Field of the Invention This invention relates to novel 2-4- (diphenyl-amino)-pyrimidinyl compounds, pharmaceutical compositions containing such compounds, and the use of those compounds and/or compositions for treating hyper-proliferative disorders.

Description of the Invention Compounds of the Invention One embodiment of this invention is a compound of Formula I (I) wherein X is selected from (CI-C3) alkyl, CF3, and halo ; R1 is H, OH, halo, CF3, C (O) R10, NR11R11, C (NH) NH2, C (N) OH, C (N) (Ci-C3) alkoxy, S (O) 2 (Ci-Ce) alkyl, S (O) 2NH2, indolyl, pyridyl, quinolyl, (Ci-Ce) alkyl optionally substituted with C (O) OH, (N) (Ci-C3) alkoxy, or with a five membered N containing heterocycle, (C1-C6) alkoxy optionally substituted with morpholinyl or with 1 or 2 substituents selected from OH and (Ci-C3) alkoxy, 2 of said alkoxy groups optionally being joined to form dimethyidioxolanyl, a five membered heterocycle optionally substituted with 1 or 2 independently selected (Cl-C6) alkyl group (s), said alkyl being optionally substituted with an OH group; a six membered heterocycle optionally substituted with C (O) OH, C (O) (Ci-C3) alkyl, S (0) 2 (Ci-Ce) alkyl,

S (O) 2-phenyl said phenyl being optionally substituted with 1 or 2 independently selected halo atoms, or (Ci-Ce) alkyl optionally substituted with 1 or 2 OH groups, phenyl substituted with one substituent selected from (Ci-Ce) alkoxy, CF3, CN, N [(C1-C6) alkyl] 2 group, and (Cl-C3) alkyl optionally substituted with CN, and 0-pyridyl optionally substituted with halo or (Ci-C3) alkoxy ; R2 is H, S (O) 2NH2, halo, ethynyl, OH, CF3, C (O) R"', a five membered heterocycle, benzodioxolyl, (C1-C6) alkyl optionally substituted with C (O) OH, morpholinyl, with a five membered N containing heterocycle, with NH (Cl-C6) alkyl optionally substituted with 1 or 2 OH groups, or with (Ci-C3) alkoxy, said alkoxy being optionally subsituted with morpholinyl or imidazole, (Cl-C6) alkoxy optionally substituted with 1 or 2 substituents selected from N [ (Ci-C6) alkyl] 2, OH and (Ci-C3) alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyidioxolanyl, or with 1 substituent selected from imidazolyl, pyrrolidinyl, morpholinyl and piperidinyl, NH (Ci-Ce) alkyl-six membered heterocycle optionally substituted with C (O) OH, C (O) (Ci-C3) alkyl, S (O) 2 (Ci-Ce) alkyl, S (O) 2-phenyl said phenyl being optionally substituted at any available C atom with 1 or 2 independently selected halo atoms, or with (Ci-C6) alkyl optionally substituted with 1 or 2 OH groups, phenyl substituted with 1 or 2 substituents independently selected from (Ci-Ce) alkoxy, CN and halo, and pyrazol optionally substituted with (Ci-Ce) alkyl ; R1 and R2 together with the C atoms to which each is attached may form a ring that is fused to the phenyl ring to which they are attached to form a fused ring optionally substituted with 1 or 2 substituents each independently selected from (CI-C3) alkyl, (N) (Ci-C3) alkoxy, (Ci-C3) alkyl-N [(C1-C3) alkyl] 2, C (O) NH2, (N) OH, OH and SH, and when the fused ring is indolyl, it may also be substituted with (Ci-Ce) alkyl said alkyl being optionally substituted with 1 or 2 groups each selected independently from OH, N [ (Ci-C3) alkyl] 2, and

(Ci-C3) alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyidioxolanyl ; R3 is selected from H, (C1-C6) alkyl, halo, S (O) 2NH2, C (O) (Ci-C3) alkyl, CF3, morpholinyl, piperazinyl, pyrazolyl optionally substituted with 1 or 2 independently selected (Ci-Ce) alkyl groups, O-phenyl said phenyl being optionally substituted with halo, (Cl-C3) alkoxy, or C (O) O (Ci-C3) alkyl, (Ci-C6) alkoxy optionally substituted with 1 or 2 substituents each independently selected from OH and (Ci-C3) alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyidioxolanyl ; R4 is selected from H, halo, ethynyl, C (O) (Ci-C3) alkyl, or with pyrazolyl optionally substituted with 1 or 2 independently selected (Ci-Ce) alkyl groups, or (Ci-Ce) alkoxy optionally substituted with 1 or 2 OH group (s); R3 and R4, together with the C atoms to which each is attached, may form a ring that is fused to the phenyl ring to which they are attached to form a fused bi-cyclic heterocycle selected from indolyl optionally substituted with (Ci-Ce) alkyl said alkyl being optionally substituted with 1 or 2 groups each selected independently from OH, N[(C1-C3)alkyl] 2, and (Ci-C3) alkoxy, and wherein 2 of said alkoxy groups may optionally be joined to form dimethyidioxolanyl, and benzotriazole optionally substituted with 1 or 2 independently selected (Ci-Ce) alkyl group (s); and with the proviso that when R3 and R4 together form a cyclic moiety fused to the phenyl ring to which they are attached, then R5, R6 and R7 must be H; R5 and R6 are each independently selected from H, halo, and CF3 ; R 7is H, halo or (Ci-Ce) alkoxy ; R8 is H, (C1-C6) alkyl, (CI-C6) alkoxy, or halo ; R9 is H, or (Ci-C3) alkoxy ; Rlo is (Ci-Ce) alkyl, OH, NH2, NHOR12, NHNHC (O) (Ci-Ce) alkyl optionally substituted with CN, or NH (Ci-C6) alkyl optionally substituted with 1 or 2 OH group (s); R"is selected from H, C (O) R10, S (O) 2 (Ci-C3) alkyl, S (O) 2N [ (Ci-C3) alkyl] 2,

S (O) 2-five membered heterocycle said heterocycle being optionally substituted with (Ci-Ce) alkyl and NHC (O) (Ci-C3) alkyl, R12 is selected from H, (CI-C3) alkyl, and tetrahydropyranyl ; Y is N [(C1-C6)alkyl]2, imidazolyl, piperidinyl, morpholinyl, pyrrolidinyl, NH-phenyl-(C1-C6)alkoxy, NH-O-phenyl-(C1-C6)alkoxy ? or NH-(C1-C6) alkoxy-phenyl ; with the provisos that a) when R1 is H then R2 must be other than H; b) when R2 is H then R1 must be other than H; c) when R3 is H then R4 must be other than H; d) when R4 is H then R3 must be other than H; e) when R'is C (O) OH then at least one of R2 R8 and R9 must be other than H; f) when R2 is C (O) OH then at least one of R1 R8 and R9 must be other than H; g) when R2 is OCH2CH2Y, then R'must be other than H; h) when R1 and R2 are fused then R8 and R9 are each H; and i) when R1 is S (O) 2NH2, and when (CH2) 0 2 is zero, then at least one of R3 and R4 must be selected from morpholinyl, pyrazolyl, and optionally substituted O- phenyl, or R3 and R4 together with the C atoms to which each is attached, must form a ring that is fused to the phenyl group to which they are attached to form optionally substituted indolyl or benzotriazole ; or a pharmaceutical acceptable salt thereof.

A prefered embodiment of this invention is a compound of Formula I wherein X is halo, R1 is selected from H, OH, C (O) R'O, NR11R11, C (N) OH, C (N) (Ci-Ce) alkoxy, indolyl, pyridyl, quinolyl, (Ci-C6) alkyl optionally substituted with C (O) OH, (N) (Ci-C3) alkoxy, or with a five membered N containing heterocycle, (CI-C6) alkoxy optionally substituted with morpholinyl or with 1 or 2 substituents selected from OH and (Ci-C3) alkoxy, 2 of said alkoxy groups optionally being joined to form dimethyldioxolanyl, a five membered heterocycle optionally substituted with 1 or 2 independently selected (Cl-C6) alkyl group (s), said alkyl being optionally substituted with an OH group; a six membered heterocycle optionally substituted with C (O) OH, C (O) (Ci-C3) alkyl, (C1-C6) alkyl optionally substituted with 1 or 2 OH groups,

phenyl substituted with one substituent selected from (Ci-Ce) alkoxy, CN, and N [(C1-C6) alkyl] 2; R2 is selected from H, OH, CF3, C (O) R10, a five membered heterocycle, (Ci-C6) alkyl optionally substituted with C (O) OH, morpholinyl, with a five membered N containing heterocycle, with NH (Ci-Ce) alkyl optionally substituted with 1 or 2 OH groups, or with (Ci-C3) alkoxy, said alkoxy being optionally subsituted with morpholinyl or imidazole, (C1-C6) alkoxy optionally subsituted with 1 or 2 substitutents selected from N [ (Ci-C6) alkyl] 2, OH and (Ci-C3) alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl, or with 1 substituent selected from imidazolyl, pyrrolidinyl, morpholinyl and piperadinyl, NH (Ci-Ce) alkyl-six membered heterocycle, phenyl substituted with 1 or 2 substituents independently selected from (Ci-Ce) alkoxy, CN and halo, and pyrazol optionally substituted with (Ci-C6) alkyl ; R1 and R2 together with the C atoms to which each is attached may form a ring that is fused to the phenyl ring to which they are attached to form a fused ring optionally substituted with 1 or 2 substituents each independently selected from (Ci-C3) alkyl, (N) (Cl-C3) alkoxy, (Ci-C3) alkyl-N [(C1-C3) alkyl] 2, C (O) NH2, (N) OH, and (N) O (Ci-C3) alkyl, and when the fused ring is indolyl, it may also be substituted with (Ci-Ce) alkyl said alkyl being optionally substituted with 1 or 2 groups each selected independently from OH, N [ (CI-C3) alky [12, and (Ci-C3) alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyldioxolanyl ; R3 is selected from H, (C1-C6)alkyl, halo, C (O) (Ci-C3) alkyl, morpholinyl, piperazinyl, pyrazolyl optionally substituted with 1 or 2 independently selected (Ci-Ce) alkyl groups, 0-phenyl said phenyl being optionally substituted with halo, (Ci-C3) alkoxy, or C (O) O (Ci-C3) alkyl, (C1-C6) alkoxy optionally subsituted with 1 or 2 substitutents each independently selected from OH and (Ci-C3) alkoxy wherein 2 of said alkoxy groups may optionally be joined to form dimethyidioxolanyl ; R4 is selected from H, halo, ethynyl, C (O) (Ci-C3) alkyl,

(Ci-Ce) alkoxy optionally substituted with 1 or 2 OH group (s), and pyrazolyl optionally substituted with 1 or 2 independently selected (Ci-Ce) alkyl groups; R3 and R4, together with the C atoms to which each is attached, may form a ring that is fused to the phenyl ring to which they are attached to form a fused bi-cyclic heterocycle selected from indolyl optionally substiuted with (Ci-Ce) alkyl said alkyl being optionally substituted with 1 or 2 groups each selected independently from OH, N [ (Ci-C3) alkyl] 2, and (Ci-C3) alkoxy, and wherein 2 of said alkoxy groups may optionally be joined to form dimethyidioxolanyl, and benzotriazole ; R5 and R5 are each H; R7 is selected from H, halo and (Ci-Ce) alkoxy ; R 8 is H; R9 is selected from H and (Ci-C3) alkoxy ; Rlo is selected from (Ci-Ce) alkyl, NHOR12, (C1-C6) alkoxy and NH (Ci-Ce) alkyl optionally substituted with 1 or 2 OH group (s); R11 is selected from H, C (O) R10, S (O) 2 (CI-C3) alkyl, S (O) 2N [(C1-C3) alkyl] 2, and S (O) 2-five membered heterocycle said heterocycle being optionally substituted with (CI-C6) alkyl and NHC (O) (Cl-C3) alkyl ; R12 is selected from H, (C1-C3) alkyl, and tetrahydropyranyl ; and Y is selected from N [(C1-C6)alkyl]2, imidazolyl, piperidinyl, and morpholinyl.

The terms identified above have the following meaning throughout: The term"optionally substituted"means that the moiety so modified may have from none to up to about the highest number of substituents indicated. When there are two or more substituents on any moiety, each substituent is chosen independently of any other substituent and can, accordingly, be the same or different.

The terms" (Cl-C3) alkyl" and" (Cl-C6) alkyl", mean linear or branched saturated carbon groups having from about 1 to about 3 or about 6 C atoms, respectively. Such groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.

The terms" (CI-C3) alkoxy" and" (CI-C6) alkoxy" mean a linear or branched saturated carbon group having from about 1 to about 3 or about 6 C atoms, said carbon

group being attached to an O atom. The O atom is the point of attachment of the alkoxy substituent to the pyridyl ring. Such groups include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tett-butoxy, and the like.

The terms"(C1-C6) alkyl optionally substituted"and"(C1-C6) alkoxy optionally substituted"mean an alkyl group or an alkoxy group, respectively, as defined above, wherein each C atom is bonded to 1,2 or 3 H atoms, as appropriate, or any H atom up to about the recited maximum number of H atoms on a C atom may be replaced with a recited substituent, or the alkyl or alkoxy groups may be substituted as otherwise described herein, with the proviso that combinations of recited substituents result in a chemically stable compound.

The term"halo"means an atom selected from Cl, Br, F and 1, where Cl, Br and F are preferred.

When" (N)"" (NH)" and" (O)" are used in a chemical formula, they mean =N, =NH and =O respectively.

The formula"N [C1-C3) alkyl] 2"and N [S (O) 2 (Ci-C6) alkyl] 2", and the like, mean that each of the 2 possible alkyl groups attached to the N atom are selected independently from the other so that they may be the same or they may be different.

The term"five membered heterocycle"means an aromatic, saturated or partially saturated ring containing about 5 atoms and having 1,2 or 3 heteroatom (s) each selected independently from O, N, and S, the rest being C atoms, with the proviso that there can be no more than 1 O atom or 1 S atom in the heterocycle. This heterocycle is attached through any available C or N atom to the rest of the molecule and is optionally substituted at any available C or N atom with the recited substituents. Such groups include pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and the like, in all their possible isomeric forms.

The term"six membered heterocycle"means a saturated or partially unsaturated ring containing about 6 atoms, 1 or 2 of which are each independently selected from N, O, and S, the rest being C atoms. There can be no more than 2 O atoms or 2 S atoms in any heterocycle, and when there are 2 0 atoms in a heterocycle, they must be non- adjacent. This ring is attached through any available C or N atom to the rest of the molecule and is optionally substituted with the recited substituents on any available C and/or N atom. This heterocycle includes piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl and the like.

The term"five membered N containing heterocycle"means a saturated or partially saturated ring containing about 5 atoms, 1,2, or 3 of which are N atoms, the rest being C, where the heterocycle is attached through any available C or N atom to the rest of the molecule. Such groups include imidazolyl, pyrrolidinyl, and the like.

The term"fused ring"means a group having from 9 to 14 atoms divided into 2 or 3 chemically stable rings, one of which is the phenyl ring to which R'and R2 are attached.

Each ring is fused to another ring through adjacent C, C-N or N atoms and 3,2 or 1 of the remaining atoms, respectively, in the fused ring are heteroatoms each independently selected from N or O, with the proviso that there can be no more than 1 O atom in any fused heterocycle. The heteroatoms may be located at any available position in the fused moiety other than in the phenyl ring to which R'and R2 are attached. When the fused ring is bicyclic, the one ring that is fused to the phenyl ring to which R1 and R are attached may be either aromatic, partially saturated or saturated. That is, if the one ring stood alone, it could be either aromatic partially saturated, or saturated. When the fused ring is tri-cyclic, the bicyclic ring that is fused to the phenyl ring to which R'and R2 are attached may be either unsaturated or partially saturated. That is, if the bicyclic ring stood alone, it could be either partially saturated or saturated. The resulting fused bi-or tri-cyclic ring is optionally substituted with the recited substituents at any available C and/or N atom (s). Such groups include but are not limited to benzimidazolyl, benzimidazoly-2-one, indolin-2-one, benzotriazolyl, dihydrobenzoindazolyl, dihydrobenzodioxinyl, dihydroinden-1-oneoxime, dihydronaphthalenone, dihydrobenzoindazolyl, tetrahydropyrrolobenzoxazinyl, indazolyl, benzotriazolyl, benzocyclopentyl, benzocyclohexyl, indolyl and the like.

When a phenyl ring may be substituted with one or more substituent, the substituent (s) may be attached to the phenyl ring at any available C atom, preferably at the 3,4, or 5 C. When there is more than 1 substituent on a phenyl ring, each is selected independently from the other so that they may be the same or different. Representative compounds of Formula I are shown in Table I Table 1 Example Structures Characterizationa Method No. CIH (M+H) + 439. 2 HN RT 2. 56 min B3, 1b 1 Br TLC Rf 0. 40 (50% c EtOAc/H EX) tN1HN<NCH3 /F HN 2 Br Rf 0. 70 (EtOAc) 2 --N-1 N I H F , OH HN N N Rf 0. 54 3 CH3 (EtoAc/HEX 1/1) N'N \ H gFChiral HN Br) 0N n JL N NH (M+H) + 489. 6 RT 2. 57 min 1b, 1c, TLC Rf 0. 59 (50% 4 EtOAc/HEX) HEX -x--o H3C F HN OH 5 Br HNfa 0 OH OH 5 -- (N" N H Example Structures Characterizationa Method No. OH Chiral (M+H) + 449. 5 RT 2. 08 min NH O TLC Rf 0. 72 (10% 1b, 1c vN A MeOH/90% CHCI3) mp = 157-158 °C , H H H HO O 8 Br I N I OH 8 HNJU O H N F Chiral (M+H) +512. 3 HN RT 2. 58 min 9 I eo TLC Rf 0. 29 (50% 9 OCH3 EtOAc/HEX) N I CH3 m p = 130-132 °C H /F Chiral OH (M+H) + 472. 4 HN RT 2. 08 min 4, g1, 10 gr \ N/N OH TLC Rf 0. 29 (50% .- 10 Br N EtOAc/HEX) lb, lc H , FChiral HN- Br) 0N N NH (M+H) + 489. 6 RT 2. 89 min 1b, 1c, TLC Rf 0. 51 (50% 4 Õ EtOAc/HEX) H3c 0 PO Hic cl3 H, H CH N O 13 ~ O mp95-116. 5°C 13 RT 2. 6 min N N H H Example Structures Characterizationa Method No. FChiral HN" Br (M+H) + 449. 5 '1 RT 1. 90 min 14. 1 TLC Rf 0. 47 (20% 1 b, 1 c MeOH/80% CHCI3) mu = 201'C HO Os OH OH F 0 CH3 (M+H) + 489. 5 RT 2. 87 min 1 b 1 c, 15 Br NH 0 TLC Rf 0. 52 (50%' N EtOAc/HEX) H X H /F N OOH 16 Br I N/I OH RT 2. 1 min 16 "N t1 N1N Jv H H /F H Br N N1NH (M+H) + 458. 8 RT 2. 62 min 1b, 1c, 17 TLC Rf 0. 22 (50% 17a, EtOAc/Hex) 17b 0 NH Hic OH CH3 CHg F H3C 18 HN43/O 00 18 Br I N/I N/N H H N N H Example Structures Characterizationa Method No. HO BER N Br I wN NNH (M+H) 484. 2 RT2. 61 min 1b, 1c, 19 r 0 TLC Rf 0. 56 (50% 17a, Hex/EtOAc) 17b, 18 u n\ 0 (3 \oo HN CH3 B7a, F (M+H) + 667 B7b, 20 Rf = 0. 34 (45/50/5 N4, H ß CH MeOH/CH3CN/H20) B7C2, o1 9, H CH3 20 Cl Cl ZON \-CL3 cl ci HN (M+H) 477 21 Rif = 0. 34 (4/1 21 Hex/EtOAc) N 0 "CL, /F F HN CH3 H RT 2. 56 min 22 r CH3 (M+H) + 386 22 \ ° H wN1N HN CHo RT 0. 32 min 23 Ci/IN/I NH2 (M+H) +344 22 23 \NON H Example Structures Characterizationa Method No. CH3 IN 24 HN N N CF RT 2. 11 min 24 Y"M rr Y' H N CH3 H N, Y ! 3 O CAF3 RT 2. 56 22, 23, 25 HN CF S-CH (M+H) + 598. 0 25 H3 N, s CH3 C--N-IN I NJN W I O O H Br HN CF3 H N= 28 BrN HN JSN-CH3 RT290 22 23 N- °° H 'Q H F 77 J' 0 RT2. 78 HN"N O (M+H) 5 557. 3 CI N/NJ N H OMe Oye 28 HN CH3 rN RT 1. 91 Br I (M+H) + 453. 2 H Example Structures Characterizationa Method No. HN N (M+H) + 463. 0 1 rif 0. 61 29 NH Q (119190 a F F TFA/MeOH/CH2Ch2) F-eN 'N ZU CIL H \ CIH (M+H) + 567 Rif 0. 70 30 NH (1/9/90 1 a p 0/0 TFA/MeOH/CHzCtz) /N RT 2. 96 I F PO NU F FHN ro F O FXN NC) (M+H) + 501. 4 Rf 0. 28 31 là n F O F 0 F O F HOF (M+H) + 439. 1 Rut 2. 36' 32 HN TLC RfO. 70 (EtOAc) Bu on N N kj/N Example Structures Characterization a Method No. F Br HN CH3 (M+H) + 471. 2 N N-i RT 1. 87 min 33 WNX nNJ TLC Rf 0. 22 (10% 1b, 1c 3 J ( N-kN-0 MeOH/EtOAc) H Hoof F F F (M+H) + 340. 2 NH N Ns RT 1. 85 min 34 Br-TLC Rf 0. 29 (50% 1 b, 1 c EtOAc/Hex) N N H ZOU F MEOH F (M+H) + 340. 2 RT 1. 85 min 35 F-0 TLC Rf 0. 29 (50% 1 b, 1 c 'NH HN'N EtOAc/Hex) Fur N (Y N"N dN F 0 H F O F F OH. (M+H) 414. 4 RT 2. 41 min 36 TLC Rf 0. 29 (50% 1 b, 1 c Hex/EtOAc) N N N/3 y N F Br CN' HO p F (M+H) + 428. 1 RT 2. 20 min 37) X rCH3 TLC Rf 0. 55 (50% 1 b, 1 c wNH XN Hex/EtOAc) Br X X N N H H Example Structures Characterizationa Method No. HNv N, N (M+H) 425. 2 38 Br II) RT 2. 47 min B3, 1 b, TLC Rf 0. 76 (EtOAc) 1c mp = >240 °C I w CIH HO HN Ber N (M+H) + 449. 2 RT 2. 54 min 39 N H TLC Rf 0. 84 (20% 1 b, 1 c MeOH/80% CHZCI2) m p > 220 °C ci OOH R I I S-NH2 J 0 (M+H) + 492. 2 RT 1. 94 min 40 Br TLC Rf 0. 03 (50% 1 b, 1 c EtOAc/Hex) N NH NH rS O 0 11 S-NH2 ) (M+H) + 506. 1 HN RT 1. 86 min 41 Br. TLC Rf 0. 11 (67% lb, Ic EtOAc/Hex) N NH O CIH OH Example Structures Characterizationa Method No. Han CIL. "Uk CIH. NH (M+H) 522. 0 bu 42 ! TLCRf0. 11 (67%'"'" N NH EtOAc/Hex) OMe I 0 OH 0 11 S, 0 , XNH2 CiH (M+H) 526. 9 RT 1. 77 min HN TLC Rf 0. 32 (67% Br CIH EtOAc/Hex) N H C02H O. SU 0 0 H2N CIH \ CIH (M+H) + 506. 0 RT 1. 90 min 44 NH OH TLC Rf 0. 17 (67% Br 3 0 EtOAc/Hex) H2Ns/° H H. g°. OS CIH (M+H) + 541. 2 RT 1. 81 min 45 NH TLC Rf 0. 27 (67% 1 b, 1 c Br N 0 k EtOAc/Hex) N N N H F Chira CIH (M+H) + 449. 2 NH OH RT 2. 54 min 1 b, 1 c 46 TLC Rf 0. 13 (50% 6 Hex/EtOAc) tNlHN) mp > 220 °C Example Structures Characterizationa Method No. n /neo HO Br O Br FF 0 (M+H) + 507. 0 47 NlNH F OH RT 2. 19 min 1b, 1c N NU F zozo w S, NHa O 0 11 S-NH2 if tJ (M+H) + 506. 1 CIH RT 1. 94 min 48 HN TLC Rf : streaks 1b, 1c (67% EtOAc/Hex) OH H H 0 \ O 4J NH2 CIH (M+H) + 493. 0 RT 1. 71 min 49 HN CIH TLC Rf : streaks 1b, 1c Br O (67% EtOAc/Hex) NH 2 Y 1 J ! 2 O H O 0 NH2 CIH (M+H) + 514. 01 RT 2. 04 min 50 HN CIH TLC Rf : streaks 1b, 1c or (67% EtOAc/Hex) H N H I/N O H N 0 11 NH2 (M+H) + 492. 2 RT 2. 49 min 51 HN 2HCI TLC Rf 0. 09 (67% 1b, 1c t EtOAc/Hex) N N neo H Example Structures Characterizationa Method No. 0 S, o I g SNH20 (M+H) 526. 2 RT 2. 69 min 52 HN 0 TLC Rf 0. 40 (67% 1 b, 1 c tN'>N 4/EtOAc/H ex) ! 0 N''N'v H 11 S,, 0 NH2 (M+H) + 506. 3 CIH RT 2. 66 min 53 HN TLC Rf 0. 60 (67% 1b, 1c Br \ N \ O EtOAc/Hex) i J N N ° H CIL CIH 1 C ! H (M+H) + 439. 2 HN'6 RT 2. 76 min B3 1 b, 54 Br TLC Rf 0. 40 (50% 1 c I EtOAc/HEX) I NH \ I NN, CH3. /F HN e Br N J F O N NH- RT 1. 74 min N CHUG N Cl 3 ci ci, cl HN CH3 () M+H + 570 B7b 56 CH3 Rf = 0. 32 (50/49/1 N4, N r MeOH/CH3CN/H20) B7c, 19, N CH 20 Y'N 0'3 Example Structures Characterizationa Method No. HN'v-O OH Br wW OH (M+H) + 449. 3 RT 1. 77 min 57 N NH TLC Rf 0. 45 (10% 1b, 1c F MeOH/90% CHCI3) F Ci cri CL3 *"3 HN B7a, HN O F I CH (M+H) + 601 B7b, 58 Rif = 0. 35 (50/45/5 N4, /N CH MeOH/CH3CN/H2O) B7c, 19, 'N N , 20 H ci HNO Han F I N CH3 N, NH B7a, CH3 (M+H) + 609 B7b, 5g I N4, N CH RT 2. 52 min. N4, I 1c N N H HN BrN H O (M+H) + 423. 2 RT 2. 20 min 60 NlNH FvOH RT 2 20 min 1 b, 1 c F MeOH/EtOAc) N 0. 11 H H Example Structures Characterizationa Method No. /F \ ci F CI F _ F>r 0 (M+H)'381. 4 61 + F RT 2. 28 min 1b, 1c H N N F \ I N. N F ( ((M+H) + 413. 1 RT 3. 18 min 62 HN TLC Rf 0. 3048 (20 % r_tN -CH3 EtOAc/Hex) N N ( (M+H) + 413. 1 HN RT 2. 69 min 63--N _ TLC Rf 0. 1359 (20 % 1 b, 1 c Br N EtOAc/Hex) H CHg tua TFA HN, fa 0 (M+H) + 433. 1 gr RT 2. 63 min OH TLC Rf 0. 38 (EtOAc) NJ. IyN \ O NlH 8 HN N /\-N N 'N F P (M+H)"450. 3 F- RT 2. 78 min 65 N NH IF OH TLC Rf 0. 86 (20% 1 b, 1 c MeOH/EtOAc) FEZ F Example Structures Characterization a Method No. HNe, N HN N Br H F 0 (M+H) + 448. 0 N RT 2. 04 min 66 N NH F F OH TLC Rf 0. 70 (10% 1b, 1c X MeOH/EtOAc) Nt ;) NON H /\-N HNiX, N eN F ° (M+H) 467. 1 t zl FlA RT 1. 88min 67 N NLH F OH TLC Rf O. 80 (10% 1b, 1c ; MeOH/EtOAc) N 0 F F I NH O (M+H) + 432. 0 RT 2. 67min 1b, 1c N TLC Rf 0. 2678 (2% tN HX H3C MeOH/CH2CI2) H HIC F u (M+H) + 418. 0 RQ ! ! ! RT2. 92mir)... RT2. 92min 1b, 1c N"N H MeOH/CH2cl2) Au H F HN Br (M+H) + 430. 2 NzlNH RT 2. 98 min 1 b, 1 c 70 TLC Rf 0. 59 (50% 7 EtOAc/HEX) NCH, 11 3 Example Structures Characterizationa Method No. F HN Br HN) (M+H) + 426. 4 TFA RT 2. 68 min 71 NMu TLCRf0. 68 (50%","' EtOAc/HEX) N zozo Ho Han gr N TFA (M+H) + 426. 2 RT 2. 71 min B. 3 1b 72 TLC Rf 0. 68 (50% i c EtOAc/HEX) 'N ZON F HN \ (M+H) + 426. 5 Br N RT 2. 91 min 73 N NH H F TLC Rf 0. 71 (50% ' F EtOAc/HEX) ! o po F HN Br (M+H) + 426. 3 RT 2. 95 min B3, lb, 74 TFA TLC Rf 0. 71 (50% B3jc1b, EtOAc/HEX) 'N Example Structures Characterizationa Method No. CIH (M+H) + 375. 2 RT 1. 98 min 75 F TLC Rf 0. 78 (20% 1b, 1c MeOH/80% CHCI3) NH mp = 245 °C Br I N, I OH H CIL CIH (M+H) + 375. 4 RT 2. 17 min 76 Fla TLC Rf 0. 78 (20% 1 b, 1 c MeOH/80% CHCI3) NH mp = 246 °C Bu HNe H HN"'a F Ber Br N F + (M+H) 428. 4 F F RT 2. 41 min 77 N NH TLC Rf 0. 37 (50% 1 b 71 c, ß O OH EtOAc/HEX) 7 N HO F Br\N Ft, F Br FF F (M+H) + 442. 1 N NH O% OH RT2. 91 min 1b 1 78 TLC Rf 0. 40 (50% a7 c, EtOAc/HEX) N HO H3C, 0 Example Structures Characterizationa Method No. CIH F (M+H) + 520. 0 /-CH RT 2. 15 min 79 NH TLC Rf 0. 31 (20% lb, Ic Br < N S S OH 3 MeOH/80% CHCI3) mp = : 86'C H F H HN 0 (M+H) + 433. 4 Br RT 2. 52 min I OH TLC Rf 0. 38 (EtOAc) NlN<O H CH3 CH3 S HN, fa Br (M+H) + 418. 0 N NH RT 2. 67min TLC Rf 0. 2678 (2%, c MeOH/CH2CI2) N > O lux H HN" Han F F O FOH (M+H) + 402. 3 F RT 2. 25 min 82 TLC Rf 0. 60 (10% 1b, 1c MEOH/CH2CI2) IF 0 0 Example Structures Characterizationa Method No. IrF HN CI N (M+H) + 418. 5 I N''NH F O RT 2. 50 min 83 FOH TLC Rf 0. 71 (10% 1 b, 1 c I F MeOH/CH2CI2) F Ap 0 ho NJ HO BrY'4N F o (M+H) + 531. 3 F OH RT 2. 22 min 84 N NH TLCRf0. 49 (50% 1b, 1c F Hex/EtOAc) F S-NH2 0 0 Hune ° HN O Br N O N NH F// (M+H) + 523. 5 F-OH RT 2. 21 min F TLC Rf 0. 38 1 b, 1 c F (50% Hex/EtOAc) F N tN) Example Structures Characterizationa Method No. F po HN HN (M+H) + 356. 1 Cl wN F ° RT 2. 16 min 86 NI vOH TLC Rf 0. 80 (20% 1 b, 1 c N NH F MeOH/CH2CI2) N-N H HN"a Brun tN-lNH (M+H) + 580. 3 B7ab, RT 2. 43 min B7b, 87 i r TLC Rf 0. 34 (9/1 B N 1, eo~NvCH3 CH2CI2/MeOH) 1 c 1c CL, w CH3 /I r HN, a (M+H) + 499. 1 Br 0 RT 1. 90 min N8, N9, 88 CH 3 TLC Rf 0. 35 (9/1 B7c, N19b', N HN O9N CH2CI2/MeOH) 1 c H N N HN"a un Bu N (M+H) + 504. 4 B7b, N NH RT 1. 90 min' 89 N TLC Rf 0. 27 (9/1 B7 , c1 b, 4° CH2CI2/MeOH) c T"P H3C'% H3CvN>CH3 Example Structures Characterizationa Method No. FUZZ aNH O Br N N'OH (M+H) + 418. 0 H RT 2. 63 min 90 N H TLC Rf 0. 0885 (20 % OH EtOAc/Hex) off IF F I NH O eH (M+H) + 432. 0 Br N N N H H3 TLC Rf 0. 2678 (2% 1 b, 1 c OH MeOH/CH2CI2) ou F F F H'F Br Brs¢4N (M+H) + 504. 4 N8, N9, 92 NNH RT 1. 94 min B7c, 1 b, lue L Je /F HO Br N B7a, (M+H)"'602. 9 B7b, gg N NH RT 2. 17 min N1, CH3 B7c, 1 b, CH C Example Structures Characterizationa Method No. HN HN-, Brun B7a N NH (M+H) + 592. 1 B7b, 94H3 RT 2. 44 min N1, 3 B7c, 1b, lu N IF Han Brun B7a, I N.-NH (M+H) + 577. 1 B7b, 95 1-., RT2. 49min N1, B B7c, 1 b, 0 3 1 c N F Ber B7a, INS (M+H) + 590. 2 B7b, 96 RT 2. 35 min NI, B7c, 1 b, N Ic N H Example Structures Characterizationa Method No. HAN HAN Br N tN, lNH (M+H) + 520. 0 N8 N9 RT 1. 90 min N8 N9, TLC Rf 0. 27 (20/1 1 c 0 CH2CI2/MeOH) Hz CN 0 ^/F HN bu BrX0N (M+H) + 429. 2 N6, 98 N NH RT 2. 40 min B7c, 1 b, H3C H/ H3C/N N (M H) 442. 1 Br N H RT 2. 21 min I TLC Rf 0. 92 (10% 1 b, 1 c 99'1-CIH OMe OMe OMe zon HN N Br N H + \¢ 4 N O (M+H) 485. 1 RT 2. 12 min 100 OH TLC Rf 0. 92 (10% 1 b, 1 c Q MeOH/EtOAc) po Example Structures Characterizationa Method No. F HAZY Ber,, tNlNH (M+H) + 591. 2 B7a, RT 2. 37 min B7b, 101 TLC Rf 0. 28 (9/1 N1, CH2CI2/MeOH with B7c, 1b, 0. 5% AmmOH) 1c N H HN Y" Br N tNlNH B7a, (M+H) 582. 2 B7b, 102 RT 2. 44 min Nl, jazz B7c, 1 b, In N-\ zizi CH3 . (CH CH3 HNJSF HN Ber N kN1NH (M+H) + 499. 3 N6, 103 RT 1. 87 min B7c, 1 b, c Hz N tCH Example Structures Characterizationa Method No. F Br¢ ! +N Br N I N-'-NH (M+H) + 500. 2 N6, 104 RT 1. 84 min B7c, 1b, lu / H3 C zon N<CH3 OH Chiral Fn VOH (M+H) + 449. 5 RT2. 11 min 1b 1c, 105 Br TLC Rf 0. 73 (20%'6 MeOH/80% CHC13) tNlHNv mp = 168-169 °C -N- 'Nb CHg Chiral 0-OH (M+H) + 484. 4 RT 2. 06 min 106 HN pH TLC Rf 0. 24 (50% 1 b, 1 c Br N e N EtOAc/HEX) mF O H F O HN /F F HN H eOH (M+H) + 441. 1 107 Br I N/I N F RT 1. 88 min 1b 1c TLC Rf 0. 73 (EtOAc)' NON H NH2 O cl zu HN CH, RT 233 22, 23 108 F I N/I NH (M+H) +344. 3 Nit H Example Structures Characterizationa Method No. Br HN CH3 109 NH2 (M+H) + 388. 2 NIN H Ci ci RT 2. 29 110 HN CH3 (M+H) + 392. 2 22, 23 NH2 NIN H HN HN, cr Brun B7a, N INH (M+H) + 594. 4 B7b, RT 2. 19 min NI, 0-B7c, 1 b, lu H3C""CHg Han N Br0tN H F ° (M+H) + 425. 1 F RT 1. 87 min 112 N NH F OH TLC Rf 0. 80 (10% 1 b, 1 c MEOH/EtOAc) ) =NU H2N Example Structures Characterization a Method No. \ I NN Xk HN-07N N N Br H F 0 (M+H) + 425. 1 F RT 1. 87 min 113"N NH'°''TLCRf0. 80 (10% 1b, 1c MEOH/EtOAc) N N H H NON i N_CHs HN \ Bro¢4N ? (M+H) + 485 1 RT 2. 01 min 114 N NH F OH TLC Rf 0. 88 (10% 1 b, 1 c N MEOH/EtOAc) Co HIC Zon N Han \ Br 0 (M+H) + 481. 7 F RT 2. 07 min 115 NlNH FeOH TLC Rf O. 88 (10% 1b, 1c 43 MEOH/EtOAc) 0 Co) F O F HN"aF HO F CI F ci N F (M+H) + 381. 4 N'NH RT 2. 32 min gg 1 b, 116 TLC Rf 0. 76 (10% in MeOH/HEX) N ZON N H Example Structures Characterizationa Method No. H N/ N I , N v NH HO F + Br (M+H) 421. 4 AN F RT 1. 82 min 117 F TLC Rf 0. 77 (10% 1b, 1c N NH MEOH/EtOAc) NH NU HN, ia '' Br N I NNH (M+H) + 618. 9 B7a, N, lNH CH3 RT 2 75 min B7ab, 118 3 TLC Rf 0. 19 (95/5 Nll eo~NCH3 CH2CI2/MeOH) 1 c F F F F HN CH3 RT 1. 96 119 F \ N/N'CH (M+H) + 370. 3 22 3 I 3 CH3 c3 HN CH3 H RT 1. 98 120 H (M-H) 366 3 22 NJN IO H Cl 3 HN CHg RTIQR HN CH3 RT 1. 98 121 N CH3 (M+H) + 366. 3 22 y NIN &H 0 H Example Structures Characterizationa Method No. CF3 122 RT 2. 34 NN"' ZAIN H Br HN CF3 H l RT 3. 30 22, 23, 123 Br N/N, SNw (M+H) + 608. 8 26 I 0 I NJN W I O H OMe 124 HNib Cl H RT 3. 17 22 124 ik X o (M+H) 402. 2 3 N"IN 0 H ber / HN CH HNw CH3 H RT 2. 45 22 \ 0 O (M+H) + 490 1 H CI - cri HN CH RT 2. 40 22 126 N NHX (M+H) + 446. 2 , ¢, CI H CRI Cri HN CI H RT 2. 72 127 Br Ny CH 3 (M+H) + 466. 1 22 i 1 0 H Example Structures Characterizationa Method No. CH3 I/. CH3 Nu (M+H) + 393. 3 NIT H Br . CH3 HN N RT 1. 66 (M+H) + 457. 3 NIT H Cl 3 HN CH3 RT +. 46 22, 23 130 F N/NH2 (M+H) 324. 3 NIT H F 131 HN CH3 RT 1. 36 22, 23 NH2 (M+H) + 328. 2 NIT H OMe 132 RT RT 2. 22 H (M+H) + 350. 4 N H N N H (M+H) + 441. 2 F (M+H) + 441. 2 HN N-N RT 2. 59 min B3, lb, 133 Br TLC Rf 0. 29 (20% 1 c N v PrOH/80% HEX) NI'N \ OH n Example Structures Characterizationa Method No. ci I/ HN RT 2. 01 134 F N +H + 398. 2 22- . I N/I (M) NN \ H H HN _O-F Br w N (M+H)"446. 6 N NH RT2. 11min 1b, 1c, 135 TLC Rf 0. 56 (80% 17a, EtOAc/Hex) 17b HN OH H'F Ber Br N (M+H) + 448. 0 RT 2. 04 min 1b, 1c, 136 TLC Rf 0. 70 (10% 17a, MeOH/EtOAc) 17b HNN O IL - =N H/N BER ZON (M+H) + 439. 1 N7, N'NH RT 1. 91 min B7 137 TLC Rf 0. 21 (95/5 B7c'1 b, CH2CI2/MeOH) N N Example Structures Characterizationa Method No. CIH fb (M+H) + 439. 7 HNw RT 2. 76 min B3, 1 b, 138 H, TLC Rf 0. 56 (20% 1c I NHN PrOH/80% HEX) CAF3 139 RT 2 37 22 HN H (M+H) + 398 H3C w N/N N N H Cl Clv 140 HN RT 2. 49 22 H (M+H) + 462 Br N zain zu N CI cri HO HNw : : : H RT 2. 44 141 N NJS (M+H) + 432. 2 N N H ZU CF3 0 rut 3. 28 22, 23, 142 HN CF3 S-CH3 Cl (M+H) + 618. 0 25 NO s I/\ Hui Example Structures Characterizationa Method No. CF3 91 RT 2. 35 22, 23, H (Hz 520. 1 26 H3 N, sCH3 //N C"Nl N 0 0 ZU CF3 XCF3 RT 1. 63 (M+H) 4 457. 4 H3 N N N H CF3 Fizz RT 2. 56 22 145 CH (M+H) + 412. 2 H3C I w N/I N 3 N ECO/ CF3 91 j '3 146 HN RT 1. 64 22 N (M+H) + 425. 3 H3 N C-1N-1 N H ci 147 HN""CHg RT1. 64 N H Ja F I N/I NHZ (M+H) 344. 2 Nit6 H Example Structures Characterizationa Method No. OMe Han O RT 2. 10 148 Br HNJD 0 CH RT 2. 10 22 N H H H H HN Br N t l (M+H) +456. 0 RT3. 17min 1b, 1c, TLC Rf 0. 78 (50% 7 EtOAc/HEX) on MHZ H ^/F Ber N Br N I N'NH (M+H) + 560. 1 N3, 150 RT 2. 21 min B7c, 1 b, I 1c N, I CNJ N N CH3 CH3 (M+H) + 414. 2 HN CH3 RT 2. 48 min B2B, 151 Br TLC Rf 0. 62 (50% N EtOAc/HEX)' N'lN4J mp = 202 °C H H JS CH3 (M+H) 440. 2 RT 2. 74 min B2B, 152 Br N TLC Rf 0. 73 50% 1 b, 1 c EtOAc/HEX) H Example Structures Characterizationa Method No. r I F Ber Br N (M+H) + 476. 6 RT 2. 05 min 1b, 1c, 153 ; \ TLC Rf O. 56 (10% 17a, MeOH/EtOAc) 17b 0 NH OH HA OMe HN N RT 1. 83 4 Br. A Y (M7. 5" N N ZAIN H HA Br I NNH (M+H) + 587. 0 N5, 155 1ß1 RT 1. 35 min B7c, 1 b, I lu (N) H N H tH~NJ CH3 Bu I/. CH3 HN N RT 0. 43 22 156 NI-Ili (M+H) + 517. 1 N N H CI O 157 HN CF S-CH3 RT 3. 24 22, 23, Br /N,, CH3 (M+H) 627. 9 25 Br N, sICH 3 '-NIN H 42 42 Example Structures Characterizationa Method No. if HN""= (M+H)"439. 3 158 Br RT 2. 89 min B3, 1b, CH TLC Rf 0. 52 (50% 1 c N N N, N EtOAc/HEX) H U CH /O (M+H) + 451. 6 HN RT 2. 41 min B3, 1b, 159 1c BroJ+N TLC CH TLC Rf 0. 52 (50% \ I N 3 EtOAc/HEX) N H /N r SQCH3 HN N-N (M+H) + 453. 2 160 Br I/RT 2. 67 min B3, 1b, '/TLC Rf 0. 45 (50% 1 c N I EtOAc/HEX) H H F HN \ I N-N (M+H) +453. 3 RT 2. 56 min B3, 1b, N TLC Rf 0. 63 (50% 1c I EtOAc/HEX) N N H3 c H HN) F N, N (M+H) 453. 3 B I ll RT2. 73 min B3, 1b 162 Br I N/I/TLC Rf 0. 68 (EtOAc) 1 c N H/ - F HUA Br (M+H) + 492. 2 RT 1. 71 min N8, N9, 163 N NH TLC Rf 0. 15 (20% B7c, 1b, MeOH/CH2CI2) 1c fi H N N'-'OH Os OH CH3 Example Structures Characterizationa Method No. X Br (M+H) + 532. 0 RT 1. 92 min N8, N9, 164 N H TLC Rf 0. 74 (100% B7c, 1 b, EtOAc) 1 c 0,,--N zu JOCH, ^/F Chiral F Chiral (M+H) + 472. 3 HN r nH RT2. 03 min i 165 Br N 5. TLC Rf 0. 36 (50% c NN EtOAc/HEX) 10 H bu /O.. O HN CF3 S-CH3 -' 3 RT 3. 95 22, 23, 166 5 D SN S CHs (M+H) + 857. 8 25 I n I NJN I O O H ci HNJ01 CH RT 2. 69 22, 23, 167 CH 3 (M+H) + 422. 2 26 Is\ NIT 00 H CH3 HN CH3 H RT 2. 15 22, 23, 168 N, ICH Is\ 3 (M+H) + 402. 2 26 I nu I NJN w I O O H H CH3 Chiral 1 3 OH (M+H) + 486. 3 HN RT 2. 06 min B1, 1b, 169 Br I g'OH TLC Rf O. 24 (50% 1c N EtOAc/HEX) H Example Structures Characterizationa Method No. F Ber BrJ<N (M+H) + 441. 9 RT 1. 86 min N7, 170 TLC Rf 0. 35 (95/5 B7c, 1 b, < CH2CI2/MeOH with 1c 0. 5% NH40H) GON HAN Br L Br (M+H) + 442. 1 N NH RT 1. 96 min N7, 171 1 TLC Rf 0. 25 @85/15 c, CH2CI2/MeOH N t N CH3 (M+H) + 588. 2 Cl, 172 CH3 TLC Rf 0. 08 (50 1 c Br Hex/EtOAc) IN H HN Br t I H (M+H) + 441. 2 N'N RT 2. 59 min 1 b, 1 c, 173 TLC Rf 0. 75 (80% 17a, EtOAc/HEX) 17b, 18 ON hic HIC H3C Example Structures Characterization a Method No. /F H (M+H)"451. 3 RT 2. 36 min B3, 1b, I TLC Rf 0. 67 (EtOAc) 1c NIT H I H (M+H) + 451. 3 RT 2. 66 min B3, 1 b, 11b < z TLC RfO. 70 (EtOAc) 1c 0'cl3 H /O. CHs HN- N (M+H) -463. 3 RT 2. 27 min B3, 1 b, N TLC Rf 0. 64 (EtOAc) 1c NON ci fez HN CF3 S-CH3 RT 3. 43 22, 23, 177 t Ó (M+H) + 614. 0 25 NSJ H ro Po zozo I o.. o 178 HN CF3 S-CH3 RT 2. 90 22, 23, Br /N, CH3 (M+H) + 665. 1 25 BrtN N"f/N S 3 N N H CI HN CH3 N N H Non H Example Structures Characterizationa Method No. F HO CL H RT228 2223 180 N, s, CH3 (M+H) + 422. 2 26 Ici.. NN O O H F N CL H ! RT 2. 71 22, 23, 181 N, s, CH3 (M+H) + 500. 1 25 p O N N H CF3 0 CF3 O 1g2 HN CI OS-CH3 RT 3. 15 22, 23, N HN H irp 00 N N H ^/F H Br (M+H) + 438. 9 N NH RT 1. 82 min TLC Rf 0. 54 (85/15 B7c1, c1 b, CH2CI2/MeOH) N Nu CH3 UM rf= T) 3 H RT74R 77 ? 3 HN CF3 H RT 2. 48 22, 23, 184 N, CH3 (M+H) + 456. 2 26 Is\ H N N H Example Structures Characterizationa Method No. F Rr J Br N BrotN (M+H) 468. 3 RT 2. 26 min N2, 185 TLC Rf 0. 40 (95/5 B7c, 1 b, CH2CI2/MeOH with 1c 0 0. 5% AmmOH) /cl3 UT3 /CRI cul HN CF3 H NEZ 186 Br N,,N-CH3 RT 2. 89 22, 23, (M+H) + 602. 0 26 6H 00 "LENIN H cul HN CH3 H N= Br N N-CHs RT 2. 49 22, 23, (M+H) + 548. 0 26 I NN \ I O O H \ cri N NH H f RT 2. 91 22, 23, 188 Br N, s CH3 (M+H) + 560. 1 25 N J N \ . p O H \ cri ci HN CH 3 H RT 2. 49 22, 23, 189 gr N/N. S. CH3 (M+H) + 482. 1 26 \ I O O N H H Example Structures Characterization a Method No. F HN (' Br ZON I NNH (M+H) + 579. 2 RT 2. 06 min N3, TLC Rf 0. 30 (9/1 B7C1XC1 b, CH2CI2/MeOH) CN -O CL3 ci ci CRI i o.. o HN CF3 S-CH3 C CF3 S-CH3 RT 3. 40 22, 23, 191 X Ó Ó (M+H) + 588. 0/590. 0 25 ils% H H CF3 N CHEZ 192 ho H f'RT2. 93 22, 23, N (M+H) + 680 26 h N r"i) \ H H H F 0 RT ! 3 O CH3 -) Q . K\ J rOZ. JJ 00 07 193 ci NI-II N/N J (M+H) 441. 3 N N H CF3 NH RT 1. 56 (M+H) + 443. 3 H3 N N N H Example Structures Characterizationa Method No. HO Chiral Ho HO 4 (M+H) + 520. 4 N H RT 2. 02 min B3, B1, 195 HN N TLCRf0. 48 (10% 1b, 1c Br N MeOH/90% EtOAc) HNXF H F HN Br BrtN'l (M+H) + 458. 1 N7 NH RT 1. 86 min B7 1b TLC Rf 0. 56 (95/5 1 c CH2CI/MeOH) (N 0 r HN X Bu YY (M-. Hr 468. 9 NNH RT 1. 85 min g7b'b, 197 TLC Rf 0. 36 (9/1 B7c, I b, CH2Ch 2/MeOH) 1c CIO N N N F HN NH RT 1. 33 198 NI-II (M+H) + 399. 2 22 N nua H Example Structures Characterization a Method No. HN'ja Zon Bu 1M+H + 490. 0 g7b N NH RT 2. 29 min' TLC Rf 0. 21 (95/5 g71 C1 b, CH2CI2/MeOH) H3 C, (N 0 F HN'6 (M+H)'499. 2 N8, N9, Br 0 RT 2. 01 min B7c, 1 b, 200 CH3 TLC Rf 0. 53 (20% lu N H O\NI MeOH/80% EtOAc) c A \c N I C'CH3 HN'ja (M+H) + 511 1 201 0 CH RT 1. 81 min N8, N9, 'n TLCRf0. 46 (20% B7c lb, N H ° 9 MeOH/80% EtOAc) N N CH3 , N Han=/ (M+H) + 460. 2 1Bb3, 8, 202 Br RT 2. 80 min lb, lc I TLC Rf 0. 46 (EtOAc) NON H CH3 N HN N N (M+H) + 486. 3 203 Br RT 2. 33 min lb, lc I TLC Rf 0. 65 (EtOAc)' NI'N \ H Example Structures Characterizationa Method No. OMe 0 I\ HN/HN H RT 1. 74 22 204 Br I N/I (M+H) 427. 3/429. 2 --N"N H F HN Br N I NNH (M+H) + 459. 0 1 b, 1 c, RT 2. 01 min TLC Rf 0. 14 (EtOAc) 17b han 0 HN HN g F Chiral HNkJ, ! (M+H)"456. 3 N RT 2. 55 min 206 TLCRf0. 63 (50% °'y' eN I Hex/EtOAc) 0 tu 0 F Chiral Br Chiral (M+H) 476. 2 Bro0N RT 2. 30 min 207 TLC Rf 0. 35 (50% 1 b 1 c 207 N N (' Hex/EtOAc) N FHOW.,,, CF 3 CF3 O, O 208 HN N CH3 RT 2. 31 22, 23, H H3C0N NJ (M+H) + 521. 2 26 N NH H Example Structures Characterizationa Method No. CF3 209 HN bN t4 RT 2 49 22 H3 (M+H)'443. 1 1 H H I N1''N I N N NHtN Y HN Y'-Br (M+H) + 473. 4 HN RT 2. 13 min B3, 1 b, 210 TLC Rf 0. 34 1 d F F (100% EtOAc) OH H OH N H H N H H N Br (M+H) + 448. 1 RT 2. 09 min 211 EH TLC Rf 0. 39 (100% EtOAc) 0 F A F Example Structures Characterizationa Method No. H N N N 'N Br HAN (M+H) + 447. 3 212 \ N RT2. 02min 1b, 1d H TLC Rf 0. 30 (100% EtOAc) 0 FI F F LU Hz HLB HN HN (M+H) + 479. 3 N RT 1. 98 min H TLC Rf 0. 31' (100% EtOAc) ICH F ZOU CL3 /CF3 214 HN CH3 RT 2. 10 < XN CH (M+H) 430 3 w I NN I O 0 H Example Structures Characterizationa Method No. zu Caf3 215 HN CH3 RT +. 72 22, 23 (M+H) 388. 3 H3C ( N, I NH2 NON Zu H HN O Br N F OH BrX H F4OH (M+H) + 504. 3 N N F RT 2. 57 min 216 TLC Rf 0. 52 (70% 1 b, 1 c N EtOAc/Hex) F O OU 0 OH \ I + HN, O (M+H) 477. 2 g4 1 b, 217 gr I _, I O-CH3 RT 2. 66 min 1c N TLC Rf 0. 40 (EtOAc) \ N H OOH /F JSF (M+H) + 463. 1 HN O RT 2. 40 min B4, 1b, 218 Br OH TLC Rf 0. 67 (20% 1c, 8 ! t ! MeOH/80% EtOAc) N H OOH SO-CH3 , "0"CHg HN8J lCH3 Ber 0 0 (M+H) + 530. 2 N8, N9, 219 N H p HO JF TLC Rf0. 13 (20% B7c, 1b, 1c MeOH/80% C HCI3) 0 j0 Example Structures Characterization a Method No. H /N N HOOF HN (M+H) + 363. 3 RT 1. 83 min 1 b, 1 d 0 TLC Rf 0. 60 F F (100% EtOAc) BK F N N H H Non Nu OH HN F M+H) + 363in 221 I RT 1. 93 min TLC Rf 0. 66 1 b, 1 d F F O (100% EtOAc) OH F \LU H NI Non H3C. 0 I/N 'w I F OH HN (M+H) 393. 3 RT 1. 9 min 1b, 1d I TLC Rf 0. 58 F Y (100% EtOAc) N ; a N9F F N H ZU NON n) Y HAN HN (M+H) + 387. 3 N RT 1. 81 min N TLC Rf 0. 25 H (100% EtOAc) 0 FF F OH ZU Example Structures Characterizationa Method No. H NH (M+H) + 420. 3 RT 2. 01 min 224 H TLC Rf 0. 46 (100% 1 b, 1 d Br N EtOAc) H H H H N (M+H) + 421. 2 RT 2. 05 min 225 HN H TLC Rf 0. 71 (100% 1b, 1d Br N EtOAc) zon NJN N H N (M+H) + 420. 3 RT 2. 00 min 226 HN H TLC Rf 0. 66 (100% 1 b, 1 d tA JSN EtOAc) N oye Non H OMe HN CH3 RT 1. 70 22, 23 227 Br I I NH2 (M+H) + 400. 3/402. 2 N1N H H O 0 HN I . H O zb (M+H) +518. 3 Nl N RT 1. 76 min N8, N9, 228 HNe TLC Rf 0. 24 (50% B7c, 1 b, EtOAc/HEX) 1 c mp = 100-101 °C F Example Structures Characterizationa Method No. my 11 HN CH3 229 H CH3 rN RT 1. 92 28, 22 H \ cl3 RT 1. 77 H s wN/ I NN \ I I-I \ CF3 HN CF3 H N RT 2. 70 22, 23, [CF ci CI h 3 (M+H) + 606. 0 26 1 00 NIT H H / CF3 CH3 J P3 N RT 2. 15 22, 23, H eN <JN S N H3 N, s N fizz ou N N H Br H Lu N f Y N N (M+H) + 381. 3 233 NH RT 2. 13 min lb, ld HC TLC Rf 0. 89 (100% EtOAc) HO F O F F Example Structures Characterizationa Method No. BrH Y Non (M+H) + 411. 3 HO/NH//RT 2. 29 min 234 HC TLC Rf 0. 87 1 b, 1 d HsC-o" (100% EtOAc) O O () F OH 111 0 CL O C oh ; Fa (M+H) 425. 3 235 NH RT 2. 47 min 1b, 1d H TLC Rf 0. 85 TLC Rf 0. 85 Br N O, CH (100% EtOAc) 3 H FEZ N BU H Nu non/ NU (M+H) +450. 3 HC RT 2. 39min 1b, 1d 236 TLC Rf 0. 79 e (100% EtOAc) 0J O FOX F F Bu N N h < (M+H) + 406. 1 RT 2. 27 min NH TLC Rf 0. 76 Hc (100% EtOAc) HO NON Example Structures Characterizationa Method No. BrH //YN I \ 4 /INH HC/ ! r He HN Hc (M+H) 407. 2 RT 2. 23 min TLC Rf 0. 73 (100% EtOAc) ICH F BUZZ BU H Bu H I II N I \ NN/ NH HN \ (M+H) + 439. 1 239 ==N RT2. 13min HS TLC Rf 0. 68 (100% EtOAc) ICH F A F F O F FCo \ N HN (M+H) + 494. 2 HN N RT 3. 21min on \N/RT3. 21min,., 240 V TLC Rf 0. 6475 (50% Br N EtOAc/Hex) OH OU F OYE orme O un N H RT 1. 90 22 Br (M+H) + 426. 3/428. 2 ZINZIN H 60 Example Structures Characterizationa Method No. Br zon NYN Ao (M+H) 429. 3 242 HO>, NH CH3 RT 2. 17 min 1 b, 1 d TLC Rf 0. 84 H3c, FF0OH (100% EtOAc) A F F Br N NYN O (M+H) + 468. 3 243 NH CH3 RT 2. 27 min B3, 1b, TLC Rf 0. 63 1 d HNC o (100% EtOAc) F OH ZOU F Br H N (/YN' /O NON (M+H) + 424. 4 HN RT 2. 25 min 244 N= : N TLC Rf 0. 66 lb, ld (100% EtOAc) F O F Br H /I N y N4Nnxo NH CH3 (M+H) + 423. 2 HN RT 2. 61 min N-TLC Rf 0. 86 (100% EtOAc) ICH F Zou F Example Structures Characterizationa Method No. Br H Y NYN NH CH3 N (M+H) + 455. 2 RT 2. 10 min 246 HS TLC Rf 0. 73 1 b, 1 d (100% EtOAc) 0 F ZOU F F F H F F H I \ N_N HN tNtNH ((M+H) + 450. 2/452. 1 247 BrA N RT 2. 73 min 1b 1c TLC Rf 0. 5312 (50% EtOAc/Hex) OH OU F F F (M+H) + 422. 3 RT 2. 41 min 248 H TLC Rf 0. 49 (100% 1b 1d N H JSN EtOAc) un H H (M+H) + 421. 4 RT 2. 31 min 249 H TLC Rf 0. 53 (100% 1b, 1d Br N EtOAc) 'N H H Example Structures Characterizationa Method No. NU HN, NH N HN \ I N. CH3 Br N (M+H) + 505. 4 RT 1. 75 min B3, 1b, ou N TLC Rf 0. 063 1 d H (100% EtOAc) Fi O OH 'OH rr HN HN JNH HO Br OU t1 JS (M+H) + 423. 4 RT 2. 00 min B3, 1b, TLC Rf 0. 25 1d (100% EtOAc) O F A F nu /wN, NH HN Br (M+H) + 423. 4 RT 2. 1 min B3, 1 b, TLC Rf 0. 31 lu N H OH (100% EtOAc) 0 FF OH ZU Example Structures Characterization3 Method No. - \ N N HN \ Br N, O. CH (M+H) + 453. 3 t RT 2. 04 min B3, 1b, TLC Rf 0. 19 1 d N N OH H (100% EtOAc) 0 FF OH F F HN Br N 0'CH3 XNlNJaO (M+H) 467. 4 H RT 2. 17 min B3, 1 b, TLC Rf 0. 40 1 d (100% EtOAc) 0 F Y, F N nu HAN w HN NH Br N N, (M+H) + 473. 4 H RT 2. 26 min B3, 1 b, 255 TLC Rf 0. 21 1 d (100% EtOAc) 0 FF F OH F Example Structures Characterization a Method No. H N N / Han \ Br CH3 (M+H) + 566. 2 Ng, N9, 256 tz v RT 1. 78 min BN78c, N19b', TLC Rf 0. 28 N H % (100% EtOAc) 1d H 0 N OH 0 N H CH3 Cl un C.3 Br' (M+H) + 524. 1 N8 N9 RT 2. 00 min'' 257 N H TLC Rf 0. 30 g7c, 1 b, (100% EtOAc) 1d cl) 0 0 FI OH F Y, F Zu C3 t Br N 0 (M+H) + 541. 1 N8, N9, I RT 1. 74 min NN 0 TLC Rf 0. 30 1 d H Q (100% EtOAc) F F0 N OU 0 F Example Structures Characterizationa Method No. CH 3 po HO C3 Bu I RT 1, 92 min RT 1. 92 min'' 259 N H O TLC Rf 0. 31 g7c, 1 b, (100% EtOAc 0 con) FI JE A F --. _ H3C O han CH3 (M+H) + 542. 1 Ber' 260 RT 1. 79 min B7c, 1 b, Hn TLCRfO. 28 '- H (100% EtOAc) F F 0 (N) 0 Cl3 0 O HN CH3 (M+H) + 572. 1 1 TLC Rf 0. 43 g7c, 1 b, -IL 1 (100% EtOAc) " H 0 con) F Jl0 ZOU FF Example Structures Characterization Method No. H /N iN ZON \ N. CH HN rN ICH3 (M+H) + 507. 2 262 Br N NJ RT 1. 60 min lb, ld TLC Rf0. 12 (100% EtOAc) N N H CL MEOH FI CL / HN \/N. CH3 HN (oN, CH3 (M+H) + 463. 2 N N RT1. 80min TLC Rf 0. 23 N H (100% EtOAc) H ZOU FF F A F PO HN//N-CH3 + J3ß0 (M+H) + 481. 2 N NJ RT 1. 74 min 264 TLC Rf 0. 21 lb, ld N N (100% EtOAc) "0 FF F OH F Example Structures Characterizationa Method No. HgCO HN N'CH3 (M+H) + 481. 2 r RT 1. 55 min 265 Br N N TLC Rf 0. 24 lb, ld (100% EtOAc) N H O Fi OH F CH3 po HN w CN, CH3 (M+H) + 511. 2 266 Br+N SNJ RT 2. 02 min 1 b, 1 d I TLC Rf 0. 23 (100% EtOAc) N N H 0 FF OH F F off CH F F (M+H) + 425. 4 RT 2. 36 min 267 HNfa TLC Rf 0. 40 1 b, 1 c Br (1 % TFA/9% I'MeOH/90% CH2cl2) I NN I N, H NH

Example Structures Characterizationa Method No. H Nv NSF N'F JH HN (M+H) + 419. 3 IRT 1. 71 mi'n lb, ld N TLC Rf 0. 22 H (100% EtOAc) H 0 FI A F a LC/MS method used: HPLC-electrospray mass spectra (HPLC ES-MS) for characterization were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120- 1200 amu using a variable ion time according to the number of ions in the source. The eluants were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.018% TFA.

Gradient elution from 10% B to 95% over 3.5 minutes at a flow rate of 1.0 mL/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes.

The structure of each compound in Table 1 is consistent with the analytical data ('H NMR and LC-MS) also presented in the table above.

Table 2 IUPAC Names of Compound Examples Example No. IUPAC Name* 1 N- {5-bromo-4- [ (4-fluorophenyl) amino]-2-pyrimidinyl}-N [3- (1-methyl-1H-pyrazol-3-yl) phenyl] amine hydrochloride 2 N-{5-bromo-4- [ (4-fluorophenyl) amino]-2-pyrimidinyl}-N [3- (1 H-pyrazol-3-yl) phenyl] amine 3 (1 E)-1- [4- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino) phenyl] ethanone oxime 4 N-{5-bromo-2-[(4-{[(4R)-2,2-dimethyl-1,3-dioxolan-4- yl] methoxy} phenyl) amino]-4-pyrimidinyl}-N-(4- fluorophenyl) amine 5 2S)-3- [4- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino) phenoxy] -1, 2-propanediol Example No. IUPAC Name* 6 (2S)-3-[3-({5-bromo-4-[(4-fluorophenyl)amino]-2- pyrimidinyl} amino) phenoxy] -1, 2-propanediol 8 4- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino)-2- (2-hydroxyethoxy) benzoic acid 9 5-bromo-N2-(1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4- yl] methyl}-1H-indol-5-yl)-N4-(4-fluorophenyl)-2, 4- pyrimidinediamine 10 (2S)-3-[5-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl} amino)-1 H-indol-1-yl]-1, 2-propanediol 5-bromo-N2-(4-{[(4R)-2,2-dimethyl-1,3-dioxolan-4- 13 yl] methoxy}phenyl)-N4-(4-fluorophenyl)-2, 4- pyrimidinediamine (2R)-3-[4-({5-bromo-4-[(4-fluorophenyl) amino] -2- 14 pyrimidinyl} amino) phenoxy3-1, 2-propanediol 5-bromo-N2-(3-{[(4R)-2,2-dimethyl-1,3-dioxolan-4- 15 yl] methoxy}phenyl)-N4-(4-fluorophenyl)-2, 4- pyrimidinediamine (S)-3-{3-[5-Bromo-4-(4-fluoro-phenylamino)-pyrimidin-2- 16 ylamino]-phenoxy}-propane-1,2-diol 4-({5-bromo-4-[(4-fluorophenyl) amino] -2- 17 pyrimidinyl}amino)-N-[1-(hydroxymethyl)-3- methylbutyl] benzamide 4-({5-bromo-4-[(4-fluorophenyl) amino] -2- 18 pyrimidinyl} amino)-N- (5-isobutyl-4, 5-dihydro-1, 3-oxazol-2- yl) benzamide N-{5-bromo-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}-N-[4- 19 (5-isobutyl-4, 5-dihydro-1, 3-oxazol-2-yl) phenyl] amine 20 ethyl 3- (4- { [2- ( {2- [2- (diethylamino) ethoxy] -4'-methoxy-1,1'- biphenyl-4-yl} amino)-5-fluoro-4- pyrimfdiny)] amino} phenoxy) benzoate 21 2-chloro-N- (2, 4-dichloro-5-methoxyphenyl)-5-fluoro-4- pyrimidinamine and N- (2, 4-dichloro-5-methoxyphenyl)-N- {2- [(2,4-dichloro-5-methoxyphenyl)amino]-5-fluoro-4- pyrimidinyl} amine Example No. IUPAC Name* 22 N [4- ( {5-chloro-4- [ (4fluorophenyl) amino] -2- pyrimidinyl} amino)-2-methylphenyl] acetamide 23 N-(4-amino-3-methylphenyl)-N-{5-chloro-4-[(4- fluorophenyl) amino]-2-pyrimidinyl} amine 24 IV (4- {5-fluoro-4- [5- (1-methylcyclopropyl)-2H-pyrazol-3- ylamino]-pyrimidin-2-ylamino}-2-methylphenyl)-acetamide 25 N-[2-methyl-4-({5-methyl-4-[(2-methylbenzyl) amino] -2- pyrimidinyl} amino) phenyl]-N- (methylsulfonyl) methanesulfonamide 26 N-[4-({5-bromo-4-[(4-bromophenyl) amino] -2- pyrimidinyl} amino)-2-methylphenyl]-1-methyl-1 H- imidazole-4-sulfonamide 27 N-{5-chloro-4- [ (4-fluorophenyl) amino]-2-pyrimidinyl}-N-(4- {4- [ (4-fluorophenyl) sulfonyl]-1-piperazinyl} phenyl) amine 28 {5-bromo-4-[(4-methoxyphenyl) amino] pyrimidin-2-yl} (4- imidazolyl-3-methylphenyl) amine 29 N-[3-(1H-pyrazol-3-yl)phenyl]-N-[2-{[3-(1H-pyrazol-3- yl) phenyl] amino}-5-(trifluoromethyl)-2-pyrimidinyl] amine 30 2-{[2-[(6-oxo-6H-benzo [c] chromen-2-yl) amino] -5- (trifluoromethyl)-4-pyrimidinyl] amino}-6H benzo [c] chromen-6-one hydrochloride 31 N2,N4-bis[4-(4-morpholinyl)phenyl]-5-(trifluoromethyl)-2, 4- pyrimidinediamine trifluoroacetate 32 N- {5-bromo-4- [ (4-fluorobenzyl) amino]-2-pyrimidinyl}-N [3- (1H-pyrazol-5-yl) phenyl] amine trifluoroacetate 33 5-bromo-N2-[4-(4-ethyl-1-piperazinyl)phenyl]-N4-(4- fluorophenyl)-2, 4-pyrimidinediamine trifluoroacetate 34 N2-(1H-1, 2, 3-benzotriazol-5-yl)-5-bromo-N4-(4- fluorophenyl)-2, 4-pyrimidinediaminehydrochloride (N2- (1 H- 1,2, 3-benzotriazol-5-yl)-5-bromo-N4- (4-fluorophenyl)-2, 4- pyrimidinediaminetrifluoroacetate) 35 N2-(1H-1, 2, 3-benzotriazol-6-yl)-5-fluoro-N4-(4- fluorophenyl)-2, 4-pyrimidinediamine trifluoroacetate Example No. IUPAC Name* 36 N-{5-bromo-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}-N-(1- methyl-1H-1, 2, 3-benzotriazol-6-yl) amine trifluoroacetate 5-bromo-N2-(2-ethyl-2H-1, 2, 3-benzotriazol-5-yl)-N4-(4- fluorophenyl)-2, 4-pyrimidinediamine trifluoroacetate 38 N-{5-bromo-4-[(4-fluorophenyl) amino]-2-pyrimidinyl}-N-[4- (1 H-pyrazol-3-yl) phenyl] amine 39 4- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino)-2-chlorobenzoic acid hydrochloride 40 4- { [4- ( {2- [4- (aminosulfonyl) phenyl] ethyl} amino)-5-bromo- 2-pyrimidinyl] amino} benzoic acid 41 (3-{[4-({2-[4-(aminosulfonyl)phenyl]ethyl} amino) -5-bromo- 2-pyrimidinyl] amino} phenyl) acetic acid dihydrochloride 42 4- { [4- (f2- [4- (aminosulfonyl) phenyl] ethyi) amino) -5-bromo- 2-pyrimidinyl] amino}-3-methoxybenzoic acid dihydrochloride 43 3-{[4-({2-[4-(aminosulfonyl)phenyl]ethyl} amino) -5-bromo- 2-pyrimidinyl] amino} benzoic acid dihydrochloride 44 4- { [4- ( {2- [4- (aminosulfonyl) phenyl] ethyl} amino)-5-bromo- 2-pyrimidinyl] amino}-3-methylbenzoic acid dihydrochloride 45 4- {2- [ (5-bromo-2- { [4- (3-pyridinyloxy) phenyl] amino} -4- pyrimidinyl) amino] ethyl} benzenesulfonamide hydrochloride 46 (2R)-3- [4- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino) phenoxy]-1, 2-propanediol hydrochloride 47 3- [ (5-bromo-4- { [4- (4-morpholinyl) phenyl] amino} -2- pyrimidinyl) amino] benzenesulfonamide trifluoroacetate 48 4-{[4-({2-[4-(aminosulfonyl)phenyl]ethyl}amino)-5-bromo- 2-pyrimidinyl] amino} phenyl) acetic acid hydrochloride 49 4-{[4-({2-[4-(aminosulfonyl)phenyl]ethyl}amino)-5-bromo- 2-pyrimidinyl] amino} benzamide dihydrochloride 50 4-{2-[(5-bromo-2-{[3-(1H-pyrazol-5-yl)phenyl]amino}-4- pyrimidinyl) amino] ethyl} benzenesulfonamide dihydrochloride Example No. IUPAC Name* 51 4- (2- { [5-bromo-2- (2, 3-dihydro-1, 4-benzodioxin-6-ylamino)- 4-pyrimidinyl] amino} ethyl) benzenesulfonamide 52 4- {2- [ (5-bromo-2-f [4- (methylsulfonyl) phenyl] amino} -4- pyrimidinyl) amino] ethyl} benzenesulfonamide hydrochloride 53 4- (2- { [5-bromo-2- (2, 3-dihydro-1, 4-benzodioxin-6-ylamino)- 4-pyrimidinyl] amino} ethyl) benzenesulfonamide hydrochloride 54 N- {5-bromo-4- [ (3-fluorophenyl) amino]-2-pyrimidinyl}-N- [3- (1-methyl-1H-pyrazol-3-yl)phenyl]amine hydrochloride 55 N {5-bromo-4- [ (4-fluorophenyl) amino]-2-pyrimidinyl}-N [4- (4-methyl-1-piperazinyl) phenyl] amine trifluoroacetate 56 N-(2, 4-dichlorophenyl)-N-[2-({2-[2-(diethylamino) ethoxy] - 4'-methoxy-1, 1'-biphenyl-4-yl} amino)-5-fluoro-4- pyrimidinyl] amine 57 3- [3- ( {5-bromo-2- [ (4-fluorophenyl) amino]-4- pyrimidinyl} amino) phenoxy]-1, 2-propanediol hydrochloride 58 N-(2, 4-dichloro-5-methoxyphenyl)-N-[2-({2-[2- (diethylamino) ethoxy] -4'-methoxy-1, 1'-biphenyl-4- yl} amino)-5-fluoro-4-pyrimidinyl] amine 59 N (2, 4-dichloro-5-methoxyphenyl)-N (2- { [3- [2- (diethylamino) ethoxy]-4- (1 H-indol-5-yl) phenyl] amino} -5- fluoro-4-pyrimidinyl) amine 60 N- (1H-1, 2, 3-benzotriazol-5-yl)--(1 H-1, 2, 3-benzotriazol- 6-yl)-5-bromo-2, 4-pyrimidinediamine trifluoroacetate 61 5-chloro-4- [ (4-fluorophenyl) amino]-N- [3- (1 H-pyrazol-5- yl) phenyl]-2-pyrimidinaminium trifluoroacetate 62 N-{5-bromo-4-[(4-fluorophenyl) amino]-2-pyrimidinyl}-N-(2- methyl-2H-indazol-5-yl) amine 63 N-{5-bromo-4-[(4-fluorophenyl)amino]-2-pyimidinyl}-N-(2- methyl-2H-indazol-6-yl) amine 64 4- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino)-2-methoxybenzoic acid compound with trifluoroacetic acid (1: 1) Example No. IUPAC Name* 65 N4-(1H-1, 2, 3-benzotriazol-6-yl)-5-bromo-N2-[4- (trifluoromethyl) phenyl]-2, 4-pyrimidinediamine trifluoroacetate 66 N4-(1H-1, 2, 3-benzotriazol-6-yl)-5-bromo-N2-[3-(1H- pyrazol-4-yl) phenyl]-2, 4-pyrimidinediamine trifluoroacetate 67 N"- (1 H-1, 2, 3-benzotriazol-6-yl)-5-bromo-N- [4- (4- morpholinyl) phenyl]-2, 4-pyrimidinediamine trifluoroacetate 68 4- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino)-N-methoxybenzamide 69 4-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl} amino)-N-hydroxybenzamide 70 (1E)-1-[4-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl} amino) phenyl] ethanone O-methyloxime 71 trifluoroacetic acid compound with N {5-bromo-4- [ (4- fluorophenyl)amino]-2-pyrimidinyl}-N-[3-(3- isoxazolyl) phenyl] amine (1: 1) 72 trifluoroacetic acid compound with N- {5-bromo-4- [ (4- fluorophenyl) amino]-2-pyrimidinyl}-N- [3- (5- isoxazolyl) phenyl] amine (1: 1) 73 N-{5-bromo-4-[(3-fluorophenyl)amino]-2-pyrimidinyl}-N-[3- (3-isoxazolyl) phenyl] amine trifluoroacetate 74 trifluoroacetic acid compound with N {5-bromo-4- [ (3- fluorophenyl)amino]-2-pyrimidinyl}-N-[3-(5- isoxazolyl) phenyl] amine (1: 1) 75 4- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino) phenol hydrochloride 76 3-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl} amino) phenol hydrochloride 77 (1 E)-5- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino) -2, 3-dihydro-1H-inden-1-one oxime trifluoroacetate 78 (1 E)-5-({5-bromo-4-[(4-fluorophenyl) amino]-2- pyrimidinyl} amino) -2, 3-dihydro-1H-inden-1-one O- methyloxime trifluoroacetate Example No. IUPAC Name* 79 1-{[4-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl} amino) phenyl] sulfanyl}-3-(diethylamino)-2- propanol hydrochloride 80 4-({5-bromo-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}amino)-2 - methoxybenzoic acid 81 4- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino)-N- (tetrahydro-2H-pyran-2- yloxy) benzamide 82 5-fluoro-N2-[3-fluoro-4-(4-morpholinyl)phenyl]-N4-(4- fluorophenyl)-2, 4-pyrimidinediamine trifluoroacetate 83 5-chloro-N2-[3-fluoro-4-(4-morpholinyl)phenyl]-N2-(4- fluorophenyl)-2, 4-pyrimidinediamine trifluoroacetate 84 5-bromo-N2-[3-fluoro-4-(4-morpholinyl)phenyl]-N4-[4-(4- morpholinyl) phenyl]-2, 4-pyrimidinediamine trifluoroacetate 85 4- [ (5-bromo-2- { [3-fluoro-4- (4-morpholinyl) phenyl] amino} - 4-pyrimidinyl) amino] benzenesulfonamide trifluoroacetate 86 N2-(1H-1, 2, 3-benzotriazol-5-yl)-5-chloro-N4-(4- fluorophenyl)-2, 4-pyrimidinediamine trifluoroacetate 87 5-bromo-N2~ {2-[2-(diethylamino) ethoxy] -3'-methoxy-1, 1'- biphenyl-4-yl}-N4-(4-fluorophenyl)-2, 4-pyrimidinediamine 88 N- {5-bromo4- [ (4-fluorophenyl) amino]-2-pyrimidinyl}-N- {3- [2- (1 H-imidazol-1-yl) ethoxy]-4-methoxyphenyl} amine 89 5-bromo-N- {3- [2- (diethylamino) ethoxy] -4- methoxyphenyl}-N4-(4-fluorophenyl)-2, 4- pyrimidinediamine 90 4- ( {5-bromo-4- [ (44luorophenyl) amino] -2- pyrimidinyl} amino)-N-hydroxybenzamide trifluoroacetate 91 4-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl} amino)-N-methoxybenzamide trifluoroacetate 92 N- {5-bromo-4- [ (4-fluorophenyl) amino]-2-pyrimidinyl}-N- {4- methoxy-3- [2- (1-pyrrolidinyl) ethoxy] phenyl} amine 93 5-bromo-N- [3- [2- (diethylamino) ethoxy]-4- (8- quinolinyl)phenyl]-N4-(4-fluorophenyl)-2, 4- pyrimidinediamine Example No. IUPAC Name* 94 {4'-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl} amino)-2'-[2-(diethylamino)ethoxy]-1,1'- biphenyl-4-yl} acetonitrile 95 4'-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl}amino)-2'-[2-(diethylamino) ethoxy] -1,1'- biphenyl-3-carbonitrile 96 N- {5-bromo-4- [ (4-fluorophenyl) amino]-2-pyrimidinyl}-N- {4- (1H-indol-5-yl)-3-[2-(1-pyrrolidinyl) ethoxy] phenyl} amine 97 N- {5-bromo-4- [ (4-fluorophenyl) amino]-2-pyrimidinyl}-N- {4- methoxy-3- [2- (4-morpholinyl) ethoxy] phenyl} amine 98 5-bromo-N2-(1-ethyl-1H-indazol-5-yl)-N4-(4-fluorophenyl)- 2,4-pyrimidinediamine 99 N4-(1H-1, 2, 3-benzotriazol-6-yl)-5-bromo-N2-(3, 5- dimethoxyphenyl)-2, 4-pyrimidinediamine hydrochloride 100 N4-(1H-1, 2, 3-benzotriazol-6-yl)-5-bromo-IV- [4- (4- morpholinyl) phenyl]-2, 4-pyrimidinediamine trifluoroacetate 101 5-bromo-N2-{2-[2-(diethylamino) ethoxy] -3'-methoxy-1, 1'- biphenyl-4-yl}-N4-(4-fluorophenyl)-2, 4-pyrimidinediamine 102 5-bromo-N2-{2-[2-(diethylamino) ethoxy] -4'-methoxy-1,1'- biphenyl-4-yl}-N4-(4-fluorophenyl)-2,4-pyrimidinediamine 103 5-bromo-N2-{1-[2-(diethylamino)ethyl]-1H-indol-5-yl}-N4-(4- fluorophenyl)-2, 4-pyrimidinediamine 104 5-bromo-N2-(1-ethyl-1H-indazol-5-yl)-N4-(4-fluorophenyl)- 2,4-pyrimidinediamine 105 (2R)-3- [3- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino) phenoxy]-1, 2-propanediol 106 (2S)-3-[5-({5-bromo-4-[(4-methoxyphenyl)amino]-2- pyrimidinyl}amino)-1H-indol-1-yl]-1,2-propanediol 107 5- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino)-1 H-indole-3-carboxamide trifluoroacetate 108 N-(4-amino-3-methylphenyl)-N-{4-[(4- chlorophenyl) amino]-5-fluoro-2-pyrimidinyl} amine Example No. IUPAC Name* 109 N-(4-amino-3-methylphenyl)-N-{4-[(4- bromophenyl) amino]-5-fluoro-2-pyrimidinyl} amine 110 N-(4-amino-3-methylphenyl)-N-{4-[(2, 4- dichlorobenzyl) amino]-5-fluoro-2-pyrimidinyl} amine N- [5-bromo-2- ( {4'- (dimethylamino)-2- [2- (l- pyrrolidinyl) ethoxy]-1, 1'-biphenyl-4-yl} amino) -4- pyrimidinyl]-N- (4-fluorophenyl) amine 113 N2-(1H-benzimidazol-5-yl)-N4-(1H-1, 2, 3-bnzotriazol-6-yl)- 5-bromo-2, 4-pyrimidinediamine trifluoroacetate 114 5-bromo-N"- (1-methyl-1H-1, 2, 3-benzotriazol-5-yl)-N- [4- (4-morpholinyl) phenyl]-2, 4-pyrimidinediamine trifluoroacetate 115 5-bromo-N4-(1-methyl-1H-1, 2, 3-benzotriazol-6-yl)-N2-[4- (4-morpholinyl) phenyl]-2, 4-pyrimidinediamine trifluoroacetate 116 5-chloro-N" (4-fluorophenyl)-N- [4- (1 H-pyrazol-3- yl) phenyl]-2, 4-pyrimidinediamine trifluoroacetate 117 N4-(1H-1, 2, 3-benzotriazol-5-yl)-5-bromo-N2-(1H-indol-5- yl)-2, 4-pyrimidinediaminetrifluoroacetate 118 5-bromo-N2-[2-[2-(diethylamino) ethoxy] -4'- (trifluoromethyl)-1, 1'-biphenyl-4-yl]-N4- (4-fluorophenyl)- 2,4-pyrimidinediamine 119 N-[4-({5-fluoro-4-[(3-fluorophenyl)amino]-2- pyrimidinyl} amino)-2-methylphenyl] acetamide 120 N [4- ( {5-fluoro-4- [ (4-methylphenyl) amino]-2- pyrimidinyl} amino)-2-methylphenyl] acetamide 121 N [4- ( {5-fluoro-4- [ (4-methylphenyl) amino]-2- pyrimidinyl} amino)-2-methylphenyl] acetamide 122 (1) N-(4-aminopheyl)-N-{5-bomo-4-[(2- methyfbenzyl) amino]-2-pyrimidinyl} amine 123 N'- [4- ( {5-bromo-4- [ (4-bromophenyl) amino] -2- pyrimidinyl} amino)-2-methylphenyl]-N, N- dimethylsulfamide Example No. IUPAC Name* 124 N [2-chloro-4- ( {5-fluoro-4- [ (3-methoxyphenyl) amino] -2- pyrimidinyl} amino) phenyl] acetamide 125 N- [4- ( {5-bromo-4- [ (4-bromophenyl) amino] -2- pyrimidinyl} amino)-2-methylphenyl] acetamide 126 N-[4-({5-bromo-4-[(4-chlorophenyl) amino] -2- pyrimidinyl} amino)-2-methylphenyl] acetamide 127 N-[4-({5-bromo-4-{(4-chlorophenyl) amino] -2- pyrimidinyl} amino)-2-chlorophenyl] acetamide 128 N-{5-fluoro-4-[(4-methylphenyl)amino]-2-pyrimidinyl}-N-[4- (4-methyl-1-piperazinyl) phenyl] amine 129 N-(4-bromophenyl)-N-(5-fluoro-2-{[4-(4-methyl-1- piperazinyl) phenyl] amino}-4-pyrimidinyl) amine 130 N-(4-amino-3-methylphenyl)-N-{5-fluoro-4-[(4- methylphenyl) amino]-2-pyrimidinyl} amine 131 N-(4-amino-3-methylphenyl)-N-{5-fluoro-4-[(3- fluorophenyl) amino]-2-pyrimidinyl} amine 132 N-[5-fluoro-2-(1H-indol-5-ylamino)-4-pyrimidinyl]-N-(3- methoxyphenyl) amine 133 5- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino)-2- (1 H-pyrazol-3-yl) phenol 134 N-(4-chlorophenyl)-N-(5-fluoro-2-{[4-(1- piperidinyl) phenyl] amino}-4-pyrimidinyl) amine 135 4- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino)-N-(2-hydroxyethyl) benzamide 4- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino)-N-(2-hydroxyethyl) benzamide 136 4- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino)-N'-(cyanoacetyl) benzohydrazide 137 N- {5-bromo-4- [ (4-fluorophenyl) amino]-2-pyrimidinyl}-N- [3- (1H-imidazol-1-yl methyl) phenyl] amine 138 N- {5-bromo-4- [ (3-fluorophenyl) amino]-2-pyrimidinyl}-N- [3- (1-methyl-1H-pyrazol-5-yl) phenyl] amine hydrochloride 139 N-(1H-indol-5-yl)-N-{5-methyl-4-[(2-methylbenzyl) amino] - 2-pyrimidinyl} amine Example No. IUPAC Name* 140 N-{5-bromo-4-[(2, 5-dichlorobenzyl) amino]-2-pyrimidinyl}- N (1H-indol-5-yl) amine 141 N- [4- ( {5-bromo-4- [ (4-chlorophenyl) amino] -2- pyrimidinyl} amino) phenyl] acetamide 142 N [4- ( {5-chloro-4- [ (2-methylbenzyl) amino] -2- pyrimidinyl} amino)-2-methylphenyl]-N- (methylsulfonyl) methanesulfonamide 143 N-[2-methyl-4-({5-methyl-4-[(2-methylbenzyl) amino] -2- pyrimidinyl} amino) phenyl] methanesulfonamide 144 N-(2-methylbenzyl)-N-(5-methyl-2-{[4-(4-methyl-1- piperazinyl) phenyl] amino}-4-pyrimidinyl) amine 145 N (2-methylbenzyl)-N- {5-methyl-2- [ (1-methyl-1H-indol-5- yl) amino]-4-pyrimidinyl} amine 146 N- [4- (l H-imidazol-1-yl) phenyl]-N- {5-methyl-4- [ (2- methylbenzyl) amino]-2-pyrimidinyl} amine 147 N-(4-amino-3-methylphenyl)-N-{4-[(3- chlorophenyl) amino]-5-fluoro-2-pyrimidinyl} amine 148 4-({5-bromo-4-[(4-methoxyphenyl) amino] -2- pyrimidinyl} amino)-N-methylbenzamide 149 (1E)-6-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl} amino) -3, 4-dihydro-1 (2H)-naphthalenone O- methyloxime 150 5'-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl) amino)-2'- (4-methyl-l-piperazinyl)-1, 1'- biphenyl-4-carbonitrile 151 N-{5-bromo-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}-N-(1- methyl-1 H-indol-5-yl) amine 152 N-{5-bromo-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}-N-(1- propyl-1 H-indol-5-yl) amine 153 4- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino)-N-(2,3-dihydroxypropyl) benzamide 154 N-(5-bromo-2-{[4-(1H-imidazol-1-yl)phenyl] amino} -4- pyrimidinyl)-N-(4-methoxyphenyl) amine Example No. IUPAC Name* 155 5-bromo-N4-(4-fluorophenyl)-N2-(4-(4-methyl-1- piperazinyl)-3-{[2-(4-morpholinyl)ethyl] amino} phenyl)-2, 4- pyrimidinediamine 156 N-{5-bromo-4-[(4-bromophenyl)amino]-2-pyrimidinyl}-N-[4- (4-methyl-1-piperazinyl) phenyl] amine 157 N [4- ( {5-bromo-4- [ (2-chlorobenzyl) amino] -2- pyrimidinyl} amino)-2-methylphenyl]-N- (methylsulfonyl) methanesulfonamide 158 N- {5-bromo-4- [ (4-fluorophenyl) amino]-2-pyrimidinyl}-N- [3- (1-methyl-1 H-pyrazol-5-yl) phenyl] amine 159 5-bromo-N4- (4-methoxyphenyl)-N2- [3- (1-methyl-1 H- pyrazol-5-yl) phenyl]-2, 4-pyrimidinediamine 160 5-({5-bromo-4-[(4-methoxyphenyl) am ino]-2- pyrimidinyl} amino)-2- (1 H-pyrazol-3-yl) phenol 161 5-bromo-N2-[4-(4-ethyl-1H-pyrazol-3-yl)phenyl]-N4-(4- fluorophenyl)-2, 4-pyrimidinediamine 162 5-bromo-N2- [4- (4-ethyl-1 H-pyrazol-3-yl) phenyl]-N4- (3- fluorophenyl)-2, 4-pyrimidinediamine 163 3-{[5-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl} amino)-2-methoxybenzyl] amino} -1,2- propanediol 164 N-{5-bromo-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}-N-(4- methoxy-3- { [2- (4-morpholinyl) ethoxy] methyl} phenyl) amine 165 (2R)-3-[5-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl}amino)-1H-indol-1-yl]-1,2-propanediol 166 N-[4-({5-bromo-4-[(4-bromophenyl) amino] -2- pyrimidinyl} amino)-2-methylphenyl]-N- (methylsulfonyl) methanesulfonamide 167 N [4- ( {4- [ (3-chlorophenyl) amino]-5-fluoro-2- pyrimidinyl} amino)-2-methylphenyl] methanesulfonamide 168 N [4- ( {5-fluoro-4- [ (4-methylphenyl) amino] -2- pyrimidinyl} amino)-2-methylphenyl] methanesulfonamide 169 (2R)-3- [5- ( {5-bromo-4- [ (4-methoxyphenyl) amino] -2- pyrimidinyl} amino)-1 H-indol-1-yl]-1, 2-propanediol Example No. IUPAC Name* 170 N-{5-bromo-4-[(4-fluorophenyl)amono]-2-pyrimidinyl}-N-[4- (1-pyrrolidinylmethyl) phenyl] amine 171 N- {5-bromo-4- [ (4-fluorophenyl) amino]-2-pyrimidinyl}-N- [3- (1-pyrrolidinylmethyl) phenyl] amine 172 N-[5-bromo-2-({4'-(dimethylamino)-2-[2-(1H-imidazol-1- yl) ethoxy]-1, 1'-biphenyl-4-yl} amino)-4-pyrimidinyl]-N- (4- fluorophenyl) amine 173 N-{5-bromo-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}-N-[4- (5-methyl-1, 3, 4-oxadiazol-2-yl)phenyl]amino 174 5-bromo-N- (4, 5-dihydro-2H-benzo [g] indazol-7-yl)-N4-(4- fluorophenyl)-2, 4-pyrimidinediamine 175 5-bromo-N2-(4, 5-dihydro-2H-benzo [g] indazol-7-yl)-N4-(3- fluorophenyl)-2, 4-pyrimidinediamine 176 5-bromo-N2-(4, 5-dihydro-2H-benzo [g] indazol-7-yl)-N- (4- methoxyphenyl)-2, 4-pyrimidinediamine 177 N [4- ( {5-bromo-4- [ (4-chlorophenyl) amino] -2- pyrimidinyl} amino)-2-methylphenyl]-N- (methylsulfonyl) methanesulfonamide 178 N-{4-[(5-bromo-4-{[4-(4-morpholinyl)phenyl]amino}-2- pyrimidinyl) amino]-2-methylphenyl}-N- (methylsulfonyl) methanesulfonamide 179 N-(4-amino-3-methylphenyl)-N-{5-bromo-4-[(4- chlorophenyl) amino]-2-pyrimidinyl} amine 180 N [4- ( {5-chloro-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino)-2-methylphenyl] methanesulfonamide 181 N- [4- ( {5-chloro-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino)-2-methylphenyl]-N- (methylsulfonyl) methanesulfonamide 182 N [4- ( {5-bromo-4- [ (2-chlorobenzyl) amino] -2- pyrimidinyl} amino)-2-chlorophenyl]-N- (methylsulfonyl) methanesulfonamide 183 N- {5-bromo-4- [ (4-fluorophenyl) amino]-2-pyrimidinyl}-N- [4- (1 H-imidazol-1-ylmethyl) phenyl] amine Example No. IUPAC Name* 184 N-[4-({5-fluoro-4-[(4-methylphenyl) amino] -2- pyrimidinyl} amino)-2-methylphenyl] methanesulfonamide 185 N-{5-bromo-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}-N-[3- methoxy-4- (4-pyridinyl) phenyl] amine 186 N [4- ( {5-bromo-4- [ (4-chlorophenyl) amino]-2- pyrimidinyl} amino)-2-methylphenyl]-1-methyl-1 H- imidazole-4-sulfonamide 187 N [4- ( {5-bromo-4- [ (4-chlorophenyl) amino] -2- pyrimidinyl} amino)-2-methylphenyl]-1-methyl-1 H- imidazole-4-sulfonamide 188 N [4- ( {5-bromo-4- [ (4-chlorophenyl) amino] -2- pyrimidinyl} amino)-2-methylphenyl]-N- (methylsulfonyl) methanesulfonamide 189 N [4- ( {5-bromo-4- [ (4-chlorophenyl) amino] -2- pyrimidinyl} amino)-2-methylphenyl] methanesulfonamide 190 N [3- (1, 3-benzodioxol-5-yl)-4- (4-methyl-1- piperazinyl) phenyl]-N- {5-bromo-4- [ (4-fluorophenyl) amino] - 2-pyrimidinyl} amine 191 N-[4-({4-[(2,4-dichlorophenyl)amino]-5-fluoro-2- pyrimidinyl} amino)-2-methylphenyl]-N- (methylsulfonyl) methanesulfonamide 192 N-[5-({[4-({5-chloro-4-[(2-methylbenzyl) amino] -2- pyrimidinyl} amino)-2-methylphenyl] amino} sulfonyl)-4- methyl-1, 3-thiazol-2-yl] acetamide 193 N-[4-(4-acetyl-1-piperazinyl)phenyl]-N-{5-chloro-4-[(4- fluorophenyl) amino]-2-pyrimidinyl} amine 194 N (2-chlorobenzyl)-N- (5-methyl-2- { [4- (1- piperazinyl) phenyl] amino}-4-pyrimidinyl) amine 195 (2R)-3- {5- [ (5-bromo-2- { [4- (1H-pyrazol-3-yl) phenyl] amino} - 4-pyrimidinyl) amino]-1 H-indol-1-yl}-1, 2-propanediol 196 N-{5-bromo-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}-N-[3- (4-morpholinylmethyl) phenyl] amine 197 N- {5-bromo-4- [ (4-fluorophenyl) amino]-2-pyrimidinyl}-N- [3- (1 H-imidazol-1-ylmethyl)-4-methoxyphenyl] amine Example No. IUPAC Name* 198 N- {5-chloro-4- [ (4-fluorophenyl) amino]-2-pyrimidinyl}-N [4- (1-piperazinyl) phenyl] amine 199 N- {5-bromo-4- [ (4-fluorophenyl) amino]-2-pyrimidinyl}-N- [4- methoxy-3- (4-morpholinylmethyl) phenyl] amine 200 N- {5-bromo-4- [ (3-fluorophenyl) amino]-2-pyrimidinyl}-N- {3- [2- (l H-imidazol-1-yl) ethoxy]-4-methoxyphenyl} amine 201 N-[5-bromo-({3-[2-(1H-imidazol-1-yl) ethoxy] -4- methoxyphenyl} amino)-4-pyrimidinyl]-N- (4- methoxyphenyl) amine 202 N- {5-bromo-4- [ (1-methyl-1 H-indol-5-yl) amino]-2- pyrimidinyl}-N-[4-(1H-pyrazol-3-yl)phenyl] amine 203 5-bromo-N- (4, 5-dihydro-2H-benzo [g] indazol-7-yl)-N4-(1- methyl-1 H-indol-5-yl)-2, 4-pyrimidinediamine 204 5-({5-bromo-4-[(4-methoxyphenyl) amino] -2- pyrimidinyl} amino) -1, 3-dihydro-2H-benzimidazol-2-one 205 N'-acetyl-4-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl} amino) benzohydrazide 206 N- [ (3aS)-2, 3,3a, 4-tetrahydro-1 H-pyrrolo [2, 1- c] [1,4] benzoxazin-7-yl]-N-{5-bromo-4- [ (4- fluorophenyl) amino]-2-pyrimidinyl} amine 207 4- [ (5-bromo-2- { [3-fluoro-4- (4-morpholinyl) phenyl] amino)- 4-pyrimidinyl) amino] benzenesulfonamide trifluoroacetate 208 N (2-chlorobenzyl)-N [5-methyl-2- ( {4- [4- (methylsulfonyl)- 1-piperazinyl] phenyl} amino)-4-pyrimidinyl] amine 209 N (2-chlorobenzyl)-N- (5-methyl-2- { [4- (1, 2, 3-thiadiazol-4- yl)phenyl]amino}-4-pyrimidinyl)amine 210 5-bromo-N4-[3-(1H-pyrazol-3-yl)phenyl]-N2-[4-(1H-pyrazol- 3-yl)phenyl]-2,4-pyrimidinediamine trifluoroacetate 211 N2-(1H-1,2,3-benzotriazol-5-yl)-5-bromo-N4-[3-(1H- pyrazol-3-yl) phenyl]-2, 4-pyrimidinediamine trifluoroacetate 212 5-bromo-N2-(1H-indazol-5-yl)-N4-[3-(1H-pyrazol-3- yl) phenyl]-2, 4-pyrimidinediamine trifluoroacetate Example No. IUPAC Name* 213 5-[(5-bromo-4-{[3-(1H-pyrazol-3-yl)phenyl]amino}-2- pyrimidinyl) amino]-1 H-benzimidazole-2-thiol trifluoroacetate 214 N-[2-methyl-4-({5-methyl-4-[(2-methylbenzyl) amino] -2- pyrimidinyl} amino) phenyl] acetamide 215 N-(4-amino-3-methylphenyl)-N-{5-methyl-4-[(2- methylbenzyl) amino]-2-pyrimidinyl} amine 216 1- [4- ( {5-bromo-4- [ (4-f (uoropheny)) amino]-2- pyrimidinyl} amino)-2-fluorophenyl]-3-piperidinecarboxylic acid trifluoroacetate 217 methyl 4- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino)-2- (2-hydroxyethoxy) benzoate 218 4- ( {5-bromo-4- [ (4-fluorophenyl) amino] -2- pyrimidinyl} amino)-2- (2-hydroxyethoxy) benzoic acid 219 5-bromo-N2- {4-methoxy-3- [2- (4- morpholinyl) ethoxy] phenyl}-N4- (4-methoxyphenyl)-2, 4- pyrimidinediamine trifluoroacetate 220 4- [ (5-fluoro-4- { [3- (1 H-pyrazol-3-yl) phenyl] amino}-2- pyrimidinyl) amino] phenol trifluoroacetate 221 3- [ (5-fluoro-4- { [3- (l H-pyrazol-3-yl) phenyl] amino} -2- pyrimidinyl) amino] phenol trifluoroacetate 222 5-[(5-fluoro-4-{[3-(1H-pyrazol-3-yl)phenyl] amino} -2- pyrimidinyl) amino]-2-methoxyphenol trifluoroacetate 223 5-fluoro-N2-(1H-indazol-5-yl)-N4-[3-(1H-pyrazol-3- yl) phenyl]-2, 4-pyrimidinediamine trifluoroacetate 224 N-[5-bromo-2- ( H-indazol-5-ylamino)-4-pyrimidinyl]-N- (1 H-indol-5-yl) amine 225 N-(1H-1, 2, 3-benzotriazol-5-yl)-N [5-bromo-4- (1H-indol-4- ylamino)-2-pyrimidinyl] amine 226 N- [5-bromo-2- ( 1 H-indazol-5-ylamino)-4-pyrimidinyl]-N- (1H-indol-4-yl) amine 227 N-(4-amino-3-methylphenyl)-N-{5-brmo-4-[(4- methoxyphenyl) amino]-2-pyrimidinyl} amine Example No. IUPAC Name* 228 N- {5-bromo-4- [ (4-fluorophenyl) amino]-2-pyrimidinyl}-N- {3- methoxy-4- [2- (4-morpholinyl) ethoxy] phenyl} amine 229 (5-chloro-4- [ (4-fluorophenyi) amino] pyrimidin-2-yl} (4- imidazolyl-3-methylphenyl) amine 230 (4-imidazolyl-3-methylphenyl)[5-methyl-4-({[2- (trifluoromethyl) phenyl] methyl} amino) pyrimidin-2-yl] amine 231 (4-{[5-chloro-4-({[2- (trifluoromethyl) phenyl] methyl} amino) pyrimidin-2- yl] amino}-2-(trifluoromethyl)phenyl][(1-methylimidazol-4- yl) sulfonyl] amine 232 [ (l-methytimidazol-4-yl) sulfonyl] (2-methyl-4- { [5-methyl-4- ({[2-(trifluoromethyl]phenyl]methyl} amino) pyrimidin-2- yl] amino} phenyl) amine 233 4-({5-bromo-4-[(3-ethynylphenyl) amino] -2- pyrimidinyl} amino) phenol trifluoroacetate 234 5-({5-bromo-4-[(3-ethynylphenyl) amino] -2- pyrimidinyl} amino)-2-methoxyphenol trifluoroacetate 235 5-bromo--(3, 4-dimethoxyphenyl)-N4-(3-ethynylphenyl)- 2, 4-pyrimidinediamine trifluoroacetate 236 5-bromo-N4-(3-ethynylphenyl)-N2-[4-(4- morpholinyl) phenyl]-2, 4-pyrimidinediaminetrifluoroacetate 237 N2-(1H-1, 2, 3-benzotriazol-5-yl)-5-bromo-N4-(3- ethynylphenyl)-2, 4-pyrimidinediamine 238 5-bromo-N'- (3-ethynylphenyl)-N- (1 H-indazol-5-yl)-2, 4- pyrimidinediamine trifluoroacetate 239 5- ( {5-bromo-4- [ (3-ethynylphenyl) amino]-2- pyrimidinyl} amino)-1 H-benzimidazol-2-ylhydrosulfide trifluoroacetate 240 5-bromo-N- [4- (4-morpholinyl) phenyl]-N4- [4- (trifluoromethyl) phenyl]-2, 4-pyrimidinediamine trifluoroacetate 241 5- ( {5-bromo-4- [ (4-methoxyphenyl) amino] pyrimidin-2- yl} amino) indolin-2-one Example No. IUPAC Name* 242 1- [4- ( {5-bromo-2- [ (3-hydroxy-4-methoxyphenyl) amino] -4- pyrimidinyl} amino) phenyl] ethanone trifluoroacetate 243 1-{4-[(5-bromo-2-{[4-(1H-pyrazol-3-yl)phenyl] amino} -4- pyrimidinyl) amino] phenyl} ethanone trifluoroacetate 244 1-(4-{[2-(1H-1, 2, 3-benzotriazol-5-ylamino)-5-bromo-4- pyrimidinyl] amino} phenyl) ethanone trifluoroacetate 245 1- (4- { [5-bromo-2- (l H-indazol-5-ylamino)-4- pyrimidinyl] amino} phenyl) ethanone trifluoroacetate 246 1- [4- ( {5-bromo-2- [ (2-sulfanyl-1 H-benzimidazol-5- yl) amino]-4-pyrimidinyl} amino) phenyl] ethanone trifluoroacetate 247 N2-(1H-1, 2, 3-benzotriazol-5-yl)-5-bromo-N4-[4- (trifluoromethyl) phenyl]-2, 4-pyrimidinediamine trifluoroacetate 248 N-(1H-1, 2, 3-benzotriazol-5-yl)-N-[5-bromo-4-(2, 3-dihydro- 1 H-inden-5-ylamino)-2-pyrimidinyl] amine 249 N-[5-bromo-4-(2, 3-dihydro-1 H-inden-5-ylamino)-2- pyrimidinyl]-N (1H-indazol-5-yl) amine 250 5-bromo-N2- [4- (4-methyl-1-piperazinyl) phenyl]-N4- [4- (1H- pyrazol-3-yl) phenyl-2, 4-pyrimidinediamine trifluoroacetate 251 4-[(5-bromo-4-{[4-(1H-pyrazol-3-yl)phenyl] amino} -2- pyrimidinyl) amino] phenol trifluoroacetate 252 3- [ (5-bromo-4- { [4- (l H-pyrazol-3-yl) phenyl] amino)-2- pyrimidinyl) amino] phenol trifluoroacetate 253 5-[(5-bromo-4-{[4-(1H-pyrazol-3-yl)phenyl]amino}-2- pyrimidinyl) amino]-2-methoxyphenol trifluoroacetate 254 5-bromo-N2-(3,4-dimethoxyphenyl)-N4-[4-(1H-pyrazol-3- yl) phenyl]-2, 4-pyrimidinediamine trifluoroacetate 255 5-bromo-N2,N4-bis[4-(1H-pyrazol-3-yl)phenyl]-2, 4- pyrimidinediamine trifluoroacetate 256 5-bromo--{4-methoxy-3-[2-(4- morpholinyl) ethoxy] phenyl}-N4-[3-(1H-pyrazol-3- yl) phenyl]-2, 4-pyrimidinediamine trifluoroacetate Example No. IUPAC Name* 257 5-bromo-N4-(3-ethynylphenyl)-N2-{4-methoxy-3-[2-(4- morpholinyl) ethoxy] phenyl}-2, 4-pyrimidinediamine trifluoroacetate 258 5-bromo-N4-(1H-indol-5-yl)-N2-{4-methoxy-3-[2-(4- morpholinyl) ethoxy] phenyl}-2, 4-pyrimidinediamine trifluoroacetate 259 5-bromo-N- {4-methoxy-3- [2- (4- morpholinyl) ethoxy] phenyl)-N4- [3- (l H-pyrazol-3- yl) phenyl]-2, 4-pyrimidinediamine trifluoroacetate 260 1- (3- { [5-bromo-2- ( {4-methoxy-3- [2- (4- morpholinyl) ethoxy] phenyl} amino) -4- pyrimidinyl] amino} phenyl) ethanone trifluoroacetate 261 1-(4-{[5-bromo-2-({4-methoxy-3-[2-(4- morpholinyl) ethoxy] phenyl} amino) -4- pyrimidinyl] amino} phenyl)-1-butanone trifluoroacetate 262 5-bromo-N2-[4-(4-methyl-1-piperazinyl)phenyl]-N4-[3-(1H- pyrazol-3-yl) phenyl]-2, 4-pyrimidinediamine trifluoroacetate 263 5-bromo-N4-(3-ethynylphenyl)-N2-[4-(4-methyl-1- piperazinyl) phenyl]-2, 4-pyrimidinediamine trifluoroacetate 264 1- {4- [ (5-bromo-2- { [4- (4-m ethyl-1- piperazinyl) phenyl] amino}-4- pyrimidinyl) amino] phenyl} ethanone trifluoroacetate+C11 265 1-{3-[(5-bromo-2-{[4-(4-methyl-1- piperazinyl) phenyl] amino} -4- pyrimidinyl) amino] phenyl} ethanone trifluoroacetate 266 1-{4-[(5-bromo-2-{[4-(4-methy-1- piperazinyl) phenyl] amino}-4-pyrimidinyl) amino] phenyl}-1- butanone trifluoroacetate 267 N-{5-bromo-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}-N-[3- (1 H-pyrazol-3-yl) phenyl] amine trifluoroacetate 268 5- [ (5-fluoro-4- { [3- (l H-pyrazol-3-yl) phenyl] amino} -2- pyrimidinyl) amino]-1 H-benzimidazole-2-thiol trifluoroacetate Example No. IUPAC Name* 112 4-{[4-(1 H-1, 2, 3-benzotriazol-6-ylamino)-5-bromo-2- pyrimidinyl] amino} benzenecarboximidamide trifluoroacetate

*The IUPAC Names were obtained using the ACD/ILab Web service.

The compounds of this invention may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration or (R, S) configuration. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. Substituents on a ring may also be present in either cis or trans form, and a substituent on a double bond may be present in either Z or E form. It is intended that all such configurations (including enantiomers and diastereomers) are included within the scope of the present invention. Preferred compounds are those with the absolute configuration of the compound of this invention which produces the more desirable biological activity. Separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention.

The use of pharmaceutical acceptable salts of the compounds of Formula I are also within the scope of this invention. The term"pharmaceutically acceptable salt"refers to either inorganic or organic acid or base salts of a compound of the present invention that have properties acceptable for the therapeutic use intended. For example, see S. M.

Berge, et al."Pharmaceutical Salts,"J. Pharm. Sci. 1977,66, 1-19.

Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts that are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleat, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylat, and undecanoate. The term acid addition salts also comprises the hydrates and the solvent addition forms which the compounds of this invention are able to form. Examples of such forms are, for example,

hydrates, alcoholates and the like.

Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, and dibutyl sulfate ; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides including benzyl and phenethyl bromides, and others.

Unless the context clearly indicates to the contrary, whenever the term "compounds of this invention, ""compounds of the present invention", and the like, are used herein, they are intended to include the chemically feasible pharmaceutically acceptable salts and/or esters as well as all stereoisomeric forms of the referenced compounds.

Method of making the compounds of the present invention In general, the compounds used in this invention may be prepared by standard techniques known in the art, by known processes analogous thereto, and/or by the processes described herein, using starting materials which are either commercially available or producible according to routine, conventional chemical methods. The following preparative methods are presented as an example of the synthesis of the compounds of the present invention.

General Experimental Procedures The compounds of this invention can be synthesized according to the general method of Reaction Scheme 1 described below.

Reaction Scheme 1 General Method of Preparation of Compounds of Formula (I) R4 Step 1. NH2 R5 R3 CI (CH) o-2 R5 R6 base, CH R R R e. g., NaOAc) (CH2) 0-2 6 + 4 7 HN X + R i# R R R3 THF/H2O tNACI N CRI Intermediate A Intermediate B Intermediate C Step 2. R4 R4 R5 R3 R5 R3 1 1 /Y (CH2) o. 2 NH2 (CH2) o-2 R$ R8 HCI, t-BuOH R9 X R 2 X"lN : RUZ N CI R N N R2 H Intermediate C Intermediate D

In Reaction Scheme 1, the R1-R9 and X groups have the same meaning as defined above for Formula I. In general, compounds of Formula (I) can be prepared in two steps. In the first step, a dichloropyrimidine, (Intermediate A), is allowed to react with an optionally substituted aniline or phenylalkylamine (Intermediate B) in the presence of a basic catalyst to give Intermediate C. In step two, Intermediate C is allowed to react with an aniline, represented as Intermediate D, in the presence of an acid catalyst.

Where Intermediates A or D are not commercially available, they may be prepared by methods well known in the art or by those methods specifically described below for the preparation of intermediates.

Using the above general methods, the specific procedures described below, together with the knowledge of one skilled in the art, all of compounds of Formula I may be prepared.

The following specific examples are presented to further illustrate the invention described herein, but they are not intended, nor should they be construed, to limit the scope of the invention in any way.

Abbreviations and Acronyms When the following abbreviations are used herein, they have the following meaning: AcOH acetic acid AgOTf silver trifluoromethanesulfonate AlMe3 trimethylaluminum abs absolute AmmOH Ammonium Hydroxide BH3THF borane-tetrahydrofuran complex BOC teff-butoxywarbonyl n-BuLi butyllithium n-BuOH 1-butanol t-BuOH tert-butyl alcohol CBr4 carbon tetrabromide CD30D methanol-d4 CDCI3 chloroform-d Celite diatomaceous earth filtering agent, registered trademark of Celite Corp.

DCE 1, 2-dichloroethane dH20 de-ionized water DMAP 4-dimethylaminopyridine DMF N, N-dimethylformamide DMSO dimethylsulfoxide dppp 1,3-bis (diphenylphosphino) propane EDCI 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride equiv equivalent (s) EPA vial A 40 mL vial sold by Fisher Scientific and other common laboratory supply vendors ESI-MS electrospray ionization mass spectrometry Et3N triethylamine EtOAc ethyl acetate Et2O diethyl ether EtOH ethanol

HEPES 4-(2-hydroxyethyl)-1-piperazineethane-sulfonic acid HEX hexanes 1H NMR proton nuclear magnetic resonance HPLC high performance liquid chromatography i-PA iso-Propyl alcohol J-Kem Block A parallel synthesis block sold by J-Kem, Inc.

KOAc potassium acetate KOH potassium hydroxide LC/MS liquid chromatography/mass spectroscopy LiAIH4 lithium aluminum hydride mCPBA 3-chloroperoxybenzoic acid MeOH methanol MMTV murine mammary tumor virus MS ES mass spectrometry with electrospray NaBH (OAc) 3 sodium triacetoxyborohydride NaCNBH3 sodium cyanoborohydride NaOAc sodium acetate NaOH sodium hydroxide NMM N-methylmorpholine Pd/C palladium on carbon Pd (dppf) C ! 2 [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium(II) Pd (OAc) 2 palladium (II) acetate Pd (PPh3) 4 tetrakis (triphenylphosphine) palladium (0) PS-NCO polystyrene isocyanate Rf TLC retention factor rt room temperature SnCl2 tin (II) chloride TFA trifluoroacetic acid THF tetrahydrofuran TMSCI chlorotrimethylsilane TMSCN trimethylsilyl cyanide TLC thin layer chromatography RT retention time (HPLC) Unless otherwise stated, the term'concentrated under reduced pressure'refers to use of a Buchi rotary evaporator at approximately 15 mm of Hg.

Thin-layer chromatography (TLC) was performed on Whatman@ pre-coated glass- backed silica gel 60A F-254 250 pm plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, and/or (d) immersion of the plate in a cerium sulfate solution followed by heating. Column chromatography (flash chromatography) was performed using 230- 400 mesh EM Science@ silica gel.

Proton (1H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me4Si (6 0.00) or residual protonated solvent (CHCI3 8 7.26 ; MeOH 8 3.30 ; DMSO & 2.49) as standard.

Carbon (13C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC13 6 77.0 ; d3-MeOD ; 8 49.0 ; d6-DMSO 8 39.5) as standard.

HPLC-electrospray mass spectra (HPLC ES-MS) for characterization were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluants were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.018% TFA. Gradient elution from 10% B to 95% over 3.5 minutes at a flow rate of 1.0 mL/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes.

Preparative HPLC, when used, was run using either a Gilson 215 Liquid Handler with a Gilson 322 pump and a Gilson UV-VIS-155 detector set at 254 nm or a Shimadzu LC-8A pump with a Shimadzu SPD-10A detector set at 220 nM both equipped with a YMC Pac ProC18 column (150 x 20 mm). Alternatively, a YMC Pac ProC18 75 x 30 mm column was used with the Gilson HPLC. Eluant A is acetonitrile with 0.01% of trifluoroacetic acid and Eluant B is water with 0. 01% trifluoroacetic acid. Typically, a gradient was run from 10% A/90% B to 90% A/10% B over a period of 15-25 min. The fractions of interest were collected and the solvent removed in vacuo to give the final compound as a trifluoroacetic acid salt.

Preparation of Nitroarene Starting Materials Synthetic Methods N1-N9 Method N1 Preparation of N,N-Diethyl-2-[(3'-methoxy-4-nitro-1,1'-biphenyl-2-yl)oxy]et hanamine

To a dry round-bottomed flask is added 4-bromo-3-(2-(diethylamino) ethoxy-1- nitrobenzene (1 equiv), 3-methoxylphenylboronic acid (1.5 equiv), sodium bicarbonate (4 equiv), and (1,1-bis (diphenylphosphino) ferrocene)-dichloropalladium (0.1 equiv). 1,4- Dioxane (0. 1M) is added and Ar is then bubbled through the solution for 15 minutes.

Water (0.02M) is added and the reaction is heated at 90°C. After 16h the reaction mixture is cooled, diluted with ethyl acetate, and washed with saturated aqueous NaHC03 (1x) followed by H20 (1x). The organic layer is collected, condensed under reduced pressure, and purified by silica gel flash chromatography. LC/MS and'HNMR confirm the product.

Method N2 Preparation of 4-(2-methoxy-4-nitrophenyl) pvridine

To a dry round-bottomed flask is added (bromo compound) (1 equiv), appropriate boronic acid (1.5 equiv), sodium bicarbonate (4 equiv), and (1,1- bis (diphenylphosphino) ferrocene)-dichloropalladium (0.1 equiv). 1,4-dioxane (0. 1M) is added and Ar is then bubbled through the solution for 15 minutes. Water (0.02M) is added and the reaction is heated at 90°C. After 16h the reaction mixture is cooled, diluted with ethyl acetate, and washed with saturated aqueous NaHC03 (1x) followed by H20 (1x). The organic layer is collected, condensed under reduced pressure, and purified by silica gel flash chromatography. LC/MS and'HNMR confirm the product.

Method N3 Preparation of 2'-(4-methyl-1-piperazinyl)-5'-nitro-1, 1'-biphenyl-4-carbonitrile

To a dry round-bottomed flask is added 1-methyl-4- (2-bromo-4- nitrophenyl) piperazine (1 equiv), 4-cyanophenylboronic acid (1.5 equiv), sodium bicarbonate (4 equiv), and (1,1-bis (diphenylphosphino) ferrocene)-dichloropalladium (0.1 equiv). 1,4-dioxane (0. 1M) is added and Ar is then bubbled through the solution for 15 minutes. Water (0. 02M) is added and the reaction is heated at 90°C. After 16h the reaction mixture is cooled, diluted with ethyl acetate, and washed with saturated aqueous NaHCO3 (1x) followed by H20 (1x). The organic layer is collected, condensed under reduced pressure, and purified by silica gel flash chromatography. LC/MS and HNMR confirm the product.

Method N4 Preparation of N,N-diethyl-2-[2-(1H-indazol-5-yl)-5-nitrophenoxy]ethanamine A two neck flask charged with the 5-bromo-1H-indazole (1 equiv), Pd (dppf) C12 (0.03 equiv), KOAc (3 equiv) and bis (pinacolato) diboron (1.1 equiv) was flushed with Ar.

DMF (0.25 M) was added via a syringe to form a red solution. The mixture was heated at 80 °C for 2h. After the reaction was cooled to rt, Pd (dppf) CI2 (0.03 equiv), the nitro bromide compound (1 equiv) and Na2CO3 aqueous solution (1 M, 5 equiv) were added.

The mixture was stirred under Ar at 80 °C overnight. The reaction mixture was allowed to cool to rt, extracted with EtOAc and washed with brine. The extract was then dried (MgS04) and concentrated under reduced pressure. The residue was purified by flash silica column chromatography (EtOAc/MeOH=9: 1) to afford the pure product which was confirmed by LC/MS and'H NMR.

Method N5 Preparation of 2- (4-methyI-1-piperazinLl)-N-r2-4-morpholinyl) ethyll-5-nitroaniline

To a dry round-bottomed flask is added 1-methyl-4-(2-bromo-4- nitrophenyl) piperazine (1 equiv), 2- (4-morpholinyl) ethylamine (1.5 equiv), potassium tert- butoxide (1.4 equiv), rac-BINAP (0. 2 equiv) and Pd2 (dba) 3 (0.1 equiv). 1,4-Dioxane (0. 1M) is added and Ar is then bubbled through the solution for 15 minutes. The reaction is heated at 80°C. After 8h the reaction mixture is cooled, diluted with ethyl acetate, filtered through a Celiez plug. The plug is washed well with EtOAc. The organic layer is collected, condensed under reduced pressure, and purified by silica gel flash chromatography. LC/MS and'HNMR confirm the product.

Method N6 Preparation of NIN-diethyl-2-(5-nitro-1H-indol-1-vl) ethanamine A slurry of 5-nitroindole (1 equiv) and NaOH pellets (1 equiv) in H20 (7 M) was stirred for 10 min after which time p-xylene (1.4 M), K2CO3 (1.5 equiv) and corresponding alkyl halide (1 equiv) was added and the reaction heated to 100 °C for 4 h. The reaction was cooled to rt then concentrated under reduced pressure. The crude residue was dissolved in p-xylene and washed with 1 N NaOH (2 x) and H20 (1 x). The organic layer was dried (MgSO4) and concentrated in vacuo to furnish the resulting crude material that was confirmed by LC/MS and'H NMR.

Method N7 Preparation of 1-(3-nitrobenzyl)-1 H-imidazole

To a round-bottomed flask is added 3-nitrobenzyl bromide (1 equiv) followed by imidazole (2 equiv) in THF (0. 4M). The solution is heated at 60 °C. After 16h the reaction mixture is cooled, diluted with ethyl acetate, and washed with saturated aqueous NaHC03 (1x) followed by H20 (1x). The organic layer is collected, condensed under reduced pressure, and purified by silica gel flash chromatography. LC/MS and 1HNMR confirm the product.

Methods N8-N9 Preparation of 4-f2- (2-methoxy-5-nitrophenoxy) ethyllmorpholine Step 1. Method N8 Preparation of 2- (2-bromoethoxy)-1-methoxy-4-nitrobenzene A solution of 2-methoxy-5-nitrophenol (1 equiv) in CH3CN (0.72 M) was added 1,2-dibromoethane (1 equiv) and Cs2CO3 (3 equiv). The mixture was refluxed overnight.

After cooling to rt, the reaction mixture was diluted by EtOAc and washed with 1 N NaOH (3x), water (1x) and brine (2x). The organic layer was dried (MgSO4) and concentrated in vacuo to afford the crude product which was confirmed by 1H NMR and used without further purification.

Step 2. Method N9 Preparation of 4-92-(2-methoxv-5-nitrophenoxv) ethyllmorpholine

A solution of 3- (2-bromoethoxy)-4-methoxynitrobenzene (1 equiv), piperidine (2 equiv) and K2CO3 (8 equiv) in acetone (0.10 M) was heated to 65 °C for 24 h. The reaction mixture was allowed to cool to rt, diluted with EtOAc and washed with H2O. The organic layer was concentrated in vacuo and the resulting crude solid or oil was purified by silica gel column chromatography to furnish the intermediate nitro derivative which was confirmed by LC/MS and'H NMR.

Preparation of Anilines : (Reactions Scheme I Intermediates B and D) Synthetic Methods B1-B7 and D1 Intermediate B-1 Method B1 Preparation of 1-rr (4S)-2, 2-dimethvl-113-dioxolan-4-vl1methylT-1H-indol-5-amine Step 1. Preparation of 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-5-nitro-1-H- indole

The compound was prepared by reaction of 5-nitroindole (1.0 equiv) with [ (4R)- 2, 2-dimethyl-1, 3-dioxolan-4-yl] methyl 4-methylbenzenesulfonate (5. 0 equiv) in the presence of cesium carbonate (2.0 equiv) in DMF at 80 °C for 48 h. A similar procedure is described in more detail in Method 4 below.

Step 2. Method B1 Preparation of 1-fr (4S)-2,2-dimethyl-1,3-dioxaolan-4-yl]methyl}-1H- indol-5-amine

To 2.8 g (10 mmol, 1.0 equiv) 1-{[(4S)-2, 2-dimethyl-1, 3-dioxolan-4-yl] methyl}-5- nitro-1H-indole in EtOH (100 mL) and THF (10 mL) was added 6.8 g (30 mmol, 3equiv) tin (II) chloride dihydrate and the reaction was heated to 100 °C for 24h. It was

concentrated, taken up in K2CO3 and filtered through Celte. The filtrate was extracted with EtOAc and the organic layers dried with MgS04, filtered and concentrated to 2.5 g (99%) 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1H-indol-5-a mine.

Intermediate B-2 Methods B2a and B2b Preparation of 1-methyl-5-amino-1H-indole

Step 1. Method B2a Preparation of 1-methyl-5-nitro-1H-indole To 1.0 g (6 mmol, 1. Oequiv) 5-nitroindole in acetone (12 mL) and H2O (3 mL) was added KOH (1.0 g, 18 mmol) followed by iodomethane (0.75 mL, 12 mmol). The reaction was allowed to stir for 24 h then was filtered to yield 0.8 g (78%-98%) 1-methyl- 5-nitro-1 H-indole.

Step 2. Method B2b Preparation of 1-methyl-5-amino-1H-indole

To 0.9 g (5mmol, 1. Oequiv) 1-methyl-5-nitro-1H-indole in 10mL MeOH was added 0. 01g 10% Pd/C (0. 09mmol, 0. 01equiv) and the reaction was stirred under 1atm hydrogen for 34 h. The reaction was filtered and concentrated to give 0.4g (43%-62%) 1- methyl-5-amino-1 H-indole.

Intermediate B-3 Method B3 Preparation of 4-aminophenyl-pyrazole Step 1: Preparation of N'-f4-r (2E)-3- (dimethvlamino)-2-propenoyllphenyl}-N, N dimethylimidoformamide

A mixture of 1- (4-amino-phenyl)-ethanone (10.0 g, 74 mmol) and dimethoxymethyl-dimethyl-amine (20.0 g, 156 mmol) was heated at 110 °C for 24 h, cooled to room temperature and concentrated under reduced pressure. The crude product was used in the next step without purification.

Step 2: Preparation of 4-aminophenyl-pyrazole

The crude product obtained from step one was treated with water (125.0 mL), 1N HCI (8.0 mL), and hydrazine monohydrate (7.4 g, 148 mmol). The mixture was heated at 110 °C for 18 h, cooled down to room temperature, neutralized with saturated NaHC03 solution (10.0 mL) and extracted with EtOAc (200 mL) three times. Combined the extract and dried over MgSO4, concentrated under reduced pressure to about 100 mL. 1N HCI in ether (74 mL) was added slowly while stirring vigorously. The precipitate was filtered and dried to give 11.5 g (80%) 4-aminophenyl-pyrazole hydrochloride as a yellow powder.

Intermediate B-4 Method B4 Preparation of methyl 4-amino-2-(2-hydroxvethoxy) benzoate

Step 1: Preparation of 8-nitro-213-dihvdro-5H-1 l4-benzodioxepin-5-one.

To a suspension of K2CO3 (3.7 g, 27 mmol) in DMF (50 mL), were added 2- hydroxy-4-nitrobenzoic acid (2.0 g, 11 mmol) and dibromoethane (5.1g, 27 mmol). The

mixture was heated at 60 °C for 18 h then cooled down to room temperature and water (200 mL) was added. The product was precipitated, filtered, washed with EtOAc, and dried to give 1.0 g (51%) 8-nitro-2,3-dihydro-benzo [e] [1,4] dioxepin-5-one as a pale yellow powder.

Step 2: Preparation of methyl 4-amino-2-(2-hydroxvethoxy) benzoate To a solution of 8-nitro-2,3-dihydro-benzo [e] [1,4] dioxepin-5-one (1.0 g, 4.8 mmol) in MeOH and THF, were added 10% Pd/C (50 mg). The mixture was stirred under hydrogen atmosphere for 48 h. The mixture was filtered and concentrated under reduced pressure, the residue was diluted with 400 mL EtOAc and filtered again. Concentrated under reduced pressure to give 0.6 g (60%) 2- (2-hydroxy-ethoxy)-4-aminobenzoic acid methyl ester.

Intermediate B-5 Method B5 Preparation of 1- ((S)-2, 2-Dimethyl-f1, 31dioxolan-4-ylmethyl)-1H-indol-5-vlamine Step 1a. Toluene-4-sulfonic acid (S)-212-dimethyl-r1l31dioxolan-4-vl methvl ester To a stirred solution of (R)- (-)-2, 2-dimethyl-1, 3-dioxolane-4-methanol. (25 g; 0.19 mol) in anhydrous dichloromethane (153 mL) cooling under argon atmosphere in ice water was added, successively, triethylamine (28.4 mL; 0.2 mol)), p-toluenesulfonyl chloride (39.27 g; 0.2 mol), and 4-dimethylaminopyridine (0.23 g; 1.9 mmol). The solution was stirred and allowed to warm to room temperature overnight, then was poured into a mixture of water (120 mL) and hexane (240 mL) stirring in ice water. The 2-phase mixture was poured into a separatory funnel, the phases separated, and the organic phase washed successively with water (75 mL), then brine (75 mL) before drying over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded toluene-4- sulfonic acid (S)-2, 2-dimethyl- [1, 3] dioxolan-4-ylmethyl ester as a thick yellow oil ;'H NMR shows the presence of residual p-toluenesulfonyl chloride.'H NMR (CD2CI2) 8 7.7 (d, 2H), 7.4 (d, 2H), 4.2 (m, 1H), 4.01 (dd, 1H), 3.97 (d, 2H), 3.7 (dd, 1H), 2.5 (s, 3H), 1.32 (s, 3H), 1.3 (d, 3H).

Step 1b. Toluene-4-sulfonic acid (R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester

To a stirred solution of (S)- (+)-2, 2-dimethyl-1, 3-dioxolane-4-methanol (20 g; 0.15 mol) in anhydrous dichloromethane (125 mL) cooling under argon atmosphere in ice water was added, successively, triethylamine (23 mL; 0.16 mol), p-toluenesulfonyl chloride (39.27 g; 0.16 mol), and 4-dimethylaminopyridine (0.23 g; 1.6 mmol). The solution was stirred and allowed to warm to room temperature; after 7 h the reaction was poured into a stirred mixture of water (125 mL) and hexane (250 mL). The 2-phase mixture was poured into a separatory funnel, the phases separated, and the organic phase washed successively with water (75 mL), then brine (75 mL) before drying over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded toluene-4- sulfonic acid (R)-2, 2-dimethyl- [1, 3] dioxolan-4-ylmethyl ester as a thick yellow oil ;'H NMR shows the presence of residual p-toluenesulfonyl chloride.'H NMR (CD2CI2) : 7. 7# (d, 2H), 7. 48 (d, 2H), 4. 28 (m, 1H), 4. 018 (dd, 1H), 3. 978 (d, 2H), 3. 78 (dd, 1H), 2. 56 (s, 3H), 1. 328 (s, 3H), 1. 38 (d, 3H).

Step 2. 1-((S)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-5-nitro-1H-ind ole To a stirred solution of 5-nitroindole (10. 41 g; 63.6 mmol) and toluene-4-sulfonic acid (S)-2, 2-dimethyl-[1, 3] dioxolan-4-ylmethyl ester (21.85 g; 76.3 mmol) in anhydrous N, N-dimethylfromamide (100 mL) was added cesium carbonate (41.86 g; 127.2 mmol), and the mixture stirred overnight under argon at 80°C. After allowing the mixture to cool to room temperature, it was poured into a stirred mixture of hexanes and ethyl acetate (200 mL each). The solids were filtered off and washed with more solvent. The filtrate was washed with water and brine (250 mL each) before drying (anhydrous sodium sulfate) ; filtration and concentration in vacuo afforded the theoretical weight of 1- ( (S)-2, 2- dimethyl- [1, 3] dioxolan-4-ylmethyl)-5-nitro-1H-indole as a cloudy orange oil. TLC: Rf 0.3 (50% EtOAc/hexanes), Rf 0. 6 (5% EtOAc/CH2CI2) ;'H NMR (CD2CI2) : 8. 65 (d, 1H), 8. 1# (dd, 1H), 7. 4rad, 1 H), 7. 3a (d, 1H), 6. 78 (dd, 1H), 4. 48 (m, 1H), 4. 38 (dd, 1H), 4. 28 (dd, 1H), 4. 18 (dd, 1H), 3. 78 (dd, 1H), 1. 48 (s, 3H), 1. 38 (d, 3H).

Step 3.1-((s)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-indol-5-y lamine To a solution of 1- ( (S)-2, 2-dimethyl- [1, 3] dioxolan-4-ylmethyl)-5-nitro-1H-indole in ethyl acetate and ethanol (50 mL each) was added 5% palladium on carbon (Degussa type), and the mixture stirred overnight at room temperature under an atmosphere of hydrogen. The mixture was filtered through Celite# and concentrated in vacuo to afford the theoretical weight of 1-((S)-2,2-dimethyl-[1, 3] dioxolan-4-ylmethyl)-1H-indol-5-ylamine as a dark red gum. TLC: Rf 0.18 (50% EtOAc/hexanes) ; H NMR (CD2C12) : 7. 28 (m, 1H), 7. 1# (d, 1H), 6. 98 (dd, 1H), 6. 65 (m, 1H), 6. 3# (dd, 1H), 5. 35 (dd, 1H), 4. 45 (m, 1H), 4. 1# (dd, 2H), 4. OS (dd, 1 H), 3. 75 (dd, 1 H), 3. 5a (broad exchangeable s, 2H), 1. 45 (d, 3H), 1. 3# (d, 3H).

Intermediate B-6 Method B6 Preparation of (3aS)-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzoxazin-7 -amine

(S)-Prolinol (1 equiv) and 3, 4-difluoronitroaniline (1 equiv) were combined with DMSO followed by addition of KOH (2.45 equiv) and heated to 100 °C for 18 h. Then, the mixture was acidified and then filtered. Next, the crude solution was then subjected to the hydrogenation procedure as described above for Method B7c. Intermediate B-7 Methods B7a. B7b, B7c Preparation of 3-r2- (Diethvlamino) ethoxy1-4- (8-auinolinyl aniline

Step 1. Method B7a Demethylation of 1-methoxy-3-nitrophenols using hydrogen bromide

To a solution of 48% HBr (0.5 M) was added 2- (8-quinolinyl)-5-nitroanisole (1 equiv). The solution was heated at reflux for 3 days. The reaction mixture was allowed to cool to rt, diluted with H20, and extracted with EtOAc. The organic layer was dried (MgS04), filtered and concentrated in vacuo to give crude organic residue. Purification by silica gel column chromatography using 20% EtOAc/80% Hex as eluent, afforded the intermediate phenol which was confirmed by LC/MS and'H NMR.

Step 2. Method B7b Preparation of 2-phenoxy ethylamines

A slurry of 2- (8-quinolinyl)-5-nitrophenol (1 equiv) and NaOH pellets (1 equiv) in H20 (7 M) was stirred for 10 min after which time p-xylene (1.4 M), K2CO3 (1.5 equiv) and aminoethylchlorideHCI (1 equiv) was added and the reaction heated to 100 °C for 4 h.

The reaction was cooled to rt then concentrated under reduced pressure. The crude residue was dissolved in p-xylene and washed with 1 N NaOH (2 x) and H20 (1 x). The organic layer was dried (MgS04) and concentrated in vacuo to furnish the resulting crude material which was confirmed by LC/MS and'H NMR.

Step 3. Method B7c Reduction of nitrophenols to anilines using Pd/C

A solution of 4- (8-quinolinyl)-3- (2- (diethylamino) ethoxy) nitrophenol in EtOH (0.2 M) was added via syringe to a flask containing Palladium on carbon (10 mol%). The reaction vessel was fitted with a balloon adapter and charged with hydrogen and evacuated three times until the reaction was under a H2 atmosphere. The reaction was allowed to stir overnight and then purged with Ar and evacuated three times until an Ar atmosphere had been achieved. The reaction solution was filtered through a pad of Celtes and washed with copious amounts of EtOH. The filtrate was concentrated in vacuo to afford the desired aniline which was confirmed by LC/MS and'H NMR.

Intermediate D-1 Method D1 Preparation of 3- (3-Aminophenox-1, 2-propanediol Step 1. To 3-nitrophenol (10.00 g, 7 mmol) in EtOH (50 mL) was added sodium hydroxide (3.59 g, 9 mmol) in water (4 mL) and the reaction was heated to 80 °C for 10 min. To this was added 3-chloro-1, 2-propanediol (3.59 g, 9 mmol) and the reaction was stirred at 80 °C for 18 h. It was then allowed to cool to room temperature, taken up in EtOAc, washed with 1 N NaOH, washed with brine, dried with MgSO4, filtered and concentrated to give 14.92 g of 3- (3-nitrophenoxy)-1, 2-propanediol (97%).

Step 2. To 3- (3-nitrophenoxy)-1, 2-propanediol (14.92 g, 70 mmol) in ethanol (560 mL) was added tin (II) chloride dihydrate (63. 17g, 280 mmol) and the reaction heated to 100 °C for 18 h. It was cooled and concentrated. The yellow oil was taken up in EtOAc and quenched with K2C03 to pH=12, filtered, and then extracted with additional EtOAc to give 6.26 g of 3- (3-aminophenoxy)-1, 2-propanediol as a yellow oil (49%).

Preparation of Specific Compounds of the Invention Example 1 Methods 1 a, 1 b, 1 c, and 1d Preparation of N-{5-bromo-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}-N-[3-(1- methyl-1h- pyrazol-3-yl) phenvllamine F ci F I CI NaOAc or KOAc Br, ". 1 HN step 1 gr N N CI NH I CI /F H N N, W H2N'YN-CH3 HN Brs>N n HCI, t-BUOH KN1NJA N step 2 H 4XN-CH3 Step 1. Two methods were used: Method 1a. To a solution of NaOAc (27.0 g, 330 mmol) in water (70 mL) and THF (140 mL), were added 5-bromo-2, 4-dichloropyrimidine (25.0 g, 110 mmol) and 4- fluoroaniline (12.2 g, 110 mmol). The mixture was stirred at room temperature for 18 h then saturated NaHC03 solution (50 mL) was added and the aqueous layer was extracted with EtOAc (150 mL x 2); the combined organic layers were dried over MgS04 ; filtered and concentrated under reduced pressure. The residue was treated with 200 mL hexane and filtered to give 5-bromo-2-chloro-4- [ (4-fluorophenyl) amino] -pyrimidine as a 30.0 g pale yellow powder (90%).

Method 1b. To a solution of K2CO3 (44.5 g, 322 mmol) in water (125 mL) and/-PA (375 mL), were added 5-bromo-2, 4-dichloropyrimidine (25.0 g, 108 mmol) and 4- fluroaniline (12.0 g, 107 mmol). The mixture was stirred at room temperature for 18 h then water (3000 mL) was added and the product was precipitated out. Filtered and dried to give 30.0 g (90%) 5-bromo-2-chloro-4- [ (4-fluorophenyl) amino] -pyrimidine as a pale yellow powder.

Step 2.

Method 1c To a solution of 5-bromo-2-chloro-4- [ (4-fluorophenyl) amino] -pyrimidine (0.85 g, 2.8 mmol) and 3- (1-methyl-1H-pyrazol-3-yi)-phenyl amine (0.49 g, 2.8 mmol) in t- BuOH (25 mL) was added concentrated HCI (0.1 mL). The mixture was heated to 100 °C for 18 h, and then cooled down to room temperature. The precipitate was filtered and dried in vacuo to give 0.95 g (71%) desired product (HCI salt). ESI-LC/MS m/e calculated for C19H14BrFN6 : 424.0 ; Found: 425.3 (M+1) + ; Rf= 0.40 (EtOAc/Hex=1/1).

Combined Steps 1 and 2.

Method 1d. In a 40 mL EPA vial, 100 mg (1 equivalent) of the 4-substituted pyrimidine intermediate was mixed with the calculated amount of amine (2 equivalent) in 2 mL 1 N HCI. The reaction mixture was capped and heated at 100 °C in a J-Kem Block with shaking for 1 or 2 days. After the reaction was completed, DMSO was added into the reaction mixture to dissolve all of the precipitate, then Et3N was added dropwise until the mixture was basic. After these steps, the mixture was purified by preparative HPLC.

Example 2 Method 2 Preparation of N-{5-bromo-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}-N-[3-(1H -pyrazol-3- yl) phenyllamine To a solution of 5-bromo-2-chloro-4- (4-fluoroanilino) pyrimidine (4.0 g, 13.2 mmol) and 3- (3-aminophenyl)-1H-pyrazole (2.3 g, 14.5 mmol) in dioxane (75 mL) was added 1 N HCI (75 mL). The mixture was heated to 100 °C for 18 h, and then cooled down to room temperature. Sodium bicarbonate (8.4 g, 100 mmol) was added in several portions while stirring. The precipitate was filtered and dried in vacuo to give 3.87 g (69%) desired product. 1H NMR (CD30D) : 5 8.16 (s, 1H), 7.80 (m, 1H), 7.67 (d, 1H), 7.56 (m, 1H), 7.48 (dd, 2H), 7.31 (m, 2H), 6.92 (t, 2H), 6.56 (d, 1 H) ; ESI-LC/MS m/e calculated for C19H14BrFN6 : 424.0 ; Found: 425.3 (M+1) + ; Rf= 0.70 (EtOAc).

Example 3 Method 3 Preparation of (1E)-1-[4-({5-bromo-4-[(4-fluorophenyl)amino]-2-pyrimidinyl} amino) phenyllethanone oxime

To a suspension of 1-[4-({5-bromo-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}- amino) phenyl] ethanone (HCI salt, 90 mg, 0.21 mmol) and NaOAc (67 mg, 0.82 mmol) in EtOH (4.0 mL) was added Hydroxylamine hydrochloride (43 mg, 0.62 mmol). The mixture was heated to 100 °C for 18 h, and then cooled down to room temperature. Water (20 mL) was added while stirring; the precipitate was filtered and washed with water; dried in vacuo to give 61 mg (71%) of (1E)-1-[4-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl} amino) phenyl] ethanone oxime.'H NMR (CD30D) : 5 8.10 (s, 1H), 7.55 (dd, 2H), 7.51 (d, 2H), 7.44 (d, 2H), 7.11 (t, 2H), 2.21 (s, 3H); ESI-LC/MS m/e calculated for deHisBrFNgO : 415.0 ; Found: 416.2 (M+1) + ; Rf= 0.54 (EtOAc/hex=1/1).

Example 4 Method 4 Preparation of N-{5-bromo-2-[(4-{[(4R)-2,2-dimethyl-1,3-dioxolan-4- yllmethoxy phenyl) aminol-4-pyrimidinyl-N-(4-fluorophenyl) amine

To 10.0g (30mmol, 1.0 equiv) 4-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl} amino) phenol in 200mL DMF (moist) was added 20. 1g (130 mmol, 5. 0equiv) (4S)-4-(chloromethyl)-2, 2-dimethyl-1, 3-dioxolane and 17.4g (50 mmol, 2. 0equiv) cesium carbonate and the mixture was heated to 80 °C for 48 h. The reaction was cooled, taken up in EtOAc and washed with a saturated solution of ammonium chloride (3x200 mL).

The organic layers were dried with MgS04, filtered and concentrated. This was purified by flash column chromatography (0 then 50% EtOAC/Hex) on alumina to yield 4.8 g (5% to 98%) N-{5-bromo-2-[(4-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]metho xy}phenyl) amino] -4- pyrimidinyl}-N-(4-fluorophenyl) amine.

The above procedure was also used to make 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4- yl] methyl}-5-nitro-1H-indole using 5-nitroindole and R (D)-2, 2-dimethyl-1, 3-dioxolane-4- methanoltoluene-4-sulfonate. Yields 90-99%.

Example 5 Method 5 Preparation of (2S)-3-94-(85-bromo-4-[(4-fluorophenyl) amino1-2- pyrimidinyamino phenoxyl-1, 2-propanediol

To 4.8 g (10 mmol, 1.0 equiv) N-{5-bromo-2-[(4-{[(4R)-2,2-dimethyl-1,3-dioxolan- 4-yl] methoxy}phenyl)amino]-4-pyrimidinyl}-N-(4-fluorophenyl) amine in 90 mL MeOH/CH2CI2 (1: 1) was added conc. HCI (2.3 mL) and the reaction was allowed to stir for 2 h. The reaction was treated with sat. NaHC03 to pH=7 and extracted with i-PA/CHCI3 (1: 3) to give 1.5 g (28-98%) (2S)-3-[4-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl} amino) phenoxy]-1, 2-propanediol.

Example 6 Method 6 Preparation of (2R)-3-[3-({5-bromo-4-[(4-fluorophenyl)amino]-2- pyrimidinylTamino) phenoxvl-1, 2-propanediol

To 0.5g (0. 1mmol, 1.0equiv) 3-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl} amino) phenol in 2.5mL EtOH was added 0.07g NaOH (2mmol, 1.25equiv) in 1mL H2O and the reaction was heated to 80°C for 1 h. To this was added 0.2g (2R) -3- chloro-1, 2-propanediol (2mmol, 1.2equiv) and the reaction continued to heat at 80°C for 24 h It was cooled and treated with 1N HCI to pH=7 and extracted with EtOAc. The organic layers were dried with MgS04, filtered and concentrated. This was taken up in MeOH and filtered to yield 0.3g (2R)-3-[3-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl} amino) phenoxy]-1, 2-propanediol (43%-61%).

Example 3 Method 7 Preparation of (1E)-1-[4-({5-bromo-4-[(4-fluorophenyl)amino]-2- pyrimidinyl phenyllethanone oxime To a suspension of 1- [4- ( {5-bromo-4- [ (4-fluorophenyl) amino]-2-pyrimidinyl)- amino)phenyl]ethanone (HCl salt, 90 mg, 0.21 mmol) and NaOAc (67 mg, 0.82 mmol) in EtOH (4.0 mL) was added hydroxylamine hydrochloride (43 mg, 0.62 mmol). The mixture was heated to 100 °C for 18 h, and then cooled down to room temperature. Water (20 mL) was added while stirring; the precipitate was filtered and washed with water; dried in vacuo to give 61 mg (71 %) of (1E)-1-[4-({5-bromo-4-[(4-fluorophenyl) amino] -2- pyrimidinyl} amino) phenyl] ethanone oxime. 1H NMR (CD30D) : # 8.10 (s, 1H), 7.55 (dd, 2H), 7.51 (d, 2H), 7.44 (d, 2H), 7.11 (t, 2H), 2.21 (s, 3H); ESI-LC/MS m/e calculated for CisHisBrFNsO : 415.0 ; Found: 416.2 (M+1) + ; Rf= 0.54 (EtOAc/hex=1/1).

Example 8 Method 8 Preparation of 4-({5-bromo-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}amino)-2 -(2- hvdroxyethoxy) benzoic acid

A suspension of 4- [5-bromo-4- (4-fluoro-phenylamino)-pyrimidin-2-ylamino]-2- (2- hydroxy-ethoxy) -benzoic acid methyl ester (3.7 g, 27 mmol) in MeOH (5.0 mL) and 1N NaOH (5.0 mL) was heated at 60 °C for 18 h then cooled down to room temperature and neutralized with 1 N HCI (5.0 mL). Extracted with EtOAc, dried over MgS04, concentrated to give 85 mg (87%) 4- [5-bromo-4- (4-fluoro-phenylamino)-pyrimidin-2-ylamino]-2- (2- hydroxy-ethoxy) -benzoic acid.

Example 9 Preparation of 5-Bromo-N2-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H -indol-5-yl]- N4-(4-fluoro-phenvl)-pvrimidine-214-diamine To a solution of 1- ( (S)-2, 2-dimethyl- [1, 3] dioxolan-4-ylmethyl)-1H-indol-5-ylamine (5.38 g; 21.8 mmol) in n-butanol (20 mL) was added (5-bromo-2-chloro-pyrimidin-4-yl)- (4- fluorophenyl) amine (6.61 g; 21.8 mmol) and 1 drop of concentrated hydrochloric acid, and the stirred mixture heated in an oil bath to reflux. After 5 minutes the bath was lowered and the mixture allowed to cool to room temperature. The solid was filtered off, triturated and washed with diethyl ether to afford a mixture of 2 products, 5-bromo-IV2- [1- ( (R)-2, 2-dimethyl- [1, 3] dioxolan-4-ylmethyl)-1 H-indol-5-yl]-N4-(4-fluoro-phenyl)-pyrimidine- 2,4-diamine and (R)-3- {5- [5-bromo-4- (4-fluoro-phenylamino)-pyrimidin-2-ylamino]-indol-1- yl}-propane-1, 2-diol, as hydrochloride salts. The solid was vigorously stirred in a mixture of ethyl acetate (300 mL) and water (100 mL), sodium bicarbonate (2 g; 23.8 mmol) was added, and the mixture stirred until no undissolved solid remained. The 2-phase mixture was poured into a separatory funnel, the phases separated, and the organic phase washed with brine (100 mL) before drying over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded solid, which was triturated and washed with dichloromethane ; the filtrate was applied to a column of silica gel. The column was eluted with dichloromethane, then a methanol/dichloromethane solvent gradient (1-5%).

The purest (by TLC) of 2 fractions was concentrated in vacuo, and the solid triturated with 50% dichloromethane/hexanes, filtered off and washed with more solvent. After drying in vacuo, there was obtained 0.82 g of 5-bromo-/\- [1- ( (R)-2, 2-dimethy !- [1, 3] dioxolan-4- ylmethyl)-1H-indol-5-yl]-N4-(4-fluoro-phenyl)-pyrimidine-2, 4-diamine as a colorless solid, mp 130-132°C ; TLC: Rf 0.28 (50% EtOAc/hexanes) ;'H NMR (CD2CI2) : 8. 18 (s, 1H),

7. 85 (d, 1H), 7. 65 (m, 2H), 7. 3# (d, 1H), 7. 26 (m, 1H), 7. 16 (broad s, 1H), 7. 08 (m, 3H), 4. 4# (m, 1H), 4. 28 (dd, 2H), 4. 08 (dd, 1H), 3. 78 (dd, 1H), 1. 48 (s, 3H), 1. 38 (s, 3H); LCMS m/z 512 + 514 (M+H+), RT = 2.6 min. Anal. Calcd. for C24H23BrFN502 : C, 56.26 ; H, 4.52 ; N, 13.67. Found: C, 55.96 ; H, 4.22 ; N, 13.66. The remaining fraction was concentrated in vacuo, and the solid triturated with 25% dichloromethane/hexanes to afford another 3.55 g (4.37 g total, 39%) of pure 5-bromo-N2-[1-((R)-2,2-dimethyl-[1, 3] dioxolan-4- ylmethyl)-1H-indol-5-yl]-N4-(4-fluoro-phenyl)-pyrimidine-2, 4-diamine.

Example 10 Method 10 Preparation of (R)-3-{5-[5-Bromo-4-(4-fluoro-phenylamino)-pyrimidin-2-ylami no]-indol-1- yl}-propane-1, 2-diol To a stirred mixture of 5-bromo-N2-[1-((R)-2,2-dimethyl-[1, 3] dioxolan-4-ylmethyl)- 1H-indol-5-yl]-N4-(4-fluoro-phenyl)-pyrimidine-2, 4-diamine (15.36 g; 30.0 mmol) in methanol (500 mL) was added 1N hydrochloric acid (120 mL); the stirred suspension was heated to 60 °C. After 30 minutes the mixture was allowed to cool to room temperature; the solid was filtered off, washed with methanol and dried. The solid was vigorously stirred in water containing sodium bicarbonate (4.1 g; 48.8 mmol) ; the resulting solid was filtered off, washed with water, ethanol and hexanes, then dried to afford 10.3 g (73%) of (R)-3-{5-[5-bromo-4-(4-fluoro-phenylamino)-pyrimidin-2-ylami no]-indol-1-yl}-propane-1, 2- diol as a colorless solid, mp 206. 5 - 209 °C. 1H NMR (DMSO-d6) : 9.1# (broad, exchangeable s, 1H), 8. 55 (broad, exchangeable s, 1H), 8. 18 (s, 1H), 7. 8ã (d, 1H), 7. 68 (t, 2H), 7. 38 (d, 1H), 7. 28 (d, 1H), 7. 1# (m, 3H), 6. 28 (d, 1H), 4. 9ã (exchangeable d, 1H), 4. 78 (exchangeable t, 1H), 4. 28 (dd, 1H), 4. 08 (dd, 1H), 3. 78 (m, 1H), 3. 3ã (m, 1H), 3. 26 (m, 1H); LCMS m/z 472 + 474 (M+H+), RT = 2.0 min. Anal. Calcd. for C21H19BrFN5O2 : C, 53.4 ; H, 4.05 ; N, 14.83. Found: C, 53.38 ; H, 4.09 ; N, 14.85 ; chiral HPLC (CHIRALPAK AD-H, 4.6 X 250 mm. , 1.0 mL/min. , 280 nm, hexane + 0. 1% TFA/ isopropanol + 0. 1% TFA gradient): RT = 12.0 min. , ee >98%.

Example 4 Method 11 5-Bromo-N2-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-p henyl]-N4-(4-fluoro-phenyl)- pyrimidine-2, 4-diamine A stirred suspension of 4- [5-bromo-4- (4-fluoro-phenylamino)-pyrimidin-2- ylamino]-phenol (11.3 g; 30.0 mmol), toluene-4-sulfonic acid (S)-2, 2-dimethyl- [1,3] dioxolan-4-ylmethyl ester (17.1 g; 60.0 mmol) and cesium carbonate (34.39 g; 100 mmol) in anhydrous N, N-dimethylformamide (120 mL) was heated under argon atmosphere at 90 °C for 1 hour, then allowed to cool to room temperature. The reaction mixture was partitioned between ethyl acetate (250 mL) and brine (500 mL), the phases separated, and the aqueous phase extracted with ethyl acetate (2 X 125 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried (anhydrous sodium sulfate), filtered and concentrated in vacuo to afford crude product.

Purification by column chromatography on silica gel (hexane/dichloromethane/ethyl acetate solvent gradient) afforded 5-bromo-N2-[4-((R)-2,2-dimethyl-[1, 3] dioxolan-4- ylmethoxy)-phenyl]-N4-(4-fluoro-phenyl)-pyrimidine-2, 4-diamine as a pastel orange solid (10.57 g; 72%). A sample purified further (colorless solid, mp 119-122° C) gave the following data: TLC: Rf 0.5 (25% EtOAc/CH2CI2) ; 1H NMR (CD2Ch) : 8. 1ã (s, 1H), 7. 58 (m, 2H), 7. 48 (m, 2H), 7. 18 (m, 4H), 6. 88 (m, 2H), 4. 48 (m, 1H), 4. 18 (dd, 1 H), 4. 08 (dd, 1H), 3. 98 (dd, 1 H), 3. 88 (dd, 1 H), 1.45 (d, 3H), 1.4 (d, 3H); LCMS m/z 489 + 491 (M+H+), RT = 2.6 min.; Anal. Calcd. for C22H22BrFN403 : C, 54.0 ; H, 4.53 ; N, 11.45. Found: C, 53.98 ; H, 4.55 ; N, 11.21.

Example 5 Method 12 (S)-3-{4-[5-Bromo-4-(4-fluoro-phenylamino)pyrimidin-2-ylamin o]-phenoxy}-propane-1,2- diol Trifluoroacetic acid (150 mL; 1.94 mol) was added to a suspension of 5-bromo- N2-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-N 4-(4-fluoro-henyl)- pyrimidine-2,4-diamine (10.57 g; 0.02 mol) in methanol (675 mL), stirring under argon.

After stirring at room temperature overnight, the mixture was concentrated in vacuo. The solid was triturated with diethyl ether, filtered, washed and dried under vacuum; it was then suspended in ethanol, and sodium bicarbonate (3.44 g; 0.04 mol) added to the stirred mixture. After stirring for 1.5 h the solid was filtered off, then stirred in water for 30 minutes. After filtering the solid and washing with water, ethanol and hexanes, 6.77 g (70%) of (S)-3- {4- [5-bromo-4- (4-fluoro-phenylamino)-pyrimidin-2-ylamino]-phenoxy}- propane-1, 2-diol as a colorless solid, mp 207-210° C, was obtained.'H NMR (DMSO-d6) : 9. 18 (broad, exchangeable s, 1H), 8. 6# (broad, exchangeable s, 1H), 8. 1# (s, 1H), 7. 6# (m, 2H), 7. 4# (d, 2H), 7. 28 (m, 2H), 6. 78 (d, 2H), 4. 98 (broad, exchangeable s, 1H), 4. 68 (broad, exchangeable s, 1H), 3. 98 (dd, 1H), 3. 88 (m, 2 H), 3. 48 (d, 2H); LCMS m/z 449 + 451 (M+H+), RT = 1.9 min.; Anal. Calcd. for C19H18BrFN403 : C, 50.79 ; H, 4.04 ; N, 12.47.

Found: C, 50.77 ; H, 3.91 ; N, 12.39 ; chiral HPLC (CHIRALPAK AD-H, 4.6 X 250 mm. , 1.0 mL/min., 280 nm, hexane + 0. 1 % TFA/isopropanol + 0. 1 % TFA gradient): RT = 12.0 min. , ee >98%.

Example 13 5-Bromo-N2-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-p henyl]-N4-(4-fluoro-phenyl)- pyrimidine-2, 4-diamine

A stirred suspension of 4- [5-bromo-4- (4-fluoro-phenylamino)-pyrimidin-2-ylamino]- phenol (11.14 g; 0.03 mol), toluene-4-sulfonic acid (R)-2, 2-dimethyl-[1, 3] dioxolan-4- ylmethyl ester (10.2 g; 0.04 mol) and cesium carbonate (29.31 g; 0.09 mol) in anhydrous N, N-dimethylformamide (120 mL) was heated under argon atmosphere at 90° C for 1.5 h, then allowed to cool to room temperature. The reaction mixture was partitioned between ethyl acetate (250 mL) and brine (500 mL), the phases separated, and the aqueous phase extracted with ethyl acetate (2 X 125 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried (anhydrous sodium sulfate), then filtered through a pad of silica gel. The pad was eluted with ethyl acetate, and the filtrate concentrated in vacuo to afford crude product. Purification by column chromatography on silica gel (hexane/dichloromethane/ethyl acetate solvent gradient) afforded 5-bromo- W- [4- ( (S)-2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy)-phenyl]-IV4- (4-fluoro-phenyl)- pyrimidine-2,4-diamine as a tan solid (11 g; 74.5%), mp slowly melts 95-116. 5° C.'H NMR (CD2Cl2) : 8. 18 (s, 1H), 7. 58 (m, 2H), 7. 38 (m, 2H), 7. 1ã (m, 3H), 7. 08 (broad, exchangeable s, 1H), 6. 88 (m, 2H), 4. 48 (m, 1H), 4. 18 (dd, 1 H), 4. 08 (dd, 1H), 3. 98 (dd, 1 H), 3. 88 (dd, 1 H), 1.45 (d, 3H), 1.4 (d, 3H); LCMS m/z 489 + 491 (M+H+), RT = 2.6 min.

Example 14 (R)-3-{4-[5-Bromo-4-(4-fluoro-phenylamino)-pyrimidin-2-ylami no]-phenoxy}-propane-1,2- diol Trifluoroacetic acid (160 mL; 2.08 mol) was added to a suspension of 5-bromo- N2-[4-((S)-2,2-dimethyl-[1, 3] d ioxolan-4-yl m ethoxy)-phenyl]-/v4- (4-fluoro-p henyl)- pyrimidine-2,4-diamine (10.9 g; 0.02 mol) in methanol (640 mL), stirring under argon.

After stirring at room temperature overnight, the mixture was concentrated in vacuo. The solid was triturated with diethyl ether and filtered; it was then suspended in water (250 mL), and sodium bicarbonate (3.74 g; 0.04 mol) added to the vigorously stirred mixture.

After 20 minutes the solid was filtered off, washed with water, ethanol and hexanes to afford (R)-3- {4- [5-bromo-4- (4-fluoro-phenylamino)-pyrimidin-2-ylamino]-phenoxy}- propane-1, 2-diol as 8.65 g (88%) of nearly colorless solid, mp 206.5-208. 5° C.'H NMR (DMSO-d6) : 9. 1# (broad, exchangeable s, 1H), 8. 68 (broad, exchangeable s, 1H), 8. 1# (s, 1 H), 7. 68 (m, 2H), 7. 48 (d, 2H), 7. 28 (m, 2H), 6. 78 (d, 2H), 4. 9# (broad, exchangeable

s, 1H), 4. 68 (broad, exchangeable s, 1H), 3. 98 (dd, 1H), 3. 8# (m, 2 H), 3. 48 (d, 2H); LCMS m/z 449 + 451 (M+H+), RT = 1.9 min.; Anal. Calcd. for C19H18BrFN403 : C, 50.79 ; H, 4.04 ; N, 12.47. Found: C, 50.57 ; H, 4.0 ; N, 12.32 ; chiral HPLC (CHIRALPAK AD-H, 4.6 X 250 mm. , 1.0 mL/min. , 280 nm, hexane + 0. 1% TFA/ isopropanol + 0. 1% TFA gradient): RT = 14.0 min. , ee >99%.

Example 15 5-Bromo-N2-[3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-p henyl]-N4-(4-fluoro-phenyl)- pyrimidine-2, 4-diamine A stirred suspension of 3- [5-bromo-4- (4-fluoro-phenylamino)-pyrimidin-2- ylamino]-phenol (14.27 g; 0.04 mol), toluene-4-sulfonic acid (S)-2, 2-dimethyl- [1,3] dioxolan-4-ylmethyl ester (21.78 g; 0.08 mol) and cesium carbonate (43.82 g; 0.13 mol) in anhydrous N, N-dimethylformamide (150 mL) was heated under argon atmosphere at 90° C for 1 hour, then allowed to cool to room temperature. The reaction mixture was partitioned between ethyl acetate (150 mL) and brine (450 mL), the phases separated, and the aqueous phase extracted with ethyl acetate (2 X 100 mL). The combined organic extracts were washed with water (200 mL) and brine (200 mL), dried (anhydrous sodium sulfate), then filtered through a pad of silica gel. The pad was eluted with ethyl acetate, and the filtrate concentrated in vacuo to afford crude product. Purification by column chromatography on silica gel (hexane/dichloromethane/ethyl acetate solvent gradient) afforded 5-bromo-N2- [3- ( (R)-2, 2-dimethyl- [1, 3] dioxolan-4-ylmethoxy)-phenyl]-N4-(4-fluoro- phenyl)-pyrimidine-2, 4-diamine as a foam (13.85 g; 74. 5%). 1H NMR (CD2Cl2) : 8.1# (s, 1H), 7. 58 (m, 2H), 7. 38 (t, 2H), 7. 28 (broad, exchangeable s, 1H), 7. 15 (m, 3H), 7. 0#m, 1H), 6. 68 (m, 1H), 4. 48 (m, 1H), 4. 1ã (dd, 1 H), 4. 08 (dd, 1H), 3. 98 (dd, 1 H), 3. 85 (dd, 1 H), 1. 436 (s, 3H), 1. 48 (s, 3H); LCMS m/z 489 + 491 (M+H+), RT = 2.9 min.

Example 16 (S)-3-{3-[5-Bromo-4-(4-fluoro-phenylamino)-pyrimidin-2-ylami no]-phenoxy}-propane-1,2- diol (add to table)

Trifluoroacetic acid (200 mL; 2.6 mol) was added to a suspension of 5-bromo-N2- [3-((R)-2,2-dimethyl-[1, 3] dioXolan-4-ylmethoxy)-phenyl]-N4-(4-fluoro-phenyl)-pyrimidin e- 2,4-diamine (13.71 g; 0.03 mol) in methanol (800 mL), stirring under argon. After stirring for 2 h at room temperature, the mixture was concentrated in vacuo. The residue was partitioned between water, ethanol and dichloromethane, and the phases separated; upon washing the organic phase with brine, solid formed. The solid was filtered off, then suspended in water (250 mL), and sodium bicarbonate (4.71 g; 0.06 mol) added to the vigorously stirred mixture. After stirring overnight, the solid was filtered off, washed with water, ethanol and hexanes to afford 7.3 g (58%) of (S)-3- {3- [5-bromo-4- (4-fluoro- phenylamino)-pyrimidin-2-ylamino]-phenoxy}-propane-1, 2-diol as a nearly colorless solid, mp 169. 5-172° C.'H NMR (DMSO-d6) : 9. 28 (exchangeable s, 1H), 8. 6ã (exchangeable s, 1H), 8. 28 (s, 1H), 7. 65 (m, 2H), 7. 2# (m, 4H), 7. 05 (t, 1H), 6. 55 (m, 1H), 4. 95 (broad, exchangeable s, 1H), 4. 65 (broad, exchangeable s, 1H), 3. 9# (d, 1H), 3. 75 (m, 2H), 3. 4# (broad s, 2H); LCMS m/z 449 + 451 (M+H+), RT = 2.1 min.; Anal. Calcd. for C19H18BrFN403 : C, 50.79 ; H, 4.04 ; N, 12.47. Found: C, 50.76 ; H, 3.91 ; N, 12.42 ; chiral HPLC (CHIRALPAK AD-H, 4.6 X 250 mm. , 1.5 mL/min. , 280 nm, hexane + 0.1% TFA/ 25% methanol : isopropanol + 0. 1% TFA gradient): RT = 19.9 min. , ee >99%.

Example 17 Methods 17a and 17b Preparation of4-({5-bromo-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}amino} -N-[1- hydroxymethy)-3-methylbutyllbenzamide Step 1. Method 17a Preparation of 4- (,5-bromo-4-f (4-fluorophenyl) aminol-2- pyrimidinyllamino) benzovi chloride

A mixture of the carboxylic acid (2. 48mmol) was treated with 20 mL of thionyl chloride and allowed to stir at room temperature for 1 hour. The solution was then allowed to stir at 50°C for 18 h. The solution was then concentrated and the crude product was used directly in amide coupling reactions.

Step 2. Method 17b Preparation of 4-({5-bromo-4-[(4-fluorophenyl)amino]-2- pyrimidinyl}amino)-N-[1-(hydroxymethyl)-3-methylbutyl]benzam ide

A solution of the acid chloride and the amine (or hydrazine) were combined, followed by the addition of pyridine and dichloromethane. The reaction was allowed to stir at rt for 18 h. The reaction was then filtered and washed with methylene chloride.

The product was purified by HPLC, and was used directly in a subsequent step without purification.

Example 18 Method 18 Preparation of 4- {5-bromo-4-f (4-fluorophenyl) aminol-2-pyrimidinyl amino--N- (5-isobutyl- 415-dihvdro-1, 3-oxazol-2-yl) benzamide (need table entry)

The amide was combined with thionyl chloride and methylene chloride. The reaction mixture was allowed to stir for 30 minutes and then warmed to room temperature. The mixture was concentrated and then dissolved in DMSO for HPLC purification.

Example 19 Method 19 Preparation of Ethyl 3-4-f (2-Chloro-5-fluoro-4-pyrimidinyl) aminolphenoxy-benzoate (19a and Ethyl 3-(4-{[2-({4-[3(Ethoxycarbonyl)phenoxy]phenyl}amino)-5-fluor o-4- pyrimidinyllaminoTphenoxy) benzoate (19b) (19b) A solution of 2, 4-dichloro-5-fluoropyrimidine (3.24 g, 19.4 mmol) and ethyl 3- (4- aminophenoxy) benzoate (1.00 g, 3.89 mmol) in 4M HCI in dioxane (20 mL) was refluxed for 1 h. TLC analysis indicates two products. The reaction was cooled, quenched with 10% K2CO3 (150 mL) and quickly extracted with EtOAc (3 X 300 mL). The organic layers were dried (Na2SO4) and concentrated. The crude products were separated and purified by silica

gel chromatography (ethyl acetate/hexane) to give ethyl 3- {4- [ (2-chloro-5-fluoro-4- pyrimidinyl) amino] phenoxy} -benzoate (19a) as a tan solid in 40% yield (0. 630 g, 1.63 mmol) and ethyl 3-(4-{[2-({4-[3(ethoxycarbonyl) phenoxy] phenyl} amino)-5-fluoro-4-pyrimidinyl]- amino} phenoxy) benzoate (19b) as a tan solid in 20% yield (0.470 g, 0.772 mmol).

Ethyl 3- {4- [ (2-chloro-5-fluoro-4-pyrimidinyl) amino] phenoxy} -benzoate (19a): TLC: Rf = 0.36 (30% EtOAc/hexane; LC-MS (ESI) : [M+H] + 388.2 @ RT 3.41 min. ; H NMR (DMSO) 6 10.03 (1H, s), 8.30 (1H, d, J = 3.3 Hz), 7.70 (3H, m), 7.53 (1H, t, J = 8.1 Hz), 7.44 (1H, s), 7.30 (1H, dd, J = 2.7, 8.4 Hz), 7.10 (2H, d, J = 8.7Hz), 4.28 (2H, quart, J = 6.9 Hz), 1.27 (3H, t, J = 6. 9 Hz).

Ethyl 3- (4- { [2- ( {4- [3 (ethoxycarbonyt) phenoxy] phenyl} amino)-5-fluoro-4-pyrimidinyl]- amino} phenoxy) benzoate (19b): TLC: Rf = 0.21 (30% EtOAc/hexane; LC-MS (ESI) : [M+H] + 609.5 @ RT 3.21 min. ; 1H NMR (DMSO) 8 9.44 (1H, s), 9.28 (1H, s), 8.10 (1H, d, J = 3.9 Hz), 7.80 (2H, d, J = 9 Hz), 7.70 (2H, d, J = 9 Hz), 7.59 (2H, t, J = 7. 8 Hz), 7.43 (2H, t, J = 7.8 Hz), 7.36 (2H, m), 7.21 (2H, m), 7.03 (2H, d, J = 9 Hz), 6.93 (2H, d, J = 9 Hz), 4.23 (4H, quart, J = 7. 2 Hz), 1.24 (6H, t, J = 6. 6 Hz).

Example 20 Method 20 Preparation of ethyl 3-(4-{[2-({2-[2-(diethylamino)ethoxy]-4'-methoxy-1,1'-biphen yl-4- yl'amino)-5-fluoro-4-pyrimidinyllaminophenoxy) benzoate To a solution of ethyl 3- {4- [ (2-chloro-5-fluoro-4-pyrimidinyl) amino] phenoxy} benzoate (51 mg, 0.13 mmol) and 2- [2- (diethylamino) ethoxy] -4'-methoxy-1, 1'-biphenyl-4- amine (33 mg, 0.10 mmol) in CH2CI2 (5 mL) was added 4M HCI in dioxane (3 mL) and the solution heated in an open vial at 110 °C. The reaction was slowly concentrated over 4 h to a gum as the solvent was boiled off. The reaction was cooled and the gum was dissolved in EtOH (10 mL) and quenched with 10% K2CO3 (50 mL). This was quickly extracted with EtOAc (2 X 150 mL), and the organic layers dried (Na2SO4) and concentrated in vacuo to give a crude amber oil. This was purified by reverse-phase prep-HPLC (RT = 6.28 min), and the TFA salt of the isolated product dissolved in CH2CI2

and free based by washing with 5% K2CO3. The organic layer was concentrated in vacuo to give the product as a hygroscopic brown solid in 54% yield (38 mg, 0.057 mmol).

TLC: Rf = 0.34 (50/45/5 CH3CN/MeOH/H2O) ; LC-MS (ESI) : [M+H] + 666. 6 @ RT 2.60 min.; 1H NMR (DMSO) 8 7.93 (1H, d, J = 3.0 Hz), 7.74 (3H, m), 7.59 (1H, d, J = 1.2 Hz), 7.41 (1H, t, J = 7. 8), 7.31 (3H, m), 7.23 (2H, m), 7.07 (1H, d, J = 8. 4 Hz), 7.01 (2H, d, J = 8. 7 Hz), 6.87 (2H, d, J = 8. 4 Hz), 4.29 (2H, quart, J = 6.9 Hz), 3.93 (2H, t, J = 6.0 Hz), 3.81 (3H, s), 2.80 (2H, t, J = 5. 7 Hz), 2.52 (4H, quart, J = 6.9 Hz), 1.32 (3H, t, J = 6.9 Hz), 0.94 (6H, t, J = 7.5 Hz).

Example 21 Method 21 Preparation of 2-chloro-N (2, 4-dichloro-5-methoxyphenyl)-5-fluoro-4-pyrimidinamine and <BR> <BR> 2, 4-dichloro-5-methoxyphenyl)-N- {2-r (2, 4-dichloro-5-methoxyphenyl aminol-5-fluoro-4- pyrimidinyl}amine A homogenous mixture of 2, 4-dichloro-5-fluoropyrimidine 1 (2.61 g, 15.5 mmol) and 2, 4-dichloro-5-methoxyaniline 7 (1.00 g, 5.16 mmol) and concentrated HCI (1.72 mL, 20.6 mmol) was heated at 110 °C for 2.5 h. The reaction was quenched with saturated K2CO3 (150 mL) and extracted with EtOAc (3 X 300 mL). The organic layers were dried (Na2SO4) and concentrated in vacuo. The crude product was suspended in CH2CI2 (100 mL) and the white solid hydrolysis by-product filtered off. The filtrate was purified by silica gel chromatography (EtOAc/hexane), and the semi-pure residue was suspended in EtOAc. N- (2, 4-dichloro-5-methoxyphenyl)-N-{2-[(2,4-dichloro-5-methoxyphe nyl)amino]-5-fluoro-4- pyrimidinyl} amine was isolated as an insoluble white solid in 5% yield (55 mg, 0.12 mmol).

The filtrate was re-purified by silica gel chromatography (MeOH/CH2CI2) to give 2-chloro-N- (2, 4-dichloro-5-methoxyphenyl)-5-fluoro-4-pyrimidinamine as a white solid in 33% yield (566 mg, 1.72 mmol).

2-Chloro-N-(2,4-dichloro-5-methoxyphenyl)-5-fluoro-4-pyrimid inamine : TLC: Rf = 0.34 (20% EtOAc/hexane; LC-MS (ESI) : [M+H] + 322. 1 @ RT 3.09 min. ;'H NMR (DMSO) 6 8.46 (1H, s), 8.18 (1H, d, J = 2.4 Hz), 7.56 (1H, b s), 7.43 (1H, s), 3.98 (3H, s). <BR> <BR> <BR> <P>N-(2, 4-dichloro-5-methOxyphenyl)-N-{2-[(2, 4-dichloro-5-methOxyphenyl) amino]-5-fluoro-4- pyrimidinyl} amine: TLC: Rf = 0.34 (20% EtOAc/hexane; LC-MS (ESI) : [M+H] + 479.2 @ RT

3.87 min. ; 1H NMR (DMSO) 8 8.23 (1H, s), 8.21 (1H, s), 8.10 (1H, d, J = 2.7 Hz), 7.43 (1H, s), 7.37 (1H, s), 7.34 (2H, b s), 3.79 (3H, s), 3.75 (3H, s).

Example 22 Method 22 Preparation of N-[4-({5-chloro-4-[(4fluorophenyl)amino]-2-pyrimidinyl}amino )-2- methylphenyl]acetamide Step 1: Preparation of 2. 5-dichloro-N- (4-fluorophenyl)-4-pyrimidinamine

To a suspension 2,4, 5-trichloropyrimidine (3.00 g, 16.4 mmol) and Na2CO3 (6.93 g, 65.4 mmol) in EtOH (200 mL) was added 4-fluoroaniline (2.18 g, 19.6 mmol) dropwise.

The reaction mixture was stirred at rt overnight. TLC and LCMS showed the reaction was complete. The mixture was filtered and the solvent evaporated in vacuo. The residue was dissolved in DCM and washed with brine. The organic layer was dried (Na2SO4) and concentrated to give 3.89 g of a white solid (92%).'H NMR (CD30D) : 8 8.20 (s, 1H), 7.59-7. 55 (q, 2H), 7.14-7. 09 (t, 2H); LCMS RT = 2.79 min; [M+H] + 258.

Step 2: Preparation of N-[4-({5-chloro-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}amin o)-2- methylphenyllacetamide

A suspension of 2, 5-dichloro-N- (4-fluorophenyl)-4-pyrimidinamine (121 mg, 0.47 mmol) and 1- (4-amino-2-methyl) phenylacetamide (93 mg, 0.56 mmol) in n-BuOH (1 mL) was stirred at 110 °C for 24 h. The resulting precipitate was filtered and washed with EtOH followed by Et2O to give 179 mg of a yellow solid (98%).'H NMR (CD30D) 6 8.07

(s, 1H), 7.55-7. 51 (q, 2H), 7.32-7. 30 (d, 1H), 7.25 (d, 1H), 7.18-7. 13 (m, 3H), 2.18 (s, 6H); LCMS RT = 2.56 min; [M+H] + 386.

Example 23 Method 23 Preparation of N-(4-amino-3-methylphenyl)-N-f5-chloro-4-r (4-fluorophenyl amino]-2- pyrimidinyl}amine To a suspension of N-[4-({5-chloro-4-[(4-fluorophenyl)amino]-2-pyrimidinyl} amino) - 2-methylphenyl]-acetamide (125 mg, 0.30 mmol) in n-BuOH (10mL) was added conc. HCI (2mL) dropwise. The mixture was stirred at 100 °C for 24 h. TLC and LCMS showed the reaction was complete. The reaction solution was evaporated in vacuo, and the residue was dissolved in DCM (210 mL). This was washed with 1M NaOH (10 mL) then brine (10 mL). The organic layers were dried (Na2SO4) and evaporated to furnish 92 mg of a white powder (89%). 1H NMR (CD30D) 6 7.90 (s, 1H), 7.61-7. 58 (q, 2H), 7.12-7. 11 (d, 1H), 7.05-7. 00 (m, 3H), 6.66-6. 64 (d, 1H), 2.11 (s, 3H); LCMS RT=0.32 min; [M+H] + 344.

Example 24 Method 24 Preparation of N-(4-{5-fluoro-4-[5-(1-methylcyclopropyl)-2H-pyrazol-3-ylami no]-pyrimidin- 2-vlaminoT-2-methylphenyl)-acetamide Step 1: Preparation of 5- 1-methylcycloprop r)-2H-pyrazol-3-vlamine

A suspension of NaH (60% dispersion in mineral oil) (4.20 g, 175 mmol) in anhydrous THF (100 mL) was treated with anhydrous CH3CN (9.14 mL, 175 mmol), and the suspension was stirred at ambient temperature for 10 min. To this was added 1- methylcyclopropane-1-carboxylic acid methyl ester (9.70 g, 83.3 mmol), and the reaction was heated to reflux for 24 h. The reaction was quenched by addition of abs EtOH (75 mL), and the slurry concentrated to a white solid. This was dissolved in H20 (100 mL) and further quenched with cone. HCI (20 mL) at 5 °C to a final pH of 2. This was extracted with EtOAc (3 X 250 mL), the combined organic layers dried (Na2SO4), and the solvent removed in vacuo to give the crude a-cyanoketone intermediate as an amber oil.

This was dissolved in abs EtOH (75 mL), hydrazine hydrate (8.62 g, 172 mmol) was added, and the solution was heated to reflux for 24 h. The reaction was concentrated in vacuo to an oil, which was purified by silica gel chromatography (5% MeOH/DCM) to give the product as an orange oil in 54% yield (7.11 g, 51.8 mmol). 1H NMR (CDC) s) 8 5.34 (s, 1H), 1.38 (s, 3H), 0.84 and 0.73 (2 m, 4H); LCMS RT = 0.77 min; [M+H] + = 138. 1.

Step 2: Preparation of (2-chloro-5-fluoropyrimidin-4-yl)-[5-(1-methylcyclopropyl)-2 H- pyrazol-3-yl]-amine A solution of 2, 4-dichloro-5-fluoropyrimidine (1.11 g, 6.58 mmol), 5- (1- methylcyclopropyl)-2H-pyrazol-3-ylamine (1.00 g, 6.58 mmol), and KOAc (0.780 g, 7.90 mmol) in H20 (10 mL) and THF (20 mL) was heated to 45 °C for 24 h. The reaction was quenched with sat. NaHC03 (100 mL) and extracted with EtOAc (2 X 250 mL). The combined organic layers were dried (Na2SO4) and concentrated to a white solid. The crude material was purified by silica gel chromatography (50% EtOAc/Hex) to give the product as a white solid in 93% yield (1.69 g, 6.31 mmol). 1H NMR (DMSO-d6) ã 12.17 (b s, 1H), 10.35 (s, 1H), 8.22 (d, J = 3.6 Hz, 1 H), 6.28 (s, 1 H), 1.37 (s, 3H), 0.87 and 0.75 (2 m, 4H); LCMS RT = 2.32 min; [M+H] + = 268.3. Step 3. Preparation of N-(4-{5-fluoro-4-[5-(1-methylcyclopropyl)-2H-pyrazol-3-ylami nol- pyrimidin-2-ylamino}-2-methylphenyl)-acetamide

The compound was prepared by the method described for Example 22, step 2, using the product of Example 24, step 2, and N-(4-amino-2-methylphenyl)-acetamide as starting materials. 1H NMR (DMSO-d6) 8 10.39 (b s, 1H), 10.04 (s, 1H), 9.43 (s, 1H), 8.19 (d, J=3. 9Hz, 1H), 7.96 (m, 2H), 7.34 (d, J = 8.7 Hz, 1H), 6.18 (s, 1H), 2.10 (s, 3H), 1.37 (s, 3H), 0.90 and 0.75 (2 m, 4H); LCMS RT = 2.11 min; [M+H] + = 450.3.

Example 25 Method 25 Preparation of N-(methylsulfonyl)-N-[4-[(5-methyl-4-{[2-(trifluoromethyl)be nzyl]amino}-2- pyrimidinyl aminol-2-(trifluoromethvl) phenYIlmethanesulfonamide To a mixture of N-[4-amino-3-(trifluoromethyl)phenyl]-N-(5-methyl-4-{[2- (trifluoromethyl) benzyl] amino}-2-pyrimidinyl) amine (200 mg, 0.45 mmol) and Et3N (44 mg, 1.36 mmol) in DCM (5 mL) was added methanesulfonyl chloride (62 mg, 0.54 mmol) at 0 °C. The solution was stirred at room temperature for 4 h then quenched with water.

DCM was added (25 mL) and the organic layer was washed with brine. The organic layer was dried (Na2SO4) and concentrated. The crude material was recrystallized from EtOAc/Hex (1: 1) to give the product as white solid in 56% yield (152 mg). H NMR (DMSO-d6) 8 9.54 (s, 1H) ; 8.26 (d, 1H) ; 7.84 (m, 2H); 7.75 (d, 1H) ; 7.61 (t, 1H) ; 7.45 (m, 3H); 7.34 (d, 1H) ; 4.87 (d, 2H); 3.48 (s, 6H); 2.06 (s, 3H); LCMS RT = 2.56 min; [M+H] + 598.0 Example 26 Method 26 Preparation of N-f5-chloro-4-f (4-fluorophenyl) aminol-2-pvrimyl-N- (4-4-f (4- fluorophenyl) sul'-1-piperazinylphenvl) amine

To a solution of N-(4-amino-3-trifluoromethylphenyl)-N-{5-bromo-4-[(4- bromophenyl) amino]-2-pyrimidinyl} amine (8.00 g, 15.9 mmol) and 4- (dimethylamino) pyridine (1.94 g, 15.9 mmol) in pyridine (250 mL) at 0 °C was added 1- methylimidazole-4-sulphonyl chloride (4.88 g, 27.0 mmol) in several portions. The reaction was stirred at rt for 48 h then quenched with MeOH. The reaction was concentrated and MeOH (100 mL) was added to the resulting residue. The resulting white precipitate was filtered and washed with Hex/EtOAc (1: 1) followed by MeOH to obtain the desired product in 84% yield (8.77 g). 1H NMR (DMSO-d6) : 8 9.69 (s, 1H), 9.47 (s, 1H), 8.80 (s, 1H), 8.29 (s, 1H), 7.90-7. 88 (dd, 2H), 7.82-7. 78 (dd, 1H), 7.69 (d, 1H), 7.57 (d, 2H), 7.48 (d, 2H), 7.11 (d, 1H), 3.72 (s, 3H); LCMS RT = 2.90 min; [M+H] + = 646.0 ; Anal.

Calcd. for C21H16Br2F3N7O2S : C, 38.97 ; H, 2.49 ; N, 15.15. Found: C, 38.97 ; H, 2.49 ; N, 15.11.

Example 27 Method 27 Preparation Preparation of N-{5-chloro-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}-N-(4-{4 -[(4- fluoropheny sulfonyll-1-piperazinyl phenvl) amine To a solution of N-{5-chloro-4-[(4-fluorophenyl)amino]-2-pyrimidinyl}-N-[4-(1 - piperazinyl) phenyl] amine (100 mg, 0.25 mmol) in DCM (2.0 mL) was added Et3N (0.10 mL, 0.75 mmol). After 5 min, 4-fluorobenzenesulfonyl chloride (146 mg, 0.75 mmol) was added, and the mixture stirred at rt for 24 h. The reaction was diluted with EtOAc (75 mL)

and washed with sat. NaHC03 (75 mL) and brine (75 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude product was rinsed with MeOH (5 mL) followed by DCM (5 mL) to afford pure product in 29% yield (40 mg). 1H NMR (DMSO-d6) 8 9.10 (s, 1H), 8.81 (s, 1H), 8.06 (s, 1H), 7.85 (t, 2H), 7.65 (t, 2H), 7.54 (t, 2H), 7.39 (d, 2H), 7.16 (t, 2H), 6.75 (d, 2H), 3.09 (b, 4H), 3.02 (b, 4H); LCMS RT = 2.78 min; [M+H] + 557.2.

Example 28 Method 28 Preparation of {5-bromo-4-f (4-methoxyphenyl)amino]pyrimidin-2-yl}(4-imidazolyl-3- methylphenyl) amine Step 1: Preparation of 1- !-1H-imidazole To a solution of 2-fluoro-5-nitrotoluene (5.00 g, 32.2 mmol) and 1H-imidazole (2.19 g, 32.2 mmol) in DMF (75 mL) was added K2CO3 (6.68 g, 48.3 mmol) in several portions. The reaction was heated to 80 °C overnight. The solvent was removed under vacuum. The residue was diluted with EtOAc (250 mL). The solution was washed with brine (75 mL X 5). The solution was concentrated in vacuo. The residue was filtered and washed with hexanes (20 mL X 3). The filter cake was then dried under vacuum to afford desired product as a yellow solid in 68% yield (4.43 g). 1H-NMR (CD30D) : 8 8.28 (d, 1 H), 8.15 (d, 1H), 7. 89 (s, 1H), 7.53 (d, 1H), 7.37 (s, 1H), 7.16 (s, 1H), 2.31 (s, 3H); LCMS RT = 0. 84 min ; [M+H] + = 204. 1.

Step 2: Preparation of 4-lmdazole-1-yl-3-methyl-phenylamine

A solution of 1-(2-methyl-4-nitro-phenyl)-1H-imidazole (3.43 g, 16.9 mmol) in EtOH (380 mL) was added to a flask containing 10% palladium on carbon (360 mg). The reaction vessel was fitted with a balloon adapter and charged with hydrogen and evacuated three times until the reaction was under a H2 atmosphere. The reaction was allowed to stir overnight and then purged with Ar and evacuated three times until an Ar atmosphere had been achieved. The reaction solution was filtered through a pad of Celite# and washed with copious amounts of EtOH. The filtrate was concentrated under vacuum to afford desired product in 94% yield (2.90 g) as a yellow solid. 1H-NMR (CD30D) : 5 7.60 (s, 1H), 7.09 (s, 1H), 7.04 (s, 1H), 6.90 (d, 1H), 6.65 (d, 1H), 6.52-6. 58 (dd, 1H), 1.97 (s, 3H); LCMS RT = 0.71 min; [M+H] + = 174.2.

Step 3: Preparation of f5-bromo-4-f (4-methoxyphenyl) aminolpyrimidin-2-yl,'(4-imidazolyl- 3-methylphenyl amine The compound was prepared by the method described for Example 22, step 2, step 2, using the product of Example 29, step 2 and 2, 5-dichloro-N- (4-methoxyphenyl)-4- pyrimidinamine as starting materials.'H NMR (CD30D) 8.06 (s, 1 H), 7.66 (s, 1 H), 7.55 (s, 1H), 7.38-7. 32 (m, 3H), 7.15 (s, 1H) 7.08 (s, 1H), 6.99 (d, 1H), 6.94 (s, 1H), 6.91 (s, 1H), 3.76 (s, 3H), 1.93 (s, 3H); LCMS RT = 1.91 min; [M+H] + = 451.3.

The compounds of Table I were made using a combination of the above described procedures, and the appropriate starting materials. The actual sequence of steps used to prepare each compound are indicated in Table I in the column labeled"method"for that compound, in which the entries refer to the specific synthetic methods described above.

Thus the preparation of each compound is achieved by carrying out each synthetic step in the order listed, using the appropriately substituted starting materials, as would be obvious to one skilled in the art.

Variations of the compounds of the invention can be readily prepared using the processes described above, or by other standard chemical processes known in the art, by employing appropriate starting materials that are readily available and/or are already described herein, as would be known by one skilled in the art.

Generally, a desired salt of a compound of this invention can be prepared in situ during the final isolation and purification of a compound by means well known in the art.

For example, a desired salt can be prepared by separately reacting the purified compound in its free base or free acid form with a suitable organic or inorganic acid, or suitable organic or inorganic base, respectively, and isolating the salt thus formed. In the case of basic compounds, for example, the free base is treated with anhydrous HCI in a suitable solvent such as THF, and the salt isolated as a hydrochloride salt. In the case of acidic compounds, the salts may be obtained, for example, by treatment of the free acid with anhydrous ammonia in a suitable solvent such as ether and subsequent isolation of the ammonium salt. These methods are conventional and would be readily apparent to one skilled in the art.

The purification of isomers of a compound of this invention, and the separation of said isomeric mixtures can be accomplished by standard techniques known in the art.

Compositions of the compounds of this invention The compounds of this invention can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment (including prophylactic treatment) for the particular condition or disease.

Therefore, another embodiment of the present invention includes pharmaceutical compositions that are comprised of a pharmaceutical acceptable carrier and a pharmaceutically effective amount of a compound, or salt or ester thereof, of the present invention.

A pharmaceutically acceptable carrier is any carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A pharmaceutical effective amount of compound is that amount which produces a result or exerts an influence on the particular condition being treated.

The compounds of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective

conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, otically, sublingually, rectally, vaginally, and the like.

For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms can be a capsule which can be of the ordinary hard-or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a 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 those sweetening, flavoring and coloring agents described above, may also be present.

The pharmaceutical compositions of this invention may also be in the form of oil- in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such

as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, 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 such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.

The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2, 2-dimethyl-1, 1-dioxolane-4-methanol, ethers such as poly (ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants.

Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil.

Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.

Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and

sulfosuccinates ; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly (oxyethylene-oxypropylene) s or ethylene oxide or propylene oxide copolymers ; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.

The parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulation ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.

Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.

The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylen oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial . ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

A composition of the 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-irritation 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 material are, for example, cocoa butter and polyethylene glycol.

Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e. g. , US Patent No. 5,023, 252, issued June 11,1991, incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations which are known in the art.

It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in US Patent No.

5,011, 472, issued April 30,1991.

The compositions of the invention can also contain other conventional pharmaceutical acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M. F. et a/,"Compendium of Excipients for Parenteral Formulations"PDA Journal of Pharmaceutical Science & Technology 1998, 52 (5), 238-311; Strickley, R. G"Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1"PDA Journal of Pharmaceutical Science & Technology 1999,53 (6), 324-349; and Nema, S. et a/,"Excipients and Their Use in Injectable Products"PDA Journal of Pharmaceutical Science & Technology 1997,51 (4), 166-171.

Commonly used pharmaceutical ingredients which can be used as appropriate to formulate the composition for its intended route of administration include:

acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine) ; adsorbents (examples include but are not limited to powdered cellulose and activated charcoal) ; aerosol propellants (examples include but are not limited to carbon dioxide, CCI2F2, F2CIC-CCIF2 and CCIF3) ; air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate) ; antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal) ; antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitat, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl galate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite) ; binding materials (examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene- butadiene copolymers) ; buffering agents (examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate); carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection); cheating agents (examples include but are not limited to edetate disodium and edetic acid); colorants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red); clarifying agents (examples include but are not. limited to bentonite);

emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate); encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate) ; flavorants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin) ; humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol) ; levigating agents (examples include but are not limited to mineral oil and glycerin); oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil) ; ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas); plasticizers (examples include but are not limited to diethyl phthalate and glycerol) ; solvents (examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax); suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures); surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono- palmitat) ; suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum);

sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (examples include but are not limited to magnesium stearate and talc) ; tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch); tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac) ; tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate); tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross- linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch); tablet glidants (examples include but are not limited to colloidal silica, corn starch and talc) ; tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); tablet/capsule opaquants (examples include but are not limited to titanium dioxide); tablet polishing agents (examples include but are not limited to carnuba wax and white wax); thickening agents (examples include but are not limited to beeswax, cetyl alcohol and paraffin); tonicity agents (examples include but are not limited to dextrose and sodium chloride) ; viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth); and wetting agents (examples include but are not limited to heptadecaethylene

oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

It is believed that one skilled in the art, utilizing the preceding information, can utilize the present invention to its fullest extent. Nevertheless, the following are examples of pharmaceutical formulations that can be used in the method of the present invention.

They are for illustrative purposes only, and are not to be construed as limiting the invention in any way.

Pharmaceutical compositions according to the present invention can be illustrated as follows : Sterile Injectable Solution A suitable amount of pure active ingredient is dissolved in sterile, injectable water to a desired concentration, for example from about 1.0 mg/ml to about 50.0 mg/ml.

U. S. P. grade sodium chloride crystals (NaCI) is added to the solution such that the final concentration of NaCI is 0.9% by weight of water. The pH of the solution is adjusted to range between approximately pH 2.0 and pH 6.0 by the addition of pure (99.999% purity) hydrochloric acid. The solution is sterilized via filtration through a sterile 0.22 micron filter.

The sterile solution is stored in sealed sterile vials wherein each vial contains the desired dosage unit of active ingredient per mi of injection solution.

Sterile Iniectable Solution U. S. P. grade sodium chloride (NaCI) is dissolved in sterile, injectable water to a final concentration of 0.9% NaCI by weight of water. An amount of pure (99.999% purity) hydrochloric acid is added to the NaCI solution to obtain a final pH in the range of approximately pH2.0 to pH6.0. An amount of U. S. P. grade potassium chloride crystals (KCL) is dissolved in the solution such that the final concentration of KCI is 0.1% by weight. From 0.5 part to about thirty parts by weight of active ingredient (depending on the desired end dosage unit) is added to the solution and is completely dissolved by agitation. The pH of the solution is adjusted again to between pH2.0 and pH6.0 using pure hydrochloric acid. The solution is sterilized via filtration through a sterile 0.22 micron filter and stored in sealed sterile injection vials, each containing approximately 0.5 mg to approximately 30 mg active ingredient, depending on the final dosage unit desired in the sterile injection solution.

Sterile IV Solution: A 5 mg/ml solution of the desired compound of this invention is made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for

administration to 1-2 mg/ml with sterile 5% dextrose and is administered as an IV infusion over 60 minutes.

Lyophilized powder for IV administration: A sterile preparation can be prepared with (i) 100-1000 mg of the desired compound of this invention as a lypholized powder, (ii) 32-327 mg/mL sodium citrate, and (iii) 300-3000 mg Dextran 40. The formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2-0. 4 mg/mL, and is administered either IV bolus or by IV infusion over 15-60 min.

Intramuscular suspension: The following solution or suspension can be prepared, for intramuscular injection: 50 mg/mL of the desired, water-insoluble compound of this invention 5 mg/mL sodium carboxymethylcellulose 4 mg/mL TWEEN 80 9 mg/mL sodium chloride 9 mg/mL benzyl alcohol Hard Shell Capsules : A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft Gelatin Capsules: A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.

Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules : These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction

techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.

Method of treating pharmacoloaical disorders The present invention also relates to a method of using the compounds or compositions described herein for the treatment or prevention of, or in the manufacture of a medicament for treating or preventing, mammalian hyper-proliferative disorders. This method comprises administering to a mammalian patient, including a human, in need thereof, an amount of a compound, a pharmaceutical acceptable salt thereof, or a composition of this invention that is effective to treat or prevent the disorder.

The present invention also relates to a method for using the compounds and compositions of this invention as prophylactic or chemopreventive agents for prevention of the mammalian hyper-proliferative disorders described herein. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt thereof, which is effective to delay or diminish the onset of the disorder.

The present compounds and compositions exhibit anti-proliferative activity and are thus useful to treat the disorders that are described below and/or otherwise known in the art. Hyper-proliferative disorders include diseases or conditions whose progression proceeds, at least in part, via proliferation.

Hyper-proliferative disorders include but are not limited to solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.

Those disorders also include lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are not limited to small- cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebella and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.

Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumors of the female reproductive organs include, but are not

limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, and urethra cancers.

Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal/hypopharyngeal /nasopharyngeal/oropharyngeal cancer, and lip and oral cavity cancer.

Lymphomas include, but are not limited to AIDS-related lymphom, non-Hodgkin's lymphom, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphom of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, and also exist with a similar etiology in other mammals which can also be treated by the administration of the compounds and/or pharmaceutical compositions of the present invention.

The utility of the compounds of the present invention can be illustrated, for example, by their activity in vitro in the in vitro tumor cell proliferation assay described below. The link between activity in tumor cell proliferation assays in vitro and anti-tumor activity in the clinical setting has been very well established in the art. For example, the therapeutic utility of taxol (Silvestrini et al. Stem Cells 1993,11 (6), 528-35), taxotere (Bissery et al. Anti Cancer Drugs 1995,6 (3), 339), and topoisomerase inhibitors (Edelman et al. Cancer Chemother. Pharmacol. 1996,37 (5), 385-93) were demonstrated with the use of in vitro tumor proliferation assays.

The following assays are two methods by which compound activity relating to treatment of the disorders identified herein can be determined.

Cellular Proliferation Assay (CTG) Protocol HCT-116 cells are seeded onto a 96-well culture plate at a density of 3000 cells per well in 100 uL DMEM medium supplemented with 10% Fetal Calf Serum and incubated overnight at 37°C in 5% C02 in a humidified incubator. To CTG measurements are taken as described below. Cells are then treated with test compounds serially diluted at 10,3. 3,1. 1,0. 33,0. 11, and 0.033uM and incubated for 3 days at 37°C in 5% C02 in a humidified incubator. Final concentration of DMSO in each well is 0. 1%. Following three days of incubation, 100 microliters of substrate/buffer mixture of CTG (Promega Cell Titer Glo Luminescents assay kit) are added to each well and incubated at room temperature for 30 minutes. Plates are then read in a luminometer to measure the amount of ATP present in the cell lysats, which corresponds to the number of viable cells. Values read at the time of compound administration to cells are subtracted as Day 0. For determination of IC50's, a linear regression analysis are used to determine drug concentration which results in a 50% inhibition of cell proliferation. Percent inhibition is calculated as follows : % inhibition = 1-(T72test-To) l (T72ctrl-To) x 100, where T72test = Value read in the presence of test compound at T = 72h T72Ctrl = Value read in the absence of test compound at T = 72h To = Value read in the absence of test compound at T = Oh This assay may also be run using HT1080 or DLD-1 cell lines following the same procedure.

In vivo assay : Groups of female Ncr nude mice [Taconic Laboratories, NY] were inoculated with 3x106 cells of HCT-116, a CRC xenograft on day 0. When tumors reached a 75 to 150 mm3 in size (typically 6-8 days), animals were administered compounds of interest p. o. in a Cremaphor (12.5% ; Sigma Aldrich, St. Louis, MO) : Ethanol (12.5%) : Saline (75%) vehicle for 14 days. The treatment volumes were 0. lmLl-test article/10g body weight. A group of 10 untreated animals was included to assess tumor response to test article vehicles. During the course of the study the animals tumor growth measurements and body weights were determined twice a week. All animals were observed for clinical signs daily and after compound administration. Tumor volume was calculated using the ellipsoid formula: (D x (d2))/2 where, D = diameter of the tumor at major axis

d = diameter of the tumor at minor axis Use of compounds of this invention in the assays described above demonstrate inhibition of cell proliferation.

Based upon the above and other standard laboratory techniques known to evaluate compounds useful for the prevention and/or treatment of the diseases or disorders described above by standard toxicity tests and by standard pharmacological assays for the determination of the prevention and/or treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for prevention and/or treatment of each desired indication. The amount of the active ingredient to be administered in the prevention and/or treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the duration of treatment (including prophylactic treatment), the age and sex of the patient treated, and the nature and extent of the condition to be prevented and/or treated.

The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 300 mg/kg, and preferably from about 0.10 mg/kg to about 150 mg/kg body weight per day. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day.

The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The daily inhalation dosage regimen will preferably be from 0. 01 to 100 mg/kg of total body weight.

Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of administration and number of doses of a compound of the present invention or a pharmaceutical acceptable salt or ester or composition thereof can be ascertained by those skilled in the

art using conventional prevention and/or treatment tests.

The compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. For example, the compounds of this invention can be combined with other anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof.

For example, optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine.

Other anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment and/or prevention of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by reference, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2', 2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine.

Other anti-hyper-proliferative agents suitable for use with the composition of this invention include but are not limited to other anti-cancer agents such as epothilone, irinotecan, raloxifen and topotecan.

It is believed that one skilled in the art, using the preceding information and information available in the art, can utilize the present invention to its fullest extent.

It should be apparent to one of ordinary skill in the art that changes and modifications can be made to this invention without departing from the spirit or scope of the invention as it is set forth herein. Numerous modifications and variations in the invention as described in the above illustrative examples are expected to occur to those skilled in the art and consequently only those limitations as appear in the appended claims should be placed thereon. Accordingly it is intended in the appended claims to cover all such equivalent variations which come within the scope of the invention as 5 claimed.