability, due to delocalization, significantly greater than that of a hypothetical localized structure, such as the Kekuld structure. [00201 The term "heterocyclic," when used to describe an aromatic ring, refers to the aromatic rings containing at least one heteroatom, as defined above. [00211 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 by between 3 and about 14 carbon atoms and at least one heteroatom described above. 100221 The term "substituted heterocyclic" refers, for both aromatic and non-aromatic structures, to heterocyclic groups further bearing one or more substituents described below. [00231 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, iso propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl (also known as n-amyl), n-hexyl, and the like. The term "lower alkyl" refers to alkyl groups having from 1 to about 6 carbon atoms. [00241 The term "substituted alkyl" refers to alkyl groups further bearing one or more substituents such as hydroxy, alkoxy, mercapto, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, halogen, cyano, nitro, amino, amido, aldehyde, acyl, oxyacyl, carboxyl, sulfonyl, sulfonamide, sulfuryl, and the like.

6 100251 The term "alkenyl" refers to straight-chained or branched hydrocarbyl groups having at least one carbon-carbon double bond, and having between about 2 and about 12 carbon atoms, and the term "substituted alkenyl" refers to alkenyl groups further bearing one or more substituents described above. [00261 The term "alkynyl" refers to straight-chained or branched hydrocarbyl groups having at least one carbon-carbon triple bond, and having between about 2 and about 12 carbon atoms, and the term "substituted alkynyl" refers to alkynyl groups further bearing one or more substituents described above. [00271 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 bearing one or more substituents described above. 100281 The term "heteroaryl" refers to aromatic rings, where the ring structure is formed by between 3 and about 14 carbon atoms and by at least one heteroatom described above, and the term "substituted heteroaryl" refers to heteroaryl groups further bearing one or more substituents described above. [0029] The term "alkoxy" refers to the moiety -0-alkyl, wherein alkyl is as defined above, and the term "substituted alkoxy" refers to alkoxy groups further bearing one or more substituents described above. 100301 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 bearing one or more substituents described above. [00311 The term "alkylaryl" refers to alkyl-substituted aryl groups and the term "substituted alkylaryl" refers to alkylaryl groups further bearing one or more substituents described above. [0032} The term "arylalkyl" refers to aryl-substituted alkyl groups and the term "substituted arylalkyl" refers to arylalkyl groups further bearing one or more substituents described above.

7 [0033] The term "arylalkenyl" refers to aryl-substituted alkenyl groups and the term "substituted arylalkenyl" refers to arylalkenyl groups further bearing one or more substituents described above. [00341 The term "arylalkynyl" refers to aryl-substituted alkynyl groups and the term "substituted arylalkynyl" refers to arylalkynyl groups further bearing one or more substituents described above. [00351 The term "arylene" refers to divalent aromatic groups having between 5 and about 14 carbon atoms and the term "substituted arylene" refers to arylene groups further bearing one or more substituents described above. [0036] The term "chemically connected" is defined as forming a chemical entity in which two moieties form a direct chemical bond between them. [00371 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. [00381 The term "JAK kinase" refers to an enzyme found in cells in the immune system that participates in the cell signaling process resulting in the development of white blood cells. [0039] The term "therapeutically effective amount" refers to the amount of the compound or pharmaceutical composition that will. elicit the biological or medical response of a tissue, system; animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, e.g., restoration or maintenance of vasculostasis or prevention of the compromise or loss or vasculostasis; reduction of tumor burden; reduction of morbidity and/or mortality. [0040] 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. [0041] The terms "administration of a compound" or "administering a compound" refer to the act of providing a compound of the invention or pharmaceutical composition to the subject in need of treatment.

8 [00421 The term "antibody" refers to intact molecules of polyclonal or monoclonal antibodies, as well as fragments thereof, such as Fab and F(ab') 2 , Fv and SCA fragments which are capable of binding an epitopic determinant. [00431 The term "vasculostasis" refers to the maintenance of the homeostatic vascular functioning leading to the normal physiologic functioning. [00441 The term "vasculostatic agents" refers to agents that seek to address conditions in which vasculostasis is compromised by preventing the loss of or restoring or maintaining vasculostasis. B. Embodiments of the Invention. [00451 According to an embodiment of the invention, compounds having the structure (A) are provided for treatment of various diseases, disorders, and pathologies: Q A R3 R6 H GG. H N N R R R2 H H (A) [00461 In the structure (A), X can be any of a bond, 0, C=O, S02, or CH 2 and Y can be a bond or NR 9 ; or X and Y taken together can be a bond. Further, in the structure (A) each of R' and R2 can be any of H, CI-C 6 substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R1 and R 2 taken together can be a bond; or R1 and R2 taken together can form a moiety such as one of (CH 2 )m, (CH 2 )rS-(CH 2 )m,

(CH

2 )rSO-(CH 2 )m, (CH 2 )rSO2-(CH 2 )m, (CH 2 )rNR-(CH 2 )m, or (CH 2 )r-O-(CH 2 )m, wherein each of p, q, r, n, m is idependently an integer having the value between 0 and 6.

9 [0047] Further, in the structure (A) R 9 can be one of H, C-C 6 alkyl, C-C 6 cycloalkyl, Ci

C

6 branched alkyl, C-C 6 substituted alkyl, C 1

-C

6 aminoalkyl, or CI-C 6 hydroxyalkyl; Go can be one of N, 0, H, of CH, with the proviso that if Go is N, then each of R 3 and R 4 can be one of H, C 1

-C

6 alkyl, C 1

-C

6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C-C 6 substituted or unsubstituted branched alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R3 and R4 taken together can form a moiety such as one of

(CH

2 )m, (CH 2 )-rS-(CH 2 )m, (CH 2 )rSO-(CH 2 )m, (CH 2 )tSOr(CH 2 )m, (CH 2 )rNR 9

-(CH

2 )m, or (CH 2 )r-O-(CH 2 )m. [00481 There are some additional provisos further directed to Go in the structure (A). More specifically, if Go is N, then R1 and R? taken together can form a moiety such as one of

(CH

2 )m, (CH 2 )rS-(CH 2 )m, (CH 2 )rSO-(CH 2 )m, CH 2 )rSO2-(CH 2 )m, (CH 2 )r-NR-(CH 2 )m, or

(CH

2

)-O--(CH

2 )m; or R 1 and R 4 taken together can form a moiety such as one of (CH 2 )m,

(CH

2 )rS-(CH 2 )m, (CH 2 )rSQ-(CH 2 )m, (CH 2 )fSOr(CH 2 )m, (CH 2 )rNR 9

-(CH

2 )m, or

(CH

2 )rO-(CH2)m; or R? and R 4 taken together can form a moiety such as one of (CH 2 )m,

(CH

2 )rS-(CH 2 )m, (CH 2 )rSO-(CH 2 )m, (CH 2 )VSOr(CH 2 ). (CH 2 )rfNR 9

-(CH

2 )m, or

(CH

2 )rO-(CH 2 )m; or R and R4 taken together can form a moiety such as one of (CH 2 )m,

(CH

2 )rS-(CH 2 )m, (CH 2 )fSO-(CH 2 )m, (CH 2 )rS0r(CH 2 )m, (CH 2 )rNR-(CH 2 )m, or

(CH

2 )rA>{CH 2 )m. [00491 If in the structure (A) Go is 0, then R3 can be one of H, C 1

-C

6 alkyl and C 1

-C

6 substituted or unsubstituted hydroxyalkyl or 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, with no group R4; R' and R9 taken together can form a moiety such as one of (CH 2 )m, (CH 2 )rS-(CH 2 )m, (CH 2 )rSO-(CH 2 )m,

(CH

2 )rSO2-(CH 2 )m, (CH 2 )rNR 9

-(CH

2 )m, or (CH 2 )rO-(CH 2 )m; or R' and R3 taken together can form a moiety such as one of (CH 2 )m, (CH 2 )rS-(CH 2 )m, (CH 2 )rS0-(CH 2 )m,

(CH

2 )r'SOr(CH 2 )m, (CH 2 )rNR 9

-(CH

2 )m, or (CH 2 )rO-(CH 2 )m; or R9 and R3 taken together can form a moiety such as one of (CH 2 )m, (CH 2 )rS-(CH 2 )m, (CH 2 )rSO-(CH 2 )m, (CH 2 )r S0 2

(CH

2 )m, (CH 2 )rNR 9

-(CH

2 )m, or (CH 2 ) 04CH 2 )m.

10 [00501 If in the structure (A) Go = CH, then each of R 3 and R 4 can be one of H, C 1

-C

6 alkyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C1-C6 substituted or unsubstituted branched alkyl, substituted or unsubstituted aryl, CI-C6 substituted or unsubstituted heterocycle connected through carbon or nitrogen, or substituted or unsubstituted heteroaryl connected through carbon or nitrogen, or R 3 and R 4 taken together can form a moiety such as one of (CHR)r(CHR 9 )m-(CHR 9 )p, (CHR 9 )rS-(CHR 9 ).,

(CHR

9 )rSO-(CHR)m, (CHR 9 ),SO2-(CHR 9 )m, (CHR 9 )rNR 9

-(CHR

9 )m, or

(CHR

9 ),4O(CHR 9 )m. 100511 Further, in the structure (A) G can be N or CR 6 , and each G is independent of each other G, with the further proviso that not more than two groups G can be N, with the further proviso that for each CR 6 , each R 6 is independent of each other group R 6 . [00521 Further, in the structure (A) R 5 is methyl and the moiety Q is as shown below

R

7 R8 R6 G2 G [00531 In the moiety Q, each of R6, R 7 , R 8 can be one of H, Cr-C6 substituted or' unsubstituted alkyl, C1-C6 substituted or unsubstituted alkenyl, C 1

-C

6 substituted or unsubstituted alkynyl, Cr-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C-C 6 substituted or unsubstituted branched alkyl, C 1

-C

6 substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl connected through carbon or a heteroatom, substituted or unsubstituted heteroaryl connected through carbon or a heteroatom, C-C6 alkoxy, a halogen,

CF

3 , -OCF 3 , CHR 3

R

4 , SR 3 , SOR 3 , S0 2

R

3 , SO 2

NR

3

R

4 , S0 3

R

3 , POR 3 , P0 2

R

3 , P0 2

NR

3

R

4 ,

PO

2

CR

3

R

4 , P0 3

R

3 , NRR 4 , NO 2 , CN, OH, CONR 3

R

4 , COR', COOR, N R 3 CO R 4 ,

NR

3

CONR

3

R

4 , OCONR 3

R

4 , CSNR 3

R

4 , CSR 3 , NR 3

CSNR

3

R

4 , SCONRR 4 , SCSNR 3

R

4 , or

SCSNR

3

R

4 ; or any of R 6 and R 7 taken together, or R 7 and R 8 taken together, or R 6 and R' taken together can form a moeity independently selected from any of-HN-CH=CH-, -HN-N=CH-, -HN-N=N-, -O(CH 2 )nO-, -S(CH 2 )nS-, -N=CH-S-, -CH=N-O-, -CH=N-S-, -N=CH-O-, -C=N-O-, -C=N-0-, -CH=CH-CH=CH-, -N=CH--CH=CH-, 11 -CH=N-CH=CH-, -O-CH=CH, and -S-CH=CH-; or R3 and R 4 taken together can form a moiety such as one of (CHR9)t(CHR)m-(CHR 9 )p, (CHR 9 )rS-(CHR 9 );n,

(CHR

9 )SO-(CHR)m, (CHR 9 )rSOr(CHR 9 )m, (CHR 9 )rNR 9

(CHR

9 ),, or (CHR 9 )r-O (CHR)m. [00541 Further, in the structure (A), A can be one of O NR 3 , CR 3

R

4 , S, SO, and SO 2 ; and in the moiety Q, G, can be any of CH, N, NH, S, and 0, and G2 can be any of CR 7 , N, NH, S, and 0, with each group R 7 being independent of every other group R7; and if G 1 or G 2 is NH, S, or 0, then Q is a five membered heteroaromatic ring, optionally fused to a six member aromatic or non-aromatic ring; and if G 1 or G2 is N, then Q is a five or a six membered aromatic ring, optionally fused to a six member aromatic or non-aromatic ring, with the further proviso that X or Go includes at least one heteroatom included with X and selected from 0, S and N, or Go comprises at least four non-hydrogen atoms, inclusive of the heteroatom, and R 3 and K 4 , or R 1 and R 9 , or R 1 and R 4 , or R! and R taken together can form an aromatic, heteroaromatic, cyclic or heterocyclic ring system, or if a noncyclic system is present, then more than one heteroatom is present, and if A is NR 3 , then any of R 6 , R 7 or R 8 , or any combination thereof independently includes at least two non-hydrogen substituents, or if A is NR3, then Q forms a fused ring from R 6 to R 7 , or from R 7 to R 8 . [00551 Some exemplary compounds described by structure (A) that can be used include, but are not limited to, the following compounds I through CLXHI shown below: INH ( N 0 No N N H .'-I IU 0 12 HO aNH 0 H 1110'aifi N N o NH0 IV 11 ' 0H H Iv O- N HO N r No vi H

VI

13 )NH H Vill 'O'I~NH H IX ZxNH H F) NH H cXI

N

0 N NH N NN

H

14 NH ' O N a H CI aNH N NH - N H CIr NH H xv N O N " O'I~NH H xviI

CII

15 N a NH N NIN H xvilI CI a NH H X (rJH H xx NC K-N--I H 0) NH NC

H

16 cI c eOa N H H XmIlI MeO~ciiNH H XXIV QO-NH HOH H xxvi CI a NH H Xxvnl 17 NH H xxvm. C' aNH H HNN NHN H xxx 18 NH 'N N~ NN H XXXII N NH H

F

3 C a NH *N -N!N'a H "NW H Xxxv 19 NHN NINa H NH r N H XXXVII .Me)&NH "N-IN'O H Me)Z"'NH 0N H

XIL

20 MeOII'I2IINHN "N -N KN) XLI MeoQDNH N H XLII[ m 0XZe"'NH N N H XLIII " aNH Me NH NN H XLIV HO >rsN NHN 0 ' NN H

XLV

21 ozz-NH 6NH 0 H XLVfl H XLVII HO0 N *~'NH rH 0 N N,) H XLIX H 0H 'A-N N N o H L HO s NH 00

LI

22 H 0 H Lfl >f N CF 3 (rNH H LMl s NH CF 3 ( H LIV HO NN s NH 00 LV HO N NH NH H LVI H NH H LVIIl 23 0 H2N 1H NH IIII HqH NaH 0 NH H H 0 S aNHN 0 -- N)NNf H NH N H

LXIII

24 NH r o t, LXIV 4 Is NHN H LXV

H

2 N N NHN H LXVI o OEt NH r H LXVIII o NH 2 NH r H

LXVII

25

F

3 C NH H LNX H2N0 &sl:NH. H LXXI &NH H /NH HNN H

LXXIII

26 /NH I N NJ N~N N ) H LXXIV HNN N NN H LXXV /NH HNN NN N3 H LXXVI 1 NH F HNN H LXXVII HN NN A N<N

H

27 HN N Na H LXXX HN HN NH '0'I~$NH N N H LXXXKI 0 ~>NH ao NH Nj N 0 NH

HXXONIH

28 NHr NH H LXXXIV HH N _N'I' N H LXXXV 'NN H LX30VI NHN 0< NJN H LXXXCVII N NH 0 H

LXXXVI

29 ",& NH 0 O N H XC H xcI H XCII ~~QNH H XCIII H NH NI NIN 'NH H

XCIV

30 cI H xcv xcv - NH HH 00 NHH N N H

XCIXIE

31 0N H H "aH H Q'NHN CIi H cm 32 H cv 4 H NH N -41N N H cr H >NSaQNH N N H CVX N, NH (N N N H cvm H JN N, NN NHN H cx11 33 H NHN NIN'N H cm' ~H NH NH >ro IH HN-i 0 "N N N! Ne H N NH HH H N _N - N H Cxv HN NH r H

CXV'

34 NH g NNH H cxvii NH N N N H Cxvm NH H N N N N H H CXX 6NH N - NN H

CXXI

35 0 NH HN H 6 NH KjN~ N- NNQ H H CXXIV H

CXXV

36 0 0 &NH -6' NH (NH N.IN.f) H cxxY1 0 1 NH r-O ~ H NH N N N N N H NHN N HO CXXJIx 37 N "NH H cxxx HN CI NH N NN KNH H ND N H N H N" NN H -~NH NH NH NN H cxxxv 38 NH N O N H CXXXVI . H H NH 0 N N H CXXXVIII S NH 0 21 K S N o H CXXXLI H N ONN NH 0 HH CXL H O a N H

-

N -N' NNH H

CXLI

39 H CXLII o NH H CXLM CO NN NH H CXLIV C NH ) ONH N'NNH H ' e kO NH H CXLVI o 1 N NH ,2N O NH H

CXLVII

40 H HaN Ii H H " N ' N H 0CXLVIII F3C N "NINH r"

F

3 C H H H CXLIEX

F

3 C NH H CL ON NH H CLI H N -rNH r 0N' N H CLII N~ YaNH Cf H

CLII

41 HNNH r H CLIV H Na H S~NH r H CLVI N'HN N H N-Na NH H CLVII 0 NH -J N N N r N H

CLVIII

42

F

3 C NH -4 NH N H CLIX C : NH riiHfN INN N H CLX CC( NH N N N H and

CLXH

43 100561 According to another embodiment of the invention, compounds having the general structure (Z): B-C (2) are provided for treatment of various diseases, disorders, and pathologies. [00571 The general structure (Z) includes two chemically connected moieties B and C. The moiety B in the general structure (Z) includes any moiety selected from the following group: C0 H 0 NH NH 0 2 N NH NN~ N N H H H H H~ HO NNH NH HH'NH N O N N N H H H H NC C1 HO NH HN N NH NH N NH NNNN N X N H H H H N II1,NH NC 1 NH NH C1 N H NH NH CI'I"NH 44 N H N"' N CaNH N--XN N X N' <X N kk H H H H c~IINH ( 2 "NH NH CKaNH NHVI N N H H H H clS"C0aNC Fa HNH CI H N H N'NYk-N N IX H H H H KaLYO

F

3 C 0 N H & NH F 3 C NH NH Hl H HH

F

3 CO a NH F 3 C a NH 0-11 NH H H H -~~ 0 N H -Ir N NH H 2 .. N NH 1 'N" NH k 0 H N N'N Nk' I-iH

H

45 HN ol"NH Cl" NH H NH NH H H QIN )N-QNH I NH ) NH H H HN H n S' -NH SN NH N N!NY\ N"Nk H H H OMe 0 0,_,e NN

F

3 C N

H

2 N 0 HFH NH &NH >Ns ~NH N Nk 0 H H H N, NHN NN," N S N NH N NY NANYk 0 H H H 46 NHNY 0 o, 1 ~ NX s H H s H H H H NH HN ANk ~ NNk HH H NH H0 N N\X N N'< H H H TNNH /.NIZ NH H-r2INH H NN H 47 HN-N HN NH N NN HWH H H ,and HO NH H NHZISiNH ON1 H f0058] The moiety C in the structure (Z), above, includes any moiety selected from the following group: 0 0,i N N H rNH OOH N N N' (NH N OH O KNH N'N N N N N N SCF3NH N, pre N N I N 0 48 O

CF

3 NK N N ON N OH 0 00 OONH 0 O N N N N N NNN N N " N O N HN N NH N nd 100591 The compounds and methods of the present invention, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, either when administered alone or in combination with other agents (e.g., chemotherapeutic agents or protein therapeutic agents described below) are useful in treating 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 types of cancer, eye disease, inflammation, psoriasis, and a viral infection. The kinds of cancer that can be treated include, but are not limited to, an alimentary/gastrointestinal tract cancer, 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.

49 [00601 Some examples of the diseases and disorders that can be treated also include ocular. neovasculariaztion, infantile haemangiomas; organ hypoxia, vascular hyperplasia, organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type 1 diabetes and complications from diabetes, inflammatory disease, acute pancreatitis, chronic pancreatitis, asthma, allergies, adult respiratory distress syndrome, cardiovascular disease, liver disease, other blood disorders, asthma, rhinitis, atopic,'dermatitits, autoimmune thryroid disorders, ulerative 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 graivs, multiple scleroiss, inflammatory bowel disease, graft vs host disease, neurodegenerative diseases including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral scelerosis, Huntington's disease, cerebral ischemia, or neurodegenerative disease caused by traumatic injury, strike, gluatamate neurtoxicity or hypoxia; ischemic/reperfusion injury in stroke, myocardial ischemica, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hyoxia, and platelet aggregation. [00611 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, ankylosing spondylitis, psoriatic arthritis), viral diseases (Epstein Barr Virus, Hepatitis B, Hepatitis C, HIV, HTLV1, Vaicella-Zoster Virus, Human Papilloma Virus), food allergy, cutaneous inflammation, and immune suppression induced by solid tumors. [00621 Embodiments of the present invention also provide articles of manufacture that can include a packaging material and a pharmaceutical composition contained within the packaging material. The packaging material can comprise a label which indicates that the pharmaceutical composition can be used for treatment of one or more disorders identified above.

50 [00631 The pharmaceutical composition can include a compound according to the present invention. In addition to a compound of the present invention, the pharmaceutical may also contain other therapeutic agents, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques known in the art of pharmaceutical formulation. [0064] Thus, in one embodiment, the invention provides a pharmaceutical composition including a therapeutic agent and a compound of the invention. The compound is present in a concentration effective to treat, for example, cancer or to treat another disease or disorder described above. [00651 The compounds of the invention may be formulated into therapeutic compositions as natural or salt forms. Pharmaceutically acceptable non-toxic salts include the base addition salts (formed with free carboxyl or other anionic groups) which may be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like. Such salts may 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 acid, oxalic, tartaric, mandelic, and the like. [0066] Salts of the invention can include amine salts formed by the protonation of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like. Salts of the invention can 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 which are contemplated for use in the practice of the present invention are those available to those of ordinary skill in the art, for example, those found in the United States Pharmacopeia Vol. XXII and National Formulary Vol. XVII, U.S. Pharmacopeia Convention, Inc., Rockville, MD (1989), the relevant contents of which is incorporated herein by reference. In addition, polymorphs of the invention compounds are included in the present invention.

51 [00671 Pharmaceutical compositions of the invention may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, intrathecal, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray, topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds may also be administered liposomally. [00681 In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens). [00691 The pharmaceutical compositions for the administration of the compounds of this embodiment, either alone or in combination with other therapeutic agents, may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into 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 upon the process or condition of diseases. 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.

52 [00701 Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable 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; binding agents, 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 delay 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 may be employed. They may also be coated to form osmotic therapeutic tablets for control release. [00711 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 active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. [0072] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- . propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, 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 polyethylene glycol, for example. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl,p- 53 hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. [00731 Oily suspensions may 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 may be preserved by the addition of an anti-oxidant such as ascorbic acid. [0074] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. 10075] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. [0076] The pharmaceutical compositions maybe in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable diluent or solvent or cosolvent or complexing agent or dispersing agent or excipient or combination thereof, for example 1,3-butanediol, polyethylene glycols, polypropylene glycols, ethanol or other alcohols, povidones, various brands of TWEEN surfactant, sodium dodecyl sulfate, sodium deoxycholate, dimethylacetamide, polysorbates, poloxamers, cyclodextrins, lipids, and excipients such as inorganic salts (e.g., sodium chloride), buffering agents (e.g., sodium citrate, sodium phosphate), and sugars (e.g., saccharose and dextrose). Among the acceptable vehicles and solvents that may be employed are water, dextrose solutions, Ringer's solutions and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be 54 employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. 100771 Depending on the condition being treated, these pharmaceutical compositions may be formulated and administered systemically or locally. Techniques for formulation and administration may be found in the latest edition of "Remington's Pharmaceutical Sciences" (Mack Publishing Co, Easton Pa.). Suitable routes may, for example, include oral or transmucosal administration; as well as parenteral delivery, including intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, or intranasal administration. For injection, the pharmaceutical compositions of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiologically buffered saline. For tissue or cellular administration, penetrants appropriate to the particular barrier to be permeated 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. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. 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 carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. [0078] The compounds of the present invention may 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-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. [00791 For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles).

55 [0080] In one embodiment, the invention compounds 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 in need of such treatment. While not wanting to be limiting, chemotherapeutic agents include antimetabolites, such as methotrexate, DNA cross-linking agents, such as cisplatin/carboplatin; alkylating agents, such as canbusil; topoisomerase I inhibitors such as dactinomicin; microtubule inhibitors such as taxol (paclitaxol), and the like. Other chemotherapeutic agents include, for example, a vinca alkaloid, mitomycin-type antibiotic, bleomycin-type antibiotic, antifolate, colchicine, demecoline, etoposide, taxane, anthracycline antibiotic, doxorubicin, daunorubicin, carninomycin, epirubicin, idarubicin, mithoxanthrone, 4-dimethoxy-daunomycin, 1 1-deoxydaunorubicin, 13-deoxydaunorubicin, adriamycin-14-benzoate, adriamycin-14-octanoate, adriamycin-14-naphthaleneacetate, amsacrine, carmustine, cyclophosphamide, cytarabine, etoposide, lovastatin, melphalan, topetecan, oxalaplatin, chlorambucil, methtrexate, lomustine, thioguanine, asparaginase, vinblastine, vindesine, tamoxifen, or mechlorethamine. While not wanting 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 targets vascular endothelial growth factor, and OSI-774, which targets epidermal growth factor, antibodies targeting integrin receptors, such as Vitaxin (also known as l\EDI-522), and the like. Classes of anticancer agents suitable for use in compositions and methods of the present invention include, but are not limited to: 1) alkaloids, including, microtubule inhibitors (e.g., Vincristine, Vinblastine, and Vindesine, etc.), microtubule stabilizers (e.g., Paclitaxel [Taxol], and Docetaxel, Taxotere, etc.), and chromatin function inhibitors, including, topoisomerase inhibitors, such as, epipodophyllotoxins (e.g., Etoposide [VP-16], and Teniposide [VM-26], etc.), and agents that target topoisomerase I (e.g., Camptothecin and Isirinotecan [CPT-1 1], etc.); 2) covalent DNA-binding agents [alkylating agents], including, nitrogen mustards (e.g., Mechlorethamine, Chlorambucil, Cyclophosphamide, Ifosphamide, and Busulfan [Myleran], etc.), nitrosoureas (e.g., Carmustine, Lomustine, and Semustine, etc.), and other alkylating agents (e.g., Dacarbazine, Hydroxymethylmelamine, Thiotepa, and Mitocycin, etc.); 3) noncovalent 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 [Idamycin], etc.), anthracenediones (e.g., 56 anthracycline analogues, such as, [Mitoxantrone], etc.), bleomycins (Blenoxane), etc., and plicamycin (Mithramycin), etc.; 4) antimetabolites, including, antifolates (e.g., Methotrexate, Folex, and Mexate, etc.), purine antimetabolites (e.g., 6-Mercaptopurine [6-MP, Purinethol), 6-Thioguanine [6-TG), Azathioprine, Acyclovir, Ganciclovir, Chlorodeoxyadenosine, 2 Chlorodeoxyadenosine [CdA], and 2'-Deoxycoformycin [Pentostatin], etc.), pyrimidine antagonists (e.g., fluoropyrimidines [e.g., 5-fluorouracil (Adrucil), 5-fluorodeoxyuridine (FdUrd) (Floxuridine)] etc.), and cytosine arabinosides (e.g., Cytosar [ara-C] and Fludarabine, etc.); 5) enzymes, including, L-asparaginase; 6) hormones, including, glucocorticoids, such as, antiestrogens (e.g., Tamoxifen, etc.), nonsteroidal antiandrogens (e.g., Flutamide, etc.), and aromatase inhibitors (e.g., anastrozole [Arimidex], etc.); 7) platinum compounds (e.g., Cisplatin and Carboplatin, etc.); 8) monoclonal antibodies conjugated with 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 tumor cell differentiation (e.g., all-trans-retinoic acid, etc.); 13) gene therapy techniques; 14) antisense therapy techniques; 15) tumor vaccines; 16) therapies directed against tumor metastases (e.g., Batimistat, etc.); and 17) inhibitors of angiogenesis. [00811 The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions. Examples of other therapeutic agents include the following: cyclosporins (e.g., cyclosporin A), CTLA4-Ig, 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 blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 (i.e., CD 154), fusion proteins constructed from CD40 and gp39 (CD40g and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NF-kappa B function, such as deoxyspergualin (DSG), cholesterol biosynthesis inhibitors such as HMG CoA reductase inhibitors (lovastatin and simvastatin), non-steroidal antiinflammatory 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 57 [00821 Other agents that may be administered in combination with invention compounds include protein therapeutic agents such as cytokines, immunomodulatory agents and antibodies. As used herein the term "cytokine" encompasses chemokines, interleukins, lymphokines, monokines, colony stimulating factors, and receptor associated proteins, and functional fragments thereof. As used herein, the term "functional fragment" refers to a polypeptide or peptide which possesses biological functionor activity that is identified through a defined functional assay. 100831 The cytokines include endothelial monocyte activating polypeptide 11 (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 is associated with a particular biologic, morphologic, or phenotypic alteration in a cell or cell mechanism. [00841 When other therapeutic agents are employed in combination with the compounds of the present invention they may be used for example in amounts as noted in the Physician Desk Reference (PDR) or as otherwise determined by one having ordinary skill in the art. [00851 In the treatment or prevention of conditions which involve cellular proliferation,*an appropriate dosage level can generally be between about 0.01 and about 1000 mg per 1 kg of patient body weight per day which can be administered in single or multiple doses. For example, the dosage level can be between about 0.01 and about 250 mg/kg per day; more narrowly, between about 0.5 and about 100 mg/kg per day. A suitable dosage level can 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 dosage can 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 can 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 dosage to the patient to be treated. The compounds can be administered on a regimen of 1 to 4 times per day, such as once or 58 twice per day. There may be a period of no administration followed by another regimen of administration. [0086] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabplic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. [0087] 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 or an immunotoxic agent, for treatment of tumors. Illustrative examples of chemotherapeutic agents that can be used for this purpose include doxorubicin, docetaxel, or taxol. It should be further understood that the invention includes combination therapy including 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 100881 The following examples are provided to further illustrate the advantages and features of the present invention, but are not intended to limit the scope of the invention. EXAMPLE 1. General Methods [0089] All experiments were performed under anhydrous conditions (i.e. dry solvents) in an atmosphere of argon, except where stated, using oven-dried apparatus and employing standard techniques in handling air-sensitive materials. Aqueous solutions of sodium bicarbonate (NaHCO 3 ) and sodium chloride (brine) were saturated. Analytical thin layer chromatography (TLC) was carried out on Merck Kieselgel 60 F254 plates with visualization by ultraviolet and/or anisaldehyde, potassium permanganate or phosphomolybdic acid dips. Reverse-phase HPLC chromatography was carried out on Gilson 215 liquid handler equipped with Waters SymmetryShield" RP 18 7pm (40 x 100mm) Prep-Pak cartridge. Mobile phase consisted of standard acetonitrile (ACN) and DI Water, each with 0.1% TFA added. Purification was carried out at a flow rate of 40mL/ min. NMR spectra: 'H Nuclear magnetic 59 resonance spectra were recorded at 500 MHz. Data are presented as follows: chemical shift, multiplicity (s = singlet, d= doublet, t = triplet, q= quartet, qn = quintet, dd = doublet of doublets, m= multiplet, br s = broad singlet), coupling constant (J/Hz) and integration. Coupling constants were taken directly from the spectra and are uncorrected. Low resolution mass spectra: Electrospray (ES+) ionization was used. The protonated parent ion (M+H) or fragment of highest mass is quoted. Analytical gradient cortsisted of 10% ACN in water ramping up to 100% ACN over 5 min unless otherwise stated. EXAMPLE 2. 1M-(4-Methoxy-phenyl)-pyrimidine-2,4-diamine (Intermediate 1) NH N NH 2 1 [00901 A mixture of 4-chloro-pyrimidin-2-ylamine (0.30 g, 2.3 mmol) and 4-methoxy phenylamine (0.30 g, 2.4 mmol) were suspended in acetic acid (10 mL) and heated at 100 *C for 2 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7 with 7M ofNaOH solution. The resulting solution was extracted with EtOAc (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (hexane to EtOAc) to afford the title intermediate 1 (0.23 g, 45%) as a white solid. 1H NMR (500 MHz, DMSO-d 6 ): 3.69 (s, 3H), 5.84 (d, J= 5.8 Hz, 1H), 6.79 (d, J= 9.1 Hz, 2H), 7.63 (d, J= 9.1 Hz, 2H), 7.78 (d, J= 5.8 Hz, 1H), 8.65 (s, 1H); MS (ESI+): m/z 217 (M+H)*.

60 EXAMPLE 3. N4-(4-Methoxy-phenyl-N 2 --4.-(2-pyrrolidin-1-yl-ethoxy)-phenyll pyrimidine-2,4-diamine (Compound I) NH N O Na H [0091] To synthesize compound I, intermediate 1 described above and intermediate 2 were used. Intermediate 2, 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine, shown below is available commercially, and was used as received. ONU Bri (2) [0092] 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 nnol) and potassium tert butoxide (80 mg, 0.71 mmnol) in dioxane/DMF (3/1; 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 *C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HIPLC to afford the title compound 1 (20 mg of TFA salt, 11%) as a brown solid. '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, 1H), 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, 1H), 9.87 (br s, 1H), 10.22 (br s, 1H), 10.44 (br s, 1H); MS (ESI+): m/z 406 (M+H) 4

.

61 EXAMPLE 4. 4-[4-(4-Methoxy-phenylamino)-pyrimidin-2-ylamino]-N-(2-pyrrolidin-1 yI-ethyl)-benzenesulfonamide (Compound II) NH 0 N N H 100931 To synthesize compound II, intermediate 1 described above and intermediate 3 were used. Intermediate 3, 4-bromo-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide, the formula of which is shown below, was synthesized from 4-bromophenylsulfonylchloride and 2-aminoethylpyrrolidine, using commonly known synthetic techniques. 0 SN N O H Br O 3 100941 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 potassium tert-butoxide (80 mg, 0.71 mmol) in dioxane/DMF (3/1; 4 mL)-was sealed in a microwave reaction tube and irradiated with microwave at 160 *C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC to afford the title compound 11 (0.16 g of TFA salt, 85%) as a white solid. 'H NMR (500 MHz, DMSO-d 6 ): 1.80-1.95 (in, 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, 1H), 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, 1H), 8.02 (d, J= 6.2 Hz, 1H), 9.64 (br s, 1H), 10.21 (br s, 1H), 10.71 (br s, 1H); MS (ESI+): m/z 469 (M+H).

62 EXAMPLE 5. 4-[4-(4-Hydroxy-phenylamino)-pyrimidin-2-ylaminol-N-(2-pyrrolidin-1 yl-ethyl)-benzenesulfonamide (Compound 11I) H 0 )N H OS N 4 " N N H [0095] To a solution of compound H described above (50 mg, 0.09 mmol) in DCM (6 mL) at room temperature was added BBr 3 (0.1 mL) and the mixture stirred at room temperature for 2.5 h. The reaction was quenched with saturated NaHCO 3 solution until the pH-7 and the mixture 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 re-dissolved in minimum of EtOAc. Hexane was added until solid crushed out and the title compound I was filtered 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 (xm, 4H), 2.43 (t, J= 7.0 Hz, 2H), 2.82 (t, J =6.6 Hz, 2H), 6.20 (d, J= 5.8 Hz, 1H), 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, 1H), 8.93 (s, 1H), 9.08 (br s, 1H), 9.70 (s, 1H); MS (ESI+): m./z 455 (M+H)+. EXAMPLE 6. 4-(4-Chloro-pyrimidin-2-ylamino)-N-(2-pyrrolidin-1-vl-ethyl) benzenesulfonamide (Intermediate 4) C0 -s N N N N N i H 4 [00961 A mixture of 4-chloro-pyrimidin-2-ylamine (1.0 g, 7.8 mmol), above-described intermediate 3 (2.6 g, 7.8 mmol), Pd(OAc) 2 (90 Ing, 0.40 mmol), Xantphos (0.50 g, 0.86 mmol) and potassium tert-butoxide (2.2 g, 20 mmol) were suspended in dioxane (30 mL) and heated at reflux under the argon atmosphere for 16 h. The mixture was poured into water (30 mL) and extracted with EtOAc (60 mL). The organic layer was separated and washed with 63 brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (DCM to 25% MeOH/DCM) to afford the title intermediate 4 (0.15 g, 5%) as a brown solid. MS (ESI+): m/z 382 (M+H)*. EXAMPLE 7. 4-[4-(3-Methoxy-phenylamino)pyrimidin-2-ylaminol-N-(2-pyrrolidin-1 yI-ethyl)-benzenesulfonamide (Contpound IV) O NH 0 N N H IV 100971 A mixture of the above described intermediate 4 (0.10 g, 0.26 mmol) and 3 methoxy-phenylamine (0.05 mL, 0.45 mmol) were suspended in acetic acid (6 mL) and heated at 100 *C for 1.5 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with EtOAc (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo anad the crude product purified by HYLC to afford the title compound IV (55 mg of TFA salt, 36%) as a white solid. 1H NMR (500 MHz, DMSO-d 6 ): 1.80-1.90 (m, 2H), 1.95-2.05 (in, 2H), 2.95-3.05 (m, 4H), 3.24 (q, J= 6.0 Hz, 2H), 3.50-3.60 (in, 2H), 3.73 (s, 3H), 6.40 (d, J= 6.3 Hz, 1H), 6.68 (d, J= 7.3 Hz, 1H), 7.18 (d, J= 8.2 Hz, 1H), 7.26 (t, J= 8.0 Hz, 1H), 7.30 (s, 1H), 7.72 (d, J= 8.9 Hz, 2H), 7.91 (t, J= 6.1 Hz, 1H), 7.95 (d, J= 8.7 Hz, 2H), 8.10 (d, J= 6.2 Hz, 1H), 9.59 (br s, 1H), 9.87 (br s, 1H), 10.38 (br s, 1H); MS (ESI+): m/z 469 (M+H)*.

64 EXAMPLE 8. 4-[4-(3-Hydroxy-phenylamino)-pyrimidin-2-ylanino]-N-(2-pyrrolidin-1 yl-ethyl)-benzenesulfonamide (Compound V) HO NH 0 N NN H V [00981 To a solution of the above-described compound IV (30 mg, 0.05 mmol) in DCM (6 mL) at room temperature was added BBr 3 (0.1 mL) and the mixture stirred at room temperature for 2.5 h. The reaction was quenched with saturated NaHCO 3 solution until the pH-7 and the mixture extracted with EtOAc (30 mL). The organic layer was separated and washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue purified by HPLC to afford the title compound V (13 mg of TFA salt, 46%) as an off white solid. 'H NMR (500 MHz, DMSO-d 6 ): 1.80-1.90 (m, 2H), 1.95-2.05 (in, 2H), 2.95 3.05 (m, 4H), 3.20-3.30 (in, 2H), 6.39 (d, J= 6.3 Hz, 111), 6.53 (d, J= 7.2 Hz, 1H), 7.01 (d, J = 9.2 Hz, 1H), 7.09 (s, 1H), 7.14 (t, J= 8.1 Hz, 1H), 7.73 (d, J= 8.8 Hz, 2H), 7.90 (t, J= 6.2 Hz, 111), 7.97 (d, J= 8.8 Hz, 2H), 8.08 (d, J= 6.4 Hz, 1H), 9.48 (br s, 1H), 9.57 (br s, 1H), 9.86 (br s, 1H), 10.41 (br s, 1H); MS (ESI+): m/z 455 (M+H)*. EXAMPLE 9. Benzofl,3]dioxol-5-yl-(2-chloro-5-methyl-primidin-4-yl)-amine (Intermediate 5) 0 NH OON 5 [00991 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 5 bromo-benzo[1,3]dioxole (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) were suspended in dioxane (15 mL) and heated at reflux under the argon atmosphere for 16 h. The reaction mixture was 65 cooled to room temperature and diluted with DCM (20 mL). The mixture was filtered and the filtrate concentrated ih vacuo. The residue was purified by flash chromatography on silica gel (hexane to 50% EtOAc/hexane) to afford the title intermediate 5 (0.10 g, 18%) as a white solid. MS (ESI+): n/z 264 (M+H)*. EXAMPLE 10. N4-Benzofl,3]dioxol-5-yl-5-methyl-N 2 - [4-(2-pyrrolidin-1-yI-ethoxy) phenyll-pyrimidine-2,4-diamine (Compound VI) Oc NH NO NO __I NjN 0 H VI [0100] To synthesize compound VI, intermediate 5 described above and intermediate 6 were used. Intermediate 6, 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine, the formula of which is shown below, was synthesized in two steps, first by alkylation of 4-nitrophenol using 2 chloroethylpyrrolidine, followed by reduction to yield the aniline derivative. / I 0

H

2 N 6 [0101] Commonly known synthetic techniques were used to synthesize intermediate 6. A mixture of the above-described intermediate 5 (90 mg, 0.34 mmol), intermediate 6 (95 mg, 0.46 mmol), Pd 2 (dba) 3 (20 mg, 0.02 mmol), Xantphos (30 mg, 0.05 mmol) and cesium carbonate (0.30 g, 0.9 mmol) were suspended in dioxane (10 mL) and heated at reflux under the argon atmosphere for 20 h. The reaction mixture was cooled to room temperature and diluted with DCM (20 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound VI (40 mg of TFA salt, 21%) as a brown solid. 1H 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, 1H), 7.37 (d, J= 9.0 Hz, 2H), 7.84 (s, 1H, 9.60 (br s, 1H), 9.89 (br s, 1H), 10.32 (br s, 1H); MS (ESI+): nz/z 434 (M+H)*.

66 EXAMPLE 11. (4-Chloro-3-methoxv-Rhenyl)-(2-chloro-5-methyl-pyrimidin-4-yl) amine (Intermediate 7) C0 NH - NIcl 7 101021 A mixture of 2-chloro-5-methyl-pyriimidin-4-ylamine (0.50 g, 3.5 mmol), 4 bromo-1 -chloro-2-methoxy-benzene (0.65 mL, 4.8 mmol), Pd 2 (dba) 3 (0.17 g, 0.19 mmol), Xantphos (0.22 g, 0.38 mmol) and cesium carbonate (2.3 g, 7.1 mmol) were suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 40% EtOAc/hexane) to afford the title intermediate 7 (0.55 g, 55%) as a yellow solid. 'H NMR (500 MHz, DMSO-d 6 ): 2.18 (s, 3H), 3.85 (s, 3H), 7.35 (dd, J= 8.6 Hz, J= 2.3 Hz, 1H), 7.39 (d, J= 8.7 Hz, 1H), 7.56 (d, J= 2.3 Hz, 1H), 8.09 (d, J= 0.9 Hz, 1H), 8.91 (s, 1H); MS (ESI+): m/z 284 (M+H)*. EXAMPLE 12. (4-Chloro-3-methoxy-phenyl)-(2-chloro-5.-methyl-pyriidin-4-yll methyl-anine (Intermediate 8)

CI

0 N 8 101031 A suspension of intermediate 7 (0.50 g, 1.8 mrnol) and sodium hydride (60% in mineral oil, 0.15 g, 3.8 mmol) in THF (10 mL) was stirred under the argon atmosphere at 0 *C for 5 min. Methyl iodide (0.15 mL, 2.4 mmol) was syringed at the same temperature to the above mixture. The resulting solution was stirred from 0 *C to room temperature over 15 mn and further stirred at room temperature for additional 17 h. The reaction was quenched 67 with water (10 mL) and then extracted with EtOAc (30 mL). The organic layer was separated and washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (hexane to 20% EtOAc/hexane) to afford the title intermediate 8 (0.20 g, 38%) as a white solid. MS (ESI+): n/z 298 (M+H)*. 4 EXAMPLE 13. N-(4-(2-(pyrrolidin-1-yllethoxy)phenyl)-V4-(4-chloro-3 methoxyvpheniyl)-N45-dimethlpyrimidine-2,4-diamine (Compound VII) C1 0 N 'N 0 N H VII [0104] A mixture of intermediate 8 (0.15 g, 0.49 mmol) and intermediate 6 (0.15 g, 0.73 mmol), each of which intermediates is described above, were suspended in acetic acid (8 mL) and heated at 100 *C for 17 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (15 mL) and neutralized to pH-7 with 7M of NaOH solution. The resulting solution was extracted with EtOAc (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound VII (0.14 g of TFA salt, 49%) as a white solid. 'H NMR (500 MHz, DMSO-d): 1.85-1.95 (in, 2H), 2.00-2.10 (in, 2H), 3.08-3.18 (m, 2H), 3.46 (s, 3H), 3.55-3.65 (in, 4H), 3.85 (s, 3H), 4.27 (t, J= 5.0 Hz, 2H), 6.86 (d, J= 7.4 Hz, 1H), 7.01 (d, J= 9.0 Hz, 2H), 7.15 (s, 1H), 7.46 (d, J= 8.4 Hz, 1H), 7.58 (d, J= 8.9 Hz, 2H), 7.83 (s, 1H), 9.85 (br s, 1H), 10.04 (br s, 1H), 10.32 (br s, 1H); MS (ESI+): mlz 468

(M+H).

68 EXAMPLE 14. (2-Chloro-5-methvi-pyrimidin-4-yl)-(4-chloro-phenyl)-amine (Intermediate 9) aNH SCI 9 (0105] 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), Pd 2 (dba)3 (95 mg, 0.10 mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) were suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 4 h. The reaction mixture was cooled to room temperature and diluted with DCM (20 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 30% EtOAc/hexane) to afford the title intermediate 9 (0.15 g, 28%) as a pale yellow solid. MS (ESI+): m/z 254 (M+H)+. EXAMPLE 15. N'-(4-Chloro-phenyl)-5-methyl-N 2 -14-(2--pyrrolidin-1-l-ethoxy) phenyll-pyrimidine-2,4-diamine (Compound VIII) C1 N NH H Vi [0106] A mixture of the above-described intermediates 9 (0.15 g, 0.60 mmol) and 6 (0.20 g, 0.97 mnol) was suspended in acetic acid (8 mL) and heated at 100 0 C for 6 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (15 mL) and neutralized to pH-7 with 7M of NaOH solution. The resulting brown solid was filtered and further purified by HPLC to afford the title compound VIII (38 mg of TFA salt, 12%) as a brown oil. 1 H NMR (500 MHz, DMSO- 69 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, 1H), 9.48 (br s, 1H), 9.84 (br s, 111), 10.10 (br s, 1H); MS (ESI+): m/z 424 (M+H)*. EXAMPLE 16. 2-(4-Amino-phenoxy)-ethanol (Intermediate 10) H2N O O 10 [0107] A solution of 2-(4-nitro-phenoxy)-ethanol (2.1 g, 12 mmol) in MeOH (30 mL) was flushed with argon and then charged with Pd/C (10% by wt). The mixture was evacuated under house vacuum and then refilled with hydrogen from hydrogen balloon. The cycle was repeated again and the mixture stirred at room temperature for 2 h. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with MeOH and concentrated in vacuo to furnish the title intermediate 10 (1.8 g, 99%) as a brown solid. MS (ESI+): rn/z 154 (M+H)*. EXAMPLE 17. 2-{4-[4-(4-Chloro-3-methoxy-phenylamino)-5-methvl-pyrimidin-2 - ylaminol-phenoxyl-ethanol (Compound IX) QZ NH N OH H IX [0108] A suspension of the above described intermediates 7 (50 mg, 0.17 mmol), 10 (40 mg, 0.26 mmol), Pd2(dba) 2 (8 ig, 0.01 mmol), Xantphos (10 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 microwave at 160 *C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel 70 (hexane to EtOAc) to afford the title compound IX (14 mg, 21%) as a light brown solid. 'H NMR (500 MHz, DMSO-d 6 ): 2.10 (s, 3H), 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, 1H), 6.78 (d, J= 9.0 Hz, 2H), 7.29 (d, J= 8.5 Hz, 1H), 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, 1H), 8.31 (s, 1H), 8.80 (s, 1H); MS (ESI+): m/z 401 (M+H)*. EXAMPLE 18. 5-Methyl-N2-[4-(2-pyrrolidin-1-yI-ethoxy)-phenyll-pyrimidine-2,4 diamine (Intermediate 11)

NH

2 N ON H 11 {0109] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.13 g, 0.87 mmol) and the above described intermediate 6 (0.30 g, 1.5 mmol) were suspended in acetic acid (8 mL) and heated at 100 *C for 2 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was. taken in water (15 mL) and neutralized to pH~7 with 7M of 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 separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated to afford the additional solid (0.2 g), which were combined with the first batch and afforded the title intermediate 11 (0.23 g, 8504) as a light brown solid. '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, 2), 6.78 (d, J= 9.1 Hz, 2H), 7.62 (d, J= 9.1 Hz, 2H), 7.64 (s, 1H), 8.50 (s, 1H); MS (ESI+): m/z 314 (M+H) 4

.

71 EXAMPLE 19. 5-Methyl-N4-phenyl-N 2 -[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl pyrimidine-2,4-diamine (Compound X) 0 I NH NO H X [0110] A suspension of the above-described intermediate 11 (25 mg, 0.08 mmol), bromobenzene (0.05 mL, 0.50 mmol), Pd 2 (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 microwave at.160 *C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (DCM to 30% MeOH/DCM) to afford the title compound X (10 mg, 32%) as a light brown solid. 'H NMR (500 MHz, DMSO-d6): 1.65-1.72 (m, 4H), 2.10 (s, 3H), 2.48-2.58 (in, 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, IH), 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, 1H), 8.20 (s, 1H), 8.76 (s, 1H); MS (ESI+): m/z 390 (M+H)*. EXAMPLE 20. (4-Chloro-3-fluoro-phenyl)-(2-chloro-5-methyl-pyrimidin-4-yl)-amine (Intermediate 12) c1 F NH N CI 12 [01111 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), Pd 2 (dba) 3 (0.16 g, 0.17 mmol), Xantphos (0.20 g, 0.34 mmol) and cesium carbonate (2.3 g, 7.0 mmol) were suspended in 72 dioxane (25 mL) and heated at reflux under the argon atmosphere for 15 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 40% EtOAc/hexane) to afford the title intermediate 12 (0.75 g, 80%) as an off white solid. MS (ESI+): iz 272 (M+H)*. EXAMPLE 21. M-(4-Chloro-3-fluoro-phenyl)-5-methyl- N2-[4-(2-pyrrolidin-1-y ethoxy)-phenyll-pyrimidine-2,4-diamine (Compound XI) C1 F NH N N H [0112] A mixture of the above-described intermediates 12 (0.20 g, 0.74 mol) and 6 (0.20 g, 0.97 mmol) was suspended in acetic acid (8 mL) and heated at 100 0C for 6 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (15 mL) and neutralized to pH-7 with 7M of NaOH solution.. The resulting solution was extracted with EtOAc (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (DCM to 30% MeOH/DCM) to afford the title compound XI (90 mg, 28%) as a white solid. '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, 1H), 7.50 (d, J= 9.0 Hz, 2H), 7.55 (dd, J= 8.9 Hz, J= 2.0 Hz, IH), 7.91 (s, 1H), 8.07 (dd, J= 12.5 Hz, J= 2.0 Hz, 1H), 8.43 (s, 1H), 8.90 (s, 1H); MS (ESI+): m/z 442 (M+H)*.

73 EXAMPLE 22. 1M-(4-Chloro-3-methoxy-phenyl)-5-methyl-N2-(4-morpholin-4 ylmethvl-phenvl)-pyrimidine-2,4-diamine (Compound XII) CONH N O~ H XII [01131 A suspension of the above-described intermediate 7 (50 mg, 0.17 mmol), 4 morpholin-4-ylmethyl-phenylamine (50 mg, 0.26 mmol), Pd 2 (dba) 2 (8 mg, 0.009 mmol), Xantphos (10 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 microwave at 160 "C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC to afford the title compound XII (40 mg of TFA salt, 43%) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d 6 ): 2.16 (s, 3H), 3.05-3.15 (m, 211), 3.10-3.20 (m, 2H), 3.60-3.70 (in, 2H), 3.90-4.00 (in, 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, 211), 7.98 (s, 1H), 9.10 (br s, 1H), 9.86 (br s, 1H), 9.95 (br s, 1H); MS (ESI+): m/z 440 (M+H) . EXAMPLE 23. Benzolblthiophen-5-vl-(2-chloro-5-methyl-pyrimidin-4-l)--amine (Intermediate 13) NH 13 74 [01141 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 5 bromo-benzo[b]thiophene (0.6 g, 2.8 mmol), Pd 2 (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 at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL) . The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 30% EtOAc/hexane) to afford the title intermediate 13 (0.23 g, 40%) as a white solid. MS (ESI+): m/z 276 (M+H). EXAMPLE 24. M-Benzo[blthiophen5-yl-5-mthvl-N 2 -4-(2-yrrolidin-1-Vl-ethoxy) phenyll-pyrimidine-2,4-diamine (Compound XEI) NH N O H XI [01151 A mixture of the above-described intermediates 13 (0.23 g, 0.83 mmol) and 6 (0.35 g, 1.7 mmol) were suspended in acetic acid (8 mL) and heated at 100 *C for I d. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (15 m.L) and neutralized to pH-7 with 7M of NaOH solution. The resulting solution was extracted with EtOAc (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (DCM to 15% MeOH/DCM) to afford the title compound XI (0.13 g, 35%) as a white solid. '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, 1H), 7.51 (d, J= 9.1 Hz, 2H), 7.61 (dd, J= 8.7 Hz, J= 2.0 Hz, IH), 7.74 (d, J= 5.4 Hz, IH), 7.85 (d, J= 0.8 Hz, IH), 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+): rn/z 446 (M+H)*.

75 EXAMPLE 25. Benzo[blthiophen-3-vl-(2-chloro-5-methyl-pyrimidin-4-vl)-amine (Intermediate 14) NH NCI 14 [01161 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), Pd 2 (dba) 3 (95 mg, 0.10 mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) were suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 30% EtOAc/hexane) to afford the title intermediate 14 (65 mg, 11%) as a yellow solid. MS (ESI+): m/z 276 (M+H)*. EXAMPLE 26. N'-Benzoblthiophen-3-l-5-methyl-N 2 -f4-(2-pyrrolidin-1-yl-ethoxy) phenyll-pyrimidine-2,4-diamine (Compound XIV) N H N N H XIV [0117] A mixture of the above-described int'ermediates 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 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (10 mL) and neutralized to pH-7 with 7M of NaOH 76 solution. The resulting solution was extracted with EtOAc (20 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO 4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (DCM to 15% MeOH/DCM) to afford the title compound XIV (10 mg, 13%) as an off white solid. '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, 211), 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 (in, 1H), 7.87 (s, 1H), 7.90-8.03 (m, IH), 8.33 (s, 1H), 8.78 (s, IH); MS (ESI+): rn/z 446 (M+H)*. EXAMPLE 27. (2-Chloro-5-methyl-pyrimidin-4-yll-(3-chloro-phenyl)-amine (Intermediate 15) CI NH NCI 15 [01181 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 at reflux under the argon atmosphere for 4 h. The reaction mixture was cooled to room temperature and diluted with DCM (20 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 40% EtOAc/hexane) to afford the title intermediate 15 (0.30 g, 56%) as a pale yellow solid. MS (ESI+): n/z 254 (M+H)*.

77 EXAMPLE 28. N-(3-Chloro-phenyl)-5-methyl-N 2 -[4-(2-pyrrolidin-1-i-ethoxy) phenvll-pyrimidine-2,4-diamine (Compound XV) Cl NH NNO H XV [01191 A mixture of the above-described intermediates 15 (0.15 g, 0.59 mmol) and 6 (0.25 g, 1.2 mmol) was suspended in acetic acid (8 mL) and heated at 100 *C for 21 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (15 mL) and neutralized to pH-7 with 7M of NaOH solution. The resulting solution was extracted with EtOAc (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (DCM to 10% MeOH/DCM) to afford the title compound XV (60 mg, 24%) as a white solid. 'H NMR (500 MHz, DMSO-d,): 1.65-1.72 (m, 4H), 2.10 (s, 311), 2.50-2.60 (m, 4H), 2.78-2.83 (i, 2H), 4.01 (t, J= 5.9 Hz, 2H), 6.81 (d, J= 9.1 Hz, 2H), 7.05-7.08 (m, 1H), 7.32 (t, J= 8.1 Hz, 111), 7.52 (d, J= 9.0 Hz, 2H), 7.71 (d, J= 8.3 Hz, 1H), 7.85 (t, J= 2.1 Hz, 1H), 7.89 (d, J= 0.7 Hz, 1H), 8.33 (s, IH), 8.86 (s, 1H); MS (ESI+): m/z 424 (M+H)*. EXAMPLE 29. 3-Bromo-N-methyl-benzamide (Intermediate 16) Br 0 16 78 [01201 A solution of 3-bromo-benzoyl chloride (2.93 g, 13.3 mmol, 1 eq) in 30mL THF was stirred vigorously and treated with 2.OM 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. Reaction was then poured onto ethyl acetate (100 mL) and washed with water (2 x 150 mL) and brine (I x 150 mL). Organic phase cut from aqueous phase and dried over sodium sulfate, filtered and evaporated to afford the title intermediate 16 as a white powder. (2.29g, 82% yield). EXAMPLE 30. 3-(2-Chloro-5-methyl-pyrimidin-4-ylamino)-N-methvl-benzamide (Intermediate 17) H I XNH ""N CI 17 [0121] In a dry 50 mL round bottom flask, 2-chloro-5-methyl-pyrimidin-4-ylamine (0.3 g, 2.09 mmol, 1 equiv), 3-bromo-N-methyl-benzamide (0.489g, 2.29 mmol, 1.1 equiv), cesium carbonate (2.04.g, 6.27 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.242 g, 0.418 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.191 g, 0.209 mmol, 0.1 equiv) were combined. Reactants were diluted with dioxane (20 mL), flushed with argon and outfitted with reflux condenser. Reaction was heated to reflux for 16 hours. Reaction was then transferred into centrifuge tube, spun down, decanted and evaporated. Resulting yellow solids were diluted with DCM and adsorbed onto silica gel. Chromatography (gradient of 50% ethyl acetate in hexanes up to 100% ethyl acetate) afforded the title intermediate 17 as a pale yellow powder (0.25 g, 43% yield). MS (ESI+): 277.01 (M+H), r.t. = 1.92 min.

79 EXAMPLE 31. N-Methyl-3-{5-methyl-2-f4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino pyrimidin-4-ylaminol-benzamide TFA salt (Compound XVI) H N O N O No 0 .NNCx H XVI [0122] The above-described intermediate 17 (0.068 g, 0.246 mmol, 1 eq), 4-(2-Pyrrolidin 1-yl-ethoxy)-phenylamine (0.061 g, 0.296 mmol, 1.2 eq), cesium carbonate (0.241 g, 0.74 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethy xanthene (0.029 g, 0.05 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.023 g, 0.025 mmol, 0.1 equiv) were combined in 15ml microwave vessel. Reactants were then diluted with 7 ml dioxane and microwaved for 15 minutes at 160 *C. Reaction vessel was then spun down, decanted and evaporated to dryness. HPLC purification afforded the TFA salt of the title product XVI (0.084 g, 76%). MS (ESI+): 447.20 (M+H), r.t. = 1.53 min. 'H NMR (DMSO-d 6 ): 8 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, 211), 7.34 (d, J=8.9 Hz, 2H), 7.47 (t, J=7.9 Hz, 1H), 7.68-7.70 (m, 2H), 7.93 (s, 1H), 8.00 (s, 1H), 8.46-8.47 (m, 1H), 9.80 (bs, 1H), 9.93 (bs, 1H) 10.41 (bs, 1H). EXAMPLE 32. N4-(4-Chloro-3-methoxy-phenyl)-5-methyl--N 2 -14-(2-pyrrolidin-1-yl ethoxy)-phenyl]-pyrimidine-2,4-diamine TFA salt (Compound XVII) C1 O NH H

XVII

80 10123] The above-described intermediate 7 (0.083 g, 0.293 mmol, 1 eq), 4-(2-Pyrrolidin 1-yl-ethoxy)-phenylamine (0.073 g, 0.352 imol, 1.2 eq), cesium carbonate (0.287 g, 0.879 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (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 15ml microwave vessel. Reactants were then diluted with 7 ml dioxane and microwaved for 15 minutes at 160 *C. Reaction vessel was then spun down, decanted and evaporated to dryness. HPLC purification afforded the TFA salt of the title product XVII (0.1 g, 75%). MS (ESI+): 454.13 (M+H), r.t.= 1.82 min. 'H NMR (DMSO-d6): 8 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, J=5.0 Hz, 3H), 6.91 (d, J=8.9 Hz, 2H), 7.23 (in, 1H), 7.34-7.4 (m, 4H), 7.93 (s, IH), 9.63 (bs, 1H), 9.96 (bs, 1H) 10.40 (bs, IH). EXAMPLE 33. N-(2-Chloro-5-methyl-pyriidin-4-vl)-N',i'-dimethyl-benzene-1,3 diamuine (Intermediate 18) NN CI 18 [01241 2-Chloro-5-methyl-pyrimidin-4-ylamine (0.343 g, 2.38 mmol, 1 equiv), (3-bromo phenyl)-dimethyl-amine (0.524g, 2.62 mmol, 1.1 equiv), cesium carbonate (2.3 g, 7.15 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.276 g, 0.476 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.218 g, 0.238 mmol, 0.1 equiv) were combined in 30ml microwave vessel. Reactants were then diluted with 12m] dioxane and microwaved for 25 minutes at 160 *C. Reaction vessel was then spun down, decanted and evaporated to dryness. Resulting solids were diluted with DCM and adsorbed onto silica gel. Chromatography (gradient of 0% methanol in DCM up to 25% methanol in DCM) afforded the title intermediate 18 as orange solid (0.184 g, 29% yield). MS (ESI+): 263.02 (M+H), r.t. 1.72 min.

81 EXAMPLE 34. N4-(3-Dimethylamino-phenyl)-5-methyl-N 2 -14-(2-pyrrolidin-1-yl ethoxy)-phenvll-pyrimidine-2,4-diamine TFA salt (Compound XVIII N ' NH NO No H xVm [01251 The above-described intermediate 18 (0.092 g, 0.35 mmol, 1 eq), 4-(2-pyrrolidin 1 -yl-ethoxy)-phenylamine (0.087 g, 0.42 minol, 1.2 eq), cesium carbonate (0.343 g, 1.05 mmol, 3 equiv), 4,5-bis(diphenyl phosphino)-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 vessel. Reactants were then diluted with 7ml dioxane and microwaved for 15 minutes at 160 *C. Reaction vessel was then spun down, decanted and evaporated to dryness. HPLC purification provided the TFA salt of the title compound XVIII (0.035 g, 23%). MS (ESI+): 433.21 (M+H), r.t. = 1.52 min. 'H NMR (DMSO-d 6 ): 8 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, 1H), 6.82-6.90 (m, 4H), 7.20 (t, J=8.0 Hz, 1H), 7.39 (d, P=9.1 Hz, 2H), 7.85 (s, 1H), 9.63 (bs, 1H); 9.90 (bs, 1H) 10.39 (bs, 1H). EXAMPLE 35. (2-Chloro-5-methyl-pyrimidin-4-l)-(3,4-dichloro-phenyl)-amine (Intermediate 19) CI C, NH 19 82 [0126] 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 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethy xanthene (0.328 g, 0.57 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.26 g, 0.283 mmol, 0.1 equiv) were combined in 30ml microwave vessel. Reactants were then diluted with 12ml dioxane and microwaved for 25 minutes at 160 0C. Reaction vessel was then spun down, decanted and evaporated to dryness. Resulting solids were diluted with DCM and adsorbed onto silica gel. Chromatography (gradient of 15% ethyl acetate in hexanes up to 80% ethyl acetate in hexanes) afforded the title intermediate 19 as a pale yellow powder (0.366 g, 45% yield). MS (ESI+): 287.97 (M+H), r.t. = 3.12 min. EXAMPLE 36. N4-(3,4-Dichloro-phenvl)-5-methyl-N-4-(2-pyolidin---l-ethoxv) phenyll-pyrimidine-2,4-diamine TFA salt (Compound XDQ CI NH H [01271 The above-described intermediate 19 (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-dimethy xanthene (0.036 g, 0.063 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.029 g, 0.0314 mmol, 0.1 equiv) were combined in 15ml microwave vessel. Reactants were then diluted with 7ml dioxane and microwaved for 15 minutes at 160 *C. Reaction vessel was then spun down, decanted and evaporated to dryness. HPLC purification provided the TFA salt of the tite compound XIX (0.056 g, 39%). MS (ESI+): 458.1 (M+H), r.t. = 1.93 min. 'H NMR (DMSO-d 6 ): 8 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, 1H), 9.89 (bs, 1H) 10.17 (bs, 1H).

83 EXAMPLE 37. 4-{3-[4-(4-Chloro-3-methoxy-phenylamino)-S-methyl-pyrimidin-2 vlaminol-benzyll-piperazine-1-carboxylic acid tert-butyl ester (Intermediate 20) C1 "O ~ NH 0 N N H 20 [0128] (4-Chloro-3-methoxy-phenyl)-(2-chloro-5-methyl-pyrimidin-4-yl)-amine (0.092 g, 0.325 mmol, 1 eq), 4-(3-amino-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (0.114 g, 0.39 mmol, 1.2 eq), cesium carbonate (0.318 g, 0.975 mmol, 3 equiv), 4,5 bis(diphenylphosphino)-9,9-dimethyl xanthene (0.038 g, 0.065 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.03 g, 0.0325 mmol, 0.1 equiv) were combined in a 15 ml microwave vessel. Reactants were then diluted with 7ml dioxane and microwaved for 15 minutes at 160 "C. Reaction vessel was then spun down, decanted and evaporated to dryness. HPLC purification afforded the TFA salt of the title intermediate 20 (0.075 g, 43%). MS (ESI+): 539.32 (M+H), r.t.= 2.09 min. EXAMPLE 38. 1/-(4-Chloro-3-methoxy-phenyl)-5-methyl-N-(3-piperazin-1-vlmethyl phenyl)-pyrimidine-2,4-dianine TFA salt (Compound XX) C NH N NH H Xx [0129] A stirring solution of the above-described intermediate 20 (0.075 g, 0.14 mmol, 1 eq) in DCM (6ml) was treated with TFA (2ml). After 2h, reaction solvents were evaporated and resulting residue triturated with ether to afford the title compound XX as white, hygroscopic solids, TFA salt. (0.05 g, 82%). MS (ESI+): 439.13 (M+H), r.t. = 1.67 min. 'H NMR (DMSO-d 6 ): S 2.17 (s, 3H), 2.89 (bs, 4H), 3.2 (bs, 4H), 3.68 (s, 3H), 3.82 (bs, 3H), 84 7.16-7.20 (m, 2H), 7.28 (t, J=7.7 Hz, lH), 7.33 (d, J=2.3Hz, 1H), 7.39 (s, 1H), 7.42 (d, J=8.5 Hz, IH), 7.49-7.51 (m, 1H), 7.98 (s, 1H), 8.87 (bs, IH), 9.79 (bs, 1H) 10.57 (bs, 1H). EXAMPLE 39. 2-(4-(2-(Pyrrolidin-1-yI)ethoxv)phenylamino)-4-aminopyrimidine-5 carbonitrile (Intermediate 21)

NH

2 4 NC N O N H 21 10130] 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 mmol), Cs 2

CO

3 (1.3 g, 4.0 mmol), Pd 2 (dba) 3 (92 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino) 9,9-dimethyxanthene (Xant Phos, 174 mg, 0.3 nmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL). The organic solution was separated and dried (Na 2

SO

4 ). The solvent was removed until 5 mL and hexane (50 mL) was added, the solid was collected by filtration. The crude product was purified by HPLC and afforded the title intermediate 21 (32 mg, 10%). EXAMPLE 40. 4-(2,4-Dichloro-5-methoxyphenylamino)-2-(4-(2-(pyrrolidin-1 vl)ethoxv)phenyl-amino)pvrimidine-5-carbonitrile (Compound XXI) C1 C1 0 NH NC H O H XXI {0131] To a solution of the above-described intermediate 21 (32 mg, 0.1 mmol) in 1,4 dioxane (10 mL) was added 1-bromo-2,4-dichloro-5-methoxybenzene (28 mg, 0.11 mmol), Cs 2

CO

3 (97 Ing, 0.3mmol), Pd 2 (dba) 3 (7 mg, 0.0074 nmol), and 4,5-bis(diphenylphosphino) 9,9-dimethyxanthene (Xant Phos, 13 mg, 0.022 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL).

85 The organic solution was separated and dried (Na 2

SO

4 ). The solvent was removed in vacuo. The crude product was purified by chromatograph (SiO 2 / CH 2 Cl 2 , then CH 2 C12: MeOH:

NH

3 .H20 = 100: 10: 1) and afforded the title compound XXI (35 mg, 67%). 'H NMR (500 MHz, DMSO-d 6 ): 1.88-1.90 (in, 2H); 2.00-2.03 (in, 2H); 3.07-3.11 (in, 2H); 3.54-3.56 (m, 411); 3.81 (s, 311); 4.25 (br, 2H); 6.68 (br, 2H); 7.32 (br, 2H); 7.33 (s, 1H); 7.75 (s, 11); 8.50 (s, IH); 9.73 (br, 1H); 9.94 (br, 1H); 10.60 (br, 1H). MS (EI): 499.0. EXAMPLE 41. 2-(3-(2-(Pyrrolidin-1-yIlethoxy)phenylamino)-4-aminopyrimidine-5 carbonitrile (Intermediate 22)

NH

2 NC N O H 22 [01321 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 rug, 1.07 mmol), Cs 2

CO

3 (1.43 g, 4.4 rmol), Pd 2 (dba) 3 (92 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino) 9,9-dimethyxanthene (Xant Phos, 174 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (I x 100 mL). The organic solution was separated and dried (Na 2

SO

4 ). The solvent was removed until 5 mL and hexane (50 mL) was added, the solid was collected by filtration. The crude product was purified by HPLC and afforded the title intermediate 22 (55 mg, 16%). EXAMPLE 42. 4-(2, 4 -Dichloro-5-methoxyphenylamino)-2-(3-(2-(pyrrolidin-1 y)ethox)phenyl-amino)pyrimidine-5-carbonitrile (Compound XXH) C) CI 0 NH NC N N O H XXll 86 [01331 To a solution of the above-described intermediate 22 (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), Cs 2 CO3 (200 mg, 0.62 mmol), Pd 2 (dba) 3 (14 mg, 0.015 mmol), and 4,5 bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 27 mg, 0.05 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL). The organic solution was separated and dried (Na 2 SO4). The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXHI (6 mg, 8%). 'H NMR (500 MHz, DMSO-d'): 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, 1H); 7.14 (br, 211); 7.34 (s, 1H); 7.74 (s, 1H); 8.54 (s, 1H); 9.70 (br, 1H); 9.95 (br, 1H); 10.83 (br, 1H). MS (El): 499.0. EXAMPLE 43. 2-Chloro-N-(2,4-dichloro-5-methoxyphenyl)-5-methvypyrimidin4 amine (Intermediate 23) CI C1 MeO NH 23 [0134] 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 mnmol), Cs 2

CO

3 (408 mg, 1.25 mmol), Pd2(dba)3 (37 mg, 0.04 mmol), and 4,5 bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 70 mg, 0.12 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL). The organic solution was separated and dried (Na 2

SO

4 ). The solvent was removed in vacuo. The crude product was used for next reaction without purification.

87 EXAMPLE 44. 1-(3-(2-(pyrrolidin-1-yl)ethoxyphenyl)--(2,4-dichloro-5methoxyphenyl)-5-methylipyrimidine-2,4-diamine (Compound XXIII) C1 C1 MeO NH N N H XXI [0135] To a solution of the above-described intermediate 23 in 1,4-dioxane (10 mL) was added 3-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (77.3 mg, 0.38 mmol), Cs 2 CO3 (488 mg, 1.25 mmol), Pd 2 (dba) 3 (28 mg, 0.03 minol), and 4,5-bis(diphenylphosphino)-9,9 dimethyxanthene (Xant Phos, 53 mg, 0.09 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL). The organic solution was separated and dried (Na2SO 4 ). The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXHI (25 mg, 15%). 1H NMR (500 MHz, DMSO-d 6 ): 1.87-1.89 (m, 2H); 1.90-2.03 (in, 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, 1H); 6.91 (s, 1H); 6.96 (d, J= 8.5 Hz, 1H); 7.02 (t, J=.8.2 Hz, 1H); 7.37 (s,.1H); 7.83 (s, 1H); 8.02 (s, 1H); 10.09 (br, 1H); 10.66 (br, 1H); 10.82 (br, 1H). MS (EI): 488.2. EXAMPLE 45. 2-Chloro-N-(3-methoxyphenyl)-5-methlprimidin-4-amine (Intermediate 24) MeO NH NCI 24 [0136] 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), Cs 2

CO

3 (2.9 g, 8.9 mmol), Pd 2 (dba)3 (201 mg, 0.22 mmol), and 4,5-bis(diphenylphosphino)-9,9- 88 dimethyxanthene (Xant Phos, 382 mg, 0.66 ramol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine'(1 x 100 mL). The organic solution was separated and dried (Na 2

SO

4 ). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 24 (500 mg, 90%), was used for next reaction without further purification. EXAMPLE 46. N 2 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-M-(3.-methoxyphenyl)-5 methyl-pyrimidine-2,4-diamine (Compound XXIV) MeO NH N O N H XXV [0137] To a solution of the above-described intermediate 24 (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), Cs 2

CO

3 (1.3 mg, 4.0 mmol), Pd 2 (dba) 3 (82 mg, 0.09 mmol), and 4,5-bis(diphenylphosphino) 9,9-dimethyxanthene (Xant Phos, 156 mg, 0.27 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL). The organic solution was separated and dried (Na 2

SO

4 ). The solvent was removed in vacuo. The crude product was purified by HPLC and afforded 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, 211); 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, IH); 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, 1H); 7.56 (d, J 7.7 Hz, 1H); 7.89 (s, 1H); 9.75 (s, 1H); 10.51 (s, 1fH); 10.96 (br, 111). MS (EI): 420.2.

89 EXAMPLE 47. 3-(2-(4-(2-(1Pyrrolidin-1-yI)ethoxv)phenylamino)-5-methylpyrimidin-4 vlamino)-phenol (Compound XXV) HO c NH I NA N Q N H XXV [0138] To a solution of the above-described compound XXIV (50 mg, 0.1 mmol) in anhydrous CH 2 C1 2 (10 mL) was added 1.0 M BBr 3 in CH 2 Cl 2 (0.3 mL, 0.3 mmol). The mixture was stirred for 3 h at room temperature. The saturated NaHCO 3 (20 mL) was added and organic layer was separated. The aqueous was extracted with CH 2 C1 2 (3 x 10 mL). Combined organic solution was dried (Na 2 SO4). The product was purified by HPLC and afforded the title compound XXV (17 mg, 35%) as yellow solid. 'H NMR (500 MHz, DMSO-d): 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, 1H); 6.91 (d, J = 8.4 Hz, 2H); 6.96 (d, J = 7.6 Hz, 1H); 7.00 (s, 1H); 7.18 (t, J = 8.0 Hz, 1H); 7.38 (d, J = 8.6 Hz, 2H); 7.88 (s, 1H); 9.70 (s, 1H); 9.74 (s, IH); 10.55 (s, 1H); 11.09 (br, 1H). MS (El): 406.2. EXAMPLE 48. 2-Chloro-5-methyl-N-(3-nitrophenvl)pvrinidin-4-amine (Intermediate 25) 0 2 N NH Me 25 [01391 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), Cs 2

CO

3 (2.1 g, 6.4 mmol), Pd 2 (dba) 3 (146 mg, 0.16 mmol), and 4,5-bis(diphenylphosphino)-9,9 dimethyxanthene (Xant Phos, 278 mg, 0.48 mmol). The mixture was heated under reflux for 90 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL). The organic solution was separated and dried (Na 2

SO

4 ). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 25, was used for next reaction without further purification. EXAMPLE 49. N-(4-(2-(pyvrrolidin-1-Yl)ethoxy)phenyl)-5-methyl-N4-(3 nitrophenyl)pyrindine-2.4-diamine (Compound XXVI) 0 2 N NH N O N H XXVI [0140] To a solution of the above-described intermediate 25 in 1,4-dioxane (40 mL) was added 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (367 mg, 1.78 mmol), Cs 2

CO

3 (2.1 g, 6.4 mmol), Pd 2 (dba) 3 (146 mg, 0.16 mmol), and 4,5-bis(diphenylphosphino)-9,9 dimethyxanthene (Xant Phos, 218 mg, 0.48 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL). The organic solution was separated and dried (Na 2

SO

4 ). The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXVI (51 mg, 7%). 'H NMR (500 MHz, DMSO-d): 1.89-1.92 (m, 2H); 1.98-2.05 (m, 211); 2.21 (s, 3H); 3.10 3.12 (m, 2H); 3.52-3.57 (m, 411); 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, 1H); 7.56 (dd, J= 8.4 Hz, J = 1.8 Hz, 11); 8.09 (d, J= 7.4 Hz, 1H); 8.45 (s, 1H); 10.14 (s, 1H); 10.60 (s, 1H); 11.17 (br, 1H). MS (El): 435.2.

91 EXAMPLE 50. 4-(2-Chloro-5-methylpyrimidin-4-vlamino)-2-chlorobenzonitrie (Intermediate 26) NC CIXaNH NCl 26 [0141] 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), Cs 2

CO

3 (1.3 g, 4.0 mmol), Pd 2 (dba) 3 (91 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9 dimethyxanthene (Xant Phos, 173 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL). The organic solution was separated and dried (Na 2

SO

4 ). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 26, was used for next reaction without further purification. EXAMPLE 51. 4

-(

2

-(

4

-(

2 -(pvrrolidin-1-yllethoxy)phenylamino)-5-methylprimidin-4 ylamino)-2-chlorobenzonitrile (Compound XXVII) NC CI .NH H XXVII [0142] To a solution of the above-described intermediate 26 (140 mg, 0.5 mmol) in 1,4 dioxane (20 mL) was added 4

-(

2 -(pyrrolidin-1-yl)ethoxy)benzenamine (113 mg, 0.55 mmol), Cs 2

CO

3 (660 mg, 2.0 mmol), Pd 2 (dba) 3 (46 mg, 0.05 mmol), and 4 ,S-bis(diphenylphosphino) 9,9-dimethyxanthene (Xant Phos, 87 mg, 0.15 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL). The organic solution was separated and dried (Na 2

SO

4 ). The solvent was removed in vacuo.

92 The crude product was purified by HPLC and afforded the title compound XXVII (11.5 mg, 5%) as a yellow solid. 'H NMR (500 MHz, DMSO-d'): 1.89-1.92 (m, 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, IH); 8.03 (s, 11); 8.16 (s, 111); 9.82 (br, 1H); 10.37 (br, 1H); 10.90 (br, 1H). MS (EI): 449.1. EXAMPLE 52. M-(4-(2-(pvrrolidin-1-yI)ethoxy)phenyl)-5-methyl-N4-p tolylpyrinidine-2,4-diamine (Compound XXVIII) NH N N H XXVIII [0143] To a solution of the above-described intermediate 11 (50 mg, 0.16 mmol) in 1,4 dioxane (20 mL) was added 1-bromo-4-methylbenzene (28 mg, 0.16 nmol), Cs 2

CO

3 (210 mg, 0.64 mmol), Pd 2 (dba) 3 (10 mg, 0.01 mmol), and 4,5-bis(diphenylphosphino)-9,9 dimethyxanthene (Xant Phos, 18 mg, 0.03 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off. The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXVMI (15.7 mg, 6%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d'); 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, 211); 6.89 (br, 2H); 7.18 (br, 2H); 7.31 (br, 2H); 7.41 (br, 2H); 7.84 (s, 1H); 9.71 (s, 111); 10.46 (s, 1H); 11.13 (br, 1H1). MS (El): 404.2.

93 EXAMPLE 53. N 2 -(4-(2-(pvrrolidin-1-yl)ethoxy)phenyl)-M-(4-chloro-3-methylphenyl) 5-methylpyrimidine-2,4-diamine (Compound XXIX) C1 NO N H XXIX [0144) To a solution of the above-described intermediate 11 (80 mg, 0.25 mmol) in 1,4 dioxane (20 mL) was added 4-bromo-1-chloro-2-methylbenzene (63 mg, 0.30 mmol), Cs 2

CO

3 (326 mg, 1.0 mmol), Pd 2 (dba) 3 (18 mg, 0.02 mmol), and 4,5-bis(diphenylphosphino) 9,9-dimethyxanthene (Xant Phos, 36 mg, 0.06 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off. The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXIX (17.5 mg, 15%) as a yellow solid. 1H NMR (500 MHz, DMSO-d'): 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, 111); 7.31 (br, 1H); 7.41 (br, 2H); 7.58 (s, 111); 7.89 (br, 1H); 9.75 (s, 1H); 10.54 (s, 1H); 11.13 (br, IH). MS (EI): 438.1. EXAMPLE 54. N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-4-benzyl-5-methylprimidin-2 amine (Compound XXX) 'N 0 N NN H XXX [01451 To a solution of 4-benzyl-2-chloropyrimidine (286 mg, 1.4 mmol) in 1,4-dioxane (20 m.L) was added 4-(2-(pyrrolidin-1-yl)ethoxy)benzenanine (288 mg, 1.4 mmol), Cs 2

CO

3 (1.82 g, 5.6 mmol), Pd 2 (dba) 3 (92 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9 dimethyxanthene (Xant Phos, 173 mg, 0.3 mmol). The mixture was heated under reflux for 4 94 h under Ar. The solid was filtered off. The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXX (42 mg, 10%) as a yellow solid. 'H NMR (500 MHz, DMSO-d'): 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, IH); 6.93 (d, J =8.8 Hz, 2H); 7.24 (in, IH); 7.32 (m, 4H); 7.62 (d, J =8.8 Hz, 2H); 8.32 (d, J =5.0 Hz, 1H); 9.66 (s, 1I); 10.92 (br, 1H). MS (EI): 375.2. 4 EXAMPLE 55. 4-((IH-indol-4-yl)methyl)-N-(4-(2-(pyvrrolidin-1-yl)ethoxy)phenl)-5 methylpyrimidin-2-amine (Compound XXXI) NH H XXXI [01461 To a solution of the above-described intermediate 11 (460 mg, 1.46 mmol) in 1,4 dioxane (20 mL) was added 4-bromo-1H-indole (288 mg, 1.46 mmol), Cs2CO 3 (1.95 g, 6.0 mmol), Pd 2 (dba) 3 (128 mg, 0.14 mmol), and 4,5-bis(diphenylphosphino)-9,9 dimethyxanthene (Xant Phos, 243 mg, 0.42 mmol). The mixture was heated under reflux for overnight under Ar. The solid was filtered off. The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXXI (66 mg, 10%) as a yellow solid. 1H NMR (500 MiHz, 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, 1H); 6.60 (br, 2H); 6.82 (br, IH); 6.92 (br, 1H); 7.02 (br, 2H); 7.16 (br, IH); 7.26 (br, IH); 7.43 (in, 1H); 7.88 (m, 1H); 10.11 (s, IH); 11.40 (s, IH). MS (El): 429.1.

95 EXAMPLE 56. 2-Chloro-5-methyl-N-(naphthalen-1-yl)pvrimidin-4-amine (Intermediate 27) NH " NIcl 27 [0147] To a solution of2-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), Cs 2

CO

3 (1.3 g, 4.0 mol), Pd 2 (dba) 3 (91 Mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 183 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL). The organic solution was separated and dried (Na 2

SO

4 ). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 27, was used for next reaction without further purification. EXAMPLE 57. N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-methyl-4-(naphthalen-1 yI)pyrimidin-2-amine (Compound XXXII NH N N H XXXII [01481 To a solution of the above-described intermediate 27 (235 mg, 0.87 mnol) in 1,4 dioxane (20 mL) was added 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (183 mg, 0.87 mmol), Cs 2

CO

3 (1.3 g, 4.0 mmol), Pd 2 (dba) 3 (46 mg, 0.05 mmol), and 4,5-bis(diphenylphosphino) 9,9-dimethyxanthene (Xant Phos, 87 mg, 0.15 mmol). The mixture was heated under reflux 96 for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL). The organic solution was separated and dried (Na 2

SO

4 ). The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXXII (89 mg, 21%) as a yellow solid. 'H NMR (500 MHz, DMSO-d'): 1.88-1.90 (in, 2H); 1.97-2.03 (in, 2H); 2.30 (s, 3H); 3.03-3.08 (m, 2H); 3.50-3.53 (in, 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, 1H); 7.63 (t, J = 7.4 Hz, 1H); 7.89 (d, J = 8.3 Hz, 2H); 7.95 (s, 1H); 8.02 (d, J = 8.3 Hz, IH); 8.08 (d, J= 7.7 Hz, 1H); 10.37 (s, 1H); 10.43 (s, 1H); 10.93 (br, 1H). MS (El): 440.1. EXAMPLE 58. 1-( 2 -Chloro-5-methylpyrimidin-4-YI)isoquinoline (Intermediate 28) NH N CI 28 [0149] To a solution of 2-chloro-5-methylpyrimidin-4-amine (144 mg, 1.0 imol) in 1,4 dioxane (40 mL) was added 1 -chloroisoquinoline (164 mg, 1.0 mmol), Cs 2

CO

3 (1.3 g, 4.0 mmol), Pd 2 (dba) 3 (91 mg, 0.1 .mmol), and.4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 183 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL). The organic solution was separated and dried (Na 2

SO

4 ). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 28, was used for next reaction without further purification.

97 EXAMPLE 59. N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-4-(isoquinolin-1-vi)-5 methylpyrimidin-2-amine (Compound XXXID N NH4 NHN N N H XXXIH [01501 To a solution of the above-described intermediate 28 (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), Cs 2 C0 3 (391 mg, 1.2 mmol), Pd 2 (dba) 3 (28 mg, 0.03 mmol), and 4,5-bis(diphenylphosphino) 9,9-dimethyxanthene (Xant Phos, 52 mg, 0.09 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL). The organic solution was separated and dried (Na 2 SO4). The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXXIH (21 mg, 15%) as a yellow solid. 'H NMR (500 Ivz, DMSO-d): 1.64-1.70 (n, 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, 1H); 6.93 (d, J = 9.0 Hz, 2H); 6.97 (d, J = 7.2 Hz, 1H); 7.45 (br, 1H); 7.57 (d, J = 8.8 Hz, Ii); 7.58-7.62 (m, 1H); 7.70-7.78 (in, 2H); 8.04 (s, IH); 8.75 (d, J 8.1 Hz, 1H); 9.06 (s, IH); 9.19 (s, IH). MS (EI): 441.2.

98 EXAMPLE 60. N 2 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-M-(3 (trifluoromethyl)phenyl)-5-methylpyrinidine-2.4-diamine (Compound XXXIV)

F

3 C NH N NN H 10151] 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), Pd 2 (dba) 3 (9.0 mg, 0.01 mmol), Xantphos (12 mg, 0.02 mmol) and cesium carbonate (650 mg, 2.0 mmol) were suspended in dioxane (15 mL) and heated at reflux under the argon atmosphere for 15 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo .The residue on purification using HPLC gave -(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 N 4 -(3-(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 mmol) were dissolved in acetic acid (5 mL) and heated under microwave at 150 *C for 10 min. The mixture was cooled to room temperature and acetic acid removed under reduced pressure. The residue was purified by HPLC to afford the title compound XXXIV as brown solid (16 mg, 35%). '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= 5.1Hz, 1H), 7.45-7.57 (m, 3H), 7.9-7.97 (in, 2H), 8.20 (d, J= 7.6 Hz, 1H), 8.41(s, 111), 8.85 (s, 111), n/z 458 (M+H)*.

99 EXAMPLE 61. 2-chloro-N-(4-(trifluoromethyl)phenyl)-5-methylpyrimidin-4-amine (Intermediate 29) NH N CI 29 [01521 A suspension of 2-chloro-5-methylpyrimidin-4-amine (159 pL, 1.2 mmol), 1 bromo4-(trifluoromethyl)benzene (150 mg, 1.0 mmol), potassium tert-butoxide (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 afford the title intermediate 29 (128.7 mg, 43%) as a white solid. MS (ESI+): m/z 288 (M+Hf). EXAMPLE 62. 1 2 -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1M-(4 (trifluoromethyl)phenyl)-5-methylpyrimidine-2,4-diamine (Compound XXXV NH I NNNQ N H XXXV [01531 A mixture of the above-described intermediates 29 (128 mg, 0.5 mmol) and 6 (212 mg, 1.0 mmol) were suspended in acetic acid (5 mL) and heated at 75 C for 18 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was basified with sat., aq NaHCO 3 (50 mL) and extracted with DCM (2x50 mL). The organic layer was concentrated in vacuo and the crude product purified by reverse phase flash chromatography on C18 (water to CH 3 CN, 0.1% TFA). The aqueous 100 fractions were neutralized with sat, aq NaHCO 3 and extracted with EtOAc. The organics were concentrated in vacuo and the residue taken up in DCM. HCI in dioxane was added along with ether and the resulting solid filtered to afford the hydrochloride salt of the title compound XXXV (166 mg, 70%) as a grey solid. 'H NMR (500 MHz, DMSO-d 6 ): 1.80 1.95 (i, 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, 1H), 9.92 (br s, IH), 10.44 (br s, 1H), 10.85 (br s, 1H); MS (ESI+): m/z 458.5 (M+H)*. EXAMPLE 63. Benzo[1,31dioxol-4-vl-(2-chloro-5-methyl-pyrimidin-4-yl)-amine (Intermediate 30) NH NC 30 [01541 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.4 g, 9.7 mmol), 4-bromo benzo[1,3]dioxole (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 mol) was suspended in dioxane (40 mL) and heated at reflux under the argon atmosphere for 5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes to 50% EtOAc/hexanes) to afford the title compound (1.0 g, 39%) as a white solid. 'H NMR (500 MHz, DMSO-d 6 ): 5 2.13 (s, 3H), 5.99 (s, 2H), 6.80-6.90 (m, 3H), 8.01 (s, 1H), 8.92 (s, 1H). MS (ES+): m/z 264 (M+H)*.

101 EXAMPLE 64. N4-Benzofl,3]dioxol-4-yl-5-methyl-N 2 -[4-(2-pyrrolidin-1-vl-ethoxy) phenyll-pyrimidine-2,4-diamine (Compound XXXVI) &NH NNQ H XXXVI [0155] 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 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken 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 separated. The organic layer was washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (DCM to 20% MeOH/DCM) to afford the title compound (0.14 g, 34%) as a white solid. [0156]. 'H NMR (500 MHz, DMSO-4): S 1.65-1.75 (m, 4H), 2.06 (s, 3H), 2.55-2.65 (m, 4H), 2.78-2.88 (in, 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, 1H-), 7.45 (d, J= 9.1 Hz, 2H), 7.81 (s, IH), 8.23 (s, IH), 8.73 (s, 1H). MS (ES+): m/z 434 (M+H)*.

102 EXAMPLE 65. NM-Benzo[l,3ldioxol-4-yl-5-methyl-N2-[4-(4-methyl-piperazin-1-vl) phenyll-pyrimidine-2,4-diamine (Compound XXXVII) 0-\ ~NH N &N N H

XXXVII

[0157] 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 microwave reaction tube and irradiated with microwave at 150 'C for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and the mixture was neutralized with 10% NaOH solution until solid precipitated. The solid was filtered and then purified by flash chromatography on silica gel (DCM to 15% MeOH/DCM) to afford the title compound (22 mg, 14%).as a light red solid. [0158] 'H NMR (500 MHz, DMSO-d 6 ): S 2.06 (s, 3H), 2.21 (s; 311), 2.44 (t, J= 4.8 Hz, 4H), 2.97 (t, J= 4.9 Hz, 4H), 5.89 (s, 2H), 6.67 (d, J= 9.1 Hz, 2H), 6.80-6.86 (m, 211), 6.91 (dd, J= 7.6, 1.7 Hz, IH), 7.41 (d, J= 9.0 Hz, 2H), 7.79 (s, 1H), 8.17 (s, 1H), 8.63 (s, 1H). MS (ES+): mz 419 (M+H)*. EXAMPLE 66. (4-Chloro-3-methoxy-phenyl)-(2-chloro-5-methyl-pyrimidin-4-yl) amine (Intermediate 31) CO NH N 31 [01591 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), Pd 2 (dba) 3 (0.17 g, 0.19 mmol), Xantphos (0.22 g, 0.38 mmol) and cesium carbonate (2.3 g, 7.1 mmol) was suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 5 h. The reaction 103 mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes to 40% EtOAc/hexanes) to afford the title compound (0.55 g, 55%) as a yellow solid. [0160] 'H NMR (500 MHz, DMSO-d 6 ): 8 2.18 (s, 3H), 3.85 (s, 3H), 7.35 (dd, J= 8.6,2.3 Hz, 1H), 7.39 (d, J= 8.7 Hz, 1H), 7.56 (d, J= 2.3 Hz, 1H), 8.09 (d, J= 0.9 Hz, 1H), 8.91 (s, 1H). MS (ES+): m/z 284 (M+H)*. EXAMPLE 67. N'-(4-Chloro-3-methoxy-phenyl)-5-meth-yl-N-(4-pyrazol-1-ylmethyl phenyl)-pyrimidine-2,4-diamine (Compound XXX VHI) C1 MeoU2NH N N H XXXVmI [01611 A suspension of intermediate 31 (0.20 g, 0.70 mmol), 4-pyrazol-1-ylmethyl phenylamine (0.14 g, 0.81 mmol), Pd 2 (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 microwave at 160 'C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO 3 solution (40 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the resulting solid was dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as an off white solid (0.13 g, 44%). 1H NMR (500 MHz, DMSO-d 6 ): 82.11 (s, 3H), 3.74 (s, 3H), 5.22 (s, 2H), 6.25 (t, J= 2.1 Hz, IH), 7.08 (d, J= 8.6 Hz, 2H), 7.27 (d, J= 9.3 Hz, 1H), 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, 1H), 8.36 (s, 11), 9.04 (s, 1H) MS (ES+): m/z 421 (M+H)*.

104 EXAMPLE 68. 5-Methyl-N 2 -[4-(4-methyl-piperazin-1-vl)-phenyll-pyrimidine-2,4 diamine (Intermediate 32)

NH

2 N NN 32 [01621 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 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and the mixture was neutralized with 10% NaOH solution until solid precipitated. After filtration and washed with water, the title compound was obtained as a grey solid (1.3 g, 63%). [01631 H NMR (500 MHz, DMSO-d6): 8 1.88 (s, 3H), 2.21 (s, 3H), 2.21 (s, 3H), 2.44 (t, J= 4.8 Hz, 4H), 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, 111), 8.42 (s, 1H). MS (ES+): m/z 299 (M+H)+. EXAMPLE 69. N4-(4-Chloro-3-methoxy-phenyl)-5-methyl-M-[4-(4-methyl-piperazin-1 yl)-phenyll-pyrimidine-2,4-diamine (Compound XXXDO .C1 MeO NH N NN" H XXXIX [01641 A suspension of intermediate 32 (0.30 g, 1.0 mmol), 4-bromo-1-chloro-2-methoxy benzene (0.20 mL, 1.5 mmol), Pd 2 (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 microwave at 160 'C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHC0 3 solution (40 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic 105 layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the residue 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%). [01651 'H NMR (500 MHz, DMSO-d 6 ): 5 2.09 (s, 311), 2.21 (s, 3H), 2.45 (t, J= 4.9 Hz, 4H), 3.02 (t, J= 4.9 Hz, 4H), 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, 1H), 8.28 (s, 1H), 8.72 (s, 1H). MS (ES+): m/z 439 (M+H)*. EXAMPLE 70. N4-(4-Chloro-3-methoxy-phenyl)-5-methyl-N-(4-morpholin-4-yl phenyI)-pyrimidine-2,4-diainne (Compound XL Meo NH o N XL [01661 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 microwave at 160 'C for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and the mixture was neutralized with 10% NaOH solution until solid precipitated. The solid was filtered and then purified by flash chromatography on silica gel (DCM to 10% MeOH/DCM) to afford the title compound (55 mg, 37%) as a light brown solid. [01671 'H NMR (500 MHz, DMSO-d 6 ): 8 2.10 (s, 3H), 3.00 (t, J= 4.8 Hz, 41), 3.71-3.76 (m, 7H), 6.80 (d, J= 9.0 Hz, 2H), 7.28 (d, J= 8.6 Hz, 1H), 7.45 (dd, J= 8.7, 2.2 Hz, 1H), 7.47-7.50 (m, 3H), 7.87 (s, 1H), 8.29 (s, 111), 8.75 (s, 1H). MS (ES+): m/z 426 (M+H)*.

106 EXAMPLE 71. M-(4-Chloro-3-methoxy-phenyl)-5-methvl-N 2 -(4-pyrazol-1-yl-phenyl) pyrimidine-2,4-diamine (Compound XLI) CI MeO NH N N H XLI [01681 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 microwave at 160 'C for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and the mixture neutralized with 10% NaOH solution until solid precipitated. The solid was filtered and then purified by HPLC. The corrected fractions were combined and concentrated to afford the title compound (40 mg of TFA salt, 24%) as a white solid. [0169] 'H NMR (500 MHz, DMSO-d 6 ): 8 2.17 (s, 3H), 3.75 (s, 3H), 6.54 (t, J= 1.9 Hz, 1H), 7.30 (d, J= 6.6 Hz, 1H), 7.39 (d, J= 2.1 Hz, 111), 7.40 (d, J= 8.6 Hz, 1H), 7.59 (d, J= 8.9 Hz, 2H), 7.71 (d, J= 8.9 Hz, 2H), 7.73 (d, J= 1.6 Hz, 1H), 7.93 (s, 1H), 8.41 (d, J= 2.5 Hz, 1H), 9.41 (s, 1H), 10.05 (s, 1H). MS (ES+): m/z 407 (M+H)*. EXAMPLE 72. N4-(4-Chloro-3-methoxy-phenyl)-5-methyl-N-(4-piperidin-1-yl phenyl)-pyrimidine-2,4-diamine (XLII) CI MeO aNH NN H XLII 101701 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 microwave at 160 'C for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) 107 and the mixture neutralized with 10% NaOH solution until solid precipitated. The solid was filtered and then purified by flash chromatography on silica gel (hexanes to 70% EtOAc/hexanes)to afford the title compound (10 mg, 6%) as a light brown solid. [0171] 'H NMR (500 MHz, DMSO-d,): 8 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.Q Hz, 2H), 7.27 (d, J= 8.7 Hz, 1H), 7.40-7.47 (m, 3H), 7.50 (d, J= 2.2 Hz, 1H), 7.86 (s, 1H), 8.28 (s, 1H), 8.71 (s, 1H). MS (ES+): m/z 424 (M+H)*. EXAMPLE 73. 1M-(4-Chloro-3-methoxy-phenyl)-5-methyl-N2-[4-(4-methyl-piperazin 1-vlmethyl)-phenyll-Dyrimidine-2,4-dianiine (XLII) C1 MeO Q NH NN, H [0172] A suspension of intermediate 31 (50 mg, 0.18 mmol), 4-(4-methyl-piperazin-1 ylmethyl)-phenylamine (50 mg, 0.24 mmol), Pd 2 (dba) 3 (10 mg, 0.011 mmol), 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 microwave-at 160 'C foir 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (DCM to 10% MeOH/DCM)to afford the title compound (35 mg, 44%) as an off white solid. [0173] 'H NMR (500 MHz, DMSO-4): 6 2.11 (s, 3H), 2.15 (s, 3H), 2.20-2.45 (m, 8H), 3.35 (s, 2H), 3.75 (s, 3H), 7.07 (d, J= 8.5 Hz, 2H), 7.28 (d, J= 8.5 Hz, 1H), 7.44 (dd, J= 8.7, 2.3 Hz, 1ff), 7.47 (d, J= 2.3 Hz, 1H), 7.57 (d, J= 8.5 Hz, 2H), 7.91 (s, 1H), 8.36 (s, 1H), 8.98 (s, 1H). MS (ES+): m/z 453 (M+H)*.

108 EXAMPLE 74. M-(4-Chloro-3-methoxy-phenyl)-5-methyl- N 2 -(4-piperazin-1-yl phenyl)-pyrimidine-2,4-diamine (Compound XLIV) C1 MeO9 NH (JNH N H XLIV [01741 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 sealed in a microwave reaction tube and irradiated with microwave at 150 'C for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCO 3 solution (40 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as an off white solid (0.10 g, 33%). [01751 'H NMR (500 MHz, DMSO-d): 8 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, 1H), 7.44 (dd, J= 8.7, 2.1 Hz, 1H), 7.49-7.52 (m, 3H), 7.88 (s, 1H), 8.32 (s, lH), 8.81 (s, 1H) MS (ES+): m/z 425 (M+H)*. EXAMPLE 75. N-tert-Butyl-3-{5-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylaminol pyrimidin-4-ylamino}-benzenesulfonamide (Compound XLV) TH 0 *1 >rNQN N0NHLV O N J

XLV

109 [0176] A suspension of intermediate 32 (0.30.g, 1.0 mmol), 3-bromo-N-tert-butyl benzenesulfonamide (0.35 g, 1.2 mmol), Pd 2 (dba) 3 (60 mg, 0.066 mmol), Xantphos (70 mg, 0.12 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 microwave at 160 'C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO 3 solution (40 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the residue 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%). [01771 1H NMR (500 MHz, DMSO-d 6 ): 8 1.12 (s, 9H), 2.11 (s, 3H), 2.22 (s, 3H), 2.45 (t, J= 4.7 Hz, 411), 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, 1H), 7.89 (s, 1H), 8.10-8.16 (m., 2H), 8.51 (s, IH), 8.70 (s, 1H) MS (ES+): m/z 510 (M+H)+. EXAMPLE 76. N-tert-Butyl-3-(2-chloro-5-methyl-pyrimidin-4-vlamino) benzenesulfonamide (Intermediate 33) N,11 'I N <S NH '0N N Cl 33 [01781 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.4 g, 2.8 mmol), 3-bromo N-tert-butyl-benzenesulfonamide (1.0 g, 3.4 mmol), Pd 2 (dba)3 (0.17 g, 0.19 mmol), Xantphos (0.2 g, 3.5 mmol) and cesium carbonate (2.0 g, 6.1 mmol) was suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc and hexanes added until solid precipitated. After filtration, the title compound (1.2 g, 98%) was obtained as a light brown solid. It was ised in the next step without purification. MS (ES+): m/z 355 (M+H)*.

110 EXAMPLE 77. N-tert-Butyl-3-[5-methyl-2-(4-morpholin-4-ylmethyl-phenylamino) pyrinidin-4-ylaminol-benzenesulfonamide (Compound XLVI) HN NN Oj H XLVI [01791 A mixture of intermediate 33 (0.50 g, 1.4 mmol), 4-morpholin-4-ylmethyl phenylamine (0.35 g, 1.8 mmol), Pd 2 (dba) 3 (0.10 g, 0.11 mmol), Xantphos (0.12 g, 0.21 mmol) and cesium carbonate (1.0 g, 3.1 mmol) was suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCO 3 solution (50 mL). The combined aqueous layers were extracted with EtOAc (2 x 50 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as an off white solid (0.23 g, 31%). [0180] . 'H NMR (500 MHz, DMSO-d 6 ): 8 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), 7.45-7.52 (m, 2H), 7.57 (s, 1H), 7.59 (d, J= 8.5 Hz, 2H), 7.94 (s, 1H), 8.10 (s, 1f), 8.13-8.16 (m, 1H), 8.58 (s, 1H), 8.95 (s, 1H). MS (ES+): n/z 511 (M+H)*.

111 EXAMPLE 78. N-tert-Butyl-3-{5-methyl-2-[4-(4-oxy-morholin-4-ylmethyl phenylaniino]-pyrimidin-4-vlaminol-benzenesulfonamide (Compound XLVII) o-NH 00 NH XLVI [0181] A solution of the above-described compound XLVI (30 mg, 0.06 mmol) and 3 chloroperbenzoic acid (77%, 14 mg, 0.06 mmol) in chloroform (30 mL) was strred at room temperature for 1 hour. The solvent was removed by rotovap and the resulting mixture was purified by silica gel with 20% CH 3 0H/CHCl 3 as an eluent to afford the title compound as an off-white solid (15 mg, 48%). [01821 'H NMR (500 MHz, DMSO-dQ): 8 1.12 (s, 9H), 2.14 (s, 3H), 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, 1H), 7.66 (d, J= 8.5 Hz, 2H), 7.96 (s, 1H), 8.13 (m, 211), 8.63 (s, 1H), 9.13 (s, 1H). MS (ES+): n/z 527 (M+H)*. EXAMPLE 79. N-tert-Butyl-3-[5-methyl-2-(4-pyrazol-1-yl-phenylamino)-pyrimidin-4 vlaminol-benzenesulfonamide (Compound XLVIII) NH O N N H XLVIII [0183} 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 microwave at 130 'C for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken up in water (20 mL) and neutralized with 10% NaOH solution until solid precipitated. The brown solid was filtered 112 and then purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (15 mg, 11%). [0184] 'H NMR (500 MHz, DMSO-d 6 ): 8 1.12 (s, 9H), 2.15 (s, 3H), 6.49 (t, J= 2.2 Hz, 1H), 7.50-7.55 (m, 2H), 7.58 (s, 1H), 7.62 (d, J= 9.1 Hz, 2H), 7.68 (d, J= 1.3 Hz, 1H), 7.77 (d, J= 9.1 Hz, 2H), 7.96 (s, 1H), 8.11 (s, lH), 8.13-8.16 (m, 1H), 8.33 (d, J= 2.5 Hz, 1H), 8.64 (s, 1H), 9.17 (s, IH). MS (ES+): m/z 478 (M+H)*. EXAMPLE 80. N-tert-Butyl-3-15-methyl-2-(6-piperazin-1-yl-pyridin-3-ylamino) pynrimidin-4-ylaminol-benzenesulfonamide (Compound XLIX) H0 N NH NH N N H XLIX [01851 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 microwave at 130 C for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was dissolved in DCM (5 mL) and 30% TFA/DCM (6 mL) added. The mixture was stirred at room temperature for lh, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (10 mg, 7%).

113 [0186] 'H NMR (500 MHz, DMSO-d 6 ): 5 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, 1H), 7.40-7.49 (m, 2H), 7.57 (s, 1H), 7.86 (dd, J =9.1, 2.7 Hz, 1H), 7.88 (s, 1H), 8.10-8.16 (m, 2H), 8.28 (d, J= 2.5 Hz, 1H), 8.53 (s, 1H), 8.72 (s, 1H). MS (ES+): m/z 497 (M+H). EXAMPLE 81. N-tert-Butyl-3-15-methyl-2-(4-pyrazol-1-ylmethyl-phenylamino) pyrimidin-4-vlaminol-benzenesulfonamide (Compund L) HoH NN N "N H L [0187] A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-pyrazol-1-ylmethyl phenylamine (50 mg, 0.29 mol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 130 'C for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (12 mg, 9%). [01881 'H NMR (500 MHz, DMSO-d 6 ): 8 1.12 (s, 9H), 2.13 (s, 3H), 5.21 (s, 2H), 6.24 (t, J= 1.9 Hz, 1H), 7.08 (d, J= 8.5 Hz, 2H), 7.27-7.50 (m, 3H), 7.56 (s, 1H), 7.60 (d, J= 8.4 Hz, 2H), 7.75 (d, J= 2.1 Hz, 1H), 7.94 (s, 1H), 8.14 (d, J= 7.9 Hz, 1H), 8.59 (s, 1H), 9.01 (s, 1H). MS (ES+): m/z 492 (M+.H).

114 EXAMPLE 82. 5-Methyl-N 2 -[3-(piperidine-1-sulfonv)-phenVI1-vvrimidine-2A-diamine (Intermediate 34)

NH

2 S N SN H 0 34 [0189] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.25 g, 1.74 mmol) and 3 (piperidine-1-sulfonyl)-phenylamine (0.50 g, 2.1 mmol) in acetic acid (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 130 'C for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and pH adjusted to -9 with 10% NaOH solution. The resulting solution was extracted with EtOAc (2 x 30 mL) and the organic layer separated. The combined organic layers were washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated in vacuo and the crude product (-0.6 g) used in the next step without purification. MS (ES+): m/z 348 (M+H)*. EXAMPLE 83. N-tert-Butyl-3-{5-methyl-2-[3-(piperidine--sulfonyl)-phenylaminol pyrimidin-4-ylaminol-benzenesulfonamide (Compound LI) HN O NNN H 0 LI 101901 A suspension of intermediate 34 (0.10 g, 0.29 mmol), 3-bromo-N-tert-butyl benzenesulfonamide (84 mg, 0.29 mmol), Pd 2 (dba) 3 (15 mg, 0.016 mmol), Xantphos (20 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 microwave at 160 'C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The 115 filtrate was concentrated and the residue dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (20 mg, 12%). [01911 'H NMR (500 MHz, DMSO-d 6 ): 8 1.12 (s, 9H), 1.30-1.40 (m, 2H), 1.50-1.56 (in, 4H), 2.16 (s, 3H), 2.88 (t, J= 5.3 Hz, 4H), 7.17 (d, J= 7.8.Hz, 1H), 7.43 (t, J= 8.0 Hz, 1H), 7.59-7.60 (in, 2H), 7.58 (s, 1H), 8.13 (s, 1H), 7.16 (dd, J= 7.9, 1.9 Hz, 1H), 8.18-8.22 (in, 1H), 8.67 (s, IH), 9.37 (s, 1H). MS (ES+): m/z 559 (M+H) 4 . EXAMPLE 84. N-tert-Butyl-3-{5-methyl-2-[4-(4-methyl-piperazin-1-ylmethyl phenylaminol-pyriniidin-4-vlaminol-benzenesulfonamide (Compound LII) HNH O0 N, H LIE [0192] A suspension of intermediate 33 (0.10 g, 0.28 nmol), 4-(4-methyl-piperazin-1 ylmethyl)-phenylamine (65 mg, 0.32 mmol), Pd 2 (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 irradiated with microwave at 170 'C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the residue dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (53 mg, 36%). [01931 'H NMR (500 MHz, DMSO-d): 8 1.12 (s, 9H), 2.13 (s, 3H), 2.15 (s, 3H), 2.20 2.45 (in, 4H), 3.25-3.40 (in, 611), 7.08 (d, J= 8.6 Hz, 211), 7.45-7.52 (in, 2H), 7.56 (s, 1H), 7.57 (d, J= 8.6 Hz, 2H), 7.94 (s, 1H), 8.09 (s, 111), 8.13-8.16 (M, 1H), 8.58 (s, 1H), 8.94 (s, 1H). MS (ES+): m/z 524 (M+H) 4

.

116 EXAMPLE 85. N-tert-Butyl-3-[5-methyl-2-(4-piperazin-1-yl-3-trifuoromethyl phenylamino)-pyrimidin-4-ylaminol-benzenesulfonaide (Compound LU1) NNH

CF

3 NH 0 NN H LIII [0194] 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), Pd 2 (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 irradiated with microwave at 170 'C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM and the filtrate concentrated. The residue was dissolved in DCM (5 mL) and 50% TFAJDCM (6 mL) added. The mixture was stirred at room temperature for 2h, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHC0 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and.the resulting solid dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (42 mg, 26%). [0195] 'H NMR (500 MHz, DMSO-d 6 ): 5 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, 111), 7.90-8.00 (m, 3H), 8.07 (s, 1H), 8.15 (d, J= 7.6 Hz, 1H), 8.63 (s, 1H), 9.22 (s, 111) MS (ES+): m/z 564

(M+H)*.

117 EXAMPLE 86. 3-{2-[4-(4-Acetyl-piperazin-1-yl)-3-trifluoromethyl-phenylaminol-5 methyl-pvrimidin-4-vlaminol-N-tert-butyl-benzenesulfonamide (Compound LIV) jNH CF3 $ N 0 NI.N H LIV [0196] 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 microwave at 160 'C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM and the filtrate concentrated and the-residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (64 mg, 38%). [0197] 'H NMR (500 MHz, DMSO-d 6 ): 6 1.12 (s, 9H), 2.04 (3, H), 2.14 (s, 3H), 2.73 (t, J = 4.9 Hz, 2H), 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, 1H), 7.90-8.00 (m, 3H), 8.07 (s, 1H), 8.14 (d, J= 7.2 Hz, 1H), 8.64 (s, 1H), 9.26 (s, 1H). MS (ES+): n/z 606 (M+H)*.

118 EXAMPLE 87. 5-Methyl-N2-[3-(4-methyl-piperazine-1-sulfonl)-phenyll-pyrimidine 2,4-diamine (Intermediate 35)

NH

2 N IN' 0 35 4 [01981 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.25 g, 1.74 mmol) and 3 (4-methyl-piperazine-l-sulfonyl)-phenylamine (0.50 g, 2.0 mmol) in acetic acid (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 130 'C for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and pH adjusted to -9 with 10% NaOH solution. The resulting solution was extracted with EtOAc (2 x 30 mL) and the organic layer separated. The combined organic layers were washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated in vacuo and the crude product (-0.42 g) used in the next step without purification. MS (ES+): m/z 363 (M+H)*. EXAMPLE 88. N-tert-Butyl-3-{5-methyl-2-[3-(4-methyl-piperazine-1-sulfonyl phenylaminol-pvrimidin-4-ylaminol-benzenesulfonamide (Compound LV) HO 0 NH 0 'o- N N H .0 LV [0199] A suspension of intermediate 35 (0.10 g, 0.28 mmol), 3-bromo-N-tert-butyl benzenesulfonamide (80 mg, 0.27 mmol), Pd 2 (dba) 3 (15 mg, 0.016 mmol), Xantphos (20 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 microwave at 160 'C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The 119 filtrate was concentrated and the residue dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (10 mg, 6%). [02001 'H NMR (500 MHz, DMSO-d 6 ): 8 1.12 (s, 9H), 2.13 (s, 3H), 2.16 (s, 3H), 2.33 2.40 (in, 4H), 2.85-2.94 (in, 41), 7.18 (d, J= 8.1 Hz, 1H), 7.44 (t, J= 8.0 Hz, 111), 7.49-7.54 (m, 2H), 7.58 (s, 111), 8.00-8.03 (m, 2H), 8.13 (s, 111), 8.15 (dd, J= 8.6, 1.6 Hz, 1H), 8.18 8.23 (in, 1H), 8.66 (s, 1H), 9.38 (s, 1H). MS (ES+): m/z 574 (M+H)*. EXAMPLE 89. N-tert-Butyl-3-j5-methyl-2-(4-piperazin-1-vlmethyl-phenvlamino) pyrimidin-4-vlaminol-benzenesulfonamide (Compound LVI) HNH 0N NH K..NH H LVI [0201] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(4-amino-benzyl)-piperazine 1-carboxylic acid tert-butyl ester (0.1 g, 0.34 mmol), Pd 2 (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 microwave at 170 'C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM and the filtrate concentrated. The residue was dissolved in DCM (6 mL) and TFA (3 mL) added. The mixture was stirred at room temperature for lh, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the resulting solid triturated in hexanes/EtOAc (10/1, 55 mL). After filtration, the title compound was obtained as a white solid (32 mg, 22%).

120 [0202] 'H NMR (500 MHz, DMSO-d 6 ): 8 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, 1H), 7.59 (d, J =8.5 Hz, 211), 7.94 (s, 1H), 8.10 (s, 1H), 8.13-8.16 (in, 1H), 8.59 (s, 1H), 8.96 (s, 1H). MS (ES+): m/z 510 (M+H). EXAMPLE 90. N-tert-Butyl-3-5-methyl-2-.4-(2-pyrrolidin-1-l-ethoxy)-phenylaminolpyrimidin-4-vlaminol-benzenesulfonamide (Compound LVII) H N NH LVII [0203] 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 microwave reaction tube and irradiated with microwave at 150 'C for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 27%). [0204] 'H NMR (500 MHz, DMSO-d 6 ): 8 1.12 (s, 9H), 1.65-1.70 (m, 4H), 2.12 (s, 311), 2.45-2.55 (m, 4H), 2.76 (t, J= 5.8 Hz, 211), 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, 1H), 7.90 (s, 1H), 8.10-8.15 (m, 21), 8.53 (s, 111), 8.77 (s, 11H). MS (ES+): m/z 525 (M+H)*.

121 EXAMPLE 91. 3-{5-Methyl-2-[4-(4-methylpierazin-1-yl)-phenylaminol-pyrimidin-4 Vlaminol-benzenesulfonamide (Compound LVIII) IH2N, S NH r N NNd 0 H LVIII [0205] A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo benzenesulfonamide (0.10 g, 0.42 mmol), Pd 2 (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 microwave at 160 'C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated to afford the title compound as a grey solid (10 mg, 7%). [0206] 'H NMR (500 MHz, DMSO-d 6 ): S 2.10 (s, 3H), 2.22 (s, 3H), 2.44 (t, J= 4.9 Hz, 4H), 3.03 (t, J= 4.9 Hz, 4H), 6.81 (d, J= 9.0 Hz, 2H), 7.34 (s, 2H), 7.45-7.50 (i, 4H), 7.89 (s, 1H), 8.06 (s, 1H), 8.13-8.18 (m, 1H), 8.54 (s, 1H), 8.70 (s, IH). MS (ES+): m/z 454 (M+H)*. EXAMPLE 92. N-Methyl-3-{5-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylaminol Pvrimidin- 4 -viamino}-benzenesulfonamide (Compound LIX) H 0 N I NH N N N H

LIX

122 [02071 A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-N-methyl benzenesulfonamide (0.11 g, 0.44 mmol), Pd 2 (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 cap was removed'and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the residue triturated in a mixture of DCM/Et 2 O (1/5, 30 mL). After filtration, the title compound was obtained as a light brown solid (65 mg, 42%). [0208] 'H NMR (500 MHz, DMSO-d 6 ): 5 2.11 (s, 3H), 2.23 (s, 3H), 2.44 (d, J= 5.0 Hz, 3H), 2.45-2.50 (in, 4H), 3.03 (t, J= 4.9 Hz, 4H), 6.81 (d, J= 9.1 Hz, 2H), 7.40-7.43 (in, 2H), 7.46 (d, J= 9.1 Hz, 2H), 7.52 (t, J= 8.0 Hz, 1H), 7.89 (s, 1H), 7.94 (t, J= 1.8 Hz, 1H), 8.29 (br d, J= 8.3 Hz, 1H), 8.56 (s, 1H), 8.72 (s, .1H). MS (ES+): m/z 468 (M+H)*. EXAMPLE 93. NN-Dimethyl-3-15-methyl-2-[4-(4-methyl-piperazin-1-vl) phenylaminol-pyrimidin-4-vlaminol-benzenesulfonamide (Compound LX) N, N N H N N N H LX [0209] A suspension of intermediate 32 (0.13 g, 0.43 mmol), 3-bromo-N,N-dimethyl benzenesulfonamide (0.14 g, 0.53 mmol), Pd 2 (dba) 3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.33 g, 1.0 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 cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the 123 combined organic layers washed with brine, dried over anhydrous Na 2 SO4 and filtered. The filtrate was concentrated and the residue 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%). [0210] 1H NMR (500 MHz, DMSO-d 6 ): 8 2.17 (s, 3H), 2.23 (s, 3H), 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, 111), 7.45 (d, J= 9.1 Hz, 2H), 7.54 (t, J= 8.0 Hz, IH), 7.84 (t, J= 1.9 Hz, 1H), 7.90 (s, 1H), 8.46 (br d, J= 7.8 Hz, 1H), 8.57 (s, 1H), 8.74 (s, 1 H). MS (ES+): m/z 482 (M+H)*. EXAMPLE 94. N-Isopropyl-3-5-methyl-2-14-(4-methyl-piperazin-1-y1)-phenylaminol pyrimidin-4-ylaminol-benzenesulfonamide (Compound LXI) HO N NH N Na H LXI [0211] A suspension of intermediate 32 (0.10 g, 0.33 nmol), 3-bromo-N-isopropyl benzenesulfonamide (0.11 g, 0.39 mmol), Pd 2 (dba) 3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 minmol) and cesium carbonate (0.25 g, 0.77 minmol) 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 cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the residue 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%). 10212] 'H NMR (500 MHz, DMSO-d 6 ): 8 0.98 (d, J= 6.6 Hz, 6H), 2.11 (s, 3H), 2.24 (s, 3H), 2.45-2.50 (in, 411), 3.03 (t, J= 4.8 Hz, 4H), 3.20-3.27 (in, 1H), 6.80 (d, J= 9.0 Hz, 211), 7.40-7.52 (m, 411), 7.59 (d, J= 7.1 Hz, 1H), 7.89 (s, 1H), 8.21 (br d, J= 7.9 Hz, 111), 8.53 (s, 111), 8.71 (s, 1H). MS (ES+): m/z 496 (M+H)*.

124 EXAMPLE 95. V4-(3-Methanesulfonyl-4-methyl-phenyl)-5-methyl-N 2 -[4-(4-methyl piperazin-1-yl)-phenvll-pyrimidine-2,4-diamine (Compound LXH) oY . NH N o C N LXII 102131 A suspension of intermediate 32 (0.10 g, 0.33 mmol), 4-bromo-2-methanesulfonyl 1-methyl-benzene (0.10 g, 0.40 mmol), Pd 2 (dba) 3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 minmol) 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 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate 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 light brown solid (41 mg, 27%). [02141 1 H NMR (500 MHz, DMSO-d): 8 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, 211), 7.35 (d, J= 8.5 Hz, 1H), 7.44 (d, J= 9.0 Hz, 2H), 7.87 (s, 111), 8.05 (d, J= 2.4 Hz, 1H), 8.21 (br d, J= 7.0 Hz, 1H), 8.55 (s, 1H), 8.71 (s, 1H). MS (ES+): m/z 467 (M+H)*. EXAMPLE 96. N-Cyclohex-y-3-{5-methyl-2-[4-(4-methyl-piperazin-1-vl) phenylaminol-pyrimidin-4-lamino-benzenesulfonamide (Compound LXUI) H0 -N, NH N N

LXII

125 [0215] A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-N-cyclohexyl benzenesulfonamide (0.13 g, 0.41 mmol), Pd 2 (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 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the residue 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%). 10216] 1H NMR (500 MHz, DMSO-d 6 ): 5 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, 1H), 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, 1H),7.89 (s, 1H), 8.05 (s, 1H), 8.18 (br d, J= 7.7 Hz, 1H), 8.52 (s, 111), 8.71 (s, 1H). MS (ES+): n/z 536 (M+H)*. EXAMPLE 97. N.-Diethyl-3-{5-methyl-2-[4-(4-methyl-Diperazin-1-yl)-phenylainol pyrimidin-4-vlaminol-benzenesulfonamide (Compound LXIV) NHO LXIV [02171 A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-N,N-diethyl benzenesulfonamide (0.12 g, 0.41 mmol), Pd 2 (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 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHC0 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the 126 combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the residue 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%). [02181 'H NMR (500 MHz, DMSO-d 6 ): 5 1.06 (t, J= 7.1 Hz, 611), 2.11 (s, 311), 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, 1H), 7.45 (d, J= 9.0 Hz, 2H), 7.50 (t, J= 8.1 Hz, 1H), 7.89 (t, J= 1.9 Hz, 1H), 7.89 (s, 1H), 8.39 (br d, J= 7.9 Hz, 1H), 8.53 (s, 1H), 8.74 (s, 1H). MS (ES+): m/z 510 (M+H)+ EXAMPLE 98. 5-Methyl-N2-[4-(4-methyl-piperazin-1-yl)-phenyll-N4-[3-(morpholine-4 sulfonyl)-phenyll-pyrimidine-2,4-diamine (Compound LXV) 0 N1 NH r N 0 ~ NIj H LXV [0219] A suspension of intermediate 32 (0.10 g, 0.33 mmol), 4-(3-bromo benzenesulfonyl)-morpholine (0.12 g, 0.39 mmol), Pd 2 (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 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the residue 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%). 102201 'H NMR (500 MHz, DMSO-d 6 ): 5 2.12 (s, 3H), 2.22 (s, 3H), 2.45 (t, J= 4.8 Hz, 4H), 2.89 (t, J= 4.6 Hz, 4H), 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, 1H), 7.45 (d, J= 9.0 Hz, 2H), 7.56 (t, J= 8.1 Hz, 111), 7.84 (t, J= 1.9 Hz, 1H), 7.91 (s, 1H), 8.47 (br d, J= 8.4 Hz, 11), 8.59 (s, 1H), 8.75 (s, 1H). MS (ES+): m/z 524 (M+H)*.

127 EXAMPLE 99. 3-{5-Methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylaminol-pyrimidin-4 ylaminol-benzoic acid ethyl ester (Intermediate 36) EtO I NH N O N 36 [02211 A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-benzoic acid ethyl ester (0.07 mL, 0.44 mmol), Pd 2 (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 microwave at 160 C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (DCM to 10% MeOH/DCM) to afford the title compound (0.10 g, 68%). MS (ES+): m/z 447 (M+H)+. EXAMPLE 100. 3-15-Methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylaminol-pyrimidin 4-ylaminol-benzamide (Compound LXVI)

H

2 N I NH

N

O N N H LXVI [02221 A mixture of intermediate 36 (0.10 g, 0.22 mmol) in concentrated NH 4 0H was sealed in a reaction tube and heated at 50 'C for 3 d. 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 purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the residue 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%).

128 [0223] 'H NMR (500 MHz, DMSO-d 6 ): S 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, 1H), 7.85 (s, 1H), 7.90 (br s, 2H), 8.03 (s, 1H), 8.37 (s, 1H), 8.71 (s, 1H). MS (ES+): m/z 418 (M+H)*. EXAMPLE 101. 2-Methyl-3-f5-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylaminol pyrimidin-4-ylaminol-benzoic acid ethyl ester (Compound LXVH) o OEt NH N NN H LXVII [0224] A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-2-methyl-benzoic acid ethyl ester (0.10 mL, 0.41 mmol), Pd 2 (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 microwave at 160 'C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (DCM to 30% MeOH and 1% TEA in DCM) to afford the title compound (0.14 g, 92%) as a light brown oil. 102251 1H NMR (500 MHz, DMSO-d 6 ): 8 1.32 (t, J= 7.1 Hz, 3H), 2.10 (s, 3H), 2.21 (s, 3H), 2.32 (s, 3H), 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= 7.8 Hz, 1H), 7.48 (dd, J= 7.9, 1.0 Hz, 1H), 7.70 (dd, J= 7.8, 1.1 Hz, 1H), 7.78 (s, 1H), 8.23 (s, 1H), 8.58 (s, 1H). MS (ES+): n/z 461 (M+H).

129 EXAMPLE 102. 2-Methyl-3-{5-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino] pyrimidin-4-ylaminol-benzamide (Compound LXVIII O

NH

2 NH N N LXVIII [0226] To a mixture of the above-described compound LXVII (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 the argon atmosphere. The mixture was stirred at the same temperature for 2 h and then at room temperature for additional 15 h. 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 purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate 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%). [0227] 'H NMR (500 MHz, DMSO-d 6 ): 8 2.09 (s, 3H), 2.21 (s, 3H), 2.23 (s, 3H), 2.40-2.45 (m, 4H), 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, 1H), 7.78 (s, 1H), 8.01 (s, 1H), 8.53 (s, 1H). MS (ES+): m/z 432 (M+H).

130 EXAMPLE 103. (2-Chloro-5-methyl-pyriidin-4-yl)-(4-chloro-3-trifluoromethyl phenyl)-amine (Intermediate 37) Co

F

3 C NH N C1 37 [02281 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 4 bromo-1-chloro-2-trifluoromethyl-benzene (0.40 mL, 2.7 mmol), Pd 2 (dba) 3 (0.10 g, 0.11 mmol), Xantphos (0.13 g, 0.22 nimol) and cesium carbonate (1.5 g, 4.6 mmol) in dioxane/DMF (6/1, 7 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 'C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (hexanes to 50% EtOAc/hexanes) to afford the title compound (0.65 g, 96%) as a white solid. MS (ES+): m/z 322 (M+H)*. EXAMPLE 104. N'-(4-Chloro-3-trifluoromethyl-phenyl)-5-methyl-M-[4-(piperidin-4 vloxy)-phenyll-pyrimidine-2,4-diamine (Compound LXIX) C1 . F 3 C NH N N O Q NH H LXIX [02291 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 microwave at 150 'C for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and neutralized with 10% NaOH solution until solid precipitated. The resulting solid was filtered and purified by HPLC. The corrected fractions were combined and poured into saturated NaHC0 3 solution (30 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried 131 over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated to afford the title compound as a white solid (30 mg, 20%). 10230 'H NMR (500 MHz, DMSO-d 6 ): 8 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, 1H), 6.84 (d, J= 9.0 Hz, 2H), 7.49 (d, J= 9.0 Hz, 2H), 7.58 (d, J= 8.8 Hz, 1H), 7.94 (s, 1H), 8.12 (d, J= 2.6 Hz, 1H), 8.21 (br d, J = 8.2 Hz, 1H), 8.64 (s, IH), 8.93 (s, 1H). MS (ES+): m/z 478 (M+H)*. EXAMPLE 105. 5-Methyl-N 2 -[4-(2-pyrrolidin-1-yI-ethoxy)-phenyll-pvrimidine-2.4 diamine (Intermediate 38)

NH

2 NO No H 38 [02311 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 microwave at 150 'C for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken 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 washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated to afford the title compound as a grey solid (0.80 g, 73%). It was used in the next step without purification. MS (ES+): n/z 314 (M+H)*. EXAMPLE 106. 3-45-Methyl-2-[4-(2-pyrrolidin-1-yI-ethoxy)-phenylamino]-pyrimidin 4-ylaminol-benzenesulfonamide (Compound LXX H2Nja NH N ONN H

LXX

132 10232] A mixture of intermediate 38 (0.10 g, 0.32 mmol), 3-bromo-benzenesulfonamide (0.10 g, 0.42 mmol), Pd 2 (dba) 3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 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 microwave at 170 'C for 25 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and solid 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%). [02331 'H NMR (500 MHz, DMSO-d 6 ): 5 1.65-1.72 (in, 4H), 2.11 (s, 31-1), 2.49-2.52 (m, 411), 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, 111), 8.05 (s, 1H), 8.10-8.15 (m, 1H), 8.57 (s, 1H), 8.77 (s, IH). MS (ES+): m/z 469 (M+H)*. EXAMPLE 107. 5-Methyl-N 2 -(4-morpholin-4-ylmethyl-phenyl)-pyrinidine-2,4 diamine (Intermediate 39)

NH

2 N N H 39 [0234] 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 at 70 *C for 17 h. After cooling to room temperature, the mixture was concentrated. The residue was taken 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 washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated to afford the title compound as a brown syrup (0.70 g, 83%). It was used in the next step without purification. MS (ES+): m/z 300 (M+H)* 133 EXAMPLE 108 N'-(1H-Indol-4-yI)-5-methyl-N2-(4-morpholin4-ylmetliyl-phenyl) pyrimidine-2,4-diamine (Compound LXXI) NH - N O~ H LX= 10235] A mixture of intermediate 39 (0.40 g, 1.3 mmol), 4-bromo-1-triisopropylsilanyl 1H-indole (0.50 g, 1.4 mmol), Pd 2 (dba) 3 (0.10 g, 0.11 mmol), Xantphos (0.12 g, 0.21 mmol) and cesium carbonate (0.90 g, 2.8 mmol) was suspended in dioxane (20 niL) and heated at reflux under the argon atmosphere for 4 h. The reaction mixture was cooled to room' temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes to EtOAc) to afford the TIPS protected precursor as a yellow oil. [0236] 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 at room temperature for 1 h and then poured into water (20 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic layers washed vith brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the residue purified by H{PLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and solid dissolved in minimum amount of EtOAc and then hexanes added until solid precipitated. After filtration, the title compound was obtained as a light brown solid (6 mg, 1% overall yield). [02371 'H NMR (500 MHz, DMSO-d 6 ): S 2.17 (s, 3H), 2.25-2.30 (in, 4H), 3.29 (s, 2H), 3.54 (t, J= 4.5 Hz, 4H), 6.40 (t, J= 2.2 Hz, 1H), 6.89 (d, J= 8.5 Hz, 2H), 7.09 (t, J= 7.8 Hz, 1H), 7.25 (d, J= 8.0 Hz, 1H), 7.27 (t, J= 2.8 Hz, 1H), 7.30 (d, J= 7.5 Hz, 1H), 7.43 (d, J= 8.5 Hz, 2H), 7.85 (s, 1H), 8.14 (s, 1H), 8.77 (s, 1H), 11.10 (s, 1H). MS (ES+): m/z 415

(M+H)*.

134 EXAMPLE 109. 4-[44 4 -Amino-5-methyl-pyrimidin-2-lamino)-benzyll-piperazine-1 carboxylic acid tert-butyl ester (Intermediate 40) H N H 40 [0238] 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 mmol) in acetic acid (20 mL) was heated at 70 'C for 1 d. After cooling to room temperature, the mixture was concentrated. The residue was taken 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 washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the title compound used in the next step without purification. MS (ES+): m/z 399 (M+H)*. EXAMPLE 110. 1/-(1K-Indol-4-yl)-5-methyl-N44-piperazin-1-vimethyl-phenyl) pyrimidine-2,4-diamine (Compound LXXI) HNH NH INH N N H LXXII [0239] A mixture of intermediate 40 (0.78 g, 2.0 mmol), 4-bromo-1-triisopropylsilanyl 1H-indole (0.70 g, 2.0 mmol), Pd 2 (dba) 3 (0.15 g, 0.16 mmol), Xantphos (0.19 g, 0.32 mmol) and cesium carbonate (1.3 g, 4.0 mmol) was suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 4.5 h. The reaction mixture was cooled to room temperature, filtered and the filtered solid was with DCM (30 mL). The filtrate was concentrated and the residue purified by flash chromatography on silica gel (hexanes to 30% EtOAc/hexanes) to afford the TIPS protected precursor.

135 [0240] To the above 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 h and then concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCO 3 solution (30 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and solid 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% overall yield). [0241] 'H NMR (500 MHz, DMSO-d 6 ): 8 2.17 (s, 3H), 2.20-2.30 (m, 4H), 2.73 (t, J= 4.6 Hz, 4H), 3.28 (s, 211), 6.41 (t, J= 2.2 Hz, IH), 6.89 (d, J= 8.5 Hz, 2H), 7.09 (t, J= 7.8 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 7.27 (t, J= 2.8 Hz, 1H), 7.31 (d, J=7.5 Hz, 1H), 7.44 (d, J= 8.5 Hz, 2H), 7.85 (s, 111), 8.13 (s, 1H), 8.77 (s, 1H), 11.10 (s, 1H) MS (ES+): m/z 414 (M+H)*. EXAMPLE 111. 5-Methyl-M-(7-methyl-1ff-indol-4-yi)-M-(4-(4-methylpiperazin-1 yl)phenvl) pyrimidine-2,4-diamine (Compound LXXIH) / NH HN N ~N N~ N H LXXIH [02421 A mixture of intermediate 32 (674 mg, 2.25 mmol), 4-bromo-7-methyl-IH-indole (522 mg, 2.48 mmol), Pd 2 (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 at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (136 mg of HCI salt, 13%) as a white solid.

136 [02431 H NMR (500 MHz, DMSO-d 6 ): 8 2.21 (s, 3H), 2.55 (s, 3H), 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, 1H), 7.83 (s, 1H), 10.04 (s, 1H), 10.24 (s, 1H), 11.08 (br s, 1H), 11.34 (s, 1H), 12.12 (br s, 1H). MS (ES+): m/z 428 (M+H)*. EXAMPLE 112. M-(7-Chloro-1K-indol-4-yl)-5-methyl-N 2 -(4-(4-methylpiperazin-1 yl'phenyI) prnimidine-2,4-diamine (Compound LXXIV) NH CI HN N LXXIV [02441 A mixture of intermediate 32 (298 mg, 1.0 mmol), 4-bromo-7-chloro-1H-indole (231 mg, 1.04 mmol), Pd 2 (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 at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (251 mg of HCl salt, 51%) as a white solid. [02451 'H NMR (500 MHz, DMSO-d6): 8 2.21 (s, 3H), 2.80 (d, J= 4.6 Hz, 3H), 3.01-3.05 (in, 211), 3.08-3.13 (m, 2H), 3.46-3.48 (m, 2H), 3.65-3.67 (m, 2H), 6.46-6.47 (m, 111), 6.64 (br s, 1H), 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, 1H), 7.87 (s, 1H), 10.13 (s, 1H), 10.27 (s, 1H), 11.00 (br s, 1H), 11.70 (s, 1H), 12.23 (br s, H). MS (ES+): n/z 448 (M+H)*.

137 EXAMPLE 113. N 2 -(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)-5-methyl-1M-(7-methyl-H indol-4-yI) pvyrimidine-2,4-diamine (Compound LXXV) NH HN H LXXV [0246] A mixture of intermediate 38 (410 mg, 1.3 mmol), 4-bromo-7-methyl-1H-indole (275 mg, 1.3 mmol), Pd 2 (dba) 3 (92 mg, 0.1 nmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford. the title compound (92 mg of HCl salt, 15%) as a white solid. 10247) 'H NMR (500 MHz, DMSO-d 6 ): 8 1.88-1.90 (m, 2H), 1.93-2.02 (m, 2H), 2.21 (s, 311), 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, 1H), 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, 1H), 10.07 (s, 1H), 10.33 (s, 1H), 10.91 (br s, 1H), 11.34 (s, 1H), 12.15 (br s, H). MS (E5+): m/z 443 (M+H)". EXAMPLE 114. M-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)-5-methyl-1-(7-chloro-1H indol-4-yl) pyrimidine-2,4-diamine (Compound LXXVI) NH C1 HN 0 NI H LLXVI [0248] A mixture of intermediate 38 (270 mg, 0.86 mmol), 4-bromo-7-chloro-1H-indole (198 mg, 0.86 mmol), Pd 2 (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 at reflux 138 under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residuewas purified by HIPLC to afford the title compound (33 mg of HCl salt, 8%) as a white solid. [0249] 'H NMR (500 MHz, DMSO-d 6 ): 5 1.88-1.90 (m, 2H), 1.93-2.02 (m, 2H), 2.22 (s, 3 H), 3.06-3.10 (m, 2H), 3.51-3.54 (m, 4H), 4.27 (t, J= 4.9 Hz, 21I), 6.46-6.47 (m, 1H), 6.63 (br d, 2H), 6.95 (d, J= 8.2 Hz, 2H), 7.06 (d, J= 8.0 Hz, IH), 7.25 (d, J= 8.0 Hz, 1H), 7.43 (t, J= 2.8 Hz, 1H), 7.90 (s, 1H), 10.13 (s, IH), 10.40 (s, 1H), 10.94 (br s, 1H), 11.70 (s, 1H), 12.33 (br s, H). MS (ES+): m/z 463 (M+H)*. EXAMPLE 115. N2-(4-(2-(Pyrrolidin-1-yl)ethox)pheny)-5-methy- -(7-fluoro-1H indol-4-yl) pyrimidine-2,4-diamine (Compound LXXVH) NH F HN NN N N H LXXVI [0250] A mixture of intermediate 38 (413 mg, 1.3 mmol), 4-bromo-7-fluoro-1H-indole (310 mg, 1.45 mmol), Pd 2 (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 at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (10 mg of HCl salt, 1.5%) as a brown solid. [0251] 'H NMR (500 MHz, DMSO-d): 8 1.88-1.90 (in, 2H), 1.93-2.02 (m, 211), 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, 1H), 6.63 (br d, 2H), 6.95-7.04 (m, 3H), 7.35 (d, J= 8.9 Hz, 1H), 7.42 (t, J= 2.8 Hz, 111), 7.89 (s, 1H), 10.08 (s, 1H), 10.41 (s, 1H), 10.90 (br s, 1H), 11.85 (s, 1H), 12.33 (br s, H). MS (ES+): m/z 447 (M+H)*.

139 EXAMPLE 116. N-(3-tert-Butylphenvi)-5-methyl-N 2 -(4-(4-methylpiperazin-1 yl)phenyl)pyrimidine-2,4-diamine (Compound LXXVIII) HN N H LXXVifI [02521 A mixture of intermediate 32 (298 mg, 1.0 mmol), 1-tert-butyl-3-bromobenzene (256 mg, 1.2 mmol), Pd 2 (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 at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (27 mg of HC1 salt, 6%) as a white solid. [0253] 'H NMR (500 MHz, DMSO-d): 8 1.25 (s, 9H), 2.16 (s, 3H), 2.80 (d, J= 4.6 Hz, 3H), 3.04-3.16 (m, 411), 3.47-3.49 (i, 2H), 3.65-3.67 (m, 21), 6.90 (d, J= 8.9 Hz, 2H), 7.26 (d, J 9.0 Hz, 21H), 7.28-7.35 (m, 2H), 7.45 (t, J= 1.8 Hz, 1H), 7.50 (d, J= 7.8 Hz, 1H), 7.86 (s, 111), 9.70 (s, 1H), 10.37 (s, 111), 11.01 (br s, 111), 12.34 (br s, H). MS (ES+): m/z 431 (M+H) . EXAMPLE 117. N-(3-tert-Butylphenyr)-2-chloro-5--methylpyrinidin-4-amine (Intermediate 41) HN N Cl 41 [02541 A mixture of 2-chloro-5-methylpyrinidin-4-amine (670 mg, 4.7 mmol), 1-tert butyl-3-bromobenzene (1.5 g, 7 mmol), Pd 2 (dba) 3 (366 mg, 0.4 mmol), Xantphos (695 mg, 1.2 mmol) and cesium carbonate (6.2 g, 19 mmol) was suspended in dioxane (150 mL) and 140 heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc (10 mL) and added hexanes (100 mL). The solid was collected by filtration and washed with hexanes to afford the crude title compound (1.2 g, 99%) as a yellow solid. EXAMPLE 118. N4-(3-tert-Butylphenyl)-5-methyl-N2-(4-(piperidin-4 yloxv)phenyl)pvrimidine-2,4-dianine (Compound LXXIX) HN I NO 3NH H LXXIX [02551 A mixture of intermediate 41 (740 mg, 2.68 mmol) and tert-butyl 4-(4 aminophenoxy)piperidine-1-carboxylate (500 mg, 1.71 mmol) was suspended in acetic acid (10 mL) and heated at 100 'C for 4 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with EtOAc (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by iPLC to afford the title compound (276 mg of HCl salt, 35%) as a yellow solid. [0256] 'H NMR (500 MHz, DMSO-d 6 ): 8 1.22 (s, 9H), 1.77-1.81 (m, 2H), 2.03-2.07 (m, 211), 2.14 (s, 3H), 3.00-3.04 (m, 2H), 3.18 (br s, 2H), 4.56-4.57 (m, 1$), 6.86 (d, J= 8.9 Hz, 2H), 7.26-7.31 (m, 4H), 7.40 (s, 1H), 7.44 (d, J= 7.5 Hz, 1H), 7.84 (s, 1H), 8.93 (br s, 1H), 8.99 (br s, 1H), 9.67 (s, 1H), 10.31 (s, IH). MS (ES+): n/z 432 (M+H)+. EXAMPLE 119. tert-Butyl 4-(4-(4-amino-5-methylpyrimidin-2 vlamino)phenoxy)piperidine-1-carboxylate (Intermediate 42)

NH

2 NO NBoc N N H 42 141 [0257] A mixture of 2-chloro-5-methylpyrimidin-4-amine (540 mg, 3.7 mmol), tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate (1.1 g, 3.7 mmol) was suspended in acetic acid (20 mL) and heated at 70 'C for I h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with EtOAc (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to afford the title compound (1.4 g, 95%) as a yellow solid. EXAMPLE 120. 1 -(1H-Indazol-4-l)-5-methyl-N-(4-(piperidin4 yloxy)phenyl)pyrimidine-2,4-diamine (Compound LXXX) N-NH HN NNIZ O NH H LXXX [0258] A mixture of intermediate 42 (480 mg, 1.2 mmol), 4-bromo-1H-indazole (236 mg, 1.2 mmol), Pd 2 (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 at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (4 mg of HCl salt, 1.2%) as a yellow solid. [0259] 1H NMR (500 MHz, DMSO-d 6 ): 8 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, 1H), 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 (in, 2H), 7.62 (d, J= 8.9 Hz, 2H), 7.92 (s, 1H), 8.02 (s, 1H), 9.00 (br s, 1H), 9.04 (br s, 1H), 10.20 (s, 1H), 10.33 (s, 1H). MS (ES+): nz 416 (M+H)*.

142 EXAMPLE 121. 4-{3-f4-(4-Chloro-3-methoxy-phenylamino)-5-methyl-pyrimidin-2 ylaminol-benzyl}-piperazine-1-carboxylic acid tert-butyl ester (Intermediate 43) C1 O NH O O NN NNN H 43 [02601 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), Pd 2 (dba) 3 (0.03 g, 0.033 mmol), Xantphos (0.038 g, 0.065 mmol) and cesium carbonate (0.32 g, 0.98 mmol) was suspended in dioxane (5 mL) and microwaved at 160 'C for 15 min. The reaction mixture was cooled to room temperature and centrifuged down. The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified by HPLC to afford the title compound (0.075 g, 43%) as a brown solid. EXAMPLE 122. M-(4-Chloro-3-methoxy-phenyl)-5-methvl-N2-(3-piiperazin-1 ylmethyl-phenyl)-pyrimidine-2,4-diamine (Compound LXXXI) C1 CO)~NNH N NN H LXXXI [0261] A solution of intermediate 43 (0.075 g, 0.14 mmol) in DCM (8 mL) was treated with TFA (2 mL). After 2 h of stirring, solvents were removed and resulting residue was triturated with diethyl ether resulting in white hygroscopic powder (0.05 g, 82%). [02621 1H NMR (500 MHz, DMSO-dr): S 2.17 (s, 3H), 2.89 (br s, 4H), 3.2 (br s, 4H), 3.68 (s, 4H), 3.82 (br s, 3H), 7.16-7.19 (m, 2H), 7.28 (t, J= 7.9 Hz, 1H), 7.33 (d, J= 2.3 Hz, 1H), 7.39 (s, 1H), 7.43 (d, J= 8.5 Hz, 1H), 7.49 (d, 8.6 Hz, 1H), 7.98 (s, 1H), 8.8 (br s, 2H), 9.78 (br s, 111), 10.57 (br s, 1H). MS (ES+): m/z 439 (M+H)+.

143 EXAMPLE 123. N4-(4-Chloro-3-methoxy-phenvl)-5-methyl-- 4-(piperidin-4-yloxy) phenyll-pyrimidine-2,4-diamine (Compound LXXXII) C0 NH N ) O-2K NH LXXXM [02631 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 microwaved at 160 'C for 15 min. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 nL) and the mixture was neutralized with 10% NaOH solution until solid precipitated. Filtration followed by column chromatography yielded the title compound as beige solids (0.51 g, 50%). [0264] 'H NMR (500 MHz, DMSO-d 6 ): & 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, 1H), 4.21-4.26 (m, 1H), 6.77 (d, J= 9 Hz, 2H), 7.27 (d, S= 8.5 Hz, 1H), 7.40-7.42 (m, 1H), 7.46-7.49 (m, 3H), 7.87 (s, 1H), 8.31 (s, 1H), 8.78 (s, 1H). MS (ES+): m/z 440 (M+H)+. EXAMPLE 124. 4

-{

3 -[4-(4-Chloro-3-methoxy-phenviamino)-5-methyl-pyrimidin-2 vlaminoj-phenyll-piperazine-1-carboxvie acid tert-butyl ester (Intermediate 44) 0)O N H N O O 0 44 10265] A mixture of intermediate 31 (0.13 g, 0.46 mmol) and 4-(3-amino-phenyl) piperazine-1 -carboxylic acid tert-butyl ester (0.19 mg, 0.68 mmol) in acetic acid (8 mL) was heated at 80 'C for 15 h. The mixture was allowed to cool to room temperature and acetic acid 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 144 acetate, washed with brine and evaporated to oily residue. Column chromatography yielded the title compound as white solids (0.12 g, 48%). EXAMPLE 125. M-(4-Chloro-3-methoxy-phenyl)-5-methyl-N 2 -(3-piperazin-1-yl phenyl)-pyrinidine-2,4-diamine (Compound LXXXUI) C1 CO NH N N H NH LXXXI [02661 A solution of intermediate 44 (0.11 g, 0.21 mmol) in DCM (8 mL) was treated with TFA (1 mL). After 3 h of stirring, solvents were removed and resulting residue was taken up in ethyl acetate and washed with 10% sodium bicarbonate solution. Organic phase then dried over sodium sulfate, filtered and evaporated to white powder. This was diluted with DCM (5 mL) and treated with 4M HCI in dioxane (0.5 mL). Solvents were imediately removed affording HCL salt of title compound as white solids (0.06 g, 67%). [02671 'H NMR (500 MHz, DMSO-d): 8 2.18 (s, 3H), 3.12 (br s, 4H), 3.22 (br s, 4H), 3.65 (s, 3H), 6.80 (d, J= 8.1 Hz, 1H), 6.95 (s, 2H), 7.14 (t, J= 8.2 Hz, 1IH), 7.23 (d, J= 7.0 Hz, 1H), 7.37-7.40 (m, 2H), 7.95 (s, 1H), 9.33 (br s,-2H), 9.88 (s; 1H), 10.62 (s, 1H). MS (ES+): n/z 425 (M+H)'. EXAMPLE 126. 2-[4-(3-Bromo-phenyl)-piperidin-1-vil-ethanol (Intermediate 45) Br N ~OH 45 [02681 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 numol). These were stirred at ambient temperature for 18 then poured onto water and extracted with ethyl acetate. Organic phase then washed with brine, dried over sodium sulfate, filtered and evaporated to clear oil (0.6 g, 44%).

145 EXAMPLE 127. 2-[4-(3-{5--Methvi-2-[4-(4-methyl-piperazin-1-yl)-phenylaminol pyrimidin-4-ylamino}-phenyl)-niperidin-1-yll-ethanol-(Compound LXXXIV) NH N H NN H LXXXIV [02691 - A mixture of intermediate 32 (0.11 g, 0.38 mmol), intermediate 45 (0.21 g, 0.75 mmol), Pd 2 (dba) 3 (0.034 g, 0.037 mmol), Xantphos (0.043 g, 0.075 mmol) and cesium carbonate (0.37 g, 1.1 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 down. The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified by HPLC.to afford the title compound (0.075 g, 43%) as a purple solid (0.02 g, 11%). [02701 'H NMR (500 MHz, DMSO-d 6 ): 8 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, 1H), 7.22 (t, J =7.8 Hz, 1H), 7.45-7.49 (m, 311), 7.66 (d, J 7.7 Hz, 11H), 7.82 (s, 1H), 8.09 (s, 1H), 8.67 (s, 1H). MS (ES+): m/z 502 (M+H)*. EXAMPLE 128. 4-(3-Bromo-benzenesulfonylamino)-piperidine-1-carboxylic acid tert butyl ester (Intermediate 46) N Br O Ok 46 [0271] 3-Bromo-benzenesulfonyl chloride (2.2 g, 8.7 mmol) and 4-amino-piperidine-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 h, reaction was poured into separatory funnel and washed with water. Organic phase was then washed with brine, dried over sodium sulfate, filtered and evaporated to clear oil which solidified upon standing (3.6 g, 98%).

146 EXAMPLE 129. 4-(3-15-Methyl-2-[4-(4-methyl-piperazin--l)-phenylaminol pyrimidin-4-ylaminol-benzenesulfonylamino)-piperidine-1-carboxvlic acid tert-butyl ester (Intermediate 47) O N 2NH O N, H 47 [02721 A mixture of intermediate 32 (0.15 g, 0.518 mmol), intermediate 46 (0.28 g, 0.67 mmol), Pd 2 (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 down. The reaction was decanted onto ice. Resulting precipitate dried and carried on directly for deprotection step (0.2 g). EXAMPLE 130. 3-{5-Methyl-2-(4-(4-methyl-piperazin-1-yl)-phenvlaniinol-pyrimidin 4-ylaminol-N-piperidin-4-yl-benzenesulfonamide (Compound LXXXV) HN Q> NH N H LXXXV [02731 Intermediate 47 (0.2 g, 0.32 mmol) was diluted with DCM (10 mL) and treated with TFA (0.3 nL). After 3 h, reaction solvents removed and resulting residue was purified by HPLC (0.01g, 6%). [0274] 'H NMR (500 MHz, DMSO-d 6 ): 8 1.30-1.35 (m, 2H), 1.56-1.58 (m, 2H), 1.98 (s, 21), 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, 1H), 7.88 (s, 1H), 8.05 (s, 1H), 8.20 (d, J= 7.6 Hz, 1H), 8.53 (s, 1H), 8.71 (s, 1H). MS (ES+): m/z 537 (M+H).

147 EXAMPLE 131. N-(4-(Trifluoromethyl-3-methylphenl)-5-methyl-N 2 -(4-(4 methylpiperazin-1-yI)phenyl)pyrimidine-2,4-diamine hydrochloride (Compound F3C NH N N N, H LXXXVI [02751 A suspension of intermediate 32 (0.12 g, 0.40 mmol), 1-bromo-3-(trifluoromethyl) 2-methylbenzene (0.14 g, 0.59 mmol), Pd 2 (dba) 3 (37 mg, 0.04 mmol), 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 for overnight. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture was purified by silica gel with 10% CH 3 0HICHC1 3 as an fluent to afford the title compound as a white solid. The white was dissolved in CHC 3 (30 mL) and titrated with 2 M HCI in dioxane to pH 1. The solvent was removed by rotovap and the solid was recrystalized from acetone (25 mg, 13%). 10276] 'H NMR (500 MHz, DMSO-d,): 8 2.20 (s, 3H), 2.26 (s, 3H), 2.77 (d, J= 4.5 Hz, 3H), 3.00-3.20 (i, 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= 7.9 Hz, 1H), 7.63 (d, J= 7.8 Hz, 1H), 7.77 (d, J =7.77 Hz,.1H), 7.94 (s, IH), 10.13 (s, 1H), 10.60 (s, 1H), 11.28 (s, 1H). MS (ES+): m/z 457 (M+H)*. EXAMPLE 132. 5-Methyl-N-(4-(4-methylpiperazin-1-yl)phenyl)-N-( (methylsulfonyl)phenyl)-pyrimidine-2,4-diamine (Compound LXXXVI) O ~S NH N N N N H

LXXXVH

148 [02771 A suspension of intermediate 32 (0.13 g, 0.44 mmol), 1-bromo-3 (methylsulfonyl)benzene (0.24 g, 1.0 mmol), Pd 2 (dba) 3 (40 mg, 0.04 mmol), Xantphos (50 mg, 0.08 mmol) and cesium carbonate (0.43 g, 1.32 mmol) in dioxane (50 mL) was degassed with argon for 2 min then refluxed for overnight. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture was purified by silica gel with 30% CH 3 0H/CHCl 3 as an fluent to afford the title compound as pale yellow solid (35 mg, 15%). [0278] 'H NMR (500 MHz, DMSO-d 6 ): 8 2.11 (s, 3H), 2.23 (s, 3H), 2.46 (br s, 411), 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, 1H), 8.05 (s, 1H), 8.36 (d, J= 6.7 Hz, 1H), 8.60 (s, IH), 8.77 (s, 1H). MS (ES+): mn/z 453 (M+H)*. EXAMPLE 133. 1-Bromo-3-(propylsulfonyl)benzene (Intermediate 48) Br 0 48 [02791 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 al 3-bromobenzenethiol reacted. The reaction was quenched with saturated NaHCO 3 solution (25 mL) and the mixture extracted with CHC1 3 (60 mL). The product in the CHCl 3 was refluxed with mCPBA (2.9 g, 13 mmol) until all starting reacted. The organic layer was washed with 2M NaOH to remove the excess of mCPBA, dried over Na 2

SO

4 and filtered. The filtrate was concentrated and the crude product was purified with silica gel column with 1:1 hexanes/CHCl 3 as an eluent to yield colorless oil (0.30 g, 43% in 2-steps). [0280] 'H NMR (500 MHz, DMSO-d): 0.92 (t, J= 7.4 Hz, 3H), 1.52-1.60 (m, 2H), 3.35 3.38 (m, 2H), 7.63 (t, J= 8.0 Hz, 1H), 7.88-7.91 (m, 1H), 7.95-7.98 (m, 1H), 8.04 (t, J= 1.8 Hz, 1H).

149 EXAMPLE 134. 5-Methyl-N 2 -(4-(4-methylpiperazin-1-ylpheny)-M-(3 (propylsulfonyl)phenyl)-pyrimidine-2,4-diamine hydrochloride (Compound LXXXVIII) o ..... fS NH r N o N,) N.N LXXXVI [0281] A suspension of intermediate 32 (0.25 g, 0.84 mmol), intermediate 48 (0.26 g, 1 mmol), Pd 2 (dba) 3 (8 mg, 0.01 mmol), Xantphos (16 mg, 0.03 mmol) and cesium carbonate (0.82 g, 2.52 mmol) in dioxane (50 mL) was degassed with argon for 2 min then refluxed for overnight. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture was purified by silica gel with 10% CH 3 0H/CHC 3 as an eluent to afford the title compound as a white solid. The white was dissolved in CHC1 3 (30 mL) and titrated with 2 M HCl in dioxane to pH 1. The solvent was removed by rotovap and the solid was recrystalized from methanol (65 mg, 15%). [02821 'H NMR (500 MHz, DMSO-d,): 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, IH), 7.73 (d, J= 7.8 Hz, 1H), 7.93 (s, 1H), 8.00 (s, 1H), 8.07 (s, 1H), 9.92 (s, 1H), 10.36 (s, 1H), 10.99 (s, 1H). MS (ES+): m/z 481 (M+H)*. EXAMPLE 135. 3-(Morpholinomethyl)benzenamine (Intermediate 49)

H

2 N N. 49 [02831 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 mL) at room temperature. The solution was heated to reflux for 1 hour. After cooling down , the reaction was quenched by water (2 mL) and the methanol was removed by rotovap. The crude product was dissolved in 2M NaOH (50 mL) and extracted by CHC1 3 , dried over Na 2

SO

4 and filtered. The filtrate was concentrated under vacuum.

150 [0284] The above crude product in methanol (200mL) was reduced by Raney Ni and hydrazine at room temperature. The reaction was monitored by TLC in ethyl acetate. After all starting material reacted, the methanol was removed by rotovap. The crude was purified by silica gel with ethyl acetate as an eluent to yield a white solid (1.5 g, 50% in 2-steps). [0285] 'H NMR (500 MHz, DMSO-d 6 ): 2.31 (s, 4H), 3.?8 (s, 2H), 3.56 (t, J= 4.6 Hz, 4H), 4.97 (s, 2H), 6.40-6.45 (m, 2H), 6.53 (t, J= 1.8 Hz, 1H), 6.93 (t, J= 7.7 Hz, 1H). EXAMPLE 136 5-Methyl-N-(3-(morpholinomethyl)phenyl)pyrimidine-2,4-diamine (Intermediate 50)

NH

2 N O H 50 [02861 A mixture of 2-chloro-5-methylpyrimidin-4-amine (0.17 g, 1.17 mmol) and intermediate 49 (0.25 g, 1.30 mnol) was suspended in acetic acid (10 mL) and heated at 100 'C for 2 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-8. The resulting solution was extracted with CHC 3 (100 mL) and the organic layer separated. The organic layer was washed with brine, dried over Na 2 SO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by silica gel column with 10 %

CH

3 0H/EtOAc as an eluent to afford the title compound as oil (0.15g, 43%). [02871 'H NMR (500 MIHz, DMSO-d 6 ): 1.91 (s, 3H), 2.35 (s, 4H), 3.17 (s, 2H), 3.57(t, J = 4.4 Hz, 4H), 6.37 (s, 2H), 6.78 (d, J= 7.5 Hz, 1H), 7.13 (t, J= 7.8 Hz, 1H), 7.59 (s, IH), 7.69 (s, 1H), 7.74 (d, J= 9.3 Hz, 1H), 8.68 (s, 1). EXAMPLE 137. N-tert-Butyl-3-[5-methyl-2-(3-morpholin-4-lmethyl-phenlvamino) pyrimidin-4-ylaminol-benzenesulfonamide hydrochloride (Compound LXXXIX) H N0 - N sNH N rO H

LXXXIX

151 [02881 A suspension of intermediate 50 (1.0 g, 3.42 mmol), 3-bromo-N-tert-butyl benzenesulfonamide (1.28 g, 4.28 mmol), Pd 2 (dba) 3 (30 mg, 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 for overnight. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture was purified by silica gel with 10% CH 3 0HI/CHC 3 as an eluent to afford the title compotnd as a white solid. The white was dissolved in hot dioxane (150 mL) and titrated with 2 M HC1 in dioxane to pH 1. The solvent was removed by rotovap and the solid was recrystalized from methanol (0.15 g, 8%). [0289] 'H NMR (500 MHz, DMSO-d,): 1.08 (s, 9H), 2.20 (s, 3H), 3.0-3.2 (i, 411), 3.7 4.0 (in, 4H), 4.23 (s, 2H), 7.33 (t, J= 7.9 Hz, 1H), 7.38 (d, J= 7.7 Hz, 1H), 7.48 (s, 1H), 7.55-7.65 (in, 3H), 7.71 (d, J= 7.9 Hz, 1H), 7.90 (d, J= 7.4 Hz, 1H), 8.01 (s, 1H), 9.96 (br s, 111), 10.61 (br s, 1H), 11.31 (br s, 1H). MS (ES+): n/z 511 (M+H)'. EXAMPLE 138. 2-Chloro-5-methyl-N-(3,5-dimethylphenyl)pyrimidin4-amine (Intermediate 51) NH NCI 51 [02901 A mixture of 1-bromo-3,5-dimethylbenzene (104 piL, 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 nmol) in dioxane (8 mL) was microwaved at 160 'C for 20 min. The reaction mixture was cooled to room temperature and filtered rinsing with DCM and methanol. The filtrate was concentrated and purified using gradient flash chromatography (0-100% ethyl acetate in hexanes) to afford the title compound as a yellow oil (89 mg, 50%). MS (ES+): m/z 248 (M+H).

152 EXAMPLE 139. 5-Methyl-N4-(3,5-dimethylphenvl)-N 2 -(4-(piperidin-4 yloxv)phenyl)pvrimidine-2,4-diamine (Compound XC) NH I )Z K NH XC [0291] A mixture of intermediate 51 (89 mg, 0.36 mmol), and 4-(4-amino-phenoxy) piperidine-1-carboxylic acid tert-butyl ester (139 mg, 0.47 mmol) in acetic acid was stirred at room temperature for 16h, then heated to 95 'C for 2 h. The reaction mixture was concentrated in vacuo, and purified by preparative HPLC. The product was basified with NaHCO 3 (aq)(10 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine (5 mL), dried (Na 2

SO

4 ), and concentrated. The freebase was taken up in MeOH (5 mL) and conc HCI (5 drops) and after 2 min was concentrated in vacuo in the presence of DCM and hexanes to afford the HCI salt of the title compound as an off white solid (63 mg, 40%). 10292] 'H NMR (500 MMz, DMSO-d 6 ): 8 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, 1H), 6.85 (s, 1H), 6.91 (d, J= 8.9 Hz, 2H), 7.20 (s, 211), 7.37 (d, J= 8.9 Hz, 2H), 7.85 (s, 1H), 8.50 (br s, 1H), 8.56 (br s, lH), 9.36 (br s, IH), 10.10 (br s, 1H). MS (ES+): m/z 404 (M+H)'*.

153 EXAMPLE 140. 2-Chloro-N-(3,5-dimethoxyphenyl)-5-methylpyrimidin-4-amine (Intermediate 52) 0 O NH 52 102931 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 mmol), 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 rinsing with DCM and methanol. The filtrate was concentrated and purified using gradient flash chromatography (0-100% ethyl acetafe in hexanes) to afford the title compound as a yellow solid (182 mg, 33%). [0294] 'H NMR (500 MHz, DMSO-d,): 8 2.17 (s, 3H), 3.74 (s, 6H), 6.27 (t, J= 2.2 Hz, 1H), 6.99 (d, J=2.2 Hz, 2H), 8.06 (s, 1H), 8.71 (s, 1H). MS (ES+): m/z 280 (M+H)*. EXAMPLE 141. V-(3,5-Dimethoxyphenyl)-5-methyl-N-(4-(piperidin4 loxyphenyl)pvrimidine-2,4-diainine (Compound XCI) 0 0 NH NN ''ONH H XCI [0295] A mixture of intermediate 52 (100 mg, 0.36 mmol), and 4-(4-amino-phenoxy) piperidine-1-carboxylic acid tert-butyl ester (106 mg, 0.36 mmol) in acetic acid was heated to 95 'C for 2 h. The reaction mixture was concentrated in vacuo, and purified by preparative 1{PLC to afford the TFA salt of the title compound as a tan solid (75 mg, 39%).

154 [02961 'H NMR (500 MHz, DMSO-d 6 ): 5 1.74-1.83 (in, 2H), 2.03-2.11 (in, 2H), 2.15 (s, 3H), 3.06-3.15 (in, 2H), 3.21-3.30 (m, 2H), 3.69 (s, 6H), 4.57-4.60 (m, 1H), 6.39 (t, J =2.2 Hz, 1H), 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, 111), 8.53 (br s, 1H), 8.58 (br s, 1H), 9.49 (br s, 1H), 10.24 (br s, 1H). MS (ES+): m/z 436 (M+H). EXAMPLE 142. 5-Methyl-N-(4-(4-methylpiperazin--yl)phenyl)-1/-(3-(piperidin-1 yl)phenyl)pyrimidine-2,4-diamine (Compound XCH) Q NH N (N~ XCII [0297] A mixture of 1-(3-bromophenyl)piperidine (91 mg, 0.38 mmol), intermediate 32 (99 mg, 0.33 mmol), Pd 2 (dba)3 (15 mg, 0.02 mnol), Xantphos (24 mg, 0.04 mmol) 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 rinsing with DCM and methanol. The filtrate was concentrated and purified by preparative HPLC to afford the TFA salt of the title compound as an off-white solid (14 mg, 8%). [02981 1 H NMR (500 MHz, DMSO-dQ): 8 1.47-1.53 (in, 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, 1H), 6.76 (d, J=9.0 Hz, 2H), 7.12 (t, J= 8.3 Hz, 1H), 7.14 (s, 1H), 7.27 (d, J=7.6 Hz, 1H1), 7.50 (d, J=9.0 Hz, 2H), 7.81 (s, 1H), 8.00 (s, 1H), 8.67 (s, 1H). MS (ES+): m/z 458 (M+H)+ EXAMPLE 143. 1M-(3-(1H-Pyrrol-1-yl)phenyl)-5-methyl-N 2 -(4-(4-methylpiperazin-1 yl)phenyl)pvrimidine-2,4-diamine (Compound XCIH) N aNH rN -- N N H

XCI

155 [0299] A mixture of 1-(3-bromophenyl)-1H-pyrrole (86 mg, 0.39 mmol), intermediate 32 (99 mg, 0.33 mmol), Pd 2 (dba) 3 (16 mg, 0.02 mmol), Xantphos (26 mg, 0.05 mmol) and cesium carbonate (215 mg, 0.66 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 rinsing with DCM and methanol. The filtrate was concentrated and purified by preparative HPLC to afford the TFA salt of the title compound as an off-white solid (32 mg, 18%). [0300] 'H NMR (500 MHz, DMSO-d 6 ): 8 2.11 (s, 3H), 2.21 (s, 3H), 2.42 (t, J=4.9 Hz, 4H), 2.95 (t, J=4.9 Hz, 4H), 6.24 (t, J=2.2 Hz, 2H), 6.58 (d, J=8.9 Hz, 2H), 7.23 (dd, J= 7.8, 1.8 Hz, 1H), 7.31 (t, J= 2.2 Hz, 2H), 7.37 (t, J=8.1 Hz, 1H), 7.43 (d, J=9.0 Hz, 21), 7.60 (d, J=8.8 Hz, IH), 7.86 (t, J=2.2 Hz, 1H), 7.87 (s, 1H), 8.30 (s, 1H), 8.74 (s, 1H). MS (ES+): m/z 440 (M+H)*. EXAMPLE 144. 5-2-[4-(1-tert-Butoxvcarbonyl-piperidin4-yloxy)-phenylaminol-5 methyl-pyrimidin-4-ylaminol-indole-1-carboxvlic acid tert-butyl ester (Intermediate 53) oO NH NHN H 0 53 [03011 A mixture of tert-butyl 5-bromo-IH-indole-1-carboxylate (161 mg, 0.54 mmol), intermediate 42 (202 mg, 0.50 mmol), Pd 2 (dba) 3 (29 mg, 0.03 mmol), 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 rinsing with DCM. The filtrate was concentrated and purified by gradient flash chromatography (0 20% MeOH in DCM) to afford the title compound as a light-brown solid (290 mg, 94%). MS (ES+): nu/z 615 (M+H)*.

156 EXAMPLE 145. N4-(1H-Indol-.5-l)-5-methyl-N-(4-(piperidin-4 yloxv)phenvl)pyrimidine-2,4-dialine (Compound XCIV) H NH N O NH H XCIV (03021 To a solution of acetyl chloride (670 iL, 9.42 mmol) in methanol (22 mL) was added intermediate 53 (290 mg, 0.47 mmol), and the reaction mixture was heated to 60 'C for 4 h. The mixture was concentrated in vacuo and purified by preparative HPLC to afford the TFA salt of the title compound as a brown solid (6 mg, 2%). [0303} 'H NMR (500 MHz, DMSO-d 6 ): 8 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, 1H), 6.43 (s, 1H), 6.75 (d, J= 8.2 Hz, 2H), 7.16 (d, J= 8.4 Hz, 1H), 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, 1H),.9.65 (br s, 1), 9.99 (br s, 1H), 11.18 (s, 1H). MS (ES+): m/z 415 (M+H)*. EXAMPLE 146. N4-(4-Chloro-3-methoxy-phenyl)-5-methyl-N2-(6-Piperazin-1-yl pyridin-3-yl)-pyrimidine-2,4-diamine (Compound XCV) C1 O N(H NH 0NHN H XCV [03041 A mixture of intermediate 31 (0.10 g, 0.35 mmol), 4-(5-amino-pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (0.10 g, 0.36 mmol), Pd 2 (dba) 3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06 mmol) and cesium carbonate (0.23 g, 0.71 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 170 'C for 30 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM and the filtrate 157 concentrated. The residue was purified by flash chromatography on silica gel (hexanes to EtOAc) to afford the Boc-protected 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 HIPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organio layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the resulting solid 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%). [0305] 'H NMR (500 MHz, DMSO-d 6 ): 82.09 (s, 3H), 2.81 (t, J= 5.0 Hz, 4H), 3.29-3.31 (m, 4H), 3.73 (s, 3H), 6.70 (d, J= 9.1 Hz, 1H), 7.26 (d, J= 8.6 Hz, 1H), 7.42 (d, J= 9.1 Hz, 1H), 7.49 (d, J= 2.2 Hz, 1H), 7.76 (dd, J= 9.1, 2.6 Hz, 1H), 7.86 (s, 1H), 8.29 (s, 1H), 8.31 (d, J =2.6 Hz, 1H), 8.71 (s, 1H). MS (ES+): m/z 426 (M+H)*. EXAMPLE 147. 4-(4-Amino-2-methoxycarbonyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (Intermediate 54) 00 $NBoc N,)

H

2 N 54 [03061 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 wt% Pd/C (0.1 equiv by wt) under argon atmosphere. The mixture was evacuated and then refilled with hydrogen (3 cycles) and stirred at room temperature for 2 h. 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+W).

158 EXAMPLE 148. 5-[4-(4-Chloro-3-methoxy-phenyamino)-5-methyl--pyrimidin-2 ylaminol-2-piperazin4-y-benzoic acid methyl ester (Compound XCVfl C1 0 NH ONH NIN H XCVI [03071 A mixture of intermediate 31 (0.10 g, 0.35 mmol), intermediate 54 (0.14 g, 0.42 mmol), Pd 2 (dba) 3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06 imol) and cesium carbonate (0.23 g, 0.71 mmol) was suspended in dioxane (15 mL) and heated at reflux under the argon atmosphere for 2.5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated. The residue was purified by flash chromatography on silica gel (hexanes to 60% EtOAc/hexanes) to afford the Boc-protected 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 h, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaIHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and then taken- up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (40.mg, 24%). [03081 'H NMR (500 MHz, DMSO-d 6 ): 8 2.11 (s, 3H), 2.80-2.90 (m, 8H), 3.73 (s, 3H), 3.74 (s, 3H), 6.98 (d, J= 8.9 Hz, IH), 7.25 (d, J= 8.5 Hz, IH), 7.40-7.48 (in, 2H), 7.69 (dd, J = 8.9, 2.6 Hz, 1N), 7.90 (d, J= 2.6 Hz, IH), 7.91 (s, 1H), 8.36 (s, 1H), 9.04 (s, IH). MS (ES+): m/z 483 (M+H) 4 . EXAMPLE 149. 5-Amino-2-(2-pyrrolidin-1-yl-ethoxy)-benzoic acid methyl ester (Intermediate 55)

H

2 N O N 55 159 [0309] 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 h. The mixture was allowed to cool to room temperature, poured into water (60 mL) and extracted with EtOAc (2 x 50 mL). The combined extracts were washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (DCM to 30% MeOH/DCM) to afford the title compound (0.2 g, 13%) as a light brown solid. MS (ES+): m/z 265 (M+H)*. EXAMPLE 150. 5-[4-(Benzo[l,3]dioxol-4-ylamino)-5-methyl-pyrimidin-2-ylaminol-2 (2-pyrrolidin-1-yl-ethoxy)-benzoic acid methyl ester (Compound XCVII) 0 NH NO N N N H XCVH [03101 A mixture of intermediate 30 (0.15 g, 0.57 mmol), intermediate 55 (0.20 g, 0.75 mmol), Pd 2 (dba) 3 (50 mg, 0.055 mmol), Xantphos (60 mg, 0.10 mmol) 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 microwave at 160 'C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as an off white solid (30 mg, 11%). [0311] 'H NMR (500 MHz, DMSO-d 6 ): 5 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, 311), 6.92 (dd, J= 8.0, 2.1 Hz, 1H), 7.75-7.80 (m, 2H), 7.83 (s, 1H), 8.22 (s, 1H), 8.89 (s, 111). MS (ES+): m/z 492 (M+H)*.

160 EXAMPLE 151. N-tert-Butyl-3--5-methyl-2-[4-(piperidin-4-vloxy)-phenylaminol pyrimidin-4-ylamino}-benzenesulfonamide (Compound XCVIIHf) SHN N SN N H H XCVII [03121 A mixture of intermediate 33 (0.15 g, 0.42 mmol) and 4-(4-amino-phenoxy) piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.51 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150 'C for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and the pH adjusted with 10% NaOH solution until solid precipitated. The solid was filtered and then purified by HIPLC. The corrected fractions were combined, poured into saturated NaHCO 3 solution (30 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (20 mg, 9%). [03131 'H NMR (500 MHz, DMSO-d): 8 1.12 (s, 911), 1.65-1.73 (in, 2H), 1.95-2.05 (m, 2H), 2.12 (s, 3H), 2.89-2.95 (m, 21), 3.10-3.20 (in, 2H), 4.40-4.45 (in, 1H1), 6.84 (d, J= 9.1 Hz, 21), 7.45-7.60 (m, 6H), 7.90 (s, 1H), 8.10-8.15 (m, 2H), 8.55 (s, 1H), 8.81 (s, 1H). MS (ES+): m/z 511 (M+H)*. EXAMPLE 152. 2-(5-Amino-pyridin-2-yloxy)-ethanol (Intermediate 56) / 0 - OH

H

2 N N, N 56 [03141 To a solution of 2-(5-nitro-pyridin-2-yloxy)-ethanol (1.0 g, 5.4 mmol) in MeOH (30 mL) was added 10 wt/o Pd/C (0.1 equiv by wt) under argon atmosphere. The mixture was evacuated and then refilled with hydrogen (3 cycles) and stirred at room temperature for 1 h. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with 161 MeOH and concentrated in vacuo. The crude amino-compound was used in the next step without purification. MS (ES+): n/z 155 (M+H). EXAMPLE 153. 2-{5-[4-(Benzo[1,3]dioxol-4-ylamino)-5-methyl-pyrimidin-2-ylaminol pyridin-2-yloxyl-ethanol (Compound XCIX) 0--\ NH N O OH H XCIX [0315] A mixture of intermediate 30 (0.10 g, 0.38 mmol), intermediate 56 (0.10 g, 0.65 mmol), Pd 2 (dba) 3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06 mmol) and cesium carbonate (0.26 g, 0.80 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 cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 nL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes Were added until solid precipitated. After filtration, the title compound was obtained as an off white solid (50 mg, 35%). [0316] 'H NMR (500 MHz, DMSO-d 6 ): 8 2.06 (s, 3H), 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, 1H), 6.78-6.90 (in, 3H), 7.82 (s, 1H), 7.96 (dd, J= 8.9,2.7 Hz, 1H), 8.22 (d, J= 2.6 Hz, 1H), 8.27 (s, 1H), 8.84 (s, 1H). MS (ES+): m/z 382 (M+H). EXAMPLE 154. 1-[2-(2-Methoxy4-nitro-phenoxv)-ethyll-pyrrolidine (Intermediate 57) 0~ 0 2 NN 57 162 [0317] 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 mmol) in DMF (35 mL) was heated at 80 *C for 16 h. The mixture was allowed to cool to room temperature, poured into water (60 mL) and extracted with EtOAc (2 x 50 mL). The combined extracts were washed with brine, dried over anhydrous Na 2

SO

4 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 (Intermediate 58'

H

2 N N 58 [03181 To a solution of intermediate 57 (1.7 g, 6.4 mmol) in MeOH (30 mL) was added 10 wt% Pd/C (0.1 equiv by wt) under argon atmosphere. The mixture was evacuated and then refilled with hydrogen (3 cycles) and stirred at room temperature for I h. 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. -Benzo[1,3]dioxol-4-yl-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxyF phenyll-5-methyl-pyrimidine-2,4-diamine (Compound C) NH ONHNO N N H C [03191 A mixture of intermediate 30 (0.10 g, 0.38 mmol), intermediate 58 (0.11 g, 0.46 mmol), Pd 2 (dba) 3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxanelDMF (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 cap was removed and the resulting mixture filtered. The filtered solid was washed with 163 DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHC0 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (50 mg, 28%). [03201 'H NMR (500 MHz, DMSO-d 6 ): 8 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, 1H), 6.78 (dd, J= 7.8, 1.1 Hz, 1H), 6.83 (t, J= 7.9 Hz, 1H), 6.92 (dd, J= 8.1, 1.1 Hz, 1H), 7.14 (dd, J= 8.7, 2.4 Hz, 1H), 7.23(d, J= 2.4 Hz, 1H), 7.83 (s, 1H), 8.21 (s, 1H), 8.69 s, 1H). MS (ES+): m/z 464 (M+H)*. EXAMPLE 157. N-tert-Butyl-3-[2-(4-imidazol-1-vl-phenylamino)-5-methyl-pyrimidin 4-ylaminol-benzenesulfonamide (Compound C) SHN N N H CI [03211 A mixture of intermediate 33 (0.40 g, 1.1 mmol), 4-imidazol-1-yl-phenylamine (0.20 g, 1.3 mmol), Pd 2 (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 microwave at 160 'C for 30 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (40 mL). The combined aqueous layers were extracted with EtOAc (2 x 40 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as an off white solid (0.15 g, 28%).

164 [0322] 'H NMR (500 MiHz, DMSO-d 6 ): 8 1.12 (s, 9H), 2.15 (s, 3H), 7.07 (s, 1H), 7.43 (d, J = 9.0 Hz, 2H), 7.50-7.60 (m, 3H), 7.61 (s, 1H), 7.79 (d, J= 9.0 Hz, 2H), 7.98 (s, 1H), 8.08 8.13 (m, 3H), 8.64 (s, 1H), 9.19 (s, 1H). MS (ES+): m/z 478 (M+H) 4 . EXAMPLE 158. N-tert-Butyl-3-[2-(4-imidazol-1-ylmethyl-phenylamino)-5-methyl pyriindin-4-ylaminol-benzenesulfonamide (Compound CI) H N < N H'' j " N Cb " N-"N NN H C11 [0323] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-imidazol-1-ylmethyl phenylamine (60 mg, 0.35 mmol), Pd 2 (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 microwave at 160 'C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 29%). [0324] 'H NMR (500 MHz, DMSO-d): S 1.12 (s, 9H), 2.13 (s, 3H), 5.07 (s, 2H), 6.89 (s, [H), 7.12 (d, J= 8.6 Hz, 2H), 7.15 (s, 1H), 7.46 (t, J= 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, 1H), 7.94 (s, IH), 8.09 (s, 1H), 8.14 (d, J= 8.1 Hz, [H), 8.60 (s, 1H), 9.02 (s, 1H). MS (ES+): m/z 492 (M+H)*. EXAMPLE 159. 2-(4-Amino-phenoxy)-ethanol (Intermediate 59)

H

2 N O O 59 165 [03251 A solution of 2-(4-nitro-phenoxy)-ethanol (2.1 g, 12 mmol) in MeOH (30 mL) was flushed with argon and then charged with 10 wt% Pd/C (0.1 equiv by wt). The mixture was evacuated under house vacuum and then refilled with hydrogen from hydrogen balloon. The cycle was repeated again and the mixture stirred at room temperature for 2 h. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with MeOH and concentrated in vacuo to furnish the title compound (1.8 g, 99%) as a brown solid. MS (ES+): m/z 154 (M+H)+. EXAMPLE 160. N-tert-Butyl-3-{2-[4-(2-hydroxy-ethoxy)-phenylaminol-5-methyl pyrimidin-4-laminol-benzenesulfonamide (Compound CIH) NS' NH N O --- OH H Cm [03261 A mixture of intermediate 33 (0.10 g, 0.28 mmol), intermediate 59 (55 mg, 0.36 mmol), Pd 2 (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 microwave at 160 *C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (15 mg, 11%). 103271 'H NMR (500 MHz, DMSO-d 6 ): 8 1.12 (s, 9H), 2.12 (s, 3H), 3.69 (q, J= 5.2 Hz, 211H), 3.91 (t, J= 5.1 Hz, 2H), 4.82 (t, J= 5.5 Hz, 2H), 6.80 (d, J= 9.1 Hz, 211), 7.45-7.50 (in, 2H), 7.52 (d, J= 9.0 Hz, 2H), 7.55 (s, 1H), 7.90 (s, 1H), 8.08-8.15 (in, 2H), 8.53 (s, 1H), 8.77 (s, 1H). MS (ES+): mn/z 472 (M+H)*.

166 EXAMPLE 161. N-(4-Chloro-3-methoxy-phenyl)-5-methyl-N2-(4-piperazin-1 ylmethyl-phenyl)-pyrimidine-2,4-diamine (Compound CIV) CO N H NHNH N1NN H CIV [0328] A mixture of intermediate 31 (0.10 g, 0.35 mmol), 4-(4-amino-benzyl)-piperazine 1-carboxylic acid tert-butyl ester (0.12 g, 0.41 mmol), Pd 2 (dba) 3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06 mmol) and cesium carbonate (0.23 g, 0.71 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 cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM and the filtrate concentrated. The residue was purified by flash chromatography on silica gel (hexanes to 60% EtOAc/hexanes) to afford the Boc-protected 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 h, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (13 mg, 9%). [0329] 'H NMR (500 MHz, DMSO-d): 8 2.11 (s, 3H), 2.30-2.40 (in, 4H), 2.83 (t, J= 4.8 Hz, 4H), 3.37 (s, 2H), 3.75 (s, 311), 7.08 (d, J= 8.6 Hz, 2H), 7.29 (d, J= 8.6 Hz, 1H), 7.43 (dd, 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, 1H), 8.37 (s, 1H), 8.99 (s, 1H). MS (ES+): m/z 439 (M+H)*.

167 EXAMPLE 162. N-tert-Butl-3-{5-methyl-2-[ 4 -(2-methvl-inidazol-1-yl)-phenylaminol pyrimidin.-4-ylaminol-benzenesulfonamide (Compound CV) H N S aNH-N QN'N H CV [0330] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(2-methyl-imidazol-1-yl) phenylamine (60 mg, 0.35 mmol), Pd 2 (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 microwave at 160 'C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 iL). The combined aqueous layers were extracted with EtOAc (2 x 30 m.L) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (30 mg, 22%). [0331] 'H NMR (500 MHz, DMSO-d 6 ): 8 1.11 (s, 9H), 2.15 (s, 3H), 2.24 (s, 3H), 6.87 (d, J= 1.2 Hz, 1H), 7.18 (d, J= 1.3 Hz, 1H), 7.22 (d, J= 8.9 Hz, 2H), 7.50-7.55 (in, 2H), 7.56 (s, 111), 7.79 (d, J= 8.9 Hz, 2H), 7.98 (s, 1f), 8.07-8.10 (i, 2H), 8.65 (s, 1H), 9.26 (s, 1H). MS (ES+): m/z 492 (M+H 4 . EXAMPLE 163. N-tert-Butyl-3-{5-methvl-2-f4-(2-methyl-inidazol-1-ylmethyl) phenylaminol-pyrimidin-4-ylamino}-benzenesulfonamide (Compound CVI) H CVI

CVIH

168 [0332] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(2-methyl-imidazol-1 ylmethyl)-phenylamine (65 mg, 0.35 mmol), Pd 2 (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 microwave at 160 'C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (30 mg, 21%). [0333] - 1H NMR (500 MHz, DMSO-d): 8 1.12 (s, 9H), 2.13 (s, 3H), 2.24 (s, 3H), 5.01 (s, 2H), 6.73 (d, J= 1.2 Hz, 1H), 7.01 (d, J= 8.6 Hz, 2H), 7.07 (d, J= 1.1 Hz, 1H), 7.44 (t, J= 7.9 Hz, 111), 7.48-7.51 (m, 1H), 7.56 (s, 1H), 7.62 (d, J= 8.6 Hz, 2H), 7.94 (s, 1H), 8.08 (s, 1H), 8.12 (d, J= 8.1 Hz, 1H), 8.60 (s, 1H), 9.02 (s, 1H). MS (ES+): n/z 506 (M+H). EXAMPLE 164. N-tert-Butvl-3-[5-methyl-2-(4-pyridin-4-ylmethyl-phenylamino) pyrimidin-4-vlaminol-benzenesulfonamide (Compound CVII) H >N N, H CVIII [0334] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-Pyridin-4-ylmethyl phenylamine (65 mg, 0.35 mmol), Pd 2 (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 microwave at 160 'C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHC03 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The 169 filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (45 mg, 32%). [03351 'H NMR (500 MHz, DMSO-d 6 ): 8 1.11 (s, 9H), 2.13 (s, 3H), 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, 1H), 7.56 (d, J= 6.3 Hz, 2H), 7.58 (s, 1H), 7.93 (s, 1H), 8.09 (s, 1H), 8.13 (d, J= 8.0 Hz, 1H), 8.44 (d, J= 5.8 Hz, 211), 8.58 (s, 1H), 8.94 (s, 1H). MS (ES+): m/z 503 (M+H). EXAMPLE 165. N-tert-Butvl-3-[5-methyl-2-(4-morphoin-4-yl-phenylamino) pyrimidin-4-vlaminol-benzenesulfonainide (Compound CVI) HH N NH N CVI [0336] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-morpholin-4-yl-phenylamine (60 ng, 0.34 mmol), Pd 2 (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 microwave at 160 'C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a grey solid (45 mg, 32%). [0337] 'H NMR (500 MHz, DMSO-d 6 ): 8 1.12 (s, 9H), 2.12 (s, 311), 3.00 (t, J= 4.8 Hz, 4H), 3.73 (t, J= 4.8 Hz, 4H), 6.82 (d, J= 9.1 Hz, 211), 7.45-7.52 (m, 411), 7.56 (s, 1H), 7.89 (s, 1H), 8.10-8.17 (m, 2H), 8.52 (s, 1H), 8.73 (s, IH). MS (ES+): m/z 497 (M+H)*.

170 EXAMPLE 166. N-tert-Butyl-3-[5-methyl-2-(4-[1,2,4triazol-1-ylmethyl-phenylamino) pyrimidin-4-ylaminol-:benzenesulfonamide (Compound CIX) HN N H CIX [0338] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-.[1,2,4]triazol-1-ylmethyl phenylamine (60 mg, 0.34 mmol), Pd 2 (dba) 3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol).in dioxane (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 cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (37 mg, 27%). [0339] 'H NMR (500 MHz, DMSO-d 6 ): 8 1.17 (s, 9H), 2.13 (s, 3H), 5.29 (s, 2H), 7.14 (d, J= 8.6 Hz, 2H), 7.46 (t, J= 7.8 Hz, 1H), 7.48-7.51 (in, 1H), 7.56 (s, IH), 7.63 (d, J= 8.6 Hz, 2H), 7.94 (s, 1H), 7.95 (s, 1H1), 8.08 (s, 1H), 8.13 (d, J= 8.0 Hz, 111), 8.59 (s, 1H), 8.60 (s, 1H), 9.04 (s, 1H). MS (ES+): m/z 493 (M+H). EXAMPLE 167. N-tert-Butyl-3-{5-methyl-2-[4-(4-methyl-imidazol-1-yl)-phenylaminol pyrimidin-4-vlaninol-benzenesulfonamide (Compound CX) H I NH 'N N H

CX

171 [0340] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(4-methyl-irnidazol- 1-yl) phenylamine (60 mg, 0.35 mmol), Pd 2 (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 microwave reaction tube and irradiated with microwave at 160 'C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and-the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc'(2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as an off white solid (20 mg, 15%). [03411 1H NMR (500 MHz, DMSO-d 6 ): 8 1.12 (s, 9H), 2.15 (s, 3H), 2.16 (s, 3H), 7.30 (s, 1H1), 7.38 (d, J= 9.0 Hz, 2H), 7.50-7.56 (m, 2H), 7.57 (s, IH), 7.76 (d, J= 9.0 Hz, 2H), 7.96 (s, 1H), 7.97 (s, 1H), 8.09-8.13 (m, 2H), 8.63 (s, 1H), 9.16 (s, 1H). MS (ES+): m/z 492 (M+H)+. EXAMPLE 168. N-tert-Butyl-3-[5-methyl-2-(4-[L2,4]triazoil--l-phenylamo) pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXI) H SN" NH N N N H CXI [0342] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-[1,2,4]triazol-1-yl phenylamine (55 mg, 0.34 mmol), Pd 2 (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 microwave reaction tube and irradiated with microwave at 160 'C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was 172 concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 29%). [0343] 'H NMR (500 MHz, DMSO-d 6 ): 8 1.12 (s, 9H), 2.15 (s, 3H), 7.50-7.58 (m, 3H), 7.63 (d, J= 9.1 Hz, 2H), 7.83 (d, J= 9.0 Hz, 2H), 7.99 (s, 1,H), 8.09 (s, 1H), 8.10-8.15 (m, 1H), 8.17 (s, IH), 8.66 (s, 1H), 9.12 (s, 1H1), 9.27 (s, IH). MS (ES+): m/z 479 (M+H)*. EXAMPLE 169. N-tert-Butvl-3-{5-methyl-2-[3-(1H-tetrazol-5-vl)-phenylaminol pyrimidin-4-ylaminol-benzenesulfonamide (Compound CX) 0N

-

N

H HN-N CXH [03441 A mixture of intermediate 33 (0.10 g, 0.28 mmol), 3-(1H-tetrazol-5-yl) phenylamine (55 mg, 0.34 mmol), Pd 2 (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 microwave reaction tube and irradiated with microwave at 160 'C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (15 mg, 11%). [03451 'H NMR (500 MHz, DMSO-d 6 ): 8 1.13 (s, 9H), 2.15 (s, 3H), 7.26 (t, J= 7.9 Hz, 1H), 7.38 (t, J= 8.0 Hz, 1H), 7.44 (dd, J= 7.9, 1.1 Hz, 1H), 7.50 (d, J= 7.6 Hz, IH), 7.58 (s, 1H), 7.79 (dd, J= 8.1, 1.4 Hz, 1H), 7.98 (s, IH), 8.16 (s, 1H), 8.22 (s, IH), 8.27 (d, J= 7.8 Hz, IH), 8.57 (s, 1H), 9.08 (s, 1H). MS (ES+): m/z 480 (M+H)+.

173 EXAMPLE 170. 4-(1H-Tetrazol-5-yl)-phenylamine (Intermediate 60) HN-N N

H

2 N N 60 [03461 To a solution of 5-(4-nitro-phenyl)-1H-tetrazole (1.0 g, 5.2 mmol) in MeOH (30 mL) was added 10 wt% Pd/C (0.1 equiv by wt) under argon atmosphere. The mixture was evacuated, refilled with hydrogen (3 cycles) and stirred at room temperature for 1.5 h. 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. N-tert-Butyl-3-{5-methyl-2-[4-(1H-tetrazol-5-l)-phenylaminol pyrimidin-4-lamino}-benzenesulfonamide (Compound CXIII H NNH HN N N H CXI [034'7] A mixture'of intermediate 33 (0.10 g, 0.28 mmol), intermediate 60 (60 mg, 0.37 mmol), Pd 2 (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 nL) was sealed in a microwave reaction tube and irradiated with microwave at 160 'C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (15 mg, 11%).

174 [03481 'H NMR (500 MHz, DMSO-d 6 ): 8 1.13 (s, 9H), 2.16 (s, 3H), 7.52-7.56 (m, 2H), 7.57 (s, 1H), 7.83 (s, 4H), 8.01 (s, 1H), 8.08 (s, 1H), 8.13-8.19 (m, 1H), 8.69 (s, 1H), 9.34 (s, 1H). MS (ES+): m/z 480 (M+H)*. EXAMPLE 172. 3-{2-[4-(4-Aceti-piperazin-1-l)-phenylamino]-5-methyl-pyrimidin-4 ylaminol-N-tert-butyl-benzenesulfonamide (Compound CXIV) He NH Nr CX1V [03491 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), Pd 2 (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 microwave reaction tube and irradiated with microwave at 160 'C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 nL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as an off white solid (55 mg, 37%). [0350] 'H NMR (500 MHz, DMSO-d): 8 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, 1H), 7.90 (s, 1H), 8.10-8.17 (m, 2H), 8.52 (s, 1H), 8.75 (s, 1H). MS (ES+): m/z 538 (M+H)*.

175 EXAMPLE 173. N-tert-Butyl-3-{5-methyl-2-[4-(1-morpholin-4-y-ethyl)-phenylaminol pvrimidin-4-ylamino}-benzenesulfonamide (Compound CXV) QlNH CXV [0351] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(1-morpholin-4-yl-ethyl) phenylamine (80 mg, 0.39 mmol), Pd 2 (dba) 3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.061 imol) and cesium carbonate (0.26 g, 0.80 mmol) in dioxane (4 nL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO 3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 nL) and the combined organic layers washed with brine, dried over anhydrous Na 2

SO

4 and filtered. The filtrate was concentrated and then taken up in minimum amount of EtOAc. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 27%). [0352] 'H NMR (500 MHz, DMSO-d,): 8 1.12 (s, 9H), 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, 1H), 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, 1H), 7.57 (d, J= 8.5 Hz, 2H), 7.93 (s, 1H), 8.09 (s, 1H), 8.15 (d, J= 7.7 Hz, 1H), 8.57 (s, 1H), 8.92 (s, 1H). MS (ES+): m/z 525 (M+H)*. EXAMPLE 174. N'-(1H-Indol-4-y)-5-methvl-N2-(4-(4-methylpiperazin-1 vl)phenvl)pvrimidine-2,4-diamine (Compound CXVI) HN NH N N N H

CXVI

176 [0353] A mixture of intermediate 32 (270 mg, 0.9 mmol), 4-bromo-1H-indole (196 mg, 0.9 mmol), Pd 2 (dba) 3 (91 mg, 0.09 mmol), Xantphos (157 mg, 0.27 mmol) and cesium carbonate (1.2 g, 3.6 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (55 mg of HCl salt, 14%) as a white solid. 103541 'H NMR (500 MHz, DMSO-d 6 ): S 2.22 (s, 3H), 2.79 (d, J= 4.3 Hz, 3H), 2.98-3.03 (m., 211), 3.08-3.14 (m, 2H), 3.46-3.48 (m, 2H), 3.64-3.66 (m, 2H), 6.35-6.36 (m, 11), 6.63 (br d, J=.8.0 Hz, 1H), 6.98 (d, J= 9.1 Hz, 2H), 7.05 (d, J= 7.4 Hz, 1H), 7.16 (t, J= 7.6 Hz, 1H), 7.36 (t, J= 2.8 Hz, 2H), 7.43 (d, J= 8.0 Hz, 1H), 7.86 (s, IH), 10.07 (s, 1H), 10.27 (s, 1H), 11.00 (br s, 1H), 11.38 (s, 1H), 12.16 (br s, H). MS (ES+): m/z 414 (M+H). EXAMPLE 175. 2-Chloro-5-methyl-N-(2,3-dimethylphenvl)pyrimidin-4-amine (Intermediate 61) &NH CI 61 103551 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 mmol), Xantphos (174 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 nmol) were suspended in dioxane (150 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc (10 mL) and added hexanes (100 mL). The solid was collected by filtration and washed with hexanes to afford the crude title compound as a yellow solid.

177 EXAMPLE 176. 5-Methyl-M-(2,3-dimethylphenyl)-N 2 -(4-(piperidin-4 yloxy)phenyl)pyrimidine-2,4-diamine (Compound CXVII) &NH N N O H H CXVII 103561 A mixture of intermediate 61 (1.0 mmol) and tert-butyl 4-(4 amninophenoxy)piperidine-1-carboxylate (292.4 mg, 1.0 mmol) were suspended in acetic acid (10 mL) and heated at 100"C for 4 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with EtOAc (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound (105 mg of HC salt, 24%) as a yellow solid. [03571 'H NMR (500 MHz, DMSO-d 6 ): 8 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, 1H1), 6.72 (d, J= 8.5 Hz, 2H), 7.11-7.14 (m, 3H), 7.19-7.24 (m, 2H), 7.87 (s, 11), 9.06 (br s, IH), 9.13 (br s, 1H), 9.92 (s, 1H), 10.43 (s, 1H). MS (ES+): n/z 404 (M+H)*. EXAMPLE 177. N'-(4-Chloro-3,5-dimethylphenyl)-5-methyl-N 2 -(4-(4-methylpiperazin 1-yl)phenvl)pvrimidine-2,4-diamine (Compound CXVIU) CI C) 5NH N N H CXVHI [0358] A mixture of intermediate 32 (240 mg, 0.8 mmol), 5-bromo-2-chloro-1,3 dimethylbenzene (212 mg, 0.96 mmol), Pd 2 (dba) 3 (92 mg, 0.1 mmol), Xantphos (170 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the 178 filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (63 mg of HCI salt, 17%) as a white solid. [0359] 'H NMR (500 MHz, DMSO-d 6 ): S 2.15 (s, 3H), 2.17 (s, 3H), 2.80 (d, J= 4.5 Hz, 3H), :3.06-3.14 (in, 4H), 3.48-3.52 (in, 2H), 3.75-3.77 (in, 2H), 6.93 (d, J= 8.9 Hz, 2H), 7.29 (d, J:= 8.9 Hz, 2H), 7.46 (s, 2H), 7.90 (s, 1H), 9.65 (s, lH), 1,0.49 (s, IH), 11.13 (br s, 2H). MS (ES+): m/z 437 (M+H)*. EXAMPLE 178. N-(4-(2-(Pyrrolidin-1-vl)ethoxv)phenylWM-(3-tert-butyliphenyl)-5 methvl-pyrimidine-2,4-diamine (Compound CXIX) NH N O' 0- N H CXIX [03601 A mixture of intermediate 41 (365 mg, 1.32 mmol) and 4-(2-(pyrrolidin-l yl)ethoxy)benzenamine (410 mg, 1.98 mmol) were suspended in acetic acid (20 mL) and heated at 1 00C for 4 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with EtOAc (30 nL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound (127 mg of HCl salt, 20%) as a white solid. [03611 'H NMR (500 MHz, DMSO-d 6 ): 6 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 (in, 4H), 7.43-7.44 (in, 111), 7.48 (d, J= 7.9 Hz, 1H), 7.89 (s, 1H), 9.75 (s, 1H), 10.51 (s, 1H), 11.07 (br, 1H). MS (ESI+): m/z 446 (M+H)*.

179 EXAMPLE 179. N 2 -(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)-N-(4-(3-tert butvlphenylamino)-5-methylpyrimidin-2-yl)-5-methylpyrimidine-2,4-diamine (Compound CXX) NH N N O0 H H CXX [03621 A mixture of intermediate 41 (210 mg, 0.67 imol), intermediate 38 (185 mg, 0.67 mmol), Pd 2 (dba) 3 (55 mg, 0.06 mmol), Xantphos (104 mg, 0.18 mmol) and cesium carbonate (782 g, 2.4 nmol) were suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (94 mg of HCI salt, 24%) as a yellow solid. [0363] 'H NMR (500 MHz, DMSO-d 6 ): 8 1.29 (s, 9H), 1.84-1.88 (in, 2H), 1.94-2.01 (i, 2H), 2.14 (s, 3H), 2.27 (s, 3H), 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, 1H), 8.39 (s, 1H), 9.82 (s, 1H), 10.21 (br s, 1H), 10.68 (br s, 1H), 10.93 (br s, 1H). MS (ES+): n/z 553 (M+H)*. EXAMPLE 180. 5-Methyl-N 2 -[4-(4-methyl-piperazin-1-yl)-phenyll-N4-[3-(piperidine-1 sulfony)-phenyll-pyrimidine-2,4-diamine (Compound CXXI) 0N SNH jN N N H CXXI [0364] A mixture of intermediate 32 (150 mg, 0.5 mmol), 1-(3-bromo-benzenesulfonyl) piperidine (152 mg, 0.5 mmol), Pd 2 (dba) 3 (46 mg, 0.05 mmol), Xantphos (87 mg, 0.15 mmol) 180 and cesium carbonate (652 mg, 2 mmol) were suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (84 mg of HCl salt, 37%) as a white solid. [03651 'H NMR (500 MHz, DMSO-d 6 ): 8 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, 1H), 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, 1H), 7.92 (s, 1H), 8.05 (d, J= 9.3 Hz, 1H), 9.94 (s, 1H), 10.38 (s, 1H), 10.88 (br s, 1H). MS (ES+): m/z 522 (M+H)*. EXAMPLE 181. 5-Methyl-N2-[4-(4-methyl-piperazin-1-ylkehenyll-Nil3-(2-methyl piperidine-1-sulfonyl-henyll-1pyrmidine-2,4-diamine (Compound CXX ) ,zz0 O N N N H CXXH [0366] A mixture of intermediate 32 (161 mg, 0.54 mmol), 1-(3-bromo-benzenesulfonyl) 2-methyl-piperidine (172 mg, 0.54 mmol), Pd2(dba) 3 (46 mg, 0.05 mmol), Xantphos (87 mg, 0. 15 mmol) and cesium carbonate (652 mg, 2 mmol) were suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (10 mg of HCI salt, 3%) as a white solid. [03671 'H NMR (500 MHz, DMSO-d,): 6 0.98 (d, J= 6.9 Hz, 3H), 1.15-1.21 (m, 1H), 1.36-1.40 (m, 3H), 1.47-1.53 (m, 211), 2.18 (s, 3H), 2.80 (d, J= 4.5 Hz, 311), 2.94-2.99 (m, 1H), 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, 1H), 6.93 (d, J= 8.9 Hz, 2H), 7.25 (d, J= 8.9 Hz, 2H), 7.58 (t, J= 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.92 (d, J= 7.1 Hz, 2H), 7.96 (br, 1H), 9.95 (s, 1H), 10.45 (s, 1H), 11.00 (br s, 1H). MS (ES+): m/z 536 (M+H)*.

181 EXAMPLE 182. N-Cyclopentyl-3-45-methyl-2-[4-(4-methvl-piperazin-1-y) phenylaminol-pyrimidine-4-ylaminol-benzenesulfonanide (Compound CXXIH) H NH N N NC H CXXIH [0368] A mixture of intermediate 32 (229 mg, 0.78 mmol), 3-bromo-N-cyclopentyl benzenesulfonamide (280 mg, 0.92 mmol), Pd2(dba) 3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 nmmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (130 mg of HCl salt, 25%) as a white solid. [0369] 'H NMR (500 MHz, DMSO-d 6 ): 8 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, 1H), 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, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.75 (d, J= 7.1 Hz, 2H), 7.92 (br, 2H), 7.93 (br, 1H), 9.96 (s, 1H), 10.45 (s, 1H), 11.98 (br s, 1H). MS (ES+): m/z 522 (M+H)+. EXAMPLE 183. 5-Methyl-M-14-(4-methyl-piperazin-1-vl)-phenyll-M-[3-(pyrrolidine 1-sulfony) phenyll-pyrimidine-2,4-diamine (Compound CXXIV) (tNH rN NNJ H CXXIV 10370] 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) were suspended in dioxane (100 mL) and 182 heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (200 mg of HCI salt, 37%) as a white solid. [0371] 'H NMR (500 MHz, DMSO-d 6 ): 8 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, 'H), 7.26 (d, J= 9.0 Hz, 2H), 7.60 (t, J= 8.0 Hz, 1H), 7.65 (d, J= 8.0 Hz, 1H), 7.91 (t, J= 1.7 Hz, 1H), 7.93 (s, 1H), 8.05 (d, J= 7.5 Hz, IH), 9.95 (s, 1H), 10.43 (s, IH), 11.07 (br s, 1H). MS (ES+): m/z 508 (M+H)*. EXAMPLE 184. V4-[3-(2,5-Dimethyl-pyrrolidine-1-sulfonvl)-phenyll-5-methyl-N 2 -4 (4-methyl-piperazin-1-yl)-phenyll-pyrimidine-2,4-diamine (Compound CXXV) - NH N N N H CXXV [0372] A mixture of intermediate 32 (298 mg, 1.0 mmol), 1-(3-bromo-benzenesulfonyl) 2,5-dimdthyl-pyrrolidine (318 mg, 1.0 mmol), Pd 2 (dba) 3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (100 mg of HC1 salt, 17%) as a white solid. [03731 'H NMR (500 MHz, DMSO-d 6 ): 8 1.26 (s, 3H), 1.27 (s, 3H), 1.45-1.48 (m, 4H), 2.19 (s, 311), 2.80 (d, J= 4.6 Hz, 311), 3.06-3.15 (in, 4H), 3.47-3.50 (in, 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, 1HI), 7.68 (d, J= 7.6 Hz, 1H), 7.93 (br, 2H), 8.02 (br, 1H), 9.97 (s, 1H), 10.47 (s, 1H), 11.07 (br s, 1H). MS (ES+): m/z 536 (M+H)*.

183 EXAMPLE 185. N-tert-Butyl-3- 5-methyl-2-(4-piperazin-1-y-phenylamino)-pyrimidin 4-ylaminol-benzenesulfonamide (Compound CXXVI) 10 O NH NH (NH - N N H CXXVI [0374] A mixture of intermediate 33 (355 mg, 1.0 mmol), tert-butyl 4-(4 aninophenyl)piperazine-1-carboxylate (278 mg, 1.0 mmol), Pd 2 (dba) 3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in CH 2 Cl 2 (10 mL) and trifuloroacetic acid (2 mL) was added. The mixture was stirred for 4 h at room temperature before 10% NaOH was added. The organic layer was separated and aqueous was extracted with CH 2 C1 2 (10 mL x 2). The combined organic layers were dried (Na 2

SO

4 ). The solvent was removed in vacuo. The residue was purified by HPLC to afford the title compound (62 mg, 12%) as a white solid. [03751 'H NMR (500 MHz, DMSO-d,): 5 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, 1H), 7.63 (s, 1H4), 7.71 (d, J= 8.1 Hz, 1H), 7.87. (br, 1H), 7.92 (br, 1H), 7.96 (br, 1H), 9.30 (br, 111), 9.96 (s, 1H), 10.46 (s, 1H). MS (ES+): m/z 496 (M+H)*. EXAMPLE 186. N-tert-Butyl-3-(2-f4-[4-(2-hydroxy-ethyl)-piperazin-1-yll phenylaminol-[5-methvl-pyrimidin-4-vlaminol-benzenesulfonanide (Compound CXXVH) O NH NH N _OH N Na H

CXXVIII

184 [03761 The above-described compound CXXVI (3 1mg, 0.06 mmol) was dissolved in DMF (10 mL) followed by adding 2-bromoethanol (16 mg, 0.13 mmol) and diisopropylethylamine (33 mg, 0.25 mmol). The mixture was stirred for 48 h at room temperature. Solvent was removed in vacuo and residue was dissolved in EtOAc (20 mL). The solution was washed with saturated NaHCO 3 and brine. The combined organic layers were dried and concentrated until 2 mL solution followed by adding Et 2 O (20 mL). The solid was collected by centrifugation and transferred to its HCI salt (10.7 mg, 30%). [03771 'H NMR (500 MHz, DMSO-d 6 ): 8 1.09 (s, 9H), 2.17 (s, 3H), 3.12-3.23 (in, 4H), 3.56-3.60 (m, 211), 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, 1H), 7.63 (s, 1H), 7.71 (d, J= 8.1 Hz, 1H), 7.87 (6r, 1H), 7.93 (br, 111), 7.95 (br, 1H), 9.98 (s, 11), 10.53 (s, 1H), 10.75 (br, 1H). MS (ES+): mlz 540 (M+H)*. EXAMPLE 187. N-tert-Butyl-3-[5-methyl-2-(3-piperazin-1-yl-phenylamino)-pyrimidin 4-ylaminol-benzenesulfonamide (Compound CXXVIII) 0 Oz NH NH z N

KNH

CXXVM [0378] A mixture of intermediate 33 (240 mg, 0.67 mmol), tert-butyl 4-(3 aminophenyl)piperazine-1-carboxylate (166 mg, 0.6 mmol), Pd 2 (dba) 3 (55 mg, 0.06 mmol), Xantphos (104 mg, 0.18 mmol) and cesium carbonate (782 mg, 2.4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in CH 2 Cl 2 (10 mL) and trifuloroacetic acid (2 mL) was added. The mixture was stirred for 4 h at room temperature before 10% NaOH was added. The organic layer was separated and aqueous was extracted with CH 2 C1 2 (10 mL x 2). The combined organic layers were dried (Na 2

SO

4 ). The solvent was removed in vacuo. The residue was purified by HPLC to afford the title compound (18 mg, 6%) as a white solid.

185 [03791 'H NMR (500 MHz, DMSO-d 6 ): 5 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, 1H), 6.87 (br, 1H), 6.96 (d,J= 8.1 Hz, 1H), 7.16'(t,J= 8.1 Hz, 1H), 7.53 (t, J= 8.3 Hz, 1H), 7.61 (s, 1H), 7.70 (d, J= 7.8 Hz, 1H), 7.94 (br, 3H), 9.19 (br, 2H), 9.93 (s, 1H), 10.48 (s, 1H). MS (ES+): n/z 496 (M+H)*. EXAMPLE 188. N-tert-Butyl-3-(2--3-[4-(2-hydroxy-ethyl)-piperazin-1-yl] phenylaminol-15-methyl-pyrimidin-4-vlaminol-benzenesulfonamide (Compound 0 OZ:g NH NH N NHN H H N -OH CX=U [0380] The above-describeed compound CXXVI (12mg, 0.024 mmol) was dissolved in DMF (10 mL) followed by adding 2-bromoethanol (6.1 mg, 0.048 mmol) and diisopropylethylamine (12 mg, 0.092 mmol). The mixture was stirred for 48 h at room temperature. Solvent was removed in vacuo and residue was dissolved in EtOAc (20 mL). The solution was washed with saturated NaHCO 3 and brine. The combined organic layers were dried and concentrated until 2 mL solution followed by adding Et 2 O (20 mL). The solid was collected by centrifugation and transferred to its HCI salt (7 mg, 5 1%). [0381] 'H NMR (500 MHz, DMSO-de 6 ): S 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, 1H), 6.88 (br, IH), 6.96 (br, 1H), 7.16 (br, 1H), 7.57 (br, 1H), 7.60 (s, 1H), 7.69 (d, J= 7.8 Hz, 1H), 7.94 (br, 3H), 9.94 (s, 1H), 10.49 (s, 11). MS (ES+): m/z 540 (M+H)*.

186 EXAMPLE 189. M-(4-(lH-Pyrazol-1-yl)phenyl)-M-(3-tert-butvlphenyl)-5 methylpyrimidine-2,4-diAmine (Compound CXXX) NH

N

H CXXX [0382] A mixture of intermediate 41 (580 mg, 2.1 mmol) and 4-(IH-pyrazol-1 yl)benzenamine (335 mg, 2.1 mmol) were suspended in acetic acid (10 mL) and heated at 100*C for 4 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with EtOAc (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound (31 mg, 4%) as a yellow solid. [03831 'H NMR (500 MHz, DMSO-d): 8 1.24 (s, 9H), 2.18 (s, 3H), 6.53 (t, J= 2.0 Hz, 11), 7.33 (d, J= 8.0 Hz, 1H), 7.38 (t, J= 7.9 Hz, 1H), 7.44 (s, 1H), 7.47 (d, J= 8.2 Hz, 1H), 7.50 (d, J= 8.9 Hz, 2H), 7.67 (d, J= 8.9 Hz, 2H), 7.73 (s, IR), 7.95 (s, 1H), 8.43 (d, J= 2.4 Hz, 1H), 9.81 (br s, 1H), 10.67 (s, 1H). MS (ES+): m/z 399 (M+H)*. EXAMPLE 190. M-(7-Chloro-IH-indol-4-yl)-5-methyl-N 2 -(4-((piperazin-1 yl)methyl)phenyl)-pyrimidine-2,4-diamine (Compound CXXXI) HN C1 NH N NH H CXXXI [0384] A mixture of intermediate 40 (150 mg, 0.37 mmol), 4-bromo-7-chloro-1H-indole (87 mg, 0.37 mmol), Pd 2 (dba) 3 (38 mg, 0.04 mmol), Xantphos (76 mg, 0.12 mmol) and cesium carbonate (521 mg, 1.6 mmol) were suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate 187 concentrated in vacuo. The residue was dissolved in CH 2 C1 2 (10 mL) and trifuloroacetic acid (2 mL) was added. The mixture was stirred for 4 h at room temperature before 10% NaOH was added. The organic layer was separated and aqueous was extracted with CH 2 C1 2 (10 mL x 2). The combined organic layers were dried (Na 2

SO

4 ). The solvent was removed in vacuo. The residue was purified by HPLC to afford the title compound (26 mg, 15%) as a white solid. 10385] 1H NMR (500 MHz, DMSO-d 6 ): 8 2.21 (s, 3H), 3.30 (br, 4H), 3.50 (br, 4H), 4.42 (br, 2H), 6.91 (s, 1H), 7.11 (d, J= 8.3 Hz, 1H), 7.40 (d, J= 7.5 Hz, IH), 7.42 (t, J= 2.7 Hz, 1H1), 7.70 (br, 4H), 8.03 (s, 1H), 9.87 (br, 1H), 9.95 (s, 1H), 10.64 (s, 1H), 11.64 (s, 1H). MS (ES+): mn/z 448 (M+H)*. EXAMPLE 191. N4-(3-tert-Butylphenyl)-5-methyl-N 2 -(4-(2-methl-H-imidazol-1 yl)phenyl)-pyrinidine-2,4-diamine (Compound CXXXI) NH ' N N H CXXXII [0386] A mixture of intermediate 41 (180 mg, 0.65 mmol) and 4-(2-methyl-1H-imidazol 1-yl)benzenamine (113 mg, 0.65 mmol), Pd 2 (dba) 3 (55 mg, 0.06 mmol), Xantphos (104 mg, 0.18 mmol) and cesium carbonate (782 mg, 2.4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (78 mg of HCl salt, 27%) as a white solid. [03871 'H NMR (500 MHz, DMSO-d 6 ): 8 1.26 (s, 9H), 2.21 (s, 3H), 2.50 (s, 3H), 7.3 1 7.36 (m, 1H), 7.40 (t, J= 7.8 Hz, 1H), 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, 1H), 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)*.

188 EXAMPLE 192. 4-(4-Methyl-1H-imidazol-1-yI)benzenamine (Intermediate 62) N

H

2 N0r 62 [0388] To a solution of 1-fluoro-4-nitrobenzene (1.7 g, 12 mmol) in DMF (100 mL) was added 4-methyl-IH-imidazole (0.82 g, 10 mmol) and K 2 C0 3 (11g, 80 mmol). The mixture was heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with brine (100 mL x 2). The organic layer was dried and concentrated. The solid was dissolved in MeOH and bubbled with Ar for 2 min. before adding 10% Pd-C. The hydrogenation was finished in 4 h. The catalyst was removed by filtration and solvent was removed in vacuo to afford title compound (1.5 g, 87%) as brown solid. EXAMPLE 193. 1M-(3-tert-Butylphenyl)-5-methyl-N 2 -(4-(4-methyl-1H-imidazol-l Vllphenyl) pyrimidine-2,4-diamine (Compound CXXXIII) NHN H CXXXI [03891 A mixture of intermediate 41 (318 mg, 1.15 mmol) and intermediate 62 (200 mg, 1.15 mmol), Pd 2 (dba) 3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (66 mg of HCl salt, 20%) as a white solid. [0390] 'H NMR (500 MHz, DMSO-d): 8 1.26 (s, 91), 2.19 (s, 3H), 2.36 (s, 3H), 7.30 (d, J= 7.9 Hz, I), 7.41 (d, J= 7.9 Hz, 1H), 7.44 (t, J= 1.8 Hz, 1H), 7.54 (d, J= 7.9 Hz, 1H), 7.59 (d, J= 9.0 Hz, 2H), 7.68 (d, J= 9.0 Hz, 2H), 7.94 (s, 1H), 7.99 (s, 1H), 9.53 (d, J= 1.3 Hz, 1H), 9.72 (br s, 1H), 10.81(br s, 1H). MS (ES+): m/z 413 (M+H).

189 EXAMPLE 194. tert-Butyl 4-(4-aminophenyl)piperidine-1-carboxylate (Intermediate 63) NBoc

H

2 N 'N 63 [0391] To a solution of 4-(4-nitrophenyl)piperidine (412 mg, 2 mmol) in CH2Cl2 (100 mL) was added di-tert-butyl carbonate (480 mg, 2.2 mmol) and NN-dimethylpyridin-4 amine (50 mg, 0.4 mol). The mixture was stirred for 20 h at room temperature. The mixture was added saturated NaHC03 (100 mL). The organic layer was separated and aqueous 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 h. The catalyst was removed by filtration and solvent was removed in vacuo to afford title compound (460 mg, 83%) as white solid. EXAMPLE 195. N4-(3-tert-Butylphenyl)-5-methyl-N 2 -(4-(piperidin-4 vl)phenyl)pvrimidine-2,4-diamine (Compound CXXXIV) .NH NH H CXXXIV 103921 A mixture of intermediate 41 (170 mg, 0.6 mmol) and intermediate 63 (170 mg, 0.6 mmol) were suspended in acetic acid (10 mL) and heated at 100*C for 4 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with EtOAc (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound (8 mg, 3%) as a white solid.

190 [03931 'H NMR (500 MHz, DMSO-d 6 ): 81.26 (s, 9H), 1.76-1.88 (m, 4H), 2.17 (s, 3H), 2.76-2.81 (m, 1H), 2.93-3.00 (m, 2H), 3.36-3.40 (m, 2H), 7.07 (d, J= 8.5 Hz, IH), 7.30-7.36 (m, 4H), 7.44 (s, 1H), 7.46 (d, J= 8.7 Hz, 111), 7.91 (s, 1H), 8.84 (br s, 1H), 8.92 (br s, IH), 9.73 (s, 1H), 10.45 (s, 1H). MS (ES+): nlz 416 (M+H)*. EXAMPLE 196. M-(3-tert-Butvlphenyl)-5-methyl-N 2 -(4-( morpholinoethvllphenyl)pyrimidine-2,4-diamine (Compound CXXXV) NH N H CXXXV [0394] A mixture of intermediate 41 (276 mg, 1.0 mmol) and 4-(1 morpholinoethyl)benzenamine (210 mg, 1.0 mmol), Pd 2 (dba) 3 (92 mg, 0.1 nmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (17 mg of HCl salt, 4%) as a yellow solid. [03951 'H NMR (500 MHz, DMSO-d 6 ): 8 1.26 (s, 9H), 1.66 (d, J= 6.8 Hz, 3H), 2.19 (s, 3H), 2.79 (br, 2H), 2.92 (br, 1H), 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, 111), 7.43 (d, J= 7.8 Hz, 1H), 7.46-7.52 (m, 5H), .7.97 (s, 1H), 9.86 (s, 1H), 10.78 (s, 1H), 11.72(br s, 1H). MS (ES+): m/z 446 (M+H)*. EXAMPLE 197. 5-Bromo-2-methyl-benzenesulfonvl chloride (Intermediate 64) c A P Br 0 0 64 [0396] Bromide (1.99 g, 11.61 mmol) was stirred vigorously and treated with chlorosulfonic acid (1.55 mL, 23.22 mmol). Once addition was complete, resulting red syrup was heated to 60*C. Reaction TLC after 10 min showed no starting material and reaction was quenched by pouring onto ice. Product was extracted by washing with EtOAc (2 x 150 mL). Organic phase dried over Na 2

SO

4 , filtered and evaporated to yellow oil (2.2g, 70%).

191 EXAMPLE 198. 5-Bromo-2.N-dimethvl-benzenesulfonamide (Intermediate 65) - SQBr 65 [0397] A stirring suspension of intermediate 64 (0.43 g, 1.58 mmol) in DCM (5 mL) was treated with 2.OM methylamine solition in THF (2.4 mL, 4.8 mmol). After 16 h reaction solvents were removed and resulting residue diluted with EtOAc (150 mL) and washed with water. Organic phase dried over Na 2

SO

4 , filtered and evaporated to white solids (0.37 g, 89%). EXAMPLE 199. 2./-Dimethyl-5-{5-methyl-2-[4-(2-pyrrolidin-1--ethox) ihenylaminol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXXXVI) NjL' NH N NN H CXXXVI [0398] A mixture of intermediate 65 (0.14 g, 0.52 mmol), intermediate 38 (0.14 g, 0.43 mmol), Pd 2 (dba) 3 (0.040 g, 0.043 mmol), Xantphos (0.050 g, 0.087 mmol) and cesium carbonate (0.43 g, 1.3 mmol) were 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 down. The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified by HPLC to afford the title compound as a white solid (0.052 g, 24%). [03991 'H NMR (500 MHz, DMSO-d 6 ): 8 1.66-1.70 (m, 4H), 2.08 (s, 3H), 2.43 (d, J= 4.9 Hz, 3H), 2.5 (br s, 4H), 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, 1H), 7.42 (q, J= 9.8 Hz, 1H), 7.49 (d, J= 9.0 Hz, 1H), 7.87 (s, IH), 7.97 (d, J= 2.3 Hz, 1H), 8.07-8.09 (m, 1H), 8.49 (s, 1H), 8.75 (s, 1H). MS (ES+): m/z 497

(M+H)*.

192 EXAMPLE 200. 5-Bromo-N-tert-butyl-2-methyl-benzenesulfonamide (Intermediate HI N, Br 66 104001 A stirring 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 h, reaction solvents were removed and resulting solids triturated with water. Solids were dried uner vacuum overnight (1.3 g, 94%). EXAMPLE 201. N-tert-Butyl-5-(2-chloro-5-methyl-pvrimidin-4-ylamino)-2-methyl benzenesulfonamide (Intermediate 67) N H 67 [04011 A mixture of intermediate 66 (0.90 g, 2.96 mmol), 2-chloro-5-methyl-pyrimidin-4 ylanine (0.33 g, 2.28 mmol), Pd 2 (dba) 3 (0.21 g, 0.23 mmol), Xantphos (0.264 g, 0.46 mmol) and cesium carbonate (2.2 g, 6.8 mmol) were suspended in dioxane (15 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 down. The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified on silica gel column to afford the title compound as a white solid (0.12 g, 14%). EXAMPLE 202 N-tert-Butyl-5-[2-(4-imidazol-1-yl-phenvlamino)-5-methyl-pyrimidi-4 ylarninol-2-methyl-benzenesulfonamide (Compound CXXXVII) H N Q NH N NNN H

CXXXVII

193 [04021 A mixture of intermediate 67 (0.113 g, 0.31 mmol), 4-imidazol- 1 -yl-phenylamine (0.059 g, 0.37 mmol), Pd 2 (dba) 3 (0.028 g, 0.03 mmol), Xantphos (0.036 g, 0.06 mmol) and cesium carbonate (0.3 g, 0.92 mmol) were 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 concentrated in vacuo. The residue was purified by HPLC to afford the title compound as a white solid (0.052.g, 24%). [04031 'H NMIR (500 MHz, DMSO-d 6 ): 8 1.11 (s, 9H), 2.13 (s, 3H), 2.58 (s, 3H), 7.07 (s, 1H), 7.34 (d, J= 8.5 Hz, 1H), 7.42 (d, J= 8.9 Hz, 2H), 7.48 (s, 1H), 7.60 (s, 1H), 7.78 (d, J= 8.9 Hz, 2H), 7.94 (s, 1H), 7.98-8.00 (m, 1H), 8.09 (s, 1H), 8.12 (d, J= 2.3 Hz, 1H), 8.56 (s, 1H), 9.16 (s, 1H). MS (ES+): m/z 492 (M+H). EXAMPLE 203. N-tert-Butyl-3-45-methyl-2-[4-(pyrrolidine-1-carbonyl)-phenylaminol pyrimidin-4-ylamino}-benzenesulfonamide (Compound CXXXVIMH H NH 0 ON N H CXXXVIII [0404] A mixture of intermediate 33 (0.11 g, 0.32 mmol), (4-amino-phenyl)-pyrrolidin-1 yl-methanone (0.072 g, 0.38 mmol), Pd 2 (dba) 3 (0.029 g, 0.032 mmol), Xantphos (0.037 g, 0.063 nmol) and cesium carbonate (0.3 g, 0.95 mmol) were 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 concentrated in vacuo. The residue was purified by HIPLC to afford the title compound as a white solid (0.040 g, 25%). 104051 'H NMR (500 MHz, DMSO-dQ): 5 1.11 (s, 9H), 1.8 (br s, 4H), 2.14 (s, 3H), 3.44 (t, J= 6.6 Hz, 4H), 7.38 (d, J= 9.0 Hz, 2H), 7.52-7.54 (i, 2H), 7.56 (s, I), 7.70 (d, J= 9.8 Hz, 2H), 7.98 (s, 1H), 8.08-8.10 (m, 2H), 8.60 (br s, iH), 9.24 (s, IH). MS (ES+): n/z 509

(M+H)*.

194 EXAMPLE 204. N-tert-Butyl-3-{5-methvl-2-[4-(morpholine-4-carbonyl)-phenvlaminol pyrimidin-4-vlaminol-benzenesulforiamide (Compound CXXXIX) H I N N N H CX IX [0406] A mixture of intermediate 33 (0.13 g, 0.37 mmol), (4-amino-phenyl)-morpholin-4 yl-methanone (0.092 g, 0.45 mmol), Pd 2 (dba) 3 (0.034 g, 0.037 mmol), Xantphos (0.043 g, 0.075 mmol) and cesium carbonate (0.37 g, 1.1 mmol) were 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 concentrated in vacuo. The residue was purifed by HPLC to afford the title compound as a white solid (0.065 g, 33%). [0407] 'H NMR (500 MHz, DMSO-d,): 8 1.11 (s, 9H), 2.14 (s, 3H), 3.49 (br s, 4H), 3.59 (br s, 4H), 5.75 (s, 1H), 7.25 (d, J= 9.0 Hz, 2H), 7.52-7.54 (m, 2H), 7.56 (s, 1H), 7.71 (d, J= 9.0 Hz, 2H), 7.98 (s, 1H), 8.06-8.08 (m, 2H), 8.65 (br s, 1H), 9.26 (s, 1H). MS (ES+): m/z 525 (M+H). EXAMPLE 205. N-tert-Butyl-3-f5-methyl-2-[4-(piperazine-1-carbonyl)-phenylaminol pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXL) HK N, N.S N H 0 SNN H CXL [0408] 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), Pd 2 (dba) 3 (0.030 g, 0.037 mmol), Xantphos (0.038 g, 0.075 mmol) and cesium carbonate (0.33 g, 1.1 mmol) were 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 concentrated in vacuo. The residue was purified by silica gel chromatography (25%-100% EtOAc in Hexanes). Product was then treated with 20 mL of 20% TFA solution in DCM.

195 Solvents then removed by rotary evaporation. Resulting material purified by HPLC to afford the title compound as a white solid (0.045 g, 26%). 104091 'H NMR (500 MHz, DMSO-d): 8 1.11 (s, 9H), 2.14 (s, 3H), 2.82 (br s, 4H), 3.48 (br s, 4H), 7.24 (d, J= 9.0 Hz, 2H), 7.51-7.53 (m, 2H), 7.55 (s, 1H), 7.71 (d, J= 9.0 Hz, 2H), 7.94 (s, 1H), 8.06-8.08 (m, 2H), 8.65 (br s, 1H), 9.25 (s, 1H). MS (ES+): m/z 524 (M+HV. EXAMPLE 206. tert-Butyl 4-(4-(4-(3-methoxyphenvlamino)-5-methylpyrimidin-2 ylamino)phenoxy)piperidine-1-carboxylate (Intermediate 68) 0O' 2 NH N N Ooo H 68 104101 A mixture of 1-bromo-3-methoxybenzene (69.5 iL, 0.56 mmol), intermediate 42 (205 mg, 0.51 mmol), Pd 2 (dba) 3 (23 mg, 0.03 mmol), Xantphos (33 mg, 0.06 mmol) 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 rinsed with DCM and MeOH. The combined liquids were concentrated in vacuo, and purified using gradient flash chromatography (0-100% ethyl acetate in hexanes) to afford 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) HOQNH H CXLI [0411] To a mixture of intermediate 68 (215 mg, 0.42 mmol) in DCM (4 mL) was added BBr 3 (120 iL, 1.27 mmol) and stirred at room temperature for 64h. The reaction was quenched with MeOH and concentrated in vacuo. The residue was purified by preparative HPLC and the fractions concentrated in vacuo to afford the TFA salt of the title compound 196 (116 mg, 56%). The TFA salt was taken up in MeOH and passed through SPE PL-HCO 3 MP-Resin cartridges, concentrated in vacuo, triturated with ether, and filtered to provide the title compound as a white solid (31 mg, 69% recovery). [0412] 'H NMR (500 MHz, DMSO-d,): S 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, 1H), 6.48 (dd, J= 8.1, 2.2 Hz ,1H), 6.79 (d, J= 9.1 Hz, 2H), 7.06-7.11 (m, 2H), 7.16 (d, J= 8.5 Hz, 1H), 7.57 (d, J= 9.1 Hz, 2H), 7.82 (s, 1H), 8.08 (s, 1H), 8.73 (s, 1H), 9.27 (br s, IJH). MS (ES+): m/z 392 (M+H)W. EXAMPLE 208. (2-Chloro-5-methyl-pvrimidin-4-yl)-(4-fluoro-3-methoxy-phenvl) amine (Intermediate 69) NH CI 69 [0413] 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), Pd 2 (dba) 3 (0.74 g, 0.81 mmol), Xantphos (0.93 g, 1.6 mmol) and cesium carbonate (7.88 g, 24.2 mmol) were suspended in dioxane (60 mL) and heated at reflux under the argon atmosphere for 5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford the title compound (0.3 g, 14%) as a beige solid. EXAMPLE 209. N-(4-Fluoro-3-methoxy-phenyl)-5-methyl-N2-[4-(2-pyrrolidin-1-vl ethoxy)-phenyll-pyrimidine-2,4-diamine (Compound CXLH) "'0QNH NN CXLII [04141 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) were suspended in acetic acid (10 mL) and heated to 110 'C for 16 h. The reaction mixture was cooled to room temperature and concentrated in 197 vacuo. The residue was purified by HPLC to afford the title compound (0.03 g, 17%) as green solids. 'H NMR (500 MHz, DMSO-d6): 8 1.88 (br s, 211), 2.0 (br s, 2H), 2.15 (s, 3H), 3.08 (br s, 2H), 3.55 (br s, 4H), 3.7 (s, 3H), 4.32 (br s, 211), 6.9 (d, J= 7.9 Hz, 2H), 7.13 (br s, 1H), 7.21-7.25 (m, 1H), 7.32-7.34 (m, 3H), 7.89 (s, 1H), 9.78 (br s, 1H1), 10.48 (br s, 111), 10.92 (br s, 1H). MS (ES+): r/z 438 (M+H)*. EXAMPLE 210. (2-Chloro-pyrimidin-4-yl)-(3-methoxy-2-methyl-phenyl)-amine (Intermediate 70) NH NC1 70 [0415] A mixture of 3-methoxy-2-methyl-phenylamine (0.68 g, 5 mmol) and 2,4-dichloro pyrimidine (0.74 g, 5 mmol) were suspended in ethyl alcohol (10 mL) and stirred at room temperature for 20 h. The reaction mixture was diluted with DCM (50 mL), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound (0.085 g, 7%) as yellow solids. EXAMPLE 211. 1-(3-Methox-2-methyl-phenyl)-N2-[4-(2-pyrrolidin-1-yl-ethoxy) phenyll-pyrimidine-2,4-diamnfle (Compound CXLIH) 0 NH N N H CXLIH 104161 A mixture of intermediate 70 (0.08 g, 0.32 mmol) and 4-(2-pyrrolidin-1-yl ethoxy)-phenylamine (0.13 g, 0.64 mmol) were suspended in acetic acid (10 nL) and heated to 80 *C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by HPLC to afford the title compound (0.03 g, 17%) as grey solids. 104171 'H NMR (500 MHz, DMSO-d 6 ): 8 1.89 (br s, 2H), 2.0 (br s, 411), 3.08 (br s, 211), 3.4 (br s, 4H), 3.54 (br s, 411), 3.83 (s, 3H), 4.31 (br s, 2H), 6.86 (br s, 2H), 6.97 (d, J= 8.1 198 Hz, 21), 7.26 (t, J= 8.1 Hz 1H), 7.34 (br s, 2H), 7.89 (s, 1H), 9.73 (br s, 1H), 10.62 (br s, 2H), 11.01 (br s, 1H). MS (ES+): n/z 420 (M+H)*. EXAMPLE 212. 4-(4-Acetylamino-benzenesulfonyl)-piperidine-1-carboxylic acid tert butyl ester (Intermediate 71) 0 NN H y 71 [04181 A mixture of 4-(4-bromo-benzenesulfonyl)-piperidine- 1-carboxylic acid tert-butyl ester (4 g, 9.92 mmol), acetamide (0.88 g, 14.9 mmol), Pd 2 (dba) 3 (0.46 g, 0.49 mmol), Xantphos (0.56 g, 0.99 mmol) and cesium carbonate (9.7 g, 29.8 mmol) were suspended in dioxane (60 mL) and heated at reflux under the argon atmosphere for 4 h. The reaction mixture was cooled to room temperature and poured onto ice. Resulting yellow solids collected by filtration and dried. Crude product was purified by flash chromatography on silica gel to afford 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) 0 0 .- H 2 N N O 0 72 [0419] A suspension of intermediate 71 (2.6 g, 6.7 mmol) was diluted with 60 mL of Claisen's alkali (88 g KOH dissolved in 63 mL H 2 0 diluted up to 250 mL with MeOH) and heated to 90 "C. After 2 h, reaction was removed from heating, cooled to room temperature and diluted with water (50 mL). Grey solids collected by suction filtration, washed with water and dried overnight (2.2 g, 97%).

199 EXAMPLE 214. 1M-(4-Chloro-3-methoxy-phenyl)-5-methyl-N 2 -[4-(piperidine-4 sulfonvl)-phenyll-pyrimidine-2,4-diamine (Compound CXLIV) C1 0 NH 0 N NH H CXLIV [04201 A mixture of intermediate 31 (0.14 g, 0.51 mmol), intermediate 72 (0.19 g, 0.56 mmol), Pd2(dba) 3 (0.046 g, 0.051 mmol), Xantphos (0.59 g, 0.1 mmol) and cesium carbonate (0.5 g, 1.52 mmol) were suspended in dioxane (8 mL) and microwaved at 160 *C for 15 min. The reaction mixture was cooled to room temperature and centrifuged down. Solvents were then decanted and evaporated. Resulting residue was purified by flash chromatography on silica gel to afford the N-protected precursor of title compound. These solids were treated with 20% TFA in DCM solution and immediately evaporated. Residue was dissolved in minimum amount to EtOAc and added dropwise to large excess of diethyl ether. Resulting light yellow powder was collected by filtration and dried (0.16 g, 55%). [0421] 'H NMR (500 MHz, DMSO-d 6 ): 5 1.61-1.69 (m, 2H), 1.98-2.01 (m, 2H), 2.16 (s, 3H), 2.86 (q, J= 12 Hz, 211), 3.35 (d, J= 12.6 Hz, 2H), 3.64 (tt, J= 11.7 Hz, J= 3.8 Hz, 11), 3.79 (s, 3H), 7.34 (dd, J= 8.7 Hz, J= 2.0 Hz, 1H), 7.39-7.41 (i, 2H), 7.6 (d, J= 8.9 Hz, 2H), 7.91 (d, J= 8.9 Hz, 2H), 8.02 (s, 11), 8.19-8.21 (m, 1H), 8.6-8.63 (m, 1H), 8.89 (br s, 1H). MS (ES+): m/z 488 (M+H)*. EXAMPLE 215. (4-Chloro-3-methyl-phenyl)-(2-chloro-5-methyl-pyrinidin-4-yl)-amine (Intermediate 73) NH N C 73 [0422] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.34 g, 2.34 mmol), 4 bromo-1-chloro-2-methyl-benzene (0.58 g, 2.8 """), Pd 2 (dba) 3 (0.21 g, 0.23 mmol), Xantphos (0.47 g, 0.47 mnol) and cesium carbonate (2.3 g, 7 mminol) were suspended in 200 dioxane (9 mL) microwaved at 160 *C for 20 min. The reaction mixture was cooled to room temperature and centrifuged down. Solvents were then decanted and evaporated. Resulting residue was purified by flash chromatography on silica gel to afford title compound as yellow solids (0.24 g, 38%). EXAMPLE 216. A-(4-Chloro-3-methyl-phenyl)-5-methyl--[4-(piperidin-4-vloxv) phenyll-pyrimidine-2,4-diamine (Compound CXLV) NH NO NH H CXLV [04231 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) were diluted with HOAc (5 mL) and microwaved at 150 0C for 15 min. Solvents then removed and resulting residue purified on HPLC. Title compound isolated as white solids (0.025 g, 22%). [0424] 'H NMR (500 MHz, DMSO-d 6 ): 8 1.76-1.83 (m, 2H), 2.05-2.09 (m, 2H), 2.13 (s, 3H), 2.27 (s, 3H), 3.10 (br s, 211), 3.16 (br s, 2H), 4.58-4.61 (m, 1H), 6.93 (d, J= 9 Hz, 2H), 7.34-7.39 (m, 3H), 7.43-7.45 (m, 11), 7.59 (s, 1H), 7.87 (s, 1H), 8.51 (br s, 1H), 8.55 (br s, 1H), 9.38 (br s, 1H), 10.0 (br s, 1H). MS (ES+): m/z 424 (M+H)*. EXAMPLE 217. N-(3-Bromo-phenyl)-acetamide (Intermediate 74) >Nck Br H 74 [0425] A solution of 3-bromo-phenylamine (1.04 g, 6 mmol) was treated with DIEA (2.3 mL, 13.3 mmol) and chilled to zero degrees. Acetyl chloride (0.47 mL, 6.7 mmol) was added dropwise via syringe. Reaction was allowed to return to room temperature and stir for 1 hour. Reaction was then poured onto water and washed once. Organic phase was evaporated to beige solids (1.25 g, 98%).

201 EXAMPLE 218. N-[3-(2-Chloro-5-methyl-pvrimidin-4-ylamino)-phenyll-acetamide (Intermediate 75) N H H NICI 75 [0426] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.71 g, 4.9 mmol), intermediate 74 (1.25 g, 5.9 mmol), Pd 2 (dba) 3 (0.45 g, 0.49 mmol), Xantphos (0.57 g, 0.98 mmol) and cesium carbonate (4.8 g, 14.7 mmol) were suspended in dioxane (40 mL) refluxed for 18 h. The reaction mixture was then cooled to room temperature, filtered and solvents evaporated. Resulting residue was purified by flash chromatography on silica gel to afford title compound as white solids (0.44, 32%). EXAMPLE 219. N-(3-{5-Methyl-2-[4-(piperidin-4-yloxy)-phenylaminol-pyrimidin-4 vlaminol-phenyl)-acetamide (Compound CXLVI) NNH H N C O NH H CXLVI [0427] A mixture of intermediate 75 (0.074 g, 0.27 rmmol) and 4-(4-amino-phenoxy) piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.35 mmol) were diluted with HOAc (5 mL) and microwaved at 150 0C for 15 min. Solvents then removed and resulting residue purified on HPLC. Title compound isolated as white solids (0.072 g, 62%). 104281 'H NMR (500 MHz, DMSO-d 6 ): 8 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 (in, 1H), 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, 1H), 7.87 (s, 1H), 8.55 (br s,~1H), 8.60 (br s, IH), 9.67 (s, 1H), 10.0 (br s, 1H), 10.2 (br s, 1H). MS (ES+): maz 433 (M+H)*.

202 EXAMPLE 220. N-(3-Bromo-2-methyl-phenvl)-acetamide (Intermediate 76) 0 AN Br H4 76 [04291 A solution of 3-bromo-2-methyl-phenylamine (4.1 g, 21.9 mmol) was treated with DIEA (8.4 mL, 48 mmol) and chilled to zero degrees. Acetyl chloride (1.7 mL, 24.1 mmol) was added dropwise via syringe. Reaction was allowed to return to room temperature and stir for 1 hour. Reaction was then poured onto water and washed once. Organic phase was evaporated to off-white solids. Trituration with hexanes afforded title compound as white solids (4.4 g, 89%). EXAMPLE 221. N-[3-(2-Chloro-5-methyl-pyrimidin-4-vlamino)-2-methvl-phenyll acetamide (Intermediate 77) 0 N NH H N Cl 77 [04301 A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.86 g, 5.9 mmol), intermediate 76 (1.6 g, 7.1 mmol), Pd 2 (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) refluxed for 16 h. The reaction mixture was then cooled to room temperature, filtered and solvents evaporated. Resulting residue was purified by flash chromatography on silica gel to afford title compound as white solids (0.56 g, 32%). EXAMPLE 222. N-(2-Methyl-3-{5-methyl-2-f4-(piperidin-4-vloxv)-phenylaminol pyrimidin-4-ylaminol-phenyl)-acetamide (Compound CXLVII) N NH H H N H

CXLVII

203 (0431] 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) were diluted with HOAc (5 mL) and microwaved at 150 *C for 15 min. Solvents then removed and resulting residue purified on HPLC. Title compound isolated as white solids (0.091 g, 41%). [0432) 'H NMR (500 MHz, DMSO-d 6 ): 8 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, 1H), 6.77 (d, J= 8.4 Hz, 2H), 7.09-7.15 (m, 3H), 7.27 (t, J= 7.9 Hz, 1H), 7.49 (d, J= 8.1 Hz, 1H), 7.86 (s, 1H), 8.54 (br s, 1H), 8.59 (br s, IH), 9.45 (s, IH), 9.84 (br s, 1H), 10.34 (br s, 1H). MS (ES+): m/z 447 (M+H)*. EXAMPLE 223. 5-Methyl-M-[4-(4-methyl-piperazin-1-vl)-phenyll-M-(3-nitro-phenyl) pyrimidine-2,4-diamine (Intermediate 78)

O

2 N NH N N H 78 [04331 A mixture of 1-bromo-3-nitro-benzene (0.77 g, 3.8 mmol), intermediate 32 (0.95 g, 3.2 mmol), Pd 2 (dba) 3 (0.29 g, 0.32 mmol), Xantphos (0.37 g, 0.64 mmol) and cesium carbonate (3.1 g, 9.6 mmol) were suspended in dioxane (40 mL) refluxed for 16 h. The reaction mixture was then cooled to room temperature, filtered and solvents evaporated. Resulting residue was purified by flash chromatography on silica gel to afford title compound as white solids (0.53 g, 40%). EXAMPLE 224. M-(3-Amino-phenyl)-5methyl-N 2 -[4-(4-methyl-piperazin-1-l) phenyll-pyrinidine-2,4-diamine (Intermediate 79)

H

2 Na NH N N N H 79 [04341 Slurry of intermediate 78 (0.23 g, 0.54 mmol) in MeOH (25 mL) was purged with argon and treated with Pd/C 10% wt. (0.18 g). Reaction atmosphere was replaced with hydrogen and stirred for 4 h. Hydrogen balloon was then removed and argon was flushed 204 through reaction before filtration through Celite. Solvents were then evaporated to pale brown solids (0.17 g, 83%). EXAMPLE 225. 1-(3-{5-Methyl-2-f4-(4-methyl-piperazin-1-yl)-phenylaminol pyrimidin-4-ylaminol-phenyl)-3-phenyl-urea (Compound CXLVIH) N N NH N H H H CXLVHI [04351 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. Reaction solvents then removed and resulting residue purified by HPLC to provide title compound as white solids (0.075 g, 33%). [0436] 'H NMR (500 MHz, DMSO-d 6 ): 8 2.09 (s, 311), 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, 1H), 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, 1H), 7.83 (s, 1H), 8.23 (s, 1H), 8.68 (s, 1H), 8.74 (s, 1H), 8.78 (s, 111). MS (ES+): m/z 509 (M+H)*. EXAMPLE 226. 1-(3-{5-Methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylaminol pyrimidin-4-vlaminol-phenyl)-3-(3-trifluoromethyl-phenyl)-urea (Compound CXLDX

F

3 C N N NH H H N N H CXLIX [0437] A suspension of intermediate 79 (0.1 g, 0.26 mnol) in DCM (8 mL) was treated with 1-isocyanato-3-trifluoromethyl-benzene (0.043 mL, 0.31 mmol) and stirred for 1 hour. Reaction solvents then removed and resulting residue purified by HPLC to provide title compound as white solids (0.039 g, 26%). [04381 'H NMR (500 MHz, DMSO-d,): 8 2.16 (s, 3H), 2.82 (s, 3H), 2.86 (br s, 2H), 3.08 (br s, 2H), 3.42 (br s, 2H), 3.69 (br s, 2H), 6.88 (d, J= 8.4 Hz, 2H), 7.20 (br s, 1H), 7.29-7.33 205 (m, 5H), 7.52 (t, J= 7.9 Hz, 1H), 7.57 (d, J= 8.5 Hz, 1H), 7.77 (s, IH), 7.84 (s, 1H), 8.09 (s, 1H), 9.42 (s, 1H), 9.66 (s, 1H), 9.71 (br s, IH), 10.1 (br s, IH). MS (ES+): m/z 577 (M+H)*.

EXAMPLE 227. (2-Chloro-5-methyl-pvrimidin-4-yl)-(2-methyl-3-trifluoromethyl phenyl)-amine (Intermediate 80)

F

3 C NH N N CI 80 [0439] 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), Pd 2 (dba) 3 (0.12 g, 0.13 mmol), Xantphos (0.15 g, 0.25 mmol) and cesium carbonate (1.23 g, 3.8 mmol) were suspended in dioxane (8 mL) microwaved at 160 "C for 18 min. Reaction vessel was then centrifuged down and decanted. Solvents then evaporated and resulting residue was purified by flash chromatography on silica gel to afford title compound as white solids (0.095 g, 25%). EXAMPLE 228. 5-Methyl-1/-(2-methyl-3-trifluoromethyl-phenyl)-N94-(piperidin-4 vloxy)-phenyll-pyrimidine-2,4-diamine (Compound CL)

F

3 C NH NO NH H CL [04401 A mixture of intermediate 80 (0.058 g, 0.2 mmol) and 4-(4-amino-phenoxy) piperidine-1-carboxylic acid tert-butyl ester (0.073 g, 0.25 mmol) were diluted with HOAc (5 mL) and microwaved at 150 *C for 15 min. Solvents then removed and resulting residue purified on HPLC. Title compound isolated as white solids (0.025 g, 30%). [0441] 'H NMR (500 MHz, DMSO-d 6 ): 8 1.71-1.78 (m, 2H), 2.00-2.04 (m, 2H), 2.18 (s, 311), 2.25 (s, 3H), 3.08 (br s, 2H), 3.22 (br s, 2H), 4.50-4.52 (m, 1H), 6.70 (d, J= 8.3 Hz, 21), 7.10 (d, J= 8.9 Hz, 211), 7.54 (t, J= 7.8, 1H), 7.62 (d, J= 7.7 Hz, 1H), 7.75 (d, J= 7.8 206 Hz, 1H), 7.91 (s, iH), 8.54 (br s, IH), 8.61 (br s, IH), 9.88 (s, 1H), 10.34 (br s, IH). MS (ES+): nlz 458 (M+H) . EXAMPLE 229. (3-Bromo-phenvl)-pyrrolidin-1-vi-methanone (Intermediate 81) N r Br 0 81 [04421 A solution of 3-bromo-benzoyl chloride (2.7 g, 12 mmol) in DCM (40 mL) was chilled to zero degrees and treated with pyrrolidine (3 mL, 36.8 mmol). Reaction was allowed to come to room temperature and stir for 4 h. Mixture was then poured onto water and washed once. Organic phase then washed with brine, dried over sodium sulfate, filtered and evaporated to amber oil (3.1g, 100%). EXAMPLE 230. f3-(2-Chloro-5-methyl-pyrimidin-4-ylamino)-phenvll-pyrrolidin-1-yl methanone (Intermediate 82) NH 0 'NICI. 82 [0443] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.22 g, 1.5 mmol), intennediate 81 (0.46 g, 1.8 mmol), Pd 2 (dba) 3 (0.14 g, 0.15 mmol), Xantphos (0.17 g, 0.3 mmol) and cesium carbonate (1.5 g, 4.5 mmol) were suspended in dioxane (8 mL) microwaved at 160 *C for 18 min. Reaction vessel was then centrifuged down and decanted. Solvents then evaporated and resulting residue was purified by flash chromatography on silica gel to afford title compound as white solids (0.25 g, 53%). EXAMPLE 231. (3-{5-Methyl-2-[4-(piperidin4-loxy)-phenylaminol-pyrimidin-4 ylaminol-phenyl)-pyrrolidin-1-yl-methanone (Compound CLI) NH N ONN H

CLI

207 [0444] A mixture of intermediate 82 (0.1 g, 0.32 nimol) and 4 -(4-amino-phenoxy) piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.41 mmol) were diluted with HOAc (6 mL) and microwaved at 150 "C for 15 min. Solvents then removed and resulting residue purified on HPLC. Title compound isolated as white solids (0.005 g, 3%). [04451 'H NMR (500 MHz, DMSO-.d 6 ): 8 1.74-1.81 (n, 4H), 1.83-1.88 (m, 211), 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, 1H), 7.43 (t, J= 7.8, 1H), 7.67 (d, J= 7.9 Hz, 1H), 7.70 (s, 1H), 7.89 (s, 1H), 8.50 (br s, 1H), 8.56 (br s, 1H), 9.64 (br s, 1H), 10.21 (br s, 1H). MS (ES+): rn/z 473 (M+H). EXAMPLE 232. 3-Bromo-N-isopropyl-benzamide (Intermediate 83) Br 83 [0446] A solution of 3-bromo-benzoyl chloride (0.83 g, 3.8 mmol) in DCM (40 mL) was chilled to zero degrees and treated with isopropylamine (0.96 mL, 11.32 mmol). Reaction was allowed to come to room temperature and stir for 24 h. Mixture was then poured onto water and washed once. Organic phase then washed with brine, dried over sodium sulfate, filtered and evaporated to white solids (0.6 g, 66%). EXAMPLE 233. N-Isopropyl-3-{5-methyl-2-14-(4-methyl-piperazin-1-yl) phenylaminol-pyrimidin-4-ylaminol-benzamide (Compound CLII) H NH O.N N-_ H CLII [04471 A mixture of intermediate 32 (0.1 g, 0.34 mmol), intermediate 83 (0.13 g, 0.54 mmol), Pd 2 (dba) 3 (0.031 g, 0.034 mmol), Xantphos (0.039 g, 0.067 mmol) and cesium carbonate (0.33 g, 1 mmol) were suspended in dioxane (8 mL) microwaved at 160 *C for 15 min. Reaction vessel was then centrifuged down and decanted. Solvents then evaporated and 208 resulting residue was purified by HPLC to afford title compound as white solids (0.011 g, 7%). [0448] 'H NMR (500 MHz, DMSO-d 6 ): 8 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, 1H), 6.85 (d, J= 8.8 Hz, 2H), 7.30-7.32 (m, 2H), 7.45 (t, J= 7.8 Hz, 111), 7.69-7.70 (m, 2H), 7.90 (s, 1H), 7.99 (s, 1H), 8.24 (d, J= 7.7 Hz, 1H), 9.70 (br s, 1H), 9.94 (br s, 1H), 10.2 (br s, 1H). MS (ES+): m/z 460 (M+H). EXAMPLE 234. 3-Bromo-N-ert-butyl-benzamide (Intermediate 84) Br 0 84 [04491 A solution of 3-bromo-benzoyl chloride (0.83 g, 3.8 mmol) in DCM (10 mL) was chilled to zero degrees and treated with tert-butylamine (1.2 mL, 11.3 mmol). Reaction was allowed to come to room temperature and stir for 4 h. Mixture was then poured onto water and washed once. Organic phase then washed with brine, dried over sodium sulfate, filtered and evaporated to amber oil (0.9 g, 94%). EXAMPLE 235. N-tert-Butl-3-{5-methyl-2-[4-(4-methvl-piperazin-1-vl) phenylaninol-pyrimidin-4-vlamino}-benzamide (Compound CLI) H NH N O -N- N H CLm 10450] A mixture of intermediate 32 (0.1 g, 0.34 mmol), intermediate 84 (0.1 g, 0.4 mmoil), Pd 2 (dba)3 (0.031 g, 0.034 mmol), Xantphos (0.039 g, 0.067 mmol) and cesium carbonate (0.33 g, 1 nmol) were suspended in dioxane (8 mL) microwaved at 160 *C for 15 min. Reaction vessel was then centrifuged down and decanted. Solvents then evaporated and resulting residue was purified by HPLC to afford title compound as white solids (0.055 g, 35%). [0451] 'H NMR (500 MHz, DMSO-d 6 ): 6 1.36 (s, 9H), 2.09 (s, 3H), 2.21 (s, 3H), 2.43 (t, J= 2.8 Hz, 4H), 3.00 (t, J= 2.8 Hz, 4H), 6.74 (d, J= 9.1 Hz, 2H), 7.35 (t, J= 7.9 Hz, 111), 209 7.44-7.48 (m, 3H), 7.67 (s, 1H), 7.85 (s, 1H), 7.88-7.92 (m, 2H), 8.36 (s, 1H), 8.74 (s, 1H). MS (ES+): m/z 474 (M+H)*. EXAMPLE 236. 5-Methyl-N2-[4-(4-methyl-piperazin-1-yl)-phenyll-N*-(3-piperidin-4 yI-phenyl)-pyrimidine-2,4-diamine (Compound CLIV) NH N HN H CLIV 104521 A mixture of intermediate 32 (0.08 g, 0.27 mmol), 4-(3-bromo-phenyl)-piperidine (0.084 g, 0.35 mmol), Pd 2 (dba) 3 (0.025 g, 0.027'mmol), Xantphos (0.031 g, 0.054 mmol) and cesium carbonate (0.26 g, 0.81 mmol) were suspended in dioxane (8 mL) microwaved at 160 *C for 15 min. Reaction vessel was then centrifuged down and decanted. Solvents then evaporated and resulting residue was purified by HPLC to afford title compound as white solids (0.007 g, 6%). [0453] 'H NMR (500 MHz, DMSO-d 6 ): 5 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, . = 7.7 Hz, 1H), 7.24 (t, J= 7.9 Hz, 11), 7.47-7.53 (m, 3H), 7.68 (d, J= 8.2 Hz, 1H), 7.82 (s, 1H), 8.18 (s, 1I), 8.67 (s, 1H). MS (ES+): rn/z 458 (M+H)*. EXAMPLE 237. 4-(3-{5-Methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino] pyrimidin-4-ylamino}-benzenesulfonyl)-piperidine-1-carboxylic acid benzyl ester (Intermediate 85) 0 O N yU NHDN Y SjaNHN O N N H 85 [0454] A mixture of intermediate 32 (0.17 g, 0.58 mmol), 4-(3-bromo-benzenesulfonyl) piperidine-1-carboxylic acid benzyl ester (0.28 g, 0.64 mmol), Pd 2 (dba)3 (0.053 g, 0.058 mmol), Xantphos (0.067 g, 0.12 mmol) and cesium carbonate (0.57 g, 1.74 mmol) were 210 suspended in dioxane (8 mL) microwaved at 160 *C for 15 min. Reaction vessel was then centrifuged down and decanted onto ice. Yellow solids collected, dried and used without further purification (0.4 g, 100%). EXAMPLE 238. 5-Methyl-N 2 -f4-(4-methyl-piperazin-1-yl)-phenyll-M-[3-(piperidine-4 sulfonyl)-phenyll-pyrinidine-2,4-diamine (Compound CLV) H ~ N I)I HN S NH rN N N H CLV [0455 A stirring solution of intermediate 85 (0.17 g, 0.26 mmol) in DCM (15 mL) was treated with 1M BBr 3 in DCM (2 mL, 2 mmol). After 4 h, reaction was quenched by slow addition of MeOH (4 mL) followed by removal of solvents. Residue purified by HPLC to provide title compound as purple powder (0.008 g, 6%). [0456] 'H NMR (500 MHz, DMSO-d,): S 1.31-1.40 (in, 2H), 1.75 (d, J= 10.8 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, J= 11.7 Hz, J= 3.8 Hz, 1H), 6.81 (d, J= 9.0 Hz, 2H), 7.44 (m, 3H), 7.56 (t, J= 8.0 Hz, 1H), 7.90-7.91 (m, 2H), 8.49 (d, J= 7.6 Hz, 1H), 8.60 (s, 1H), 8.74 (s, 1H). MS (ES+): m/z 522 (M+H)*. EXAMPLE 239. tert-Butyl 4-(4-(4-(1II-indol-4-Vlamino)-5-methylpyrimidin-2 . lamino)phenoxy)piperidine.--carboxylate (Intermediate 86) NH H O 0 86 [0457] A mixture of 4-bromo-1H-indole (41 gL, 0.33 mmol), intermediate 42 (131 mg, 0.33 mmol), Pd 2 (dba) 3 (30 mg, 0.03 mmol), Xantphos (60 mg, 0.10 mmnol) and cesium carbonate (428 mg, 1.31 mmol) in dioxane (3 mL) was irradiated in the microwaved at 160 211 *C for 20 min. The reaction mixture was cooled to room temperature and filtered rinsing with DCM. The filtrate was concentrated and purified by gradient flash chromatography (0 15% MeOH in DCM) to afford the title compound as a white solid (30 mg, 17%). EXAMPLE 240. M-(1H-Indol-4-yl)-5-methyl-N 2 -(4-(piperidin-4 yloxv)phenyl)pyrimidine-2,4-diamine (Compound CLVI) NH H CLVI [04581 A mixture of intermediate 86 (27 mg, 0.05 mmol) in 30% TFA/DCM (1 mL) was stirred for 3 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC. The resulting fractions were concentrated in vacuo to obtain the TFA salt of the title compound as a tan solid (11 mg, 43%). [0459] 'H NMR (500 MHz, DMSO-d 6 ): 8 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, 1H), 6.34-6.37 (m, 1H), 6.64 (br d, J= 8.3 Hz, 2H), 7.08 (t, J= 7.2 Hz, 3H), 7.14 (t, J= 7.8 Hz, 1H), 7.36 (t, J= 2.7 Hz, 1H), 7.39 (d, J= 8.1 Hz, 1H), 7.84 (s, 1H), 8.48 (br s, 1H), 8.55 (br s, 1H), 9.85 (br s, 1H), 9.98 (br s, 1H), 11.27 (s, 1H). EXAMPLE 241. 2-Chloro-N-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylaminol-pyrimidin 5-yl}-5 (3-trifluoromethyl-benzoylamino)-benzamide (Compound CLVII) NH H CLVII [04601 A mixture of 3-bromopyridine (379 mg, 2.4 mmol), 4-amino-2-chloro-5 methylpyrimidine (287 mg, 2.0 mmol), Pd 2 (dba) 3 (18 mg, 0.02 mnol), xantphos (23 mg, 0.04 mmol) and cesium carbonate (975 mg, 3.0 mmol) in dioxane (15 mL) was heated under refluxed for I h under argon. The solvent was removed and the residue on purification by 212 HIPLC gave an intermediate, 2-chloro-5-methyl-N-(pyridin-3-yl)pyrimidin-4-amine as yellow solid (252 mg, 57%). For second Buckwald, a mixture of 2-chloro-5-methyl-N-(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) was heated under refluxed for 1 h under argon. The crude reaction mixture on purification using HPLC gave the title compound as light brown solid (28 mg, 20%). [0461] 'H NMR (500 MHz, DMSO-d 6 ): 8 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, 1H),7.92-7.96 (m, 1H), 8.08-8.15 (m, 1H), 8.45 (dd, J= 4.8, 1.4, 1H), 8.84, 9.75, 9.85, 10.24(4 br s, 1H each). MS (ES+): m/z 329 (M+H)*. EXAMPLE 242. M-(442-(pyrrolidin-1-vlethoxv)phenyl)-5-methvl-M-(3 (trifluoromethoxy)phenyl) pyrimidine-2,4-diamine (Compound CLVIH)

F

3 C, '-.. H 0s NH N N N H

CLVI

[04621 A mixture of 1-bromo-3-(trifluoromethoxy)benzene (241 mg, 1.0 mmol), 4-amino 2-chloro-5-methylpyrimidine (143 mg, 1.0 mmol), Pd 2 (dba)3 (9 mg, 0.01 mmol), xantphos (14 mg, 0.02 mmol) and cesium carbonate (650 mg, 2.0 nmol) in dioxane ( 15 mL) was heated under refluxed for 10 h under argon. The solvent was removed and the residue on purification by HPLC gave an intermediate, 2-chloro-5-methyl-N-(pyridin-3-yl)pyrimidinA amineas 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 refluxed for 3 h under argon. The crude reaction mixture on purification using HPLC gave the title compound as white solid (11 mg, 7 %). [0463] 'H NMR (500 MHz, DMSO-d 6 ): 8 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, 211), 6.79 (d, J= 8.9 Hz, 2H), 6.98 (d, J= 213 8.0 Hz, 111), 7.40 (dd, J=7.6, 7.4 Hz, 1H), 7.50 (d, J= 8.9 Hz, 2H), 7.76 (br s, 1H), 7.87 (d, J= 8.4 1H), 7.90, 8.31, 8.41, 8.84 (4 s, lH each). MS (ES+): m/z 474 (M+H)*. EXAMPLE 243. N 2 -(4-(2-(pyrrolidin-1-yl)ethoxv)phenyl)-N4-(4-chloro-3 (trifluoromethvl)phenyl)-5-methylpyrimidine-2.4-diamine (Compound CLIX) C1

F

3 C NH N N H CLIX [0464] 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), Pd 2 (dba) 3 (9 Ing, 0.01 mmol), xantphos (14 mg, 0.02 mmol) and cesium carbonate (650 mg, 2.0 mmol) in dioxane ( 15 mL) was heated under refluxed for 10 h under argon. The solvent was removed and the residue was purified by HFLC to give an intermediate 2-chloro-N-(4-chloro-3-(trifluoromethyl) phenyl)-5-methylpyrimidin-4-amine as brown solid (200 mg, 62 %). A mixture of this intennediate (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 refluxed for 3 h under argon. The crude reaction mixture on purification using PLC gave the title compound as brown solid (75 mg, 31 %). [04651 'H NMR (500 MHz, DMSO-d,): 8 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, 21), 7.58 (d, J= 9.0 Hz, 21), 7.93 (s, 1H), 8.01 (d, J =2.5 Hz, 1H), 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. IC 5 9 Value Determinations for Jak2 Kinase 10466] The ICso values for compounds were determined using a luminescence-based kinase assay with recombinant JAK2 obtained from Upstate Cell Signaling Solutions. In white, flat-bottom, 96-well plates (Nunc) parallel assays were run at room temperature at a final volume of 50 pL. Each well contained 40 pL of buffer consisting of 40 mM Tris buffer, pH 7.4, containing 50 mM MgCl 2 , 800 p.M EGTA, 350 [LM Triton X-100, 2 mM p- 214 mercaptoethanol, 100 pM peptide substrate (PDKtide; Upstate Cell Signaling Solutions) and an appropriate amount of JAK2 (75 -25 ng/well) such that the assay was linear over 60 min. The final concentrations of TargeGen compounds for ICso value determinations ranged from 1000 to 0.01 p.M by adding the appropriate amount of compound in 2.5 p.L of DMSO; the DMSO present in each assay was constant at 5%. The reaction was initiated by the addition of 10 p.L of ATP to a final assay concentration.of 3 PM. After the reaction had proceeded for 60 min, 50 pL 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. [04671 Values were then measured using an Ultra 384 instrument (Tecan) set for luminosity measurements. Two control reactions were also ran: one reaction containing no compound and the second containing neither inhibitor nor peptide substrate. IC 5 o values were derived from experimental data using the non-linear curve fitting capabilities of Prism (Version 4; GraphPad Software). The results are shown.in Table 1. TABLE 1. Compounds of the Invention And Their IC Values for Jak2 Kinase Structure .Name* CI C1 -O . NH 4-(2,4-Dichloro-5-metoxy NC NO phen.ylamino)-2-[4-(2-pyrrolidin- 6240 1 -yl-ethoxy)-phenylamino] N N pyrimidine-5-carbonitrile H 4-(2,4-Dichloro-5-methoxy NC H phenylamino)-2-[3-(2-pyrrolidin- 10500 N 1-yl-ethoxy)-phenylamino] N N O N pyrimidine-5-carbonitrile H C1 C1H 'I~a NHN4-(2,4-Dichloro-5-methoxy e NH phenyl)-5-methyl-N2-[3-(2- 2040 Me N ~pyrrolidin-1-yl-ethoxy)-phenyl] S NN pyrimidine-2,4-diamine

H

215 Structure Name ICSO N2-.(4-(2-(pyrrolidin-l a N H yl)ethoxy)phenyl)-N4-(3 rn-- 3 ethoxyphenyl)-5- 52.8 ~ J~jN~)methylpyrimidine-2,4-diamine N'Na Hydrochloride H )C§IJL.N2-(4-(2-(pyi-rolidin-l 0 2 N a NH 0yl)ethoxy)phenyl)-5-methyl-N4- 61.1 NN Y~ N27 (3-nitrophenyl)pyrimidine-2,4 j~ %. JJ' ~ diamine Hydrochloride N' NH N4-(4-Methoxy-pheny)-N2-14 0(2-pyrrolidin-1-yl-ethoxy)- ' 4330 "-N r ' 0 ~ <\ phenyl3-pyrimidine-2,4-diamine tfluoroacetate, N NL 4.{4-(4-Methoxy-phenylaxnino) p: N pyrirnidin-2-ylamino]-N-(2 s N pyrtolidin-1-yL-ethyl)- 10700 11 N benzenesulfonamide N N trifluoroacetate 4-(44-(3-Methoxy-phenylamino) 0 NH ~0 prmdn2yaio- S' N--'-- Npyrmidin--ylnino]--( 638 N bp y rr o ld i n-l- i- e )6 3 I N-' N berieulfoanete OII~ha NH N4-Benzo[l ,3]dioxoI-5-yl-5 0,,- NNo methyl-.N2-[4-(2-pyrrolidin-17YI 87.2 I ~ ) ethoxy)-phenyl]-pyrimaidine-2,4 O r diamnine trifluoroacetate H NH0 4-[4-(4-Hydroxy-phenylanaino) 11pyrimidin-2-ylamino]-N-(2- 94 s N40 pyrrolidin-1 -yl-ethyl)- 94 I)~%~)OI1benzenesulfonaniide N 'N H -_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 216 Structure Name JC50 )ZIIIIL.3-{2-(4-(2-(pyrrolidin-I HO J NH 0yl)ethoxy)phenylaxnino)-5- 203 <IY..)C~O''sNC) methylpyrimidin-4 N 'N ylarnino)phenol Hydrochloride H0r NH 04-[4-(3-Hydroxy-phenylaznino) 11 'D pyrimidin-2-ylainino]-N-(2 NN1 <~ N"- pyrrolidin-l-yl-ethyl)- 3620 I0 ~ H benzenesulfonam~ide N -1N tilooct H tilooctt IN-a NH N-Methyl-3- {5-methyl-2-[4-(2 0pyrrolidin-l-y-ethoxy)- 257 "~N O.O'~ NC phenylamnino]-pyrimidin-4 0 N' N ylamino)-benzamide H _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ " O N4-(4-Chloro-3-methoxy 0~N phenyl)-5-methyl-N2-[4-{2- 7.96 No pyrrolidin-1 -yl-ethoxy)-phenyl] N N pyrimidine-2,4-diainine H ~N NH N2-(4-(2-(pyrrolidin-l K- yl)ethoxy)phenyl)-N4- 15 N N methylpyrimidine-2,4-diamine Na NH N4-(3-Dimnethylanmino -phenyl)-5 NHmethyl-N2-[4-(2-pyrrolidin-1-yl- 1. ~N--N N ethoxy)-phenyl]-pyrimidine-2,4- 1. I N diamine NN CI : NH 4-(2-(4-(2-(Pyrrolidin-l 0 No yl)ethoxy)phenylarnino)-5- 67.5 A ~ 1 1 N~jmethylpyrimidin-4-ylamino)-2 N ~ cblorobenzonitrile Hydrochloride

H

217 Structure Name JAIC2 1C50 'N NHN2-(4-(2-(pyrrolidin- I 0yl)ethoxy)phenyl)-5-methyl-N4- 20 'N (naphthalen-1-yl)pyrimidine-2,4 I ~L. j~ 1 L2diamine Hydrochloride NN C, H N4-(3,4-Dicbloro-phenyl)-5 CI NH 0methyl-N2-[4-(2-pyrrolidin-1-Yl- 25.7 N ~ 9'--~ NN ethoxy)-phenyl]-pyrimidine-2,4 ji~ ~ K!diamine ~iiui~i,..N4-(4-Cbloro-3-methoxy 0 N H phenyI)-5-Methyl-N2-(3- 15.8 ~ N ~ <NH piperazin-1-yhnethyl-phenyl) ~N. pyhmnidine-2,4-diarnine NN H HN NHN2-(4-(2-fpyrrodin-l HN NHyI)ethoxy)phenyl)-N4-( 1H-indol- 19.2 NN 4-yl)-5-methylpyrirnidine-2,4 diainine Hydrochloride N-(4-(2-(pyrrolidin-- 702.0 NZN0-, Nyl)ethoxy)phenyl)-4- 00000 benzylpyfinaidin-2-amine N2H-2(yrldnl o ) N yl)ethoxy)phenyl)-N4-(4-chloro NN 3-methoxyphenyl)-N4,5- 4900 N ) dimethylpyrixnidine-2,4-diamine N N trifluoroacetate C1H ''Z'NH N4-(4-Gbloro-phenyl)-5 -methyl 0 N2[4-2-pyroldin--ylethoy)- 18.2 -- IN phenyl]-pyrinmidine-2,4-diamine NC> ifluoroacetate

NN

218 Structure Name 1C50 'I~aNH2- {444-(4-Chloro-3-mnethoxy o0N phenylarnino)-5-methyl- 9.14 -, OH pyrimidin-2-ylamino]-phenoxy) NANI~>ethanol QL NH 5-Methyl-N4-phenyl-N2-[4-(2 pyrrolidin-1-yl-ethoxy)-phenyl]- 16.7 pyrimidine-2,4-diamine H- NH N2-(4-(2-(pyrrolidin-1 0 ~ yI)ethoxy)phenyl)-5-mnethyl-N4- 35.7 N3 p-tolylpyrimidine-2,4-diamine N N jj ~ uHydrochloride H __ _ __ _ __ __ _ __ _ __ _ N2-(4-(2-(pyrrolidin-1 .) NH yl)ethoxy)phenyl)-N4-(4-chloro 03-methylphenyl)-5- 12.4 N3 JQJ NC)die-,-damn '- N' N Hydrochloride F~a NHN4-(4-Cbloro-3-fluoro-phenyl) F H5-mnethyl-N2-[4-(2-pyrrohidin-I- 40.1 ~0N - y-ethoxy)-phenyl]-pyrimidine A -~2,4-diamnine N4-(4-Chloro.-3-methoxy 0 a NH phenyl)-5-methyl-N2-(4 rI Nmorpholn-4-ylmethyl-phenyl)- 13.3 00 pyfirn-idine-2,4-diaxnine " N" N trifluoroacetate -H__ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ N4-Benzo[b]tbiophen-5-yl-5 N H 0methyl-N2-[4-{2-pyrrohidm-1 yl 28.5 "N N<O N< ethoxy)-phenyl]-pyrimidine-2,4 I NI<N~>daie H________________ _ _ _ 219 Structure Name JA K2 __________________________ C50 - 9 N4-Benzo[bjthiophen-3-yl-5. S R NH methyl-N2-[4-(2-pyrrolidin-1 -yl- 12.4 ethoxy)-phenyl]-pyrimidine-2,4 Cl)ZI1NH N4-(3-Chloro-phenyl)-5-methyl 0-~ .- N N2-[4--(2-pyrrolidin-1-yl-ethoxy)- 20.8 jj~J~No) phenyl]-pyfimidine-2,4-diamie N - 2-Chloro-N- {2-[4-(2-pyrrolidin N H 1-yl-ethoxy)-phenylamino] 0pyrnmidin-5-yl}-5-(3- 304 f~'[ff~)trifluoromethyl-benzoylaxnino) benzamide 71T)IIZI..N4-(4.-Fluoro-3-methoxy 0 NH 0phenyl)-5-methyl-N2-[4-(2- 14.8 - NNo pyrroidin-1-yl-ethoxy)-phenyl] N NCpyritnidine-.2,4-diamine N- N I N4-Benza[1,3ldiaxol-4-yl-5 NH methyl-N2-[4-(2-pyrrolidin-1-yl- 16.9 NZIN 0- Noethoxy)-pheny1]-pyriniidine-2,4 N J~ J N Cdiamine N-J N H Iia N N4-(4-Cbloro-3-methoxy Nphenyl)-5-methyl-N2-(3- 9.52 pyrimidine-2,4-dianiine

F

3 C a N N2-(4-(2-{pyrrolidin-1 0yl)ethoxy)phenyl)-N4-(3- 17.6 (trifluoromethyl)phenyl)-5 "-N IN methylpyrimidine-2,4-diainine 220 Structure Name -FaC :1,-I 5 N2-(4-(2-(pyrrolidin-1 NH yl)ethoxy)phenyl)-N4-(4 0 (trifluoromethyl)phenyl)-5- 39.8 N Njmethylpyrimidine-2,4-diamine N N hydrochloride H Cl HN4-(4-Chloro-3-methoxy N N phenyl)-5-methyl-N2-(4-pyrazol- 18.9 N N' 1-ylmethyl-phenyl)-pyrimidine N NN 2,4-diamine .... H N2-(4-(2-(pyrrolidin-1 a NH , yl)ethoxy)phenyl)-5-methyl-N4 (3- 20.7 SNo (trifluoromethoxy)phenyl)pyrn 2. NAN dine-2,4-dianine hC I I N N2-(4-(2-(pyrrolidin-1

F

3 C NH yl)ethoxy)phenyl)-N4-(4-chloro- 23.4 N O N 3-(trifluoromethyl)phenyl)-5 NU %JJ methylpyrimidine-2,4-diamine

H

NH N4-(3-Methoxy-2-methyl H 0phenyl)-N2-[4-(2-pyrrolidin-1-yl- 371 N O -- "N ethoxy)-phenyll-pyrimidine-2,4 LN )diamine H ' : NH N4-(4-Chloro-3-methoxy NH .

phenyl)-5-methyl-N2-[4- 1 N (piperidine-4-sulfonyl)-phenyl] N ~NH pyrimidine-2,4-diamine -N' NH H I N4-(4-Chloro-3-methoxy 0 NH N pheny1)-5-mnethyl-N2-[4-(4- 5.5 methyl-piperazin-1-yl)-phenyl) I pyrimidine-2,4-diamine H 221 Structure Name JAK.2 IcI ji~j ii...N4-(4-Chloro-3-methoxy O0 N phenyl)-5-methyl-N2-(4- 13 N~> NJ morpholin-4-yl-phenyl)- 13 pyrimidine-2,4-di amine N4-(4-Chloro-3-methoxy NHD phenyl)-5-methy1-N2-(4-pyrazol- 35 N 1-yl-phenyl)-pyriniidine-2,4- 3. NJ diamnine frifluoroacetate N4-(4--Chloro-3-methoxy-. o NH phenyl)-5-maethyl-N2-(4- 35.3 piperidin-1 -yI--phenyl) pyrimidine-2,4-di amine H' N4.-(4-.Cloro-3-methoxy 0. NH phenyl)-5-methyl-N2-[4-(4- 1 N N ~ N ~ phenyl]-pyrimidine-2,4-di amine H N4-(l H-indol-4-yl)-5-methyl NH N< N2-(4-(4-methylpiperazin-l- 9.53 N,,) yl)phenyl)pyrixnidine-2,4-. I AI~9Jdiarmne Hydrochloride N~IIIKII~k f~JHN4-(4-Ghloro-3-methoxy 0 NH phenyl)-5-methyl-N2-(4 ~NK YNpiperazin-1-yl-phenyl)- 6.15 pyrimicline-2,4-diainine N N H ________________ ___ 222 Structure Name JC50

H

2 N NH 3- {5-Methyl-2-[4-(4-methyl o N N piperazin-1-yl)-phenylamino]- 23 N N pyrimidin-4-ylamino)-benzamide H2N N' 3- {5-Methyl-2-[4-(4-methyl s NHN N piperazin-1-yl)-phenylamino]- 6 o N N pyrimidin-4-ylamino)- 13. N a Nbenzenesulfonamide -Nl N H N4-(4-Chloro-3-methyl-phenyl) H 5-methyl-N2-(4-(piperidin-4 8 N ON yloxy)-phenyl]-pyrimidine-2,4- '41 N NH diamine H N NH N-(3-{5-Methyl-2-[4-(piperidin H 4-yloxy)-pbenylamino]- 137 N~'<I Hacetaynide 137nl) N O pyrimidin-4-ylamino}-phenyl) H - N4-Benzo[1,3]dioxol-4-yl-5- NH r N methyl-N2-[4-(4-methyl- 14.2 N piperazin-1-yl)-phenyll N N pyrimidine-2,4-diamine -N N H -l N4-(4-Chloro-3-trifluoromethyl

F

3 NH phenyl)-5-methyl-N2-[4- 1 'N rr N >(piperidin-4-yloxy)-phenyl]- 1. N N NK H pyrimidine-2,4-diamine N N HN -IN_________________________) _he__ HN C N N4-(7-chloro-1H-indol-4-yl)-5 C' NH N/ methyl-N2-(4-(4 N methylpiperazin-1- 5.36 N yl)phenyl)pyrimidine-2,4 diamine

N

223 Structure Name JK Ic50 "I, N-(2-Methyl-3- {5-nmethyl-2-[4 (piperidin-4-yloxy)-14 NH phenylamino]-pyrimidin-4- 14 -~N ylaniinol-phenyl)-acetamide N N'j N 5-methyl-N4-(2,3 & NH dimethylphenyl)-N2-(4 0(piperidin-4- 4.38 jNN~Nj(Yloxy)Phenyl)pyrimidine-2,4 N N K.H diarnine Hydrochloride H 5-methyl-N4-(3,5 N & NH dimethylphenyl)-N2-(4 (piperidin-4- 37.2 N N yloxy)phenyl)pyfiinidine-2,4 H diamine hydrochloride -- N'Na N~ H H~ N l'y 1-(3- {5-Methyl-2-[4-(4-rnethyl a N__) piperazin-1-yl)-phenylamino]- 6 N<N91 2 1Y pynnimdin-4-ylanol-phenyl)-3- 6. H C1 N40(-chloro-3,5 NH r Ndimethylphenyl)-5-xnethyl-N2 (4-(4-methylpiperazin-I - 38 Ja N yl)phenyl)pyrimidine-2,4 NI~~N~IIIXdianiine Hydrochloride -H NH N4-(3-tert-butylphenyl)-5 NHN methyl-N2-(4-(4 methylpiperazin-1 - 4.7 I yl)phenyl)pyrimidine-2,4 H di amine Hydrochloride 224 Structure Name JK NO , - N-Methy1-3-{5-methyl-2-1 4

-(

4 NH methyl-piperazin--l )- 16.1 0 N")phenylainino]-.pyriinidin- 4 I ylamino}-benzenesulfonamide NI~1uI3N ~N,N-Dixnethyl-3- {5-methyl-2-[4 It(4-niethyl-piperazin-l-Yl)- 9.5 0 N_,Jphenylalnino]-pyrimnidin-4 NAKN)&yiarnino}-benzenesulfonamide N HN HNH 5-methyl-N4-(7-methyl-1H indol-.4-yl)-N2-(4-(4 -' N Nmethylpiperazin-1- 3.84 yl)phenyl)pyrimidine-2,4 diamine Hydrochloride H N4.-(3-tert-butylphenyl)-5 -~NH methyl-N2-(4-&piperidin-4- 2.73 yloxy)phenyl)pyrimidiie-2,4 I ~ diamine Hydrochloride NIN 0 H ___ A N4-(3,5-dimethoxyphenyl)-5 NHmethyl-N2-(4-(piperidin-4- 137 .0 NH 0yloxy)phenyl)pyrimidine-2,4 N diarnine trifluoroacetate N N N H (3-trifluoromethyl-phenyl)-urea 225 JAK2 -Structure Name IC50 2-Methyl-3- {5-methyl-2-[4-(4 NHNmethyl-piperazin-1 -yl)- 27.8 r phenylamino]J-pyrixidin4 N ylaraino)-b~nzoic acid ethyl ester 2-Methyl-3- {5-methyl-2-[4-(4 methyl-piperazin-l-yl)- 2. S NH r Nphenylamino]-pyrimidin-4- 2. N ylamino)-benzamide N4-(IH-indol-4-yl)-5-methyl & NH N2-(4-(piperidin-4- 42 0yloxy)phenyl)pyrimidine-2,4- 42 dianine trifluoroacetic acid salt N N - NNH H N2-(4-(2-(pyrrolidin-l yl)ethoxy)phenyl)-N4-(3-tert NH .butylphenyl)-5- 6.71 I0 y JDI Hydrochloride N Nj N2-(4-{2-Cpyrrolidin-1 ~L yl)ethoxy)phenyl)-N4-(4-(3-tert NH butylphenylamino)-5-15 -0-- N j~ N- methylpyrimidin-2-yl)-5- 15 LD methylpyrimidine-2,4-diamine N_ N Hydrochloride H H

CF

3 'N 5-Methyl-N4-(2-rnethyl-3 NH trifluoroxnethyl-phenyl)-N2-[4- 52.9 0 (piperidin-4yloxy)-phenyll a-11 TO H pyrimidine-2,4-dianiine N N

H-

226 Structure Name JAK2 H2N 1 IXNH3- {5-Methyl-2-[4-(2-pyrrolidin IIN 0 ~ 1 -yl-ethoxy)-phenylaxmno]- 72.2 pyriniidin-4-ylami o ~~L~f Libenzenesulfonaniide rN~ (4-methyl-piperazin-1 -yl)- 11.8 N,) phenylamino]-pyrimidin-4 I j~j~jIylaniino}-benzenesulfonamide N "I NN~ H N-tert-Butyl-3- {5-methyl-2-[4 11 r 6.06 0 N,)phenylaniino]-pyrinidin-4 I ylainino}-benzenesulfonamide OzL -j5-Methyl-N2-[4-(4-methyl I piperazin-1-yl)-phenyl]-N4-[3 6 NH r N(piperidine-1 -sulfony)-phenyll- 24.8 N ~ pyrimidine-2,4-diarnine I Hydrochloride 0 Ozz N 5-Methyl-N2-[4-(4-methyl NH' N~ piperzin-1-yl)-phenyl]-N4-[3 NH N (2-methyl-piperidine-l- sulfony)- 33.5 N phenyl]-pyrimidine-2,4-diaine NlNI) Hydrocloride H ~ ..- N4-(3-Methanesulfonyl-4 11 r methyl-phenyl)-5-methyl-N2-[4- 16 0 N,)(4-methyl-piperazin-l-yl)- 16 phenyl]-pyrimidine-2,4-diamine 227 Structure Name JC50 0jOjja -.. N-Cyclohexyl-3- {5-methyl-2-[4 NH (4-methyl-piperazin-1-yl)- 39 cr'y phenylamino]-pyrimidin-4- 3. I ylamino}-benzenesulfonamide NIN( 11r(4-methyl-piperazin-1 -y1)- 6. 0-%-1 phenylamnno]_pyrndin_4- 1. ylaniino} -benzenesulfonamide

C

3 N4-(-(trifluoromethyl)-2 N methylphenyl)-5-methyI-N2-(4 N(4-methylpiperazin-l- 87.1 yl)phenyl)pyrimidine-2,4 diamnine hydrochloride -NY N H OH (3-{5-MethyI-2-[4-(piperidin-4 NHyloxy)-phenylamino]-pyrixnidin- 113 H N-Cyclopentyl3-{5-MethyI-2-[4 (4-methyl-piperazin-1-yl) N NH < N ~ phenylamino]-pyrixnidine-4- 19.8 N ylamino}-benzenesulfbnamide N<N 'I Hydrochloride -H 5-MethyI-N2-[4-(4-mnethyl piperazin-1-yl)-phenyl]-N4-[3 -~NH r N (pyrrolidine-l-sulfony)-phenyl]- 17.1 pyrirnidine-2,4-diamine Hydrochloride 'NIN H__ _ _ _ _ _ _ _ _ _ _ _ _ _ 228 Structure Name 1A5K 0<>5 K.Na, kN N 5-Methyl-N2-[4-(4-methyl piperazin-1-yl)-phenyl]-N4-[3- 2 ON 5O N (morpholine-4-sulfonyl)-phenyl] N N pyrinidine-2,4-diamine H N NH N N-Isopropyl-3-{5-methyl-2-[4 'I (4-methyl-piperazin-1-yl) 0 . ~ phenylamino]-pyrimidin-4- 541 N ylamino}-benzamide H o=s=o 5-methyl-N2-(4-(4 methylpiperazin-1-yl)phenyl) NH N N4-(3- 215 NN (methylsulfonyl)phenyl)pyrimidi ne-2,4-diamine H N NH N-tert-Butyl-3-{5-methyl-2-[4 'N (4-methyl-piperazin-1-yl)- 890 phenylamino]-pyrimidin-4 Nt~ N ylamino)-benzanide 0S==0 5-methyl-N2-(4-(4 methylpiperazin-1-yl)phenyl) 6NH N4-(3- 8 NHN (propylsulfonyl)phenyl)pyrimidin N N~ e-2,4-diamine H aN NH 5-Methyl-N2-[4-(4-methyl HNN piperazin-1-yl)-phenyl]-N4-(3 N Npiperidin-4-yl-phenyl) pyrimidine-2,4-diamine

H

229 Structure Name JC50 HN N-tert-Butyl-3-[5-rethyl-2-(4 s morpholin-4-ylmethyl 01 - ':- r, phenylamino)-pyrimidin-4- 12.5 I ylamnino]-benzenesulfonamide 0 OH piperazin-1 -yl-phenylaxnino) -: NH('NH pyrimidin-4-ylamino]-. 7.59 N,) benzenesulfonamide I Hydrochloride N N4-[3-(2,5-Dinaethyl-pyrrolidine 1-sulfonyl)-phenyl]-5-inethyl Nrf NH N2-[4-(4-methlyl-piperazin-1-yl)- 18.8 phenyl]-pyrimidine-2,4-diamine * I N~j~y.Hydrochloride OZZAHN-tert-Butyl-3 -(2- {4-[4-(2 hydroxy-ethyl)-piperazin-1 -yl] '~ H (N~~O pheaylarnino}-[5-mnethyl- 7.09. NJ pyrimidin-4-ylamino] benzenesulfonamide N~N~ Hydrochloride HNJIC N-tert-Butyl-3-[5-mnethyl-2-(4 SN HN> pyrazol-1-yl-phenylamino) 0 NN ~ N pyrimidin-4-ylaxnino]- 1 N~N ~'benzenesulfonamide

H

1 N j1J piperazin-1.y..pyridin-3 0 N N N-__) '2Ylanuino)-pyrimidin-4-ylamino]- 10 benzenesulfonamide 230 Structure Name 1C50 NH methyl-piperazin-l-yl) HO'-"NNr N phenylanaino]-pyrimidin-4- 8.46 N N Ylamino)-phenyl)-piperidin-1 H ?1-ethanol 0+ zt:-NH N-tert-Butyl-3-[5-naethyl-2-(3 morpholin-4-ylmethyl- 70 NH phenylamino)-pyrimidin-4 N ylamino]-benzenesulfonamide N___N'[:__ ro *, IN-tert-Butyl-3-[5-methyl-2-(4 It H pyrazol-1-ylmethyl 0 , NNphenylamino)-pyrimidin-4- 18.6 ylamino)-benzenesufonamide HN.. ''l N N-tert-Butyl-3- {5-methyl-2-[3 NI H .~ 1IIA (piperidine-1-slfonyl)- 1 0 H316lmio-yimdn4 N ylamino}-benzenesulfonamide HN NH [(4-methylpiperazin-l I~o yl)methyl]phenyl) amino)pyrixnid 29.8 N n4 NN ". yllamino)benzenesulfonamide NVO N-tert-butyl-3-[(5-'methyl-2- {[4 HN, 's'- 2 H 3 NH piperazin-.1-yl-3 N N..,) (trifluoromethyl)phenyl]aniino}p 22.5 1 * -j r NH Wiidifl-4 "-Nl N Yl)aininolbenzenesulfonamide H _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 231 Structure Name 1C50 00 3-[(2- {[4-(4-acetylpiperazin-1 H %QNH-3 s NI CF r N)' I f, N ) (trifluoromethyl)phenyl]amino) - 35.7 5-methylpyrimidin-4-yl)axnino] N N N-tert-butylbenzenesulfonanide H ____ ____ ___N NH N-tert-Butyl-3-[5-methyl-2-(3 K~~NH piperazin-1 -yl-phenylaxnino) pyrimidin-4-ylamino]- 18 benzenesulfonaniide Hydrochloride H QNH N N-tert-Butyl-3-(2- {3-[4-(2 hydroxy-ethyl)-piperazin-1-yl] ~ Hphenylamino) -[5-methyl- 4. pyriniidin-4-ylaniino] 7V11benzenesulfonamide Hydrochloride 0N~II. N-tert-butyl-3- {[5-methyl-2-({3 S NH .[(4-methylpiperazin-1 I I .N yl)sulfonyljphenyl}amino)pyrimi 650 N~K N~)din-4 N, yl]amino}benzenesulfonamide 0 -" "N'H HN~I2~ NHN-tert-butyl.3-[(5-rnethyl-2- {[4 ylmethylpeylarin-~yInid . 0 NH "QNN K~H yl)aniinoljbenzenesulfonamide NH N 5-Methyl-N2-[4-(4-xnethyl 0 "epiperazin-1-yl)-phenyl]-N4-[3- 198 HN - ~ - (piperidine-4-sulfonyl)-phenyl] , N, N ~pyrimidn-,-im 232 Structure Name AC 5-meffhyl-N2-(4-( 4 Na N ~ methylpiperazin-1-yl)pheflyl) NN4..{3-(pipericiin-1- 46.3 I yI)plienyl)pyrirnidine-2, 4 N~ N0 diamnine N4-(3-(IH-pyrroil- yl)phenyl)-5 N~a N r Nmcthyl-N2-(4-(4 methylpiperazin-1 - 33.8 yl)phenyl)pyrimidine-2,4 N diamine H 3- {5-Methyl-2-[4-(4--methYl H r'Is H iprzn-Yl)-Phenylamino] - NN~2pyrimidin-4-ylamino}-N- 543 piperidin4-yl H' -I benzenesulfonaxnide HN-N N4.-(lH-indazol4-yl)-5-rnethyl & H N2-(4-(piperidin-4 yloxy)phenyl)pyrimidine-2,4 I ~ diarninie Hydrochloride N4-(1H-Indol-4-yl)-5-methyl N - phenyl)-pyrim~idine-2,4-diamine -F NH N2-(4..piperazin-1-yhnethyl- 10.1 N -~ N~>phenyl)-pyriniddine-2,4-diamine N IN O

H_______________

233 Structure Name JC50 Nca NH N-tert-Butyl-3- {5-methyl-2-[4. ,e(2-pyrrohidin-l -yl-ethoxy)- 12.5 N * phenylamino]-pyrimidin4 -K ~ K 'w ,' yfamino}-benzenesulfonamide HO NH0yloxy~phenylarnino)-S- 51.9 ' ,O methylpyrimidin-4 NH ylaiino)phenol H /NH IC1 N2-(4-(2-(pyrrolidin-l-. HN yI)ethoxy)phenyl)-N4.(7-choro HN 1H-indol-4-yl)-5- 1.16 methylpyrimidine-2,4-diaxnine NAN~ K, Hydrochloride N2-(4-(2-(pyrrolidin-1 HN yl)etlioxy)phenyl)-5-methyl-N4 0(7-methyl-!H-indol-4- 6.98 ~N - yl)pyrimidine-2,4-dianiine I U Hydrochloride rF N2-(4-(2-(pyrolidin-l HN yl)ethoxy)phenyl)-N4-(7-fluoro 0N 1H-indol-4-yl)-5- 9.28 ~N 0 '-~N-Nmethylpyfrmidine-2,4-diamine U- - j Hydrochloride 'I~a NHN4-(4-Chloro-3-methoxy tjJ(""H phenyl)-5-methyl-N2-(6 I N r N,_)~ piperazin-1 -yl-pyridin-3-yl)- 12.1 N pyrimidine-2,4-diainine N N H _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 234 Structure Name JC50 IC5 , c 5-[ 4 -(4-Chloro-3-methoxy ',aN phenylarnino)-5-methyl N Hpyllirnidin-2-ylaniino] -2- 5.12 ~~ piperazin-1I-yl-benzoic acid N~N ~grethyl ester H I 5-[4-(Benzo[I ,3]dioxol-4 & NH ylamlillo)-5-methyl-pyriniidin-27 16.4 ylamino-2-(2-pyrrolidin- l-yl N~N NC) ethoxy)-benzoic acid methyl ester HH > N,,N-tert-Butyl-3- 5-methyl-2-[4 >rKIiJN N 0_hhI0 (piperidin-4-yloxy)- 7 pbenylamino]-pyimidn_4_ . NH ylainino}-benzenesulfonamide 0H HNR NH N4-(1H-Indol-5-yl)-5-methyl NH N2-[4-(piperidin-4-yloxy) N rN~~~Nphenyl]-pyrimidine-2,4-diamine H' N 2- {5-[4-(iBenzo[1,3]dioxol-4 & NH ylainino)-5-methyl-pyrin'idin-2- 116 N r"Y, OHylamino]-pyridin-2-loy ~ 0 '~"OHethanol -- N' N N4-Benzo[1 ,3]dioxol-4-yI-N2-[3 b N H 0 methoxy-4-(2-pyrrolidin-l-yl- 9.34 N ~ ethoxy)-phenyl]-5-methyl N*N xpy-rimidine-2,4-diamine 235 Structure Namne 1C50 H N, 1N-tert-Butyl-3-[2-(4-irnidazol-l < '~ H ltyl-phenylamino-h- 8.2 -~ ~ N ethypyriaidin-4-ylamino] N" benzenesulfonaxnide H i >rNS~QN N-tert-Butyl-3-{2-[4-i(ydox A N ethoxy-phenylamino -5-ty- 2. D, benzenesulfonamide OH N,, N-tert-Butyl-3- {5-h2-[4-doy 3"'a(4-toxy-mphlain--methyl- 48.6 peyao]pyrimidin-4-ylmn) NH" O ynanbenzeneslfonamide 0:4-NH 0 NH pen1-By-5-methy-2-4- 1. * 4 N piperhoin-1- ylphyl)- 4. (:bNHphenylaniino]-pyriinidin-4 0-ylamino) -benzenesulfonamide H ~N4-r-utlo-3-methoyl-4 >~ ~~ NS1ItL N- (2ezi-tnehyl-iidazl- yletyl)- 2. 5111N phenylamino]-pyrmnidin-4- 3. NA N.'a ylamino)-benzenesulfonamide "N' N 236 SrcueName JAK2 ______________________IC50 H N-tert-Butyl-3-[5-methyl- 2

-(

4 N,,SjNH >r, 0; ~pyridin-4-ylmnethyl- 8. phenylaxnino)-pyrimidin- 4 - 8. N ylamino]-benzenesulfonanmide N!Ho H N-tert-Butyl-3-[5-methyl-2-( 4 ,, N S I NHr'O morpholin-4-yl-phenylaniino) N NH N~' N2-(4-(IH-pyrazol-1-yl)phenyl) IN4-{3-tert-butylphenyl)-5- 151 NN N4-(7-chloro-IH-indol-4-yl)-5 NHmethyl-N2-(4-((piperazin-1- 69 yl)methyl)phenyl)pyrimidine-2,4- 69 N~N I <..NHdianiine Hydrochloride N .N N4-(3-tert-butylphenyl)-5 NH methyl-N2-(4-(2-methyl-lH- 3. - N N iniidazol-1-yl)phenyl)pyrimidine- 3. -N 2,4-diamine Hydrochloride NH N N4-(3-tert-butylphenyl)-5 * C / methyl-N2-(4-(2-methyl-IH- 94.1 -~ N K~YNixidazol-1-yl)phenyl)pyrinaidine 2,4-diamine Hydrochloride H > F ja iNHN-tert-Butyl-3-[5-methyl-2-(4 [1,2,4]triazol-1-yhnethyl- 34 NNN\) phenylamino)-pyrimidin-4 N N ylamino]-benzenesulfonainide N _ _ __ _ _ _ 237 Structure Namue 1C50 H, N-tert-Butyl-3-.{5-naethyl-2- [4 6 bjII1NN (4-methyl-imnidazol- I1-yl)- 4. 0 N phenylarnino]-primnidin-4- 4. ylamino)-benzeaesulfonanmide HH ~N (2-pyrrolidin-1 -yl-ethoxy)- 127 -" N phenylamino]-pyrimidin-4 }k. ) )J LI y1amino}-benzenesulfonamide 0- methyl-2-[4-(2-pyrrolidin-l-yl- 44.4 N N- -'o 4-ylainino}-benzenesulfonaxriide H H N-tcrt-Butyl-3-15-methyl-2-(4 >fNJZII1..I N 1,2,4]triazol- 1-yl-phenylarnino)- 41.4 N Z I/pyrimidin-4-ylarnino] benzenesulfonamide N~IC NH N-tert-Butyl-3- {5-.methyl-2-[3 a (1H-tetrazol-5-yl)-phenylamino]- 55. I pyrimidi-n-4-ylaxnino} N~N ~- ~benzenesulforiaride N-tert-Budtyl-5-[2-(4-ixuidazol- 1 Nj~~11 2 1 HjN yl-phenylan-ino)-5-methyl- 8. -~~ N pyrimidin-4-ylaminol-2-methyl- 8. NXN~~>benzenesulfonamide H~ N~ ~ NH N-tert-Butyl-3-{5-niethyl-2-[4 S NH0(pyrrolidine-1 -carbonyl)- 35 -~~ phenylmxnno]-pyrm dn-4 N'I N e oylaxnino}-.benzncsulfonaniide 238 Structure NameJA(

>

1 s$ ~ H -tert-Butyl-3- {S-methyl-2- [4 00 ~ N0 (morpholine-4-carbonyl)- 3. phenylamino]-pyimridin-4- 3. ylamino) -benzenesulfonamide N, N-tert-Butyl-3- (5.iethyl-2-[4 S' (piperazine-1 -carbonyl) (,,N ylamino}-benzenesulfonamide HH H N-tert-Butyl-3- {5-methyl-2-[4 IS, NH HN(Ht~l5y)-hnlmn) 1 ~ ~ ' N N ( I H t e r a z o i- -y l p ya n iin o ) - 9 6 .7 N<N't*J benzen'esulfonamide H N4-(3-tert-butylpheayl}-5 NH methyl-N2-(4-(1 -~ '~ N~\morpholinoethyl)- 19.9 \__/O phenyl)pyrimidine-2,4-dianiine N N Hydrochloride H________________ ___ H 0 N 3- {2-[4-(4-Acetyl-piperaziin-l N HNK yi)-phemylamino]--5-methyI- 1. >~N~~i N pyframdin_4_ylamno}-N-tert- 8. NAN II butyl-benzenesulfonamide NH NH N4-(3-tert-butylphenyl)-5 methyl-N2-(4-(piperidin-4- 2. -' N ~-. yl)phenyl)pyrimidine-2,4- 2. diamine Hydrochloride HH N N-tert-Butyl-3-{5-methyl-2-[4 S' NH (I -xorpholin-4-yI-ethyl) NN -' N~ phenylamino]-pyrimidin-4- 29.7 - L 1 p ylamino)-benzenesulfonamide ' N. N 239 Structure Name 5-methyl-N4-(2,3 NH N dimethylphenyl)-N2-(4-(4 N methylpiperazin-1- 16 N yl)phenyl)pyrimidine-2,4 NIN diamixge Hydrochloride H N4-(4-chloro-2-methylphenyl)-5 -N methyl-N2-(4-(4 NN~ methylpiperazin-l- 15.9 yl)phenyl)pyrimidine-2,4 N N diamine Hydrochloride H 5-methyl-N4-(3,4 __& NH N dimethylphenyl)-N2-(4-(4 N .methylpiperazin-1- 16.6 ~N N yl)phenyl)pyrimidine-2,4 diamine Hydrochloride EXAMPLE 245. Determination Of Efficacy Of Selected Ccompounds [0468] HEL, CTLL-2 & normal human dermal fibroblasts (NHDF) were from the American Tissue Culture Collection Rockville, MD). BaF/3 cells were obtained from DKFZ Cancer Research Center (Heidelberg, Germany). [0469] BaF/3, HEL & NHDF cells were grown in RPMI 1640 medium (Gibco BRL, Gaithersburg, MD) supplemented with penicillin, streptomycin, L-glutamine, and 10% fetal bovine serum (FBS). CTLL-2 cells were grown in the same media further supplemented with 20 U/mL recombinant IL-2 (Hoffnann-LaRoche, Nutley, NJ). Plasmid containing the human JAK2 coding sequence was purchased from Invitrogen (Madison, WI). JAK2v"l 7 cDNA was generated by using site-directed mutagenesis to introduce the V617F mutation into the human JAK2 coding sequence followed by verification using two-directional sequencing. This cDNA was subsequently subcloned into a retroviral vector and transduced into BaF/3 cells. Permanently transduced BaF/3 cells expressing JAK2v 6 1 7 F were selected and maintained with 1 mg/ml G418. GFP was introduced into this cells by lentiviral transduction using pLenti6-GFP (Invitrogen) followed by selection with blasticidin and confirmation of GFP expression using FACs analysis.

240 [0470] Cell proliferation assay was performed using the XTT cell proliferation kit according to the manufacturer's instructions (Roche, Alameda, CA). In brief, approximately 2.5 x 103 cells were plated in triplicate into microtiter-plate wells in 100 IiL RPMI growth media plus various doses of XLV. After 72 hour incubation twenty microliters of XTr was added to the wells and allowed to incubate for 4-6 hours. The colored formazan product that is formed was measured spectrophotometrically using the Vfnax spectrophotometer (Molecular Devices, Sunnyvale, CA) at 450 nm with correction at 650 rm. IC50 values were determined using the GraphPad Prism 4.0 software (San Diego, CA), wherefore OD values were plotted on y-axis (linear scale) and concentration (mM) on the x-axis (log scale). Data was subjected to a non-linear regression fit analysis and ICso values were determined as the concentration which inhibited proliferation 50%. [04711 . Proliferation EC50: HEL -270 nM Baf3:JAK2V617F - 297 nM Control data: IL-2-induced JAK3-dependent proliferation - 3395 nM Control data: Normal human dermal fibroblast control - 6487 nM Apoptosis assays [04721 BaF/3-JAKv 6 17F cells cultured in growth medium (RPMI, 10%FBS, 1 mg/ml G418 and 10 pg/ml blasticidin) were treated with XLV at 1, 3 and 10 pM for 24 h. Following harvesting cells by centrifugation at 890 RCF (relative centrifugation force) for 5 min, genomic DNA was isolated from cell pellets using a DNA isolation kit (Puregen, Chino, CA). 5 pig genomic DNA of each sample was subjected to 1.2% agarose gel electrophoresis to detect genomic DNA fragmentation (DNA laddering assay). As a control, adherent normal human dermal fibroblasts (NHDF) cultured in growth medium (Cambrex, Walkersville, MD) at 60% confluence were treated with XLV as described above. Following 2 washes with ice cold PBS, genomic DNA was isolated from the NHDF cells for agarose gel electrophoresis. Immunoblotting [04731 BaF/3-JAKV61 7 F cells treated with XLV or vehicle control were centrifuged, washed 2X with ice-cold PBS and lysed using RIPA buffer. Protein concentration was determined using the BCA method (Pierce, Rockford, IL) and 100 pg of total cellular protein of each sample in IX Laemmli buffer were subjected to Western blot analysis. The protein blot was probed with an anti-phospho-STAT5 (Tyr694/699) (Upstate Biotechnology, 241 Charlottesville, VA), subsequently stripped and re-probed with an anti-STAT5 antibody (Cell Signaling Technology, Danvers, MA). The phospho-STATS or STAT5 protein was visualized by the enhanced chemoluminescence method (Pierce). In vivo signaling studies were done in a similar fashion. Briefly, on day 11 after cell injection, animals were orally dosed with either vehicle or 100 mg/kg of XLV. Spleens were harvested 7 h after dosing and quickly homogenized in a FastPrep machine (Qbiogen, Irvine, CA). 100 ±g of each spleen homogenate were subjected to Western blot analysis. The protein blot was probed with an anti-phospho-STAT5 (Tyr694/699) and subsequently with an anti-STATS antibody and visualized by the enhanced chemoluminescence method. FACs analysis of circulating tumor burden [0474] On day 11 after injection of BaF/3-JAK2V 6 7 cell suspension, 1 mL blood was collected by a terminal cardiac bleeding method from one mouse that received vehicle, moreover, 0.1 mL blood was collected by a non-lethal retro-orbital collection method from 10 mice of each of the three groups dosed with 10, 30 or 100 mg/kg of XLV and pooled together within the dose groups. Blood mono-nucleated cells were isolated by a Ficoll (Sigma-Aldrich, St. Louis, MO) cushion centrifugation method (600 RCF and 30 min). The isolated cells were subjected to FACS analysis to determine the percentage of GFP positive BaF/3:JAK2v 6 7 cells. The results are shown on the following chart. Orally Administered XLV Reduces the Number of Circulating JAK2v61 Tumor Cells in a Dose-Dependent Manner C 80 70 0 60 50 c 40 30 2 20) 10 Vehicle 10 n-'kg 30 rrgkg 100 rrg/kg Compound XLV 242 Circulating Tumor Model [0475] SCID mice were intravenously injected with BaF/3 cells expressing JAK2V6 17 F and GFP. XLV was dosed orally at the indicated doses beginning 3 days after infusion and ending 20 days after infusion. On day 11 blood was taken from animals in each group and subjected to FACs analysis to determine the percentage of circulating cells which were GFP positive. In a parallel study animals were treated as described above with the exception that they were given a single 100 mg/kg dose of drug on day 11 followed 4 hours later by sacrifice and analysis of STAT5 phosphorylation in the tumor-bearing enlarged spleen. The results are shown on the following chart. XLV in vivo study data using a circulating tumor model 0010 ,5 20 0 . 1 0 10V 20. 20 -Deth idu 8o asplia0en of neachea dufdt oral gae. Drug given orally bid beginning on day 3 after tumor Injection Ocular exposure and efficacy data [0476] Exposure data of compounds at 0.1% via eye drop administration: [0477] On topical dosing of compounds formulated as 0.1% doses in 0.2% tyloxapol/1 % IPMC/4% Mannitol, exposure levels in found in back of the eye tissues of the mouse are shown at two different time points, namely at 2 h and at 7 h. The efficacy data for selected compounds are shown in Table 2.

243 TABLE2 Concentration (nM) in mouse ocular tissues following bilateral topical instillation of 0.1% formulation QDX1 Concentration (nM) Formulation concentration for selected compounds Time (hr) retina Sclera/choroid Cornea 0.1% XVII 2 495 *6040 8840 6 351 2970 3780 0.1% XXXVI 2 816 7250 7870 7 11200 34800 18600 0.1% XLIV 2 406 4840 103000 26600 7 321 3180 0.1% LXXXII 2 267 2340 69900 7 592 2250 45400 0.1% LXXIV 2 2120 6090 45000 7 2150 7350 21000 EXAMPLE 246. Compound XVII in an Ocular efficacy study in an oxygen-induced retinopathy (OIR) model [04781 Compound XVII was tested using the mouse oxygen-induced retinopathy (OIR) model, in which retinal neovascularization is triggered by cycling mouse pups from normoxia to hyperoxia and then back to normoxia. Litters of C57BL/6 mice were transferred to a hyperoxic environment (70% 02) starting on postnatal day 7 (P7). After 5 days, litters were returned to a normoxic environment (21% 02), where they were then maintained 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, retinal whole-mounts 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 analysis software program in order to quantify 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 as compared to vehicle-treated animals (P<0.05, n= 11-15); in a second study, a 22% reduction was observed (P<0.02, n= 6). The results are summarized in Table 3.

244 TABLE 3 Vascular Area % Change vs. Study # Treatment Group (n 2 mean E SD) Vehicle Control Vehicle 4.9 ± 1.6 - OIR-004 0.1% XVII 3.510.6 -29% Vehicle 8.3 0.8 OIR-007 0.1% XVII 6.461.6, -22% 104791 Although the invention has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited onlyby the following claims.

Claims (10)

1. A compound, or a salt thereof, wherein the compound is of the formula selected from the group consisting of: 0 N NH N CI, 5 5 CI CO NH N CI, 7 CC 'I N 8 C1 NH N 10 N CI, 9 C1 F NH 12 246 NH 13 8 NH NCI, 14 H N N NH 5 N CI, 17 N NH NCI, 18 c I c I MeO NH S CI, 10 23 247 MeO NH N CI, 24 0 2 N NH Me'C 25 NC CI NH 5 N CI, 26 NH N- CI, 27 N NH N CI, 10 28 248 F 3 C NH NCI, 29 NH 30 NH 2 N A, N N N 5 H 32 HNH O N CI, 33 CI F 3 C NH S CI, 10 37 249 HN NICI, 41 NH "N N 'lCl, 51 O O NH 5 N CI, 52 NH NICI, 61 N H r , NH N C, 10 67 250 XaNH N CI, 69 O NH (I rIC, 70 Cl NH 5 N' CI, 73 N NH H 75 021 N NH H -~N N CI, 10 77 F 3 C NH -~N N C, and 80 251 N NH N CI. 82

2. The compound of claim 1, or a salt thereof, wherein the compound is of the formula: NH N CI. 5 33

3. The compound of claim 1, or a salt thereof, wherein the compound is of the formula: NH 2 N N N H 32

4. A method for making a compound of the formula XLV: H O N NH N N N 10 H XLV comprising reacting 3-bromo-N-tert-butyl-benzenesulfonamide with a compound of the formula 32: 252 NH 2 N N N H 32

5. The method of claim 4, further comprising purifying a crude product from the step of reacting the compound of the formula 32 with 3-bromo-N-tert-butyl-benzenesulfonamide. 5

6. A method for making a compound of the formula LVII: H N O NH 0 0 _N N N a H LVII comprising reacting 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine with a compound of the formula 33: HH S aNH 10 'N CI. 33

7. The method of claim 6, further comprising purifying a crude product from the step of reacting the compound of the formula 33 with 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine.

8. A compound or salt according to claim 1 substantially as hereinbefore described. 15

9. A method according to claim 4 substantially as hereinbefore described.

10. A method according to claim 6 substantially as hereinbefore described.