DERIVATIVES OF MACROCYCLIC N-ARYL-2-AMINO-4-ARYL-PYRIMIDINE POLYETHERS AS INHIBITORS OF FTL3 AND JAK

Abstract

The present invention relates to a compound with the following formula: formula (I) or a salt and/or a pharmaceutically acceptable solvate thereof, in particular for use as a drug, in particular in the treatment of cancer, as well as to the pharmaceutical compositions that contain same and to the methods for preparing same.

Claims

1-17. (canceled)

18. A compound of the following general formula (I): ##STR00080## or a pharmaceutically acceptable salt and/or solvate thereof, wherein: W represents an oxygen or sulfur atom, Y represents a nitrogen atom or a CRy group wherein Ry represents a hydrogen atom, a halogen atom, a (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)haloalkoxy, OH, CN, NO.sub.2, NR.sub.12R.sub.13, CO.sub.2H or CO.sub.2((C.sub.1-C.sub.6)alkyl) group, Z represents a (CR.sub.Q1R.sub.Q2).sub.nQ(CR.sub.Q3R.sub.Q4).sub.m group, wherein n and m represent, independently of each other, an integer between 0 and 3, Q represents O, S, S(O) or S(O).sub.2, R.sub.Q1, R.sub.Q2, R.sub.Q3 and R.sub.Q4 represent, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group, R.sub.1, R.sub.2, R.sub.1′ and R.sub.2′ represent, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group, R.sub.3, R.sub.4, R.sub.3′ and R.sub.4′ represent, independently of each other, a hydrogen atom, a (C.sub.1-C.sub.6)alkyl or OH group or R.sub.3 and R.sub.4 and/or R.sub.3′ and R.sub.4′ together form, with the carbon atom that bears them, an optionally substituted monocyclic carbocycle or heterocycle, R.sub.5 and R.sub.6 represent, independently of each other, a hydrogen atom, a halogen atom, a (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)haloalkoxy, (C.sub.1-C.sub.6)thioalkoxy, (C .sub.1-C.sub.6)halothioalkoxy, OH, SH, CN, NO.sub.2, or NR.sub.7R.sub.8 group, R.sub.9 and R.sub.10 represent, independently of each other, a hydrogen atom, a halogen atom, an optionally substituted (C.sub.1-C.sub.6)alkyl, optionally substituted (C.sub.2-C.sub.6)alkenyl, optionally substituted (C.sub.2-C.sub.6)alkynyl, optionally substituted (C.sub.1-C.sub.6)alkoxy, optionally substituted (C.sub.1-C.sub.6)thioalkoxy, CN, NO.sub.2, OH, SH, NR.sub.14R.sub.15, CO.sub.2R.sub.54, CONR.sub.55R.sub.56 group, an optionally substituted carbocycle or an optionally substituted heterocycle, R.sub.11 represents a hydrogen atom, a halogen atom, or a (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl, (C.sub.1-C.sub.6)alkoxy or (C.sub.1-C.sub.6)haloalkoxy group, and R.sub.7, R.sub.8, R.sub.12, R.sub.13, R.sub.14, R.sub.15, R.sub.54, R.sub.55 and R.sub.56 represent, independently of each other, a hydrogen atom or an optionally substituted (C.sub.1-C.sub.6)alkyl, optionally substituted (C.sub.2-C.sub.6)alkenyl, or optionally substituted (C.sub.2-C.sub.6)alkynyl group, or R.sub.7 and R.sub.8, R.sub.12 and R.sub.13, R.sub.14 and R.sub.15 and/or R.sub.55 and R.sub.56, independently of each other, form with the nitrogen atom that bears them an optionally substituted nitrogen containing heterocycle.

19. The compound according to claim 18, wherein Z represents an oxygen atom and R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.1′, R.sub.2′, R.sub.3′ and R.sub.4′ each represent a hydrogen atom.

20. The compound according to claim 18, wherein Y represents a CRy group wherein Ry represents a hydrogen atom or a halogen atom.

21. The compound according to claim 18, wherein R.sub.11 represents a hydrogen atom or a halogen atom.

22. The compound according to claim 18, wherein R.sub.5 and R.sub.6 represent, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group.

23. The compound according to claim 18, wherein R.sub.9 and R.sub.10 represent, independently of each other, a hydrogen atom, a halogen atom, CO.sub.2R.sub.54, CONR.sub.55R.sub.56, or a (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)thioalkoxy, (C.sub.1-C.sub.6)alkyl-amino, di((C.sub.1-C.sub.6)alkyl)amino or heterocycle group, said group being optionally substituted by one or more substituents selected from: a halogen atom, a (C.sub.1-C.sub.6)alkyl group optionally substituted by one or more groups selected from a halogen atom, OR.sub.16, SR.sub.17, NR.sub.18R.sub.19, a carbocycle and a heterocycle, oxo (═O), CN, NO.sub.2, OR.sub.20, SR.sub.21, NR.sub.22R.sub.23, C(O)R.sub.24, CO.sub.2R.sub.25, OC(O)R.sub.26, S(O)R.sup.27, SO.sub.2R.sub.28, NR.sub.29C(O)R.sub.30, C(O)NR.sub.31R.sub.32, NR.sub.33CO.sub.2R.sub.34, OC(O)NR.sub.35R.sub.36, NR.sub.37CONR.sub.38R.sub.39 and OCO.sub.2R.sub.40 groups, a carbocycle optionally substituted by one or more groups selected from a halogen atom, a (C.sub.1-C.sub.6)alkyl group, oxo (═O), OR.sub.41, SR.sub.42 and NR.sub.43R.sub.44, a heterocycle optionally substituted by one or more groups selected from a halogen atom, a (C.sub.1-C.sub.6)alkyl group, oxo (═O), OR.sub.45, SR.sub.46 and NR.sub.47R.sub.48, and an —O(CH.sub.2).sub.nO— group wherein n represents an integer between 1 and 5, wherein: R.sub.16 to R.sub.48 represent, independently of each other, a hydrogen atom, a (C.sub.1-C.sub.6)alkyl, aryl, aryl-(C.sub.1-C.sub.6)alkyl, heterocycle or heterocycle-(C.sub.1-C.sub.6)alkyl group, the aryl ring of these groups being optionally substituted by one or more groups selected from a halogen atom and a (C.sub.1-C.sub.6)alkyl group, and the heterocyclic ring of these groups being optionally substituted by one or more groups selected from a halogen atom, a (C.sub.1-C.sub.6)alkyl group, and oxo (═O), or R.sub.22 and R.sub.23, R.sub.31 and R.sub.32, R.sub.35 and R.sub.36, R.sub.38 and R.sub.39, R.sub.43 and R.sub.44, and/or R.sub.47 and R.sub.48 together form, with the nitrogen atom that bears them, a nitrogen containing heterocycle optionally substituted by one or more groups selected from a halogen atom, a (C.sub.1-C.sub.6)alkyl group, and oxo (═O).

24. The compound according to claim 18, wherein R.sub.9 and R.sub.10 represent, independently of each other: a hydrogen or halogen atom, a CO.sub.2R.sub.54 group wherein R.sub.54 represents a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group, a CONR.sub.55R.sub.56 group wherein R.sub.55 and R.sub.56 form with the nitrogen atom that bears them a nitrogen containing heterocycle having 5, 6 or 7 members, comprising 1 or 2 heteroatoms selected from N and O of which at least one is a nitrogen atom, optionally substituted by one or more substituents selected from a halogen atom, (C.sub.1-C.sub.6)alkyl, oxo (═O), OR.sub.20, NR.sub.22R.sub.23, CO.sub.2R.sub.25, C(O)NR.sub.31R.sub.32, NR.sub.33CO.sub.2R.sub.34, OC(O)NR.sub.35R.sub.36, NR.sub.37CONR.sub.38R.sub.39 and OCO.sub.2R.sub.40, a —Z.sub.1—(CH.sub.2).sub.m—R.sub.49 group wherein Z.sub.1 represents a single bond, CH.sub.2—CH.sub.2, CH═CH, C≡C, O, S or NR.sub.50; m represents an integer between 1 and 6; R.sub.50 represents a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group; and R.sub.49 represents a halogen atom, OR.sub.20, NR.sub.22R.sub.23, C(O)R.sub.24, CO.sub.2R.sub.25, OC(O)R.sub.26, NR.sub.29C(O)R.sub.30, C(O)NR.sub.31R.sub.32, NR.sub.33CO.sub.2R.sub.34, OC(O)NR.sub.35R.sub.36, NR.sub.37CONR.sub.38R.sub.39 or OCO.sub.2R.sub.40, or a heterocycle having 5, 6 or 7 members, comprising 1 or 2 heteroatoms selected from N and O, optionally substituted by one or more substituents selected from: a halogen atom, a (C.sub.1-C.sub.6)alkyl group optionally substituted by one or more groups selected from a halogen atom, OR.sub.16, NR.sub.18R.sub.19, a C.sub.3 to C.sub.6 monocyclic carbocycle and a 3- to 6-membered monocyclic heterocycle comprising 1 or 2 heteroatoms selected from N and O, oxo (═O), OR.sub.20, NR.sub.22R.sub.23, C(O)R.sub.24, CO.sub.2R.sub.25, OC(O)R.sub.26, NR.sub.29C(O)R.sub.30, C(O)NR.sub.31R.sub.32, NR.sub.33CO.sub.2R.sub.34, OC(O)NR.sub.35R.sub.36, NR.sub.37CONR.sub.38R.sub.39 or OCO.sub.2R.sub.40 groups, a C.sub.3 to C.sub.6 carbocycle optionally substituted by one or more groups selected from a halogen atom, a (C.sub.1-C.sub.6)alkyl group, oxo (═O), OR.sub.41 and NR.sub.43R.sub.44, a 3- to 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O, optionally substituted by one or more groups selected from a halogen atom, a (C.sub.1-C.sub.6)alkyl group, oxo (═O), OR.sub.45 and NR.sub.47R.sub.48, and an —O(CH.sub.2).sub.nO— group wherein n represents an integer equal to 2 or 3, wherein: R.sub.16, R.sub.18 to R.sub.20, R.sub.22 to R.sub.26, R.sub.29 to R.sub.40, R.sub.45 and R.sub.47 to R.sub.48 represent, independently of each other, a hydrogen atom, a (C.sub.1-C.sub.6)alkyl, aryl, or aryl-(C.sub.1-C.sub.6)alkyl group, the aryl ring of these groups being a phenyl group and being optionally substituted by one or more groups selected from a halogen atom and a (C.sub.1-C.sub.6)alkyl group, or R.sub.22 and R.sub.23, R.sub.31 and R.sub.32, R.sub.35 and R.sub.36, R.sub.38 and R.sub.39, R.sub.43 and R.sub.44, and/or R.sub.47 and R.sub.48 together form, with the nitrogen atom that bears them, a 5- or 6-membered nitrogen containing heterocycle, optionally comprising 1 heteroatom in addition to the nitrogen atom selected from N and O, the heterocycle being optionally substituted by one or more groups selected from a halogen atom, a (C.sub.1-C.sub.6)alkyl group, and oxo (═O).

25. The compound according to claim 18, wherein it is selected from the following compounds: ##STR00081## ##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088## and the pharmaceutically acceptable salts and/or solvates thereof.

26. A pharmaceutical composition comprising at least one compound according to claim 18 and at least one pharmaceutically acceptable excipient.

27. A method for preparing a compound of formula (I) according to claim 18 comprising the coupling reaction between: a compound of the following formula (II): ##STR00089## wherein W, Y, R.sub.5, R.sub.6, R.sub.9, R.sub.10 and R.sub.11 are as defined in claim 1, and a compound of the following formula (III): ##STR00090## wherein Z, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.1′, R.sub.2′, R.sub.3′ and R.sub.4′ are as defined in claim 1, and LG.sub.1 and LG.sub.2 each represent, independently of each other, a leaving group.

28. A method for preparing a compound according to claim 18 comprising the cyclization reaction of a compound of the following formula (VIa) or (VIb): ##STR00091## wherein W, Y, Z, R.sub.1 to R.sub.6, R.sub.9 to R.sub.11 and R.sub.1′ to R.sub.4′ are as defined in claim 1, and LG.sub.1 and LG.sub.2 each represent, independently of each other, a leaving group.

29. A method for preparing a compound according to claim 18, wherein R.sub.9 and/or R.sub.10 represents an optionally substituted (C.sub.1-C.sub.6)alkoxy, optionally substituted (C.sub.1-C.sub.6)thioalkoxy or NR.sub.14R.sub.15 group or an optionally substituted heterocycle comprising a heteroatom directly attached to the phenyl ring, comprising the coupling between a compound of the following formula (IVa) or (IVb): ##STR00092## wherein W, Y, Z, R.sub.1 to R.sub.6, R.sub.9 to R.sub.11 and R.sub.1′ to R.sub.4′ are as defined in claim 1 and X.sub.1 represents a halogen atom, and respectively a compound of formula R.sub.9H or R.sub.10H wherein R.sub.9 and R.sub.10 are as defined above.

30. A method for preparing a compound according to claim 18, wherein R.sub.9 and/or R.sub.10 represents an optionally substituted (C.sub.1-C.sub.6)alkyl, optionally substituted (C.sub.2-C.sub.6)alkenyl or optionally substituted (C.sub.2-C.sub.6)alkynyl group, an optionally substituted carbocycle or an optionally substituted heterocycle attached to the phenyl ring by means of a carbon atom, comprising the coupling between a compound of the following formula (Va) or (Vb): ##STR00093## wherein W, Y, Z, R.sub.1 to R.sub.6, R.sub.9 to R.sub.11 and R.sub.1′ to R.sub.4′ are as defined in claim 1 and X.sub.2 represents Br, Cl, I or OTf (OSO.sub.2CF.sub.3), and respectively a compound of formula R.sub.9—BR.sub.52R.sub.53 or R.sub.10—BR.sub.52R.sub.53 wherein R.sub.9 and R.sub.10 are as defined above and R.sub.52 and R.sub.53 represent, independently of each other, an OH, (C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkoxy group or R.sub.52 and R.sub.53 together form an —X.sub.3— or —O—X.sub.3—O— chain wherein X.sub.3 represents a divalent hydrocarbon group comprising 2 to 15 carbon atoms.

31. The method for preparing a compound according to claim 24, wherein R.sub.9 and/or R.sub.10 represents —Z.sub.1—(CH.sub.2).sub.m—R.sub.49 wherein Z.sub.1 represents CH.sub.2—CH.sub.2, CH═CH or C≡C, comprising the following steps: (1) Sonogashira coupling between a compound of formula (Va) or (Vb) as defined in claim 15, and a compound of formula HC≡C—(CH.sub.2).sub.m—R.sub.19 wherein m and R.sub.49 are as defined in claim 7, to give a compound of formula (I) wherein R.sub.9 or R.sub.10 represents —C≡C—(CH.sub.2).sub.m—R.sub.49, and (2) optionally reduction of the alkyne function of the compound of formula (I) obtained in the preceding step to give a compound of formula (I) wherein R.sub.9 or R.sub.10 represents —CH═CH—(CH.sub.2).sub.m—R.sub.49 or —(CH.sub.2).sub.m+2—R.sub.49.

32. A method for preparing a compound according to claim 18, wherein R.sub.9 and/or R.sub.10 represents a CO.sub.2R.sub.54 or CONR.sub.55R.sub.56 group, which comprises at least one of the following steps: (a) to obtain a compound of formula (I) wherein R.sub.9 and/or R.sub.10 represents a CO.sub.2H group, the reaction of a compound of formula (I) wherein R.sub.9 and/or R.sub.10 represents a halogen atom with CO.sub.2; (b) to obtain a compound of formula (I) wherein R.sub.9 and/or R.sub.10 represents a CO.sub.2R.sub.54 group with R.sub.54≠H, the substitution reaction of a compound of formula (I) wherein R.sub.9 and/or R.sub.10 represents a CO.sub.2H group, optionally obtained according to step (a), optionally in an activated form, with an alcohol of formula R.sub.54OH; (c) to obtain a compound of formula (I) wherein R.sub.9 and/or R.sub.10 represents a CONR.sub.55R.sub.56 group, the substitution reaction of a compound of formula (I) wherein R.sub.9 and/or R.sub.10 represents a CO.sub.2H group, optionally obtained according to step (a), optionally in an activated form, with an amine of formula HNR.sub.55R.sub.56.

33. The compound according to claim 23, wherein n represents an integer equal to 2 or 3.

34. The compound according to claim 24, wherein R.sub.9 and R.sub.10 represent, independently of each other: a hydrogen or halogen atom, a CO.sub.2R.sub.54 group wherein R.sub.54 represents a hydrogen atom, a CONR.sub.55R.sub.56 group wherein R.sub.55 and R.sub.56 form with the nitrogen atom that bears them a saturated nitrogen containing heterocycle having 5, 6 or 7 members, comprising 1 or 2 heteroatoms selected from N and O of which at least one is a nitrogen atom, optionally substituted by one or more substituents selected from a halogen atom, (C.sub.1-C.sub.6)alkyl, oxo (═O), OR.sub.20, NR.sub.22R.sub.23, CO.sub.2R.sub.25 and C(O)NR.sub.31R.sub.32, a —Z.sub.1—(CH.sub.2).sub.m—R.sub.49 group wherein Z.sub.1 represents a single bond, CH.sub.2—CH.sub.2, C≡C, O or NR.sub.50; m represents an integer between 1 and 4; R.sub.50 represents a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group; and R.sub.49 represents OR.sub.20, NR.sub.22R.sub.23, CO.sub.2R.sub.25, C(O)NR.sub.31R.sub.32, NR.sub.33CO.sub.2R.sub.34, OC(O)NR.sub.35R.sub.36, NR.sub.37CONR.sub.38R.sub.39 or OCO.sub.2R.sub.40, or a saturated or aromatic heterocycle having 6 or 7 members, comprising 1 or 2 heteroatoms selected from N and O and comprising at least one nitrogen atom, optionally substituted by one or more substituents selected from: a halogen atom, a (C.sub.1-C.sub.6)alkyl group optionally substituted by one or more groups selected from a halogen atom, OR.sub.16, NR.sub.18R.sub.19, a C.sub.3 to C.sub.6 monocyclic carbocycle and a 3- to 6-membered monocyclic heterocycle comprising 1 or 2 heteroatoms selected from N and O, oxo (═O), OR.sub.20, NR.sub.22R.sub.23, CO.sub.2R.sub.25, C(O)NR.sub.31R.sub.32, NR.sub.33CO.sub.2R.sub.34, OC(O)NR.sub.35R.sub.36, NR.sub.37CONR.sub.38R.sub.39 or OCO.sub.2R.sub.40 groups, a C.sub.3 to C.sub.6 carbocycle optionally substituted by one or more groups selected from a halogen atom, a (C.sub.1-C.sub.6)alkyl group, oxo (═O), OR.sub.41 and NR.sub.43R.sub.44, a saturated 3- to 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O, optionally substituted by one or more groups selected from a halogen atom, a (C.sub.1-C.sub.6)alkyl group, oxo (═O), OR.sub.45 and NR.sub.47R.sub.48, and an —O(CH.sub.2).sub.nO— group wherein n represents an integer equal to 2 or 3, wherein: R.sub.16, R.sub.18 to R.sub.20, R.sub.22 to R.sub.26, R.sub.29 to R.sub.40, R.sub.45 and R.sub.47 to R.sub.48 represent, independently of each other, a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group, or R.sub.22 and R.sub.23, R.sub.31 and R.sub.32, R.sub.35 and R.sub.36, R.sub.38 and R.sub.39, R.sub.43 and R.sub.44, and/or R.sub.47 and R.sub.48 together form, with the nitrogen atom that bears them, a heterocycle selected from piperazine, piperidine, morpholine and pyrrolidine, the heterocycle being optionally substituted by one or more groups selected from a halogen atom, a (C.sub.1-C.sub.6)alkyl group, and oxo (═O).

35. The compound according to claim 34, wherein R.sub.49 represents NR.sub.22R.sub.23, NR.sub.33CO.sub.2R.sub.34, or NR.sub.37CONR.sub.38R.sub.39.

36. The method according to claim 28, wherein LG.sub.1 and LG.sub.2 each represent, independently of each other, a halogen atom.

37. A method for the treatment of cancer comprising the administration to a person in need thereof of an effective dose of a compound according to claim 18.

Description

EXAMPLES

[0268] 1. Synthesis of the Compounds According to the Invention

[0269] The following abbreviations were used:

[0270] DMSO: Dimethylsulfoxide

[0271] EI: Electron impact

[0272] LCMS: Liquid chromatography coupled to mass spectrometry

[0273] NMR: Nuclear magnetic resonance

[0274] Compound 1:

##STR00013##

[0275] Step 1: 3-(2-chloropyrimidin-4-yl)phenol (intermediate 1)

##STR00014##

[0276] To 5 g (33.6 mmol) of 2,4-dichloropyrimidine in 250 mL of anhydrous tetrahydrofuran (THF) is added 4.41 g (32 mmol) of (3-hydroxyphenyl)boronic acid. The reaction mixture is stirred at room temperature for 10 minutes then 8.47 g (80 mmol) of sodium carbonate dissolved in 20 mL of water then 462 mg (1.59 mmol) of tetrakis(triphenylphosphine)palladium(0) is added at room temperature. The reaction mixture is stirred at 90° C. for 16 hours. Ethyl acetate is added and the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate is evaporated and the residue purified by silica column chromatography using Companion® (eluent: cyclohexane/ethyl acetate: 0 to 10%) to afford 1.54 g (23%) of 3-(2-chloropyrimidin-4-yl)phenol as a white solid.

[0277] LCMS (EI, m/z): (M+1) 207.62

[0278] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.82 (1H, s, OH), 8.79-8.80 (1H, d, CH.sub.arom), 8.06-8.08 (1H, d, CH.sub.arom), 7.61-7.62 (2H, m, CH.sub.arom), 7.35-7.39 (1H, d, CH.sub.arom), 6.99-7.01 (1H, t, CH.sub.arom)

[0279] Step 2: 3-(2-((3-hydroxyphenyl)amino)pyrimidin-4-yl)phenol (intermediate 2)

##STR00015##

[0280] In a microwave reactor are mixed 150 mg (0.726 mmol) of 3-(2-chloropyrimidin-4-yl)phenol, 103 mg (0.944 mmol) of 3-aminophenol and 0.5 mL of N-methyl-2-pyrrolidinone. The reaction mixture is heated to 150° C. for 15 minutes. After returning to room temperature, the reaction mixture is hydrolyzed by addition of water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: dichloromethane/methanol: 95:5) to afford 129 mg (63%) of 3-(2-((3-hydroxyphenyl)amino)pyrimidin-4-yl)phenol as a yellow solid.

[0281] LCMS (EI, m/z): (M+1) 280.29

[0282] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.68 (1H, s, OH), 9.50 (1H, s, NH), 9.24 (1H, s, OH), 8.50-8.51 (1H, d, CH.sub.arom), 7.54-7.58 (2H, m, CH.sub.arom), 7.28-7.35 (4H, m, CH.sub.arom), 7.07-7.09 (1H, m, CH.sub.arom), 6.93-6.95 (1H, m, CH.sub.arom), 6.37-6.39 (1H, d, CH.sub.arom)

[0283] Step 3: Compound 1

[0284] To a stirred solution of 47.7 mg (0.171 mmol) of 3-(2-((3-hydroxyphenyl)amino)pyrimidin-4-yl)phenol in 12.5 mL of N,N-dimethylformamide is added 54.3 mg (0.393 mmol) of potassium carbonate then 21.47 μL (0.171 mmol) of 1-bromo-2-(2-bromoethoxy)ethane in 0.2 mL of N,N-dimethylformamide for one hour. The reaction mixture is stirred at 80° C. for 5 hours. After returning to room temperature, the solvent is evaporated, water is added and the solid formed is filtered and dried under vacuum to afford 5.3 mg (9%) of compound 1 as a beige powder.

[0285] LCMS (EI, m/z): (M+1) 350.38

[0286] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.83 (1H, s, NH), 8.68 (1H, m, CH.sub.arom), 8.58-8.59 (1H, d, CH.sub.arom), 8.29 (1H, S, CH.sub.arom), 7.73-7.75 (1H, m, CH.sub.arom), 7.42-7.50 (2H, m, CH.sub.arom), 7.10-7.21 (2H, m, CH.sub.arom), 6.84-6.85 (1H, m, CH.sub.arom), 6.53-6.55 (1H, m, CH.sub.arom), 4.31-4.35 (2H, t, CH.sub.2), 4.04 (2H, m, CH.sub.2), 3.93 (4H, m, CH.sub.2).

[0287] Compound 2:

##STR00016##

[0288] Step 1: 3-((2-(2-bromoethoxy)ethyl)thio)aniline (intermediate 3)

##STR00017##

[0289] To a stirred solution of 3 g (23.9 mmol) of 3-aminobenzenethiol in 30 mL of NA dimethylformamide is added 3.97 g (28 mmol) of potassium carbonate then 5.56 g (23.9 mmol) of 1-bromo-2-(2-bromoethoxy)ethane. The reaction mixture is stirred at 25° C. for 4 hours. The reaction mixture is hydrolyzed by addition of water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate/cyclohexane: 70:30) to afford 1.4 g (21%) of 3-((2-(2-bromoethoxy)ethyl)thio)aniline in the form of an oil.

[0290] LCMS (EI, m/z): (M+1) 277.19

[0291] .sup.1H NMR: dH ppm (400 MHz, DMSO): 7.01-7.05 (1H, s, CH.sub.arom), 6.69-6.72 (1H, m, 6.61-6.64 (1H, d, CH.sub.arom), 6.51-6.53 (1H, d, CH.sub.arom), 3.68-3.75 (2H, m, CH.sub.2), 3.54-3.68 (4H, m, CH.sub.2), 3.07-3.09 (2H, m, CH.sub.2).

[0292] Step 2: 3-(2-((3-((2-(2-bromoethoxy)ethyl)thio)phenyl)amino)pyrimidin-4-yl)phenol (intermediate 4)

##STR00018##

[0293] In a microwave reactor are mixed 134 mg (0.484 mmol) of 3-((2-(2-bromoethoxy)ethyl)thio)aniline and 0.1 g (0.484 mmol) of 3-(2-chloropyrimidin-4-yl)phenol in 0.5 mL of N-methyl-2-pyrrolidinone. The reaction mixture is heated to 150° C. for 15 minutes. After returning to room temperature, the reaction mixture is hydrolyzed by addition of water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate/cyclohexane: 70:30) to afford 27 mg (12%) of 3-(2-((3-((2-(2-bromoethoxy)ethyl)thio)phenyl)amino)pyrimidin-4-yl)phenol as a yellow solid.

[0294] LCMS (EI, m/z): (M+1) 447.36

[0295] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.70 (1H, s, NH), 9.70 (1H, s, CH.sub.arom), 8.54-8.55 (1H, d, CH.sub.arom), 7.91 (1H, s, CH.sub.arom), 7.67 (1H, d, CH.sub.arom), 7.54-7.58 (2H, m, CH.sub.arom), 7.33-7.34 (2H, m, CH.sub.arom), 7.26 (1H, t, CH.sub.arom), 6.94-6.96 (2H, m, CH.sub.arom), 3.66-3.68 (6H, m, CH.sub.2), 3.14-3.17 (2H, m, CH.sub.2).

[0296] Step 3: Compound 2

[0297] In a 50 mL round-bottom flask and under nitrogen are mixed 27 mg (0.060 mmol) of 3-(2-((3-((2-(2-bromoethoxy)ethyl)thio)phenyl)amino)pyrimidin-4-yl)phenol, 5.09 mg (0.091 mmol) of potassium hydroxide and 1.027 mg (3.02 μmol) of tetrabutylammonium hydrogensulfate in 1 mL of tetrahydrofuran. The reaction mixture is heated to 80° C. for 2 hours. After returning to room temperature, the reaction is hydrolyzed by addition of water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate/cyclohexane: 50:50) to afford 7 mg (31%) of compound 2 as a yellow solid.

[0298] LCMS (EI, m/z): (M+1) 366.44

[0299] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.77 (1H, s, NH), 8.53-8.57 (2H, m, CH.sub.arom), 8.03 (1H, s, CH.sub.arom), 7.64-7.66 (1H, s, CH.sub.arom), 7.41-7.47 (2H, m, CH.sub.arom), 7.22-7.26 (1H, m, CH.sub.arom), 7.16-7.18 (1H, m, CH.sub.arom), 7.04-7.08 (2H, d, CH.sub.arom), 4.25-4.28 (2H, t, CH.sub.2), 3.75-3.77 (2H, t, CH.sub.2), 3.69-3.72 (2H, t, CH.sub.2), 3.17-3.21 (2H, t, CH.sub.2).

[0300] Compound 3:

##STR00019##

[0301] Step 1: (E)-3-(dimethylamino)-1-(3-methoxyphenyl)prop-2-en-1-one (intermediate 5)

##STR00020##

[0302] In a microwave reactor are mixed 2 g (13.32 mmol) of 1-(3-methoxyphenyl)ethanone and 11.50 mL (87 mmol) of N,N-dimethylformamide dimethyl acetal. The reaction mixture is heated to 200° C. for 10 minutes. After returning to room temperature, the residue is concentrated to afford 2.250 g (82%) of (E)-3-(dimethylamino)-1-(3-methoxyphenyl)prop-2-en-1-one as a yellow oil,

[0303] LCMS (EI, m/z): (M+1) 206.25

[0304] .sup.1H NMR: dH ppm (400 MHz, DMSO): 7.69-7.72 (1H, d, CH.sub.arom), 7.44-7.46 (2H, m, CH.sub.arom and CH vinyl), 7.28-7.32 (1H, t, CH.sub.arom), 6.98-7.01 (1H, dd, CH.sub.arom), 5.67-5.70 (1H, d, CH vinyl), 3.84(3H, s, CH.sub.3), 3.12 (3H, s, CH.sub.3), 2.90 (3H, s, CH.sub.3).

[0305] Step 2: 4-(3-methoxyphenyl)-2-(methylthio)pyrimidine (intermediate 6)

##STR00021##

[0306] To 2.70 g (13.15 mmol) of (E)-3-(dimethylamino)-1-(3-methoxyphenyl)prop-2-en-1-one in 20 mL of N,N-dimethylformamide is added 5.49 g (19.73 mmol) of 5-methylisothiourea hemisulfate then 3.23 g (32.9 mmol) of potassium acetate. The reaction mixture is heated to 85° C. overnight. After returning to room temperature, the solvent is evaporated, the reaction is hydrolyzed by addition of water, basified and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated to afford an oil which is used as such for the following step,

[0307] LCMS (EI, m/z): (M+1) 233.30

[0308] Step 3: 4-(3-methoxyphenyl)-2-(methylsulfonyl)pyrimidine (intermediate 7)

##STR00022##

[0309] To 2.091 g (9 mmol) of 4-(3-methoxyphenyl)-2-(methylthio)pyrimidine in 30 mL of dichloromethane is added 4.66 g (27.0 mmol) of meta-chloroperbenzoic acid at 0° C. in small portions. The reaction mixture is stirred at 25° C. for 3 hours. The solvent is evaporated, the reaction is hydrolyzed by addition of water, basified and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated to afford 0.600 g (25.2%) of 4-(3-methoxyphenyl)-2-(methylsulfonyl)pyrimidine as a yellow solid.

[0310] LCMS (EI, m/z): (M+1) 265.30

[0311] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.11-9.12 (1H, d, CH.sub.arom), 8.42-8.43 (1H, m, CH.sub.arom), 7.88-7.90 (1H, d, CH.sub.arom), 7.81-7.82 (1H, t, CH.sub.arom), 7.51-7.55 (1H, t, CH.sub.arom), 7.21-7.24 (1H, dd, CH.sub.arom), 3.87 (3H, s, CH.sub.3), 3.50 (3H, s, CH.sub.3).

[0312] Step 4: N-(4-bromo-3-methoxyphenyl)-4-(3-methoxyphenyl)pyrimidin-2-amine (intermediate 8)

##STR00023##

[0313] In a microwave reactor are mixed 150 mg (0.57 mmol) of 4-(3-methoxyphenyl)-2-(methylsulfonyl)pyrimidine, 149 mg (0.73 mmol) of 4-bromo-3-methoxyaniline and 83 mg (0.73 mmol) of potassium tert-butylate in 3 mL of N,N-dimethylformamide. The reaction mixture is heated to 120° C. for 60 minutes. After returning to room temperature, the residue is concentrated to afford 165 mg (43%) of N-(4-bromo-3-methoxyphenyl)-4-(3-methoxyphenyl)pyrimidin-2-amine as a yellow solid.

[0314] LCMS (EI, m/z): (M+1) 387.24

[0315] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.86 (1H, s, NH), 8.59-8.60 (1H, d, CH.sub.arom), 7.87 (1H, s, CH.sub.arom), 7.73-7.87 (2H, m, CH.sub.arom), 7.46-7.50 (3H, m, CH.sub.arom), 7.35-7.37 (1H, d, CH.sub.arom), 7.13-7.16 (1H, d, CH.sub.arom), 3.87 (3H, s, CH.sub.3), 3.86 (3H, s, CH.sub.3).

[0316] Step 5: 2-bromo-5-((4-(3-hydroxyphenyl)pyrimidin-2-yl)amino)phenol (intermediate 9)

##STR00024##

[0317] To a solution of 5.67 g (14.68 mmol) of N-(4-bromo-3-methoxyphenyl)-4-(3-methoxyphenyl)pyrimidin-2-amine in 160 mL of dichloromethane is added 6.94 mL of tribromo-borane at −78° C. The reaction mixture is then stirred at 45° C. for 5 h then overnight at room temperature. 20 mL of methanol is added to the reaction mixture at 0° C. which is then heated to 35° C. for 25 minutes. The solid formed is filtered then washed twice with 20 mL of ether to afford 6.45 g (100%) of 2-bromo-5-((4-(3-hydroxyphenyl)pyrimidin-2-yl)amino)phenol as a yellow powder.

[0318] LC-MS (EI, m/z): (M+1) 440.10

[0319] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.72 (1H, s, NH), 8.53-8.54 (1H, d, CH.sub.arom), 7.53-7.60 (3H, m, CH.sub.arom), 7.26-7.38 (4H, m, CH.sub.arom), 6.94-6.96 (1H, d, CH.sub.arom).

[0320] Step 6: Compound 3

[0321] To a stirred solution of 0.93 g (2.11 mmol) of 2-bromo-5-((4-(3-hydroxyphenyl)pyrimidin-2-yl)amino)phenol in 100 mL of N,N-dimethylformamide is added 1.46 g (10.59 mmol) of potassium carbonate then 0.49 g (2.11 mmol) of 1-bromo-2-(2-bromoethoxy)ethane in 50 mL of N,N-dimethylformamide for one hour. The reaction mixture is stirred at 75° C. for 20 hours. After returning to room temperature, the solvent is evaporated, water is added and the solid formed is filtered and dried under vacuum to afford 0.85 g (94%) of compound 3 as a beige powder.

[0322] LCMS (EI, m/z): (M+1) 429.27

[0323] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.97 (1H, s, NH), 8.69 (1H, s, CH.sub.arom), 8.59-8.60 (1H, m, CH.sub.arom), 8.01 (1H, s, CH.sub.arom), 7.63-7.65 (1H, d, CH.sub.arom), 7.43-7.48 (3H, m, CH.sub.arom), 7.19-7.21 (1H, d, CH.sub.arom), 6.83-6.85 (1H, d, CH.sub.arom), 4.24-4.25 (4H, m, CH.sub.2), 3.81-3.85 (4H, m, CH.sub.2).

[0324] Compound 4:

##STR00025##

[0325] In a 50 mL round-bottom flask are mixed 80 mg (0.168 mmol) of 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl, 308 mg (0.336 mmol) of (dppf).sub.2PdCl.sub.2.CH.sub.2Cl.sub.2, 1.8 g (4.2 mmol) of compound 3 and 5.89 g (58 mmol) of 1-methylpiperazine under argon. 23 mL of tetrahydrofuran and 33 mL (33 mmol) of lithium bis(trimethylsilyl)amide (LiHMDS) are added at room temperature. The reaction mixture is heated to 85° C. for 5 hours. After returning to room temperature, the reaction is hydrolyzed by slow addition of water at 0° C. and the medium is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate/methanol/ammonia: 94:4:2) to afford 692 mg (37%) of compound 4 as a yellow solid.

[0326] LCMS (EI, m/z): (M+1) 448.53

[0327] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.63(1H, s, NH), 8.52-8.54 (1H, m, CH.sub.arom), 8.47 (1H, m, CH.sub.arom), 8.11 (1H, s, CH.sub.arom), 7.63-7.65 (1H, d, CH.sub.arom), 7.44-7.46 (1H, m, CH.sub.arom), 7.35-7.36 (1H, d, CH.sub.arom), 7.10-7.20 (1H, d, CH.sub.arom), 6.51-6.87 (2H, m, 4.21-4.27 (4H, m, CH.sub.2), 3.84 (4H, m, CH.sub.2), 3.67 (4H, m, CH.sub.2), 2.46 (4H, m, CH.sub.2), 2.22 (3H, m, CH.sub.3).

[0328] Compound 5:

##STR00026##

[0329] Compound 5 was prepared according to the protocol described for the preparation of compound 3 starting with 150 mg of compound 3 and 107 mg of the amine N1,N1,N2-trimethylethane-1.2-diamine to afford 8.2 mg (5%) of compound 5.

[0330] LCMS (EI, m/z): (M+1) 450.54

[0331] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.60 (1H, s, NH), 8.52-8.53 (1H, d, CH.sub.arom), 8.44 (1H, s, CH.sub.arom), 8.11 (1H, s, CH.sub.arom), 7.63-7.65 (1H, d, CH.sub.arom), 7.44-7.47 (1H, m, CH.sub.arom), 7.34-7.35 (1H, d, CH.sub.arom), 7.18-7.20 (1H, d, CH.sub.arom), 6.78-6.87 (2H, m, CH.sub.arom), 4.19-4.26 (4H, m, CH.sub.2), 3.79-3.87 (4H, m, CH.sub.2), 3.03-3.07 (2H, m, CH.sub.2), 2.69 (3H, s, CH.sub.2), 2.34-2.38 (2H, m, CH.sub.2), 2.19 (6H, s, CH.sub.2).

[0332] Compound 6:

##STR00027##

[0333] Compound 6 was prepared according to the protocol described for the preparation of compound 3 starting with 150 mg of compound 3 and 193 mg of the amine 1-(1-methylpiperidin-4-yl)piperazine to afford 45 mg (23%) of compound 6.

[0334] LCMS (EI, m/z): (M+1) 431.66

[0335] .sup.1H NMR: dH ppm (400 MHz, DMSO); 9.62 (1H, s, NH), 8.52-8.53 (1H, d, CH.sub.arom), 8.46 (1H, s, CH.sub.arom), 8.10 (1H, s, CH.sub.arom), 7.63-7.65 (1H, d, CH.sub.arom), 7.43-7.47 (1H, m, CH.sub.arom), 7.34-7.35 (1H, d, CH.sub.arom), 7.17-7.19 (1H, d, CH.sub.arom), 6.84 (2H, m, CH.sub.arom), 4.20-4.26 (4H, m, CH.sub.2), 3.81-3.84 (4H, m, CH.sub.2), 2.93 (4H, m, CH.sub.2), 2.77-2.80 (2H, m, CH.sub.2), 2.60 (4H, m, CH.sub.2), 2.13 (4H, m, CH.sub.2), 1.73-1.86 (4H, m, CH.sub.2), 1.40-1.43 (2H, m, CH.sub.2).

[0336] Compound 7:

##STR00028##

[0337] Compound 7 was prepared according to the protocol described for the preparation of compound 3 starting with 150 mg of compound 3 and 92 mg of the amine morpholine to afford 25 mg (16%) of compound 7.

[0338] LCMS (EI, m/z): (M+1) 435.48

[0339] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.97 (1H, s, NH), 8.48-8.54 (2H, m, CH.sub.arom), 8.10 (1H, s, CH.sub.arom), 7.63-7.65 (1H, d, CH.sub.arom), 7.45 (1H, t, CH.sub.arom), 7.35-7.36 (1H, d, CH.sub.arom), 7.17-7.19 (1H, d, CH.sub.arom), 6.84 (2H, m, CH.sub.arom), 4.25 (4H, m, CH.sub.2), 3.84 (4H, m, CH.sub.2), 3.72-3.80 (4H, m, CH.sub.2), 2.93 (4H, m, CH.sub.2).

[0340] Compound 8:

##STR00029##

[0341] In a microwave reactor are mixed 150 mg (3.5 mmol) of compound 3, 66.7 mg (0.36 mmol) of cuprous iodide and 0.4 mL of (hydroxyethyl)pyrrolidine (5.13 mmol). The reaction mixture is heated to 200° C. for 30 minutes. After returning to room temperature, the reaction is hydrolyzed by addition of water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate/methanol/ammonia: 94:4:2) to afford 24 mg (15%) of compound 8 as a yellow solid.

[0342] LCMS (EI, m/z): (M+1) 463.54

[0343] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.64 (1H, s, NH), 8.52-8.54 (1H, d, CH.sub.arom), 8.49 (1H, s, CH.sub.arom), 8.09 (1H, s, CH.sub.arom), 7.63-7.65 (1H, d, CH.sub.arom), 7.43-7.47 (1H, m, CH.sub.arom), 7.35-7.36 (1H, d, CH.sub.arom), 7.16-7.18 (1H, d, CH.sub.arom) 6.94-6.97 (1H, m, CH.sub.arom), 6.82-6.84 (1H, m, CH.sub.arom), 4.20-4.27 (4H, m, CH.sub.2), 4.03-4.04 (2H, m, CH.sub.2), 3.80 (4H, m, CH.sub.2), 2.68 (2H, s, CH.sub.2), 2.50 (4H, m, CH.sub.2), 1.68 (4H, s, CH.sub.2).

[0344] Compound 9:

##STR00030##

[0345] Compound 9 was prepared according to the protocol described for the preparation of compound 3 starting with 200 mg of compound 3 and 294 mg of the amine 4,4-difluoropiperidine to afford 26 mg (12%) of compound 9.

[0346] LCMS (EI, m/z): (M+1) 469.50

[0347] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.68 (1H, s, NH), 8.53-8.55 (1H, d, CH.sub.arom), 8.50 (1H, s, CH.sub.arom), 8.11 (1H, s, CH.sub.arom), 7.64-7.66 (1H, d, CH.sub.arom), 7.44-7.48 (1H, m, CH.sub.arom), 7.36-7.38 (1H, d, CH.sub.arom), 7.18-7.20 (1H, d, CH.sub.arom), 6.91-6.93 (1H, m, CH.sub.arom), 6.81-6.83 (1H, m, CH.sub.arom), 4.24-4.25 (4H, m, CH.sub.2), 3.80-3.88 (4H, m, CH.sub.2), 3.06 (4H, m, CH.sub.2), 2.10 (4H, m, CH.sub.2), 2.50 (4H, m, CH.sub.2).

[0348] Compound 10:

##STR00031##

[0349] Compound 10 was prepared according to the protocol described for the preparation of compound 3 starting with 400 mg of compound 3 and 561 mg of the amine tert-butyl 1,4-diazepane-1-carboxylate to afford 90 mg (18%) of compound 10.

[0350] LCMS (EI, m/z): (M+1) 548.64

[0351] Compound 11:

##STR00032##

[0352] To 90 mg (0.16 mmol) of compound 10 is added dropwise 10 mL of a solution of hydrochloric acid in isopropanol (5N). The solution is stirred at 20° C. for 8 h. After evaporation to dryness, the solid formed is triturated in ether then recrystallized in isopropanol to obtain 80 mg (92%) of compound 11 as a yellow powder.

[0353] LCMS (EI, m/z): (M+1) 448.53

[0354] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.71 (1H, s, NH), 8.88 (1H, s, CH.sub.arom), 8.53-8.55 (1H, d, CH.sub.arom), 8.49 (1H, s, CH.sub.arom), 8.10 (1H, s, CH.sub.arom), 7.63-7.66 (1H, d, CH.sub.arom), 7.44-7.48 (1H, t, CH.sub.arom), 7.37-7.38 (1H, d, CH.sub.arom), 7.18-7.20 (1H, dd, CH.sub.arom), 6.78-6.80 (1H, d, CH.sub.arom), 4.25 (4H, m, CH.sub.2), 3.25-3.26 (6H, m, CH.sub.2), 3.06 (4H, m, CH.sub.2), 2.50 (4H, m, CH.sub.2).

[0355] Compound 12:

##STR00033##

[0356] Compound 12 was prepared according to the protocol described for the preparation of compound 3 starting with 600 mg of compound 3 and 2.08 g of the amine tert-butyl piperazine-1-carboxylate to afford 312 mg (42%) of compound 12.

[0357] LCMS (EI, m/z): (M+1) 534.62

[0358] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.65 (1H, s, NH), 8.48-8.53 (2H, m, CH.sub.arom), 8.10-8.11 (1H, d, CH.sub.arom), 7.62-7.64 (1H, d, CH.sub.arom), 7.43-7.47 (1H, t, CH.sub.arom), 7.35-7.36 (1H, d, CH.sub.arom), 7.18-7.20 (1H, d, CH.sub.arom), 6.82-6.84 (2H, m, CH.sub.arom), 4.21-4.26 (4H, m, CH.sub.2), 3.80-3.86 (4H, m, CH.sub.2), 3.44 (4H, m, CH.sub.2), 2.28 (4H, m, CH.sub.2), 1.42 (9H, s, CH.sub.3).

[0359] Compound 13:

##STR00034##

[0360] To 312 mg (0.58 mmol) of compound 12 is added dropwise 3 mL of a solution of hydrochloric acid in isopropanol (5N). The solution is stirred at 45° C. for 1 h. After evaporation to dryness, the solid formed is triturated in ether then recrystallized in isopropanol to obtain 296 mg (95%) of compound 13 as a yellow powder.

[0361] LCMS (EI, m/z): (M+1) 434.21

[0362] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.98 (1H, s, NH), 9.45 (1H, s, NH), 8.57-8.58 (1H, d, CH.sub.arom), 8.51-8.52 (1H, m, CH.sub.arom), 8.09 (1H, t, CH.sub.arom), 7.66-7.68 (1H, d, CH.sub.arom), 7.43-7.48 (2H, m, CH.sub.arom), 7.19-7.21 (1H, dd, CH.sub.arom), 7.11-7.12 (1H, d, CH.sub.arom), 6.85-6.88 (1H, d, CH.sub.arom), 4.24-4.27 (4H, m, CH.sub.2), 3.88-3.91 (2H, m, CH.sub.2), 3.78-3.81 (2H, m, CH.sub.2), 3.31 (8H, m, CH.sub.2).

[0363] Compound 14:

##STR00035##

[0364] Compound 14 was prepared according to the protocol described for the preparation of compound 3 starting with 400 mg of compound 3 and 159 mg of the amine 4-(piperidine-4-yl)morpholine to afford 58 mg (12%) of compound 14.

[0365] LCMS (EI, m/z): (M+1) 518.61

[0366] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.60 (1H, s, NH), 8.51-8.52 (1H, d, CH.sub.arom), 8.45-8.46 (1H, d, CH.sub.arom), 8.10 (1H, s, CH.sub.arom), 7.62-7.64 (1H, d, CH.sub.arom), 7.43-7.47 (1H, t, CH.sub.arom), 7.33-7.35 (1H, d, CH.sub.arom), 7.18-7.20 (1H, d, CH.sub.arom), 6.81-6.83 (2H, m, CH.sub.arom), 4.21-4.26 (4H, m, CH.sub.2), 3.79-3.85 (4H, m, CH.sub.2), 3.85 (4H, m, CH.sub.2), 3.33 (8H, m, CH.sub.2), 2.17-2.24 (1H, t, CH.sub.2), 1.83-1.86 (2H, d, CH.sub.2), 1.47-1.56 (2H, d, CH.sub.2).

[0367] Compound 15:

##STR00036##

[0368] Compound 15 was prepared according to the protocol described for the preparation of compound 3 starting with 400 mg of compound 3 and 109 mg of the amine N1,N1,N3-trimethyl-propane-1,3-diamine to afford 53 mg (12%) of compound 15.

[0369] LCMS (EI, m/z): (M+1) 464.57

[0370] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.58 (1H, s, NH), 8.51-8.52 (1H, d, CH.sub.arom), 8.43 (1H, s, CH.sub.arom), 8.10 (1H, s, CH.sub.arom), 7.62-7.64 (1H, d, CH.sub.arom), 7.42-7.46 (1H, t, CH.sub.arom), 7.33-7.34 (1H, d, CH.sub.arom), 7.16-7.18 (1H, d, CH.sub.arom), 6.78-6.86 (2H, m, CH.sub.arom), 4.18-4.25 (4H, m, CH.sub.2), 3.80-3.86 (4H, m, CH.sub.2), 2.93-2.96 (2H, m, CH.sub.2), 2.21-2.22 (2H, t, CH.sub.2), 2.09 (9H, s, CH.sub.3), 1.55-1.58 (2H, m, CH.sub.3).

[0371] Compound 16:

##STR00037##

[0372] Compound 16 was prepared according to the protocol described for the preparation of compound 3 starting with 400 mg of compound 3 and 160 mg of the amine 4-[3-(N,N-dimethylamino)-propyl]-piperazine to afford 90 mg (19%) of compound 16.

[0373] LCMS (EI, m/z): (M+1) 519.65

[0374] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.61 (1H, s, NH), 8.51-8.52 (1H, d, CH.sub.arom), 8.46-8.47 (1H, d, CH.sub.arom), 8.09-8.10 (1H, t, CH.sub.arom), 7.62-7.64 (1H, d, CH.sub.arom), 7.42-7.46 (1H, t, CH.sub.arom), 7.33-7.35 (1H, d, CH.sub.arom), 7.16-7.18 (1H, dd, CH.sub.arom), 6.82-6.85 (2H, m, CH.sub.arom), 4.20-4.26 (4H, m, CH.sub.2), 3.79-3.83 (4H, m, CH.sub.2), 2.29 (4H, m, CH.sub.2), 2.30-2.33 (2H, t, CH.sub.2), 2.49 (4H, m, CH.sub.2), 2.19-2.23 (2H, d, CH.sub.2), 2.11 (6H, s, CH.sub.3), 1.54-1.60 (2H, m, CH.sub.2).

[0375] Compound 17:

##STR00038##

[0376] Compound 17 was prepared according to the protocol described for the preparation of compound 3 starting with 400 mg of compound 3 and 122 mg of the amine N1,N1-diethyl-N2-methyl-ethane-1,2-diamine to afford 53 mg (12%) of compound 17.

[0377] LCMS (EI, m/z): (M+1) 478.59

[0378] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.66 (1H, s, NH), 8.53-8.54 (1H, d, CH.sub.arom), 8.46-8.47 (1H, d, CH.sub.arom), 8.09-8.10 (1H, t, CH.sub.arom), 7.62-7.64 (1H, d, CH.sub.arom), 7.43-7.47 (1H, t, CH.sub.arom), 7.35-7.36 (1H, d, CH.sub.arom), 7.17-7.20 (1H, dd, CH.sub.arom), 6.96-6.98 (1H, m, CH.sub.arom), 6.80-6.82 (1H, dd, CH.sub.arom), 4.16-4.25 (4H, m, CH.sub.2), 3.87-3.90 (2H, t, CH.sub.2), 3.79-3.81 (2H, m, CH.sub.2), 3.13-3.32 (8H, t, CH.sub.2), 2.27 (3H, s, CH.sub.3), 1.11-1.20 (6H, m, CH.sub.3).

[0379] Compound 18:

##STR00039##

[0380] Compound 18 was prepared according to the protocol described for the preparation of compound 3 starting with 400 mg of compound 3 and 171 mg of the amine 1-methyl-4-(piperidine-4-yl)piperazine to afford 63 mg (12%) of compound 18.

[0381] LCMS (EI, m/z): (M+1) 531.30

[0382] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.60 (1H, s, NH), 8.51-8.53 (1H, d, CH.sub.arom), 8.45 (1H, s, CH.sub.arom), 8.10 (1H, s, CH.sub.arom), 7.62-7.64 (1H, d, CH.sub.arom), 7.42-7.47 (1H, t, CH.sub.arom), 7.33-7.34 (1H, d, CH.sub.arom), 7.16-7.18 (1H, dd, C.sub.arom), 6.79-6.85 (2H, m, CH.sub.arom), 4.20-4.25 (4H, m, CH.sub.2), 3.80-3.84 (4H, m, CH.sub.2), 3.32-3.37 (4H, m, CH.sub.2), 2.20-2.32 (8H, t, CH.sub.2), 2.20-2.27 (1H, t, CH.sub.2), 2.12 (3H, s, CH.sub.3), 1.81-1.83 (2H, m, CH.sub.2), 1.51-1.53 (2H, m, CH.sub.2).

[0383] Compound 19:

##STR00040##

[0384] Compound 19 was prepared according to the protocol described for the preparation of compound 3 starting with 400 mg of compound 3 and 107 mg of the amine N,N-dimethyl-pyrrolidin-3-diamine to afford 28 mg (6%) of compound 19.

[0385] LCMS (EI, m/z): (M+1) 462.24

[0386] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.51 (1H, s, NH), 8.49-8.50 (1H, d, CH.sub.arom), 8.41 (1H, s, CH.sub.arom), 8.10 (1H, s, CH.sub.arom), 7.61-7.63 (1H, d, CH.sub.arom), 7.42-7.46 (1H, t, CH.sub.arom), 7.30-7.31 (1H, d, CH.sub.arom), 7.16-7.18 (1H, d, CH.sub.arom), 6.68-6.78 (1H, m, CH.sub.arom), 6.65-6.67 (1H, m, CH.sub.arom), 4.09-4.24 (4H, m, CH.sub.2), 3.79-3.85 (4H, m, CH.sub.2), 3.19-3.21 (2H, m, CH.sub.2), 3.11-3.15 (1H, t, CH.sub.2), 2.22 (6H, s, CH.sub.3), 1.99-2.07 (2H, m, CH.sub.2), 1.68-1.77 (2H, m, CH.sub.2).

[0387] Compound 20:

##STR00041##

[0388] Compound 20 was prepared according to the protocol described for the preparation of compound 3 starting with 200 mg of compound 3 and 374 mg of the amine tert-butyl methyl(pyrrolidin-3-yl)carbamate to afford 60 mg (22%) of compound 20.

[0389] LCMS (EI, m/z): (M+1) 548.64

[0390] Compound 21:

##STR00042##

[0391] To 60 mg (0.11 mmol) of compound 20 in 2 mL of dichloromethane is added 25 μL (0.329 mmol) of trifluoroacetic acid (TFA) at 0° C. in small portions. The reaction mixture is stirred at 25° C. for 12 hours. The solvent is evaporated, the reaction is hydrolyzed by addition of water, basified and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate/methanol/ammonia: 90:8:2) to afford 24 mg (48%) of compound 21 as a yellow solid.

[0392] LCMS (EI, m/z): (M+1) 448.53

[0393] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.51 (1H, s, NH), 8.50-8.51 (1H, d, CH.sub.arom), 8.41-8.42 (1H, d, CH.sub.arom), 8.11 (1H, s, CH.sub.arom), 7.62-7.64 (1H, d, CH.sub.arom), 7.43-7.47 (1H, t, CH.sub.arom), 7.30-7.31 (1H, d, CH.sub.arom), 7.17-7.19 (1H, d, CH.sub.arom), 6.77-6.79 (1H, m, CH.sub.arom), 6.63-6.66 (1H, m, CH.sub.arom), 4.25-4.27 (2H, m, CH.sub.2), 4.13-4.14 (2H, m, CH.sub.2), 3.79-3.86 (4H, m, CH.sub.2), 3.20 (2H, m, CH.sub.2), 3.10-3.21 (3H, m, NH and CH.sub.2), 3.01-3.03 (1H, m, CH), 2.31 (3H, s, CH.sub.3), 2.01-2.05 (1H, m, CH), 1.64-1.68 (1H, m, CH).

[0394] Compound 22:

##STR00043##

[0395] To a solution of 120 mg (0.24 mmol) of compound 13 and 41 mg (0.71 mmol) of propan-2-one in 3 mL of 1,2-dichloroethane are added 68 μL of acetic acid (1.18 mmol) and, in small fractions, 201 mg (0.95 mmol) of sodium triacetoxyborohydride. The reaction mixture is stirred for 16 hours at room temperature. The solvent is then concentrated, the reaction mixture extracted with ethyl acetate and washed using saturated sodium hydroxide solution. The organic phases are combined, dried over magnesium sulfate then concentrated. The residue is purified by chromatography on silica gel (eluent: dichloromethane/methanol/ammonia: 95:4:1) to afford 24 mg (21%) of compound 22 as a yellow solid,

[0396] LCMS (EI, m/z): (M+1) 476.58

[0397] .sup.1H NMR: dH ppm (400 MHz, CDCl.sub.3): 8.58-8.60 (1H, d, CH.sub.arom), 8.42-8.43 (1H, d, CH.sub.arom), 8.23-8.24 (1H, t, CH.sub.arom), 8.44-8.46 (1H, d, CH.sub.arom), 7.36-7.39 (1H, t, CH.sub.arom), 7.20 (1H, s, NH), 7.12-7.14 (1H, d, CH.sub.arom), 7.05-7.07 (1H, dd, CH.sub.arom), 6.88-6.90 (1H, d, CH.sub.arom), 6.51-6.54 (1H, dt, CH.sub.arom) 4.39-4.42 (2H, t, CH.sub.2), 4.29-4.31 (2H, m, CH.sub.2), 3.96-4.00 (2H, m, CH.sub.2), 3.89-3.91 (2H, m, CH.sub.2), 2.62-3.22 (8H, m, CH.sub.2), 2.49-2.58 (1H, m, CH), 1.17 (6H, s, CH.sub.3).

[0398] Compound 23:

##STR00044##

[0399] In a 10 mL vial are mixed 107 mg (0.25 mmol) of compound 3, 27 mg (0.058 mmol) of 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl, 4.79 mg (0.013 mmol) of benzonitrile palladium(II) chloride, 48 μL (0.450 mmol) of dimethylamino-2-propyne and 244 mg (0.75 mmol) of cesium carbonate in 0.3 mL of dimethylformamide at room temperature. 81 mg (0.250 mmol) of tetrabutylammonium bromide is added to the reaction mixture. The reaction mixture is heated to 80° C. for 15 hours. After returning to room temperature, the reaction is hydrolyzed by slow addition of water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate/methanol/ammonia: 95:4:1) to afford 9 mg (9%) of compound 23 as a yellow solid.

[0400] LCMS (EI, m/z): (M+1) 431.50

[0401] .sup.1H NMR: dH ppm (400 MHz, DMSO): 10.00 (1H, s, NH), 8.63-8.64 (1H, d, CH.sub.arom), 8.59-8.60 (1H, d, CH.sub.arom), 8.11 (1H, m, CH.sub.arom), 7.64-7.65 (1H, d, CH.sub.arom), 7.44-7.48 (2H, m, CH.sub.arom), 7.23-7.25 (1H, d, CH.sub.arom), 7.18-7.20 (1H, d, CH.sub.arom), 6.83-6.85 (1H, dd, CH.sub.arom), 4.23-4.28 (4H, m, CH.sub.2), 3.80-3.86 (4H, m, CH.sub.2), 3.42 (2H, m, CH.sub.2), 2.24 (6H, s, CH.sub.3).

[0402] Compound 24:

##STR00045##

[0403] In a round-bottom flask and under argon, introduce 40 mg (0.09 mmol) of compound 23 in 10 mL of a mixture of THF/MeOH (1:1). Degas the mixture under argon and under vacuum. Add 9.8 mg (0.009 mmol) of Pd—C. Degas the mixture under argon and under vacuum then place in a round-bottom flask of hydrogen. The reaction mixture is stirred at 25° C. overnight then filtered on silica and rinsed with ethyl acetate then concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate/methanol/ammonia: 90:8:2) to afford 5.1 mg (12%) of compound 24 as a yellow solid.

[0404] LCMS (EI, m/z): (M+1) 435.53

[0405] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.70 (1H, s, NH), 8.54-8.55 (1H, d, CH.sub.arom), 8.47-8.48 (1H, d, CH.sub.arom), 8.12 (1H, s, CH.sub.arom), 7.63-7.64 (1H, d, CH.sub.arom), 7.44-7.48 (1H, t, CH.sub.arom), 7.37-7.38 (1H, d, CH.sub.arom), 7.17-7.20 (1H, d, CH.sub.arom), 7.00-7.03 (1H, dd, CH.sub.arom), 6.76-6.78 (1H, dd, CH.sub.arom), 4.10-4.24 (4H, m, CH.sub.2), 3.79-3.87 (4H, m, CH.sub.2), 2.18-2.21 (2H, m, CH.sub.2), 2.45 (2H, m, CH.sub.2), 2.11 (6H, s, CH.sub.3), 1.60-1.64 (2H, m, CH.sub.2).

[0406] Compound 25:

##STR00046##

[0407] To a solution of 70 mg (0.13 mmol) of compound 11 in 2 mL of 1,2-dichloroethane is added 37.5 μL (0.269 mmol) of triethylamine. Stir for 10 minutes then add 29.3 μL (0.403 mmol) of aqueous formaldehyde solution and 38.5 μL (0.672 mmol) of acetic acid, then 114 mg (0.538 mmol) of sodium triacetoxyborohydride. The reaction mixture is stirred for 24 hours at room temperature. The solvent is then concentrated, the reaction mixture extracted with ethyl acetate and washed using 1N saturated sodium hydroxide solution. The organic phases are combined, dried over magnesium sulfate then concentrated. The residue is purified by chromatography on silica gel (eluent: dichloromethane/methanol: 90:10) to afford 29 mg (43%) of compound 25 as a yellow solid,

[0408] LCMS (EI, m/z): (M+1) 462.56

[0409] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.57 (1H, s, NH), 8.50-8.81 (1H, s, CH.sub.arom), 8.42-8.43 (1H, d, CH.sub.arom), 8.10 (1H, dd, CH.sub.arom), 7.62-7.64 (1H, d, CH.sub.arom), 7.43-7.47 (1H, dd, CH.sub.arom), 7.32-7.35 (1H, d, CH.sub.arom), 7.16-7.17 (1H, dd, CH.sub.arom), 6.74-6.83 (2H, d, CH.sub.arom), 4.17-4.25 (4H, m, CH.sub.2), 3.79-3.84 (4H, m, CH.sub.2), 3.16-3.21 (4H, m, CH.sub.2), 2.55-2.67 (4H, m, CH.sub.2), 2.28 (3H, m, CH.sub.3), 1.83-1.90 (2H, m, CH.sub.2).

[0410] Compound 26:

##STR00047##

[0411] To a solution of 120 mg (0.13 mmol) of compound 13 in 3 mL of 1,2-dichloroethane is added 61 μL (0.47 mmol) of triethylamine. Stir for 10 minutes then add 53 μL (0.71 mmol) of cyclopropane carbaldehyde and 136 μL (2.37 mmol) of acetic acid, then 201 mg (0.94 mmol) of sodium triacetoxyborohydride. The reaction mixture is stirred for 24 hours at room temperature. The solvent is then concentrated, the reaction mixture extracted with ethyl acetate and washed using 1N saturated sodium hydroxide solution. The organic phases are combined, dried over magnesium sulfate then concentrated. The residue is purified by chromatography on silica gel (eluent: dichloromethane/methanol/ammonia: 90:8:2) to afford 28 mg (24%) of compound 26 as a yellow solid.

[0412] LCMS (EI, m/z): (M+1) 488.59

[0413] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.62 (1H, d, CH.sub.arom), 8.51-8.53 (1H, d, CH.sub.arom), 8.46-8.47 (1H, d, CH.sub.arom), 8.10 (1H, t, CH.sub.arom), 7.62-7.64 (1H, d, CH.sub.arom), 7.42-7.46 (1H, t, CH.sub.arom), 7.34-7.35 (1H, d, CH.sub.arom), 7.16-7.18 (1H, dd, CH.sub.arom), 6.80-6.86 (2H, m, CH.sub.arom), 4.20-4.26 (4H, m, CH.sub.2), 3.78-3.86 (4H, m, CH.sub.2), 2.94 (4H, m, CH.sub.2), 2.56 (4H, m, CH.sub.2), 2.22 (2H, m, CH), 0.85 (1H, s, CH), 0.47 (2H, m, CH.sub.2), 0.09 (2H, s, CH.sub.2).

[0414] Compound 27:

##STR00048##

[0415] Compound 27 was prepared according to the protocol described for the preparation of compound 3 starting with 400 mg of compound 3 and 577 mg of the amine 4-(pyrrolidin-1-yl)piperidine to afford 63 mg (13%) of compound 27.

[0416] LCMS (EI, m/z): (M+1) 502.62

[0417] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.61 (1H, s, NH), 8.51-8.52 (1H, d, CH.sub.arom), 8.45-8.46 (1H, d, CH.sub.arom), 8.10 (1H, s, CH.sub.arom), 7.62-7.64 (1H, d, CH.sub.arom), 7.42-7.46 (1H, t, CH.sub.arom), 7.33-7.35 (1H, d, CH.sub.arom), 7.16-7.18 (1H, dd, CH.sub.arom), 6.79-6.85 (2H, m, CH.sub.arom), 4.21-4.26 (4H, m, CH.sub.2), 3.79-3.84 (4H, m, CH.sub.2), 3.27-3.32 (4H, m, CH.sub.2), 2.25-2.58 (5H, m, CH and CH.sub.2), 1.89-1.94 (2H, m, CH.sub.2), 1.68 (4H, m, CH.sub.2), 1.46-1.57 (2H, m, CH.sub.2).

[0418] Compound 28:

##STR00049##

[0419] Compound 28 was prepared according to the protocol described for the preparation of compound 3 starting with 400 mg of compound 3 and 637 mg of the amine 1-((tetrahydrofuran-2-yl)methyl)piperazine to afford 108 mg (22%) of compound 28.

[0420] LCMS (EI, m/z): (M+1) 518.62

[0421] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.62 (1H, s, NH), 8.51-8.52 (1H, d, CH.sub.arom), 8.45-8.46 (1H, d, CH.sub.arom), 8.10 (1H, s, CH.sub.arom), 7.62-7.64 (1H, d, CH.sub.arom), 7.42-7.46 (1H, t, CH.sub.arom), 7.34-7.35 (1H, d, CH.sub.arom), 7.16-7.18 (1H, dd, CH.sub.arom), 6.80-6.85 (2H, m, CH.sub.arom), 4.20-4.26 (4H, m, CH.sub.2), 3.90-3.97 (1H, m, CH), 3.78-3.84 (4H, m, CH.sub.2), 3.71-3.77 (1H, m, CH), 3.58-3.62 (1H, m, CH), 2.92 (4H, m, CH.sub.2), 2.47-2.67 (4H, m, CH.sub.2), 2.38-2.42 (2H, m, CH.sub.2), 1.89-1.97 (1H, m, CH), 1.73-1.83 (2H, m, CH.sub.2), 1.44-1.53 (1H, m, CH).

[0422] Compound 29:

##STR00050##

[0423] Step 1: Intermediate 10

##STR00051##

[0424] To 1.12 g (6.91 mmol) of 2,4-dichloro-5-methylpyrimidine in 50 mL of anhydrous THF is added 1 g (6.58 mmol) of 3-methoxyphenylboronic acid. The reaction mixture is stirred at room temperature for 10 minutes, then 1.74 g (16.45 mmol) of sodium carbonate dissolved in 8 mL of water and then 0.38 g (0.329 mmol) of tetrakis(triphenylphosphine)palladium(0) are added at room temperature. The reaction mixture is stirred at 90° C. for 16 hours. Ethyl acetate is added and the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered. The filtrate is evaporated and the residue purified by silica column chromatography using Companion® (eluent: cyclohexane/ethyl acetate: 0 to 10%, then cyclohexane/ethyl acetate: 95:5) to afford 1.2 g (77%) of intermediate 10 as a white solid.

[0425] LCMS (EI, m/z): (M+1) 235.68

[0426] .sup.1H NMR: dH ppm (400 MHz, DMSO): 8.72 (1H, s, CH.sub.arom), 7.44-7.48 (1H, d, CH.sub.arom), 7.21-7.23 (1H, d, CH.sub.arom), 7.18 (1H, m, CH.sub.arom), 7.10-7.13 (1H, dd, CH.sub.arom), 3.83 (3H, s, CH.sub.3), 3.33 (3H, s, CH.sub.3).

[0427] Step 2: Intermediate 11

##STR00052##

[0428] To a solution of 15 mL of n-butanol comprising 0.6 g (2.56 mmol) of intermediate 10 and 0.52 g (2.56 mmol) of 4-bromo-3-methoxyaniline is added 0.5 mL of hydrochloric acid solution (5N). The reaction mixture is stirred at 80° C. overnight. After returning to room temperature, the solid formed is filtered, rinsed with n-butanol to afford 0.79 g (78%) of intermediate 11 as a yellow powder.

[0429] LCMS (EI, m/z): (M+1) 401.26

[0430] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.76 (1H, s, NH), 8.46 (1H, d, CH.sub.arom), 7.92 (1H, s, CH.sub.arom), 7.38-7.46 (2H, m, CH.sub.arom), 7.24-7.28 (3H, m, CH.sub.arom), 7.06-7.08 (1H, d, CH.sub.arom), 3.81 (3H, s, CH.sub.3), 3.87 (3H, s, CH.sub.3), 2.24 (3H, s, CH.sub.3).

[0431] Step 3: Intermediate 12

##STR00053##

[0432] To a solution of 0.25 g (0.62 mmol) of intermediate 11 in 7 mL of dichloromethane is added 0.3 mL (3.12 mmol) of tribromo-borane at −78° C. The reaction mixture is then stirred at 45° C. for 5 h then overnight at room temperature. 20 mL of methanol is added at 0° C. to the reaction mixture which is then heated to 35° C. for 25 minutes. The solid formed is filtered then washed twice with 20 mL of ether to afford 0.27 g (99%) of intermediate 12 as a yellow powder.

[0433] LC-MS (EI m/z): (M+H.sup.+): 372.02+374.02

[0434] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.62 (1H, s, NH), 8.40 (1H, s, CH.sub.arom), 7.49-7.50 (1H, m, CH.sub.arom), 7.28-7.32 (2H, m, CH.sub.arom), 7.18-7.21 (1H, m, CH.sub.arom), 7.03-7.08 (2H, m, CH.sub.arom), 6.86-6.89 (1H, d, CH.sub.arom), 2.20 (3H, s, CH.sub.3).

[0435] To a stirred solution of 0.25 g (0.67 mmol) of intermediate 12 in 19 mL of N,N-dimethylformamide is added 0.46 g (3.37 mmol) of potassium carbonate then 0.15 g (0.67 mmol) of 1-bromo-2-(2-bromoethoxy)ethane in 8 mL of NM-dimethylformamide for one hour. The reaction mixture is stirred at 75° C. for 20 hours. After returning to room temperature, the solvent is evaporated, water is added and the solid formed is filtered and dried under vacuum to afford 0.25 g (64%) of compound 29 as a beige powder.

[0436] LCMS (EI, m/z): (M+1) 443.30

[0437] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.84 (1H, s, NH), 8.70 (1H, s, CH.sub.arom), 8.47 (1H, s, CH.sub.arom), 7.59 (1H, s, CH.sub.arom), 7.37-7.43 (2H, m, CH.sub.arom), 7.29-7.32 (1H, m, CH.sub.arom), 7.18-7.20 (1H, d, CH.sub.arom), 6.77-6.79 (1H, d, CH.sub.arom), 4.30 (2H, m, CH.sub.2), 4.09-4.11 (2H, m, CH.sub.2), 3.77-3.85 (4H, m, CH.sub.2), 2.30 (3H, s, CH.sub.3).

[0438] Compound 30:

##STR00054##

[0439] Compound 30 was prepared according to the protocol described for the preparation of compound 3 starting with 124 mg of compound 3 and 393 mg of the amine 1-methylpiperazine to afford 29 mg (22%) of compound 30.

[0440] LCMS (EI, m/z): (M+1) 462.55

[0441] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.46 (1H, s, NH), 8.46-8.47 (1H, d, CH.sub.arom), 8.39 (1H, s, CH.sub.arom), 7.59 (1H, s, CH.sub.arom), 7.38-7.42 (1H, t, CH.sub.arom), 7.28-7.30 (1H, d, CH.sub.arom), 7.14-7.17 (1H, dd, CH.sub.arom), 6.73-6.80 (2H, m, CH.sub.arom), 4.29-4.31 (2H, m, CH.sub.2), 4.07-4.10 (2H, m, CH.sub.2), 3.80-3.82 (4H, m, CH.sub.2), 2.89 (4H, m, CH.sub.2), 2.42 (4H, m, CH.sub.2), 2.29 (3H, m, CH.sub.3), 2.19 (3H, m, CH.sub.3).

[0442] Compound 31:

##STR00055##

[0443] Compound 31 was prepared according to the protocol described for the preparation of compound 3 starting with 400 mg of compound 3 and 536 mg of the amine 1,4-dioxa-8-azaspiro[4.5]decane to afford 33 mg (7%) of compound 31.

[0444] LCMS (EI, m/z): (M+1) 491.55

[0445] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.63 (1H, s, NH), 8.51-8.52 (1H, d, CH.sub.arom), 8.45-8.46 (1H, d, CH.sub.arom), 8.10 (1H, s, CH.sub.arom), 7.62-7.64 (1H, d, CH.sub.arom), 7.43-7.47 (1H, t, CH.sub.arom). 7.34-7.35 (1H, d, CH.sub.arom), 7.17-7.19 (1H, dd, CH.sub.arom). 6.79-6.88 (2H, m, CH.sub.arom), 4.22-4.27 (4H, m, CH.sub.2), 3.90 (4H, s, CH.sub.2), 3.79-3.85 (4H, m, CH.sub.2), 2.98 (4H, m, CH.sub.2), 1.73-1.76 (4H, m, CH.sub.2).

[0446] Compound 32:

##STR00056##

[0447] In a microwave reactor is mixed 95 mg (0.771 mmol) of pyridin-4-ylboronic acid dissolved in 10 mL of a 2:1 dioxane/H.sub.2O mixture and are added successively 72 mg (0.17 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl, 64 mg (0.070 mmol) of Pd.sub.2(dba).sub.3, 297 mg (1.4 mmol) of K.sub.3PO.sub.4 and 300 mg (0.77 mmol) of compound 3. The reaction mixture is heated to 150° C. for 20 minutes. After returning to room temperature, the reaction is hydrolyzed by addition of water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate/methanol/ammonia: 94:4:2) to afford 96 mg (32%) of compound 32 as a yellow solid.

[0448] LCMS (EI, m/z): (M+1) 427.47

[0449] .sup.1H NMR: dH ppm (400 MHz, DMSO): 10.04 (1H, s, NH), 8.71-8.22 (1H, d, CH.sub.arom), 8.60-8.62 (1H, d, CH.sub.arom), 8.50-8.54 (2H, d, CH.sub.arom), 8.14 (1H, m, CH.sub.arom), 7.64-7.66 (1H, d, CH.sub.arom), 7.55-7.57 (2H, d, CH.sub.arom), 7.45-7.49 (2H, m, CH.sub.arom), 7.37-7.39 (1H, d, CH.sub.arom), 7.18-7.21 (1H, dd, CH.sub.arom), 6.98-7.01 (1H, dd, CH.sub.arom), 4.22-4.26 m, CH.sub.2), 3.78-3.84 (4H, m, CH.sub.2).

[0450] Compound 33:

##STR00057##

[0451] Compound 33 was prepared according to the protocol described for the preparation of compound 3 starting with compound 3 and the amine 1-cyclopropylpiperazine.

[0452] LCMS (EI, m/z): (M+1) 474.57

[0453] .sup.1H NMR: dH ppm (400 MHz, CDCl.sub.3): 8.57-8.58 (1H, d, CH.sub.arom), 8.41-8.43 (1H, d, CH.sub.arom), 8.24 (1H, m, CH.sub.arom), 7.44-7.46 (1H, d, CH.sub.arom), 7.36-7.39 (1H, t, CH.sub.arom), 7.19 (1H, s, NH), 7.12-7.14 (1H, d, CH.sub.arom), 7.05-7.08 (1H, dd, CH.sub.arom), 6.85-6.88 (1H, m, CH.sub.arom), 6.51-6.55 (1H, d, CH.sub.arom), 4.40-4.43 (2H, t, CH.sub.2), 4.30-4.32 (2H, t, CH.sub.2), 3.97-4.00 (2H, t, CH.sub.2), 3.90-3.92 (2H, t, CH.sub.2), 3.04 (4H, m, CH.sub.2), 2.81 (4H, m, CH.sub.2), 1.61 (1H, m, CH), 0.47 (4H, m, CH.sub.2).

[0454] Compound 34:

##STR00058##

[0455] To 400 mg (0.93 mmol) of compound 3 in 10 mL of tetrahydrofuran is added 1.12 mL (2.8 mmol) of a solution of butyllithium in hexane (2.5 M) at −78° C. The reaction mixture is stirred at −78° C. for 30 minutes then CO.sub.2 is bubbled through the solution for 3 hours. After returning to room temperature, the reaction is hydrolyzed by slow addition of water at 0° C. then a mixture of methanol/acetic acid is added. The solvents are evaporated, the solid formed is filtered and dried under vacuum to afford 367 mg (100%) of compound 34 as a beige powder.

[0456] LCMS (EI, m/z): (M+1) 394.39

[0457] Compound 35:

##STR00059##

[0458] In a microwave reactor are added successively 367 mg (0.933 mmol) of compound 34, 815 μL of diisopropylethylamine (IDEA) (4.66 mmol), 333 μL (1.119 mmol) of T3P® and 112 mg (1.12 mmol) of 1-methylpiperazine. The reaction mixture is heated to 120° C. for 120 minutes. After returning to room temperature, the reaction is hydrolyzed by addition of water and extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: dichloromethane/methanol/ammonia: 94:4:2) to afford 38 mg (9%) of compound 35 as a yellow solid.

[0459] LCMS (EI, m/z): (M+1) 476.57

[0460] .sup.1H NMR: dH ppm (400 MHz, CDCl.sub.3): 8.71-8.72 (1H, d, CH.sub.arom), 8.47-8.48 (1H, d, CH.sub.arom), 8.22 (1H, m, CH.sub.arom), 7.45-7.47 (1H, d, CH.sub.arom), 7.37-7.41 (1H, t, CH.sub.arom), 7.33 (1H, s, NH), 7.18-7.21 (2H, m, CH.sub.arom), 7.06-7.09 (1H, dd, CH.sub.arom), 6.54-6.57 (1H, dd, CH.sub.arom), 4.25-4.38 (4H, m, CH.sub.2), 3.89 (6H, m, CH.sub.2), 3.39 (2H, m, CH.sub.2), 2.35-2.52 (4H, t, CH.sub.2), 2.33 (3H, s, CH.sub.3).

[0461] Compound 36:

##STR00060##

[0462] To 70 mg (0.14 mmol) of compound 31 is added dropwise 1 mL of a solution of hydrochloric acid in isopropanol (5N). The solution is stirred at 100° C. for 12 h. The solid formed is placed in basic medium and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated to afford 38 mg (57%) of compound 36 as a yellow solid.

[0463] LCMS (EI, m/z): (M+1) 447.50

[0464] .sup.1H NMR: dH ppm (400 MHz, DMSO) 9.67 (1H, s, NH), 8.52-8.54 (1H, d, CH.sub.arom), 8.51-8.52 (1H, d, CH.sub.arom), 8.11 (1H, s, CH.sub.arom), 7.63-7.65 (1H, d, CH.sub.arom), 7.43-7.47 (1H, t, CH.sub.arom), 7.35-7.37 (1H, d, CH.sub.arom), 7.17-7.20 (1H, dd, CH.sub.arom), 6.91-6.93 (1H, d, CH.sub.arom), 6.80-6.83 (1H, dd, CH.sub.arom), 4.24-4.29 (4H, m, CH.sub.2), 3.86-3.89 (2H, t, CH.sub.2), 3.80-3.82 (2H, m, CH.sub.2), 3.23-3.26 (4H, t, CH.sub.2), 2.45 (4H, m, CH.sub.2).

[0465] Compound 37:

##STR00061##

[0466] In a 50 mL round-bottom flask are mixed 1 g (2.335 mmol) of compound 3, 0.256 g (0.537 mmol) of 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl, 0.045 g (0.117 mmol) of benzonitrile palladium(II) chloride, 0.652 g (4.20 mmol) pro-2-yl-carbamic acid tent-butyl ester and 2.28 g (7 mmol) of cesium carbonate in 10 mL of dimethylformamide at room temperature. 0.90 g (2.80 mmol) of tetrabutylammonium bromide is added to the reaction mixture. The reaction mixture is heated to 80° C. for 15 hours. After returning to room temperature, the reaction is hydrolyzed by slow addition of water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate/cyclohexane: 40:60) to afford 144 mg (12%) of compound 37 as a yellow solid.

[0467] LCMS (EI, m/z): (M+1) 503.56

[0468] .sup.1H NMR: dH ppm (400 MHz, DMSO): 10.02 (1H, s, NH). 8.58-8.62 (2H, m, CH.sub.arom), 809 (1H, s, CH.sub.arom), 7.64-7.66 (1H, d, CH.sub.arom), 7.44-7.48 (2H, m, CH.sub.arom), 7.33 (1H, m, CH.sub.arom), 7.17-7.24 (2H, m, CH.sub.arom), 6.83-6.86 (1H, m, CH.sub.arom), 4.25-4.27 (4H, m, CH.sub.2), 3.96-3.97 (2H, m, CH.sub.2), 3.80-3.86 (4H, m, CH.sub.2), 1.40 (9H, s, CH.sub.3).

[0469] Compound 38:

##STR00062##

[0470] In a round-bottom flask and under argon, introduce 144 mg (0.28 mmol) of compound 37 in 10 mL of a mixture of THF/MeOH (1:1). Degas the mixture under argon and under vacuum. Add 30.5 mg (0.029 mmol) of Pd—C. Degas the mixture under argon and under vacuum then place in a round-bottom flask of hydrogen. The reaction mixture is stirred at 25° C. overnight then filtered on silica and rinsed with ethyl acetate, the solvent is evaporated and the solid formed is filtered and dried under vacuum to afford 132 mg (91%) of compound 38 as a yellow solid.

[0471] LCMS (EI, m/z): (M+1) 507.59

[0472] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.70 (1H, s, NH), 8.54-8.55 (1H, d, CH.sub.arom), 8.45-8.47 (1H, d, CH.sub.arom), 8.12 (1H, s, CH.sub.arom), 7.62-7.64 (1H, d, CH.sub.arom), 7.43-7.47 (1H, t, CH.sub.arom), 7.36-7.38 (1H, d, CH.sub.arom), 7.17-7.18 (1H, dd, CH.sub.arom), 7.00-7.02 (1H, dd, CH.sub.arom), 6.76-6.80 (2H, m, CH.sub.arom), 4.17-4.25 (4H, m, CH.sub.2), 3.79-3.89 (4H, m, CH.sub.2), 2.89-2.93 (2H, m, CH.sub.2), 2.40 (2H, m, CH.sub.2), 1.56-1.67 (2H, m, CH.sub.2), 1.38 (9H, s, CH.sub.3).

[0473] Compound 39:

##STR00063##

[0474] To 132 mg (0.261 mmol) of compound 38 is added dropwise 2 mL of a solution of hydrochloric acid in isopropanol (5N). The solution is stirred at 40° C. for 2 h 45 min. Evaporate to dryness. The solid formed is triturated in ether then recrystallized in isopropanol to obtain 100 mg (87%) of compound 39 as a yellow powder.

[0475] LCMS (EI, m/z): (M+1) 407.20

[0476] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.78 (1H, s, NH), 8.56-8.57 (1H, d, CH.sub.arom), 8.50-8.51 (1H, d, CH.sub.arom), 8.12 (1H, m, CH.sub.arom), 7.64-7.66 (1H, d, CH.sub.arom), 7.45-7.49 (1H, t, CH.sub.arom), 7.39-7.41 (1H, d, CH.sub.arom), 7.18-7.21 (1H, dd, CH.sub.arom), 7.04-7.06 (1H, d, CH.sub.arom), 6.79-6.81 (1H, dd, CH.sub.arom), 4.21-4.25 (4H, m, CH.sub.2), 3.88-3.91 (2H, t, CH.sub.2), 3.80-3.82 (2H, m, CH.sub.2), 2.73-2.79 (2H, m, CH.sub.2), 2.54-2.58 (2H, t, CH.sub.2), 1.76-1.84 (2H, m, CH.sub.2).

[0477] Compound 40:

##STR00064##

[0478] Compound 40 was prepared according to the protocol described for the preparation of compound 3 starting with 115 mg of compound 3 and 177 mg of the amine (1-((tetrahydrofuran-2-yl)methyl)piperazine) to afford 21 mg (15%) of compound 40.

[0479] LCMS (EI, m/z): (M+1) 532.64

[0480] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.46 (1H, s, NH), 8.46-8.47 (1H, d, CH.sub.arom), 8.40 (1H, s, CH.sub.arom), 7.59 (1H, s, CH.sub.arom), 7.39-7.43 (1H, t, CH.sub.arom), 7.28-7.30 (1H, d, CH.sub.arom), 7.15-7.17 (1H, dd, CH.sub.arom), 6.74-6.81 (2H, m, CH.sub.arom), 4.29-4.31 (2H, m, CH.sub.2), 4.07-4.12 (2H, m, CH.sub.2), 3.90-3.97 (1H, m, CH), 3.78-3.82 (4H, m, CH.sub.2), 3.70-3.76 (1H, m, CH), 3.57-3.62 (1H, m, CH), 2.89 (4H, m, CH.sub.2), 2.49-2.68 (5H, m, CH.sub.2), 2.38-2.41 (1H, m, CH), 2.29 (3H, m, CH.sub.3), 1.88-1.96 (1H, m, CH), 1.73-1.83 (2H, m, CH.sub.2), 1.43-1.52 (1H, m, CH).

[0481] Compound 41:

##STR00065##

[0482] Step 1: Intermediate 13

##STR00066##

[0483] In a 50 mL round-bottom flask, introduce 1 g (4.48 mmol) of 5-bromo-2,3-difluoroanisole in 25 mL of dioxane then add 1.708 g (6.73 mmol) of bis(pinacolato)diboron, 1.320 g (13.45 mmol) of potassium acetate and 0.183 g (0.224 mmol) of bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex. The reaction mixture is stirred at 80° C. overnight. After returning to room temperature, the reaction is hydrolyzed by slow addition of water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate: 95:5) to afford 197 mg (15%) of intermediate 13 as a yellow solid.

[0484] LCMS (EI, m/z): (M+1) 271.08

[0485] .sup.1H NMR: dH ppm (400 MHz, DMSO): 7.13-7.17 (2H, m, CH.sub.arom), 3.90 (3H, m, CH.sub.3), 1.30 (12H, m, CH.sub.3).

[0486] Step 2: Intermediate 14

##STR00067##

[0487] In a microwave reactor are mixed 114 mg (0.771 mmol) of 2,4-dichloropyrimidine, 197 mg (0.729 mmol) of intermediate 13, 42.1 mg (0.036 mmol) of Pd(PPh.sub.3).sub.4 and 6 mL of tetrahydrofuran. The reaction mixture is heated to 150° C. for 30 minutes. After returning to room temperature, the reaction is hydrolyzed by addition of water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate: 70:30) to afford 112 mg (60%) of intermediate 14 as a white solid.

[0488] LCMS (EI, m/z): (M+1) 257.63

[0489] .sup.1H NMR: dH ppm (400 MHz, DMSO): 8.88-8.90 (1H, d, CH.sub.arom), 8.27-8.28 (1H, d, CH.sub.arom), 7.85-7.90 (1H, m, CH.sub.arom), 7.79-7.81 (1H, m, CH.sub.arom), 4.02 (3H, m, CH.sub.3).

[0490] Step 3: Intermediate 15

##STR00068##

[0491] To a solution of 1.25 g (4.87 mmol) of intermediate 14 and 0.984 g (4.87 mmol) of 4-bromo-3-methoxyaniline in 28 mL of n-butanol is added 0.97 mL of hydrochloric acid solution (5N). The reaction mixture is stirred at 80° C. overnight. After returning to room temperature, the solid formed is filtered then rinsed with n-butanol to afford 1.4 g (68%) of intermediate 15 as a yellow powder.

[0492] LCMS (EI, m/z): (M+1) 423.22

[0493] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.90 (1H, s, NH), 8.92-8.94 (1H, d, CH.sub.arom), 7.82-7.87 (1H, m, CH.sub.arom), 7.78-7.80 (1H, d, CH.sub.arom), 7.74-7.75 (1H, d, CH.sub.arom), 7.57-7.58 (1H, d, CH.sub.arom), 7.47-48 (1H, d, CH.sub.arom), 7.38-7.41 (1H, dd, CH.sub.arom), 4.01 (3H, s, CH.sub.3), 3.86 (3H, s, CH.sub.3).

[0494] Step 4: Intermediate 16

##STR00069##

[0495] To a solution of 1.4 g (3.32 mmol) of intermediate 15 in 36 mL of dichloromethane is added 1.56 mL (16.58 mmol) of tribromo-borane at −78° C. The reaction mixture is then stirred at 45° C. for 4 h then overnight at room temperature. 20 mL of methanol is added at 0° C. to the reaction mixture which is then heated to 35° C. for 25 minutes. The solid formed is filtered then washed twice with 20 mL of ether to afford 1.54 g (98%) of intermediate 16 as a yellow powder.

[0496] LC-MS (EI m/z): (M+H.sup.+): 395.17+397.2

[0497] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.75 (1H, s, NH), 8.55-8.56 (1H, d, CH.sub.arom), 7.61-7.63 (2H, m, CH.sub.arom), 7.49-7.50 (1H, d, CH.sub.arom), 7.35-7.37 (2H, m, CH.sub.arom), 7.23-7.26 (1H, dd, CH.sub.arom).

[0498] Step 5: Compound 41

[0499] To a stirred solution of 0.7 g (1.47 mmol) of intermediate 16 in 70 mL of N,N-dimethylformamide is added 0.34 g (1.47 mmol) of potassium carbonate then 0.32 g (1.47 mmol) of 1-bromo-2-(2-bromoethoxy)ethane in 35 mL of N,N-dimethylformamide for one hour. The reaction mixture is stirred at 75° C. for 20 hours. After returning to room temperature, the solvent is evaporated, water is added and the solid formed is filtered and dried under vacuum to afford 0.53 g (78%) of compound 41 as a beige powder.

[0500] LCMS (EI, m/z): (M+1) 465.26

[0501] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.98 (1H, s, NH), 8.60-8.60 (1H, d, CH.sub.arom), 8.54 (1H, s, CH.sub.arom), 8.05-8.07 (1H, d, CH.sub.arom), 7.81-7.85 (1H, m, CH.sub.arom), 7.43-7.47 (2H, m, CH.sub.arom), 6.83-6.85 (1H, dd, CH.sub.arom), 4.41 (2H, m, CH.sub.2), 4.23 (2H, m, CH.sub.2), 3.81 (4H, m, CH.sub.2).

[0502] Compound 42:

##STR00070##

[0503] Compound 42 was prepared according to the protocol described for the preparation of compound 3 starting with 272 mg of compound 41 and 117 mg of the amine 1-methylpiperazine to afford 14 mg of compound 42 with a yield of 8%.

[0504] LCMS (EI, m/z): (M+1) 484.51

[0505] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.66 (1H, s, NH), 8.53-8.55 (1H, d, CH.sub.arom), 8.34-8.35 (1H, d, CH.sub.arom), 8.07-8.09 (1H, d, CH.sub.arom), 7.82-7.87 (1H, m, CH.sub.arom), 7.39-7.40 (1H, d, CH.sub.arom), 6.82-6.87 (2H, m, CH.sub.arom), 4.37-4.41 (2H, m, CH.sub.2), 4.21-4.23 (2H, m, CH.sub.2), 3.75-3.81 (4H, m, CH.sub.2), 2.95 (4H, m, CH.sub.2), 2.46 (4H, m, CH.sub.2), 2.21 (3H, m, CH.sub.3).

[0506] Compound 43:

##STR00071##

[0507] Step 1: Intermediate 17

##STR00072##

[0508] To a solution of 0.44 g (1.79 mmol) of intermediate 10 and 0.446 g (1.790 mmol) of 3-iodo-5-methoxyaniline in 10 mL of n-Butanol is added 0.35 mL of hydrochloric acid solution (5N). The reaction mixture is stirred at 80° C. overnight. After returning to room temperature, the reaction is hydrolyzed by slow addition of NaHCO.sub.3 solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate: 90:10) to afford 441 mg (55%) of intermediate 17 as a white solid.

[0509] LCMS (EI, m/z): (M+1) 448.27

[0510] Step 2: Intermediate 18

##STR00073##

[0511] To a solution of 441 mg (0.98 mmol) of intermediate 17 in 11 mL of dichloromethane is added 0.47 mL (4.94 mmol) of tribromo-borane at −78° C. The reaction mixture is then stirred at 45° C. for 5 hours then overnight at room temperature. 20 mL of methanol is added at 0° C. to the reaction mixture which is heated to 35° C. for 25 minutes. The solid formed is filtered then washed twice with 20 mL of ether to afford 0.50 g (99%) of intermediate 18 as a yellow powder.

[0512] LCMS (EI, m/z): (M+1) 420.01

[0513] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.58 (1H, s, NH), 8.42 (1H, s, CH.sub.arom), 7.70 (1H, s, CH.sub.arom), 7.29-7.33 (2H, m, CH.sub.arom), 7.04-7.09 (2H, m, CH.sub.arom), 6.87-6.90 (1H, d, CH.sub.arom), 6.69 (1H, d, H.sub.arom), 2.21 (3H, s, CH.sub.3).

[0514] Step 3: Compound 43

[0515] To a stirred solution of 0.54 g (1.09 mmol) of intermediate 18 in 55 mL of N,N-dimethylformamide is added 0.75 g (5.47 mmol) of potassium carbonate then 0.137 mL (1.09 mmol) of 1-bromo-2-(2-bromoethoxy)ethane in 23 mL of N,N-dimethylformamide for one hour. The reaction mixture is stirred at 80° C. for 20 hours. After returning to room temperature, the solvent is evaporated, water is added and the solid formed is filtered and dried under vacuum to afford 0.25 g (64%) of compound 43 as a beige powder.

[0516] LCMS (EI, m/z): (M+1) 490.30

[0517] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.74 (1H, s, NH), 8.62 (1H, s, CH.sub.arom), 8.47 (1H, s, CH.sub.arom), 7.74 (1H, s, CH.sub.arom), 7.41-7.42 (2H, m, CH.sub.arom), 7.20 (1H, s, CH.sub.arom), 7.09-7.14 (1H, m, CH.sub.arom), 6.82 (1H, s, CH.sub.arom), 4.30-4.33 (2H, t, CH.sub.2), 4.00-4.02 (2H, t, CH.sub.2), 3.82-3.86 (4H, m, CH.sub.2), 2.38 (3H, s, CH.sub.3).

[0518] Compound 44:

##STR00074##

[0519] Compound 44 was prepared according to the protocol described for the preparation of compound 3 starting with 490 mg of compound 43 and 401 mg of the amine 1-methylpiperazine to afford 156 mg (34%) of compound 44.

[0520] LCMS m/z): (M+1) 462.5

[0521] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.36 (1H, s, NH), 8.42 (1H, s, CH.sub.arom), 8.07 (1H, s, CH.sub.arom), 7.76 (1H, s, CH.sub.arom), 7.40-7.41 (1H, d, CH.sub.arom), 7.08-7.12 (1H, m, CH.sub.arom), 6.41 (1H, s, CH.sub.arom), 6.10 (1H, s, CH.sub.arom), 4.30-4.32 (2H, t, CH.sub.2), 3.99-4.00 (2H, t, CH.sub.2), 3.81-3.86 (4H, m, CH.sub.2), 3.79 (4H, m, CH.sub.2), 2.44 (4H, m, CH.sub.2), 2.36 (3H, m, CH.sub.3), 2.22 (3H, m, CH.sub.3).

[0522] Compound 45:

##STR00075##

[0523] Step 1: 2-chloro-4-(3-methoxyphenyl)pyrimidine (Intermediate 19)

##STR00076##

[0524] To 11.32 g (76 mmol) of 2,4-dichloropyrimidine in 550 mL of anhydrous THF is added 11 g (72.4 mmol) of 3-methoxyphenyl-boronic acid. The reaction mixture is stirred at room temperature for 10 minutes then 19.1 g of sodium carbonate dissolved in 80 mL of water then 4.18 g (3.62 mmol) of tetrakis(triphenylphosphine)palladium(0) is added at room temperature. The reaction mixture is stirred at 90° C. for 16 hours. Ethyl acetate is added and the organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered. The filtrate is evaporated and the residue purified by silica column chromatography using Companion® (eluent: heptane/ethyl acetate: 0 to 10%, then dichloromethane/ethyl acetate: 10%) to afford 15.23 g (95%) of 2-chloro-4-(3-methoxyphenyl)pyrimidine as a white solid.

[0525] LCMS (EI, m/z): (M+1) 221.65

[0526] .sup.1H NMR: dH ppm (400 MHz, DMSO): 8.82-8.84 (1H, d, CH.sub.arom), 8.17-8.19 (1H, d, 7.77-7.79 (1H, d, CH.sub.arom), 7.70-7.71 (1H, d, CH.sub.arom), 7.47-7.51 (1H, d, CH.sub.arom), 7.17-7.20 (1H, t, CH.sub.arom), 3.86 (3H, s, CH.sub.3).

[0527] Step 2: Intermediate 20

##STR00077##

[0528] To a solution of 0.5 g (2.26 mmol) of intermediate 19 and 0.56 g (2.26 mmol) of 3-iodo-5-methoxyaniline in 13 mL of n-butanol is added 0.45 mL of hydrochloric acid solution (5N). The reaction mixture is stirred at 80° C. overnight. After returning to room temperature, the reaction is hydrolyzed by slow addition of NaHCO.sub.3 solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate: 80:20) to afford 693 mg (70%) of intermediate 20 as a yellow solid.

[0529] LCMS (EI, m/z): (M+1) 434.24

[0530] Step 3: Intermediate 21

##STR00078##

[0531] To a solution of 693 mg (1.6 mmol) of intermediate 20 in 18 mL of dichloromethane is added 0.75 mL (1.6 mmol) of tribromo-borane at −78° C. The reaction mixture is then stirred at 45° C. for 5 h then overnight at room temperature. 20 mL of methanol is added at 0° C. to the reaction mixture which is then heated to 35° C. for 25 minutes. The solid formed is filtered then washed twice with 20 mL of ether to afford 0.76 g (98%) of intermediate 21 as a yellow powder.

[0532] LCMS (EI, m/z): (M+1) 406.,18

[0533] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.69 (1H, s, NH), 8.54-8.55 (1H, d, CH.sub.arom), 7.79 (1H, s, CH.sub.arom), 7.58-7.60 (1H, d, CH.sub.arom), 7.52 (1H, m, CH.sub.arom), 7.32-7.36 (3H, m, CH.sub.arom), 6.94-6.96 (1H, dd, CH.sub.arom), 6.75 (1H, t, CH.sub.3).

[0534] Step 4: Compound 45

[0535] To a stirred solution of 0.76 g (1.56 mmol) of intermediate 21 in 78 mL of N,N-dimethylformamide is added 1.08 g (7.82 mmol) of potassium carbonate then 0.19 mL (1.56 mmol) of 1-bromo-2-(2-bromoethoxy)ethane in 34 mL of N,N-dimethylformamide for one hour. The reaction mixture is stirred at 80° C. for 20 hours. After returning to room temperature, the solvent is evaporated, water is added and the solid formed is filtered and dried under vacuum to afford 0.30 g (40%) of compound 45 as a beige powder,

[0536] LCMS (EI, m/z) 476.28

[0537] Compound 46:

##STR00079##

[0538] Compound 46 was prepared according to the protocol described for the preparation of compound 3 starting with 300 mg of compound 45 and 253 mg of the amine 1-methylpiperazine to afford 115 mg of compound 46 with a yield of 41%,

[0539] LCMS (EI, m/z): (M+1) 448.52

[0540] .sup.1H NMR: dH ppm (400 MHz, DMSO): 9.54 (1H, s, NH), 8.54-8.55 (1H, d, CH.sub.arom), 8.27 (1H, S, CH.sub.arom), 8.14 (1H, s, CH.sub.arom), 7.70-72 (1H, d, CH.sub.arom), 7.44-7.46 (1H, d, CH.sub.arom), 7.40-7.42 (1H, d, CH.sub.arom), 7.08-7.11 (1H, dd, CH.sub.arom), 6.44 (1H, s, CH.sub.arom), 6.16 (1H, s, CH.sub.arom), 4.28-4.31 (2H, t, CH.sub.2), 4.02-4.05 (2H, t, CH.sub.2), 3.87-3.93 (4H, m, CH.sub.2), 3.16 (4H, m, CH.sub.2), 2.45 (4H, m, CH.sub.2), 2.23 (3H, m, CH.sub.3)

[0541] 2. Biological Activity of the Compounds According to the Invention

[0542] The following abbreviations were used:

[0543] ATP: Adenosine-5′-triphosphate

[0544] IMDM: Iscove's Modified Dulbecco's Medium

[0545] PSFG: Penicillin Streptomycin FunGizone

[0546] RPMI: Roswell Park Memorial Institute medium

[0547] FCS: Fetal calf serum

[0548] Measurement of the In Vitro Inhibitory Activities of the Compounds According to the Invention:

[0549] FLT3 (#PV3182), JAK2 (#FV4210) and JAK3 (#PV3855) recombinant enzymes were purchased from Life Technologies, FLT3-ITD (#0778-0000-1) and FLT3.sup.D835Y (#14-610) proteins were purchased from ProQinase and Merck Millipore, respectively. All the tests were carried out in 384-well plates. The principle of these binding tests is based on the LanthaScreen® TR-FRET methodology from Life Technologies.

[0550] FLT3 tests. The reaction mixture (15 μL total volume) contains the following compounds: 15 nM FLT3, FLT3-ITD or FLT3.sup.D835Y, 3 nM kinase tracer 236 (Life Technologies, #PV5592) and 6 nM LanthaScreen® anti-GST antibody coupled to a europium chelate (Life Technologies, #PV5594) for FLT3-ITD and FLT3.sup.D835Y or 6 nM LanthaScreen® anti-His antibody coupled to a europium chelate (Life Technologies, #PV5596) for FLT3.

[0551] JAK tests. The reaction mixture (15 μL total volume) contains the following compounds: 15 nM JAK2 or JAK3, 150 nM kinase tracer 236 (Life Technologies, #PV5592) for JAK2 or 3 nM for JAK3 and 6 nM LanthaScreen® anti-GST antibody coupled to a europium chelate (Life Technologies, #PV5594) for both enzymes.

[0552] The compounds are evaluated at 8 different concentrations prepared by making dilutions from a starting 10 mM stock solution in dimethylsulfoxide (DMSO) (Sigma, #D8418). The final DMSO concentration in the test is 1%. The reaction is carried out at 25° C. for 1 hour and detected on the EnVision® reader (Perkin Elmer) according to the recommendations of the supplier, Life Technologies.

[0553] The results are presented (Table 1) as the concentration values of the compound at which 50% of the kinase activity is inhibited, IC.sub.50 (μM), generated using the PRISM software (GraphPad).

TABLE-US-00001 TABLE 1 JAK3 Compound/ FLT3 FLT3-ITD FLT3.sup.D835Y JAK2 IC.sub.50 enzyme IC.sub.50 (μm) IC.sub.50 (μm) IC.sub.50 (μm) IC.sub.50 (μm) (μm) 4 0.0255 0.0145 0.035 0.0077 0.05 46 0.0047 0.0016 0.0062 0.060 0.10 6 0.11 0.12 0.0412 0.0052 0.05

[0554] In Vitro Measurement of the Antiproliferative Activity of the Compounds According to the Invention:

[0555] Cell Lines.

[0556] The characteristics of the cell lines used are as follows (Table 2).

TABLE-US-00002 TABLE 2 Basal Seeding Tumor Oncogene culture (Cell Cell lines Supplier origin expressed medium density/well) MV4-11 DSMZ Acute FLT3-ITD IMDM, 0.4 .Math. 10.sup.5 myeloid 10% FCS, cells/well leukemia PSFG (100 μL) MOLM-13 DSMZ Acute FLT3-ITD RPMI 0.3 .Math. 10.sup.5 myeloid 1640, 15% cells/well leukemia FCS, (100 μL) PSFG

[0557] Measurement of Antiproliferative Activity.

[0558] MV4-11 and MOLM-13 cell lines are cultured in the culture medium specified in Table 2 above and according to the supplier's recommendations. The tests are carried out in 96-well plates. The cells are divided in two at D0. At D1, they are seeded and treated with the compounds at various concentrations and incubated for 72 h at 37° C. and 5% CO.sub.2. The dilution of the compounds from stock solutions in DMSO (Sigma, #D8418) was made semi-logarithmically for a final concentration in the culture medium of 0.1%. At day 4, cell viability is evaluated by assaying the ATP released by the living cells using the ATPLite® kit (Perkin Elmer, #6016947). The EC.sub.50 values (concentration of the compound necessary to obtain 50% of the maximum effect) are calculated using curve-fitting software. The results in the form of EC.sub.50 values (in M) are presented in Table 3.

TABLE-US-00003 TABLE 3 Compound/line MV411 MOLM13 4 5.73E−08 1.89E−08 46 1.80E−09 3.90E−09 6 2.46E−07 1.45E−07